epothilone-a and Breast-Neoplasms

Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer.. A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed.. Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin.. Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Drug Administration Schedule; Epothilones; Female; Furans; Humans; Ketones; Paclitaxel; Survival Analysis; Treatment Outcome

Azaepothilone B, also known as ixabepilone, is a semi synthetic second generation epothilone B analogue. Azaepothilone B, its derivatives, and analogues, are used for treating advance metastatic breast cancer. It has been used as a chemotherapeutic medication for cancer.. This review highlights the patents on different routes for synthesis of azaepothilone B, its derivatives and analogues. The review will also provide the reported pharmacological activity and its polymorphs in the treatment of several cancers, such as breast cancer (metastatic or locally advanced), non-Hodgkin's lymphoma, and pancreatic cancer. In addition, it considers other proliferative diseases such as viral infections, degenerative diseases of the musculoskeletal system, kidney disease, and immune response related diseases. Different databases such as Espacenet, ISI Web of Knowledge, Patbase, and Thomson Innovation have been searched extensively to review the patents. The analysis has been done to indicate the patenting trend across years and the comparison of active assignees.. Azaepothilone B, along with its derivatives and analogues, can damage cancer cells in very low concentrations and retain its activity when tumor cells are insensitive to paclitaxel. Hence, it is highly potent agent. Azaepothilone B alone, in combination with other chemotherapeutics, or in the form of formulations, led to applications in various types of cancer. Also, antiproliferative activity of azaepothilone B has great potential for the treatment of proliferative diseases, such as skin diseases and infections. Recent progress in synthesizing azaepothilone B has encouraged researchers to develop new methods for the synthesis of azaepothilone B, its derivatives, and analogues, to obtain maximum yield in minimum steps.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Design; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Neoplasms; Patents as Topic

Chemotherapeutic agents, such as anthracyclines, taxanes and fluoropyrimidines, have significantly improved the outcome of breast cancer patients. However, mechanisms of resistance limit the effectiveness of these drugs. The microtubule-stabilizing agent ixabepilone has been approved for treatment of metastatic breast cancer (MBC) patients resistant or refractory to taxanes, anthracycline and capecitabine.. In this review, we summarized data on pharmacodynamics, pharmacokinetics, preclinical and clinical studies of ixabepilone in breast cancer. This article was compiled through searches on ixabepilone up to March 2015 in the PubMed and the clinicaltrials.gov databases; the FDA and European Medicine Agency (EMA) websites; and the ASCO and AACR proceedings.. Ixabepilone is a well-tolerated and effective drug in MBC at the approved dose. The most important challenges that ongoing clinical trials are still addressing are: the optimal dosing schedule that might improve the risk/benefit ratio, the clinical efficacy of ixabepilone in early breast cancer, the efficacy in triple-negative breast cancer (TNBC) patients and the identification of biomarkers predictive of response.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Neoplasm Metastasis; Tubulin Modulators

Chemotherapy is the mainstay of treatment for numerous cancer types, but resistance to chemotherapy remains a major clinical issue and is one of the driving influences underlying the development of new anticancer medications. One of the most important classes of chemotherapy agents is the taxanes, which target the cytoskeleton and spindle apparatus of tumor cells by binding to the microtubules, thereby disrupting key cellular mechanisms, including mitosis. Taxane resistance, however, limits treatment options and creates a major challenge for clinicians. Ongoing research has identified several newer classes of microtubule-targeting chemotherapies that may retain activity despite clinical resistance to taxanes. Among these classes, the epothilones have been studied most extensively in the clinical setting. Like taxanes, epothilones stabilize microtubulin turnover, and they have properties favoring their development as anticancer agents. The most clinically advanced epothilone analog is ixabepilone, which is currently the only approved epothilone derivative. Ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in combination with capecitabine after failure of an anthracycline and a taxane, or as monotherapy after failure of an anthracycline, a taxane, and capecitabine. In phase II and III trials, ixabepilone showed efficacy in several patient subgroups and in various stages of breast cancer. Common adverse reactions include peripheral sensory neuropathy and asthenia. This paper will discuss the preclinical and clinical development of epothilones and their derivatives across a variety of cancer types.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; Drug Discovery; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Microtubules; Mitosis; Neoplasm Metastasis; Neoplasms; Tubulin Modulators

Ixabepilone is a synthetic analogue of epothilone B approved for the treatment of patients with metastatic or locally advanced breast cancer in combination with capecitabine for cancer resistant to an anthracycline and a taxane, and as monotherapy for cancer resistant or refractory to anthracyclines, taxanes, and capecitabine. The principal dose-limiting adverse events (AEs) of ixabepilone's standard dose (40 mg/m(2) administered by 3-hour infusion once every 3 weeks) are peripheral neuropathy, neutropenia, and fatigue. An effective strategy to manage ixabepilone-related AEs is dose reduction by 20% (from 40 to 32 to 25 mg/m(2)); this does not appear to affect treatment efficacy and enables continuation of treatment after recovery (grade 1 or resolved). When appropriate, treatment can be restarted with a 20% dose reduction (to 32 mg/m(2)). For heavily pretreated patients, especially those with a low performance status, 32 mg/m(2) is an appropriate initial dose; the dose of capecitabine should also be lowered by 20%. Weekly ixabepilone (15-20 mg/m(2) on days 1, 8, and 15 every 28 days) may have an improved tolerability profile, but prospective studies with a large number of patients are required to determine whether it has therapeutic benefit comparable with the current approved regimen. More information is required on dosage and scheduling of ixabepilone in combination with other agents, including novel targeted therapies.

Topics: Breast Neoplasms; Disease Management; Dose-Response Relationship, Drug; Epothilones; Female; Humans

Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician's treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epothilones; Female; Humans; Neoplasm Metastasis; Taxoids; Tubulin Modulators

Ixabepilone 40 mg/m(2) (every 3 weeks) is approved for use in metastatic breast cancer as monotherapy as early as third line and in combination with capecitabine as early as first line in tumors that are resistant or refractory to anthracyclines and taxanes. This article seeks to familiarize oncology pharmacists with the options at their disposal to aid in management of ixabepilone therapy. Toxicity with ixabepilone is reversible and responsive to dose reduction or delay, and the 40 mg/m(2) dose may be reduced to 32 mg/m(2) and subsequently to 25 mg/m(2) should toxicities arise. However, available clinical data cannot support beginning ixabepilone therapy at a reduced dose to mitigate toxicity. Because ixabepilone's mechanism of action and adverse event profile resemble those of the taxanes, it has been postulated that weekly administration of ixabepilone (15-20 mg/m(2) weekly for 3 weeks with a 1 week break) may provide similar advantages to those seen with weekly metronomic paclitaxel administration. Within the last year, preliminary data has emerged that begins to answer questions regarding the use of weekly ixabepilone. The regimen appears to be effective and well-tolerated in metastatic breast cancer and other tumor types, although data from definitive head-to-head studies with the approved regimen are not yet available. Moreover, a recent label change now incorporates alternative infusion liquids to Lactated Ringer's Solution into the approved dilution protocol for ixabepilone, and similarities and differences from taxane administration are discussed. It is hoped that the influx of new data regarding dosing, scheduling, and administration options for ixabepilone will continue to increase the pharmacist's ability to optimize treatment outcomes for breast cancer patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Drug Compounding; Epothilones; Female; Humans; Infusions, Parenteral; Time Factors; Treatment Outcome; Tubulin Modulators

Manifestations of non-equilibrium polarity, random transgressions, and catastrophes are not conditions usually associated with a sense of normalcy. Yet these disquieting features distinguish a utilitarian behavior known as dynamic instability, the signature characteristic of the microtubule. Long known to be a tumor target, disruption of this fragile attribute is associated with some of the most effective agents used to treat breast cancer today. Although the biology of the microtubule is under intense investigation much still remains unknown. As such, our understanding of regulatory molecules and resistance mechanisms are still rudimentary, further compromising our ability to develop novel therapeutic strategies to improve microtubule inhibitors. This review focuses on several classes of anti-microtubule agents and their effects on the functional dynamics of the targeted polymer. The primary objective is to critically examine the molecular mechanisms that contribute to tumor cell death, tumor-resistance, and incident neurotoxicity.

Topics: Antineoplastic Agents; Blood Vessels; Breast Neoplasms; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Maytansine; Microtubules; Taxoids; Vinca Alkaloids

Ixabepilone approval in a number of countries across the world as monotherapy and in combination with capecitabine has led to widespread uptake in the later-line breast cancer setting. However, individualized data for ixabepilone in different ethnic groups are limited. Overall, data from small numbers of ethnic subgroups including Hispanic, Japanese and Chinese patients have revealed no clinically significant variation in the disposition, efficacy or tolerability of ixabepilone from that established in pivotal trials. Global use of ixabepilone, while usually along the lines of standard practice, may vary because of local regulatory decisions, clinical practice guidelines and cost considerations. Further information on the global patterns of use of ixabepilone will assist in optimizing the use of this novel therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Approval; Epothilones; Ethnicity; Female; Global Health; Humans; Practice Guidelines as Topic

Patients with breast cancer that becomes resistant to taxanes and anthracyclines experience considerable morbidity and mortality. The Food and Drug Administration has approved the use of ixabepilone for the treatment of patients with locally advanced or metastatic breast cancer that is refractory or resistant to taxanes and anthracyclines. The purpose of this review is to summarize the evidence from published studies on the pharmacological data and clinical activity of ixabepilone in patients with breast cancer. The conclusion of this review is that ixabepilone demonstrated a high efficacy in combination with capecitabine and as a single agent in breast cancer refractory to taxanes and anthracyclines. The clinical activity of ixabepilone combined with bevacizumab for advanced breast cancer was very promising.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Taxoids

The US Food and Drug Administration has approved three agents for treatment of patients with metastatic breast cancer refractory to anthracyclines and taxanes: capecitabine, ixabepilone, and eribulin mesylate. There is no fixed algorithm of therapeutic choices. Median survival remains measured in months, not years. Individual patient performance status, toxicity (to past regimens and any residual toxicity), preferences, and quality of life are factors in determining optimal treatment options for metastatic breast cancer. Ongoing research is seeking to improve outcomes in this patient population.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Drug Approval; Epothilones; Female; Humans; Neoplasm Metastasis; Tubulin Modulators; United States; United States Food and Drug Administration

Ixabepilone has shown promising clinical data in metastatic breast cancer (MBC) and may be particularly valuable in patients showing progression after treatment with standard chemotherapy. This article reviews the developing clinical profile of ixabepilone in MBC. Unlike taxanes and anthracyclines, ixabepilone has low susceptibility to multiple mechanisms of tumor cell resistance and has activity against tumors resistant to taxanes and/or anthracyclines. In phase II studies, single-agent ixabepilone resulted in objective response rates ranging from 11.5% to 57% in patients who had locally advanced or metastatic breast cancer, including patients who were treated as first-line therapy or in resistant patients who had received multiple lines of previous treatment. In two large phase III studies in women who had locally advanced or MBC pretreated with or resistant to taxanes and/or anthracyclines, a combination of ixabepilone plus capecitabine was superior to capecitabine alone in terms of progression-free survival and response rates. The efficacy of ixabepilone has also been shown in subsets, including patients with poor prognosis, the first-line metastatic setting, and in triple-negative disease. Studies are underway to investigate this agent in combination with biologics. A recent three-arm study has shown the activity and tolerability of ixabepilone plus bevacizumab; however, comparative data are not yet available. The toxicity profile of ixabepilone is generally manageable and predictable. The most common adverse events associated with ixabepilone include peripheral neuropathy and neutropenia. Ixabepilone appears to offer a promising alternative chemotherapeutic agent for patients with MBC who progress on various taxanes, anthracyclines, and capecitabine.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Neoplasm Metastasis

Although taxanes and anthracyclines have dramatically improved the treatment of breast cancer, resistance to these agents upon continued exposure is almost inevitable. The epothilone ixabepilone was US FDA approved in 2007 based on its demonstrated activity in metastatic breast cancer that is resistant to other approved agents, including taxanes and anthracyclines. Over 2000 patients have now received this agent in clinical trials, clarifying that ixabepilone has efficacy in minimally and heavily pretreated patients and can overcome chemotherapy-induced drug resistance, while maintaining a manageable safety profile. These clinical trials identified a progression-free survival advantage with ixabepilone/capecitabine combination therapy over capecitabine monotherapy. Moreover, certain hard-to-treat subgroups of patients may derive additional benefit from ixabepilone therapy. The objective of this report is to review the updated body of ixabepilone clinical data in breast cancer, as well as key considerations for ixabepilone administration and side-effect management.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Drug Approval; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Neoplasm Metastasis; United States; United States Food and Drug Administration

Patients with metastatic breast cancer (MBC) who develop resistance to anthracyclines and taxanes have limited therapeutic options. There is an unmet need for agents that can overcome tumor resistance and are effective in treating drug-resistant disease. The novel epothilone B analog, ixabepilone, binds to β-tubulin and stabilizes microtubules, leading to growth inhibition and apoptosis. Ixabepilone is able to overcome common mechanisms of resistance that limit the efficacy of many chemotherapeutic agents such as anthracyclines, taxanes, and capecitabine. Single-agent ixabepilone has clinical activity and a manageable safety profile against several different solid tumors including MBC, nonsmall cell lung cancer (NSCLC), and prostate cancer. Several phase II and III trials have demonstrated that ixabepilone-as monotherapy and in combination with capecitabine-is active in patients with pretreated or resistant MBC. Ixabepilone is the first epothilone approved for use as monotherapy or in combination with capecitabine in the treatment of metastatic or locally advanced breast cancer that is resistant or refractory to anthracyclines, taxanes, and/or capecitabine. Further clinical studies are evaluating the combination of ixabepilone with targeted agents such as trastuzumab or bevacizumab to further define the role of this novel agent in the treatment of MBC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Epothilones; Female; Fluorouracil; Humans; Multicenter Studies as Topic

Breast cancer consists of a heterogeneous group of diseases, with a number of tumor-specific and patient-specific factors, which influence response to therapy and survival. Ixabepilone is a member of a novel class of antineoplastic agents, the epothilones, that has demonstrated activity in a number of human solid tumor types and is the first agent in this class to be approved by the Food and Drug Administration (FDA) for the treatment of metastatic or locally advanced breast cancer, that is resistant/refractory to anthracyclines, taxanes, and/or capecitabine. Both retrospective and prospective studies have been conducted to evaluate the efficacy of ixabepilone in various populations. The role of ixabepilone in poor prognosis subgroups of the metastatic breast cancer population is reviewed in this article.

Topics: Adult; Aged; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Drug Approval; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome; United States; United States Food and Drug Administration

Ixabepilone is currently FDA-approved in metastatic breast cancer, and most patients in the registrational trials were Caucasian. Studies in Asian populations receiving other cytotoxic agents have revealed differential pharmacokinetics and clinical outcomes. As such, clinicians should understand the possible contributions of Asian ethnicity and culture to the clinical profile of ixabepilone.. Studies in Asian patients receiving other chemotherapeutics reported altered toxicity profiles for myelosuppression, neurotoxicity and gastrointestinal symptoms. Encouragingly, the limited clinical data in Asian patients receiving ixabepilone suggest that efficacy and toxicity in these women resemble those reported in the ixabepilone registrational trials.. The reader will better understand how Asian genetics and culture may influence treatment outcomes and patient attitudes toward therapy and interaction with caregivers. Management of ixabepilone-related adverse events is also discussed with an emphasis on special considerations for Asian patients.. Awareness of possible altered drug response in Asian patients will aid clinicians in monitoring for toxicity, recognizing the need for dose modification and educating patients. Sensitivity to cultural aspects that are unique to Asians may improve adherence, reporting of adverse events and trust among Asian patients receiving ixabepilone.

Topics: Asian People; Breast Neoplasms; Disease Management; Epothilones; Female; Humans; Lymphatic Metastasis; Neuralgia; Treatment Outcome

Patterns of breast cancer care continue to be amended because of the more frequent use of anthracyclines and taxanes in earlier lines of therapy (particularly in the adjuvant setting) and the emergence of multidrug resistance. When treating women with recurrent or metastatic breast cancer that is resistant to anthracyclines and taxanes, nurses have a unique opportunity to foster a sense of hope by helping patients understand available treatment options and what to expect during therapy. This article presents information on the use of an epothilone agent, ixabepilone (Ixempra, Bristol-Myers Squibb), a new treatment option for metastatic breast cancer after anthracycline and taxane failure. The information will allow nurses and their patients to collaborate as a team to help prevent or effectively manage side effects. In addition, nurses can take a proactive approach in educating patients about treatment options to enhance their quality of life.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Therapy, Combination; Epothilones; Female; Fluorouracil; Humans; Peripheral Nervous System Diseases; Taxoids; Tubulin Modulators

Patients with metastatic breast cancer (MBC) have poor prognoses and 5-year survival rates of approximately 20%. The site(s) and degree of metastatic dissemination are among the principal prognostic factors for patients with MBC. Patients with visceral metastases to the liver and/or lung have a very poor prognosis. Although good performance status, restricted disease dissemination, and limited extent of metastatic infiltration are associated with higher responses to chemotherapy, responses are generally short lived, with rapid disease progression after treatment failure. Thus, novel strategies for the management of patients with MBC with visceral disease are urgently needed. We have analyzed outcomes of trials that evaluated various chemotherapeutic agents as monotherapy or in combination with capecitabine in patients with MBC with primary visceral disease involvement. Treatment with microtubule inhibitors such as paclitaxel, docetaxel, and albumin-bound paclitaxel, generally administered in earlier lines of treatment, resulted in comparable responses. Lower response rates (RRs) were reported with other agents such as capecitabine, vinorelbine, and gemcitabine. Adverse events consistent with known toxicities of each agent were observed in the selected trials and related to dose and administration schedule. The epothilone B analogue ixabepilone has demonstrated clinical efficacy and manageable safety in populations of heavily pretreated patients with MBC with high visceral disease burdens to liver and/or lung (61%-86% of patients). Objective RRs ranging from 12% to 57% have been reported for ixabepilone, as monotherapy and in combination with capecitabine, depending on degree of pretreatment. Responses to ixabepilone in patients with visceral metastases were comparable to those observed in overall study patient populations.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Liver Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Viscera

We conducted a systematic review to estimate efficacy and safety of ixabepilone plus capecitabine compared with capecitabine alone for patients of anthracycline- and/or taxane-resistant metastatic breast cancer.. PubMed, Cochrane Library, EMBASE, ClinicalTrials.gov and other databases were searched. Randomized controlled trials containing ixabepilone plus capecitabine for anthracycline- and/or taxane-resistant metastatic breast cancer were eligible. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Overall response rates and toxicity were analyzed as dichotomous variables. Overall survival and time to progression data were analyzed as inverse variables. Meta-analyses were carried out by Review Manager 5.0 Software.. This report included two large clinical trials (1973 patients) for patients with metastatic breast cancer resistant to taxanes and resistant to or pretreated with anthracyclines. Ixabepilone plus capecitabine has prolonged the median time to progression, increased overall survival and significantly increased response rates compared with capecitabine alone. Adverse events observed with the combination arm were generally manageable and well tolerated with neutropenia and febrile neutropenia, and peripheral neuropathy, myalgia, diarrhea, stomatitis and hand-foot syndrome were easily controlled.. Ixabepilone plus capecitabine demonstrated clinical activity with an acceptable safety profile, which seems to be a valid option for patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Randomized Controlled Trials as Topic

Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23% in triple-negative patients. A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. Ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

The treatment of recurrent, progressing, metastatic breast cancer, which has previously been exposed to anthracyclines and/or taxanes is not only a major clinical challenge, but has a significant social impact too. In the absence of formal guidelines, this review has aimed to summarize the published evidence that is needed to guide clinical decision-making. Four new agents are approved for use in this setting: capecitabine, gemcitabine, ixabepilone, and nanoparticle albumin-bound paclitaxel. Nevertheless this review summarizes the results of studies with other active agents, as liposomal doxorubicin, rotation of taxanes, larotaxel, vinorelbine, and other biological agents.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease Progression; Doxorubicin; Epothilones; Female; Fluorouracil; Gemcitabine; Humans; Paclitaxel; Salvage Therapy; Taxoids; Vinblastine; Vinorelbine

Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases. TNBC is an immunohistochemically defined subtype, with significant diversity within the subtype. Generally TNBC occurs in younger women and is marked by high rates of relapse, visceral and CNS metastases, and early death. Current therapy fails to curtail the innate aggressive behaviour of TNBC in the majority of patients. The poor prognosis coupled with a lack of targeted use of therapies is reflected in the high mortality. In a minority of patients with highly chemosensitive disease, no robust clinical evidence exists to guide use of current cytotoxics. Critical to optimal future management are accurate identification of truly triple negative disease and adequately powered prospective TNBC trials to establish treatment efficacy and define predictive biomarkers.

Topics: Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Epothilones; ErbB Receptors; Female; Gene Expression Profiling; Genes, BRCA1; Humans; Immunohistochemistry; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Receptors, TNF-Related Apoptosis-Inducing Ligand; Taxoids

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Marrow; Breast Neoplasms; Capecitabine; Clinical Trials, Phase II as Topic; Deoxycytidine; Disease Progression; Drug Administration Schedule; Drug Interactions; Epothilones; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Lymphatic Metastasis; Peripheral Nervous System Diseases; Quinazolines; Treatment Failure; Treatment Outcome; Tubulin Modulators

Despite recent advances in treating patients with metastatic breast cancer (MBC), outcomes remain poor. Ixabepilone is a semisynthetic analogue of epothilone B with low susceptibility to multiple mechanisms of tumor-cell resistance. This review examined the results of 2 phase III clinical trials of ixabepilone in patients with drug-resistant or heavily pretreated, locally advanced breast cancer or MBC.. In both studies, women with locally advanced breast cancer or MBC pretreated with, or resistant to, taxanes or anthracyclines were randomly assigned to ixabepilone plus capecitabine, or capecitabine alone, until disease progression or unacceptable toxicity occurred.. Ixabepilone plus capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone. The median PFS was prolonged by 1.5 months and 1.8 months in the 2 studies (hazard ratio, < 0.8 in both studies; P ≥ .001). These observations remained valid within several patient subsets: those receiving ixabepilone as first-line therapy, those with taxane-resistant disease, and those with particularly poor prognostic features. Ixabepilone plus capecitabine significantly improved overall survival (OS) compared with capecitabine in patients with symptomatic disease (12.3 vs. 9.5 months, respectively; P = .015). Peripheral neuropathy with ixabepilone was generally reversible and was effectively managed by dosage reduction in most patients. Ixabepilone did not exacerbate capecitabine-induced hand-foot syndrome or diarrhea.. The results of these 2 large phase III trials suggest that ixabepilone plus capecitabine may improve treatment outcomes for patients with locally advanced breast cancer or MBC resistant to, or heavily pretreated with, taxanes or anthracyclines, even in those with poor prognostic features.

Topics: Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Chemotherapy, Adjuvant; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Treatment Failure; Tubulin Modulators

Resistance to chemotherapy is a major obstacle to the effective treatment of many tumor types. Although many anticancer therapies can alter tumor growth, in most cases the effect is not long lasting. Consequently, there is a significant need for new agents with low susceptibility to common drug resistance mechanisms in order to improve response rates and potentially extend survival. Approximately 30% of the women diagnosed with early-stage disease in turn progress to metastatic breast cancer, for which therapeutic options are limited. Current recommendations for first-line chemotherapy include anthracycline-based regimens and taxanes (paclitaxel and docetaxel). They typically give response rates of 30 to 70% but the responses are often not durable, with a time to progression of 6 to 10 months. Patients with progression or resistance may be administered capecitabine, gemcitabine, vinorelbine, albumin-bound paclitaxel, or ixabepilone, while other drugs are being evaluated. Response rates in this setting tend to be low (20 to 30%); the median duration of responses is <6 months and the results do not always translate into improved long-term outcomes. The present article reviews treatment options in taxane-resistant metastatic breast cancer and the role of ixabepilone in this setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Neoplasm Metastasis

The epothilones are a new class of microtubule-stabilizing drugs that exert potent antitumor activity against taxane-resistant and multidrug resistant cell lines. The most clinically advanced member of this class is the semisynthetic epothilone B derivative ixabepilone.. This article reviews the preclinical and clinical data on ixabepilone in patients with locally advanced and metastatic breast cancer (MBC) and provides guidance for pharmacists on its optimal use.. PubMed and conference proceedings through August 2008.. In preclinical studies, ixabepilone has demonstrated potent antitumor activity and low susceptibility to mechanisms that confer tumor resistance. Clinically meaningful benefits have been achieved with ixabepilone monotherapy in phase 2 trials of patients with MBC who have failed previous chemotherapies (anthracyclines, taxanes, or capecitabine). In a randomized, phase 3 trial, the combination of ixabepilone and capecitabine proved more effective than capecitabine alone after the failure of taxane and anthracycline regimens. At the recommended dose and schedule, the therapeutic ratio of ixabepilone is generally favorable, and its adverse effects (notably neutropenia and peripheral neuropathy) are generally manageable and reversible.. Ixabepilone represents an advance in the treatment of anthracycline - and taxane-pretreated MBC. Future studies will define its efficacy in combination with other drugs used in the treatment of MBC, as well as in other types of cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Premedication; Tubulin Modulators

Regardless of stage of disease, cytotoxic chemotherapy remains an important part of the treatment paradigm for breast cancer. Anthracyclines and taxanes are the most active agents; however, limitations with their use exist. These include a maximum lifetime dose and tumor resistance with anthracycline, hypersensitivity reactions and cumulative toxicity with taxanes. Therefore, to meet these challenges, the development of new cytotoxics and novel taxane formulations is an important area of active research. Several recent advances have been made. Epothilones represent a novel group of cytotoxic agents, with proven activity in breast cancer. Nanoparticle drug delivery systems have led to the development of ABI-007, which has demonstrated superior response rates than 3-weekly paclitaxel, with a lower risk of hypersensitivity reactions. To circumvent the problem of taxane resistance, larotaxel, a semisynthetic taxoid, and vinflunine, a synthetic vinca alkaloid, have been developed with encouraging clinical results to date. Eribulin, a synthetic derivative of halichondrin has recently entered Phase III trials based on encouraging activity in heavily pretreated patients. A further novel approach is the conjugation of cytotoxic agents to targeted agents, such as with trastuzumab-MCC-DM1. Elucidating the relative importance of these agents and incorporating them into existing treatment paradigms is a significant challenge for the future.

Topics: Albumin-Bound Paclitaxel; Albumins; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Delivery Systems; Epothilones; Female; Furans; Humans; Ketones; Nanoparticles; Paclitaxel; Taxoids; Tubulin Modulators; Vinca Alkaloids

Ixabepilone is a semisynthetic analogue of epothilone B, a novel microtubule-stabilizing agent. Preclinical data suggest that its mechanisms of actions are different from those of the most commonly used microtubule-stabilizing agent, paclitaxel. This information in addition to the cytotoxicity of this drug in taxane-resistant cell lines in multiple solid tumors supports the fact that ixabepilone may be active in taxane-resistant tumors. Breast and gynecologic malignancies are leading causes of morbidity and mortality in women. Clinical studies demonstrate significant activity of ixabepilone monotherapy in these heavily pretreated patients. The toxicity profile of ixabepilone seems to be similar to that of taxanes and manageable by supportive methods.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Genital Neoplasms, Female; Humans

Ixabepilone (BMS247550) is a semisynthetic derivative of the natural product that optimizes the properties observed with epothilone B. This compound has some similarities with taxanes in targeting and stabilizing microtubules, but it also has major differences. Interestingly, ixabepilone was evaluated in patients with well-characterized resistance to taxanes and was able to overcome the overexpression of multidrug resistance and was unaffected by mutations in the beta-tubulin genes. The interest in ixabepilone was clinically confirmed in Phase II and III clinical studies, which have demonstrated a strong activity in patients with metastatic breast cancer resistant to taxanes and in patients suffering from other types of chemoresistant tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Tubulin Modulators

Ixabepilone is a novel microtubule-stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single-agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H(1) and H(2) antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor-containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Breast Neoplasms; Clinical Trials as Topic; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Epothilones; Female; Humans; Liver; Peripheral Nervous System Diseases; Tubulin Modulators

Ixabepilone, an analogue of the natural product epothilone B, stabilizes microtubules resulting in cell cycle arrest and apoptosis. It is indicated for the treatment of locally advanced or metastatic breast cancer in the US. Ixabepilone has shown antitumour activity in tumour cell lines in vitro and in several animal tumour models, including those that display key mechanisms of resistance to other anticancer agents. In a randomized, nonblind, multicentre, phase III trial in women with locally advanced or metastatic breast cancer that was pretreated with, or resistant to, anthracyclines and resistant to taxanes, progression-free survival was significantly longer in ixabepilone plus capecitabine recipients compared with recipients of capecitabine monotherapy (median 5.8 vs 4.2 months). The response rate to ixabepilone monotherapy was 11.5% in a noncomparative, multicentre, phase II trial in women with locally advanced or metastatic breast cancer resistant to anthracyclines, taxanes and capecitabine. The most common grade 3 or 4 treatment-related adverse events in both trials were myelosuppression and peripheral sensory neuropathy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Capecitabine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Drug Therapy, Combination; Epothilones; Female; Fluorouracil; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic

To review the role of combination therapy in the treatment of metastatic breast cancer and to describe strategies to help manage adverse events associated with combination therapy.. Although the median survival of patients with metastatic breast cancer has increased over the last several decades, new treatment options are needed to further improve survival and quality of life for these patients. Novel cytotoxic and noncytotoxic agents have recently been evaluated in combination regimens for patients with metastatic breast cancer. Combinations for metastatic breast cancer that appear in recently approved labeling include ixabepilone with capecitabine, and the targeted biological agent lapatinib in combination with capecitabine. Ixabepilone is the first of a new family of cytotoxic agents--the epothilones--to enter clinical practice. Similar to the taxanes, ixabepilone binds to and stabilizes intracellular microtubules, resulting in decreased DNA replication and cell proliferation. Ixabepilone possesses antitumor activity in taxane-resistant tumor cells and has been shown to significantly improve progression-free survival when used in combination with capecitabine in patients with taxane-resistant tumors. Lapatinib, an oral small-molecule inhibitor of human epidermal growth factor receptors-1 and -2, has been shown, when combined with capecitabine, to improve progression-free survival in patients with advanced metastatic breast cancer who had progressed on prior therapy. The combination of paclitaxel and bevacizumab carries approved labeling for treatment of metastatic breast cancer, although there are concerns about bevacizumab and the risk of toxicity.. Ongoing clinical trials continue to define the role of novel antitumor agents in combination regimens for patients with metastatic breast cancer. Targeted agents are less likely to produce adverse events that are typical of cytotoxic chemotherapy but, because of their effects on specific molecular targets, may cause toxicities that were previously uncommon in cancer therapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Capecitabine; Cytotoxins; Deoxycytidine; Diarrhea; Drug Delivery Systems; Epothilones; Female; Fluorouracil; Humans; Lapatinib; Quinazolines; Signal Transduction; Skin Diseases; Trastuzumab

Despite advances in treatment of patients with metastatic breast cancer (MBC), prognosis remains poor and median survival is 2-3 years. Resistance to antineoplastics mediated by many factors, potentially including overexpression of drug efflux proteins or altered beta-tubulin isotype expression limits the effectiveness of MBC chemotherapy. Capecitabine, approved for anthracycline- and taxane-resistant MBC, has produced modest responses, highlighting the need for more effective treatments for MBC resistant to multiple chemotherapeutic agents. Agents with potential to reverse drug resistance have not proven effective. Albumin-bound paclitaxel is a formulation that may enhance delivery to tumor tissues. Conversely, ixabepilone, an epothilone analog, has been reported to have lower susceptibility to at least some mechanisms of tumor resistance and clinical activity in resistant/refractory MBC. The topoisomerase-I inhibitor irinotecan also has low cross-resistance with other antineoplastics, and has shown some activity against refractory MBC. Development of new agents and identification of genetic biomarkers in translational studies promise to improve management of patients with resistant/refractory breast cancer.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Taxoids; Tubulin Modulators

The ephothilones are a novel class of agents that bind to beta-tubulin, promote microtubule stabilization and cause cell-cycle arrest in G2/M phase. Ixabepilone (Ixempra) is an epothilone B that has demonstrated preclinical activity against a variety of tumor types and has recently been US FDA approved (application for registration ongoing in Europe) as a single agent for the treatment of taxane-refractory metastatic breast cancer, or in combination with capecitabine for patients with advanced breast cancer refractory to anthracyclines and taxanes. This review will provide an overview of the clinical development of ixabepilone, and emphasize the drug's utility for the treatment of advanced breast cancer.

Topics: Animals; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Taxoids

Chemotherapeutic agents that disrupt the assembly or disassembly of microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapy is limited principally by problems with formulation, slow administration, cumulative neurotoxicity, and resistance in part through induction of P-glycoprotein. The broad-spectrum anticancer activity of taxane therapy has encouraged investigators to identify a class of structurally novel microtubulin-stabilizing agents that could produce comparable outcomes with fewer problems. Preclinical studies indicate that epothilones have a broad spectrum activity in paclitaxel-resistant breast cancer models. Several epothilone analogues have displayed promising antitumor activity in initial clinical trials. Ixabepilone, an epothilone derivative in the later stages of clinical development, has exhibited antitumor activity in breast cancers, with or without previous taxane therapy. The most common adverse events associated with ixabepilone are reversible sensory neuropathy and neutropenia. This review briefly outlines the basic science behind microtubule-targeting agents and examines the preclinical studies of several of these agents in breast cancer models. Also discussed are results from clinical trials of epothilones alone and in combination in patients with breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cytotoxins; Epothilones; Female; Humans; Tubulin Modulators

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.

Topics: Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Treatment Outcome; Tubulin Modulators

To evaluate the safety and efficacy of ixabepilone as a new antimitotic chemotherapeutic agent for the treatment of breast cancer.. Data were identified by searches of MEDLINE, PubMed, and American Society of Clinical Oncology abstracts from 1966 to March 2008, using the primary search terms ixabepilone, epothilones, BMS-247550, and breast cancer.. Phase 1, Phase 2, and Phase 3 clinical trials examining the safety and efficacy of ixabepilone and its place in cancer treatment were reviewed. Preference was given to large Phase 2 and 3 clinical trials in the breast cancer population. Manufacturer product information was used to supplement data lacking in published trials.. Ixabepilone belongs to a novel class of drugs, the epothilones, which are nontaxane microtubule-stabilizing agents. Ixabepilone, in combination with capecitabine, has been approved by the Food and Drug Administration for treatment in patients with metastatic or locally advanced breast cancer that progresses after anthracycline and taxane therapy, or in patients with taxane-resistant cancer with contraindication to further anthracycline therapy. Ixabepilone has also been approved as monotherapy in patients with metastatic and locally advanced breast cancer refractory to taxanes, anthracyclines, and capecitabine. The most common adverse reactions reported by 20% or more of the patients receiving ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities seen in more than 40% of the patients include neutropenia, leukopenia, anemia, and thrombocytopenia. Premedication with histamine H(1) and H(2) antagonists is recommended to prevent hypersensitivity reactions.. Based on the clinical trials reviewed here and the current information available, ixabepilone is a welcome addition to the options available for the treatment of patients with metastatic breast cancer refractory to standard therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Epothilones; Humans

Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Dogs; Drug Screening Assays, Antitumor; Epothilones; Female; Humans; Male; Mice; Microtubules; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Rats; Structure-Activity Relationship; Tubulin Modulators

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.

Topics: Breast Neoplasms; Clinical Trials as Topic; Epothilones; Humans; Tubulin Modulators; United States; United States Food and Drug Administration

Breast cancer is the second leading cause of cancer death in women. Treatment options for advanced-stage disease, although numerous, remain suboptimal. Lapatinib and ixabepilone are two new agents approved by the United States Food and Drug Administration (FDA) in 2007 for the treatment of locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). When added to the existing endocrine therapies-single--agent cytotoxic therapies and combination chemotherapy regimens--lapatinib and ixabepilone offer potential treatment strategies for disease that has become resistant to trastuzumab and the taxanes, respectively. Lapatinib is an oral dual tyrosine kinase inhibitor against members of the human epidermal growth factor receptor (HER) family (HER1 or epidermal growth factor receptor [EGFR], and HER2). It is indicated for combination therapy with capecitabine for the treatment of patients with HER2-overexpressing LABC or MBC whose disease has progressed after receiving previous treatment with an anthracycline, a taxane, and trastuzumab. Of note, lapatinib is the first FDA-approved tyrosine kinase inhibitor indicated for use in MBC. Ixabepilone, the first FDA-approved analog of the antimicrotubule agent epothilone B, is indicated as monotherapy for the treatment of LABC or MBC in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for treatment of LABC or MBC that is resistant to anthracycline and taxane. Both lapatinib and ixabepilone are fairly well tolerated. The most common toxicities with lapatinib are diarrhea (65%) and hand-and-foot syndrome (53%), whereas peripheral neuropathy (62%), fatigue (56%), and neutropenia (54%) are most common with ixabepilone. Though the conventional standard end point of overall survival has not yet been assessed in clinical trials, these agents have been shown to improve surrogate markers of clinical benefit: progression-free survival and the related time to progression. Future clinical trials should focus on elucidation of optimal combination or sequential therapies, as well as patient-specific therapies based on tumor characteristics, such as biomarkers and tumor subtypes.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Lapatinib; Neoplasm Metastasis; Quinazolines

Ixabepilone is the first member of the epothilones, a new class of anticancer drugs. It is approved for use as monotherapy in patients with locally advanced or metastatic breast cancer that has failed to respond to therapy with a taxane, an anthracycline, and capecitabine, or in combination with capecitabine in patients with locally advanced or metastatic breast cancer that has failed to respond to therapy with a taxane and an anthracycline.. This paper reviews available information on the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of ixabepilone when used for its approved indication. It also reviews clinical studies of ixabepilone in other cancers, including prostate, lung, and ovarian cancers, sarcoma, and lymphoma. Finally, the dosing and administration of ixabepilone and pharmacoeconomic considerations are discussed.. MEDLINE and EMBASE (1950-present) were searched in November 2007 and again in March and June 2008 to identify clinical trials, abstracts, and case reports involving ixabepilone. The search terms included ixabepilone, BMS-247550, and epothilone. The reference lists of identified articles and meeting abstracts were reviewed to identify additional publications.. In a Phase III trial of the combination of ixabepilone 40 mg/m2 IV + capecitabine 1000 mg/m2 PO BID versus capecitabine 1250 mg/m2 PO BID, both given on days 1 through 14 of a 21-day cycle, the combination arm had significantly greater progression-free survival (5.8 vs 4.2 months, respectively; P < 0.001) and a significantly greater objective response rate (32% vs 14%; P < 0.001). In a Phase II trial of monotherapy with ixabepilone 40 mg/m2 IV given every 21 days, 50% of patients had stable disease, with a median progression-free survival of 3.1 months. Grade 3/4 hematologic adverse effects occurring during use of ixab epilone included neutropenia (54%),leukopenia (49%), anemia (8%), and thrombocytopenia (7%). The most common nonhematologic adverse effects included peripheral neuropathy (72%), fatigue (56%), myalgia/arthralgia (49%), alopecia (48%), nausea (42%), stomatitis/mucositis (29%), vomiting (29%), diarrhea (22%), and musculoskeletal pain (20%). Dose adjustment is required in the presence of toxicity (grade 2 or higher neuropathy; grade 3 or higher myalgia/arthralgia, fatigue, or palmar-plantar erythrodysesthesia; prolonged neutropenia, febrile neutropenia, or severe thrombocytopenia). Use of ixabepilone is contraindicated in patients with hepatic impairment.. Ixabepilone, a new antineoplastic agent with antimitotic capabilities, is approved for use with or without capecitabine in the management of metastatic or locally advanced breast cancer. It has also been evaluated for antitumor activity in a number of other cancers. The potential for significant toxicity with ixabepilone requires close clinical observation to assess the need for dose adjustment.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasms

The taxanes that target microtubules are among the most active drugs in breast cancer treatment; however, resistance to these agents remains a significant issue for many patients. The epothilones are a novel class of nontaxane, microtubule-targeting agents, currently being evaluated in varying stages of clinical trials. Ixabepilone is the first epothilone analogue to receive US Food and Drug Administration approval in the United States for the treatment of metastatic breast cancer and as such will be the primary focus of this review.. Multiple phase II trials evaluating ixabepilone in different populations of patients with metastatic breast cancer as well as a phase III trial in combination with capecitabine have recently been published.. Phase II trials clearly demonstrate the activity of single-agent ixabepilone in both taxane-untreated and taxane-treated metastatic breast cancer. Although the highest activity was seen in early lines of therapy, there was also clear evidence of activity in heavily pretreated patients. Ixabepilone has also been evaluated in combination with capecitabine in a randomized, phase III trial demonstrating a benefit for the combination compared with single-agent capecitabine for patients resistant to anthracyclines and taxanes. In general, ixabepilone administered as a single-agent and in combination with capecitabine has been reasonably well tolerated.

Topics: Antineoplastic Agents; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Microtubules; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome; Tubulin Modulators

The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ixabepilone in patients with metastatic breast cancer are examined.. The clinical utility of the three main classes of chemotherapeutic agents used in breast cancer (i.e., anthracyclines, taxanes, and fluorinated pyrimidines) is limited in some patients by the emergence of drug resistance which leads to disease progression. A recent addition to the available drugs for the treatment of advanced breast cancer is the epothilone B analog ixabepilone, which has demonstrated clinical activity in patients who have tumors that have progressed while on other chemotherapy regimens, including anthracyclines and taxanes. In Phase II clinical trials of ixabepilone in patients with metastatic breast cancer, clinically meaningful benefits have been achieved with ixabepilone monotherapy in patients in whom anthracyclines, taxanes, and capecitabine are no longer effective. Ixabepilone has demonstrated activity in first-, second-, and subsequent-lines of therapy and in different subtypes of patients with advanced disease. In a Phase III trial in patients who had previously received taxanes and anthracyclines, the combination of ixabepilone and capecitabine was significantly more effective in producing an objective response and in prolonging progression-free survival than capecitabine alone. At the recommended dose and administration schedule, ixabepilone is generally well tolerated. The most clinically relevant adverse events associated with its use have been myelosuppression and peripheral neuropathy, which is primarily sensory and cumulative but reversible within six weeks of a dosage reduction or the discontinuation of therapy.. Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy.

Topics: Breast Neoplasms; Epothilones; Humans; Microtubules; Randomized Controlled Trials as Topic; Tubulin Modulators

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Neoplasm Metastasis; Taxoids; Tubulin Modulators

Primary drug resistance, defined as disease progression as best response to treatment, presents an important problem in everyday clinical practice. Primary taxane resistance, reported in up to 55% of patients with breast cancer, plays a critical role in minimizing the efficacy of taxane-based chemotherapy for metastatic breast cancer (MBC). The epothilones are a novel class of antineoplastic agents, developed to overcome tumor-resistance mechanisms. Ixabepilone, the first drug in this class, stabilizes microtubule polymerization, and induces cell-cycle arrest and apoptosis. Ixabepilone demonstrates low susceptibility to different and multiple mechanisms of drug resistance that play a crucial role in primary taxane resistance, such as tumor overexpression of neuronal-specific beta-tubulin isotype III and drug-efflux transporters. In phase II trials, ixabepilone demonstrated proven activity in patients with MBC whose tumors had primary or secondary resistance to taxanes and other agents. Ixabepilone also demonstrated activity in patients with tumor types such as renal-cell cancer and pancreatic cancer that are usually intrinsically insensitive to chemotherapy, including taxanes. To determine the activity of ixabepilone in patients with primary taxane resistance, a retrospective analysis of patient subsets from 2 clinical trials was conducted. Ixabepilone demonstrated clinical activity as monotherapy, and in combination with capecitabine, in patients with MBC who had disease progression as best response to previous taxane therapy. Response rates in patients with primary taxane resistance were comparable to responses observed in total patient populations. The clinical results support the hypothesis that ixabepilone can overcome or circumvent primary mechanisms of resistance to taxanes and other chemotherapeutic agents.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Taxoids; Tubulin Modulators

The introduction of modern chemotherapy agents, including the taxanes, has improved the prognosis of women with metastatic breast cancer (MBC). Ultimately, however, inevitable intrinsic or acquired resistance to chemotherapy limits treatment options. The epothilones, a novel class of microtubule-stabilizing agents that have incomplete cross-resistance with taxanes and are less susceptible to common mechanisms of resistance, have demonstrated activity in breast cancer. Ixabepilone, the best studied epothilone to date, has been approved for use as a single agent or in combination with capecitabine in anthracycline- and taxanepretreated or refractory MBC. Ixabepilone is relatively well tolerated, with the most common side effects being peripheral neuropathy and neutropenia. Other epothilones such as KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584 are being evaluated as therapy for patients with breast cancer, with promising preliminary data. Ongoing research aims to define and optimize the efficacy of the epothilones in an attempt to improve the quality of life and overall survival of individuals with breast cancer.

Topics: Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Tubulin Modulators

Taxanes have been broadly used in the treatment of breast cancer. However, the majority of initially responsive breast cancer patients eventually develop resistance to taxanes (acquired resistance) and a non-negligible percentage of patients are primarily resistant to these agents (de novo resistance). Additionally, taxanes require pre-medication and may cause important side effects such as febrile neutropenia and neuropathy. Hence, new agents with better efficacy and/or a better toxicity profile and/or are easier to administer need to be developed. Epothilones are a novel class of microtubule-targeting agents sharing a similar mechanism of action to the taxanes and having a more potent antiproliferative activity in various tumour cells lines, particularly in cases of taxane-resistant breast cancer. This review will focus on clinical development of epothilones in breast cancer, particularly ixabepilone which is in the late stages of development, their potential impact in clinical practice, advantages and limitations.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Maximum Tolerated Dose; Middle Aged; Taxoids; Treatment Outcome; Tubulin Modulators

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Neoplasm Metastasis; Treatment Outcome

The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. Among the epothilone family, ixabepilone (BMS247550) is a semisynthetic derivative of the natural product epothilone B. Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.

Topics: Animals; Bone Marrow; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Hypersensitivity; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Neoplasms; Paclitaxel; Peripheral Nervous System Diseases; Taxoids; Tubulin Modulators

Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing cell death. Ixabepilone (BMS-247550, Ixempra) is an epothilone analog that optimizes the properties naturally observed with epothilone B.. To provide an overview of the results achieved by ixabepilone in metastatic breast cancer.. A PubMed search was performed to provide an extensive review of all published data on ixabepilone, in addition to all data reported from international congresses, from 2003 to 2007.. There is a clear need for new agents active against resistant metastatic breast cancer and ixabepilone might be a welcome new compound in this situation.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Death; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Epothilones; Female; Humans; Molecular Structure; Neoplasm Metastasis; Treatment Outcome; Tubulin Modulators

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.

Topics: Antineoplastic Agents; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Fluorouracil; Humans; Taxoids; Treatment Failure; Tubulin Modulators

Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.

Topics: Breast Neoplasms; Capecitabine; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Tubulin Modulators

The epothilones constitute a novel class of microtubule inhibitors that act like the taxanes by hyperstabilizing tubulin polymerization, thus disrupting functioning of the mitotic spindle. Natural epothilones produced by myxobacteria, and second- or third-generation partially or fully synthesized analogs, have been explored as cancer chemotherapy agents to replace or follow the taxanes. For those epothilones that have gone on to clinical development (epothilone B, ixabepilone, BMS-310705, ZK-EPO, KOS-862, and KOS-1584), preclinical investigations in breast cancer models are reviewed. All of these epothilones improve upon the cytotoxic activity of paclitaxel in various human breast cancer cell lines in vitro, but are also highly active in lines that are resistant to paclitaxel. Comparable antitumor activity has been demonstrated against nude mouse xenografts of paclitaxel-sensitive and -resistant breast cancer lines. Additionally, some analogs have reduced toxicity or increased water solubility that may permit oral administration, while others with enhanced tissue penetration show promise in animal models of breast cancer brain or bone metastasis and may provide benefits in patients with poor-prognosis advanced breast cancer.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Capecitabine; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Deoxycytidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Epothilones; Female; Fluorouracil; Humans; Mice; Mice, Nude; Microtubules; Paclitaxel; Tubulin Modulators

Despite the recent trend toward treatment of early stage breast cancer aggressively with anthracyclines and taxanes, nearly half of those women will have metastatic recurrence. Moreover, because of the increasing prior exposure to these drugs, far more women facing first-line therapy for recurrent disease will now have developed anthracycline- and taxane-refractory metastatic breast cancer (ATRMBC), presenting a major therapeutic challenge. A number of established drugs are showing promise in this setting: capecitabine alone or combined with lapatinib; gemcitabine; vinorelbine; and oxaliplatin. At the same time, a variety of new drugs are emerging for potential use in ATRMBC. Among the drugs in clinical development that have shown promising activity include novel classes of compounds (camptothecins and epothilones), newer members of established classes (pemetrexed and vinflunine), and agents with novel mechanisms of action (the mitosis inhibitor E7389 and the ascidian-derived anticancer compound trabectedin). Several molecularly targeted agents are also being evaluated in ATRMBC, including interleukin-2 receptor-binding denileukin diftitox, and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which inhibits the protein chaperone heat shock protein 90.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Camptothecin; Clinical Trials as Topic; Deoxycytidine; Dioxoles; Diphtheria Toxin; Drug Resistance, Neoplasm; Drugs, Investigational; Epothilones; Female; Furans; Gemcitabine; Glutamates; Guanine; Humans; Interleukin-2; Ketones; Lapatinib; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Quinazolines; Recombinant Fusion Proteins; Tetrahydroisoquinolines; Trabectedin; Vinblastine; Vinorelbine

The epothilones are effective antitumor medications for patients with breast cancer, including patients who have been previously treated with or are resistant to anthracyclines or the taxanes.. With the best currently available therapies, the median survival time for patients with metastatic breast cancer is only 2-3 years, and many patients develop resistance to taxanes or other chemotherapy drugs. The epothilones are a novel class of antitumor medications, similar to the taxanes in some respects, but that also possess several advantages. Like taxanes, epothilones are believed to produce antitumor effects by binding to and stabilizing intracellular microtubules, which are essential in DNA replication and cell division. Several in vitro and animal studies have shown that the epothilones are more potent microtubule stabilizers than the taxanes, they are effective against cancer cell lines with high levels of drug resistance, and they induce the regression of taxane-resistant human tumors. Preclinical studies also have demonstrated synergistic increases in tumor cell killing when the epothilones are combined with other antitumor medications. Epothilone B (patupilone) has been evaluated in a series of phase I and II clinical trials, which demonstrated disease stabilization or objective responses in patients with a variety of cancers, including ovarian, prostate, breast, colon, stomach, and kidney cancers. This agent is currently being evaluated in phase III clinical trials. A second epothilone, ixabepilone, was recently approved by the FDA for the treatment of metastatic breast cancer. Ixabepilone was evaluated as monotherapy for the treatment of breast cancer in phase II clinical trials of previously untreated patients and in taxane-experienced and taxane-resistant disease. A phase III clinical trial demonstrated that the combination of ixabepilone and capecitabine was superior to capecitabine alone in heavily pretreated, taxane-resistant patients.. Ongoing clinical trials will continue to define the role of the epothilones in cancer therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Humans; Neoplasm Metastasis

Results of clinical trials over the past 15 years demonstrate that the taxanes are among the most effective new class of cytotoxic drugs to treat breast cancer and other solid tumors. Moreover, the efficacy of the taxanes added further credence to the relevance of the microtubule as a tumor target. In spite of the significant benefits observed in early and advanced breast cancer, a number of factors contribute to disease relapse and, perhaps more discouragingly, disease refractoriness. After exhausting cytotoxic chemotherapy, hormonal therapy, and other molecular-based-therapies, patients whose tumors exhibit taxane resistance had virtually no additional options. This paper, a product of the ongoing advances in the treatment of breast cancer, reviews two important areas: first, molecular concepts and relevance of the microtubule in breast cancer and second, clinical implications of ixabepilone, a novel, nontaxane tubulin-stabilizing agent in patients with taxane-resistant breast cancer.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Microtubules; Taxoids; Tubulin Modulators

Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), nd KOS-1584, have been testedf or the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.

Topics: Antineoplastic Agents; Breast Neoplasms; Epothilones; Humans; Neoplasms; Tubulin Modulators

Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Epothilones; Female; Humans; Microtubules; Tubulin Modulators

The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but they also have important differences. Among the epothilone family, ixabepilone has emerged to be a semisynthetic epothilone analogue of interest. Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensible and taxane-resistant cell lines, including those with overexpression of multidrug resistance and with mutations in the beta-tubulin gene. The interest of this ixabepilone has been confirmed clinically. Phase II clinical studies have demonstrated high activity in patients with taxane-resistant metastatic breast cancer and in patients with other chemotherapy-resistant tumor types.

Topics: Breast Neoplasms; Clinical Trials, Phase II as Topic; Epothilones; Female; Humans; Microtubules; Treatment Outcome; Tubulin Modulators

Drugs that target microtubules, including paclitaxel (Taxol) and docetaxel (Taxotere), are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones are a novel class of antimicrotubule agents that have demonstrated antitumor activity in the setting of resistance.. This review summarizes clinical studies of epothilones in patients with metastatic breast cancer. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006.. The epothilones have demonstrated promising antitumor activity and manageable toxicity in phase II studies of heavily pretreated patients with metastatic breast cancer, including patients with resistance to taxanes and other cytotoxic agents. Neuropathy associated with ixabepilone appears to be schedule dependent and comparable to that observed with paclitaxel. Ixabepilone appears to be active in combination with capecitabine.. Ongoing and planned trials promise to elucidate the benefits of ixabepilone in combination with other agents including capecitabine, bevacizumab, and trastuzumab in patients with metastatic breast cancer as well as those receiving neo-adjuvant therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Therapy, Combination; Epothilones; Female; Humans; Neoadjuvant Therapy; Treatment Outcome; Tubulin Modulators

Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment.. This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design.. Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin.. The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Epothilones; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Neoplasms; Ovarian Neoplasms; Tubulin Modulators

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Monitoring; Drug Resistance, Neoplasm; Epothilones; Humans; Neoplasm Metastasis; Nursing Assessment; Oncology Nursing; Taxoids

Although targeted therapies are becoming increasingly important in oncology, cytotoxic agents are likely to remain a valuable element in the treatment paradigm of cancer. However, resistance to chemotherapy is a major obstacle to the successful treatment of cancer. Therefore, there is a need for novel antineoplastic agents that are able to overcome mechanisms of tumor resistance. Drugs that target microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones and their analogues are a novel class of antimicrotubule agents that has demonstrated antitumor activity in the setting of resistance. These antimicrotubule agents are structurally unrelated to the taxanes, with a distinct beta-tubulin-binding mode. Ixabepilone is a rationally designed, semisynthetic analogue of natural epothilone B, which displays reduced susceptibility to a range of common tumor resistance mechanisms. Promising phase II activity and a manageable safety profile with ixabepilone have been seen in a wide range of tumor types, including heavily pretreated/resistant and early-stage breast cancer. Moreover, encouraging phase III results with ixabepilone and capecitabine for patients with breast cancer have recently been presented. Clinical trials are also planned for ixabepilone in combination with targeted agents, such as trastuzumab and bevacizumab. Ixabepilone is likely to be the first available drug in its class, with the potential to bring clinical benefit to patients with a wide range of malignancies.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans

Epothilones are cytotoxic macrolides with a similar mechanism of action to paclitaxel but with the potential advantage of activity in taxane-resistant settings in preclinical models. The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment. Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting. Neuropathy induced by ixabepilone may be schedule dependent. Over 20 Phase II studies of epothilones in cancer treatment have been reported, and significant activity in taxane-sensitive tumour types (such as breast, lung and prostate cancers) has been noted. Response rates in taxane-refractory metastatic breast cancer are relatively modest, but ixabepilone and patupilone have shown promising efficacy in hormone-refractory metastatic prostate cancer and in taxane-refractory ovarian cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Male; Prostatic Neoplasms; Tubulin Modulators

A number of novel microtubule-targeting agents are currently under investigation. These agents can potentially evade the mechanisms underlying the development of the multidrug resistance (MDR) phenotype commonly associated with recurrent breast cancer. Epothilones are among the most advanced of the new agents in clinical development. Structurally unrelated to taxanes, epothilones may be poor substrates for MDR, and the expression of MDR proteins is not altered in epothilone-resistant in vitro models. Cross resistance between epothilones and taxanes is not observed in vitro or in vivo. Ixabepilone (BMS-247550) is a semisynthetic analog of epothilone B that has shown antitumor activity both in vitro and in vivo, including taxane-resistant human tumor xenograft models. Ixabepilone is currently being studied in phase III trials in patients with metastatic breast cancer as monotherapy and in combination with capecitabine. Activity has also been observed in other solid tumors. Patupilone (EPO906, epothilone B) and epothilone D (KOS-862) are in early phase I/II clinical studies in patients with a variety of solid tumors. The development of these novel agents may evade MDR and may improve the outcome of patients with breast cancer.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Humans; Taxoids

Obesity and inactivity are associated with increased risk of cancer-related and overall mortality in breast cancer, but there are few data in metastatic disease.. Cancer and Leukemia Group B 40502 was a randomized trial of first-line taxane-based chemotherapy for patients with metastatic breast cancer. Height and weight were collected at enrollment. After 299 patients enrolled, the study was amended to assess recreational physical activity (PA) at enrollment using the Nurses' Health Study Exercise Questionnaire. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using stratified Cox modeling (strata included hormone receptor status, prior taxane, bevacizumab use, and treatment arm). All statistical tests were 2-sided.. A total of 799 patients were enrolled, and at the time of data lock, median follow-up was 60 months. At enrollment, median age was 56.7 years, 73.1% of participants had hormone receptor-positive cancers, 42.6% had obesity, and 47.6% engaged in less than 3 metabolic equivalents of task (MET) hours of PA per week (<1 hour of moderate PA). Neither baseline body mass index nor PA was statistically significantly associated with PFS or OS, although there was a marginally statistically significant increase in PFS (hazard ratio = 0.83, 95% confidence interval = 0.79 to 1.02;. In a trial of first-line chemotherapy for metastatic breast cancer, rates of obesity and inactivity were high. There was no statistically significant relationship between body mass index and outcomes. More information is needed regarding the relationship between PA and outcomes.

Topics: Adult; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Body Height; Body Mass Index; Body Weight; Breast Neoplasms; Epothilones; Exercise; Female; Humans; Middle Aged; Obesity; Paclitaxel; Progression-Free Survival; Proportional Hazards Models; Treatment Outcome; Young Adult

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; China; Cost-Benefit Analysis; Disease-Free Survival; Epothilones; Female; Humans; Markov Chains; Models, Economic; Quality-Adjusted Life Years

Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.. HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m. Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of -9.4 and -10.8 points, respectively.. There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression.. NCT01492101.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Albumins; Anorexia; Antineoplastic Agents; Body Image; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cancer Pain; Deoxycytidine; Docetaxel; Dyspnea; Epothilones; Fatigue; Female; Furans; Gemcitabine; Health Status; Heterocyclic Compounds, 4 or More Rings; Humans; Ketones; Liver Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Paclitaxel; Polyethylene Glycols; Quality of Life; Reproductive Health; Sleep Initiation and Maintenance Disorders; Taxoids; Vinblastine; Vinorelbine; Vomiting

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S

Topics: Albumins; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Epothilones; Female; Humans; Models, Biological; Neoplasm Metastasis; Paclitaxel; Peripheral Nervous System Diseases

The purposes of the present phase I/II trial were (1) to define tolerable doses of ixabepilone and sorafenib when used in combination and (2) to evaluate the efficacy and toxicity of this combination in the treatment of patients with human epidermal growth factor receptor-negative metastatic breast cancer (MBC).. The eligible patients had human epidermal growth factor receptor-negative MBC and had not received previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase II received the maximum doses identified in phase I. The patients were reevaluated after the completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. A total of 67 patients were required in phase II to demonstrate increased median progression-free survival from 4.2 to 6.2 months (90% power, α = 0.05).. Ten patients entered the phase I portion; the maximum tolerated doses were ixabepilone 32 mg/m(2) and sorafenib 400 mg orally twice daily. A total of 76 patients were treated at the phase II dose. The median progression-free survival was 4.8 months (95% confidence interval, 3.5-6.3 months). The overall response rate was 37%. The regimen was difficult to tolerate for many patients; 20 patients discontinued because of toxicity, and dose reductions were frequent. The common toxicities included neutropenia, fatigue, rash, and neuropathy.. The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single-agent ixabepilone or taxanes. Further development of this combination is not recommended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Kaplan-Meier Estimate; Maximum Tolerated Dose; Middle Aged; Niacinamide; Phenylurea Compounds; Receptor, ErbB-2; Sorafenib; Treatment Outcome

The treatment of metastatic breast cancer (MBC) remains a great clinical challenge as drug resistance frequently develops. Alternative agents that can overcome drug resistance would offer new therapeutic options. The primary aim of this phase II study was to evaluate the efficacy and safety of utidelone as a monotherapy or in combination with capecitabine in metastatic breast cancer patients previously treated with and resistant to anthracyclines and taxanes.. In two open-label, noncomparative clinical studies, patients with metastatic breast cancer who previously received anthracycline- and/or taxane-containing regimens were given (1) 25 to 35 mg/m(2)/day intravenously infused utidelone, once daily for 5 days, in combination with 14 days of 2000 mg/m(2) capecitabine, divided in two equal daily oral doses or (2) 40 mg/m(2)/day intravenously infused utidelone, once daily for 5 days. These regimens were administered per each 21-day treatment cycle, and the maximum of treatment cycles allowed per protocol is 6. Objective response rate (ORR), progression-free survival (PFS), and tolerability were evaluated.. In the combination study, 33 patients completed a median of 6 cycles of therapy, which was the highest cycles a trial patient could receive under the criteria of the study protocol. Efficacy was evaluated (n = 32) with an ORR of 42.4 % (FAS, 95 % CI, 26.6, 60.9) and a median PFS of 7.9 (FAS, 95 % CI, 6.1, 9.8) months. The monotherapy study (n = 63) resulted in an ORR of 28.57 % (FAS, 95 % CI, 18.4, 40.6) and a median PFS of 5.4 (FAS, 95 % CI, 2.9, 9.8) months. In both studies, common toxicities associated with utidelone administration included peripheral neuropathy, fatigue, myalgia, and arthralgia, but the toxicities were limited and manageable. Notably, very mild myelosuppression, low liver and renal toxicities, and very limited gastrointestinal toxic effect were observed, in contrast to other agents in the same class.. Utidelone showed promising efficacy, tolerability, and advantageous safety profiles in the treatment of patients with advanced anthracycline/taxane-refractory metastatic breast cancer and may offer new treatment options to overcome drug resistance.. CHiCTR-TRC-13004205 , registered on August 15, 2013.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome; Young Adult

Ixabepilone is a member of the epothilone class of antineoplastic agents with activity against taxane-resistant tumors, and low susceptibility to common mechanisms of tumor resistance. This study evaluated ixabepilone in lieu of a taxane in combination with carboplatin and trastuzumab as neoadjuvant treatment for operable HER2-positive breast cancer.. Patients ≥ 18 years of age with histologically-confirmed HER2-positive adenocarcinoma of the breast (clinical T1-T3, N0-N2, M0), normal left ventricular ejection fraction, and adequate organ function received trastuzumab 6 mg/kg intravenous (I.V.) (with 8 mg/kg loading dose cycle 1), ixabepilone 40 mg/m(2) I.V., and carboplatin area under the curve = 6.0 I.V. on day 1 of each 21-day cycle. Prophylactic growth factor support was permitted. After completing 6 cycles, patients underwent definitive surgery. After surgery, patients continued trastuzumab every 3 weeks for a total of 1 year. Locoregional radiation therapy and endocrine therapy was administered per institutional guidelines. The primary end point was the rate of pCR.. Fifty-eight eligible women (median tumor size, 3.0 cm; clinical axillary lymph node involvement, 67%) initiated treatment between April 2009 and February 2010. Fifty-two patients (90%) underwent surgery, and pCR was observed in 27 patients (52%). Grade 3/4 neutropenia was the most common toxicity, occurring in 69% of patients and complicated by fever in 4 patients.. The combination of ixabepilone, carboplatin, and trastuzumab was feasible and active as a neoadjuvant regimen. Although the pCR rate of 52% falls within the range reported with other taxane/trastuzumab-based regimens, the greater incidence of severe neutropenia is a disadvantage for this regimen.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Epothilones; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Trastuzumab

Residual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes-resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer.. A phase II study in patients with residual cancer burden II or III randomized to ixabepilone versus observation was conducted. Circulating tumor cells (CTCs) were measured at baseline and at 9 and 18 weeks. Survival probabilities were estimated by Kaplan-Meier product limit. Toxicities were reported as proportions in the ixabepilone arm.. Accrual was stopped because of ixabepilone toxicity. Sixty-seven patients were registered; 43 were randomized, 19 received ixabepilone, and 24 went to observation. One patient (9.1%) in the observation arm versus 2 patients (18.2%) in the ixabepilone arm had CTCs at 18 weeks (P = 1.0). Three-year recurrence-free survival and overall survival were 94% and 82%, and 100% and 79% in the observation and ixabepilone arms (P = .35 and .18), respectively. Most common adverse events (AEs) included fatigue, pain, neuropathy, constipation, nausea, rash, anorexia, and diarrhea. Serious AEs included pain (63.2%), fatigue (31.6%), and neuropathy (31.6%).. Adjuvant ixabepilone in patients with significant RD after neoadjuvant chemotherapy was difficult to administer because of AEs and did not change the presence of CTC or affect survival outcomes. NCT00877500.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2

We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel.. Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m(2) (arm A), nab-paclitaxel 150 mg/m(2) (arm B), or ixabepilone 16 mg/m(2) (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73.. In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions.. In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Drug Administration Schedule; Epothilones; Female; Humans; Middle Aged; Nanoparticles; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Treatment Outcome

Ixabepilone and the taxanes have similar activity in the first-line treatment of metastatic breast cancer, and ixabepilone is sometimes effective in taxane-refractory patients. We conducted a phase 2 trial to evaluate ixabepilone in combination with cyclophosphamide as neoadjuvant treatment for patients with locally advanced HER2-negative breast cancer. Response to neoadjuvant treatment was correlated with the baseline 21-gene Recurrence Score® (Oncotype DX; Genomic Health Inc, Redwood City, CA). Eligible women with HER2-negative locally advanced breast cancer received ixabepilone 40 mg/m(2) plus cyclophosphamide 600 mg/m(2) on day 1 of each 21-day cycle. Following 6 cycles, patients underwent definitive surgery. Primary endpoint was rate of pathologic complete response (pCR). Breast biopsy tumor samples were obtained at pretreatment and at surgery in patients with residual disease. Tumor specimens were analyzed using the 21-gene assay. One hundred sixty-eight patients (median age 52 years; 45 % triple-negative) were enrolled; 161 (96 %) underwent definitive surgery following neoadjuvant ixabepilone/cyclophosphamide. Overall, 27 patients (17 %) achieved pCR, including 19 of 73 (26 %) triple-negative patients. The most frequently occurring grade 3/4 toxicity was neutropenia (98 patients; 58 %). Recurrence Scores were highly correlated with achievement of pCR (0/36 with low or intermediate Recurrence Scores vs. 19/72 with high Recurrence Scores; p = 0.002). There was high concordance between baseline and post-treatment Recurrence Scores in the 72 patients with paired samples. The combination of ixabepilone and cyclophosphamide yielded a pCR rate of 17 %, similar to other neoadjuvant chemotherapy regimens. Pathologic complete responses occurred only in patients with high-risk baseline Recurrence Scores.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Epothilones; Female; Gene Expression Profiling; Humans; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Receptor, ErbB-2; Treatment Outcome

For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT.. This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria.. Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events.. Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cohort Studies; Epothilones; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Staging; Prognosis; Survival Rate

The prognostic utility of vascular endothelial growth factor A (VEGF-A) splice variants in patients with advanced breast cancer treated with bevacizumab has not been studied.. A total of 111 patients with metastatic breast cancer treated with weekly docetaxel or ixabepilone without bevacizumab (cohort A) and 100 treated with weekly paclitaxel and bevacizumab (cohort B) were studied. Formalin-fixed tumors were macrodissected for reverse transcription quantitative polymerase chain reaction relative quantification of VEGF-A165, -189, and -206 isoforms spliced at exon 8 proximal splice site (VEGF-Axxxa) and at exon 8 distal splice site (VEGF-Axxxb).. For high VEGF-Axxxa, the hazard ratios (HRs) for progression were 1.08 (P = .71) in non-bevacizumab-treated patients (cohort A) and 0.66 (P = .22) in bevacizumab-treated patients (cohort B), and the HRs for death were 1.45 (P = .13) and 0.50 (P = .049), respectively. The interaction of VEGF-Axxxa with bevacizumab administration was significant (P = .011) for overall survival (OS). High tissue VEGF-Axxxb was not prognostic in cohort A but was predictive for bevacizumab benefit in cohort B (HR for progression, 0.57 [P = .04]; HR for death, 0.51 [P = .02]). Exploratory analyses done only in cohort B suggested that abundance of VEGFR1 messenger RNA (mRNA) in peripheral blood and low VEGFR2 mRNA in tissue correlated with poor outcome. In multivariate analysis, high tissue mRNA of angiogenic VEGF-Axxxa in the presence of bevacizumab therapy predicted for favorable progression-free survival (HR for progression, 0.39; P = .0227) and OS (HR for death, 0.32; P = .0140).. Tissue mRNA expression of angiogenic VEGF-Axxxa isoforms was retrospectively associated with adverse prognosis in the absence of bevacizumab and with favorable outcome when bevacizumab was administered in patients with advanced breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Disease-Free Survival; Docetaxel; Epothilones; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Paclitaxel; Prognosis; Proportional Hazards Models; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor A

Anthracycline and taxane resistance is a key issue in the treatment of metastatic breast cancer (MBC), particularly in Asian patients who often present with advanced disease. The objective of this study was to investigate the efficacy and safety of ixabepilone monotherapy in Japanese patients with taxane-resistant MBC previously treated with anthracycline.. Japanese patients with taxane-resistant MBC previously treated with anthracycline were treated with 40 mg/m(2) ixabepilone every 3 weeks. Primary endpoint was overall response rate. Secondary endpoints included duration of response, time to progression (TTP), and safety.. Fifty-two patients were treated with ixabepilone. Overall response rate was 11.5 % (95 % confidence interval 4.4-23.4), stable disease rate was 38.5 %, duration of response was 3.6 months (range 2.4-5.3 months), and TTP was 2.8 months (range 0.7-8.1 months). The most frequent grade 3/4 toxicities were neutropenia (82.7 %), leukopenia (75 %), myalgia (19.2 %), and peripheral neuropathy (19.2 %).. Ixabepilone monotherapy was effective and toxicities were manageable in this phase II study of Japanese patients with taxane-resistant metastatic breast cancer previously treated with anthracyclines.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Japan; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.. Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1-2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m(2) as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored.. Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%).. This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Trastuzumab; Treatment Outcome

The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Breast Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Paclitaxel; Treatment Outcome

This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated.. Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. βIII-Tubulin expression was assessed using immunohistochemistry.. There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6-30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4-31.7). βIII-Tubulin-positive patients obtained higher pCR rates compared with βIII-tubulin-negative patients in both treatment arms; however, βIII-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy.. Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among βIII-tubulin-positive patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Epothilones; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Prognosis; Tubulin

Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m(2), 2-5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m(2), 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.

Topics: Adult; Breast Neoplasms; Epothilones; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Survival Rate

To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies.. ClinicalTrials.gov NCT 00790894.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Epothilones; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Metastasis; Patient Compliance; Receptor, ErbB-2; RNA, Messenger; Treatment Outcome; Tubulin

Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors.. A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) ("FEC" in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m(2) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted.. Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3-4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3-4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23 (47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors.. Despite high activity, DD ixabepilone after DD FEC is poorly tolerated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Epirubicin; Epothilones; Female; Fluorouracil; Humans

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Epothilones; Female; Humans; Middle Aged; Neutropenia; Peripheral Nervous System Diseases; Treatment Outcome

Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged ≥ 65 years.. A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m(2) as a 3-hour intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m(2) administered twice each day), or capecitabine alone (1250 mg/m(2) twice each day).. In total, 251 randomized patients were aged ≥ 65 years (ixabepilone plus capecitabine, n=116; capecitabine monotherapy, n=135). Efficacy results were consistent in patients aged <65 and ≥ 65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged ≥ 65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand-foot syndrome.. The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged < 65 years.

Topics: Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Retrospective Studies; Taxoids; Treatment Outcome

Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent.. Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on predefined biomarker sets: TUBB3, TACC3, and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression, and other potential markers of sensitivity. βIII-tubulin protein expression is reported separately but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy. Gene expression profiling data were used for molecular subtyping.. There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin-positive patients. Higher pCR rates were observed among βIII-tubulin-positive patients than in βIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3, and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen receptor-negative subset.. These results indicate that βIII-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multigene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Epothilones; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Microfilament Proteins; Microtubule-Associated Proteins; Neoadjuvant Therapy; Neoplasm Proteins; Nuclear Proteins; Paclitaxel; Prognosis; Tubulin

Combination therapy with ixabepilone and capecitabine (cape) is approved for use in patients with locally advanced/metastatic breast cancer that is resistant to treatment with anthracyclines or taxanes. The current study evaluated the trade-off between quality and quantity of life using quality-adjusted time without symptoms or toxicity (Q-TWiST) outcomes.. Within the trial, 752 women were randomly assigned to receive either the combination of ixabepilone and cape (once every 21 days) or cape alone (on days 1-14). The area under the survival curve was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity, and recurrence (relapse [REL]). The mean time in each health state was weighted by a range of utilities and summed to estimate quality-adjusted survival (QAS). Patient-reported outcomes were also evaluated using the Functional Assessment of Cancer Therapy (FACT)-Breast Symptom Index (FBSI).. A statistically significant difference between groups with regard to change from baseline FBSI scores favoring the cape group was observed (P = .0002), but no differences were observed after adjusting for deaths in the analysis. All combinations of utilities for REL and TOX resulted in an observed difference in QAS favoring combination therapy. Differences were found to be statistically significant for comparisons, with higher tolerance for TOX. QAS was found to be greater for the combination therapy group (42.2 weeks vs 38.4 weeks), assuming the base case scenario of utility equal to 0.5 for both TOX and REL (P = .0227).. The Q-TWiST analysis supports a positive benefit-risk ratio for the combination of ixabepilone plus cape in patients with advanced/metastatic breast cancer that is refractory to anthracyclines and taxanes versus cape alone, despite the potential for added toxicities with combination therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Quality of Life

Metastatic breast cancer (MBC) patients with rapid disease relapse after neo/adjuvant chemotherapy including anthracyclines and taxanes have limited treatment options and their efficacy is marginal. Two phase III studies compared ixabepilone plus capecitabine vs. capecitabine alone as first-line treatment in MBC patients pretreated with anthracyclines and taxanes in the neo/adjuvant setting. Here we report the efficacy and safety of these treatments in a prespecified subset of patients whose disease relapsed within 12 months.. Of 1973 patients across two studies, 293 relapsed within 12 months of neo/adjuvant treatment and received ixabepilone plus capecitabine (n = 149) or capecitabine alone (n = 144) as first-line chemotherapy for MBC. Analysis included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and toxicity.. In 293 patients, ixabepilone plus capecitabine, as compared to capecitabine alone, increased PFS (median: 5.6 months vs. 2.8 months; hazard ratio, 0.58; p < 0.0001), ORR (46% vs. 24%) and OS (median: 15.1 months vs. 12.5 months; hazard ratio, 0.84; p = 0.208). Major toxicities of this regimen included neuropathy, neutropenia and hand-foot syndrome, but were manageable.. Patients with breast cancer with early relapse following neo/adjuvant treatment with anthracyclines and taxanes may benefit from ixabepilone plus capecitabine. (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433.).

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Chemotherapy, Adjuvant; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Taxoids; Young Adult

In this phase I trial, 42 women with metastatic breast cancer were treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). The maximum-tolerated dose of ixabepilone in combination with epirubicin was 30 mg/m2 (the recommended dose for phase II evaluation), and the dose-limiting toxicity dose was 35 mg/m2 with grade 4 neutropenia.. The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer.. Patients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m(2)) and escalating doses of ixabepilone (25, 30, and 35 mg/m(2)).. Forty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m(2) (n = 6) in combination with 75 mg/m(2) epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m(2) was 30 mg/m(2), and the DLT dose was 35 mg/m(2) with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels.. The combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m(2), followed by ixabepilone 30 mg/m(2) every 3 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Epirubicin; Epothilones; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Treatment Outcome

This retrospective analysis aimed to determine whether early dose reduction impacts the efficacy of ixabepilone plus capecitabine in women with metastatic breast cancer (MBC).. In 2 phase III trials, patients (N = 1973) with anthracycline/taxane-pretreated MBC were randomized to receive ixabepilone 40 mg/m(2) on day 1 plus capecitabine 1000 mg/m(2) twice daily (BID) on days 1 to 14 or single-agent capecitabine 1250 mg/m(2) BID on days 1 to 14 of a 3-week course. Because of the similar design and populations, data from trials were pooled to evaluate efficacy of the combination regimen among women who did or did not undergo ixabepilone dose reduction during the first 4 courses. To adjust for bias resulting from selecting patients with inherently better outcome based on longer treatment durations, these analyses were restricted to patients who received ≥ 4 courses of ixabepilone.. The pooled cohort included 566 patients with measurable disease who were evaluable for efficacy. Patients who had early dose reduction showed similar objective response rates (ORRs) and progression-free survival (PFS) as did those with no/late dose reduction. ORRs were 62.6% (95% confidence interval [CI], 55.8%-69.0%) and 55.3% (95% CI, 49.9%-60.6%), respectively; median PFS was 7.2 months (95% CI, 6.6-8.0) and 7.0 months (95% CI, 6.5-7.5), respectively (hazard ratio = 0.98; 95% CI, 0.83-1.17).. These data suggest that early ixabepilone dose reduction did not affect the overall efficacy of ixabepilone plus capecitabine in patients with MBC who received ≥ 4 courses of treatment. By making appropriate dose reductions, ixabepilone-related toxicities can be minimized while maintaining clinical efficacy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cohort Studies; Confidence Intervals; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Odds Ratio; Survival Rate; Taxoids; Treatment Outcome; Tubulin Modulators

Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky's performance status (KPS) 70-80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70-80 subset (n = 606) or KPS 90-100 subset (n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70-80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90-100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70-80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433).

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Microtubules; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

Treatments for women with recurrent brain metastases from breast cancer are limited. In this phase II study,we administered sagopilone to patients with breast cancer and brain metastases. We observed modest activity with a central nervous system objective response rate of 13.3%; however, median PFS was disappointing. Further studies should focus on other agents to treat this challenging clinical problem.. Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options.. We conducted a phase II study of sagopilone, an epothilone B analogue that crosses the blood-brain barrier, in patients with breast cancer brain metastases. Women were treated with 16 mg/m(2) or 22 mg/m(2) intravenously every 21 days. The primary endpoint was CNS objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Using modified, high-resolution magnetic resonance angiography (MRA), we also evaluated changes in vessel tortuosity with treatment.. Fifteen women were enrolled; all had progressive CNS disease despite whole-brain radiotherapy. Two patients achieved a partial response (ORR, 13.3%) and remained in the study for 6 cycles. Responses were not associated with normalization of tumor-associated vessels on correlative imaging studies. Median PFS and OS were 1.4 months and 5.3 months, respectively. The most common grade 3 toxicities were lymphopenia and fatigue. Enrollment was stopped prematurely because of limited observed activity and slow accrual.. Sagopilone was associated with modest CNS activity in patients with breast cancer; however median PFS was disappointing. Further studies should examine other potentially active agents and/or combinations for this challenging clinical problem.

Topics: Adult; Aged; Antineoplastic Agents; Benzothiazoles; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Outcome

The epothilone B analogue, ixabepilone, binds to b-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31-58%), median time to progression was 8.2 months (95% CI 6.3-9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2? cancers. Grade 3-4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Epothilones; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Middle Aged; Receptor, ErbB-2

Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.. Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.. Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.. Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Polyethylene Glycols; Survival Rate; Taxoids; Treatment Outcome

Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were randomized to ixabepilone (40 mg/m(2) intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m(2) on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a median survival of 12.9 months compared to 11.1 months for patients receiving capecitabine alone (HR = 0.9; 95%CI: 077-1.05; P = 0.19). This observed increase in median OS favored the combination; however, the difference was not statistically significant. Predefined subset analyses showed a clinically meaningful increase in OS in KPS 70-80 patients receiving ixabepilone plus capecitabine (HR = 0.75; 95% CI: 0.58-0.98). Ixabepilone plus capecitabine did not show a significant improvement in survival compared to capecitabine alone in patients with MBC resistant to anthracyclines and taxanes. The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asia; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Europe; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Middle Aged; Proportional Hazards Models; Risk Assessment; Risk Factors; South America; Taxoids; Time Factors; Treatment Outcome; Tubulin Modulators; United States

Effective treatment options for patients with metastatic breast cancer pretreated with or resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of ixabepilone plus capecitabine in both anthracycline-pretreated and resistant and taxane-resistant metastatic breast cancer of Chinese women.. Patients with measurable disease who had anthracycline and taxanes as prior neoadjuvant, adjuvant or metastatic therapy were treated with ixabepilone at 40 mg/m(2) intravenously on day 1 of 21-day cycle plus capecitabine 2,000 mg/m(2) orally on day 1 through 14 of a 21-day cycle. The primary end point was the objective response rate. The secondary end points were time to progression, overall survival, and toxicity profiles.. Twenty-one patients received 146 cycles with a median of 5 cycles (range 1-13 cycles) per patients. Fourteen patients (66.7%) had partial response, 5 patients (23.8%) had stable disease, and 2 patients (9.5%) had progressive disease. Median time to progression and duration of response were 6.2 and 6.0 months, respectively. The median overall survival was 16.7 months. Eight (38.1%) patients required dose reduction and 14 (66.7%) patients discontinued treatment for adverse effect. Grade 3/4 treatment-related events included fatigue (28.6%), peripheral sensory neuropathy (33.3%), neutropenia (61.9%), anemia (4.7%), hypokalemia (4.7%), hand and foot syndrome (19.0%) and infection (9.5%). Resolution of grade 3/4 peripheral neuropathy was reversible after a median period of 6 weeks.. Ixabepilone plus capecitabine demonstrated a clear activity and an acceptable safety profile in Chinese patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer, and the majority of patients completed 6 cycles of the therapy with manageable neuropathy toxicities.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asian People; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; China; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Prospective Studies; Survival Rate; Taxoids; Treatment Outcome

We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.. A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m(2) intravenously on day 1) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14) or capecitabine alone (2,500 mg/m(2) on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death.. There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible.. This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Retreatment; Taxoids

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models, including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose previous chemotherapy regimen included a taxane and an anthracycline received sagopilone 16 or 22 mg/m(2) as a 3-h intravenous infusion every 21 days. Efficacy (using modified Response Evaluation Criteria in Solid Tumors), safety, and tolerability were assessed in this population. A total of 65 patients received sagopilone at either 16 mg/m(2) (N = 39) or 22 mg/m(2) (N = 26). Patients received a median of two cycles of sagopilone. Among the 65 patients who were evaluable for efficacy, there were three confirmed tumor responses over both treatment arms; however, the primary target of the study was not reached. The main treatment-related adverse events were sensory neuropathy (81.5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Breast Neoplasms; Canada; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Epothilones; Fatigue; Female; Germany; Humans; Infusions, Parenteral; Kaplan-Meier Estimate; Middle Aged; Nervous System Diseases; Prospective Studies; Time Factors; Treatment Failure; United States

This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations.. Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles.. One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Neoadjuvant Therapy; Predictive Value of Tests; Receptors, Estrogen; RNA, Messenger

Using data from a recent randomized trial, we evaluated the cost effectiveness of ixabepilone plus capecitabine versus capecitabine alone in patients with predominantly metastatic breast cancer considered to be taxane-resistant and previously treated with or resistant to an anthracycline.. We developed a stochastic decision-analytic model to represent data collected in the trial on medical resource use, health-related quality of life, and clinical outcomes. Estimates of overall survival were conditional on level of tumor response. We assigned monthly costs and utility weights according to periods defined by the duration of study treatment, time from discontinuation of the study drug until disease progression, and from progression until death and were specific to the level of response and receipt of subsequent therapy. Medical resources were valued in 2008 US dollars. We performed Monte Carlo simulations and sensitivity analyses to evaluate model uncertainty.. Overall survival was significantly associated with level of tumor response (P < .001). Total costs were estimated at $60,900 for patients receiving ixabepilone plus capecitabine and $30,000 for patients receiving capecitabine alone. The estimated gain in life expectancy with ixabepilone was 1.96 months (95% CI, 1.36 to 2.64 months); the estimated gain in quality-adjusted survival was 1.06 months (95% CI, 0.09 to 2.03 months). The resulting incremental cost-effectiveness ratio was $359,000 per quality-adjusted life-year (95% CI, $183,000 to $4,030,000). In sensitivity analyses, the results were robust to changes in numerous inputs and assumptions.. Addition of ixabepilone to capecitabine adds approximately $31,000 to overall medical costs and affords approximately 1 additional month of quality-adjusted survival.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Drug Costs; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Quality-Adjusted Life Years; Taxoids

Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epidemiologic Methods; Epothilones; ErbB Receptors; Female; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome

To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies.. Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies.. In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia.. On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC).. A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle).. No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption.. Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Taxoids; Time Factors; Treatment Failure

Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m(2)/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m(2)/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m(2), 8 mg/m(2) and 10 mg/m(2) dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.

Topics: Adult; Aspartate Aminotransferases; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Epothilones; Female; Hematologic Diseases; Humans; Injections, Intravenous; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Time Factors; Transaminases; Treatment Outcome; Tubulin Modulators

Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer.. Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m(2)/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated alpha-tubulin, tau-1, and p53 expression when possible.. Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor alpha-tubulin acetylation after treatment. Baseline or cycle 2 acetylated alpha-tubulin, tau-1, or p53 expression did not correlate with clinical response.. Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Cohort Studies; Disease Progression; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Time Factors; Treatment Outcome

There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline.. Patients were age >or= 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m(2) intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival.. All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature.. Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Cohort Studies; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Time Factors; Treatment Outcome

To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study.. Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m(2) monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF).. A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD >or= 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received >or= eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks.. Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of naturally occurring epothilone B. Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing apoptosis. This international phase II trial assessed the activity of ixabepilone in patients with metastatic breast cancer (MBC) that was resistant to taxane therapy.. MBC patients, who had experienced disease progression while receiving or within 4 months of taxane therapy (6 months if adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone (1- or 3-hour infusion of 50 mg/m(2) or 3-hour infusion of 40 mg/m(2) every 3 weeks).. Of 49 patients treated with 40 mg/m(2) ixabepilone during 3 hours, 35 (73%) had experienced disease progression within 1 month of their last taxane dose. The response rate was 12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial; five of six patients had not responded to prior taxane therapy. In responders, the median response duration was 10.4 months. In 20 patients (41%), stable disease was the best outcome. Median time to progression was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For treated patients across all cohorts (intent-to-treat population), the response rate was also 12% (eight of 66). Treatment-related adverse events in the study were manageable and primarily grade 1/2. Treatment-related neuropathy was mostly sensory and mild to moderate.. Ixabepilone (40 mg/m(2) as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity and an acceptable safety profile in patients with taxane-resistant MBC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.. Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.. Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

To investigate baseline factors and neurologic function tests (NFTs) that may predict the development of grade 2 or higher peripheral neuropathy (PN) after treatment with ixabepilone, an epothilone microtubule-stabilizing agent with antitumor activity.. Advanced breast cancer patients were treated with ixabepilone (6 mg/m2) for 5 consecutive days every 3 weeks in a phase II clinical trial. Physical examinations, questionnaires, nerve conduction studies, and NFTs, including the Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT), were performed at baseline and during subsequent cycles.. Forty-seven patients assessable for PN received a median of five cycles of therapy (range, one to 22 cycles). Nine of these patients developed grade 2 PN, and two developed grade 3 PN, with a median time to onset of 144 days (range, 6 to 189 days). Among these 11 patients, PN resolved in eight patients, with a median of 15 days (range, 6 to 346 days) after onset, but PN did not resolve in three patients during follow-ups at 76, 361, and 746 days after onset. GPT and changes of JTH scores at onset of PN were significantly different between patients with and without PN at comparable follow-up times (P = .006 and P = .002, respectively). Changes in GPT and JTH scores over the first two cycles were often associated with the development of PN by exploratory actuarial analysis.. Serious ixabepilone-induced neuropathy was relatively rare on the treatment schedule used. NFTs, such as JTH and GPT, may have utility for predicting PN, but further testing is needed.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Epothilones; Female; Humans; Middle Aged; Peripheral Nervous System Diseases; Prospective Studies

Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer.. Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated alpha-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies.. Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy.. An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.

Topics: Adult; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Docetaxel; Epothilones; Female; Humans; Immunohistochemistry; Infusions, Intravenous; Middle Aged; Nervous System; Paclitaxel; Taxoids; Treatment Outcome

Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Epothilones; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Receptors, Vascular Endothelial Growth Factor; Taxoids; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A

The new therapeutic solutions for breast cancer treatment are needed, for example, combined therapy consisted of several drugs that characterize different mechanisms of action and modern drug delivery systems. Therefore, we used combination of epothilone B (EpoB) and rapamycin (Rap) to analyze the cytotoxic effect against breast cancer cells (MCF-7; MDA-MB-231). Also, the effect of drugs co-delivered in bioresorbable micelles functionalized with biotin (PLA-PEG-BIO; poly(lactide)-co-poly(ethylene glycol)-biotin) was studied. The comparison of effects of the mixture of free drugs and the micelles co-loaded with EpoB and Rap revealed a significant decrease in the cell metabolic activity and survival. Moreover, the dual drug-loaded PLA-PEG-BIO micelles enhanced the cytotoxicity of EpoB and Rap against the tested cells as compared with the free drugs. The blank PLA-PEG-BIO micelles did not affect the tested cells. We expect that mixture of EpoB and Rap may be promising in breast cancer treatment and PLA-PEG-BIO micelles as carrier of these two drugs can be applicable for successful targeted delivery.

Topics: Biocompatible Materials; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Survival; Drug Carriers; Drug Delivery Systems; Epothilones; Female; Humans; Micelles; Nanoparticles; Proton Magnetic Resonance Spectroscopy; Sirolimus

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

Topics: Albumins; Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Computer Simulation; Drug Administration Schedule; Drug Tapering; Epothilones; Female; Humans; Models, Biological; Paclitaxel; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Precision Medicine

Evidence shows that the anticancer effects of microtubule targeting agents are not due solely to their antimitotic activities but also their ability to impair microtubule-dependent oncogenic signalling.. The effects of microtubule targeting agents on regulators of TGF-β-induced epithelial-to-mesenchymal transition (EMT) were evaluated in breast cancer cell lines using high content imaging, gene and protein expression, siRNA-mediated knockdown and chromatin immunoprecipitation.. Microtubule targeting agents rapidly and differentially alter the expression of Snail and Slug, key EMT-promoting transcription factors in breast cancer. Eribulin, vinorelbine and in some cases, ixabepalone, but not paclitaxel, inhibited TGF-β-mediated Snail expression by impairing the microtubule-dependent nuclear localisation of Smad2/3. In contrast, eribulin and vinorelbine promoted a TGF-β-independent increase in Slug in cells with low Smad4. Mechanistically, microtubule depolymerisation induces c-Jun, which consequently increases Slug expression in cells with low Smad4.. These results identify a mechanism by which eribulin-mediated microtubule disruption could reverse EMT in preclinical models and in patients. Furthermore, high Smad4 levels could serve as a biomarker of this response. This study highlights that microtubule targeting drugs can exert distinct effects on the expression of EMT-regulating transcription factors and that identifying differences among these drugs could lead to their more rational use.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Chromatin Immunoprecipitation; Epithelial-Mesenchymal Transition; Epothilones; Female; Furans; Gene Expression; Genes, jun; Humans; Ketones; Microtubules; Paclitaxel; Smad2 Protein; Smad3 Protein; Smad4 Protein; Snail Family Transcription Factors; Transforming Growth Factor beta; Tubulin Modulators; Vinorelbine

The histopathologic characteristics of reactions caused by the many novel anticancer agents are under-recognized. We report a case of a 67-year-old female with locally advanced metastatic breast cancer, who initially presented with an extensive reticulated erythematous patch on the trunk caused by intravascular metastases confirmed by a skin biopsy. Owing to disease progression, she was started on ixabepilone, a mitotic inhibitor. While receiving ixabepilone, another skin biopsy was obtained and initially interpreted as extramammary Paget's disease. However, the biopsy showed metaphase arrest of numerous keratinocytes in the basilar and suprabasilar epidermis. Atypical epithelial cells were only present in the intravascular spaces similar to the initial biopsy. Given the temporal association between the initiation of ixabepilone therapy and the epidermal mitotic arrest, a diagnosis of chemotherapy reaction to ixabepilone was rendered. Ixabepilone is an analog of epothilone, a microtubule stabilizer causing mitotic arrest of the cell cycle approved for the treatment of metastatic and locally advanced treatment-resistant breast cancer. The demonstration of epidermal mitotic arrest caused by ixabepilone is without precedent. The case emphasizes the importance of considering a chemotherapy reaction in the histologic differential diagnosis of epidermal mitotic arrest in a cancer patient receiving chemotherapy.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Diagnosis, Differential; Drug Eruptions; Epothilones; Female; Humans; Paget Disease, Extramammary

This study is a longitudinal follow-up of metastatic breast cancer patients treated with ixabepilone as first-line chemotherapy, with the aim to evaluate the association between a mechanism-based neurotoxicity and the efficacy of ixabepilone.. At the 2 main investigational sites of a phase II clinical trial, 50 patients previously treated with anthracycline received ixabepilone. A chart review was performed to evaluate overall survival (OS) and time to progression (TTP) and to describe the subsequent treatments.. The severe neurotoxicity induced by ixabepilone (38%) is correlated with a higher overall response rate to ixabepilone (79 vs. 48%; p = 0.042), a longer TTP (11.4 vs. 6.8 months; p = 0.023) and a longer OS (36.6 vs. 19.9 months; p = 0.05). After ixabepilone discontinuation, patients received a median of 4 subsequent chemotherapy lines (range 1-12). Among the 31 patients who received taxanes, neither the neurotoxicity incidence under treatment with taxanes nor the response was affected by a previous occurrence under ixabepilone treatment.. These findings suggest that neurotoxicity development under ixabepilone treatment is a predictor of treatment outcomes as well as a favorable prognostic factor. It highlights the risk-to-benefit ratio issue of ixabepilone. We noticed the possibility to treat patients with taxanes after ixabepilone without systematic recurrent neurotoxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase II as Topic; Epothilones; Female; Follow-Up Studies; Humans; Longitudinal Studies; Middle Aged; Neoplasm Metastasis; Neurotoxicity Syndromes; Survival Analysis; Taxoids; Treatment Outcome

In a landmark article published in the May 1, 2001, issue of Clinical Cancer Research, Lee and colleagues reported the original preclinical studies demonstrating anticancer activity of BMS-247550 (ixabepilone) against taxane-sensitive and taxane-resistant cancers. Subsequent clinical trials established the clinical efficacy of ixabepilone, leading to its regulatory approval for the treatment of drug-resistant metastatic or locally advanced breast cancers.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Epothilones; Female; HCT116 Cells; Humans; Microtubules; Taxoids; Tubulin Modulators

The tumor-suppressor protein p53 is considered to be one of the most important transport hubs of cell signal transduction, playing critical roles in the control of cell cycle arrest, apoptosis and many other processes as a nuclear transcription factor. p53 also acts in the cytoplasm to trigger apoptosis. Paclitaxel and other microtubule inhibitors can inhibit the growth of different types of cancer cells and induce apoptosis which is believed to be p53-independent. In the present study, we demonstrated that UTD1, a genetically engineered epothilone analog and a new microtubule inhibitor, activated p53 as a transcription factor at low concentrations demonstrated by its enhanced transcriptional activity and accumulation of p21, which led to cell cycle arrest. However, at high concentrations of UTD1, p53 was accumulated in the cytoplasm which contributed to induction of apoptosis. These observations indicate that the epothilone analog has differential effects on intracellular signaling and implies that p53 plays different roles in cells exposed to different concentrations of the anticancer agent.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cyclin-Dependent Kinase Inhibitor p21; Epothilones; Female; Humans; MCF-7 Cells; Paclitaxel; Signal Transduction; Tumor Suppressor Protein p53

Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.

Topics: Adaptor Proteins, Signal Transducing; Breast Neoplasms; Epothilones; Female; Formins; Gene Silencing; Humans; Male; Microtubules; Prostatic Neoplasms; Taxoids

Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the βIII isotype of tubulin. The βIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of βIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of βIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, βIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased βIII-tubulin may be an important contributor to the development of resistance to ixabepilone.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antineoplastic Agents; Brain Chemistry; Breast Neoplasms; Cattle; Drug Resistance, Neoplasm; Epothilones; Female; Humans; MCF-7 Cells; Microtubules; Molecular Structure; Paclitaxel; Protein Binding; Protein Isoforms; RNA Interference; RNA, Small Interfering; Structure-Activity Relationship; Transfection; Tubulin; Tubulin Modulators

The aim of this study was the preparation of novel polyester nanoparticles based on folic acid (FA)-functionalized poly(ethylene glycol)-poly(propylene succinate) (PEG-PPSu) copolymer and loaded with the new anticancer drug ixabepilone (IXA). These nanoparticles may serve as a more selective (targeted) treatment of breast cancer tumors overexpressing the folate receptor. The synthesized materials were characterized by (1)H-NMR, FTIR, XRD and DSC. The nanoparticles were prepared by a double emulsification and solvent evaporation method and characterized with regard to their morphology by scanning electron microscopy, drug loading with HPLC-UV and size by dynamic light scattering. An average size of 195 nm and satisfactory drug loading efficiency (3.5%) were observed. XRD data indicated that IXA was incorporated into nanoparticles in amorphous form. The nanoparticles exhibited sustained drug release properties in vitro. Based on in vitro cytotoxicity studies, the blank FA-PEG-PPSu nanoparticles were found to be non-toxic to the cells. Fluorescent nanoparticles were prepared by conjugating Rhodanine B to PEG-PPSu, and live cell, fluorescence, confocal microscopy was applied in order to demonstrate the ability of FA-PEG-PPSu nanoparticles to enter into human breast cancer cells expressing the folate receptor.

Topics: Breast Neoplasms; Cell Line, Tumor; Epothilones; Female; Folic Acid; Humans; Nanoparticles; Polyesters; Polyethylene Glycols; Proton Magnetic Resonance Spectroscopy; Receptors, Cell Surface; Spectroscopy, Fourier Transform Infrared

Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy.. We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008-2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity.. Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99.. Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.

Topics: Breast Neoplasms; Chemoradiotherapy; Chemotherapy, Adjuvant; Epothilones; Female; Humans; Retrospective Studies

To report a case of cardiogenic shock and fulminant heart failure associated with a single dose of ixabepilone.. A 32-year-old woman presented to the emergency department (ED) with abdominal pain and difficulty breathing within 1 hour after receiving a partial dose of ixabepilone (26 mg/m(2)) at an oncologist's office. She had breast cancer, with metastases to the bone and liver and evidence of early liver failure. While in the ED, she developed acute respiratory failure requiring intubation. Bedside ultrasound imaging showed free abdominal fluid. Computed tomography (CT) scans showed evidence of right-sided heart failure and abdominal fluid consistent with ascites but no evidence of pulmonary embolism. After the CT scan, the patient experienced pulseless electrical activity cardiac arrest. All attempts at resuscitation were unsuccessful.. Ixabepilone is a novel drug for treatment of advanced breast cancer. The most commonly reported adverse effects are peripheral neuropathies and hematologic issues such as neutropenia. To our knowledge, this is the first detailed report of a severe adverse cardiac event associated with ixabepilone use. Many other chemotherapeutic agents have cardiotoxic effects. An objective causality assessment, using the Naranjo probability scale, revealed that an adverse drug event was probable.. Clinicians should maintain broad differential diagnoses that include adverse reactions to drugs relatively new to the market. Ixabepilone may have cardiotoxic effects that necessitate further study, particularly when the drug is administered after cardiotoxic chemotherapy.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Epothilones; Female; Heart Failure; Humans

Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Combinatorial Chemistry Techniques; Computer Simulation; Crystallography, X-Ray; Epothilones; Female; Humans; Inhibitory Concentration 50; Models, Biological; Molecular Structure

Radiation recall dermatitis (RRD) is an inflammatory reaction occurring in a previously irradiated area, precipitated by the administration of certain drugs. The drugs most commonly associated with RRD are intravenous antineoplastic agents. The frequency of development of this toxicity in clinical practice is unclear. We report a case of RRD induced by ixabepilone, an epothilone antineoplastic agent, with successful rechallenge utilizing an alternative dosing regimen.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Combined Modality Therapy; Drug Administration Schedule; Drug Monitoring; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lymphatic Metastasis; Neoplasm Recurrence, Local; Radiodermatitis; Trastuzumab; Treatment Outcome; Tubulin Modulators

Eribulin was FDA approved in 2012 as a treatment for patients with MBC who have previously received at least two prior chemotherapy regimens. The aim of this analysis was to assess the cost effectiveness of eribulin versus the three most commonly utilized drugs (TPC) in the EMBRACE trial: vinorelbine, gemcitabine, and capecitabine (X); and to other branded FDA approved drugs: ixabepilone (I), liposomal-doxorubicin (D), and nab-paclitaxel. We created a decision-analytical and a Markov model using clinical data from the EMBRACE trial. Health utilities were derived from the published literature. Costs for drug acquisition, physician visits, and laboratory tests were obtained from Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2012 USD. Life-years saved (LY), quality-adjusted life years (QALY), and incremental cost effectiveness ratio (ICER) were calculated. Eribulin added 0.208 LY and 0.119 QALY with an incremental cost over TPC of $25,458, and therefore an ICER of $213,742 per QALY. The main drivers of the model were drug cost, PFS, OS, and health utility values. The results of the model were robust in sensitivity analyses. Relative to I, D, A, and X, the ICER for eribulin was $76,823, $109,283, $129,773, and $167,267, respectively. Even with a more contemporary willingness-to-pay threshold of approximately $120,000 per QALY, eribulin was not found to be cost effective in the treatment of MBC relative to TPC; relative to some more expensive branded drugs, eribulin appears to be cost effective.

Topics: Albumins; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Cost-Benefit Analysis; Decision Making, Computer-Assisted; Deoxycytidine; Disease-Free Survival; Doxorubicin; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Furans; Humans; Ketones; Markov Chains; Neoplasm Metastasis; Paclitaxel; Quality of Life; Treatment Outcome

Microtubule-targeting agents, including taxanes (Tax) and ixabepilone (Ixa), are important components of modern breast cancer chemotherapy regimens, but no molecular parameter is currently available that can predict for their efficiency. We sought to develop pharmacogenomic predictors of Tax- and Ixa-response from a large panel of human breast tumor cell lines (BTCL), then to evaluate their performance in clinical samples. Thirty-two BTCL, representative of the molecular diversity of breast cancers (BC), were treated in vitro with Tax (paclitaxel (Pac), docetaxel (Doc)), and ixabepilone (Ixa), then classified as drug-sensitive or resistant according to their 50% inhibitory concentrations (IC50s). Baseline gene expression data were obtained using Affymetrix U133 Plus 2.0 human oligonucleotide microarrays. Gene expression set (GES) predictors of response to taxanes were derived, then tested for validation internally and in publicly available gene expression datasets. In vitro IC50s of Pac and Doc were almost identical, whereas some Tax-resistant BTCL retained sensitivity to Ixa. GES predictors for Tax-sensitivity (333 genes) and Ixa-sensitivity (79 genes) were defined. They displayed a limited number of overlapping genes. Both were validated by leave-n-out cross-validation (n = 4; for overall accuracy (OA), P = 0.028 for Tax, and P = 0.0005 for Ixa). The GES predictor of Tax-sensitivity was tested on publicly available external datasets and significantly predicted Pac-sensitivity in 16 BTCL (P = 0.04 for OA), and pathological complete response to Pac-based neoadjuvant chemotherapy in BC patients (P = 0.0045 for OA). Applying Tax and Ixa-GES to a dataset of clinically annotated early BC patients identified subsets of tumors with potentially distinct phenotypes of drug sensitivity: predicted Ixa-sensitive/Tax-resistant BC were significantly (P < 0.05, Fischer's exact test) more frequently ER/PR-positive, Ki67-negative, and luminal subtype than predicted Ixa-resistant/Tax-sensitive BC. Genomic predictors for Tax- and Ixa-sensitivity can be derived from BTCL and may be helpful for better selecting cytotoxic treatment in BC patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Computer Simulation; Docetaxel; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Profiling; Genetic Association Studies; Humans; Inhibitory Concentration 50; Middle Aged; Models, Biological; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Paclitaxel; Phenotype; Receptor, ErbB-2; Receptors, Estrogen; Taxoids; Tubulin Modulators

Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib±cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Breast Neoplasms; Butadienes; Cell Line, Tumor; Chromones; Dasatinib; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Epothilones; Female; Humans; Morpholines; Niacinamide; Nitriles; Paclitaxel; Phenylurea Compounds; Pyridines; Pyrimidines; Signal Transduction; Sirolimus; Sorafenib; Tamoxifen; Thiazoles

Peloruside A (PelA), a novel microtubule-stabilizing agent and potential anti-cancer drug, isolated from the marine sponge Mycale hentscheli, binds to a distinct, non-taxoid binding site on tubulin. Using live-cell confocal microscopy, the effects of PelA on microtubule dynamics were quantified in a human breast adenocarcinoma cell line (MCF7) stably expressing GFP-α-tubulin. Changes in microtubule length were tracked over time in cells treated with PelA concentrations ranging from 3.8-100 nM. As with other microtubule-targeting drugs like paclitaxel and epothilone B, microtubule dynamics were suppressed in a concentration-dependent manner. At the PelA IC₅₀ concentrations for cell proliferation (3.8 nM) and G₂/M block (25 nM), PelA inhibited dynamicity by 23% and 45%, respectively. At 25 nM PelA, effects included a 24% and 41% reduction in average growth rate and growth length, respectively. Additionally, the total time spent in pause increased by 53% and coincided with a 36% reduction in the average amount of time spent growing. Rescue and catastrophe frequencies were not significantly affected by PelA, except for length-based catastrophe (67% increase). The results provide further insight into PelA's unique mode of stabilization and contribute to our understanding of how microtubule-targeting agents exert their anti-mitotic effects.

Topics: Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Epothilones; Female; Humans; Lactones; Microtubules; Time Factors

Ixabepilone 40 mg/m(2) administered on an every 3-week schedule is approved for use in metastatic breast cancer (MBC) as monotherapy, or in combination with capecitabine in anthracycline/taxane resistant tumors. Because the mechanism of action and toxicity profile is similar to the taxanes, it has been suggested that weekly administration (15-20 mg/m(2) on days 1, 8, 15 for 28 days/cycle) may provide a therapeutic advantage while minimizing toxicity. We report 24 MBC patients treated with weekly ixabepilone. Demographics, ER/PR/HER-2/neu, ECOG performance status (PS), sites of metastatic disease, lines of previous therapy, dosage, treatment duration, dose reductions/interruptions, hematologic/non-hematologic toxicities, growth factor use, reasons for discontinuation, time to progression (TTP), and response rate were recorded. Median age was 61 years (33-79). 0-1 ECOG PS was 54%. Sixty-seven percent of patients received ≥ 4 previous chemotherapy regimens. Median treatment duration was 1.4 months (0.5-10.8). Median dose was 16 mg/m(2) (15-20). In 37.5% of patients, the dose was held due to toxicities with median missed dose of 2. Partial response and stable disease were 4 and 48%. Median TTP was 2.1 months (0.9-16.4). Majority of patients discontinued therapy due to disease progression (84%). Grade 3-4 neutropenia and neuropathy were 4% and 8%. It is not yet clear whether the weekly administration of ixabepilone impacts the risk/benefit profile. There are clinical data to suggest that weekly ixabepilone is efficacious and tolerable. Upcoming clinical trials will continue to inform the question. Our data suggest that weekly ixabepilone is well tolerated with a manageable side-effect profile in this small, heavily pretreated population.

Topics: Adult; Aged; Breast Neoplasms; Drug Administration Schedule; Epothilones; Female; Humans; Middle Aged; Retrospective Studies; Survival Rate

Ixabepilone is the first epothilone to be approved for clinical use. Current data suggest the epothilones have a role in treating taxane-resistant cancers and ixabepilone is unaffected by at least some of the mechanisms underlying chemoresistance. Here, we report a series of cytotoxicity and transport studies to assess the potential role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in ixabepilone resistance. A significant decrease in ixabepilone-mediated cytotoxicity was observed in Madin-Darby canine kidney cells transfected with human multidrug resistance 1 (MDR1) comparative with the parental cells (IC(50) > 2000 nM versus 90 nM). Overexpression of P-gp also resulted in significantly decreased cell susceptibility to docetaxel, paclitaxel, and vinblastine. Bidirectional transport of ixabepilone across monolayers of porcine kidney-derived cells expressing human MDR1 showed a significantly increased efflux ratio relative to the parental cells. A BCRP-overexpressing cell line was developed by transfecting human embryonic kidney (HEK)-293 cells with BCRP cDNA and confirmed by immunoblotting and bodipy prazosin and mitoxantrone uptake. Neither P-gp nor multidrug resistance protein 2 was detected in the cells by corresponding polyclonal antibodies. This HEK-BCRP cell line demonstrated resistance to docetaxel, paclitaxel, vinblastine, and mitoxantrone, in comparison with the parental cell line (7.3, 4.3, 2.9, and 11.9 resistance factor, respectively). Transport inhibition by BCRP inhibitor fumitremorgin C and broad efflux inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) restored drug sensitivity. In contrast, ixabepilone was far less susceptible to BCRP-mediated resistance, resulting in a resistance factor of only 1.2-fold. In summary, these results suggest that P-gp could cause resistance to ixabepilone in tumors and affect the disposition of the drug, but it is unlikely that BCRP mediates any drug resistance to ixabepilone.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport, Active; Blotting, Western; Breast Neoplasms; Cell Line; Cell Survival; Dogs; Drug Resistance, Neoplasm; Epithelium; Epothilones; Humans; Neoplasm Proteins; Taxoids; Transfection; Tubulin Modulators

Topics: Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Breast Neoplasms; Camptothecin; Chemistry, Pharmaceutical; Disease-Free Survival; Epothilones; Female; Genes, BRCA1; Humans; Irinotecan; Parity; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Risk Factors; Treatment Outcome; Tubulin Modulators

Topics: Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Drug Costs; Epothilones; Female; Humans; Medical Oncology; Neoplasms; Quality of Life

The optimal duration of ixabepilone and capecitabine chemotherapy combination is currently not known and will most likely be patient-specific based on efficacy, toxicity, quality of life, and patient preference.. We report an extremely long duration of chemotherapy with ixabepilone and capecitabine (42 cycles) in a patient with triple-negative metastatic breast cancer previously treated with anthracyclines and taxanes. Partial remission was achieved, and acceptable toxicity was observed.. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer regimen, especially with respect to the optimal duration of its use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Carcinoma, Ductal; Carcinoma, Papillary; Combined Modality Therapy; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Epothilones; Female; Fluorouracil; Follow-Up Studies; Humans; Long-Term Care; Lung Neoplasms; Middle Aged; Neoplasms, Second Primary; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

Topics: Antineoplastic Agents; Breast Neoplasms; Combined Modality Therapy; Epothilones; Female; Humans; Neoplasms; Radiodermatitis; Radiotherapy

Topics: Antineoplastic Agents; Breast Neoplasms; Capecitabine; Cost-Benefit Analysis; Costs and Cost Analysis; Deoxycytidine; Epothilones; Female; Fluorouracil; Humans; Quality-Adjusted Life Years

Taxanes, derived from the bark of the Pacific yew tree, were the last major group of cytotoxic agents to be developed. Their proven efficacy in a variety of malignancies has constituted a real breakthrough in the treatment of cancer. Wider clinical use of taxanes has several important limitations, including acquired and intrinsic tumor resistance, hypersensitivity reactions, and cumulative neurotoxicity and hematopoietic toxicity. Epothilones, naturally occurring macrolide antibiotics that also act on the microtubule, are a novel class of compounds that may circumvent some of these problems. Many synthetic and semisynthetic epothilone analogs have been formulated and have undergone varying degrees of testing. These compounds have demonstrated activity in a variety of tumors, including in tumors and cell lines resistant to taxanes. So far only ixabepilone has been tested in phase II and III trials and licensed by the US Food and Drug Administration for the treatment of metastatic breast cancer. The main dose-limiting toxicity appears to be a sensory peripheral neuropathy, as commonly seen with drugs that act on the microtubule. Further clinical studies assessing the role of ixabepilone in other settings, as well as the clinical investigation of other epothilones, are eagerly awaited.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Design; Epothilones; Female; Humans; Imidazoles; Neoplasm Metastasis; Ornithine; Tubulin Modulators

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Drug Approval; Drug Interactions; Epothilones; Female; France; Humans; Neoplasm Metastasis; Tubulin Modulators

The anti-human epidermal growth factor receptor 2 (HER2) agent trastuzumab has improved outcomes in breast cancer patients with HER2 over-expressing tumours. However, systemic treatment for patients with HER2-negative disease is still limited to endocrine and cytotoxic therapies. The increasing use of the anthracyclines and taxanes in early stage disease has reduced the available therapeutic options for patients with relapsed disease, and choices are further limited for patients with triple-negative tumours, who typically have a poor prognosis. The novel agents bevacizumab and ixabepilone were recently approved for metastatic breast cancer, and numerous other agents are currently in clinical development that may contribute further valuable therapeutic options.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cytotoxins; Drug Carriers; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Estradiol; Female; Fulvestrant; Humans; Intracellular Signaling Peptides and Proteins; Nanoparticles; Neoplasm Proteins; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Salvage Therapy; TOR Serine-Threonine Kinases

Ixabepilone is a novel microtubule-stabilising agent used as monotherapy or in combination with capecitabine to treat taxane- and anthracycline-refractory breast cancer. We report the case of a patient who experienced an unusual motor neuropathy after the first cycle. This is a very uncommon secondary effect, but it must be taken into account as a possible complication of treatment with ixabepilone.

Topics: Axons; Breast Neoplasms; Epothilones; Fatal Outcome; Female; Humans; Microtubules; Middle Aged; Neurons, Afferent; Peripheral Nervous System Diseases; Treatment Outcome; Tubulin Modulators

Resistance to chemotherapy is a complex and very frequent problem in the treatment of breast cancer. It is associated with a poor prognosis and short overall survival. We report a patient with advanced breast cancer without response to anthracyclines or taxanes but who controlled the disease for 15 months with the combination of ixabepilone and capecitabine.

Topics: Adult; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Taxoids; Treatment Outcome

The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to beta-tubulin.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Epothilones; Humans; Hydrogen Bonding; Tubulin; Tubulin Modulators

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Docetaxel; Epothilones; Everolimus; Female; Fluorouracil; Humans; Letrozole; Nitriles; Sirolimus; Tamoxifen; Taxoids; Trastuzumab; Triazoles

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Costs; Drug Interactions; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Infusions, Intravenous; Treatment Outcome; Tubulin Modulators

Patupilone is a microtubule stabilizer (MTS) currently in clinical development. Here, we evaluate the anti-cancer activity in vitro and in vivo in comparison to paclitaxel and describe the pharmacokinetics (PK) of patupilone in tumor-bearing nude mice and rats.. The potency in vitro of patupilone and two other MTS, paclitaxel and ixabepilone, was determined using human colon carcinoma cell lines with low (HCT-116, HT-29, RKO) and high (HCT-15) P-glycoprotein expression (P-gp), as well as two multi-drug resistance (MDR) model cell pairs, MCF7/ADR and KB-8511 cells and their respective drug-sensitive parental counterparts. The PK of patupilone was investigated in nude mice bearing HCT-15 or HT-29 xenografts and in rats bearing s.c. pancreatic CA20498 tumors or A15 glioma tumors. Anti-cancer activity in vivo was compared to that of paclitaxel using three different human tumor colon models. The retention and efficacy of patupilone was compared in small and large HT-29 xenografts whose vascularity was determined by non-invasive magnetic resonance imaging.. Patupilone was highly potent in vitro against four different colon carcinoma cell lines including those showing multi-drug-resistance. In contrast, paclitaxel and ixabepilone displayed significantly reduced activity with markedly increased resistance factors. In both rats and mice, a single i.v. bolus injection of patupilone (1.5-4 mg/kg) rapidly distributed from plasma to all tissues and was slowly eliminated from muscle, liver and small intestine, but showed longer retention in tumor and brain with no apparent elimination over 24 h. Patupilone showed significant activity against three human colon tumor models in vivo, unlike paclitaxel, which only had activity against low P-gp expressing tumors. In HT-29 tumors, patupilone activity and retention were independent of tumor size, blood volume and flow.. The high potency of patupilone, which is not affected by P-gp expression either in vitro or in vivo, and favorable PK, independent of tumor vascularity, suggest that it should show significant activity in colorectal cancer and in other indications where high P-gp expression may compromise taxane activity.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Glioma; Magnetic Resonance Imaging; Mice; Mice, Nude; Microtubules; Neoplasm Proteins; Paclitaxel; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Tissue Distribution; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Design; Epothilones; Female; Humans; Lung Neoplasms; Neoplasms; Tubulin

A Taxol-resistant cell line, K20T, which does not express P-glycoprotein, was selected with Taxol from human MDA-MB-231 breast adenocarcinoma cells and maintained in the presence of 20nM Taxol. K20T cells were approximately 18-fold resistant to Taxol, displayed cross-resistance to Taxotere and the epothilones, but little cross-resistance to discodermolide. Sequence analysis of the class I beta-tubulin indicated that it harbored an A593G mutation resulting in a change from glutamate to glycine at amino acid 198, which is near the intradimer interface within the alpha/beta-tubulin heterodimer. An HA-tagged wild-type class I beta-tubulin expression vector was transfected into the K20T cells. Immunofluorescence studies demonstrated that this exogenous tubulin was incorporated into cellular microtubules and Western blot analysis indicated that the K20T transfectants predominantly expressed the exogenous wild-type class I beta-tubulin. The transfected cells were only approximately 5-fold resistant to Taxol. Our results, plus the knowledge that Glu198 is the target for other anti-tubulin agents, suggest that glutamate198 in beta-tubulin is a critical determinant for microtubule stability and Taxol resistance.

Topics: Adenocarcinoma; Alkanes; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carbamates; Cell Line, Tumor; Cell Survival; Dimerization; Docetaxel; Drug Resistance, Neoplasm; Epothilones; Fluorescent Antibody Technique, Indirect; Glutamic Acid; Glycine; Humans; Lactones; Models, Molecular; Mutation, Missense; Paclitaxel; Protein Structure, Quaternary; Pyrones; Taxoids; Transfection; Tubulin; Tubulin Modulators

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Contraindications; Deoxycytidine; Drug Approval; Drug Labeling; Epothilones; Fluorouracil; Humans; Tubulin Modulators; United States; United States Food and Drug Administration

We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Colonic Neoplasms; Epothilones; Humans; Mice; Mycobacterium; Xenograft Model Antitumor Assays

Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK signaling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlated to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Death; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Paclitaxel; Signal Transduction; Tumor Cells, Cultured

The molecular mechanisms underlying the cell cycle growth-inhibitory and apoptotic effects of flavopiridol (FP) were determined in human breast cancer cells. Treatment with FP caused accumulation in the G(1) phase of the cell cycle and induced apoptosis of SKBR-3 and MB-468 cells. This was associated with down-regulation of the levels of cyclins D1 and B1, as well as with inhibition of cyclin-dependent kinase (cdk) 1, cdk2, and cdk4. FP-induced apoptosis was accompanied by a conformational change and mitochondrial localization of Bax. This resulted in the accumulations of cytochrome c, Smac, and Omi/HtrA2 in the cytosol and induced the poly(ADP-ribose) polymerase cleavage activity of caspase-3. Treatment with FP also attenuated the mRNA and protein levels of XIAP, cIAP-2, Mcl-1, Bcl-x(L), and survivin. In MB-468 cells with overexpression of Bcl-2 (468/Bcl-2), FP-induced Bax conformational change and apoptosis were inhibited, whereas the FP-mediated decline in the levels of IAP proteins, Mcl-11 and Bcl-x(L) remained unaltered. The effects of cotreatment with FP and the nontaxane tubulin-polymerizing agent epothilone (Epo) B were also determined in MB-468 cells. Sequential treatment with Epo B followed by FP induced significantly more apoptosis of MB-468 cells than treatment with the reverse sequence of FP followed by Epo B or treatment with either agent alone (P < 0.05). Treatment with Epo B followed by FP induced more Bax conformational change and was associated with a greater decline in the levels of XIAP, cIAP-2, Mcl-1, and Bcl-x(L). However, MB-468/Bcl-2 cells remained relatively resistant to Epo B followed by FP. Taken together, these findings suggest that the superior sequence-dependent anti-breast cancer activity of Epo B followed by FP may be due to FP-induced Bax conformational change and down-regulation of the antiapoptotic IAP, Bcl-x(L), and Mcl-1 proteins, but this treatment may not overcome the resistance to apoptosis of breast cancer cells conferred by overexpression of Bcl-2.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; CDC2 Protein Kinase; CDC2-CDC28 Kinases; Cell Cycle; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Epothilones; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Piperidines; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Messenger; Tumor Cells, Cultured

Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Chemistry, Organic; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Epothilones; Female; Humans; Indicators and Reagents; Macrolides; Molecular Structure; Paclitaxel; Porifera; Spindle Apparatus; Stereoisomerism; Taxoids; Tumor Cells, Cultured

The epothilones are a group of novel microtubule-targeted, antimitotic compounds that have a paclitaxel-like, assembly enhancing effect on tubulin in vitro as well as in cultured cells. We hypothesize that epothilones induce mitotic arrest by suppressing microtubule dynamics. To test this hypothesis, we used MCF7 cells stably transfected with GFP-alpha-tubulin to analyze microtubule dynamics at three concentrations of epothilone B, one that induced no mitotic arrest (0.2 nM, 20 h), one that induced one-third maximal mitotic arrest (IC(33,) 2 nM, 20 h), and one that induced half-maximal mitotic arrest (IC(50,) 3.5 nM, 20 h). We found that epothilone B suppressed microtubule dynamics in a concentration-dependent manner coincident with mitotic block. At 0.2 nM epothilone B, dynamics were not significantly altered. At 2 nM epothilone B (IC(33)), the mean growth and shortening rates were decreased by 38 and 27%, respectively. Dynamicity was decreased by 47%. At the IC(50), 80% of the cells had nearly complete stabilization of microtubule dynamics, and no anaphase or telophase figures were observed. Comparison of the effects of epothilone B on microtubule dynamics with those of paclitaxel indicated that both drugs alter the same microtubule dynamic parameters to a similar extent. At the IC(50) for mitotic arrest, dynamicity was reduced by 54% by paclitaxel compared with 62% for epothilone B. In 65% of the cells treated with paclitaxel, the microtubules were completely stabilized. Thus, the effects of epothilone B on microtubule dynamics are remarkably similar to those of paclitaxel, suggesting that both drugs induce mitotic block by a similar mechanism.

Topics: Anaphase; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Epothilones; Humans; Microtubules; Mitosis; Paclitaxel

Histone deacetylase inhibitors induce hyperacetylation of the amino-terminal lysine residues of the core nucleosomal histones, which results in chromatin remodeling and altered gene expression. Present studies demonstrate that exposure to a novel hydroxamic acid analogue histone deacetylase inhibitor, LAQ824, induced p21WAF1 and p27KIP1 and caused growth arrest and apoptosis of human breast cancer SKBR-3 and BT-474 cells that possess amplification and overexpression of Her-2/neu. Treatment with LAQ824 depleted the mRNA and protein levels of Her-2/neu-encoded Her-2, which was associated with attenuation of pAKT, c-Raf-1, and phosphorylated mitogen-activated protein kinase levels. LAQ824 also induced the acetylation of heat shock protein (hsp) 90, resulting in inhibition of its binding to ATP, which has been shown to impair the chaperone association of hsp 90 with its client proteins, Her-2, AKT, and c-Raf-1. Consistent with this, treatment with LAQ824 shifted the binding of Her-2 from hsp 90 to hsp 70, promoting proteasomal degradation of Her-2. Thus, LAQ824 depletes Her-2 through two mechanisms: attenuation of its mRNA levels and promotion of its degradation by the proteasome. Following LAQ824 treatment, the cell membrane association, autotyrosine phosphorylation, and colocalization of Her-2 with HER-3 also declined. Cotreatment with LAQ824 significantly increased trastuzumab-induced apoptosis of BT-474 and SKBR-3 cells. This was associated with greater attenuation of Her-2, c-Raf-1, and pAKT levels. LAQ824 also enhanced taxotere-induced, epothilone B-induced, and gemcitabine-induced apoptosis of BT-474 and SKBR-3 cells. These findings suggest that LAQ824 is active against human breast cancer cells and has the potential to improve the efficacy of trastuzumab, taxotere, gemcitabine, and epothilone B against breast cancer with Her-2/neuamplification.

Topics: Annexin A5; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Northern; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Chromatin; Coloring Agents; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cysteine Endopeptidases; Deoxycytidine; Detergents; Docetaxel; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Epothilones; Flow Cytometry; Gemcitabine; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Microscopy, Fluorescence; Multienzyme Complexes; Phosphorylation; Precipitin Tests; Proteasome Endopeptidase Complex; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Sepharose; Taxoids; Tetrazolium Salts; Thiazoles; Time Factors; Trastuzumab

A new epothilone, 10,11-didehydroepothilone D (5), was isolated from a strain of the heterologous host Myxococcus xanthus genetically engineered to produce epothilone D (4). The structure of 5 was determined from NMR and MS data. The epothilone polyketide synthase was further modified in a recombinant M. xanthus strain to produce 5 as the major epothilone-related metabolite. The cytotoxicity of 5 against a panel of tumor cell lines, including several with multidrug resistance, and its effect on tubulin polymerization were comparable to epothilone D (4).

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Breast Neoplasms; Drug Screening Assays, Antitumor; Epothilones; Epoxy Compounds; Female; Genetic Engineering; Glioma; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Lung Neoplasms; Mass Spectrometry; Molecular Sequence Data; Molecular Structure; Multienzyme Complexes; Myxococcus xanthus; Nuclear Magnetic Resonance, Biomolecular; Thiazoles; Tubulin; Tumor Cells, Cultured

Recent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs ("metronomic" dosing) can affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects (e.g., myelosuppression) involving other tissues, even after chronic treatment. This suggests that activated endothelial cells may be more sensitive, or even selectively sensitive, to protracted ("high-time") low-dose chemotherapy compared with other types of normal cells, thus creating a potential therapeutic window. To examine this hypothesis, we assessed the effects of several different chemotherapeutic drugs--namely paclitaxel, 4-hydroperoxycyclophosphamide, BMS-275183 (an oral taxane), doxorubicin, epothilone B (EpoB) and its analogue 5-methylpyridine EpoB--on human microvascular or macrovascular endothelial cells, fibroblasts, and drug-sensitive or multidrug-resistant breast cancer cell lines in cell culture, using both short-term (24 h) versus long-term (144 h), continuous exposures, where drug-containing medium was replaced every 24 h. Whereas little differential and only weak effects were observed using the short-term exposure, a striking trend of comparative vascular endothelial cell hypersensitivity was induced using the continuous long-term exposure protocol. Potent differential growth inhibition effects as well as induction of apoptosis were observed with IC(50) values in the range of 25-143 pM for paclitaxel, BMS-275183, EpoB, and 5-methylpyridine-EpoB. In contrast, the IC(50) values for tumor cells and fibroblasts tested were in the range of 500 pM to >1 nM for these drugs. Similar differential IC(50) values were noted using 4-hydroperoxycyclophosphamide. The results are consistent with the possibility that continuous low-dose therapy with various chemotherapeutic drugs may have a highly selective effect against cycling vascular endothelial cells, and may be relevant to the use of continuous or frequent administration of low doses of certain types of drugs as an optimal way of delivering antiangiogenic therapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Division; Cell Survival; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Endothelium, Vascular; Epothilones; Humans; Paclitaxel; Tumor Cells, Cultured

Epothilone B is a novel nontaxane antimicrotubule agent that is active even against paclitaxel (Taxol)-resistant cancer cells. The present study further explores the mechanisms underlying epothilone B-mediated cytotoxicity in human breast cancer cells. We show that BMS-247550 (EpoB), a novel epothilone B analogue, induces cell cycle arrest at the G(2)-M phase transition and subsequent apoptotic cell death of MDA-MB-468 (468) cells. Treating cells with EpoB triggers a conformational change in the Bax protein and its translocation from the cytosol to the mitochondria, which is accompanied by cytochrome c release from the inter-membrane space of mitochondria into the cytosol. Overexpression of Bcl-2 delays Bax conformational change, cytochrome c release, and apoptosis induced by EpoB. Conversely, the Bcl-2 antagonist Bak-BH3 peptide or HA14-1 compound abrogates the antiapoptotic effects of Bcl-2 and enhances apoptosis of 468 cells pretreated with EpoB (to induce mitotic arrest). In synchronized 468 cells, EpoB is more potent in inducing Bax conformational change and apoptosis at G(2)-M phase compared with G(1)-S phase of the cell cycle. Taken together, these findings demonstrate that EpoB induces apoptosis through a Bcl-2-suppressible pathway that controls a conformational change of the proapoptotic Bax protein. The enhanced cytotoxicity of EpoB by blocking Bcl-2 at mitochondria implies a potential application of the combination of EpoB and Bcl-2 antagonists in the treatment of human breast cancer.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Epothilones; Epoxy Compounds; G2 Phase; Humans; Mitochondria; Mitosis; Protein Conformation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Thiazoles; Tumor Cells, Cultured

In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent. The resistant cells did not express P glycoprotein or multidrug resistance-associated protein (MRP) which are known mediators of multidrug resistance (MDR). Two groups of epothilone A-resistant cells were selected: cells which exhibited low resistance to both epothilone A and Taxol, and cells which exhibit low resistance to Taxol but high resistance to epothilone A. cDNA microarrays of epothilone A-resistant and Taxol-resistant cells were utilized to further characterize epothilone A resistance. Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins. Genes whose expression increased with increasing epothilone A resistance include microtubule-associated GTPases, cytoskeletal proteins, cell signalling proteins and a drug metabolising enzyme. The majority of the genes that were repressed in both epothilone A- and Taxol-resistant cells encode proteins regulating cellular growth signalling mechanisms.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Cytoskeletal Proteins; Drug Resistance, Neoplasm; Epothilones; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Growth Substances; GTP Phosphohydrolases; HL-60 Cells; Humans; Interferons; Male; Microtubules; Neoplasm Proteins; Paclitaxel; Tumor Cells, Cultured

BMS-247550, a novel epothilone derivative, is being developed by Bristol-Myers Squibb Company (BMS) as an anticancer agent for the treatment of patients with malignant tumors. BMS-247550 is a semisynthetic analogue of the natural product epothilone B and has a mode of action analogous to that of paclitaxel (i.e., microtubule stabilization). In vitro, it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentrations. Importantly, BMS-247550 retains its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or that have developed resistance to paclitaxel, both in vitro and in vivo. Tumors for which BMS-247550 demonstrated significant antitumor activity encompass both paclitaxel-sensitive and -refractory categories, i.e., (a) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-21 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resistance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); (b) paclitaxel-insensitive: Pat-26 human pancreatic carcinoma (clinical isolate) and M5076 murine fibrosarcoma; and (c) paclitaxel sensitive: A2780 ovarian, LS174T, and HCT116 human colon carcinoma. In addition, BMS-247550 is p.o. efficacious against preclinical human tumor xenografts grown in immunocompromised mice or rats. Schedule optimization studies indicate that BMS-247550 is efficacious when administered frequently (every 2 days x 5) or intermittently (every 4 days x 3 or every 8 days x 2). These efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol in both clinical efficacy and ease of use (i.e., less frequent treatment schedule and/or oral administration).

Topics: Administration, Oral; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Cycle; Cell Survival; Colonic Neoplasms; Disease Models, Animal; Drug Resistance, Neoplasm; Epothilones; Epoxy Compounds; Female; Humans; Infusions, Parenteral; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Pancreatic Neoplasms; Sarcoma; Thiazoles; Tubulin; Tumor Cells, Cultured; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX-1 human mammary and HT-29 colon tumor), its effects were clearly superior against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Survival; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lactones; Leukemia P388; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Structure-Activity Relationship; Thiazoles; Transplantation, Heterologous; Tumor Cells, Cultured