epothilone-a and Neoplasm-Metastasis

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

The management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor. In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone, an epothilone B analog, with promising results. Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism. Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility. The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising. Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy. The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan) and biologic therapy (dasatinib, sunitinib) at the Phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit. A single Phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit. Although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work is still to be done. Importantly, this work bears the burden of not only validating the clinical benefit of ixabepilone, but also of determining whether this benefit is enhanced in any way by combination therapy, and where ixabepilone fits in the sequence of management for patients with metastatic pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Epothilones; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Tubulin Modulators

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

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) 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

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

Microtubules are vital and dynamic cellular organelles and many agents have been developed that target them. The cytotoxic effects of taxanes and epothilones are mediated by stabilization of microtubule dynamics. Taxanes are one of the most effective cytotoxic agents, and have a broad spectrum of antitumor activity. However, their efficacy is limited by the development of resistance to these effects. Epothilones have a similar mechanism of action to taxanes, but a decreased propensity for drug resistance. Epothilones are macrolides, and have in vitro and in vivo activity in taxane-resistant or taxane-insensitive human cancer cell lines. Several epothilones are in clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO. Multiple dosing schedules of ixabepilone and patupilone have been studied. The toxicity profiles of epothilones are quite diverse and depend on the compound and the administration schedule. The epothilones have demonstrated a wide range of clinical activity, including important antitumor effects, in advanced prostate cancer. Epothilones are particularly useful in patients with prostate cancer who have previously been treated with taxanes or who have taxane-refractory tumors. In the setting of castrate metastatic prostate cancer, ixabepilone and patupilone showed encouraging clinical activity in the phase II setting and further studies are needed to determine if they provide additional clinical benefit to patients with advanced disease.

Topics: Antineoplastic Agents; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Epothilones; Humans; Inhibitory Concentration 50; Male; Molecular Structure; Neoplasm Metastasis; Neutropenia; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tubulin

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

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

There is an urgent need for systemic treatment options for patients with castration-resistant prostate cancer who have progressed after receiving first-line docetaxel chemotherapy. The purpose of this article is to review recent developments in this area.. Retreatment with docetaxel has been employed with evidence of activity in selected populations. Mitoxantrone, the previous first-line standard based on its palliative effect, has also been used with clinical responses observed; however, the symptom benefit in this setting has not been established. Several classes of cytotoxic agents have been tested including platinum agents (satraplatin), epothilones (ixabepilone and patupilone) and taxanes (XRP-6258). A number of targeted therapies have also been clinically evaluated including inhibitors of cytoprotective chaperones (OGX-011) and the vascular endothelial growth factor receptor (sorafenib, sunitinib, and cediranib). An area generating great interest has been the development of agents that target the androgen receptor axis more effectively (MDV3100 and abiraterone) with encouraging early phase trial results.. There is no accepted standard systemic treatment for patients with castration resistant prostate cancer and progressive disease after docetaxel. Novel agents are in phase II and III clinical testing in this setting.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Epothilones; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Organoplatinum Compounds; Prostatic Neoplasms; Receptors, Vascular Endothelial Growth Factor; Taxoids; Testosterone; Thionucleotides

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

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

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

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

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

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

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

Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.

Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Endothelin Receptor Antagonists; Epothilones; ErbB Receptors; Humans; Male; Neoplasm Metastasis; Palliative Care; Prostatic Neoplasms; Receptor, ErbB-2

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 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

Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer.. Women were randomly assigned to receive either ixabepilone (40 mg/m(2)) every 21 days (n = 40), or ixabepilone (40 mg/m(2)) every 21 days with cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2)) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy.. Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events.. Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Disease Progression; Disease-Free Survival; Epothilones; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Treatment Outcome; Triple Negative Breast Neoplasms

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

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

Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients.. Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics.. Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD.. Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Epothilones; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prospective Studies

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

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

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

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.. Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.. Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.. These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Epothilones; Humans; Male; Middle Aged; Mitoxantrone; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

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

New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent.. Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5-10.0 mg m(-2)) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed.. Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm (n=31), as no DLTs were observed. Three patients in the CI-1D arm (n=26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m(-2), but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m(-2) after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m(-2)). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%.. Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colonic Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Epothilones; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Treatment Outcome

Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naïve (previously untreated) and previously treated patients with metastatic melanoma.. Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea.. Ixabepilone has no meaningful activity in either chemotherapy-naïve (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted.. Clinical Trials.gov NCT00036764.

Topics: Adult; Aged; Cohort Studies; Epothilones; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Tubulin Modulators

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 with promising preclinical activity and a favourable toxicity profile in phase I testing.. A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity.. Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).. Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

Topics: Antineoplastic Agents; Benzothiazoles; Disease Progression; Epothilones; Female; Half-Life; Humans; Male; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Prospective Studies; Risk Assessment; Treatment Outcome; Tubulin Modulators

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

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

Based on the pre-clinical spectrum of activity in taxane-resistant cell lines, we evaluated KOS-862 (epothilone D; 12,13-desoxyepothilone B) as second-line chemotherapy in androgen-independent prostate cancer.Thirty-eight men with metastatic androgen-independent prostate cancer and evidence of progression following docetaxel-based chemotherapy were treated with KOS-862, 100 mg/m(2) (maximum of 240 mg) i.v. weekly for 3 weeks, repeated every 4 weeks. The primary objective for this study was to determine the antitumor activity, measured by PSA decline by more then 50% confirmed 4 weeks later. Two patients (5.3%, 90% CI 1-16%) met criteria for confirmed PSA decline. While both of these patients had previously been treated with docetaxel, neither had confirmed docetaxel-refractory disease. None of the 24 patients with measurable disease had a confirmed partial response. Seventy-three percent of patients had an adverse event leading to dose delay, reduction, or treatment discontinuation. Neurological toxicity and fatigue predominated. Seventeen patients (44.7%) had treatment related grade 3 neurological adverse events including peripheral sensory neuropathy (n = 4, 10.5%), ataxia (n = 3, 7.9%), peripheral motor neuropathy (n = 1, 2.6%), involuntary muscle contractions (n = 1, 2.6%) and neuropathic pain (n = 1, 2.6%). One subject (2.6%) had a grade 4 treatment peripheral motor neuropathy. Further study of this dose and schedule of KOS-862 in this patient population cannot be recommended due to both lack of activity and excessive toxicity.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Epothilones; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Treatment Outcome

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 evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Epothilones; Estramustine; Fatigue; Humans; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Prostatic Neoplasms; Thrombosis

The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL).. Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks.. Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%).. Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Failure

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

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F(11); parental), MDA-MB-231 (F(11)) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F(11)) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F(11)) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinases; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Metastasis; Paclitaxel; Phosphorylation; Phthalazines; Polyploidy; Protein Kinase Inhibitors; Triple Negative Breast Neoplasms; Tubulin Modulators; Xenograft Model Antitumor Assays

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

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

Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone.. Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response.. In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 +/- 5% decrease (P < 0.001) in tumor blood volume and a 32 +/- 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P < or = 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (-21% to -70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 +/- 4%), tumor blood volume (50 +/- 6%), and vessel diameter (40 +/- 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged. Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005).. Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blood Vessels; Caspase 3; Caspases; Contrast Media; Disease Models, Animal; Endothelium, Vascular; Epothilones; Female; Immunohistochemistry; Lymphatic Metastasis; Magnetic Resonance Imaging; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Pressure; Rats; Time Factors

A convergent ring-closing metathesis strategy has been employed for the highly concise syntheses of 10,11-dehydro-13,14-[17]desoxyepothilone B ([17]ddEpoB) and 10,11-dehydro-14,15-[18]desoxyepothilone B ([18]ddEpoB), which are 17- and 18-membered ring homologues of 10,11-dehydro-12,13-desoxyepothilone B ([16]ddEpoB or epothilone 490). We have demonstrated that the ring-closing metathesis (RCM) provides [17]ddEpoB or [18]ddEpoB with a high level of stereocontrol in the generation of the desired olefin in the products. These analogues were evaluated for antitumor activity. The results from the in vitro assays revealed that the [17]ddEpoB analogue is highly active against various tumor cell lines with a potency comparable to that of [16]ddEpoB. This is the first example of a 17-membered ring macrolactone epothilone that has retained its antitumor activity. In contrast, the biological data revealed that [18]ddEpoB is significantly less active than either [17]ddEpoB or the parent [16]ddEpoB.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Epothilones; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasm Metastasis; Structure-Activity Relationship