epothilone-a and Kidney-Neoplasms

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

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

In the United States, advanced kidney cancer accounts for over 12,000 deaths each year. Immunotherapy with either interferon or interleukin-2 (IL-2) has been the standard of care for over two decades. High-dose IL-2 can apparently cure 10% to 15% of patients treated, but due to the required inpatient care and the attendant toxicities, it is only administered to less than 1,000 patients per year in the United States (Chiron, personal communication). Interferon is a less active agent than IL-2 but it has still been shown to be superior to therapy with either megesterol or vinblastine. Interferon typically results in very few long-term responses and is given to most patients with metastatic kidney cancer. Median survival after interferon therapy is dependent on risk group but is typically 12 to 15 months. Thus, new therapies are urgently needed in this refractory disease. Novel compounds currently being tested in clinical trials are showing promise in advanced kidney cancer. The molecular targets of these drugs include interfering with the vascular endothelial growth factor receptors or the raf kinase pathway, angiogenesis inhibition, and antimicrotubule agents. A review of the preclinical and early clinical development of some of these novel compounds will be discussed.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Drug Administration Schedule; Epothilones; Erlotinib Hydrochloride; Humans; Indoles; Kidney Neoplasms; Lenalidomide; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thalidomide

Advanced kidney cancer accounts for over 12,000 deaths in the United States each year. Immunotherapy, typically interleukin-2 or interferon-alpha, have been the mainstay of treatment. Response rates are low for these immune-based treatments, and most patients with advanced kidney cancer succumb to their disease. There are several novel agents currently in clinical trials that show promise in this refractory disease. These compounds include antiangiogenic agents, raf kinase pathway inhibitors, and novel antimicrotubule agents. This review discusses some of the agents currently being explored for the treatment of advanced kidney cancer.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Clinical Trials as Topic; Epothilones; Gefitinib; Humans; Indoles; Kidney Neoplasms; Lenalidomide; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thalidomide

Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma.. Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m(2) ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing.. Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response.. Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma, Renal Cell; Epothilones; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Tubulin

The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.. Patients >or= 2 and 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours.. The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

Topics: Adolescent; Child; Child, Preschool; Epothilones; Female; Hepatoblastoma; Humans; Kidney Neoplasms; Liver Neoplasms; Male; Maximum Allowable Concentration; Neuroblastoma; Sarcoma; Wilms Tumor

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cohort Studies; Deoxycytidine; Dose-Response Relationship, Drug; Epothilones; Female; Gemcitabine; Humans; Kidney Neoplasms; Leukopenia; Lung Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Sarcoma; Urinary Bladder Neoplasms; Uterine Neoplasms; Water-Electrolyte Imbalance

Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies.. Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over three hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with alpha = 0.1, beta = 0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed.. A median of five cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was nine weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue and anemia.. Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Epothilones; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Treatment Outcome; Tubulin Modulators

Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. alpha-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra).. Levels of posttranslationally modified alpha-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis.. In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated alpha-tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated alpha-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated alpha-tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined.. Assessing the levels of detyrosinated and/or acetylated alpha-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Electrophoresis, Polyacrylamide Gel; Epothilones; Humans; Kidney Neoplasms; Microtubules; Protein Processing, Post-Translational; Tubulin