Dataset Information

A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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. RESULTS: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. CONCLUSION:Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies.

SUBMITTER: Huang H

PROVIDER: S-EPMC7006234 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.

Huang Hui H Menefee Michael M Edgerly Maureen M Zhuang Sen S Kotz Herb H Poruchynsky Marianne M Huff Lyn Mickley LM Bates Susan S Fojo Tito T

Clinical cancer research : an official journal of the American Association for Cancer Research 20100223 5

<h4>Purpose</h4>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.<h4>Experimental design</h4>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) ixabe ...[more]

PMID: 20179242

Similar Datasets

Project description: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.

Project description:Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance.Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC.Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot.In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated.Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.

Project description:Lessons learnedAccrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.BackgroundTreatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.MethodsWe enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination.ResultsThe median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).ConclusionThe combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

Project description:BACKGROUND:RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting. METHODS:Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis. RESULTS:Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug). CONCLUSIONS:These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience. CLINICAL TRIAL NAME AND IDENTIFIER:Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

Dataset Information

A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.

Publications

A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets