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A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma.

ABSTRACT: 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.

SUBMITTER: Ott PA

PROVIDER: S-EPMC2808339 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma.

Ott Patrick A PA Hamilton Anne A Jones Amanda A Haas Naomi N Shore Tsiporah T Liddell Sandra S Christos Paul J PJ Doyle L Austin LA Millward Michael M Muggia Franco M FM Pavlick Anna C AC

PloS one 20100120 1

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>Eligible patients had ...[more]

PMID: 20098694

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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:UnlabelledIxabepilone is an epothilone B analogue with activity in a variety of solid malignancies, including prostate cancer. The main dose-limiting toxicity of ixabepilone is myelosuppression when administered by using an every 3-week schedule. Here we evaluate the activity of a weekly ixabepilone in men with metastatic castrate-resistant prostate cancer to minimize hematologic toxicity.PurposeBMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistant cancer cell lines. Here we report the activity and toxicity of ixabepilone, administered by using a weekly schedule, in men with metastatic castrate-resistant prostate cancer (CRPC).Experimental designPatients with metastatic CRPC received ixabepilone at 20 mg/m(2) intravenous weekly x 3, in 4-week cycles. This noncomparative study stratified patients to either a chemotherapy naive (CN), prior taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The primary endpoint was prostate-specific antigen response by using PCWG (Prostate Cancer Working Group) 1 criteria. Secondary endpoints included radiographic response when using RECIST (Response Evaluation Criteria In Solid Tumors).ResultsIn total, 124 patients were enrolled, of whom, 109 were eligible (35 CN, 42 Tax, and 32 TCx) for the primary response determination in this study. Prostate-specific antigen responses were seen in 12 (34.3%) of 35, 12 (28.6%) of 42, and 7 (21.9%) of 32 patients with the partial objective response in 5 (22.7%) of 22, 2 (8.0%) of 25, and 0 (0.0%) of 24 patients for the CN, Tax, and TCx arms, respectively. Significant (grade 3/4) neutropenia was seen in 6 (15.4%), 7 (14.6%), and 9 (25.0%); and grade 3/4 sensory neuropathy was seen in 8 (20.5%), 12 (25.0%), and 12 (33.3%) for CN, Tax, and TCx, respectively. Grade 3/4 thrombocytopenia was infrequent and seen in only one patient on the CN and the TCx arm.ConclusionIxabepilone was found to have an acceptable toxicity profile when administered by using a weekly schedule with less myelosuppression compared with prior studies when using the every 3-week schedule. Single-agent activity was observed and met prespecified activity levels for the Tax treated arm.

Dataset Information

A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma.

Publications

A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma.

Similar Datasets

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