Peter,
I think you are basically right. BMS' Epo B seems to have similar problems. OK for taxane resistant folks, but less so for folks with prior platinum therapy.
>>J Clin Oncol. 2003 May 1;21(9):1866-73.
Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.
Abraham J, Agrawal M, Bakke S, Rutt A, Edgerly M, Balis FM, Widemann B, Davis L, Damle B, Sonnichsen D, Lebwohl D, Bates S, Kotz H, Fojo T.
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA.
PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.<<
Ann Oncol. 2004 Jun;15(6):928-32. Related Articles, Links
A phase II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer.
Eng C, Kindler HL, Nattam S, Ansari RH, Kasza K, Wade-Oliver K, Vokes EE.
Department of Medicine, Section of Hematology/Oncology and Department of Health Studies, University of Chicago, Chicago, IL.
BACKGROUND: 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 AND METHODS: 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 </=1; peripheral neuropathy grade </=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. RESULTS: 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%). CONCLUSIONS: Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.<<
>>Ann Oncol. 2003 Oct;14(10):1518-24.
Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration.
Smaletz O, Galsky M, Scher HI, DeLaCruz A, Slovin SF, Morris MJ, Solit DB, Davar U, Schwartz L, Kelly WK.
Department of Medicine, Division of Solid Tumor, Memorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10021, USA.
BACKGROUND: Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer. PATIENTS AND METHODS: Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks. RESULTS: Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%). CONCLUSIONS: The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).<<
>>Clin Cancer Res. 2004 Feb 15;10(4):1289-98.
Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors.
Mani S, McDaid H, Hamilton A, Hochster H, Cohen MB, Khabelle D, Griffin T, Lebwohl DE, Liebes L, Muggia F, Horwitz SB.
Albert Einstein College of Medicine, Department of Molecular Pharmacology, and Albert Einstein Comprehensive Cancer Center, Bronx, New York 10461, USA. smani@montefiore.org
PURPOSE: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. RESULTS: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naive breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. CONCLUSIONS: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.<<
The breast cancer trial is monotherapy and should be OK. However, the NSCLC trial is also for patients who have had platinum therapy, and that one could also be in trouble:
cancer.gov
Cheers, Tuck |
