bms-275183 and Neutropenia

BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s).. This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days.. Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis.. BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Sepsis; Treatment Outcome

BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity.. A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m2, etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1 and 15.. A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and 160 mg/m2 (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m2 experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m2, as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non-small cell lung cancer, prostate carcinoma, and other tumor types.. BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m2. Promising activity was observed in several tumor types, and a phase II trial in non-small cell lung cancer has been initiated.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Neutropenia; Pain; Treatment Outcome