A phase I trial of the novel oral taxane BMS-275183 in patients with advanced solid tumors

Abstract

2029 Background: BMS-275183, a novel orally administered taxane, has been studied in this phase I trial to assess its safety, tolerability, pharmacokinetics (PK) and possible anti-tumor activity. Methods: BMS-275183 was given in a continuous, weekly schedule to adult patients (pts) with advanced solid tumors refractory to standard therapy. Plasma samples were collected on weeks 1 and 3 for 48 h after drug administration and analyzed using a LC/MS/MS assay. Results: To date, 31 pts have been treated at escalating dose levels of 5 mg (n=1) and 5 (n=2), 10 (n=1), 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1) and 320 mg/m2 (n=6), and at subsequent intermediate dose levels of 240 (n=2) and 200 mg/m2(n=15). Most common and dose limiting toxicity (DLT) consists of peripheral neuropathy, which was severe (CTC grade 3) in 1/6 pts at 320 and 2/2 pts at 240 mg/m2, and developed rapidly after the first dose but generally recovered to gr 1 after dose reduction or discontinuation. Severe hematological toxicity was infrequent with gr 3 - 4 neutropenia in 4/31 pts, all treated at doses ≥ 200 mg/m2. At the 200 mg/m2dose level (n=15), 5 DLTs were observed consisting of 3 cases of delayed recovery (> 1 week) from gr 2 neuropathy, 1 gr 4 malaise and 1 gr 3 diarrhea / gr 4 neutropenia. Other side effects included gr 1 - 2 arthralgia, myalgia, anemia, alopecia, gastrointestinal symptoms, fatigue, fever, epistaxis, skin rash and nail changes. PK analysis at the 200 mg/m2dose level (n=15) revealed a rapid uptake with a median Tmax of 1 h and a mean T½ of 20.3 h. The mean AUC is 4595 ng.h/mL with an interpatient variability of 56%. Interestingly, a correlation between the AUC and the severity of the side effects was observed, as most patients with a DLT or dose reduction, had an AUC > 5600 ng.h/mL following the first dose. Seven confirmed partial responses were observed in 23 evaluable pts, all treated at a dose ≥ 160 mg/m2: 4/8 evaluable NSCLC pts (duration 26, 28, 20 and 26+ weeks), 1/3 NSCLC pts with non-measurable disease (16 weeks), 1/1 sarcoma pt (50 weeks) and 1/1 prostate/NSCLC pt (19 weeks). Conclusions: BMS-275183 is a novel oral taxane with promising activity in NSCLC. The recommended dose for future phase II trials currently is 200 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb