A phase I trial investigating a twice weekly administration of the oral taxane BMS-275183 in patients with advanced solid tumors

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Abstract
2040 Background: BMS-275183, a novel oral taxane, had peripheral neuropathy as the main side effect on a weekly regimen with the recommended phase II dose being 200 mg/m2. Considerable anti-tumor activity was observed in non-small cell lung cancer and other tumor types (Bröker et al., ASCO 2004, #2029). In the current phase I trial, we evaluated the safety, dose limiting toxicity (DLT), pharmacokinetics (PK) and possible anti-tumor activity of BMS-275183 given on a twice weekly schedule, in an effort to reduce its neurotoxicity. Methods: BMS-275183 was given on a continuous twice weekly regimen to adult patients with advanced solid tumors refractory to standard therapy. Plasma samples were collected on week 1 and 3 for 72 h after drug administration and analyzed using an LC/MS/MS assay. Results: To date, 16 patients have been treated at escalating dose levels of 60 (n=3), 80 (n=10) and 100 mg/m2 (n=3). At the 80 mg/m2 dose level, 2 DLTs have been observed consisting a grade (gr) 3 fatigue and a dose-omission due to gr 2 peripheral neuropathy, respectively. No DLTs have been observed in the first 3 patients treated at 100 mg/m2. Other side effects in the first 10 patients treated at 60 (n=3) and 80 mg/m2 (n=7) have included gr 1–2 fatigue (n=5), peripheral neuropathy (n=3), diarrhea (n=6), anorexia (n=5), taste disturbance (n=4), nausea (n=3), vomiting (n=2), stomatitis (n=1), epistaxis (n=3), neutropenia (n=1), myalgia (n=1), skin rash (n=1) and alopecia (n=2). PK analysis at the 80 mg/m2 dose level (n=7), revealed a rapid uptake with a median Tmax of 1 h and a mean T½ of 23 h. The mean AUC was 1264 ng.h/mL with an interpatient variability of 39%. These PK parameters are comparable to those obtained when BMS-275183 is administered once weekly at similar dose levels. One confirmed PSA-response has been observed in a patient with prostate carcinoma treated at 80 mg/m2 with a duration of 5+ months. Conclusions: Neurotoxicity appears to occur less frequently and to be less severe on a twice weekly regimen of BMS-275183 than on a weekly schedule. At present, the 100 mg/m2 dose level is being explored further to better define the safety of a dose to be recommended in phase II trials.

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