Phase I study of a novel taxane BMS-188797 in adult patients with solid malignancies

Purpose: Preclinical studies show that BMS-188797 has a broad spectrum of antitumor activity in in vitro cytotoxicity assays and tumor xenograft models. We did a phase I trial designed to determine the maximum tolerated dose and the pharmacokinetics of BMS-188797 when administered i.v. Materials and Methods: BMS-188797 was administered i.v. over 60 minutes once every 21 days to 51 patients. The initial dose cohort of 3.75 mg/m2 was set at approximately one third the lethal dose in dogs. Doses were subsequently escalated in cohorts according to a modified Fibonacci design. Results: Fifty-one patients received a total of 160 cycles of therapy. The dose-limiting toxicity of febrile neutropenia occurred in two patients at the 200 mg/m2 cohort. Moderate to severe sensory neuropathy occurred in 12 patients (24%). Four radiographic partial responses based on the Response Evaluation Criteria in Solid Tumors occurred: two in subjects with breast cancer, one in a subject with non–small cell lung cancer, and one in a subject with renal cell carcinoma. The duration of the partial responses observed were 24.1 months (renal cell carcinoma), 5.7 and 4.3 months (breast cancer), and 4.5 months (non–small cell lung cancer). Pharmacokinetics appear linear at doses through 110 mg/m2 but not at higher doses. Conclusion: The dose-limiting toxicity in this single-agent study of BMS-188797 was febrile neutropenia. The recommended phase II dose of BMS-188797 as a single agent is 175 mg/m2 i.v. for 1 hour administered every 3 weeks.