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Phase I and Pharmacokinetic Study of BMS-188797, a New Taxane Analog, Administered on a Weekly Schedule in Patients with Advanced Malignancies

Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California [R. A., G. A. F., B. L. L., C. J., C. D. C., B. I. S.], and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey [M. C.] and Wallingford, Connecticut [A. G.]

Purpose: The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly.

Experimental Design: Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797.

Results: Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m². The number of patients evaluated at each dose level was as follows: 35 mg/m² (n = 3); 50 mg/m² (n = 9); and 65 mg/m² (n = 6). At 65 mg/m², three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m² dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C_max) and area under the curve (AUC_0–48) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC.

Conclusions: The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m². The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.

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