A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.