title: A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors.
abstract: 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=2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m2 and BMS-247550 20 mg/m2. Grade 4 neutropenia lasting >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.
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. gynbreast@mskcc.org
authors.forename: Martee L
authors.initials: ML
authors.lastname: Hensley
authors.forename: Don
authors.initials: D
authors.lastname: Dizon
authors.forename: Felicia
authors.initials: F
authors.lastname: Derosa
authors.forename: Ennapadam
authors.initials: E
authors.lastname: Venkatraman
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Chi
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: David
authors.initials: D
authors.lastname: Spriggs
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy; D014594:Uterine Neoplasms / Q000188:drug therapy; D014883:Water-Electrolyte Imbalance / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D034261:Epothilones; D003841:Deoxycytidine; C430592:ixabepilone; D000093542:Gemcitabine