Hensley Martee L, Dizon Don, Derosa Felicia, Venkatraman Ennapadam, Sabbatini Paul, Chi Dennis S, Dupont Jakob, Colevas A Dimitrios, Spriggs David, Aghajanian Carol
Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Invest New Drugs. 2007 Aug;25(4):335-41. doi: 10.1007/s10637-007-9035-x. Epub 2007 Mar 16.
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.
本研究的目的是确定研究性埃坡霉素BMS-247550与固定剂量率吉西他滨联合使用时的最大耐受剂量，并明确剂量限制性毒性。在一项I期研究中，患有晚期复发性实体瘤且针对复发性疾病接受过≤2种先前细胞毒性治疗方案的患者，在第1天和第8天接受90分钟的吉西他滨治疗，第8天接受3小时的BMS-247550治疗，每21天重复一次。剂量限制性毒性的定义基于严重骨髓抑制、3级或4级治疗相关非血液学毒性，或由于在第一个治疗周期中观察到的治疗毒性导致剂量延迟超过2周。剂量组1接受吉西他滨900mg/m²和BMS-247550 20mg/m²治疗。6名患者中有1名出现持续≥7天的4级中性粒细胞减少症。剂量组2（吉西他滨900mg/m²加BMS-247550 30mg/m²）的3名患者中有2名出现4级中性粒细胞减少症的剂量限制性毒性。另外3名患者在剂量水平1接受治疗，未观察到额外的剂量限制性毒性。在中间剂量水平（吉西他滨750mg/m²加BMS-247550 30mg/m²），6名患者中有2名出现剂量限制性毒性（1名患者为发热性中性粒细胞减少症和3级低磷血症，1名患者为3级低磷血症和3级低钠血症），6名患者中有5名出现剂量延迟。在最后一个剂量组（吉西他滨750mg/m²加BMS-247550 25mg/m²），2名患者中有2名出现剂量限制性毒性。治疗相关毒性包括中性粒细胞减少症、血小板减少症、中性粒细胞减少性发热、低磷血症和低钠血症。14名可评估疗效的患者中有9名病情稳定。该给药方案的最大耐受剂量为第1天和第8天90分钟内给予吉西他滨900mg/m²，第8天给予BMS-247550 20mg/m²。试图通过降低吉西他滨剂量来增加BMS-247550的剂量并不能充分改善骨髓抑制情况。在一些先前接触过紫杉烷的患者中观察到病情稳定。
