Plummer Ruth, Woll Penella, Fyfe David, Boddy Alan V, Griffin Melanie, Hewitt Paula, Carmichael James, Namouni Fouad, Cohen Marvin, Verrill Mark
Northern Centre for Cancer Treatment, Newcastle upon Tyne, United Kingdom.
Clin Cancer Res. 2008 Dec 15;14(24):8288-94. doi: 10.1158/1078-0432.CCR-08-0471.
To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.
Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).
Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).
Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
根据最大耐受剂量、药代动力学、最佳给药方案和安全性，确定伊沙匹隆联合卡铂的推荐II期剂量。
晚期实体恶性肿瘤患者接受递增剂量的卡铂联合伊沙匹隆治疗，在21天周期的第1天（方案A）或第1天和第8天（方案B）给药。在第1周期采集血液样本，用于伊沙匹隆（两种方案）和卡铂（方案B）的药代动力学分析。
52例患者接受了每21天周期伊沙匹隆剂量为30至50mg/m²联合卡铂曲线下面积（AUC）5或6（卡尔弗特公式）的治疗。在方案A（伊沙匹隆40mg/m²静脉滴注1小时联合卡铂AUC 6）中，2例患者中有2例出现剂量限制性毒性（DLT）。在方案B（伊沙匹隆25mg/m²静脉滴注1小时，第1天和第8天联合卡铂AUC 6）中，3例患者中有3例出现DLT。DLT为骨髓抑制；然而，累积感觉神经病变限制了方案A的延长给药。伊沙匹隆和卡铂的药代动力学与单药使用时相似，表明不存在药代动力学药物相互作用。基于DLT和重复给药的耐受性，推荐剂量为伊沙匹隆30mg/m²（静脉滴注1小时）第1天，每3周1次联合卡铂AUC 6（方案A）和伊沙匹隆20mg/m²（静脉滴注1小时）第1天、第8天，每3周1次联合卡铂AUC 6（方案B）。
本研究数据显示了伊沙匹隆联合卡铂的可行性和耐受性，伊沙匹隆在21天周期的第1天或第1天和第8天给药。
