Nemunaitis John, Cunningham Casey, Senzer Neil, Gray Megan, Oldham Fred, Pippen John, Mennel Robert, Eisenfeld Amy
Mary Crowley Medical Research Center, Dallas, TX 75201, USA.
Cancer Invest. 2005;23(8):671-6. doi: 10.1080/07357900500359935.
The primary objective of this study was to determine the maximum tolerated dose (MTD) of CT-2103 (poly L-glutamic acid-paclitaxel) in combination with carboplatin in patients with histologically proven solid tumors that were either refractory to conventional treatment or for which no conventional therapy was available.
Twenty-two adult patients with advanced solid tumors were treated in this dose escalation study. Patients were treated every 21 days with CT-2103 at 175, 210, 225, or 250 mg/m2 (doses expressed as units of conjugated-paclitaxel) via 10-20 minute intravenous (IV) infusion, followed one hour later with carboplatin administered at AUC 5 or 6 via 30 minute IV infusion. No prophylaxis for hypersensitivity was administered with initial treatment. Doses were administered every 21 days until progressive disease or dose-limiting toxicity (DLT) was observed. Toxicity was evaluated using NCI Common Toxicity Criteria for Adverse Events v2.0 (CTCAE v2.0); response to treatment was evaluated using Response Criteria in Solid Tumors (RECIST).
The MTD was determined to be 225 mg/m2. DLTs observed at 250 mg/m2 were neutropenia and thrombocytopenia. No hypersensitivity reactions were observed. Three patients achieved partial responses (PR). Fifteen patients received at least 3 cycles of treatment without observation of progressive disease. Median survival time was 5.9 months. Patients that demonstrated partial responses were all ovarian cancer patients that had previously failed paclitaxel therapy. The only Grade 4, nonhematologic treatment-related toxicity was febrile neutropenia. Grade 4 neutropenia (9 patients) was observed across all dose groups. Twelve patients developed thrombocytopenia (Grade 3/4) while receiving combination therapy. All had resolution of thrombocytopenia with discontinuation of carboplatin, suggesting that carboplatin, and not CT-2103, contributed mainly to platelet toxicity.
CT-2103 administered at 225 mg/m2 every 21 days in combination with carboplatin administered at AUC 6 has a manageable safety profile in patients with solid tumors; further clinical investigation is recommended, especially in patients with ovarian or non-small cell lung cancer.
本研究的主要目的是确定CT-2103（聚L-谷氨酸-紫杉醇）与卡铂联合使用时，在组织学确诊的实体瘤患者中的最大耐受剂量（MTD），这些患者对传统治疗无效或没有可用的传统疗法。
22例晚期实体瘤成年患者参与了本剂量递增研究。患者每21天接受一次CT-2103治疗，剂量分别为175、210、225或250mg/m²（剂量以共轭紫杉醇单位表示），通过10 - 20分钟静脉输注，1小时后通过30分钟静脉输注给予卡铂，AUC为5或6。初始治疗时未给予过敏反应预防措施。每21天给药一次，直至观察到疾病进展或剂量限制毒性（DLT）。使用美国国立癌症研究所不良事件通用毒性标准第2.0版（CTCAE v2.0）评估毒性；使用实体瘤疗效评价标准（RECIST）评估治疗反应。
确定MTD为225mg/m²。在250mg/m²剂量时观察到的DLT为中性粒细胞减少和血小板减少。未观察到过敏反应。3例患者获得部分缓解（PR）。15例患者接受了至少3个周期的治疗且未观察到疾病进展。中位生存时间为5.9个月。显示部分缓解的患者均为先前紫杉醇治疗失败的卵巢癌患者。唯一的4级非血液学治疗相关毒性是发热性中性粒细胞减少。在所有剂量组中均观察到4级中性粒细胞减少（9例患者）。12例患者在接受联合治疗时出现血小板减少（3/4级）。所有患者在停用卡铂后血小板减少均得到缓解，这表明主要是卡铂而非CT-2103导致了血小板毒性。
每21天给予225mg/m²的CT-2103与AUC为6的卡铂联合使用，在实体瘤患者中具有可控的安全性；建议进一步进行临床研究，尤其是在卵巢癌或非小细胞肺癌患者中。
