Cleary James M, Lima Caio Max S Rocha, Hurwitz Herbert I, Montero Alberto J, Franklin Catherine, Yang Jianning, Graham Alison, Busman Todd, Mabry Mack, Holen Kyle, Shapiro Geoffrey I, Uronis Hope
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Invest New Drugs. 2014 Oct;32(5):937-45. doi: 10.1007/s10637-014-0110-9. Epub 2014 Jun 11.
To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors.
Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax.
Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39).
The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.
研究维托克洛司（ABT - 263）联合吉西他滨方案治疗实体瘤患者的安全性、最佳剂量、药代动力学及临床活性。
吉西他滨被认为是合适治疗方案的实体瘤患者被纳入两种不同给药方案之一（21天给药方案：维托克洛司在第1 - 3天和第8 - 10天口服，吉西他滨1000mg/m²在第1天和第8天；28天给药方案：维托克洛司在第1 - 3天、第8 - 10天和第15 - 17天口服，吉西他滨1000mg/m²在第1天、第8天和第15天）。维托克洛司剂量从150mg递增至425mg。针对21天给药方案，在维托克洛司的最大耐受剂量（MTD）下进行了一个扩大的安全性队列研究。
在美国三个中心共纳入46例患者。最常见的不良事件包括：血液学异常（血小板减少、中性粒细胞减少和贫血）、肝酶升高（ALT和AST）以及胃肠道紊乱（腹泻、恶心和呕吐）。在第1周期观察到的剂量限制性毒性（DLT）为4级血小板减少（2例患者）、4级中性粒细胞减少（1例患者）和3级AST升高（2例患者）。对于21天给药方案，维托克洛司的MTD为325mg与吉西他滨1000mg/m²联合使用。未观察到具有临床意义的药代动力学药物相互作用。未出现客观缓解。在第2周期末报告的疾病稳定是54%可评估患者（n = 39）的最佳反应。
维托克洛司325mg与吉西他滨1000mg/m²联合使用总体耐受性良好，在晚期实体瘤患者中显示出良好的安全性。
