Ramalingam Suresh S, Parise Robert A, Ramanathan Ramesh K, Lagattuta Theodore F, Musguire Lori A, Stoller Ronald G, Potter Douglas M, Argiris Athanassios E, Zwiebel James A, Egorin Merrill J, Belani Chandra P
Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Clin Cancer Res. 2007 Jun 15;13(12):3605-10. doi: 10.1158/1078-0432.CCR-07-0162. Epub 2007 May 17.
The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel.
Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized.
Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics.
Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.
本研究的主要目的是确定新型组蛋白脱乙酰酶抑制剂伏立诺他与卡铂和紫杉醇联合使用时推荐的II期剂量。
28例晚期实体恶性肿瘤患者接受伏立诺他治疗，每3周口服一次，持续2周，或每日两次，持续1周。卡铂和紫杉醇每3周静脉注射一次。伏立诺他和紫杉醇的剂量在连续的3例患者队列中逐步增加。对伏立诺他及其代谢物和紫杉醇的药代动力学进行了表征。
伏立诺他与卡铂和紫杉醇联合使用时，安全剂量可达每日400mg或每日两次300mg。在每日400mg剂量方案的12例患者中，有2例出现3级呕吐和4级中性粒细胞减少伴发热的剂量限制性毒性。非剂量限制性毒性包括恶心、腹泻、疲劳、神经病变、血小板减少和贫血。在25例可评估反应的患者中，11例出现部分缓解（10例非小细胞肺癌和1例头颈癌），7例病情稳定。在所研究的剂量范围内，伏立诺他的药代动力学呈线性。当伏立诺他与卡铂和紫杉醇联合使用时，伏立诺他的浓度-时间曲线下面积和半衰期增加，但伏立诺他不改变紫杉醇的药代动力学。
伏立诺他的两种给药方案（每日口服400mg×14天或每日两次300mg×7天）与卡铂（浓度-时间曲线下面积=6mg/mL×min）和紫杉醇（200mg/m²）联合使用时耐受性良好。在先前未治疗的非小细胞肺癌患者中观察到了令人鼓舞的抗癌活性。
