Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics.
Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics.
复制标题
DOI：
10.1007/s10637-012-9850-6
复制
发表时间：
2013-06
影响因子：
3.4
通讯作者：
Carducci, Michael A.
中科院分区：
文献类型：
--
作者：
Nwankwo, Nwabundo;Zhang, Zhe;Wang, Ting;Collins, Connie;Resta, Lee;Ermisch, Sabine;Day, Jeannette;Decker, Rodney;Kornberg, Lori;Nicol, Steven;Thornton, Donald;Armstrong, Deborah K.;Carducci, Michael A.
目的 鉴于恩扎妥林和贝伐单抗的作用机制不同，临床前研究表明联合使用可增强抗肿瘤活性。该第一阶段研究评估了该组合的安全性和有效性。患者和方法 11 个队列中每组可纳入 6 名晚期癌症患者。患者接受恩扎妥林负荷剂量。每个队列中口服恩扎妥林（500 mg 每日一次 [QD]、250 mg 每日两次 [BID]、375 mg BID、500 mg BID 和 750 mg BID）的剂量逐渐增加，并与每 2 周 5 mg/kg、每 2 周 10 mg/kg 或每 15 mg/kg 剂量的贝伐单抗联合使用。 3 周后，任何队列中的 6 名患者中有 2 名出现剂量限制性毒性 (DLT)。结果 67 名患者（31 名卵巢癌 [ovcar]）的安全性和有效性可进行评估。发生了 6 例与治疗相关的 DLT：3 级疲劳（n = 4）、4 级脑出血和 3 级天冬氨酸转氨酶升高。常见的药物相关毒性包括尿液和粪便颜色的变化、疲劳、疼痛、腹泻和恶心。 enzastaurin 的最大耐受剂量为 750 mg BID 与任何测试的贝伐单抗剂量/时间表组合。总体响应率为 19.4%（ovcar 为 32.3%）。进展的中位时间为 3.7 个月（95% 置信区间 [CI]，2.7–5.5），ovcar 为 8.3 个月（95% CI，3.7–11.1）。总体而言，35.9%（50.4% ovcar）的患者在 6 个月后仍未出现疾病进展。结论 Enzastaurin 的推荐 II 期剂量为 500 mg QD 至 500 mg BID，以及任何贝伐珠单抗测试剂量/时间表。这种组合表现出令人鼓舞的临床活性，特别是在 ovcar 中。本文的在线版本 (doi:10.1007/s10637-012-9850-6) 包含补充材料，可供授权用户使用。
Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination’s safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7–5.5), with 8.3 months (95 % CI, 3.7–11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar. The online version of this article (doi:10.1007/s10637-012-9850-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
6.1
作者：
Wu Jian-yu;Wu Xiao-nan;Cheng Gang
通讯作者：
Cheng Gang
影响因子：
11.2
作者：
Graff, JR;McNulty, AM;Thornton, D
通讯作者：
Thornton, D
影响因子：
50.5
作者：
Hanauske, A. -R.;Lahn, M.;Giaccone, G.
通讯作者：
Giaccone, G.
影响因子：
3
作者：
Keyes, KA;Mann, L;Teicher, BA
通讯作者：
Teicher, BA
影响因子：
11.5
作者：
Rademaker-Lakhai, Jeany M.;Beerepoot, Laurens V.;Voest, Emile E.
通讯作者：
Voest, Emile E.