START Madrid-FJD, Hospital Fundación Jimenez Diaz, Madrid, Spain.
Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Ann Oncol. 2020 Jun;31(6):780-788. doi: 10.1016/j.annonc.2020.03.294. Epub 2020 Mar 30.
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor.
CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics.
This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months.
CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.
溴结构域和末端（BET）蛋白是表观遗传学读体，调节参与致癌的基因表达。CC-90010 是一种新型的、口服的、可逆的小分子 BET 抑制剂。
CC-90010-ST-001（NCT03220347；2015-004371-79）是一项在晚期或不可切除的实体瘤和复发性/难治性（R/R）非霍奇金淋巴瘤（NHL）患者中进行 CC-90010 的剂量递增和扩展研究。我们报告了剂量递增阶段的结果，该阶段探索了 11 个剂量水平和四种给药方案，两种每周（2 天 ON/5 天 OFF；3 天 ON/4 天 OFF），一种每两周（3 天 ON/11 天 OFF），一种每月（4 天 ON/24 天 OFF）。主要目标是确定安全性、最大耐受剂量（MTD）和/或推荐的 II 期剂量（RP2D）和方案。次要目标是评估早期抗肿瘤活性、药代动力学和药效学的信号。
这项研究纳入了 69 名患者，其中 67 名患有实体瘤，2 名患有弥漫性大 B 细胞淋巴瘤（DLBCL）。中位年龄为 57 岁（范围，21-80），中位既往治疗方案数为 4 个（范围，1-9）。与治疗相关的不良事件（TRAEs）大多为轻度且可管理；报告超过两名患者的 3/4 级 TRAEs 为血小板减少症（13%）、贫血和疲劳（各 4%）。6 名患者出现剂量限制毒性。MTD 分别为 15mg（2 天 ON/5 天 OFF）、30mg（3 天 ON/11 天 OFF）和 45mg（4 天 ON/24 天 OFF）。选定扩展的 RP2D 和方案为 45mg（4 天 ON/24 天 OFF）。截至 2019 年 10 月 8 日，一名 2 级星形细胞瘤患者达到完全缓解，一名子宫内膜癌患者部分缓解，6 名患者疾病稳定≥11 个月。
CC-90010 耐受性良好，在既往治疗广泛的晚期实体瘤患者中具有单药活性。
