Authors' Affiliations: Tufts University School of Medicine, Boston, Massachusetts; Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas; Institute of Cancer Research, Royal Marsden Hospital, London, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, New York; University of California San Diego; Biogen Indec, San Diego, California; University of Texas M.D. Anderson Cancer Center, Houston, Texas; and TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale, Arizona.
Clin Cancer Res. 2014 Jan 15;20(2):445-55. doi: 10.1158/1078-0432.CCR-13-1257. Epub 2013 Oct 4.
BIIB021 is the first oral, synthetic, non-geldanamycin-based HSP90 inhibitor that showed activity in preclinical models at low nanomolar concentrations. We performed a phase 1 trial of BIIB021 administered to subjects with advanced solid tumors.
Sixty patients received BIIB021 capsules orally on days 1, 4, 8, 11, 15, and 18 of each course in schedule 1, and on days 1, 4, 8, 11, 15, 18, 22, and 25 of each course in schedule 2. The treatment schedules were repeated every 28 days. In addition to determining the MTD, we evaluated pharmacokinetics of BIIB021 and pharmacodynamic effects of BIIB021 [Hsp70, HER2 extracellular domain (HER2-ECD)].
The MTD was 700 mg twice weekly when BIIB021 was dosed for 3 weeks out of each 4-week course. The MTD for continuous dosing regimen was established at 600 mg twice weekly. Gastrointestinal (nausea, vomiting), hot flashes, and neurologic (dizziness) events characterize the safety profile of BIIB021 dosed twice weekly, with events mostly mild or moderate. Plasma exposure to BIIB021 was dose-dependent. Cmax occurred at approximately 90 minutes and t1/2 was approximately 1 hour across dosing cohorts of 25 to 800 mg BIIB021 twice weekly. The biologic activity of BIIB021 was demonstrated in serum, PBMCs, and tumor tissue. Hsp70 levels were increased (>150% from baseline) and serum HER2-ECD was significantly decreased (>15% inhibition from baseline).
BIIB021 twice weekly, given with or without the 1 of 4-week rest period was tolerated in subjects with advanced solid tumors at doses that are pharmacodynamically active.
BIIB021 是首个口服、合成、非格尔德霉素类 HSP90 抑制剂，在临床前模型中以低纳摩尔浓度显示出活性。我们进行了一项 BIIB021 治疗晚期实体瘤患者的 I 期试验。
60 名患者在第 1、4、8、11、15 和 18 天接受方案 1 中的 BIIB021 胶囊口服治疗，在第 1、4、8、11、15、18、22 和 25 天接受方案 2 中的 BIIB021 胶囊口服治疗。每个疗程每 28 天重复一次。除了确定最大耐受剂量外，我们还评估了 BIIB021 的药代动力学和 BIIB021 的药效学（Hsp70、HER2 细胞外结构域（HER2-ECD））。
当 BIIB021 在每个 4 周疗程中给药 3 周时，700mg 每日两次是最大耐受剂量。连续给药方案的最大耐受剂量确定为 600mg 每日两次。胃肠道（恶心、呕吐）、热潮红和神经系统（头晕）事件是 BIIB021 每周两次给药的特征，大多数为轻度或中度。BIIB021 的血浆暴露与剂量呈依赖性。在 25 至 800mg BIIB021 每日两次的给药队列中，Cmax 出现在约 90 分钟，t1/2 约为 1 小时。BIIB021 的生物学活性在血清、PBMC 和肿瘤组织中均有表现。Hsp70 水平升高（比基线高 150%），血清 HER2-ECD 显著下降（比基线抑制 15%以上）。
BIIB021 每周两次给药，有或没有每 4 周的 1 周休息期，在晚期实体瘤患者中耐受良好，剂量具有药效学活性。
