Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Ave N Suite 200, Nashville, TN, 37203, USA.
Br J Cancer. 2018 Jun;118(12):1571-1579. doi: 10.1038/s41416-018-0102-1. Epub 2018 May 24.
We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia.
We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations.
17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy.
Conducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.
我们研究了种族对北美/欧洲（NA/EU）和亚洲单药分子靶向药物（MTA）最大耐受剂量（MTD）和最终批准剂量（FAD）的影响。
我们检索了 PubMed 和监管数据库，以确定在全球范围内批准的靶向药物，并比较了它们在 NA/EU 和亚洲分别进行的相应 I/II 期研究中的 FAD 和 MTD。为了进一步评估这一点，我们在美国和日本进行了 DS-7423 的平行、前瞻性、首次人体研究，DS-7423 是一种双重 PI3K/mTOR 抑制剂，用于治疗晚期实体瘤患者。我们对这些人群的药代动力学（PK）、药效学（PD）、毒性和疗效进行了汇总和比较。
2001 年至 2015 年，在 NA/EU 和亚洲共批准了 17 种 MTA。在 17 项研究中的 14 项（80%）研究中，种族之间的推荐 II 期剂量（RP2D）是相同的，差异没有临床意义。FAD 在所有地区都是相同的。来自美国和日本的 42 名和 27 名患者分别参加了 DS-7423 的 I 期研究。尽管存在种族、体重和体重指数的差异，但 RP2D 均为 240mg/天，毒性、PK、PD 或疗效无差异。
在白人和亚洲人群中分别进行单药 MTA 的临床试验可能是多余的。
