Impact of race on dose selection of molecular-targeted agents in early-phase oncology trials

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.