Dose- and regimen-finding phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) advanced tumors

Background: HDM201 is a potent and selective small molecule that inhibits the interaction between HDM2 and p53, leading to tumor regression in preclinical models when administered as either low-dose continuous or high-dose pulsed regimens. This study aims to determine the optimal dose and regimen of HDM201 for lurther clinical development. Pts with solid and hematological tumors were enrolled in independent dose escalations; here we report results from pts with solid tumors. Material and Methods: First-in-human, multicenter. open-label, ongoing study of HDM201 in pts with advanced TP53 wt tumors, progressing on standard therapy or for whom no standard therapy exists (NCT02143635, sponsored by Novartis Pharmaceuticals Corporation). Four oral treatment regimens of HDM201 are explored: Regimen (Reg) 1 comprising Reg 1A (single dose [SO] on Day 1 in a 3-week [wk] cycle) and Reg 1B (SD on Days 1 and 8 in a 4-wk cycle); and Reg 2 comprising Reg 2A (SD every day for first 2 wks in a 4-wk cycle) and Reg 2C (SD every day for first wk in a 4-wk cycle). Results: As of the data cul-off(April 1. 2016). 74 pts received HDM201 (Reg 1; Reg 2: 38; 36 pts: 21% and 22% were still receiving treatment, respectively). For both regimens (Reg 1; Reg 2), common grade 3/4 adverse events (AEs) suspected to be study drug-related, lypically occurring during Cycle 2. were anemia (8%; 17%), neutropenia (26%; 14%), and thrombocytopenia (24%; 28%); the latter two were dose limiting. Nevertheless, Cycle 2 hematological AEs were taken into account for decisions on dose escalation and regimen selection. Gastrointestinal toxicity was common but not dose limiting; the most common AE reported was nausea (66%: 36%). Median duration of exposure was similar: 8.4 wks (2.4-61.6) on Reg 1; 8.1 wks (2.3-61.4) on Reg 2. However, compared with Reg 2, the average plasma concentration per cycle reached with Reg 1 was closer to the predicted preclinical target efficacious levels required for tumor regression. HDM201 showed approximate dose-proportional pharmacokinetics. Exposure correlated with blood concentrations of GDF15 and hematological toxicity. Preliminary efficacy was observed at dose levels above or equivalent to predicted average concentrations for tumor stasis: Reg 1: 1 (3%) and 11 (29%) pts had a partial response and stable disease, respectively; Reg 2: 9 (25%) pts had stable disease. Conclusions: Preliminary data suggest that hematological toxicity is of late onset and is regimen-dependent; th