Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction, and has demonstrated potent single-agent activity in various in vitro and in vivo tumor models dependent on wild-type (wt) TP53. This study aims to determine the optimal dose and schedule of NVP-HDM201 for treating patients (pts) with TP53 wt tumors for further clinical study. Here we report results from pts with solid tumors.

Methods: In this multicenter, open-label, Phase I, ongoing study, pts with advanced TP53 wt tumors progressing on standard therapy or for whom no standard therapy exists were treated with single-agent oral NVP-HDM201. Four treatment regimens of NVP-HDM201 are explored: two high-dose intermittent regimens, Regimen (Reg) 1A (single dose [SD] on Day 1 in a 3-week [wk] cycle) and Reg 1B (SD on Days 1 and 8 in a 4-wk cycle); and two low-dose extended regimens, 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 cut-off (Sep 19, 2016), 85 pts received NVP-HDM201 (Reg 1A n=26; Reg 1B n=20; Reg 2A n=20; Reg 2C n=19); 13% were still receiving treatment. Common Grade 3/4 adverse events (AEs) suspected to be treatment related (Reg 1A; Reg 1B; Reg 2A; Reg 2C) included neutropenia (23%; 25%; 15%; 5%), thrombocytopenia (23%; 10%; 20%; 11%), and anemia (12%; 0%; 20%; 16%); the first two were dose limiting in 4 pts (2; 1; 0; 1). Gastrointestinal toxicity was predominantly low grade, and not dose limiting; the most common treatment-related AE reported was nausea (62%; 60%; 40%; 42%). Median duration of exposure across all regimens was 8.5 weeks (range: 2-86 weeks). Partial responses were observed in 2 (2%) pts (1 in Reg 1A and 1 in Reg 1B). Stable disease was achieved by 29 (34%) pts (8 in Reg 1A, and 7 each in Reg 1B, Reg 2A and Reg 2C). Furthermore, the average plasma concentration per cycle reached with Reg 1A/Reg 1B was closer to the predicted preclinical target efficacious levels required for tumor regression compared with Reg 2A/Reg 2C, and is associated with the observed clinical activity. NVP-HDM201 showed approximate dose-proportional pharmacokinetics, and exposure correlated with blood concentrations of the GDF-15 biomarker on day 1.

Conclusions: NVP-HDM201 demonstrated a manageable safety profile and clinical activity in a heavily pretreated population. Dose-limiting toxicities consisted primarily of neutropenia and thrombocytopenia. Reg 1B was chosen for the expansion phase as it achieved the most favorable therapeutic index: the lowest incidence of Grade 3/4 thrombocytopenia while achieving therapeutically relevant exposures. The recommended dose for expansion was declared as 120 mg NVP-HDM201 and the expansion phase is enrolling. To enhance the safety and efficacy of NVP-HDM201, a separate cohort combining NVP-HDM201 with eltrombopag to mitigate thrombocytopenia is being investigated and will be reported.

Citation Format: David M. Hyman, Manik Chatterjee, Filip de Vos, Chia-Chi Lin, Cristina Suárez, David Tai, Philippe Cassier, Noboru Yamamoto, Vincent A. de Weger, Sébastien Jeay, Christophe Meille, Ensar Halilovic, Luisa Mariconti, Matthieu Klopfenstein, Nelson Guerreiro, Rajkumar Radhakrishnan, Emil T. Kuriakose, Sebastian Bauer. Optimizing the therapeutic index of HDM2 inhibition: Results from a dose- and regimen-finding Phase I study of NVP-HDM201 in pts with TP53 wt advanced tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT150. doi:10.1158/1538-7445.AM2017-CT150