Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction, demonstrating potent preclinical activity, and is currently in Phase I clinical development. As delayed thrombocytopenia is the primary dose-limiting toxicity (DLT) of NVP-HDM201 treatment, reducing the incidence, severity, and duration of thrombocytopenia is critical to maximizing the therapeutic effect. Using data from the ongoing Phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) tumors, a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model describing drug-induced longitudinal platelet changes and tumor growth kinetics was developed to complement the clinical data in guiding dose escalation decisions and selection of an optimal dosing regimen for NVP-HDM201.
Methods: In the ongoing Phase I study of NVP-HDM201 in pts with advanced TP53 wt solid and hematologic tumors, 4 oral treatment regimens of NVP-HDM201 are being explored: Regimen (Reg) 1A (single dose [SD] on Day 1 every 3 weeks [wks]); Reg 1B (SD on Days 1 and 8 every 4 wks); Reg 2A (SD daily on Days 1-14 every 4 wks); Reg 2C (SD daily on Days 1-7 every 4 wks). Population PK and PK/PD models of thrombocytopenia and GDF-15 (a transcriptional target of activated p53) were developed based on data from 85 pts with solid tumors. The PK/PD relationship for plasma GDF-15 was quantitatively integrated into a thrombocytopenia model to explore the link between cellular drug potency on platelets and stimulation of plasma GDF-15 levels. In addition, a PK/PD model of tumor growth kinetics was explored.
Results: As of the data cut-off (September 19, 2016), 85 pts with solid tumors have been enrolled in the study (Reg 1A/1B; Reg 2A/2C: 46; 39) and treatment is ongoing in 11 (13%) pts. Thrombocytopenia and neutropenia were the main DLTs observed. The PK/PD model accurately reproduced the platelet time course after NVP-HDM201 administration and was used to guide dose escalation and regimen/dose selection for expansion phase. Model simulations predicted Reg 1B to achieve target exposures while having the lowest rate and duration of thrombocytopenia, as observed subsequently during dose escalation. Interestingly, greater induction of circulating GDF-15 was associated with greater platelet count reduction, suggesting GDF-15 might be a possible early indicator of delayed thrombocytopenia.
Conclusions: The PK/PD model performed well as a reliable predictor of regimen-dependent hematologic toxicity, and was a valuable tool in guiding decisions around dose escalation dose/regimen selection for expansion during the Phase I study. This work provided an integrated quantitative understanding of regimen-dependent thrombocytopenia, PD modulation using the GDF-15 biomarker, and efficacy. The model continues to be developed as a platform for optimizing dose/schedule in ongoing and future clinical studies with NVP-HDM201.
Citation Format: Christophe Meille, Nelson Guerreiro, Astrid Jullion, Sebastian Bauer, Manik Chatterjee, Filip de Vos, Chia-Chi Lin, Cristina Suárez Rodríguez, David Tai, Philippe Cassier, Noboru Yamamoto, Vincent A. de Weger, Matthieu Klopfenstein, Luisa Mariconti, Emil T. Kuriakose, David M. Hyman. Optimization of the dose and schedule of an HDM2 inhibitor NVP-HDM201 in a first-in-human Phase I study using a mechanism-based PK/PD model [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 CT154. doi:10.1158/1538-7445.AM2017-CT154