Abstract 3021: Integrated pharmacokinetic (PK)/pharmacodynamic (PD) modeling leveraging PK, biomarker, and safety data to support dose and schedule selection for the BET inhibitor BMS-986158
Authors: Chen Xi (Cindy) , Hamuro Lora , Coker Shodeinde , Hilton John , Diamond Jennifer R. , Baldini Capucine , Voskoboynik Mark , Cristea Mihaela , Edenfield William , Unsal-Kacmaz Kezi , Jackson Donald , Apfel Abraham , Xu Ke , Zhu Li , Roy Amit , Bello Akintunde , Fleming Ronald , Statkevich Paul 
Published: September 2020

Abstract
Background: BMS-986158 is a potent, selective, and orally bioavailable small-molecule inhibitor of the bromodomain and extraterminal (BET) family of transcription modulators being evaluated in patients with various tumors in a phase 1 clinical study (NCT02419417). An integrated PK/PD analysis leveraging PK, biomarker, and safety data from the phase 1 study was performed to support dose and schedule (Sch) selection further clinical studies with BMS-986158.
Methods: Five doses (0.75-4.5 mg) and 3 dosing regimens (Sch A: 5 days on, 2 days off over 21 days; Sch B: 14 days on, 7 days off; Sch C: 7 days on, 14 days off) were evaluated. Reversible thrombocytopenia (TTP) was the primary safety signal observed, and peripheral gene expression modulation was a PD biomarker indicative of drug target engagement. BMS-986158 serum PK was characterized with a 2-compartment population PK (PPK) model. A semimechanistic PK/PD model describing the platelet-reducing effect with BMS-986158 was developed to characterize platelet profiles for individual patients and to simulate and project the incidence of TTP at different doses and dosing regimens. The association of BMS-986158 exposure with expression modulation of select peripheral BET target genes, including HEXM1 and CCR2, was also examined.
Results: BMS-986158 exhibited linear PK with rapid oral absorption (Tmax ≈ 2-4 h) and a terminal half-life of ≈ 60 h over the dose range of 0.75-4.5 mg. PPK modeling and simulation suggested that at the same dose level, Sch A led to comparable Cmax, with a higher Ctrough and Cavg at steady state compared with Sch B and C across the dosing interval. The semimechanistic PK/PD model predicted a higher incidence rate of TTP with Sch A than Sch C at the same dose level, and the predictions agreed with observed primary safety data from the phase 1 study. The model predicted grade 4 TTP incidence rates of 24% (95% CI, 21%-26%) and 43% (95% CI, 38%-45%) at 4.5 and 6 mg, respectively, with Sch A. This suggests that 4.5 mg would be the maximum tolerated dose, given that a 6 mg dose was predicted to exceed the target dose-limiting toxicity (DLT) rate of grade 4 TTP at 27%. The exploratory analysis of BMS-986158 exposure and expression of selected peripheral genes associated with the BET pathway suggested a direct association between BMS-986158 exposure and the magnitude of peripheral gene expression modulation.
Conclusions: An integrated PK/PD analysis of BMS-986158 incorporating incidence of reversible TTP and modulation of peripheral BET target genes identified a maximum dose of 4.5 mg at Sch A for further clinical development. With the assumption that sustained gene expression modulation is desirable for BMS-986158 efficacy, Sch A, which provides sustained drug exposure, is recommended to enable continuous BET target gene expression modulation.
Citation Format: Xi (Cindy) Chen, Lora Hamuro, Shodeinde Coker, John Hilton, Jennifer R. Diamond, Capucine Baldini, Mark Voskoboynik, Mihaela Cristea, William Edenfield, Kezi Unsal-Kacmaz, Donald Jackson, Abraham Apfel, Ke Xu, Li Zhu, Amit Roy, Akintunde Bello, Ronald Fleming, Paul Statkevich. Integrated pharmacokinetic (PK)/pharmacodynamic (PD) modeling leveraging PK, biomarker, and safety data to support dose and schedule selection for the BET inhibitor BMS-986158 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3021.