BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial

John Hilton, Mihaela Cristea, Sophie Postel-Vinay, Capucine Baldini, Mark Voskoboynik, William Edenfield, Geoffrey I. Shapiro, Michael L. Cheng, Jacqueline Vuky, Bradley Corr, Sharmila Das, Abraham Apfel, Ke Xu, Martin Kozicki, Keziban Ünsal-Kaçmaz, Amy Hammell, Guan Wang, Palanikumar Ravindran, Georgia Kollia, Oriana EspositoShodeinde Coker, Jennifer R. Diamond

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75–4.5 mg), B (14 days on, 7 days off; 2.0–3.0 mg), and C (7 days on, 14 days off; 2.0–4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1–4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

Original languageEnglish (US)
Article number4079
JournalCancers
Volume14
Issue number17
DOIs
StatePublished - Sep 2022

Keywords

  • BET inhibitor
  • BRD2
  • BRD3
  • BRD4
  • NUT carcinoma
  • bromodomain
  • dose escalation
  • pan tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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