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

Simple Summary Bromodomain and extraterminal domain (BET) proteins can regulate cancer-related genes to make tumors grow. BMS-986158, an experimental anticancer therapy, blocks BET protein function. We researched BMS-986158′s potential anticancer effects, side effects, what happens to BMS-986158 in the body, and whether treatment causes any changes in gene activity. To determine the proper dose, 5 different doses were tested using 3 schedules (days taking and not taking therapy). Among 83 patients across all dose schedules, BMS-986158 was generally well tolerated. The most common side effects were diarrhea (43% of patients) and lower platelet cell numbers (blood clotting cells; 39%). Schedule A (cycles of 5 days on and 2 days off therapy) provided stable levels of BMS-986158 in the blood and showed some preliminary anticancer effects, with 30% of patients showing a clinical benefit (a period without meaningful tumor growth in 12 patients and tumor shrinkage by at least 30% in 2 patients). 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.