Background: Bromodomain and extraterminal (BET) proteins play roles in cell proliferation, survival, and oncogenic progression. BET inhibitors (BETi) alone and combined with JAKi demonstrate reduction in inflammatory signalling and disease burden in mouse MF models, and inhibition of BET+JAK-STAT pathways has shown benefits for patients (pts) with MF. BMS-986158 is an orally bioavailable, potent, selective small-molecule BETi with a dose-proportional pharmacokinetic profile, linear increases in exposure, and time- and dose-dependent modulation of BET target gene expression. BMS-986158 is being evaluated in pts with MF, alone and in combination with JAKi ruxolitinib (RUX) or fedratinib (FED), in the CA011-023 study (NCT04817007).
Aims: To present safety and efficacy data from the dose-escalation parts of CA011-023.
Methods: CA011-023 has a dose-escalation phase with BMS-986158+RUX in RUX-naive pts (Part 1A) or BMS-986158+FED in pts refractory, relapsed, or intolerant to prior RUX treatment (Part 1B), and a dose-expansion phase at the recommended phase 2 dose (RP2D) evaluating BMS-986158+RUX (Part 2A) or BMS-986158±FED (Part 2B). Eligible pts had primary or secondary MF, splenomegaly (spleen volume ≥450 cm3), ECOG PS ≤2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. Planned doses for Part 1A are BMS-986158 2.0, 3.0, and 3.75mg QD 5d on/2d off and RUX 15mg BID. Planned doses for Part 1B are BMS-986158 0.5, 0.75, and 1.25 QD 5d on/2d off and FED 400mg QD. Primary objectives in dose escalation are safety, tolerability, and determination of the maximum tolerated dose and/or RP2D of BMS-986158+RUX or FED. Secondary objectives include spleen volume reduction (SVR) from baseline. Assessment of JAK2 variant allele frequency (VAF) is an exploratory objective. JAK2V617 VAF is measured longitudinally in peripheral blood CD34+ stem cells using next generation sequencing.
Results: As of Sep 2, 2022, 23 pts were treated, 11 in Part 1A (median age 67 y [range, 36–81]) and 12 in Part 1B (median age 69 y [range, 37–77]). Any grade (G) treatment-related adverse events (TRAEs) were reported in 9 (82%) pts in Part 1A and 9 (75%) pts in Part 1B. G 3/4 TRAEs in Part 1A were thrombocytopenia (n=5, 45%), neutropenia, hypertension, and anemia (n=1 each, 9%). G 3/4 TRAEs in Part 1B were thrombocytopenia, anemia (n=5 each, 42%), diarrhea, and blood bilirubin increase (n=1 each, 8%). DLTs were reported in 2 pts in Part 1A (both thrombocytopenia with dose reduction of BMS-986158 in the 2.0 and 3.75mg groups), and in 3 pts in Part 1B (diarrhea, thrombocytopenia, and elevated bilirubin; all in the 1.25mg group). SVR was observed at wk 12 in all evaluable pts in Part 1A and continued to deepen at wk 24. In Part 1A, 5/6 (83%) pts treated with BMS-986158 (2.0 or 3.0mg)+RUX met SVR35 at wk 12; 6/6 (100%) met SVR35 at wk 24. In Part 1B, 0/6 (0%) pts treated with BMS-986158 (0.5 or 0.75mg)+FED met SVR35 at wk 12; 1/3 (33%) met SVR35 at wk 24 (Table). Pts in Part 1B were treated at lower BMS-986158 dose levels vs Part 1A. Analysis of JAK2 VAF showed reductions in the frequency of JAK2V617F in both Parts 1A (35% max reduction by C10, n=4) and 1B (22% max reduction by C7, n=2).
Summary/Conclusion: BMS-986158 in combination with RUX or FED had acceptable and manageable safety profiles; most TRAEs were G 1/2 in severity. Initial results demonstrate that BMS-986158+RUX produced robust SVR in pts with MF, with responses that deepened beyond wk 12 under continued treatment. The trial is ongoing with dose-expansion phases (Parts 2A and 2B) to be opened for enrollment soon.
Keywords: Fedratinib, Myelofibrosis, Ruxolitinib