Bromodomain and extra-terminal (BET) inhibitor INCB057643 in patients with relapsed or refractory myelofibrosis (MF) and other advanced myeloid neoplasms: A phase 1 study.

6576 Background: In a previous phase 1/2 clinical trial, the small-molecule oral BET inhibitor INCB057643, as monotherapy and with ruxolitinib (RUX), had favorable tolerability and encouraging clinical activity in patients (pts) with advanced malignancies. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates INCB057643 (4 mg → 12 mg once daily qd) in adults as (1) monotherapy (part 1) in relapsed/refractory (R/R) MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. Primary endpoints are safety/tolerability. Secondary endpoints in pts with MF include spleen volume response (SVR35; ≥35% reduction from baseline BL at Wk 24), symptom response (TSS50; ≥50% reduction from BL at Wk 24 in MPN-Symptom Assessment Form Total Symptom Score), and anemia response (hemoglobin increase ≥1.5 g/dL from baseline if transfusion independent at BL or achieving transfusion independence if dependent at BL for ≥12 wk). Results: As of 6NOV2023 data cutoff, 18 pts were treated in part 1 (4 mg, n=6; 6 mg, n=1; 8 mg, n=4; 10 mg, n=5; 12 mg, n=2), and 11 in part 2 (4 mg, n=5, 6 mg, n=6). In part 1, median (range) age was 70 (50–79) years and study treatment duration was 175 (15–504) d; in part 2, pt age and treatment duration were 70 (50–76) y and 127 (23–369) d, respectively. 24 pts overall had MF. 5 pts discontinued treatment due to treatment emergent adverse events (TEAEs; 4 with monotherapy). Thrombocytopenia was the most common TEAE (n=15) and most common leading to discontinuation (n=4). Grade ≥3 TEAEs occurred in 19 pts, most commonly thrombocytopenia (n=8) and anemia (n=6). Serious AEs occurred in 6 pts; all but 1 (pneumonia) was considered unrelated to study treatment. There were 2 dose-limiting toxicities with 12 mg monotherapy and 1 with 6 mg combination therapy (hyperbilirubinemia, n=1; thrombocytopenia, n=2). No treatment-related fatal TEAEs have occurred. At Wk 24, SVR35 was achieved by all 3 evaluable pts receiving ≥10 mg monotherapy, and 3/12 achieved a best response of SVR35. In the combination group, 1/5 evaluable pts achieved Wk 24 SVR35 and 1/7 achieved best response of SVR35. Best response of TSS50 was achieved by 6/10 evaluable monotherapy pts (3/4 receiving doses ≥10 mg) and 6/11 combination therapy pts. Anemia response occurred in 2/15 monotherapy pts. Conclusions: INCB057643 monotherapy (4–10 mg qd) and combined (4 and 6 mg qd) with RUX was generally well tolerated, with no treatment-related fatal events. Improvements in spleen size and symptom burden were observed in both the monotherapy and combination therapy groups. Dose finding is complete for monotherapy and dose escalation is ongoing in the combination therapy group. Clinical trial information: NCT04279847 .