Bromodomain and Extra-Terminal Inhibitor INCB057643 (LIMBER-103) in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

Introduction: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of myelofibrosis (MF) and other hematologic malignancies including B-lymphoma-2, nuclear factor kappa, and c-Myc. In a previous phase 1/2 clinical trial, the small-molecule oral BET inhibitor INCB057643, evaluated as monotherapy and in combination with ruxolitinib, was associated with favorable tolerability and encouraging clinical activity in patients with advanced malignancies. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating the safety and tolerability of INCB057643 (4 mg once daily [qd] with escalation up to 12 mg qd) in patients aged ≥18 years as (1) monotherapy (part 1) in relapsed or refractory (R/R) MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to ruxolitinib (part 2) in patients with MF and suboptimal response to ruxolitinib. The primary endpoints are safety and tolerability, including identification of dose-limiting toxicities (DLTs). Secondary endpoints in patients with MF include spleen volume response (≥35% reduction from baseline at Week 24 per magnetic resonance imaging/computed tomography scan) and symptom response (≥50% reduction from baseline at Week 24 in MPN-Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]). Results: As of data cutoff on June 1, 2023, 14 patients were treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=2; 12 mg, n=2), and 6 were treated in part 2 (4 mg, n=3, 6 mg, n=3). In part 1, patients had a median (range) age of 69.5 (50.0-79.0) years and a median (range) study treatment duration of 177 (9-375) days; 8 were men. In part 2, patients had a median (range) age of 71 (64-76) years; median (range) study treatment duration of 92.5 (46-274) days; 3 were men. 16 patients had MF; 4 had MDS/MPN, including 1 with chronic myelomonocytic leukemia. A total of 10 patients discontinued treatment, 4 for lack of efficacy or disease progression and 4 due to adverse events (AEs; 3 in the monotherapy group, 1 in the combination group). Thrombocytopenia (n=3) and anemia/thrombocytopenia (n=1) were the only treatment-emergent AEs (TEAEs) leading to discontinuation, and thrombocytopenia was the most common TEAE (n=11). Grade ≥3 TEAEs occurring in ≥1 patient were thrombocytopenia (n=5), anemia (n=4), and hypokalemia (n=2). 12 serious AEs occurred across 5