Preliminary Results of Patients with Myelofibrosis (MF) from a Phase I Trial of Jab-8263, a Potent BET Inhibitor

Introduction Bromodomain and extra-terminal (BET) proteins play roles in epigenetic regulation in critical genes involved in inflammation and various oncogenic processes. JAB-8263 is a highly potent, orally available, small molecule BET inhibitor that is being evaluated as monotherapy in patients with solid tumors and hematological malignancies (NCT04686682). Methods In the dose escalation portion of phase 1/2a trial, patients with intermediate-/high risk MF received JAB-8263 at doses ranging from 0.125 mg once daily (QD) to 0.4 mg QD. The key criteria included: ECOG PS ≤ 2, splenomegaly (spleen volume ≥ 450 cm3), and Dynamic International Prognostic score (DIPSS) ≥ intermediate-1. Primary objectives of phase I portion include safety, tolerability, and determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of JAB-8263. The secondary objectives include evaluating spleen volume reduction (SVR) at 24 weeks and the total symptoms score (TSS) at 24 weeks. Results As of Jul 11, 2024, 12 patients with intermediate-/high-risk MF have been enrolled across 4 dose levels of JAB-8263 (0.125mg QD: 1 patient; 0.2 mg QD: 2 patients; 0.3 mg QD 6 patients; 0.4 mg QD: 3 patients). Most patients (11/12) harbored a JAK2 mutation, and 7/12 (58.3%) previously received JAK inhibitors. DLTs occurred in one patient at the 0.4mg dose level including grade 3 alanine aminotransferase (ALT) and grade 3 aspartate aminotransferase (AST). The common (>20%) treatment-related adverse events (TRAEs) included ALT increase, blood bilirubin increase, AST increase, and prolonged prothrombin time. Grade 3 TRAEs observed were ALT increase (8.3%), AST increase (8.3%) and blood fibrinogen decrease (8.3%). The study drug is generally well tolerated, and no patients were discontinued from the treatment due to TRAE. As of Jul 11, 2024, 11 patients are on active treatment. Ten patients have undergone at least one post-treatment efficacy assessment. All patients showed a mean SVR -25.84% (range: -7.1% to-56.5%) and two patients achieved ≥35% SVR. Among the 10 patients assessed, 3 (30%) experienced a ≥50% reduction in TSS (TSS50) at week 12, and 5 of 9 (55.6%) patients did so at week 24. Among seven MF patients treated with JAK inhibitors, the mean SVR was -19.86% and -20.33% at week 12 and week 24, respectively. Meanwhile, total symptom improvement was observed in this group, with a mean TSS reduction of -22% at week 12 and -41% at week 24. At week 24, 3 of 6 (50%) patients previously treated with JAK inhibitors achieved TSS50. Conclusion: The preliminary results indicate that JAB-8263 is well tolerated in MF patients, with 16.7% experiencing grade 3 TRAEs. No patients discontinued from the study due to TRAEs. Promising efficacy signals were observed in patients previously treated with JAK inhibitors. The safety, efficacy (SVR 35 and TSS50) and PK data will be available at the presentation.