A multicenter, open-label phase 1 study of INCB160058, a first-in-class JAK2V617F mutant–selective inhibitor, in patients with myelofibrosis, polycythemia vera, or essential thrombocythemia

Abstract Background and Significance: Current Janus kinase (JAK) inhibitors provide clinical benefit for patients (pts) with myeloproliferative neoplasms (MPNs), including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), but they are not curative. Unmet need exists for mutant-selective therapies that target JAK2V617F, a key driver of these MPNs. Wild-type JAK2 signaling is regulated through autoinhibition by the pseudokinase domain. The JAK2V617F mutation occurs in the pseudokinase domain and interferes with autoinhibition, leading to cytokine-independent signaling and oncogenic cell proliferation. INCB160058 is a first-in-class small-molecule JAK2V617F mutant–selective inhibitor. It uniquely binds the JAK2 pseudokinase domain and selectively inhibits oncogenic JAK2V617F signaling while preserving physiological, cytokine-dependent signaling. Preclinically, INCB160058 inhibited aberrant signaling and proliferation in JAK2V617F+ cells with minimal impact on signaling and growth of wild-type counterparts, offering the potential to eradicate malignant clones while minimizing treatment-associated adverse events related to broader wild-type JAK inhibition. Study Design and Methods: The INCB160058-101 phase 1, multicenter, global, open-label, dose-escalation/expansion study will investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical efficacy of INCB160058 in pts with JAK2V617F-positive MF, PV, or ET (NCT06313593). The study is open and enrolling adults with MF, PV, or ET for treatment with INCB160058 monotherapy; it will enroll pts with MF for treatment with INCB160058 as an add-on to ruxolitinib after suboptimal response to ruxolitinib (MF SubOpt R). Pts receiving MF monotherapy must have primary MF of intermediate-1 or higher risk per Dynamic International Prognostic Scoring System DIPSS or secondary MF (post-ET or post-PV) of intermediate-1 or higher risk per Myelofibrosis Secondary to PV and ET Prognostic Model MYSEC-PM; have evaluable splenomegaly (≥450 mL per radiographic imaging or palpable ≥5 cm below left subcostal margin); be refractory, resistant, intolerant, or lost response to ≥1 JAK inhibitor after ≥12 wk of treatment; and have platelet count (PLT) ≥50×109/L. The MF SubOpt R cohort will include pts with the same criteria as for MF monotherapy but requires ruxolitinib treatment for ≥12 wk (stable ruxolitinib dose in the last 8 wk) with no expected benefit from further ruxolitinib monotherapy, and PLT ≥75×109/L. Pts with PV must be refractory, resistant, intolerant, or lost response to ≥1 standard cytoreductive therapy and have PLT ≥50×109/L. Pts with ET must be high risk (≥1 of the following: age ≥60 years, history of thrombosis, history of ET-related major bleeding, or bleeding risk ie, PLT 1000×109/L or history of PLT 1000×109/L and ongoing cytoreductive therapy); refractory, resistant, intolerant, or lost response to ≥1 standard cytoreductive therapy; and have PLT 450×109/L. Select exclusion criteria include previous or planned hematopoietic stem cell transplantation and MPN-directed therapy within a washout period before the first study dose (exception for ruxolitinib in MF SubOpt R). Part 1 (dose escalation) will enroll up to ~66 pts (~36 in MF monotherapy, ~12 in MF SubOpt R, ~18 with PV or ET). Part 1 uses a statistical hybrid design with a 28-day dose-limiting toxicity (DLT) window to assess safety and tolerability of INCB160058 and identify the maximum tolerated dose and/or recommended dose(s) for expansion (RDE); ≥3 pts will be enrolled at each dose level. Part 2 will enroll ~15 pts per RDE and disease type. INCB160058 will be administered in 1 or multiple RDEs, with pts randomized 1:1 if 1 RDE is chosen. The primary endpoint is safety/tolerability (DLTs, treatment-emergent adverse events TEAEs, TEAEs leading to study drug modifications and discontinuation). Key secondary endpoints are standard PK parameters, overall response per International Working Group–MPN Research and Treatment and European LeukemiaNet criteria, and ≥50% reduction in MPN Symptom Assessment Form total symptom score at Wk 24. For pts with MF, an additional secondary endpoint is the percentage of pts achieving ≥25% or ≥35% reduction in spleen volume at Wks 12 and 24. Change in JAK2V617F variant allele frequency is an exploratory endpoint. This study will explore the potential of this novel JAK2V617F-selective approach.