A Phase 1/2 Study of INCB000928 As Monotherapy or Combined with Ruxolitinib (RUX) in Patients (Pts) with Anemia Due to Myelofibrosis (MF)

Background: Management of MF is complicated by disease-associated anemia, which is reported in more than one-third of pts at MF diagnosis and can be exacerbated by currently available MF therapies. Further, anemia is associated with poor prognosis in MF. Activation of activin receptor-like kinase (ALK)-2 (also known as ACVR1) may contribute to MF-associated anemia via up-regulated levels of hepcidin. We evaluated the safety and activity of INCB000928, a selective, oral ALK2 inhibitor, in pts with anemia due to MF.

Methods: INCB 00928-104 (NCT04455841) is an ongoing, open-label, multicenter, phase 1/2 dose-escalation and -expansion study evaluating INCB000928 alone (treatment group A [TGA]) or in combination with RUX (treatment group B [TGB]). Eligible pts were ≥18 years old with histologically confirmed diagnosis of primary or post-polycythemia vera/essential thrombocythemia MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) per the Dynamic International Prognostic Scoring System, and were transfusion-dependent (≥4 units of red blood cell transfusions during the 28 days or 8 weeks before Cycle 1 Day 1 for hemoglobin [Hgb] <8.5 g/dL in the absence of bleeding or treatment-induced anemia) or presented with symptomatic anemia (Hgb <10 g/dL during screening on 3 separate occasions ≥7 days apart). In TGA, pts were resistant, refractory, or had lost response to Janus kinase inhibitor (JAKi) treatment (≥12 weeks), or were intolerant of or not eligible for JAKi; in TGB, pts were on a therapeutic and stable regimen of RUX for ≥12 weeks. The TGA INCB000928 starting dose was 50 mg once daily (qd), with dose increases of ≤2-fold performed until a grade ≥2 toxicity with reasonable probability of being related to the treatment group was observed; subsequent dose increases were limited to ≤50% until the maximum tolerated dose (MTD) was reached or the recommended dose for expansion (RDE) was identified. The TGB starting dose was 100 mg qd after this dose was evaluated in ≥3 pts as monotherapy. The primary endpoint was safety and tolerability of INCB000928 (± RUX), including laboratory abnormalities, dose-limiting toxicities (DLTs), MTD, and RDE. Secondary endpoints include efficacy (as assessed by anemia response parameters), pharmacokinetics, and pharmacodynamics.

Results: A total of 15 pts enrolled at the time of analysis, including 11 in TGA at doses of 50 mg qd (n=4), 100 mg qd (n=4) and 200 mg qd (n=3) and 4 in TGB at dose of 100 mg qd in combination with RUX; median (range) age was 68 years (53-84) for TGA and 76 years (68-79) for TGB. 73% of pts in TGA received prior RUX therapy for MF. Overall, 87% of pts had Int-2 risk MF, and the remainder had high-risk MF (1 pt each in TGA and TGB). 64% of pts in TGA and 25% in TGB were transfusion-dependent at the time of enrollment (transfusion burden range during the 12 weeks prior to first dose of study treatment was 1 to 5 units per month); the remainder of pts were not transfusion-dependent. Median baseline Hgb was 8.1 g/dL (range, 6.5-9.2 g/dL) in TGA and 8.3 g/dL (range, 7.9-8.7 g/dL) in TGB. High baseline hepcidin was observed in both treatment groups (median [range]: TGA, 238 [113-390] ng/mL; TGB, 157 [146-169] ng/mL; normal range, 0-50 ng/mL). At the time of analysis, dose escalation was ongoing in both treatment groups. No DLTs or study drug-related SAEs occurred in either treatment group during dose escalation. Treatment-related AEs were mainly grade 1 laboratory abnormalities and gastrointestinal events (ie, anorexia, flatulence, diarrhea), with 1 case each of grade 2 bone pain and grade 3 thrombocytopenia (grade 2 at baseline). The MTD had not been reached at the time of analysis. Reduction in hepcidin was observed in both treatment groups. Considering patients with hepcidin data beyond Cycle 2, best percentage change in hepcidin level from baseline ranged from −3% to −86% in TGA and −36% to −74% in TGB.

Conclusions: These data demonstrate that treatment with INCB000928 monotherapy or in combination with RUX in this patient population was generally well-tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Reduction in hepcidin levels was observed at all dose levels, suggesting potential for therapeutic activity, even at this early dose escalation stage.

Mohan:Incyte: Research Funding; Astex: Research Funding. Oh:Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgne/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ali:Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri:AOP: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kartos/Telios: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Lamothe:Incyte: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Cui:Incyte: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Seguy:Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. McBride:Incyte: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Savona:Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: serves on Data and Safety Monitoring Boards; Forma: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Sierra Oncology: Other: serves on Data and Safety Monitoring Boards; ALX Oncology: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Verstovsek:PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; NS Pharma: Research Funding; ItalPharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; CTI BioPharma Corp.: Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Pragmatist: Consultancy.

INCB000928 is a selective, oral ALK2 inhibitor, under clinical evaluation for the treatment of pts with anemia due to MF