INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis: A Phase 1 Study

Background: Bromodomain and extra-terminal (BET) proteins are a class of epigenetic readers that regulate expression of regulatory proteins, such as B-cell lymphoma-2, c-Myc, and nuclear factor kappa B, that are implicated in oncogenesis of hematologic malignancies, including myelofibrosis (MF). INCB057643 is a small-molecule inhibitor of BET that was evaluated as monotherapy and in combination with ruxolitinib in patients with advanced malignancies in 2 previous phase 1/2 clinical trials.

Aim: This ongoing, phase 1, dose-confirmation/expansion study (NCT04279847) is evaluating the safety and tolerability of INCB057643 as monotherapy in patients with relapsed/refractory MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes and in combination with ruxolitinib in patients with advanced MF and suboptimal response to ruxolitinib.

Methods: The study includes a 3+3 design dose-escalation phase (part 1) followed by dose-expansion (part 2). Eligible patients in part 1 are aged ≥18 years with histologically confirmed MF and palpable spleen ≥5 cm below the left subcostal margin, MDS or MDS/MPN, Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 line of prior therapy with no available subsequent therapy known to provide clinical benefit. Exclusion criteria include prior BET inhibitor treatment within 5 half-lives, platelet counts <50 × 10⁹/L, absolute neutrophil count <0.75 × 10⁹/L, and allogeneic transplant ≤6 months before enrollment. The initial part 1 dose is INCB057643 4 mg once daily (qd; escalation up to 12 mg qd), administered continuously in 28-day cycles. Doses deemed safe and tolerable in part 1 will be further evaluated in part 2 as monotherapy or in combination with ruxolitinib in patients with MF. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs); pharmacokinetics (PK) are evaluated as a secondary endpoint. Additional secondary endpoints include overall response rate, symptom response, anemia response, red blood cell transfusion requirement, and change in spleen volume and length. PK data were analyzed using noncompartmental analysis.

Results: Six patients have been evaluated in part 1 (age range, 59-77 years; men, n=4; study treatment duration range, 29-169 days); 4 had a diagnosis of MF, and 1 each had MDS/MPN unclassifiable and chronic myelomonocytic leukemia (CMML). All patients received INCB057643 4 mg qd. Four patients remain on treatment; treatment was discontinued in the remaining 2 patients for progressive disease. The most common treatment-emergent adverse events (TEAEs) occurring in >1 patient were thrombocytopenia (n=3), anemia (n=2), and hyperuricemia (n=2). Grade ≥3 TEAEs occurred in 1 patient each: acute myeloid leukemia (AML), anemia, chronic obstructive pulmonary disease, hypokalemia, leukocytosis, pancytopenia, and thrombocytopenia. There were 3 serious AEs (SAEs) across 2 patients (chronic obstructive pulmonary disease in 1 patient [dose was not changed; patient recovered with sequelae], pancytopenia and AML transformation from CMML in a second patient [study drug was interrupted; patient death followed related to disease progression]); none were considered related to study treatment. No DLTs were observed. The mean steady-state maximum plasma concentration (C_max) and area under the curve (AUC) for a 4-mg qd dose were 92.4 nM and 1260 h·nM, respectively, indicating a dose proportionality from 4 mg to 12 mg.

Conclusions: Treatment with a 4-mg qd dose of INCB057643 monotherapy in this patient population was generally well tolerated, with no treatment-related SAEs, no DLTs, and no TEAEs leading to treatment discontinuation. INCB057643 will be further evaluated at higher doses in dose-escalation and dose-expansion phases as monotherapy and in combination with ruxolitinib in patients with MF (preliminary combination data to be available for presentation).

Watts:Immune System Key (ISK) Ltd.: Research Funding; Reven Pharma: Consultancy; Rafael Pharma: Consultancy; BMS/Celgene: Consultancy; Takeda: Consultancy, Research Funding. Palandri:Novartis: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AOP: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria; Kartos/Telios: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Reeves:Incyte, BMS, PharmaEssentia, CTI Biopharma: Honoraria; Hemostasis & Thrombosis Research Society Mentored Research Award sponsored by CSL Behring: Research Funding. Vannucchi:Blueprint: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphans Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Chen:Incyte Corporation: 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. Zhou:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zheng:Incyte Corporation: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Vachhani:Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees.

INCB057643 is a small-molecule inhibitor of BET that was evaluated as monotherapy and in combination with ruxolitinib in patients with advanced malignancies in 2 previous phase 1/2 clinical trials