A Phase 1 Study of INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis (INCB 57643-103)

Background: Activation of transcription factors that regulate oncogenic processes is frequently observed in cancers such as myelofibrosis (MF). In preclinical studies, tumors associated with dysregulation of transcription factors appear to be responsive to inhibition of bromodomain and extra-terminal motif (BET) protein [Delmore JE, et al. Cell 2011; Shimamura T, et al. Clin Cancer Res 2013]. In addition to exerting a direct effect on tumor cells, BET inhibitors may also modulate tumorigenic inflammation; in a mouse model of MF, BET inhibition in combination with the Janus kinase inhibitor ruxolitinib resulted in decreased inflammation and reduced disease burden [Kleppe M, et al. Cancer Cell 2018]. In the first-in-human study INCB 57643-101, the small-molecule BET inhibitor INCB057643, was safe and generally well tolerated as monotherapy, and demonstrated preliminary efficacy in 2 out of 3 patients with MF when administered alone or in combination with ruxolitinib [Falchook G, et al. Clin Cancer Res 2020]. The INCB 57643-103 trial is designed to further evaluate the safety and tolerability of INCB057643 monotherapy in patients with relapsed or refractory MF.

Methods: INCB 57643-103 (NCT04279847) is a phase 1, single-arm, open-label, two-part dose confirmation and expansion study evaluating INCB057643 in patients with measurable histologically or cytologically confirmed (World Health Organization criteria 2016), relapsed or refractory primary MF or secondary MF (post-polycythemia vera, post-essential thrombocythemia). Patients must be ≥18 years of age, have received ≥1 line of prior therapy including ruxolitinib and have no option for therapy known to provide clinical benefit, have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System, have an Eastern Cooperative Oncology Group performance status 0-2, have a life expectancy of 24 weeks or more, and be willing to provide a pretreatment bone marrow biopsy and/or aspirate at baseline (or an archival sample obtained after most recent therapy).

Patients will be excluded if they have received prior treatment with a BET inhibitor; received anticancer treatment within specified intervals before the first administration of study drug or receiving concurrent anticancer therapy; received allogeneic hematopoietic stem cell transplant (6 months or less before enrollment) or have active graft versus host disease or received immunosuppressive therapy after allogeneic transplant 2 weeks or less before study drug treatment; have significant and uncontrolled medical events such as gastrointestinal or cardiovascular; have a history of bleeding disorder or at a high risk of bleeding; or have abnormal hematologic, hepatic, renal, coagulation, or metabolic laboratory values.

Approximately 15 patients will be enrolled. Part 1 will evaluate initial safety and tolerability of INCB057643. Up to 6 patients will self-administer oral INCB057643 4 mg once daily (QD) continuously. Doses will be declared tolerable if dose-limiting toxicities (DLT) occur in ≤2 patients and discontinuation due to treatment-related adverse events (TRAEs) occurs in ≤2 patients during the DLT evaluation period. Part 2 will further characterize safety and tolerability as well as evaluate preliminary efficacy. Up to 9 patients will receive INCB057643 at 4 mg QD if the dose is deemed tolerable in Part 1; if not, the starting dose will be 2 mg QD. Treatment may continue as long as benefit is derived and discontinuation criteria are not met.

The primary study objective is assessment of safety and tolerability of INCB057643 monotherapy by monitoring the frequency and severity of AEs, performing physical examinations, and collecting vital signs and laboratory values. Secondary objectives include evaluation of anemia response by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) Consensus Report, red blood cell transfusion dependence, spleen volume, rate of spleen response and duration of spleen response by IWG-MRT and ELN Consensus Report, and impact on quality of life. Patients will be assessed every 3 cycles and will receive follow-up for safety for 30-35 days after last dose of study drug.