Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms (LIMBER)

Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

A Phase 1, Open-Label, Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms

The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of INCB057643 as monotherapy or combination with ruxolitinib for participants with myelofibrosis and other myeloid neoplasms.

Myelofibrosis, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm Overlap Syndrome, Myeloproliferative Neoplasm, Relapsed or Refractory Primary Myelofibrosis, Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis)

Myelofibrosis, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm overlap syndrome, myeloproliferative neoplasm, BET protein inhibitor, relapsed primary myelofibrosis, refractory primary myelofibrosis, secondary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, LIMBER

Ruxolitinib will be administered twice a day using the dose designated as the stable dose at the time of the screening visit for each subject. Acceptable doses are 5 mg BID to 25 mg BID.

Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with ruxolitinib.

Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug.

Defined as the proportion of participants who achieve a protocol defined reduction in Total Symptomatic Score (TSS) relative to baseline as measured by the MPN-SAF TSS

Hemoglobin increase of 1.5 g/dL relative to baseline for any "rolling" 12-week period during the first 24 weeks of treatment, if Transfusion Independent (TI) at baseline or achieving TI for any rolling 12 week period during the first 24 weeks of treatment if Transfusion Dependent (TD) at baseline

The interval from the first onset of anemia response to the earliest date of loss of anemia response that persists for at least 4 weeks or death from any cause for the TI participants at baseline or duration of RBC-TI period for participants achieving RBC-TI for at least 12 consecutive weeks during the first 24 weeks of treatment for the TD participants at baseline, or Mean change from baseline in the hemoglobin value over 12-week treatment periods

Defined as the proportion of participants achieving a protocol defined reduction in spleen length at any visit relative to baseline as measured by palpation

Inclusion Criteria: Age 18 years and older at the time of signing the informed consent. Part 1: Relapsed or refractory MF, MDS, or MDS/MPN a. Disease type: •MF Primary MF or secondary MFs (post-PV MF, post-ET MF), histologically or cytologically confirmed according to WHO 2016 criteria with measurable disease and risk category of intermediate-2 or high according to DIPSS. Measurable disease is defined: For dose escalation as having a palpable spleen of ≥ 5 cm below the left subcostal margin (ribs). MDS Very low-, low-, intermediate-, or high risk MDS as per the IPSS-R criteria MDS/MPN Low-, intermediate-, or high-risk chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis, and MDS/MPN unclassifiable as per the WHO 2016 criteria. Exception: Participants presenting with juvenile myelomonocytic leukemia will be excluded. b. Prior therapy Received at least 1 line of prior therapy; is refractory, relapsed, or intolerant to the last therapy; and there is no further available therapy known to provide clinical benefits, in the opinion of the investigator. Participants with MF must have received a JAK inhibitor(s) such as ruxolitinib. Part 2: MF - dose escalation and expansion a. Disease type Primary MF or secondary MFs (post-PV MF, post-ET MF), histologically or cytologically confirmed according to WHO 2016 criteria. Measurable disease is defined as having a palpable spleen of > 10 cm below the left subcostal margin. 2 subgroups of participants in Part 2 - dose expansion will be enrolled: bone marrow myeloblast percentage between 5% (≥ 5%) and less than 20% (< 20%) or myeloblast percentage ≥ 10% in peripheral blood in 2 occasions at least 2 weeks apart. b. Prior therapy Must currently be treated with ruxolitinib monotherapy at a stable dose for ≥ 8 weeks immediately preceding the first dose of study treatment. Must not be a candidate for potentially curative therapy, including hematopoietic stem-cell transplantation. Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate at screening/baseline, or archival sample obtained since completion of most recent therapy. Willingness to avoid pregnancy or fathering children based on the criteria below. Exclusion Criteria: Prior receipt of a BET inhibitor within 5 half-lives of the compound, and/or experienced BET inhibitor-related AE(s) resulting in dose discontinuation. Note: For participants in Part 2, ruxolitinib will continue at the participants' current, ongoing doses. No ruxolitinib washout is needed. Concurrent anticancer therapy Participants who have received allogeneic hematopoietic stem cell transplantation within 6 months of enrollment Active HBV or HCV infection or at risk for HBV reactivation.