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

Inclusion Criteria:

• Age 18 years and older at the time of signing the informed consent.
• Part 1: Participants with relapsed or refractory MF, MDS, MDS/MPN, or ET who have received at least 1 prior line of therapy; are either refractory, relapsed, or intolerant to the last therapy; and there is no available therapy that would provide clinical benefit in the opinion of the investigator.

•a. MF

• Primary MF or secondary MFs (post-PV MF and post-ET MF) that is 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). -Must have received a JAK inhibitor(s), such as ruxolitinib. (Except for participants being enrolled in Cohorts C, H, and I).

• b. MDS
• Very low-, low-, intermediate-, or high risk MDS as per the IPSS-R criteria
• c. 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.
• d. ET
• Confirmed diagnosis of ET as per the WHO 2016 criteria.
• Participants should have disease refractory to hydroxyurea, are intolerant to hydroxyurea or for whom treatment with hydroxyurea is contraindicated as determined by the treating physician OR participants who have refused treatment with hydroxyurea due to side effects.
• Peripheral blood blast count < 1% at screening hematology assessment.
• Part 2: Combination with ruxolitinib
• a. Primary MF or secondary MFs (post-PV MF and post-ET MF), histologically or cytologically confirmed according to WHO 2016 criteria with measurable disease, either currently receiving ruxolitinib with suboptimal response or JAKi-naive.
• b. Part 2 dose escalation: Risk category of intermediate-2 or high according to DIPSS.
• c. Part 2 dose expansion: Risk category of intermediate-1, intermediate-2, or high.
• d. Part 2 dose expansion Cohorts D and E participants with chronic MF are defined as participants with bone marrow myeloblast percentage < 5% and no blasts detected/not persistent blast count in peripheral blood at screening or baseline, AND who are currently receiving ruxolitinib and having suboptimal response.
• e. Part 2 dose expansion Cohorts F and G participants with accelerated-phase MF are defined as having either a bone marrow myeloblast percentage ≥ 5% to < 20% or a myeloblast percentage ≥ 10% in peripheral blood on 2 occasions at least 2 weeks apart, AND are currently receiving ruxolitinib and have a suboptimal response.
• f. 2 dose expansion Cohorts H and I participants with JAKi-naive MF are eligible to receive ruxolitinib, with peripheral blood blast count of < 10% at the screening hematology assessment.
• Must not be a candidate for potentially curative therapy, including hematopoietic stem-cell transplantation.
• ECOG performance status 0 to 2.
• Life expectancy ≥ 24 weeks.
• 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 criteria.

Exclusion Criteria:

• Prior receipt of a BET inhibitor. Note: For Part 1 monotherapy dose escalation, prior receipt of a BET inhibitor is allowed, as long as it is not within 5 half-lives of the compound and/or the participant has not experienced BET inhibitor-related AE(s) resulting in dose discontinuation.
• 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. Other protocol-defined Inclusion/Exclusion Criteria may apply.