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 Monotherapy: Participants with confirmed diagnosis of relapsed or refractoryMF (primary, or post-PV and post-ET), MDS, MDS/MPN, or ET who have received at least 1 prior line of therapy; are either refractory, relapsed, or intolerant to the lasttherapy; and there is no available therapy that would provide clinical benefit inthe opinion of the investigator.

• a. MF with measurable disease (palpable spleen and symptoms) as defined in theprotocol and risk category of intermediate 2 or high according to DIPSS. MFparticipants must have received a JAK inhibitor(s), such as ruxolitinib.

• b. ET participants should have disease refractory to hydroxyurea as defined bythe protocol.

• Part 2 Combination with ruxolitinib.

• a. Primary MF or secondary MFs (post-PV MF and post-ET MF), histologically orcytologically confirmed, with measurable disease (palpable spleen and symptoms)as defined in the protocol, either currently receiving ruxolitinib withsuboptimal response or JAKi-naive.

• b. Suboptimal response is defined as currently being treated with ruxolitinibmonotherapy at a stable dose for ≥ 8 weeks immediately preceding the first doseof study treatment. One dose reduction due to toxicities within 8 weeks priorto Study Day 1 is permitted.

• c. JAKi-naive is defined as those participants that have no prior use of anyJAK inhibitor, including ruxolitinib, and;

• d. Part 2 dose escalation: Risk category of intermediate-2 or high according toDIPSS.

• e. Part 2 dose expansion: Risk category of intermediate-1, intermediate-2, orhigh according to DIPSS.

• f. Part 2 dose expansion participants with chronic MF are defined asparticipants with bone marrow myeloblast percentage < 5% (not applicable if drytap or blast count deemed not reliable by the investigator) and blast count inperipheral blood < 1% at screening and who are currently receiving ruxolitiniband having a suboptimal response.

Note: Study treatment should be delayed if peripheral blood blast count at baseline is > 3%; treatment should only be started with medical monitor approval.

• g. Part 2 dose expansion participants with accelerated-phase MF are defined ashaving either a bone marrow myeloblast percentage ≥ 5% to < 20% or a myeloblastpercentage ≥ 10% in peripheral blood on 2 occasions at least 2 weeks apart, AND arecurrently receiving ruxolitinib and have a suboptimal response.

• h. Part 2 dose expansion participants with JAKi-naive MF are eligible to receiveruxolitinib, with peripheral blood blast count of < 10% at the screening hematologyassessment.

• Must not be a candidate for potentially curative therapy, includinghematopoietic stem cell transplantation.

• ECOG performance status 0 to 2.

• Life expectancy ≥ 24 weeks.

• Willingness to avoid pregnancy or fathering children based on criteria.

• a. Men must agree to take appropriate precautions to avoid fathering children (withat least 99% certainty) from screening through 90 days after the last dose of studytreatment and must refrain from donating sperm during this period. Permitted methodsthat are at least 99% effective in preventing pregnancy should be communicated tothe participants and their understanding confirmed.

• b. Women of childbearing potential must have a negative serum pregnancy test atscreening and before the first dose on Day 1 and must agree to take appropriateprecautions to avoid pregnancy (with at least 99% certainty) from screening throughsafety follow-up. Permitted methods that are at least 99% effective in preventingpregnancy should be communicated to the participants and their understandingconfirmed.

• c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomyand/or bilateral oophorectomy OR ≥ 12 months of amenorrhea without any other medicalreasons such as treatment with anticancer agents) are eligible.

Exclusion Criteria:

• Prior receipt of a BET inhibitor.

• Receipt of anticancer medications or investigational drugs within theprotocol-defined interval before the first dose of study treatment. For Part 2JAKi-naive, prior use of a JAK inhibitor (including ruxolitinib) and no use ofexperimental drug therapy for MF or any other standard drug (except hydroxyurea)used for MF or another indication within 3 months of starting study drug. Forparticipants with suboptimal response to ruxolitinib, ruxolitinib will continue atthe participants' current ongoing doses, no ruxolitinib washout is needed.

• Participants with exclusionary laboratory values at screening defined as, including,but not limited to,

• a. Platelets. Part 1 (monotherapy dose expansion, MF): < 75 × 109/L. Part 1 (monotherapy dose expansion, ET): < 450 × 109/L. Part 2 (combination doseescalation and expansion): < 75 × 109/L. Part 2 (combination dose expansion,JAKi-naïve MF): < 100 × 109/L.

• b. Hemoglobin: Participants unwilling to receive red blood cell transfusion totreat low hemoglobin levels are excluded.

• c. ANC < 0.75 × 109/L.

• inadequate renal, hepatic and coagulation functions as defined in the protocol.

• Concurrent anticancer therapy other than the therapies being tested in this study.

• Participants who have received allogeneic hematopoietic stem cell transplantationwithin 6 months of enrollment (unless approved by the medical monitor), or haveactive graft versus-host disease, or have received immunosuppressive therapyfollowing allogeneic transplant within 2 weeks of the first dose of study treatment.

• Unless approved by the medical monitor, may not have received autologoushematopoietic stem-cell transplant within 3 months before the first dose of studytreatment.

• Significant concurrent, uncontrolled medical condition, including but not limitedto, significant GI disorder, history of or current clinically significant oruncontrolled cardiac disease, history or presence of an abnormal ECG that, in theinvestigator's opinion, is clinically meaningful, and history of bleeding disorderor at a high risk of bleeding.

• Active bacterial, fungal, parasitic, or viral infection that requires therapy.

• Current use of prohibited medication as described in the protocol, including the useof any potent CYP3A4 inhibitors or inducers within 14 days or 5 half lives (whichever is longer) before the first dose of study treatment.

Other protocol-defined Inclusion/Exclusion Criteria may apply.