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 refractory MF (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 last therapy; and there is no available therapy that would provide clinical benefit in the opinion of the investigator.

• - a.

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

• - b.

ET participants should have disease refractory to hydroxyurea as defined by the protocol.

• - Part 2 Combination with ruxolitinib.

• - a.

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

• - b.

Suboptimal response is defined as currently being treated with ruxolitinib monotherapy at a stable dose for ≥ 8 weeks immediately preceding the first dose of study treatment. One dose reduction due to toxicities within 8 weeks prior to Study Day 1 is permitted.

• - c.

JAKi-naive is defined as those participants that have no prior use of any JAK inhibitor, including ruxolitinib, and;

• - d.

Part 2 dose escalation: Risk category of intermediate-2 or high according to DIPSS.

• - e.

Part 2 dose expansion: Risk category of intermediate-1, intermediate-2, or high according to DIPSS.

• - f.

Part 2 dose expansion 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.

• - g.

Part 2 dose expansion 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.

• - h.

Part 2 dose expansion 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 avoid pregnancy or fathering children based on criteria.

• - a.

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

• - b.

Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed.

• - c.

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

Exclusion Criteria:

• - Prior receipt of a BET inhibitor.

• - Receipt of anticancer medications or investigational drugs within the protocol-defined interval before the first dose of study treatment.

For Part 2 JAKi-naive, prior use of a JAK inhibitor (including ruxolitinib) and no use of experimental drug therapy for MF or any other standard drug (except hydroxyurea) used for MF or another indication within 3 months of starting study drug. Hydroxyurea must be discontinued 3 weeks prior to starting study treatment. For participants with suboptimal response to ruxolitinib, ruxolitinib will continue at the 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 dose escalation 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 to treat 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 transplantation within 6 months of enrollment (unless approved by the medical monitor), or have active graft versus-host disease, or have received immunosuppressive therapy following allogeneic transplant within 2 weeks of the first dose of study treatment.

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

• - Significant concurrent, uncontrolled medical condition, including but not limited to, significant GI disorder, history of or current clinically significant or uncontrolled cardiac disease, history or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful, and history of bleeding disorder or 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 use of 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.

Arms

Experimental: Part 1 : INCB057643 Monotherapy

INCB057643 dose escalation and dose expansion

Experimental: Part 2 : INCB057643 Combination with Ruxolitinib

Combination arm in dose escalation and dose expansion

Interventions

Drug: - INCB057643

INCB057643 dose escalation and dose expansion.

Drug: - Ruxolitinib

Ruxolitinib will be administered twice a day using the dose described for each Cohort in the protocol for Part 2.