Inclusion Criteria:

• Men and women, aged 18 or older.
• Subjects in the Part 4 C-TGB Expansion Cohort 1 (C-TGB E1) and the optional C-TGA Expansion Cohort 2 (C-TGA E2) must be ≥ 65 years old.
• Part 1 monotherapy dose escalation:
  • TGA: Subjects with histologically confirmed diagnosis of acute leukemia, high-risk MDS, or MDS/MPN (including atypical chronic myeloid leukemia [aCML], chronic myelomonocytic leukemia [CMML], myelodysplastic/myeloproliferative neoplasm unclassifiable [MDS/MPN-U], and refractory anemia with ring sideroblasts and thrombocytosis [RARS-T]);
  • TGB: Subjects with MM, lymphoma, and other lymphoproliferative neoplasms.
• Part 2 monotherapy dose expansion Subjects with histologically confirmed and measureable/evaluable disease:
  • TGA Expansion Cohort 1 (TGA E1): AML;
  • TGA Expansion Cohort 2 (TGA E2): MDS/MPN;
  • TGA Expansion Cohort 3 (TGA E3): MF;
  • TGB Expansion Cohort 1 (TGB E1): MM;
  • TGB Expansion Cohort 2 (TGB E2): DLBCL.
• Part 3 combination dose-finding Subjects with histologically confirmed and measureable/evaluable disease:
  • Combination Treatment Group A (C-TGA): relapsed/refractory AML. Subjects with acute promyelocytic leukemia are excluded;
  • Combination Treatment Group B (C-TGB): relapsed/refractory AML or subjects ≥ 65 years of age with newly diagnosed AML (de novo or secondary) and unfit for intensive chemotherapy. Subjects with acute promyelocytic leukemia are excluded.
  • Combination Treatment Group C (C-TGC): primary or secondary MF who have had a suboptimal response to ruxolitinib monotherapy defined as follows:
    • Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the screening visit; OR
    • Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening Symptom Form.
• Part 4 combination expansion Subjects with histologically confirmed and measureable/evaluable disease:
  • C-TGA Expansion Cohort 1 (C-TGA E1): relapsed/refractory AML. Subjects with acute promyelocytic leukemia are excluded;
  • C-TGB Expansion Cohort 1 (C-TGB E1): newly diagnosed AML (de novo or secondary) who are ≥ 65 years and unfit to receive intensive chemotherapy. Subjects with acute promyelocytic leukemia are excluded.
  • C-TGC Expansion Cohort 1 (C-TGC E1): primary or secondary MF and a suboptimal response to ruxolitinib monotherapy defined as follows:
    • Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the screening visit; OR
    • Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening Symptom Form.
• Parts 1 and 2:
  • Must be unresponsive to currently available therapy, and there is no further SOC therapy available in the judgment of the investigator;
  • Must not currently be a candidate for curative treatment, including hematopoietic stem cell transplant.
• Parts 3 and 4:
  • Subjects with relapsed/refractory AML must have received either induction chemotherapy for AML or hypomethylating agents for hematologic disease before AM;
  • Elderly subjects (≥65 years) with newly diagnosed AML must be treatment-naive and unfit for intensive chemotherapy;
  • Subjects with MF must have been treated with ruxolitinib at a stable dose for ≥ 8 weeks. One dose reduction due to toxicities within the 8 weeks before Study Day 1 will be permitted. Acceptable doses are 5 mg BID to 25 mg BID; QD doses are not allowed.
• Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate (as appropriate to disease), or archival sample obtained since completion of most recent therapy (as appropriate to subjects with existing bone marrow disease or for whom bone marrow examination is a component of disease status assessment). If a biopsy is not possible or contraindicated, or the tissue requirement cannot be satisfied, this requirement may be waived with approval from the medical monitor.
• ECOG performance status:
  • Part 1: 0 or 1.
  • Parts 2 through 4: 0, 1, or 2.
• Life expectancy > 12 weeks or ≥ 24 weeks for Part 3 and Part 4 MF subjects.
• Willingness to avoid pregnancy or fathering children based on the following criteria:
  • Postmenopausal woman (i.e., surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age);
  • Woman of childbearing potential who has a negative serum pregnancy test at screening and before the first dose on Day 1 who agrees 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 subject and their understanding confirmed;
  • Man who agrees to take appropriate precautions to avoid fathering children (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 subject and their understanding confirmed.

Exclusion Criteria:

Inadequate bone marrow function demonstrated by any of the following:

• Laboratory Parameter | TGB (Part 1) | TGB (Part 2) | C-TGC (Parts 3 and 4):
  • Hemoglobin (g/dL) | < 8.0 | < 8.0 | Subjects unwilling to receive red blood cell transfusions to treat low hemoglobin levels are excluded
  • Platelets (× 109/L) | < 75 | < 50 | < 50 in 2 weeks before screening or platelet transfusions within 4 weeks of screening;
  • Absolute neutrophils (× 109/L) | < 1.0 | < 1.0 | < 0.5 in the 2 weeks before screening.
• Note: No specific hematologic exclusion criteria apply for TGA (Parts 1 and 2), Part 3 C-TGA and C-TGB, and Part 4 C-TGA E1 and C-TGB E1 cohorts.
• Inadequate organ function demonstrated by any of the following, unless approved by the medical monitor:
• Part 1 and Part 3:
  • Total bilirubin > upper limit of normal (ULN; except total bilirubin > ULN is acceptable if direct bilirubin is ≤ 1.2 × ULN. Subjects with Gilbert's syndrome who have total bilirubin ≤ 2 × ULN may be enrolled with medical monitor approval);
  • AST or ALT > 1.5 × ULN;
  • Creatinine clearance < 50 mL/min (< 30 mL/min for MM) based on Cockroft-Gault formula or 24-hour urine analysis.
• Part 2 and Part 4:
  • Total bilirubin > ULN (except total bilirubin > ULN is acceptable if direct bilirubin is ≤ 1.2 × ULN. Subjects with Gilbert's syndrome who have total bilirubin ≤ 2 × ULN may be enrolled with medical monitor approval);
  • AST or ALT > 1.5 × ULN;
  • Creatinine clearance < 40 mL/min (< 30 mL/min for MM) based on Cockroft-Gault formula or 24-hour urine analysis.
• Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:
  • < 5 half-lives or 14 days, whichever is longer, for any investigational agent;
  • < 28 days for any antibodies or biological therapies;
  • < 5 half-lives for all other nonbiologic anticancer medications, or sponsor approval;
  • < 6 weeks for mitomycin-C or nitrosoureas;
  • The following are allowed: hydroxyurea for controlling proliferative disease and low-dose corticosteroids (prednisone or equivalent ≤ 10 mg per day). Hydroxyurea should not be used within 48 hours before and on the day of PD sample collection or during or 72 hours before or after azacitidine administration.
    • Note: Concomitant hydroxyurea is prohibited in subjects with MF within 8 weeks before enrolling (Day 1) into C-TGC.
• Unless approved by the medical monitor, may not have received an allogeneic hematopoietic stem cell transplant within 6 months before treatment, or have active graft-versus-host disease following allogeneic transplant, or have received immunosuppressive therapy (including, but not limited to, cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids [> 10 mg/day prednisone equivalent]) following allogeneic transplant within 2 weeks of Cycle 1 Day 1.
• Unless approved by the medical monitor, may not have received autologous hematopoietic stem cell transplant within 3 months before treatment.
• Has any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy.
• Radiotherapy within the 2 weeks before initiation of treatment. Palliative radiation treatment to nonindex or bone lesions performed less than 2 weeks before treatment initiation may be considered with medical monitor approval. In Part 3 and Part 4, MF subjects may not have had splenic irradiation within 6 months of the first dose of INCB053914.
• Part 1 and Part 3 only: Hemoglobin A1c (HbA1c) > 8.0% (all subjects will have HbA1c tested at screening).
• Part 1 and Part 3: Any history of disease involving the central nervous system (CNS).
• Part 2 and Part 4: Known active disease involving the CNS, for example, brain metastasis or spinal cord compression, except primary CNS lymphoma.
• Known HIV infection.
• Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Active and uncontrolled infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 470 milliseconds is excluded. For subjects with an intraventricular conduction delay (QRS interval 120 msec), the JTc interval may be used in place of the QTc with sponsor approval. Subjects with left bundle branch block are excluded. QTc prolongation due to a pacemaker may enroll if the JT is normal or with MM approval.
• History of clinically significant or uncontrolled cardiac disease, including recent (within last 12 months) unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV congestive heart failure, or clinically significant arrhythmias not controlled by medication. Subjects with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study drug will be allowed.
• Part 1 and Part 3: Current diagnosis of any chronic or acute respiratory condition or ongoing sequelae from any previously diagnosed respiratory condition that is significant in the judgment of the investigator or the sponsor's medical monitor.
• Part 2 and Part 4: Current diagnosis of any severe or uncontrolled obstructive or restrictive respiratory condition (e.g., Global Initiative for Chronic Obstructive Lung Disease [GOLD] 3 or GOLD 4 chronic obstructive pulmonary disease).
• Gastroesophageal reflux disease not controlled by medication (ie, currently symptomatic or endoscopic evidence of esophagitis) within 30 days before Cycle 1 Day 1.
• Prior receipt of a PIM inhibitor.
• Current use of prohibited medication.
• Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of study drug.
• Subject has known hypersensitivity or severe reaction to any of the active substances or excipients in INCB053914, cytarabine, azacitidine, ruxolitinib, or similar compounds as appropriate to the relevant treatment group.
• Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the dose regimen and study evaluations.
• Currently breastfeeding.
• Any condition in the investigator's judgment that would interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
• Unable to swallow and retain oral medication.
• Unable to comprehend or unwilling to sign the informed consent form (ICF).
• Any known contraindications to the use of cytarabine, azacitidine, or ruxolitinib as appropriate to the relevant treatment group.
• Excessive alcohol use (e.g., > 2 drinks per day).
• Excessive chronic acetaminophen use (> 2 g per day).
• Part 1 and Part 3 only: Type 1 diabetes or uncontrolled Type 2 diabetes.