The purpose of this study is to determine the safety, tolerability, maximum tolerated doses (MTDs) and recommended Phase 2 doses (RP2Ds) of JNJ-74856665 as monotherapy and/or in combinations.

This is first-in-human (FIH) Phase 1, dose escalation study of JNJ-74856665 alone or in combination with Azacitidine or Venetoclax in participants with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). Participants with Chronic Myelomonocytic Leukemia (CMML) are also eligible and will either receive JNJ-74856665 as monotherapy or in combination with Azacitidine. AML is a heterogeneous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells (myeloid blasts) in the peripheral blood, bone marrow, and other tissues and is the second most common form of leukemia. MDS are a heterogeneous group of malignant hematopoietic stem cell disorders that are characterized by cytopenias, myeloid dysplasia, and a risk of transformation to AML. JNJ-74856665 is an orally bioavailable, potent, and selective dihydroorotate dehydrogenase (DHODH) inhibitor that binds to the enzyme's ubiquinone binding site promoting AML/MDS differentiation as well as cell cycle arrest and apoptosis. Azacitidine (5-azacytidine) is a nucleoside metabolic inhibitor that has been US Food and Drug Administration-approved for several MDS subtypes. Venetoclax (VEN) is a BCL-2 inhibitor that can restore activation of apoptosis in malignant cells, the survival of which often depends on dysregulation of this pathway. The study is divided into 3 periods: a Screening Phase (within 28 days before the first dose of study drug), a Treatment Phase (first dose of study drug until the completion of the end-of-treatment visit) and a Post-treatment Follow-up Phase (up to the end of study participation or end of study). The end of study is defined as the last study assessment for the last participant in the study. Total duration of study is up to 2 years and 10 months. Efficacy, safety, pharmacokinetics (PK), and biomarkers will be assessed at specified time points during this study. Participants safety and study conduct will be monitored throughout the study.

Inclusion Criteria:

• A diagnosis of: Arms A and C: Acute Myeloid Leukemia (AML) according to the World Health Organization (WHO) 2016 criteria with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; or newly transformed secondary AML according to the WHO 2016 criteria and have exhausted standard therapeutic options for AML during their treatment prior to transformation; or high-risk or very high-risk Myelodysplastic Syndrome (MDS) according to the WHO 2016 criteria and the revised International Prognostic Scoring System (IPSS-R) with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; or Arm A only: chronic myelomonocytic leukemia-2 (CMML-2) according to the WHO 2016 criteria with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; Arm B: Eligible participants must be considered unsuitable for intensive treatment with a curative intent (including stem cell transplantation), but eligible to receive Azacitidine (AZA) treatment with the following underlying diseases: AML (newly diagnosed or relapsed/refractory) according to the 2016 WHO classification only if Venetoclax (VEN) + hypomethylating agent (HMA) (or low-dose cytarabine) is not indicated or available; or high-risk or very high-risk MDS according to the 2016 WHO classification and IPSS-R; or CMML-2 according to the WHO 2016 criteria; Arm D: Very low, low, or intermediate-risk MDS according to the 2016 WHO classification and IPSS-R and the following: Transfusion dependence defined as requiring at least 3 red blood cell (RBC) units transfused within 16 weeks prior to C1D1; pre-transfusion hemoglobin (Hb) should be less than (<) 9.0 grams per decilitre (g/dL) to count towards the 3 units total, Relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment or endogenous serum erythropoietin (EPO) level greater than (>) 500 milliunits per milliliter (mU/mL). Exception: Del(5q) karyotype is allowed, provided prior treatment with lenalidomide has failed or participant was ineligible to receive lenalidomide
• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
• Women of childbearing potential (WOCBP) must have a negative highly sensitive serum (beta-human chorionic gonadotropin) at screening and again within 48 hours prior to the first dose of study treatment. A urine or serum test is acceptable at subsequent time points
• A WOCBP must agree to all the following during the study and for 6 months after the last dose of study treatment: a) use a barrier method of contraception; b) use a highly effective preferably user-independent method of contraception; c) not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction; d) not plan to become pregnant; e) not breast-feeding
• A male must agree to all the following during the study and for 90 days after the last dose of study treatment: a) wear a condom when engaging in any activity that allows for passage of ejaculate to another person; b) not to donate sperm or freeze for future use for the purpose of reproduction; c) not plan to father a child. In addition, the participant should be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak

Exclusion Criteria:

• Acute promyelocytic leukemia according to World Health Organization 2016 criteria
• Known central nervous system involvement
• Prior treatment with a dihydroorotate dehydrogenase (DHODH) inhibitor for an oncology indication or intolerance to a DHODH inhibitor given for non-oncology indication
• Toxicities (except for alopecia, peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapies that have not resolved to baseline or to Grade 1 or less
• Known allergies, hypersensitivity, or intolerance to JNJ-74856665, AZA, or VEN or the excipients of these treatments

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinicaltrials/ transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu