The purpose of this study is to determine safety, tolerability, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of ZEN003365 in patients with relapsed/refractory lymphoproliferative malignancies (LPM) or relapsed/refractory acute myeloid leukemia (AML).

Inclusion Criteria:

Dose Escalation and Expansion Stages:

• ECOG performance status ≤ 1 for LPM patients, ≤ 2 for AML patients
• Age 18 years or older
• Adverse events (AEs), except for alopecia, from any previous treatments must have recovered to eligibility levels from prior toxicity
• Adequate renal, hepatic and coagulation function, as specified per protocol
• Written informed consent granted prior to any study-specific screening procedures

LPM Patients:

• Histologically confirmed lymphoproliferative malignancy
• Have received prior protocol-specified disease-dependent prior treatments
• Have measurable disease
• Platelets ≥ 75,000/µL (≥50,000/µL if bone marrow involvement), absolute neutrophil count (ANC) ≥ 1,000/ µL, and hemoglobin (Hgb) ≥ 8 g/dL
• Patients must have been off previous anticancer therapy for at least 3 weeks or 5 half-lives, whichever is longer, and the subject must have recovered to eligibility levels from prior toxicity

AML:

• Refractory or relapsed AML patients, without curative intent, e.g., not a stem cell transplant candidate
• Any prior chemotherapy must have been completed ≥ 2 weeks, any therapy with biologics must have been completed ≥ 4 weeks prior to day 1 of study treatment, and the participant must have recovered to eligibility levels from prior toxicity
• Blast count ≤ 10,000/µL prior to initiation of therapy

Exclusion Criteria

Dose Escalation and Expansion Stages:

• Prior exposure to a BET inhibitor
• Prior allogeneic hematopoietic cell transplant
• Chronic graft versus host disease
• Known, active fungal, bacterial, and/or viral infection
• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
• Current subdural hematoma
• CNS or leptomeningeal metastases
• Requirement for medications or agents known to be sensitive CYP3A4 substrate drugs, CYP3A4 substrate drugs with a narrow therapeutic range or to be strong inhibitors/inducers of CYP3A4
• Requirement for immunosuppressive agents
• Evidence of significant cardiovascular disease or significant screening ECG abnormalities
• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient.

AML patients:

• Acute promyelocytic leukemia (APL)
• Chronic myeloid leukemia (CML) in blast crisis