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The purpose of this research study is to see how safe and tolerable, and to find the highest or best dose, of an investigational combination of drugs called enasidenib and venetoclax, in patients with relapsed (the cancer has come back) or refractory (the cancer does not respond or have stopped responding to treatment) acute myeloid leukemia (AML, a type of blood cancer). This study will also see how useful the combination of enasidenib and venetoclax is in the treatment of patients with relapsed or refractory AML.

This study will have two parts: Phase 1b and Phase 2. The part that patients may participate in will depend on when they join the study.

In the phase 1b portion of the study, small groups participants will receive increasing doses of venetoclax in combination with a flat dose of enadisenib until the highest dose or best dose of venetoclax that is safe and tolerable in combination with enadisenib is found.

In the phase 2 portion of the study, an additional group of participants will receive the highest or best dose of venetoclax found in the Phase 1b portion of the study with a flat dose of enadisenib to see how useful the combination is in treating relapsed or refractory acute myeloid leukemia (AML).

Inclusion Criteria:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤2
• IDH2 (R140 or IDH R172) mutated AML disease status as determined by local laboratory
• Relapsed and/or refractory acute myeloid leukemia (AML). Treatment-naïve patients who are not eligible for standard induction chemotherapy or high-risk myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) may also be eligible.
• Adequate hepatic function
• Adequate renal function
• Willing and able to provide informed consent
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic and non-cytotoxic (immunotherapy) agents

Exclusion Criteria:

• Known allergy or hypersensitivity to enasidenib or venetoclax
• Previously received either an IDH2 inhibitor or BCL2 inhibitor
• With any uncontrolled clinically significant medical conditions
• The use of other chemotherapeutic agents or anti-leukemic agents, radiotherapy or other investigational therapy is not permitted during study with exceptions
• Receiving concomitant treatment with strong cytochrome P450 2A (CYP3A4) inhibitors within 3 days of start of study therapy
• Receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John's Wort) within 3 days of start of study therapy.
• Taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
• Active graft-versus-host-disease (GVHD) status post stem cell transplant
• Severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Concurrent active malignancy under treatment
• Administration or consumption of any of the following within 3 days prior to first dose of study drug: grapefruit or grapefruits products, Seville oranges (including marmalade containing Seville oranges) and start fruit
• Heart-rate corrected QT (QTc) interval ≥480 msec (Fridericia's formula) except for underlying right-bundle branch block (RBBB).
• Positive for HIV
• Subject has an unacceptable white blood cell count
• Positive urine pregnancy test,
• Participants who not willing to maintain adequate contraception