Inclusion Criteria:
- Signed informed consent and ability to comply with protocol requirements.
- Histologically or pathologically confirmed diagnosis of acute myeloid leukemia based on World Health Organization classification that has relapsed after, or is refractory to, up to 2 prior induction regimens that may have included intensive chemotherapy (e.g., "7+3" cytarabine and daunorubicin), epigenetic therapy (i.e., azacitidine or decitabine with/without venetoclax), or targeted therapy (e.g., FLT-3, IDH 1/2, BCL-2, monoclonal antibody).
(Relapse is defined as reemergence of ≥5% leukemia blasts in bone marrow or ≥1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete hematologic recovery. Refractory acute myeloid leukemia is defined as persistent disease ≥28 days after initiation of intensive induction therapy (up to 2 induction cycles) or relapse <90 days after first complete remission or complete remission with incomplete hematologic recover. Refractory disease for patients undergoing hypomethylating agent induction is defined as lack of remission following at least 2 cycles of epigenetic therapy without reduction in bone marrow blast status).
- Adequate organ function as defined by the following laboratory values:
- Creatinine clearance >30 mL/min (by Cockcroft-Gault method),
- Total serum bilirubin <1.5 × upper limit of normal unless due to Gilbert's syndrome, leukemic organ involvement, hemolysis or considered an effect of regular blood transfusions,
- Alanine aminotransferase and aspartate aminotransferase <3 × upper limit of normal, unless due to leukemic organ involvement.
- Eastern Cooperative Oncology Group performance status of 0, 1, or 2).
- Projected life expectancy of ≥12 weeks.
- Female patients of childbearing potential must:
- Have a negative serum or urine pregnancy test prior to study treatment initiation.
- Agree to use at least 1 highly effective form of contraception during study treatment and for 3 months after the last dose.
- Male patients with female partners of childbearing potential must -- Agree to use at least 1 highly effective form of contraception during study treatment and for at least 3 months after the last dose.
Exclusion Criteria:
- Any >Grade 1 persistent clinically significant toxicities from prior chemotherapy.
- Leukemic blast count >25 × 109/L. Hydroxyurea permitted to control leukocytosis.
- Known history of human immunodeficiency virus or active hepatitis B or active hepatitis C infection.
- Concomitant malignancies for which patients are receiving active therapy at the time of signing consent. Patients with adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ (e.g., cervix), breast cancer receiving adjuvant endocrine therapy or prostate cancer not under active systemic treatment other than hormonal therapy may enroll irrespective of the time of diagnosis, with Medical Monitor approval.
- Known active central nervous system involvement by leukemia. Patients with previously diagnosed central nervous system leukemia are eligible if the central nervous system leukemia is under control and intrathecal treatment may continue throughout the study.
- Diagnosis of acute promyelocytic leukemia.
- Prior exposure to anticancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents within 14 days of the first day of study treatment or within 5 half-lives prior to first dose of study treatment. Note that hydroxyurea up to 5 g daily × 3 days is permitted to reduce elevated white blood cell (WBC) count.
- Venetoclax exposure in more than 1 prior regimen.
- Prior exposure to biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent within 14 days prior to first dose of study drug.
- Prior hematopoietic stem cell transplantation.
- Malabsorption syndrome or other condition that precludes enteral route of administration.
- Pregnancy or lactation.
- Active uncontrolled systemic infection (viral, bacterial, or fungal).
- Ongoing treatment with strong or moderate CYP3A inhibitors or CYP3A inducers, P-gp inhibitors, or narrow therapeutic index P-gp substrates that cannot be discontinued at least 1 week prior to start of venetoclax dosing excluding antifungal prophylaxis.