Inclusion Criteria:

• Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
• Adult male or female, and at least 18 years old.
• Laboratory values meeting the following criteria on clinical laboratory tests:
  • Serum alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN);
  • Serum total bilirubin ≤ 1.5 × ULN (subjects with Gilbert's syndrome may have a bilirubin > 1.5 × ULN);
  • Serum creatinine < 1.5 × institutional ULN;
  • White blood cell (WBC) count no greater than 25 × 109/L at time of start of study drug (venetoclax or gilteritinib).
    • Note: Hydroxyurea is permitted from screening through completion of Cycle 1 in order to meet this criterion.
• Subject is suitable for oral administration of drug.
• Subject is willing and able to comply with procedures required in this protocol.
• Subject has a diagnosis of AML per World Health Organization criteria (2016).
• Subject meets the following disease activity criteria:
  • Subject should have failed at least 1 line of prior therapy (defined as failure to respond to therapy, and/or progression during or after therapy); and
  • Subject should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

For subjects enrolling into the Expansion Cohort only:

• Subject should have a documented FLT3 mutation (ITD or TKD) in bone marrow or peripheral blood, as measured by local laboratory assay using the established threshold of the chosen assay (i.e., PCR, NGS, etc.).
• No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
• Subject does not have a diagnosis of acute promyelocytic leukemia (APL).
• Subject does not have a diagnosis of BCR-ABL-positive leukemia.
• Subject does not have a history of other malignancies within 2 years prior to study entry, with the exception of:
  • Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  • Any malignancy that was surgically resected (or otherwise treated) with curative intent (such cases should be discussed with the medical monitor/Therapeutic Area Medical Director [TAMD] prior to enrollment).
• Subject does not have active central nervous system leukemia.
• Subject does not have a history of chronic New York Heart Association (NYHA) class IV heart failure.
• Subject does not have a corrected QT interval of > 450 ms (as calculated using QT interval corrected for heart rate using Fridericia's formula [QTcF]).
• Subject does not have a history of long-QT syndrome.
• Subject does not have any significant medical condition that in the opinion of the investigator would adversely affect his/her participation in the study, including no known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Note: HIV and hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to hepatitis B virus (i.e., hepatitis B surface antigen [HBsAg] negative, anti-hepatitis B surface [HBs] positive, and anti-hepatitis B core [HBc] negative) may participate.
• Subject does not have a chronic respiratory disease that requires continuous oxygen use.
• A negative serum pregnancy test for all female subjects of childbearing potential at the screening visit and a negative urine pregnancy test for all female subjects of childbearing potential on Day 1, before the first dose of study drug.
• If female, subject must be either postmenopausal or permanently surgically sterile or, for women of childbearing potential, practicing at least 1 protocol-specified method of birth control that is effective from study Day 1 through at  least 6 months after the last dose of study drug.
• Female subjects who are not pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 6 months after the last dose of study drug (venetoclax and gilteritinib).
• No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
• Male subjects who are sexually active must agree, from Study Day 1 through at least 4 months after the last dose of study drug, to practice protocol-specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 4 months after the last dose of study drug (venetoclax and gilteritinib).
• Subject cannot have received treatment with anti-leukemia therapy, including chemotherapy, radiotherapy or any investigational therapy, within 14 days or 5 half-lives of that prior therapy, whichever is shorter, prior to initiation of study treatment, with the exception of hydroxyurea. Prior exposure to any FLT3 inhibitor (including gilteritinib) is allowed during dose escalation; prior exposure to any FLT3 inhibitor except gilteritinib is allowed during dose expansion.
• Subject must not have received prior treatment with any BCL-2 inhibitor except venetoclax (both dose escalation and dose expansion). Previous venetoclax exposure is allowed as long as subjects were not on a randomized trial that included venetoclax.

For those in the Dose Escalation Cohort only:

• Subject has the ability to stop or hold from any moderate/strong cytochrome P450 (CYP)3A inhibitors (e.g., fluconazole, posaconazole, ketoconazole) or moderate/strong inducers (e.g., rifampin, carbemazepine, phenytoin, St. John's wort), starting from 1 week prior to first dose, until after completion of the DLT evaluation period.
• Subject is not in receipt of any of the above moderate/strong CYP3A inhibitors/inducers within 7 days of start of study therapy. 
• Subject is not in receipt of strong inhibitors and inducers of P-glycoprotein (P-gp), with the exception of drugs that are considered absolutely essential for the care of the subject.
• Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or starfruit within 3 days before anticipated first dose of study drug and must consent not to consume through the last dose of study drug.
• Subject must not have received any live vaccines within 4 weeks before the first dose of study drug, or have an expected need for a live vaccination during study participation including at least 4 weeks after the last dose of venetoclax.

Exclusion Criteria: 

• Subject has a diagnosis of acute promyelocytic leukemia (APL) or BCR-ABL-positive leukemia.
• Subject has a history of other malignancies within 2 years prior to study entry, with exceptions as described in the protocol. 
• Subject has active central nervous system leukemia. - Subject has a history of chronic New York Heart Association (NYHA) class IV heart failure. 
• Subject has a corrected QT interval of > 450 ms. 
• Subject has a chronic respiratory disease that requires continuous oxygen use.