Current enrollment is open only to FLT3-ITD positive, Cohort 1.

Inclusion Criteria:

1. Males and females age ≥18 years in second relapse or refractory.
2. Males and females age ≥60 years in first relapse or refractory.
3. Must have baseline bone marrow sample taken.
4. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS with ≥20% bone marrow or peripheral blasts), as defined by the World Health Organization (WHO) criteria, confirmed by pathology review at treating institution.
5. Able to swallow the liquid study drug.
6. ECOG performance status of 0 to 2
7. In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic agents other than hydroxyurea is not permitted during the study with the possible exception of intrathecal (IT) therapy at the discretion of the Investigator and with the agreement of the Sponsor.
8. Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade 1.
9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.
10. Serum creatinine ≤1.5 × ULN and glomerular filtration rate (GFR) > 30 mL/min
11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.
12. Total serum bilirubin ≤1.5 × ULN
13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN
14. Females of childbearing potential must have a negative pregnancy test (urine β-hCG).
15. Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.
16. Written informed consent must be provided.

Exclusion Criteria:

1. Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.
2. Diagnosis of acute promyelocytic leukemia
3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis
4. AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment
5. AML or antecedent MDS secondary to prior chemotherapy
6. Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy
7. Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity related to the transplant
8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.
9. Patients who have previously received AC220
10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
11. Major surgery within 4 weeks prior to enrollment in the study
12. Radiation therapy within 4 weeks prior to, or concurrent with study
13. Use of concomitant drugs that prolong QT/QTc interval and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
14. Uncontrolled or significant cardiovascular disease
15. Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential
16. Men who are unwilling to use contraception if their partners are of childbearing potential
17. Active, uncontrolled infection
18. Human immunodeficiency virus positivity
19. Active hepatitis B or C or other active liver disease
20. History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission