Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)

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