A Phase I Study of AC220 in Patients With Relapsed/Refractory Acute Myeloid Leukemia Regardless of FLT3 Status

This is a multi-center clinical study conducted in the USA and possibly two international
sites. It is open-label, dose escalation study designed to characterize the safety,
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered AC220 as
a single agent given daily for 14 days. Cohorts of 3 patients receive AC220 until dose
limiting toxicity is noted (DLT). At that point cohorts will expand to 6 patients until MTD
is determined. Patients not experiencing DLT or significant disease progression at Day 15 may
continue receiving AC220 at the discretion of the Investigator and Sponsor. FLT3 positive and
negative patients are allowed to participate.

Inclusion Criteria:

1. Males and females age ≥ 18 years;

2. Histopathologically documented primary or secondary AML, as defined by WHO criteria
(Jaffe et al, 2001), confirmed by pathology review at treating institution, meeting at
least one of the following:

1. Refractory to at least 1 cycle of induction chemotherapy, or

2. Relapsed after at least 1 cycle of induction chemotherapy, or

3. Patient is not, according to the clinical judgment of the Principal Investigator,
a candidate for induction chemotherapy due to age, comorbidity, or other factors;

3. Patients for whom no standard therapies are anticipated to result in a durable
remission, or who have failed potentially curative therapy, or who refuse standard
therapy or patients for whom there is no known therapy of documented treatment
benefit;

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3;

5. In the absence of rapidly progressing disease, the interval from prior treatment to
time of AC220 administration should be at least 2 weeks for cytotoxic agents (other
than hydroxyurea, per Section 8.8), or at least 5 half-lives for noncytotoxic agents;

6. Persistent chronic clinically significant toxicities from prior chemotherapy or
surgery must be less than Grade 2;

7. Serum creatinine ≤ 2.0 mg/dL;

8. Total serum bilirubin ≤ 1.5 × ULN unless considered due to Gilbert's syndrome or
leukemic organ involvement;

9. Serum AST or ALT ≤ 3.0 × ULN unless considered due to leukemic organ involvement;

10. Females of childbearing potential must have a negative pregnancy test (urine β-hCG);

11. Females of childbearing potential and sexually mature males must agree to use a
medically accepted method of contraception throughout the study;

12. Written informed consent must be provided.

Exclusion Criteria:

1. Histologic diagnosis of acute promyelocytic leukemia;

2. Clinically active central nervous system leukemia;

3. Persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or
higher by the National Cancer Institute Common Terminology Criteria for Adverse Events
(CTCAE v3);

4. Bone marrow transplant within 2 months prior to study;

5. Active, uncontrolled infection;

6. Major surgery within 4 weeks prior to study;

7. Radiation therapy within 4 weeks prior to, or concurrent with, study;

8. Human immunodeficiency virus positivity;

9. Active hepatitis B or C or other active liver disease;

10. Women who are pregnant, lactating, or unwilling to use contraception if of
childbearing potential;

11. Medical condition, serious intercurrent illness, or other extenuating circumstance
that, in the judgment of the Principal Investigator, could jeopardize patient safety
or interfere with the objectives of the study.