A Phase I Study of AC220 for Children With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

This is a study for patients with relapsed acute lymphoblastic leukemia (ALL) or acute
myelogenous leukemia (AML). Some people diagnosed with leukemia have changes in a receptor
located on the surface of white blood cells called FLT3. This is known as a FLT3 mutation.
FLT3 plays an important role in the way cells grow and divide. In normal cells, the FLT3
receptor is switched off most of the time and only switches on when it gets a chemical
signal from outside. But cells with the FLT3 mutation have the grow signal permanently
switched on. This means leukemia cells with the FLT3 mutation are growing and dividing all
the time. Doctors have found that people with leukemia cells that carry FLT3 mutations are
less likely to go into remission with chemotherapy and have a higher risk of the leukemia
coming back after treatment.

This is a study of an investigational drug called AC220. AC220 is considered
investigational because it has not been approved in the United States by the Food and Drug
Administration (FDA). AC220 is a drug which is able to "turn off" the FLT3 grow signal.
AC220 will be given with cytarabine and etoposide to treat the relapsed leukemia. This is a
phase I study, which means that the study is being done to find the highest dose of AC220
that can be given safely with the drugs cytarabine and etoposide to children and young
adults.

Inclusion Criteria:

- Patients must be greater than 1 month and ≤ 21 years of age at study entry.

- Patients must have a diagnosis of relapsed/refractory AML, ALL or acute leukemia of
ambiguous lineage and meet the following criteria:

1. Patients with AML or leukemia with ambiguous lineage must have greater than or
equal to 5% blasts in the bone marrow.

2. Patients with ALL must have an M3 marrow (marrow blasts >25%).

3. Patients with ALL must have MLL gene rearrangement or hyperdiploid >50
chromosomes.

4. Patients with treatment related AML (t-AML) are eligible, provided they meet all
other eligibility criteria.

- Karnofsky > 50% for patients >16 years of age and Lansky >50% for patients ≤16 years
of age.

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

- Myelosuppressive chemotherapy:

- Patients with ALL who relapse during standard maintenance therapy are
eligible at time of relapse.

- For patients with ALL and AML who relapse while they are receiving
cytotoxic therapy, at least 14 days must have elapsed since the completion
of cytotoxic therapy.

- Cytoreduction with hydroxyurea can be initiated and continued for up to 24
hours prior to the start of AC220.

- Patients who have received other FLT3 inhibitors (ex. lestaurtinib,
sorafenib) are eligible for this study.

- Hematopoietic growth factors: At least 7 days since the completion of therapy
with a growth factor.

- Biologic (anti-neoplastic agent): At least 7 days since the completion of
therapy with a biologic agent. For agents that have known adverse events
occurring beyond 7 days after administration, this period must be extended
beyond the time during which adverse events are known to occur. The duration of
this interval must be discussed with the study chair.

- XRT: 2 wks must have elapsed since local palliative XRT for CNS chloromas; No
washout period is necessary for other chloromas; at least 3 months must have
elapsed if prior TBI, craniospinal XRT.

- Hematopoetic Stem Cell Transplant: At least 90 days must have elapsed since
hematopoietic stem cell transplant (HSCT) and patients must not have active
GVHD.

- Patient must have adequate renal and hepatic functions as indicated by the following
laboratory values:

- Patients must have a calculated creatinine clearance or radioisotope GFR
≥70mL/min/1.73m2 or a normal serum creatinine based on age/gender.

- Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin.

- Alanine transaminase (ALT) <5 × ULN (unless related to leukemic involvement).

- Patient must have a shortening fraction of ≥ 27% by echocardiogram, OR an ejection
fraction of ≥ 50% by radionuclide angiogram.

- Reproductive Function

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed within 2 weeks prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on
this study.

- Male and female patients of child-bearing potential must agree to use an
effective method of contraception approved by the investigator during the study
and for a minimum of 6 months after study treatment.

Exclusion Criteria:

- Patients will be excluded if they have CNS 3 disease.

- Patients will be excluded if they have uncontrolled or significant cardiovascular
disease, including:

- A myocardial infarction within 12 months.

- Uncontrolled angina within 6 months.

- Diagnosed or suspected congenital long QT syndrome or any history of clinically
significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or torsades de pointes [TdP]); any history of
arrhythmia will be discussed with the Sponsor's Medical Monitor prior to
patient's entry into the study.

- Prolonged QTcF interval on pre-entry ECG (≥450 ms).

- Any history of second or third degree heart block (may be eligible if the
patient currently has a pacemaker).

- Heart rate < 50/minute on pre-entry ECG.

- Uncontrolled hypertension.

- Complete left bundle branch block.

- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or TdP.

- Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to
be off pressors and have negative blood cultures for 48 hours.

- Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy,
or immunotherapy other than as specified in the protocol.

- Any significant concurrent disease, illness, psychiatric disorder or social issue
that would compromise patient safety or compliance, interfere with consent, study
participation, follow up, or interpretation of study results.

- Patients who are concurrently receiving CYP3A4 and 5 inhibitors and inducers