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