AC220 for Children With Relapsed/Refractory ALL or AML
Condition: Lymphoblastic Leukemia, Acute, Childhood; Myelogenous Leukemia, Acute, Childhood
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Acute Disease
Intervention: AC220; Cytarabine; Etoposide; Methotrexate
Intervention description: Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.; All patients receive 1000 mg/m2/day IV given every 12 hours on days 1 through 5. Additionally, AML patients and patients with ambiguous leukemia receive cytarabine intrathecally on day "1" of course 1 and 2. Dose defined by age:
20 mg for patients age <1 yr
30 mg for patients age 1-1.99 years of age
50 mg for patients age 2-2.99 years of age
70 mg for patients >3 years of age; 150 mg/m2/day IV on days 1 through 5.; IT methotrexate given intrathecally to patients with ALL on day "0" of course 1 and 2. Dose defined by age
6 mg for patients age < 1yr
8 mg for patients age 1-1.99
10 mg for patients age 2-2.99
12 mg for patients 3-8.99 years of age
15 mg for patients >9 years of age
Intervention MeSH terms: Cytarabine; Methotrexate; Etoposide; Etoposide phosphate
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 1 Month
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapse; Lymphoblastic; Leukemia; AC220; Refractory; Myelogenous; Acute; Childhood; Pediatric; ALL; AML

Summary:

      This is a phase I study of the investigational drug AC220 combined with cytarabine and
      etoposide in pediatric patients with relapsed acute lymphoblastic leukemia (ALL) and acute
      myelogenous leukemia (AML).
    

Eligibility criteria:

        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