Dasatinib in Combination With Chemotherapy for Relapsed or Refractory Core Binding Factor Acute Myeloid Leukemia

This Phase I study is for children and adolescents who have acute myelogenous leukemia (AML)
that has come back (relapsed) or has become resistant (refractory) to standard therapies.
Researchers want to know if a drug called dasatinib is safe when used together with standard
chemotherapy in treating patients who have relapsed or have resistant AML. Their leukemia has
a particular genetic mutation, called core-binding factor.

This type of leukemia has an increase of a cancer promoting protein called c-KIT. Dasatinib
can target this protein in laboratory experiments. Laboratory and other studies suggest that
dasatinib may prevent acute myeloid leukemia cells from growing and may lead to the
destruction of leukemia cells.

The main goal of this study is to find a safe dose of dasatinib and to find out the side
effects of dasatinib when it is given in combination with standard chemotherapy to children
and adolescents. Similar studies are currently being done in adult patients. Dasatinib has
been proven safe and effective in the treatment of other types of leukemia, both by itself
and in combination with standard chemotherapy. It is not, however, FDA-approved for use in
children.

Three to six participants will receive the starting dose of the drug. If the side effects are
not too severe, the next group of participants will take the study drug at a higher dose
level. Up to two dose levels of the study drug will be tested. Dasatinib is given by mouth
once daily on days 6 to 29 of each 42-day cycle. Participants may receive two cycles in this
study.

In addition to dasatinib, participants receive chemotherapy intravenously (IV) with
fludarabine, cytarabine, idarubicin, as well as in the spinal fluid (intrathecal or IT
chemotherapy). Intrathecal chemotherapy includes cytarabine at the start of each cycle. These
drugs are part of standard AML treatment. If at the time of study entry a subject has
leukemia cells in their spinal fluid (CNS leukemia), they may receive additional intrathecal
chemotherapy with cytarabine, methotrexate, and hydrocortisone (IT triples) during each
cycle.

Required research tests include pharmacokinetic (PK) and pharmacodynamics (PD) blood draws
(about 1 teaspoon each time) during cycle 1. Optional research tests include extra marrow
(about 1 teaspoon each time) for genetic testing and banking of marrow (1 teaspoon) for
future studies about cancer.

Primary Objectives of this study are:

- To evaluate the safety of combining dasatinib with reinduction chemotherapy comprised of
idarubicin, fludarabine and cytarabine (Ida - FLU/Ara) in children with relapsed or
refractory core binding factor acute myeloid leukemia (CBF AML)

- To characterize the toxicity profile of this combination in pediatric patients with
relapsed or refractory CBF AML

Secondary Objectives of this study are:

- To estimate the response rates to the combination chemotherapy in the context of a Phase
I study, in children with AML in first or greater relapse or refractory to induction
chemotherapy

- To determine the genotype of c-KIT exons 8 and 17 and correlate with response rate

- To characterize c-KIT expression of bone marrow blasts at study entry and at the end of
course 1 of therapy and describe any correlation with response to therapy

Exploratory Objectives are:

- To investigate descriptively the pharmacodynamic modulation of c-KIT target, Stat3, in a
cell line by patient-derived plasma

- To perform RNA sequencing on bone marrow samples at study entry in order to describe the
prevalence of mutations in AML associated genes, including c-KIT, and correlate
descriptively with progression free survival

- To collect biology specimens at study entry and completion of therapy for future biology
studies

Inclusion Criteria:

- Histologically confirmed relapsed or refractory Acute Myeloid Leukemia (AML) and meet
the following criteria: Relapsed disease is defined as AML in 1st or greater marrow
relapse; Refractory disease is defined as AML which failed to go into remission after
1st or greater relapse, OR AML which failed to go into remission after two or more
induction attempts from original diagnosis

- ≥ 5% blasts by morphology in the bone marrow or molecular evidence of at least 0.1%
leukemic blasts in the bone marrow

- Definitive evidence of t(8;21) or inv(16) by a CLIA approved cytogenetics laboratory
from initial diagnosis

- CNS or other sites of extramedullary disease. No cranial irradiation is allowed during
the protocol therapy

- Lansky ≥ 50 for patients ≤ 16 years old; Karnofsky ≥ 50 for patients > 16 years old

- Have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiation therapy prior to entering this study

- Have adequate renal and hepatic functions

- A shortening fraction greater than or equal to 27% by echocardiogram, OR ejection
fraction greater than or equal to 50% by radionuclide angiogram (MUGA)

- Must not have any evidence of dyspnea at rest, exercise intolerance, and must have a
pulse oximetry > 94% at sea level

- Patients with a seizure disorder may be enrolled if well controlled on anticonvulsants
at a dose that has been stable for at least 14 days

- Female participants of childbearing potential must have a negative urine or serum
pregnancy test confirmed within 24 hours prior to enrollment

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

- Male and female participants 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:

- Known allergy to any of the drugs used in the study

- Systemic fungal, bacterial, viral or other infection of which they exhibit ongoing
signs/symptoms related to the infection without improvement despite appropriate
antibiotics or other treatment

- Any clinically significant cardiovascular disease including: myocardial infarction or
ventricular tachyarrhythmia within 6 months, prolonged QTc > 480 msec by the
Fridericia correction, major conduction abnormality, such as 2nd or 3rd degree heart
block or symptomatic bundle branch block, unless a cardiac pacemaker is present

- Plans to administer non-protocol chemotherapy, radiation therapy, or immunotherapy
during the study period

- Refractory to red blood cell or platelet transfusions

- Receiving anti-coagulation therapy

- A need to administer drugs that inhibit platelet function, such as aspirin or
clopidogrel

- Receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin,
clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St.
John's Wort

- Significant concurrent disease, illness, psychiatric disorder or social issue that
would compromise patient safety or compliance with the protocol treatment or
procedures, interfere with consent, study participation, follow up, or interpretation
of study results

- Individuals with Down syndrome and DNA fragility syndromes (such as Fanconi anemia,
Bloom syndrome)