Dasatinib and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine the feasibility and toxicity of an intensified chemotherapeutic regimen that
incorporates dasatinib for treatment of children, adolescents, and young adults (up to age
30) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).

II. To determine whether the intensification of tyrosine kinase inhibition through the
addition of dasatinib in Induction (Days 15-28) and substitution of dasatinib for imatinib
during post-Induction therapy, in the context of intensive cytotoxic therapy (according to
AALL0031) and a good early response to therapy, will lead to a 3-year event-free survival
(EFS) of at least 60% in patients with Ph+ ALL.

SECONDARY OBJECTIVES:

I. To determine whether the addition of dasatinib during Induction therapy (Days 15-28) will
decrease levels of minimal residual disease (MRD) present at end of Induction therapy as
compared with COG AALL0031.

II. To determine whether early intensified tyrosine kinase inhibitor (TKI) therapy will
lower end-Consolidation MRD levels as compared to patients on COG AALL0031 that received
imatinib in Consolidation Blocks 1 and 2 (Cohorts 3-5).

III. To determine the overall 3-year EFS rate for the whole cohort of Standard- and
High-Risk patients treated with dasatinib.

IV. To determine the long-term effects of dasatinib on growth, development, and bone
metabolism.

V. To assess BCR-ABL mutation status at time of diagnosis and progression/relapse.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (standard
risk vs high risk) at the end of consolidation therapy.

INDUCTION THERAPY (weeks 1-4): Patients receive initial induction therapy on days 1-14 prior
to beginning the study. Patients then receive vincristine intravenously (IV) and
daunorubicin hydrochloride* IV over 15 minutes on days 15 and 22; dasatinib orally (PO) once
daily (QD) and prednisone PO (or methylprednisolone IV) twice daily (BID) on days 15-28;
methotrexate intrathecally (IT) on day 29; and some patients receive methotrexate,
hydrocortisone, and cytarabine IT on days 15 and 22. After completion of induction therapy,
patients undergo bone marrow aspiration for evaluation of disease. Patients with M1 bone
marrow and minimal residual disease (MRD) < 1% (standard-risk disease) proceed to block 1
consolidation therapy 1 week after completion of induction therapy or when blood counts
recover (whichever occurs later). Patients with M2 or M3 bone marrow or MRD >= 1% (high-risk
disease) proceed immediately to block 1 consolidation therapy, regardless of blood counts.
Patients with clinically evident or biopsy-proven testicular leukemia at diagnosis that
persists at the end of induction therapy undergo 12 fractions of testicular radiotherapy
beginning within 4 days prior to starting block 1 consolidation therapy.

NOTE: *Patients who receive initial induction therapy on a DFCI Childhood ALL Consortium
trial do not receive daunorubicin hydrochloride during induction therapy on this study.

CONSOLIDATION THERAPY:

BLOCK 1 CONSOLIDATION THERAPY: (weeks 6-8) Patients receive etoposide IV over 1 hour and
ifosfamide IV over 1 hour on days 1-5, dasatinib PO on days 1-14 OR on days 1-21, and some
patients receive methotrexate, hydrocortisone, and cytarabine IT on days 8 and 15. Patients
also receive filgrastim (G-CSF) subcutaneously (SC) or IV QD beginning on day 6 and
continuing until blood counts recover.

After completion of block 1 consolidation therapy, patients proceed to block 2 consolidation
therapy.

BLOCK 2 CONSOLIDATION THERAPY: (weeks 9-11) Patients receive high-dose methotrexate IV
continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses
on days 2-3; methotrexate, hydrocortisone, and cytarabine IT on day 1; cytarabine IV over 3
hours every 12 hours for 4 doses on days 2 and 3; and dasatinib PO on days 1-14 OR on days
1-21. Patients also receive G-CSF SC or IV QD beginning on day 4 and continuing until blood
counts recover. After completion of block 2 consolidation therapy and recovery of blood
counts, patients undergo bone marrow aspiration for evaluation of disease. Patients with MRD
< 0.01% (standard-risk disease) with a matched related donor and who are willing to undergo
hematopoietic stem cell transplantation (HSCT) proceed to HSCT off study. Standard-risk
patients without a suitable donor or those who elect not to undergo HSCT proceed to
post-consolidation therapy. Patients with MRD >= 0.01% (high-risk disease) with a matched
related or unrelated donor proceed to HSCT off study. High-risk patients without a suitable
donor proceed to post-consolidation therapy.

POST-CONSOLIDATION THERAPY:

REINDUCTION BLOCK 1 THERAPY: (weeks 12-14) Patients receive vincristine IV on days 1, 8, and
15; daunorubicin hydrochloride IV over 15 minutes on days 1 and 2; cyclophosphamide IV over
1 hour every 12 hours for 4 doses on days 3 and 4; pegaspargase intramuscularly (IM) on day
4; methotrexate, hydrocortisone, and cytarabine IT on days 1 and 15; dexamethasone PO or IV
BID on days 1-7 and 15-21; and dasatinib PO on days 1-14 OR on days 1-21. Patients also
receive G-CSF SC or IV QD beginning on day 5 and continuing until blood counts recover.

After completion of reinduction block 1 therapy, patients proceed to intensification block 1
therapy.

INTENSIFICATION BLOCK 1 THERAPY: (weeks 15-23) Patients receive high-dose methotrexate IV
continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses
on days 2-3; methotrexate, hydrocortisone, and cytarabine IT on days 1 and 22; etoposide IV
over 1 hour and cyclophosphamide IV over 1 hour on days 22-26; cytarabine IV over 3 hours
every 12 hours for 4 doses on days 43 and 44; asparaginase IM on day 44; and dasatinib PO on
days 1-14, 22-35, and 43-56 OR on days 1-63. Patients also receive G-CSF SC or IV QD
beginning on day 27 and continuing until blood counts recover. After completion of
intensification block 1 therapy, patients proceed to reinduction block 2 therapy.

REINDUCTION BLOCK 2 THERAPY: (weeks 24-26) Patients receive reinduction block 2 therapy as
per reinduction block 1 therapy. After completion of reinduction block 2 therapy, patients
proceed to intensification block 2 therapy.

INTENSIFICATION BLOCK 2 THERAPY: (weeks 27-35) Patients receive intensification block 2
therapy as per intensification block 1 therapy. After completion of intensification block 2
therapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY:

MAINTENANCE COURSES 1-4: (weeks 36-67) Patients receive high-dose methotrexate IV
continuously over 24 hours on day 1; leucovorin calcium PO or IV every 6 hours for 3 doses
on days 2-3; methotrexate, hydrocortisone, and cytarabine IT and vincristine IV on days 1
and 29; prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 8-28;
methotrexate PO on days 8, 15, and 22; etoposide IV over 1 hour and cyclophosphamide IV over
1 hour on days 29-33; and dasatinib PO on days 1-14 and 29-42 OR on days 1-56. Patients also
receive G-CSF SC or IV QD beginning on day 34 and continuing until blood counts recover.
Courses repeat every 56 days. After completion of maintenance courses 1-4, patients proceed
to maintenance course 5.

MAINTENANCE COURSE 5: (weeks 68-75) Patients receive vincristine IV on days 1 and 29;
prednisone PO or IV BID on maintenance courses 6-12.

MAINTENANCE COURSES 6-12: (weeks 76-131) Patients receive vincristine IV on days 1 and 29;
prednisone PO or IV BID on days 1-5 and 29-33; mercaptopurine PO on days 1-56; methotrexate
PO on days 1, 8, 15, 22, 29, 36, 43, and 50; and dasatinib PO on days 1-14 and 29-42 OR on
days 1-56.

Courses repeat every 56 days. Patients long-term growth, development, and bone metabolism
are assessed after completion of study therapy and then annually for 5 years.

After completion of study therapy, patients are followed up periodically for up to 10 years.

Inclusion Criteria:

- Newly diagnosed acute lymphoblastic leukemia (ALL)

- Definitive evidence of BCR-ABL fusion (Philadelphia chromosome positive [PH+])
from an approved Children's Oncology Group (COG) cytogenetics laboratory

- Meets one of the following criteria:

- Concurrent enrollment on Clusters of Orthologous Groups (COG)-AALL03B1 (or a
successor trial) AND COG-AALL0232, COG-AALL0331, COG-AALL0434 or other
front-line COG ALL clinical trial

- Concurrent enrollment on COG-AALL03B1 (or a successor trial) AND scheduled to
receive a 3 or 4-drug standard induction regimen

- Concurrent enrollment on a Dana-Farber Cancer Institute (DFCI) Childhood ALL
Consortium trial (or scheduled to be treated as per a DFCI Childhood ALL
Consortium induction regimen)

- All patients must have definitive evidence of BCR-ABL fusion from an approved COG
cytogenetics laboratory; patients may NOT have received Day 15 of Induction
chemotherapy (or day 18 vincristine if enrolled on a DFCI Childhood ALL Consortium
trial) prior to enrollment on AALL0622

- Patients must have a performance status of 0, 1 or 2 at completion of two weeks of
Induction; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16
years of age

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >=
70mL/min/1.73 m^2 or maximum serum creatinine based on age and gender as follows:

- 0.4 mg/dL (for patients 1 to 5 months of age)

- 0.5 mg/dL (for patients 6 to 11 months of age)

- 0.6 mg/dL (for patients 1 year of age)

- 0.8 mg/dL (for patients 2 to 5 years of age)

- 1.0 mg/dL (for patients 6 to 9 years of age)

- 1.2 mg/dL (for patients 10 to 12 years of age)

- 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)

- 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients >= 16 years of age)

- Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5
times ULN for age

- Shortening fraction >= 27% by echocardiogram or ejection fraction >= 50% by gated
radionuclide study

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94%
at sea level if there is clinical indication for determination

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine,
phenytoin, primidone, phenobarbital) should be avoided

- Patients will start AALL0622 therapy on day 15 of induction therapy (or day 18 if
enrolled on a DFCI Childhood ALL Consortium trial); patients must have received the
first 2 weeks of Induction therapy

Exclusion Criteria:

- Females of childbearing potential must have a negative pregnancy test; patients of
childbearing potential must agree to use an effective birth control method

- Female patients who are lactating must agree to stop breast-feeding

- Patients with Down syndrome

- Patients with any clinically significant cardiovascular disease including the
following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Ejection fraction less than institutional normal

- Major conduction abnormality (unless a cardiac pacemaker is present)