Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To compare disease-free survival (DFS) of standard risk pediatric Philadelphia chromosome
(Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib)
combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or
the more intensive European (Es)PhALL chemotherapy backbone.

SECONDARY OBJECTIVES:

I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic
stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

II. To determine event-free survival (EFS) of high risk pediatric Ph+ ALL patients treated
with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

III. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients
between the two randomized arms.

IV. To evaluate event free survival (EFS) and overall survival (OS) of all enrolled
participants.

V. To evaluate OS in SR patients. VI. To evaluate OS in high risk (HR) patients.

TERTIARY OBJECTIVES:

I. To describe the toxicities associated with post-HSCT administration of imatinib.

II. To evaluate the long-term toxicities in SR patients treated with chemotherapy plus
imatinib (no transplant), overall and between both randomized arms.

III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at
various time points during therapy.

IV. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT
and explore the association of these measurements with long-term outcome.

V. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase
chain reaction (PCR) assay and next generation sequencing (NGS) assays.

VI. To determine prognostic significance of IKZF1 gene aberrations and deletions.

VII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion
variants in pediatric Ph+ ALL.

VIII. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and
methotrexate) during the maintenance phase in SR Ph+ ALL patients.

IX. To identify factors associated with poor adherence. X. To determine association between
relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

XI. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and
identify factors associated with poor adherence.

OUTLINE:

INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days
1-14.

INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice
daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone
intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22,
daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate
intrathecally (IT) on day 29.

INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide
IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or
subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and
22.

POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients
with high risk are assigned to Arm C.

ARM A:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21,
methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6,
dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4,
leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and
pegaspargase IV over 1-2 hours on day 5, and filgrastim SC on days 7-11 in the absence of
disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21,
methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine
sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin
calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and
daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours on
day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected
toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high
dose cytarabine IV over 3 hours on days 1-2, dexamethasone PO BID or IV on days 1-5,
etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic
hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on
days 7-11 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days
1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in
the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63,
cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28,
methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence
of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days
1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in
the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49,
cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV
over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the
absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO
once weekly (QW) and IT on days 1 and 43 of courses 1, 2, and 3, and mercaptopurine PO on
days 1-84. Courses with imatinib mesylate and mercaptopurine repeat every 84 days for up to
104 weeks from the start of Induction IA in the absence of disease progression or unexpected
toxicity.

ARM B:

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63,
vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1,
15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46,
mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of
disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28,
methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine
sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV
over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours on day 4 in the
absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56,
cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV
over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36,
vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours on
day 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or
BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes
on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2
hours on days 2 and 22 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine
sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV
for course 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84,
methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for course 1 and 2). Courses
repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of
disease progression or unexpected toxicity.

ARM C:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine,
therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone,
leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1,
and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine,
therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate,
ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride,
pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease
progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide,
methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm
A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence
of disease progression or unexpected toxicity.

HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed
Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm
A.

POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in
the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every year for 3 years.

Inclusion Criteria:

- For patients enrolled on AALL08B1 or APEC14B1 (if open for ALL patients) prior to
enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled

- For patients who have not previously enrolled on AALL08B1 or APEC14B1 (if open
for ALL patients) prior to enrollment on AALL1631, a baseline diagnostic sample
must be available to develop an MRD probe

- In addition, laboratory reports detailing evidence of BCR-ABL1 fusion must be
submitted for rapid central review within 72 hours of study enrollment

- Newly diagnosed de novo ALL (B-ALL or T-ALL) with definitive evidence of BCR-ABL1
fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse
transcriptase (RT)-PCR

- Patient must have previously started induction therapy, which includes vincristine, a
corticosteroid, pegaspargase, with or without anthracycline, and/or other standard
cytotoxic chemotherapy

- Patient has not received more than 14 days of multiagent induction therapy beginning
with the first dose of vinCRIStine

- Patient may have started imatinib prior to study entry but has not received more than
14 days of imatinib

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2

- Direct bilirubin =< 2.0 mg/dL

- Shortening fraction of >= 27% by echocardiogram

- Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram

- Corrected QT interval, QTc < 480 msec

- Note: Repeat echocardiogram is not required if echocardiogram was obtained within
21 days of study enrollment

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2

- Serum creatinine within normal limits based on age/gender, as follows:

- 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)

- 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)

- 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)

- 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)

- 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)

Exclusion Criteria:

- Known history of chronic myelogenous leukemia (CML)

- ALL developing after a previous cancer treated with cytotoxic chemotherapy

- Active, uncontrolled infection, or active systemic illness that requires ongoing
vasopressor support or mechanical ventilation

- Down syndrome

- Pregnancy and breast feeding

- Female patients who are pregnant; a pregnancy test is required for female
patients of childbearing potential

- Lactating females who plan to breastfeed their infants

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation

- Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart
block

- Prior treatment with dasatinib, or any BCR-ABL1 inhibitor other than imatinib

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met