Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To estimate the 3-year event-free survival (EFS) of infants with mixed lineage
leukemia-rearranged (MLL-R) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus
the fms-related tyrosine kinase 3 (FLT3) inhibitor lestaurtinib.

SECONDARY OBJECTIVES:

I. To compare the 3-year EFS of infants with MLL-R ALL treated with chemotherapy plus the
FLT3 inhibitor lestaurtinib to MLL-R patients treated with chemotherapy alone.

II. To determine a safe, tolerable and biologically active dose of lestaurtinib given in
sequential combination with chemotherapy in MLL-R infants.

III. To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants
when given at the proposed dose in sequential combination with chemotherapy.

IV. To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts.

V. To describe levels of minimal residual disease in infants with ALL within the context of
the proposed therapy, and correlate with outcome.

VI. To identify gene expression patterns in diagnostic infant leukemia samples that correlate
with outcome within the context of the proposed therapy.

VII. To describe the outcome of infants with MLL-G ALL treated with a modified P9407
chemotherapy backbone that includes an extended continuation phase.

OUTLINE:

INDUCTION THERAPY (WEEKS 1-5): All patients receive induction therapy comprising vincristine
sulfate intravenously (IV) over 1 minute on days 8, 15, 22, and 29; daunorubicin
hydrochloride IV over 30 minutes on days 8 and 9; cyclophosphamide IV over 30 minutes every
12 hours on days 3 and 4 (closed as of 05/19/09); pegaspargase or asparaginase
intramuscularly (IM) on days 15, 18, 22, 25, 29, and 33; prednisone orally (PO) thrice daily
(TID) or methylprednisolone IV on days 1-7; dexamethasone IV or PO TID on days 8-28;
cytarabine IV over 30 minutes on days 8-21; methotrexate intrathecally (IT) on days 1 and 29;
cytarabine IT on day 15; hydrocortisone IT on days 15 and 29; and filgrastim IV or
subcutaneously (SC) beginning on day 5 and continuing until blood counts recover.
Standard-risk patients are non-randomly assigned to receive a less intensive chemotherapy
regimen without lestaurtinib (post-induction therapy A).

POST-INDUCTION THERAPY A: (for standard-risk patients MLL-germline [G])

INDUCTION INTENSIFICATION (WEEKS 6-9): Patients receive high-dose methotrexate IV
continuously over 24 hours on days 1 and 8; triple IT chemotherapy comprising methotrexate,
cytarabine, and hydrocortisone on days 1 and 8; leucovorin calcium IV or PO every 6 hours
beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate
level is < 0.1 uM; cyclophosphamide IV over 30 minutes on days 15-19; etoposide IV over 2
hours on days 15-19; and filgrastim IV or SC beginning on day 20 and continuing until blood
counts recover. Patients in morphologic remission proceed to re-induction therapy.

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate IV over 1 minute on days 1,
8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV
over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase IM on day 4;
dexamethasone IV or PO twice daily (BID) on days 1-7 and 15-21; triple IT chemotherapy
comprising methotrexate, cytarabine, and hydrocortisone on days 1 and 15; and filgrastim IV
or SC beginning on day 5 and continuing until blood counts recover.

CONSOLIDATION (WEEKS 13-19): Patients receive high-dose methotrexate IV continuously over 24
hours on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of
high-dose methotrexate and continuing until methotrexate level is < 0.1 uM; triple IT
chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on day 1; etoposide IV
over 2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19; high-dose
cytarabine IV over 3 hours every 12 hours on days 29 and 30; pegaspargase or asparaginase IM
on day 30; and filgrastim IV or SC beginning on day 20 and day 31 and continuing until blood
counts recover.

CONTINUATION I (WEEKS 20-41): Patients receive vincristine sulfate IV on day 1 in weeks 20
and 24; dexamethasone IV or PO BID on days 1-5 in weeks 20, and 24; triple IT chemotherapy
comprising methotrexate, cytarabine, and hydrocortisone on day 1 in weeks 20 and 24;
methotrexate IV on day 1 in weeks 21-24 and 25-27; etoposide IV over 2 hours on day 1-5 in
week 28; cyclophosphamide IV over 30 minutes on days 1-5 in week 28; mercaptopurine PO on
days 1-7 in weeks 21-23 and 25-27; and filgrastim SC or IV beginning on day 6 in week 28 and
continuing until blood counts recover.

CONTINUATION II (WEEKS 42-104): Patients receive vincristine sulfate IV on days 1, 29, and
57; dexamethasone IV or PO BID on days 1-5, 29-33, and 57-61; methotrexate IT on day 1;
methotrexate PO on days 8, 15, 22, 36, 43, 50, 64, 71, and 78; and mercaptopurine PO on days
8-28, 36-56, and 64-84. Treatment repeats every 12 weeks for 2 years from diagnosis.

A safety/activity phase is conducted separately for the intermediate-risk (IR) and high-risk
(HR) patients to identify a safe, tolerable, and biologically active dose of lestaurtinib
combined with chemotherapy backbone. Once a tolerable/active dose of lestaurtinib has been
identified for IR patients, subsequent IR patients are eligible to proceed to an efficacy
phase, where they are randomized (or non-randomly assigned as of 7/16/2014) to chemotherapy
with or without lestaurtinib. HR patients separately proceed to the randomized efficacy phase
if a tolerable/active dose is identified for the HR stratum. IR and HR patients are
randomized (or non-randomly assigned as of 7/16/2014) to 1 of 2 post-induction therapy
regimens (post-induction therapy B or C).

POST-INDUCTION THERAPY B: (chemotherapy only for IR/HR patients classified as MLL-R; age >=
90 days at diagnosis):

INDUCTION INTENSIFICATION (WEEKS 6-9): Patients receive high-dose methotrexate, leucovorin
calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy A induction
intensification. Patients in morphologic remission proceed to re-induction. (Retired as of
7/16/2014)

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate, daunorubicin hydrochloride,
cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and
filgrastim as in post-induction therapy A re-induction. (Retired as of 7/16/2014)

CONSOLIDATION (WEEKS 13-19): Patients receive high-dose methotrexate, leucovorin calcium,
triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or
asparaginase, and filgrastim as in post-induction therapy A consolidation. (Retired as of
7/16/2014)

CONTINUATION I (WEEKS 20-49): Patients receive vincristine sulfate IV over 1 minute on day 1
in weeks 20, 24, 33, 37, and 46; dexamethasone PO or IV BID on days 1-5 in weeks 20, 24, 33,
37, and 46; triple IT chemotherapy on day 1 in weeks 20, 24, 33, 37, and 46; methotrexate IV
on day 1 in weeks 21-23, 25-26 and 37-45; mercaptopurine PO on days 1-7 in weeks 21-23, 25-26
and 37-45; etoposide IV over 2 hours on days 1-5 in week 27; cyclophosphamide IV over 2 hours
on days 1-5 in week 27: high-dose cytarabine IV over 3 hours every 12 hours on days 1 and 2
in week 30; pegaspargase or asparaginase IM on day 2 in week 30: and filgrastim SC or IV
beginning on day 3 in weeks 30 and continuing until blood counts recover. (Retired as of
7/16/2014)

CONTINUATION II (WEEKS 50-104): Patients receive vincristine sulfate, dexamethasone, IT
methotrexate, methotrexate PO, and mercaptopurine PO as in post-induction therapy A
continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis. (Retired as of
7/16/2014)

POST-INDUCTION THERAPY C: (chemotherapy and lestaurtinib for IR/HR patients classified as
MLL-R; age < 90 days at diagnosis)

INDUCTION INTENSIFICATION THERAPY (WEEKS 6-9): Patients receive high-dose methotrexate,
leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy
B induction intensification. Patients also receive lestaurtinib PO BID on days 20-27.
Patients in morphologic remission proceed to re-induction.

RE-INDUCTION (WEEKS 10-12): Patients receive vincristine sulfate, daunorubicin hydrochloride,
cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and
filgrastim as in post-induction therapy B re-induction. Patients also receive lestaurtinib PO
on days 5-20.

CONSOLIDATION (WEEKS 13-19) Patients receive high-dose methotrexate, leucovorin calcium,
triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or
asparaginase, and filgrastim as in post-induction therapy B consolidation. Patients also
receive lestaurtinib PO on days 20-27 and 31-42.

CONTINUATION I (WEEKS 20-49): Patients receive vincristine sulfate, dexamethasone, triple IT
chemotherapy, methotrexate, mercaptopurine, etoposide, high-dose cytarabine, pegaspargase or
asparaginase, and filgrastim as in post-induction therapy B continuation I. Patients also
receive lestaurtinib PO on days 2-6 in weeks 20 and 24; days 27-41 in weeks 27-29; days 45-56
in weeks 30-32.

CONTINUATION II (WEEKS 50-104): Patients receive vincristine sulfate, dexamethasone, IT
methotrexate, methotrexate PO, and mercaptopurine PO as in post-induction therapy B
continuation II. Treatment repeats every 12 weeks for 2 years from diagnosis.

After completion of study treatment, all patients are followed up every 1-6 months for 4
years and then annually thereafter.

Inclusion Criteria:

- Patients must be enrolled on a Children's Oncology Group (COG) ALL Classification
Study (AALL08B1) prior to enrollment on AALL0631

- Patients must be newly diagnosed with acute lymphoblastic leukemia (ALL) or acute
undifferentiated leukemia (AUL); patients with T-cell ALL are eligible; patients with
bilineage or biphenotypic acute leukemia are eligible, provided the morphology and
immunophenotype are predominately lymphoid

- Patients with mature B-cell ALL or acute myelogenous leukemia (AML) are NOT eligible

- Patients with Down syndrome are NOT eligible

- Patients must be previously untreated with the exception of steroids and intrathecal
chemotherapy; no other systemic chemotherapy may have been administered; patients
receiving prior steroid therapy are eligible for study; any amount of steroid
pretreatment will not affect initial induction assignment as long as the patient meets
all other eligibility criteria; IT chemotherapy per protocol is allowed for patient
convenience at the time of the diagnostic bone marrow or venous line placement to
avoid second lumbar puncture; (note: the central nervous system [CNS] status must be
determined based on a sample obtained prior to administration of any systemic or
intrathecal chemotherapy, except for steroid pretreatment); systemic chemotherapy must
begin within 72 hours of this IT therapy

- 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