Trial Information

A Phase III Study of Risk Directed Therapy for Infants With Acute Lymphoblastic Leukemia (ALL): Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib; IND#76431; NSC#617807)

OBJECTIVES:

Primary

- To compare the 3-year event-free survival of infants with mixed lineage leukemia
rearranged (MLL-R) acute lymphoblastic leukemia (ALL) randomized to treatment with a
modified P9407 chemotherapy backbone with or without the FLT3 inhibitor lestaurtinib.

Secondary

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

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

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

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

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

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

OUTLINE: Patients are stratified according to risk group (standard risk [MLL-G: germline or
non-rearranged] vs intermediate risk [MLL-R: rearranged, age ≥ 90 days at diagnosis] vs high
risk [MLL-R, age < 90 days at diagnosis]).

All patients receive induction therapy (weeks 1-5) comprising vincristine IV 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; pegaspargase intramuscularly (IM) on days
15, 18, 22, 25, 29, and 33; oral prednisone or methylprednisolone IV three times daily (TID)
on days 1-7; dexamethasone IV or orally TID on days 8-28; cytarabine IV over 30 minutes on
days 8-21; triple intrathecal (IT) chemotherapy comprising methotrexate, cytarabine, and
hydrocortisone on days 1, 15, and 29; and filgrastim IV or subcutaneously (SC) beginning on
day 5 and continuing until blood counts recover.

Standard-risk patients are nonrandomly assigned to receive a less-intensive chemotherapy
regimen without lestaurtinib (post-induction therapy A).

- Post-induction therapy A (for standard-risk patients [MLL-G]):

- Induction intensification (weeks 6-9): Patients receive high-dose methotrexate IV
continuously over 24 hours on days 1 and 8; triple IT chemotherapy 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 μM; 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 IV 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 IM on day 4;
dexamethasone IV or orally twice daily on days 1-7 and 15-21; triple IT
chemotherapy 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 μM; triple IT chemotherapy 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 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 IV on day 1 in weeks 20
and 24; dexamethasone IV or orally twice daily on days 1-5 in weeks 20 and 24;
triple IT chemotherapy on day 1 in weeks 20 and 24; methotrexate IV on day 1 in
weeks 21-23 and 25-27; etoposide IV over 2 hours on days 1-5 in week 28;
cyclophosphamide IV over 30 minutes on days 1-5 in week 28; oral mercaptopurine 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. This course is repeated in
weeks 31-41.

- Continuation II (weeks 42-104): Patients receive vincristine IV on days 1, 29, and
57; dexamethasone IV or orally twice daily on days 1-5, 29-33, and 57-61;
intrathecal methotrexate (IT MTX) on day 1; oral methotrexate on days 8, 15, 22,
36, 43, 50, 64, 71, and 78; and oral mercaptopurine 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 P9407-based 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 (efficacy phase began on 01/28/2011), where they are randomized
to P9407-based chemotherapy backbone with or without lestaurtinib. HR patients separately
proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR
stratum (efficacy phase began on 02/03/2012). IR and HR patients are randomized 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.

- Re-induction (weeks 10-12): Patients receive vincristine, daunorubicin
hydrochloride, cyclophosphamide, pegaspargase, dexamethasone, triple IT
chemotherapy, and filgrastim as in post-induction therapy A re-induction.

- Consolidation (weeks 13-19): Patients receive high-dose methotrexate, leucovorin
calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose
cytarabine, pegaspargase, and filgrastim as in post-induction therapy A
consolidation.

- Continuation I (weeks 20-49): Patients receive vincristine on day 1 in weeks 20,
24, 33, 37, and 46; dexamethasone orally or IV twice daily 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; oral
mercaptopurine 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 30 minutes 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 IM on day 2 in week 30; and filgrastim SC or IV beginning on
day 3 in week 30 and continuing until blood counts recover.

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

- 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 oral
lestaurtinib twice daily on days 20-27. Patients in morphologic remission proceed
to re-induction.

- Re-induction (weeks 10-12): Patients receive vincristine, daunorubicin
hydrochloride, cyclophosphamide, pegaspargase, dexamethasone, triple IT
chemotherapy, and filgrastim as in post-induction therapy B re-induction. Patients
also receive oral lestaurtinib on days 5-20.

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

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

- Continuation II (weeks 50-104): Patients receive vincristine, dexamethasone, IT
methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction
therapy B continuation II. Patients also receive lestaurtinib on days 2-6, 30-34,
and 58-62. Treatment repeats every 12 weeks for 2 years from diagnosis.

Blood samples are collected periodically for pharmacokinetic studies and plasma inhibitory
activity assay.

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