AALL0631: 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)


all patients will be treated with a common 5 week induction course after enrollment. Based on age at diagnosis and MLL gene rearrangement status, patients will be stratified into risk groups as follows:
Standard Risk (SR): MLL-G (germline, or non-rearranged)
intermediate Risk (iR): MLL-R (rearranged), age [GreaterThanorequalTo] 90 days at diagnosis
High Risk (HR): MLL-R, age [Less Than] 90 days at diagnosis

SR patients will be non-randomly assigned to receive chemotherapy alone. There will be some patients for whom MLL status is indeterminate. These patients are to be taken off study.

During the initial safety/activity phase, iR and HR patients who enroll during periods where lestaurtinib is unavailable due to toxicity evaluations will receive chemotherapy alone. iR and HR patients enrolled at this institution will be assigned to receive a combination of chemotherapy and lestaurtinib. The safety/activity phase will be done separately and independently for iR and HR patients.

The dose for each new group of patients will be gradually increased or decreased from the dose of the previous group until a dose is found that is safe and is able to turn off the FLT3 gene.
Dosing for lestaurtinib will be based upon dose levels indicated in the protocol.

Patients in all the risk groups will receive standard combination chemotherapy with the following changes:
1. The last block of treatment called Continuation therapy will be extended, increasing the total duration of therapy from 1 year to 2 years.
2. The new form (PeG-asparaginase) will replace the older form (L-asparaginase) during stages of therapy given after induction (called 'Post-induction Therapy'). PeG-asparaginase is a standard drug for treating all children with aLL.
3. Two additional 3-day cycles of chemotherapy will be added to the Continuation block of standard therapy. These 2 cycles include 2 drugs, cytarabine and PeG-asparaginase, that are commonly used to treat leukemia in children and adults.

When the safety/activity phase identifies a dose of lestaurtinib that is safe, tolerable and biologically active for the iR and HR arms, then the study will proceed to an efficacy phase for that arm. During the efficacy phase, iR and HR patients enrolled at institutions in the uS and Canada will non-randomly be assigned to receive a combination of chemotherapy and lestaurtinib (at the dose identified in the safety/activity phase).

We plan to enroll five subjects on this study locally. a maximum of 244 patients are anticipated to be enrolled from all participating CoG sites within 5 years. a subject is expected to receive therapy for two years. We would like to continue to find out about the subject's health after he/she completes this study. We plan to keep in touch with the subject and check on how he/she is doing, the status of his/her tumor and if he/she had serious medical complications, every year for 10 years after the last subject starts the study.

Treatment Plan as of amendment #5:
all iR and HR patients will be non-randomly assigned to receive intensified standard combination chemotherapy PLuS the experimental drug lestaurtinib (arm C). iR patients will receive lestaurtinib at 5 mg/kg/day. HR patients will receive lestaurtinib at 4.25 mg/kg/day.

Revised efficacy Phase as of amendment #5:
iR and HR patients (at institutions in the uS and Canada) will be eligible for the lestaurtinib efficacy phase. Patients will be nonrandomly assigned to post-induction therapy with chemotherapy plus lestaurtinib.

arm C Continuation ii updates:
Lestaurtinib will no longer be administered with Continuation ii therapy as of amendment #5. all newly enrolled patients and patients that have not yet reached Continuation ii will cease lestaurtinib treatment following Continuation i. Patients currently receiving Continuation ii as of amendment #5 will cease lestaurtinib as of the activation of the amendment.[Quote]

Participant Eligibility

Patients must be enrolled on AALL08B1 (IRB File# STU 092010-005, AALL08B1: Classification of Newly Diagnosed Acute Lymphoblastic Leukemia, This study provides an administrative base to capture classification data for correlative studies accompanying current COG ALL treatment protocols and a central reference guide for all required and research only studies that will be conducted at local and reference laboratories for all newly diagnosed patients with ALL, as well as provides a mechanism for optional banking of leukemia and germline specimens for current and future research.) prior to enrollment on AALL0631. Patients must be < 366 days of age at the time of diagnosis; for neonates in the first month of life, patients must be > 36 weeks gestational age at the time of diagnosis. 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 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 pretreawtment will not affect initial Induction assignment as long as the patient meets all other eligibility criteria. All patient[Single Quote]s parents or legal guardians must sign a written informed consent. All institutional, FDA, and NCI requirements for human studies must be met.