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

Phase 3

Completed

Conditions: Acute Undifferentiated Leukemia
Acute Lymphoblastic Leukemia
Childhood T Acute Lymphoblastic Leukemia

Interventions: Drug: Asparaginase
Procedure: Biospecimen Collection
Procedure: Bone Marrow Biopsy
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Dexamethasone
Procedure: Echocardiography
Drug: Etoposide
Biological: Filgrastim
Other: Laboratory Biomarker Analysis
Drug: Leucovorin Calcium
Drug: Lestaurtinib
Drug: Mercaptopurine
Drug: Methotrexate
Drug: Methylprednisolone
Procedure: Multigated Acquisition Scan
Drug: Pegaspargase
Other: Pharmacological Study
Drug: Prednisone
Drug: Therapeutic Hydrocortisone
Drug: Vincristine Sulfate

Registration Number: NCT00557193

Lead Sponsor: Children's Oncology Group

Brief Summary: This phase III trial studies combination chemotherapy with or without lestaurtinib with to see how well they work in treating younger patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of stop cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without lestaurtinib in treating acute lymphoblastic leukemia.

Detailed Description: 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). Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), blood sample collection and bone marrow biopsy on day 1 week 1.

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. Patients may undergo bone marrow biopsy on day 1 week 6.

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. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10.

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. Patients may undergo bone marrow biopsy on day 1 week 20.

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 Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 6. (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. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10. (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. Patients may undergo bone marrow biopsy on day 1 of weeks 20, 33 and 46. (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.Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 6.

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. Patients undergo ECHO or MUGA, blood sample collection and bone marrow biopsy on day 1 week 10.

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. Patients may undergo bone marrow biopsy on day 1 of weeks 20, 33 and 46.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 218

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B (IR/HR MLL-R chemotherapy)	Daunorubicin Hydrochloride	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm A (standard risk MLL-G)	Vincristine Sulfate	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Therapeutic Hydrocortisone	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Biospecimen Collection	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Bone Marrow Biopsy	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Laboratory Biomarker Analysis	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Vincristine Sulfate	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm A (standard risk MLL-G)	Daunorubicin Hydrochloride	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Filgrastim	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Leucovorin Calcium	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Echocardiography	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Pharmacological Study	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm B (IR/HR MLL-R chemotherapy)	Biospecimen Collection	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Bone Marrow Biopsy	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Biospecimen Collection	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm A (standard risk MLL-G)	Multigated Acquisition Scan	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm B (IR/HR MLL-R chemotherapy)	Filgrastim	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Vincristine Sulfate	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Laboratory Biomarker Analysis	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Echocardiography	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Leucovorin Calcium	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Multigated Acquisition Scan	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Pharmacological Study	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Filgrastim	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Therapeutic Hydrocortisone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Leucovorin Calcium	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Pharmacological Study	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Therapeutic Hydrocortisone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Bone Marrow Biopsy	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Echocardiography	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Multigated Acquisition Scan	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Laboratory Biomarker Analysis	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Daunorubicin Hydrochloride	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm A (standard risk MLL-G)	Asparaginase	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Cyclophosphamide	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Cytarabine	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Mercaptopurine	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Dexamethasone	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Etoposide	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Methotrexate	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Pegaspargase	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm A (standard risk MLL-G)	Prednisone	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm B (IR/HR MLL-R chemotherapy)	Asparaginase	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Cyclophosphamide	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Cytarabine	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Dexamethasone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Etoposide	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Mercaptopurine	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Methotrexate	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Pegaspargase	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm B (IR/HR MLL-R chemotherapy)	Prednisone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Asparaginase	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Cytarabine	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Dexamethasone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Cyclophosphamide	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Etoposide	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Lestaurtinib	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Methotrexate	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Mercaptopurine	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Pegaspargase	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Prednisone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm A (standard risk MLL-G)	Methylprednisolone	Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Arm B (IR/HR MLL-R chemotherapy)	Methylprednisolone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.
Arm C (IR/HR MLL-R chemotherapy and lestaurtinib)	Methylprednisolone	Population Description: Eligible patients with MLL-R (rearranged). Considered Intermediate Risk (IR) if age \>= 90 days at diagnosis and High Risk (HR) if age \< 90 days at diagnosis.

Primary Outcome Measures

Name	Time	Method
Percent Probability for Event-free Survival (EFS) for Patients on Arm C at Dose Level 2 (DL2)	From start of post-induction therapy for up to 10 years	EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. EFS is constructed using the Kaplan-Meier life table method with confidence interval based on standard errors computed using the method of Peto and Peto.

Secondary Outcome Measures

Name	Time	Method
Identification of Gene Expression Patterns in Diagnostic Infant Leukemia Samples That Correlate With PIA Values	At 3 years	Means and standard deviations of Plasma Inhibitory Activity (PIA) will be given by genotype
Percent Probability for Event-free Survival (EFS) of MLL-R Infants Treated With Combination Chemotherapy With or Without Lestaurtinib at DL2	From start of post-induction therapy for up to 10 years.	Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. EFS is constructed using the Kaplan-Meier life table method with confidence interval based on standard errors computed using the method of Peto and Peto. EFS will be compared between patients on treatment Arm C at DL2 to those on Arm B.
Number of Patients Who Experienced Lestaurtinib-related Dose Limiting Toxicity (DLT)	Up to 12 weeks from start of induction	Lestaurtinib-related dose-limiting toxicity proportions, as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, will by summarized by dose level for Safety phase patients.
Describe FLT3 Protein Expression as a Molecular Mechanism of Acquired Resistance to Lestaurtinib in Leukemic Blasts	At relapse (up to 3 years)	Described via means and standard deviations in available Arm C relapse samples
Describe in Vitro Sensitivity as a Molecular Mechanism of Acquired Resistance to Lestaurtinib in Leukemic Blasts	At relapse (up to 3 years)	Described via means and standard deviations in samples which have acquired resistance to lestaurtinib
Pharmacokinetic AGP Levels in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy	Up to 12 weeks	Pharmacokinetic AGP levels in infants given lestaurtinib at DL2 in combination with chemotherapy will be described with mean and standard deviation for those with available data.
Describe FLT3 Protein Expression as a Molecular Mechanism of Primary Resistance to Lestaurtinib in Leukemic Blasts	Sampled at the start of induction	Described via mean and standard deviation by group.
Describe in Vitro Sensitivity as a Molecular Mechanism of Primary Resistance to Lestaurtinib in Leukemic Blasts	Sampled at the start of induction	Described via means and standard deviations in samples which have primary resistance to lestaurtinib
Percent Probability of Event Free Survival (EFS) by MRD Status and Treatment Arm	3 Years from end of Induction)	Three-year EFS estimates and 90% CI will be reported by treatment arm and end-induction MRD status.
Identification of Gene Expression Patterns in Diagnostic Infant Leukemia Samples That Correlate With Survival Outcomes	At 3 years	EFS outcomes will be reported by genotype.
Percent Probability for Event-free Survival (EFS) for Patients on Arm A	From start of post-induction therapy for up to 10 years	EFS time is defined as time from treatment assignment to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. EFS is constructed using the Kaplan-Meier life table method with confidence interval based on standard errors computed using the method of Peto and Peto.
Pharmacokinetic Albumin in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy	Up to 12 weeks	Pharmacokinetic albumin in infants given lestaurtinib at DL2 in combination with chemotherapy will be described with mean and standard deviation for those with available data.
Pharmacodynamics PIA Levels in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy	Sampled between weeks 6-12 from start of induction	Summarized with mean and standard deviation for those with available data in Arm C

Trial Locations

Locations (170): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
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Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States