Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
- Conditions
- Acute Undifferentiated LeukemiaAcute Lymphoblastic LeukemiaChildhood T Acute Lymphoblastic Leukemia
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow BiopsyProcedure: EchocardiographyBiological: FilgrastimOther: Laboratory Biomarker AnalysisProcedure: Multigated Acquisition ScanOther: Pharmacological Study
- 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
- 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
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
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.
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.
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 Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
Advocate Children's Hospital-Park Ridge
🇺🇸Park Ridge, Illinois, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
Lee Memorial Health System
🇺🇸Fort Myers, Florida, United States
Mercy Children's Hospital
🇺🇸Toledo, Ohio, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
Overlook Hospital
🇺🇸Summit, New Jersey, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸Oak Lawn, Illinois, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Saint Peter's University Hospital
🇺🇸New Brunswick, New Jersey, United States
Columbia Regional
🇺🇸Columbia, Missouri, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Greenville Cancer Treatment Center
🇺🇸Greenville, South Carolina, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
West Virginia University Charleston Division
🇺🇸Charleston, West Virginia, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
Texas Tech University Health Sciences Center-Amarillo
🇺🇸Amarillo, Texas, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Inova Fairfax Hospital
🇺🇸Falls Church, Virginia, United States
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
Madigan Army Medical Center
🇺🇸Tacoma, Washington, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, 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
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Tufts Children's Hospital
🇺🇸Boston, Massachusetts, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Hurley Medical Center
🇺🇸Flint, Michigan, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Kalamazoo Center for Medical Studies
🇺🇸Kalamazoo, Michigan, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
Children's Hospital
🇨🇦London, Ontario, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
Nevada Cancer Research Foundation NCORP
🇺🇸Las Vegas, Nevada, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
UCSF Medical Center-Parnassus
🇺🇸San Francisco, California, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
University of Rochester
🇺🇸Rochester, New York, United States
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Legacy Emanuel Hospital and Health Center
🇺🇸Portland, Oregon, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Nemours Children's Clinic - Pensacola
🇺🇸Pensacola, Florida, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Saint Mary's Hospital
🇺🇸West Palm Beach, Florida, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Nemours Children's Clinic - Orlando
🇺🇸Orlando, Florida, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Yale University
🇺🇸New Haven, Connecticut, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Tulane University School of Medicine
🇺🇸New Orleans, Louisiana, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Tripler Army Medical Center
🇺🇸Honolulu, Hawaii, United States
Children's Hospital New Orleans
🇺🇸New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States