Overview

This trial is active, not recruiting.

Conditions acute undifferentiated leukemia, t-cell childhood acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia
Treatments vincristine sulfate, daunorubicin hydrochloride, cyclophosphamide, pegaspargase, asparaginase, prednisone, methylprednisolone, dexamethasone, cytarabine, methotrexate, therapeutic hydrocortisone, filgrastim, leucovorin calcium, etoposide, mercaptopurine, lestaurtinib, laboratory biomarker analysis, pharmacological study
Phase phase 3
Targets FLT-3, JAK2, JAK3, TRKA
Sponsor Children's Oncology Group
Collaborator National Cancer Institute (NCI)
Start date January 2008
End date September 2018
Trial size 242 participants
Trial identifier NCT00557193, AALL0631, CDR0000573996, COG-AALL0631, NCI-2009-00313, U10CA098543, U10CA180886

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
See Detailed Description
vincristine sulfate leurocristine sulfate
Given IV
daunorubicin hydrochloride Cerubidin
Given IV
cyclophosphamide CPM
Given IV
pegaspargase L-asparaginase with polyethylene glycol
Given IM
asparaginase ASNase
Given IV, IM, or PO
prednisone DeCortin
Given PO
methylprednisolone Depo-Medrol
Given IV
dexamethasone Aeroseb-Dex
Given IV or PO
cytarabine ARA-C
Given IV or IT
methotrexate amethopterin
Given IV, IT, or PO
therapeutic hydrocortisone Aeroseb-HC
Given IT
filgrastim G-CSF
Given IV or SC
leucovorin calcium CF
Given IV
etoposide EPEG
Given IV
mercaptopurine 6-mercaptopurine
Given PO
laboratory biomarker analysis
Correlative studies
pharmacological study pharmacological studies
Correlative studies
(Active Comparator)
See Detailed Description
vincristine sulfate leurocristine sulfate
Given IV
daunorubicin hydrochloride Cerubidin
Given IV
cyclophosphamide CPM
Given IV
pegaspargase L-asparaginase with polyethylene glycol
Given IM
asparaginase ASNase
Given IV, IM, or PO
prednisone DeCortin
Given PO
methylprednisolone Depo-Medrol
Given IV
dexamethasone Aeroseb-Dex
Given IV or PO
cytarabine ARA-C
Given IV or IT
methotrexate amethopterin
Given IV, IT, or PO
therapeutic hydrocortisone Aeroseb-HC
Given IT
filgrastim G-CSF
Given IV or SC
leucovorin calcium CF
Given IV
etoposide EPEG
Given IV
mercaptopurine 6-mercaptopurine
Given PO
laboratory biomarker analysis
Correlative studies
pharmacological study pharmacological studies
Correlative studies
(Experimental)
See Detailed Description
vincristine sulfate leurocristine sulfate
Given IV
daunorubicin hydrochloride Cerubidin
Given IV
cyclophosphamide CPM
Given IV
pegaspargase L-asparaginase with polyethylene glycol
Given IM
asparaginase ASNase
Given IV, IM, or PO
prednisone DeCortin
Given PO
methylprednisolone Depo-Medrol
Given IV
dexamethasone Aeroseb-Dex
Given IV or PO
cytarabine ARA-C
Given IV or IT
methotrexate amethopterin
Given IV, IT, or PO
therapeutic hydrocortisone Aeroseb-HC
Given IT
filgrastim G-CSF
Given IV or SC
leucovorin calcium CF
Given IV
etoposide EPEG
Given IV
mercaptopurine 6-mercaptopurine
Given PO
lestaurtinib CEP 701
Given PO
laboratory biomarker analysis
Correlative studies
pharmacological study pharmacological studies
Correlative studies

Primary Outcomes

Measure
Lestaurtinib-related dose limiting toxicity as graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 12 weeks
Event-free survival (EFS) of MLL-R infants randomized to combination chemotherapy with or without lestaurtinib
time frame: At 3 years
EFS of patients treated on Arm C
time frame: At 3 years

Secondary Outcomes

Measure
EFS
time frame: At 3 years
Incidence of grade 3/4 non-hematologic adverse events as assessed by the NCI CTCAE version 4.0
time frame: Up to 11 years
Incidence of toxic death
time frame: Up to 11 years
Proportion of infants who received prophylactic treatment for prevention of fungal infections
time frame: Up to 11 years
Minimal residual disease (MRD) assessed by multiparameter flow cytometry and by quantitative reverse transcriptase-polymerase chain reaction
time frame: Up to 11 years

Eligibility Criteria

Male or female participants up to 1 year old.

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

Additional Information

Official title 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; NSC#617807)
Principal investigator Joanne Hilden, MD
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). 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.
Trial information was received from ClinicalTrials.gov and was last updated in September 2015.
Information provided to ClinicalTrials.gov by Children's Oncology Group.