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

Location:

Rochester, Minn.

Trial status:
Open for Enrollment
Why is this study being done?

PRIMARY OBJECTIVES: I. To compare the 3-year event-free survival (EFS) of infants with MLL-R ALL randomized to treatment with a modified P9407 and the Interfant-99 chemotherapy backbone with or without the FLT3 inhibitor lestaurtinib. SECONDARY OBJECTIVES: I. To determine a safe, tolerable and biologically active dose of lestaurtinib given in sequential combination with chemotherapy in MLL-R infants. II. To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants when given at the proposed dose in sequential combination with chemotherapy. III. To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts. IV. To describe levels of minimal residual disease in infants with ALL within the context of the proposed therapy, and correlate with outcome. V. To identify gene expression patterns in diagnostic infant leukemia samples that correlate with outcome within the context of the proposed therapy. VI. To describe the outcome of infants with MLL-G ALL treated with a modified P9407 chemotherapy backbone that includes an extended Continuation phase. OUTLINE: Patients are stratified according to risk group (standard risk [MLL-G: germline or non-rearranged] vs intermediate risk [MLL-R: rearranged, age ≥ 90 days at diagnosis] vs high risk [MLL-R, age < 90 days at diagnosis]). All patients receive induction therapy (weeks 1-5) comprising vincristine intravenously (IV) on days 8,15, 22, and 29; daunorubicin hydrochloride IV over 30 minutes on days 8 and 9; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4 (closed as of 05/19/09); pegaspargase or asparaginase intramuscularly (IM) on days 15, 18, 22, and 25; prednisone orally (PO) or methylprednisolone IV three times daily on days 1-7; dexamethasone IV or PO on days 8-28; cytarabine IV over 39 minutes on days 8-21; triple intrathecal (IT) chemotherapy comprising methotrexate, cytarabine, and hydrocortisone on days 1, 15, and 29; and filgrastim IV or subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. Standard-risk patients are nonrandomly assigned to receive a less intensive chemotherapy regimen without lestaurtinib (post-induction therapy A). POST-INDUCTION THERAPY A: (for standard-risk patients [MLL-G]) INDUCTION INTENSIFICATION: (weeks 6-9) Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; triple IT chemotherapy on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; cyclophosphamide IV over 30 minutes on days 15-19; etoposide IV over 2 hours on days 15-19; and filgrastim IV or SC beginning on day 20 and continuing until blood counts recover. Patients in morphologic remission proceed to re-induction therapy. RE-INDUCTION: (weeks 10-12) Patients receive vincristine IV on days 1, 8, and 15; daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase or asparaginase IM on day 4; dexamethasone IV or PO twice daily on days 1-7 and 15-21; triple IT chemotherapy on days 1 and 15; and filgrastim IV or SC beginning on day 5 and continuing until blood counts recover. CONSOLIDATION: (weeks 13-19) Patients receive high-dose methotrexate IV continuously over 24 hours on days 1 and 8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose methotrexate and continuing until methotrexate level is < 0.1 μM; triple IT chemotherapy on day 1; etoposide IV over 2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19; high-dose cytarabine IV over 3 hours every 12 hours on days 29 and 30; pegaspargase 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 IV on day 1 in weeks 20 and 24; dexamethasone IV or PO twice daily on days 1-5 in weeks 20, and 24; triple IT chemotherapy on day 1 in weeks 20 and 24; methotrexate IV on day 1 in weeks 21-24 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 IV on days 1, 29, and 57; dexamethasone IV or PO twice daily on days 1-5, 29-33, and 57-61; intrathecal methotrexate (IT MTX) 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 P9407-based chemotherapy backbone. Once a tolerable/active dose of lestaurtinib has been identified for IR patients, subsequent IR patients are eligible to proceed to an efficacy phase, where they are randomized to P9407-based chemotherapy backbone with or without lestaurtinib. HR patients separately proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR stratum. IR and HR patients are randomized to 1 of 2 post-induction therapy regimens (post-induction therapy B or C). POST-INDUCTION THERAPY B: (chemotherapy only for IR/HR patients classified as MLL-R; age ≥ 90 days at diagnosis): INDUCTION INTENSIFICATION (weeks 6-9) Patients receive high-dose methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in post-induction therapy A induction intensification. Patients in morphologic remission proceed to re-induction. RE-INDUCTION: (weeks 10-12) Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase or asparaginase, dexamethasone, triple IT chemotherapy, and filgrastim as in post-induction therapy A re-induction. CONSOLIDATION: (weeks 13-19) Patients receive high-dose methotrexate, leucovorin calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose cytarabine, pegaspargase or asparaginase, and filgrastim as in post-induction therapy A consolidation. CONTINUATION I: (weeks 20-49) Patients receive vincristine on day 1 in weeks 20, 24, 33, 37, and 46; dexamethasone PO or IV twice daily on days 1-5 in weeks 20, 24, 33, 37, and 46; triple IT chemotherapy on day 1 in weeks 20, 24, 33, 37, and 46; methotrexate IV on day 1 in weeks 21-23, 25-26 and 37-45; 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. CONTINUATION II: (weeks 50-104) Patients receive vincristine, 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. 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 twice daily on days 20-27. Patients in morphologic remission proceed to re-induction. RE-INDUCTION: (weeks 10-12) Patients receive vincristine, daunorubicin hydrochloride, cyclophosphamide, pegaspargase 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, 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, dexamethasone, IT methotrexate, methotrexate PO, and mercaptopurine PO as in post-induction therapy B continuation II. Patients also receive lestaurtinib on days 2-6, 30-34, and 58-62. Treatment repeats every 12 weeks for 2 years from diagnosis. Blood samples are collected periodically for pharmacokinetic studies and plasma inhibitory activity assay. After completion of study treatment, all patients are followed up every 1-6 months for 4 years and then annually thereafter.

Who is eligible to participate?

Inclusion Criteria: - Patients must be enrolled on a 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 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 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, FDA, and NCI requirements for human studies must be met

Last updated:
2/5/2014
NCT ID:
NCT00557193
IRB Number:
08-000659