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)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Children's Oncology Group
- Enrollment
- 218
- Locations
- 170
- Primary Endpoint
- Percent Probability for Event-free Survival (EFS) for Patients on Arm C at Dose Level 2 (DL2)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- — to 1 Year (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Asparaginase (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Biospecimen Collection (Procedure)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Bone Marrow Biopsy (Procedure)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Cyclophosphamide (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Cytarabine (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Daunorubicin Hydrochloride (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Dexamethasone (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Echocardiography (Procedure)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Etoposide (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Filgrastim (Biological)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Laboratory Biomarker Analysis (Other)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Leucovorin Calcium (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Mercaptopurine (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Methotrexate (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Methylprednisolone (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Multigated Acquisition Scan (Procedure)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Pegaspargase (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Pharmacological Study (Other)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Prednisone (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Therapeutic Hydrocortisone (Drug)
Arm A (standard risk MLL-G)
Population Description: Eligible patients with MLL-G (germline, or non-rearranged)
Intervention: Vincristine Sulfate (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Asparaginase (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Biospecimen Collection (Procedure)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Bone Marrow Biopsy (Procedure)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Cyclophosphamide (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Cytarabine (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Daunorubicin Hydrochloride (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Dexamethasone (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Echocardiography (Procedure)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Etoposide (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Filgrastim (Biological)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Laboratory Biomarker Analysis (Other)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Leucovorin Calcium (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Echocardiography (Procedure)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Mercaptopurine (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Methotrexate (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Methylprednisolone (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Multigated Acquisition Scan (Procedure)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Pegaspargase (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Pharmacological Study (Other)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Prednisone (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Therapeutic Hydrocortisone (Drug)
Arm B (IR/HR MLL-R chemotherapy)
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.
Intervention: Vincristine Sulfate (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Asparaginase (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Biospecimen Collection (Procedure)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Bone Marrow Biopsy (Procedure)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Cyclophosphamide (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Cytarabine (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Daunorubicin Hydrochloride (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Dexamethasone (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Etoposide (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Filgrastim (Biological)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Laboratory Biomarker Analysis (Other)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Lestaurtinib (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Leucovorin Calcium (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Mercaptopurine (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Methotrexate (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Methylprednisolone (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Multigated Acquisition Scan (Procedure)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Pegaspargase (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Pharmacological Study (Other)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Prednisone (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Therapeutic Hydrocortisone (Drug)
Arm C (IR/HR MLL-R chemotherapy and 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.
Intervention: Vincristine Sulfate (Drug)
Outcomes
Primary Outcomes
Percent Probability for Event-free Survival (EFS) for Patients on Arm C at Dose Level 2 (DL2)
Time Frame: 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 Outcomes
- Identification of Gene Expression Patterns in Diagnostic Infant Leukemia Samples That Correlate With PIA Values(At 3 years)
- 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.)
- Number of Patients Who Experienced Lestaurtinib-related Dose Limiting Toxicity (DLT)(Up to 12 weeks from start of induction)
- Describe FLT3 Protein Expression as a Molecular Mechanism of Acquired Resistance to Lestaurtinib in Leukemic Blasts(At relapse (up to 3 years))
- Describe in Vitro Sensitivity as a Molecular Mechanism of Acquired Resistance to Lestaurtinib in Leukemic Blasts(At relapse (up to 3 years))
- Pharmacokinetic AGP Levels in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy(Up to 12 weeks)
- Describe FLT3 Protein Expression as a Molecular Mechanism of Primary Resistance to Lestaurtinib in Leukemic Blasts(Sampled at the start of induction)
- Describe in Vitro Sensitivity as a Molecular Mechanism of Primary Resistance to Lestaurtinib in Leukemic Blasts(Sampled at the start of induction)
- Percent Probability of Event Free Survival (EFS) by MRD Status and Treatment Arm(3 Years from end of Induction))
- Identification of Gene Expression Patterns in Diagnostic Infant Leukemia Samples That Correlate With Survival Outcomes(At 3 years)
- Percent Probability for Event-free Survival (EFS) for Patients on Arm A(From start of post-induction therapy for up to 10 years)
- Pharmacokinetic Albumin in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy(Up to 12 weeks)
- Pharmacodynamics PIA Levels in Infants Given Lestaurtinib at DL2 in Combination With Chemotherapy(Sampled between weeks 6-12 from start of induction)