Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia

Official Title

Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

Summary:

This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Monoclonal antibodies, such as blinatumomab, may interfere with the ability of tumour cells to grow and spread. It is not yet known whether standard combination chemotherapy is more effective than blinatumomab in treating relapsed B-cell acute lymphoblastic leukemia.

Trial Description

Primary Outcome:

  • DFS of HR and IR relapse patients
  • DFS of LR relapse patients
Secondary Outcome:
  • OS of HR and IR relapse patients
  • OS of LR relapse patients
PRIMARY OBJECTIVES:
I. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse B-cell acute lymphoblastic leukemia (B-ALL) patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization). II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). SECONDARY OBJECTIVES:
I. To compare overall survival (OS) of HR and IR relapse B-ALL patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization). II. To compare OS of LR relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). TERTIARY OBJECTIVES:
I. To compare the rates of minimal residual disease (MRD) >= 0.01% at the end of block 2 and block 3 for HR and IR relapse B-ALL patients in HR/IR randomization. II. To estimate, for treatment failure (TF) patients not previously receiving blinatumomab, the hematologic complete remission rate (CR), rate of MRD < 0.01%, and proportion able to proceed to hematopoietic stem cell transplant (HSCT) in CR after treatment with blinatumomab. III. To assess the feasibility and safety of rapid taper of immune suppression for the subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host disease (aGVHD). IV. To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response relationships for measures of safety and effectiveness. OUTLINE:

All patients receive Block 1 over 4 weeks. BLOCK 1: Patients receive dexamethasone orally (PO) twice daily (BID) or intravenously (IV) on days 1-5 and 15-19; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 3 and 17; and mitoxantrone hydrochloride IV over 15-30 minutes on days 1-2. Patients with central nervous system (CNS) 1 or CNS2 also receive methotrexate intrathecally (IT) on days 1 and 8. Patients with CNS3 or isolated CNS relapse also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, and 22. High risk and intermediate risk patients are then assigned to randomization R1. Low risk patients are assigned to randomization R2. RANDOMIZATION R1 (HR and IR patients): Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. ARM B: Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT. RANDOMIZATION R2 (LR patients): Patients are then randomized to 1 of 2 treatment arms. ARM C: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance. ARM D: Patients receive Block 2 over 4 weeks, Blinatumomab Block 2 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Block 3 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Block 3 over 5 weeks, and then Maintenance. BLOCK 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; methotrexate IV over 36 hours on day 8; leucovorin calcium IV or PO on days 10-11; pegaspargase IV over 1-2 hours on day 9 or 10; cyclophosphamide IV over 15-30 minutes on days 15-19; and etoposide IV over 1-2 hours on days 15-19. Patients with CNS1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 22. BLOCK 3: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9; asparaginase intramuscularly (IM) or IV over 1 hour on days 2, 4, 9, 11, and 23; methotrexate IT on day 1 and IV over 36 hours on day 22; leucovorin calcium PO or IV on days 24-25. Patients with CNS1 or CNS2 also receive methotrexate IT on day 22. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 22. BLINATUMOMAB BLOCK 1: Patients blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1. Patients with CNS1 or CNS2 also receive methotrexate IT on days 15 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 15 and 29. BLINATUMOMAB BLOCK 2: Patients blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1. Patients with CNS1 or CNS2 also receive methotrexate IT on days 8 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 29. BLINATUMOMAB BLOCK 3: Patients blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1. CONTINUATION 1 & 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; mercaptopurine tablet PO on days 1-42; methotrexate PO on days 8, 15, 29, and 36; leucovorin calcium PO or IV on day 24-25 (patients with CNS1, CNS2, or CNS3); cyclophosphamide IV over 15-30 minutes on days 43 and 50; etoposide IV over 1-2 hours on days 43 and 50; thioguanine PO once daily on days 43-49; and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. Patients with CNS1 or CNS2 also receive methotrexate IT on days 1 and 43. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1 and 43; methotrexate PO every 6 hours on day 22; and methotrexate IV over 36 hours on day 22. MAINTENANCE: Patients receive dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; vincristine sulfate IV over 1 minute on days 1, 29, and 57; mercaptopurine tablet PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients with CNS1 or CNS2 also receive methotrexate IT on day 1. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Courses repeat every 12 weeks for up to 2 years since the beginning of treatment in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up annually for 10 years.

View this trial on ClinicalTrials.gov

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Resources

Canadian Cancer Society

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