A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults

Brief Summary

Detailed Description

PRIMARY OBJECTIVE: I. To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with BCR-ABL-negative B cell precursor acute lymphoblastic leukemia (ALL) who are minimal residual disease (MRD) negative after induction and intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of residual blasts. SECONDARY OBJECTIVES: I. To compare the relapse-free survival (RFS) of blinatumomab in conjunction with chemotherapy to chemotherapy alone in MRD negative patients after induction and intensification chemotherapy. II. To compare the OS and RFS of those patients who are MRD positive (+) at step 3 randomization/registration and then convert to MRD negative (-) after 2 cycles of blinatumomab to those patients who are MRD- at randomization and remain MRD- after 2 cycles of blinatumomab or consolidation chemotherapy. III. To assess the toxicities of blinatumomab in this patient population. IV. To assess the toxicities of the modified E2993 chemotherapy regimen in this patient population. V. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant after treatment with or without blinatumomab. LABORATORY OBJECTIVES: I. To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage ALL, and to compare the OS (and RFS) of patients with BCR-ABL-like phenotype with those without BCR-ABL-like phenotype. II. To evaluate the incidence of anti-blinatumomab antibody formation. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive cytarabine intrathecally (IT) on day 1; daunorubicin hydrochloride intravenously (IV) over 10-15 minutes on days 1, 8, 15, and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-7 (and 15-21 for patients age \< 55 years only); methotrexate IT on day 14; pegaspargase intramuscularly (IM) or IV on day 18 (patients age \< 55 years); and CD20 positive patients may optionally receive rituximab IV on day 8 and 15. Beginning on day 29, patients with absolute neutrophil count (ANC) \>= 0.75 x 10\^9/L and platelets \> 75 x 10\^9/L (patients with delayed hematologic recovery) (patients with residual disease that is delaying count begin treatment immediately) receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14, 29-42, pegaspargase IM or IV on day 15 (patients age \< 55 years), patients receiving treatment for central nervous system (CNS) 2 or 3 leukemia in cycle 1 receive methotrexate IT on days 1, 8, 15, and 22, and CD20 positive patients may optionally receive rituximab IV on days 8 and 15. INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of cycle 2 of induction therapy, patients receive intensification therapy comprising high-dose methotrexate IV over 2 hours on days 1 and 8, and pegaspargase IM or IV on day 9. Patients are then randomized to 1 of 2 treatment arms. Patients randomized to the blinatumomab group receive blinatumomab IV continuously on days 1-28. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may then undergo allogeneic stem cell transplant (SCT) or proceed to consolidation therapy per investigator discretion. CONSOLIDATION THERAPY: Beginning after the second cycle of blinatumomab (patients randomized to the blinatumomab group) or after intensification therapy (patients not randomized to blinatumomab), patients receive cytarabine IV over 30 minutes or SC on days 1-5, etoposide IV over 1 hour on days 1-5, methotrexate IT on day 1, and pegaspargase IM or IV on day 5, and CD20 positive patients may optionally receive rituximab IV on day 5. Beginning 4 weeks from day 1 of cycle 1, patients receive cytarabine, etoposide, methotrexate, and CD20 positive patients may receive rituximab as in cycle 1. Beginning 4 weeks from day 1 of cycle 2, patients receive daunorubicin hydrochloride IV over 10-15 minutes on day 1, 8, 15, and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-7 (and 15-21 for patients age \< 55 years); methotrexate IT on day 2; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 30 minutes or SC on days 30-33 and 37-40; mercaptopurine PO on days 29-42 and CD20 positive patients may receive rituximab on day 8. Beginning 8 weeks from day 1 of cycle 3, patients receive cytarabine, etoposide, methotrexate, and CD20 positive patients may optionally receive rituximab as in cycle 1. Patients randomized to blinatumomab repeat cycle 4 and then receive blinatumomab IV continuously on days 1-28. MAINTENANCE THERAPY: Within 6 weeks after beginning last cycle of consolidation therapy, patients receive mercaptopurine PO daily, methotrexate PO or IV over 2 hours once weekly for 2.5 years, vincristine sulfate IV on day 1 every 3 months, prednisone PO on days 1-5 every 3 months, and methotrexate IT on day 1 every 3 months. Treatment continues for up to 2.5 years in the absence of disease progression or unacceptable toxicity. Patients undergo x-ray imaging during screening, lumbar puncture while on study, and bone marrow aspiration, bone marrow biopsy, and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Primary Outcomes

Secondary Outcomes

• Relapse-free Survival (RFS) Among Patients Who Were MRD Negative After Induction and Intensification Chemotherapy(Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 5 years)
• RFS Among of Those Who Are MRD+ at Randomization and Then Convert to MRD- After 2 Cycles of Blinatumomab to Those Patients Who Are MRD- at Randomization and Remain MRD- After 2 Cycles of Blinatumomab or Consolidation Chemotherapy(Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 5 years)
• OS Among of Those Who Are MRD+ at Randomization and Then Convert to MRD- After 2 Cycles of Blinatumomab to Those Patients Who Are MRD- at Randomization and Remain MRD- After 2 Cycles of Blinatumomab or Consolidation Chemotherapy(Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 5 years)
• OS Among MRD Negative Patients Who Proceed to Allogeneic Transplant on Study(Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 5 years)