Last updated on August 2019

Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia


Brief description of study

This randomized phase III trial studies combination chemotherapy with blinatumomab to see how well it works compared to induction chemotherapy alone in treating patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.

Detailed Study Description

PRIMARY OBJECTIVES:

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) positive 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 positive patients, MRD negative patients and overall population after induction and intensification chemotherapy.

II. To compare the OS and RFS of those patients who are MRD+ at step 3 randomization/ registration 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.

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 assess the efficacy of blinatumomab in each molecular subgroup.

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 course 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 course 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 courses 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 course 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 course 1, patients receive cytarabine, etoposide, methotrexate, and CD20 positive patients may receive rituximab as in course 1. Beginning 4 weeks from day 1 of course 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 PO or 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 course 3, patients receive cytarabine, etoposide, methotrexate, and CD20 positive patients may optionally receive rituximab as in course 1. Patients randomized to blinatumomab repeat course 4 and then receive blinatumomab IV continuously on days 1-28.

MAINTENANCE THERAPY: Within 12 weeks after beginning last course of consolidation therapy, patients receive mercaptopurine PO daily, methotrexate PO or IV over 6 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.

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.

Clinical Study Identifier: NCT02003222

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