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

Status
Active
Cancer Type
Acute Lymphoblastic Leukemia
Leukemia
Trial Phase
Phase III
Eligibility
35 to 70, Male and Female
Study Type
Treatment
NCD ID
NCT02003222
Protocol IDs
NCI-2013-02229 (primary)
ECOG-E1910
E1910
U10CA021115
U10CA180820
Study Sponsor
National Cancer Institute

Summary

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. Monoclonal antibodies, such as blinatumomab, may block cancer growth in different ways by targeting certain cells. It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.

Objectives

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.

II. If superiority of blinatumomab in the MRD positive group is shown, to compare the OS of blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with BCR-ABL-negative B cell precursor ALL who are MRD negative after induction and intensification chemotherapy, based on MFC assessment of residual blasts.

III. If superiority of blinatumomab in the MRD positive group is not shown, to compare the OS of blinatumomab in conjunction with chemotherapy to chemotherapy alone in the overall population of patients with BCR-ABL-negative B cell precursor ALL.

SECONDARY OBJECTIVES:

I. To determine if blinatumomab can convert patients who are MRD positive by MFC assessment of residual blasts after induction and intensification chemotherapy to MRD negativity.

II. To assess the toxicities of blinatumomab in this patient population. III. To assess the toxicities of the modified E2993 chemotherapy regimen in this patient population.

IV. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant after treatment with or without blinatumomab.

TERTIARY 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 day 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; and pegaspargase intramuscularly (IM) or IV on day 18 (patients age =< 55 years). 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) receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine tablet PO on days 1-14, 29-42, pegaspargase IM or IV on day 15 (patients age < 55 years), and methotrexate IT or IV over 6 hours on days 1, 8, 15, and 22.

INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of course 2 of induction therapy, patients achieving complete response (CR) or complete response with incomplete recovery (CRi) 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 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. Beginning 4 weeks from day 1 of course 1, patients receive cytarabine, etoposide, and methotrexate 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 or IV over 6 hours on day 1; cyclophosphamide PO or IV over 30 minutes on day 29; cytarabine IV over 30 minutes on days 31-34 and 38-41; and mercaptopurine tablet PO on days 29-42. Beginning 8 weeks from day 1 of course 3, patients receive cytarabine, etoposide, and methotrexate 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 tablet PO daily, methotrexate PO or IV over 6 hours once weekly for 2.5 years, vincristine sulfate IV once every 3 months, prednisone PO on days 1-5 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.

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