Blinatumomab, Inotuzumab Ozogamicin, and Combination Chemotherapy as Frontline Therapy in Treating Patients with B Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVE:

I. To evaluate the clinical efficacy of the sequential combination of hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) + blinatumomab + inotuzumab ozogamicin (inotuzumab) in patients with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in terms of relapse-free survival (RFS).

SECONDARY OBJECTIVE:

I. To evaluate other efficacy endpoints such as overall survival, overall response rate, minimal residual disease (MRD) negativity rate as well as the safety of this combination.

EXPLORATORY OBJECTIVES:

I. To identify genomic alterations in adult ALL predictive for response and long-term outcomes with the combination of hyper-CVAD plus blinatumomab and inotuzumab.

II. To evaluate the impact of next generation sequencing (NGS)-based MRD assay on outcomes and to compare with standard flow cytometry MRD assays.

OUTLINE: Patients are randomized to 1 of 2 cohorts.

COHORT I:

INTENSIVE PHASE: Patients receive cyclophosphamide intravenously (IV) over 3 hours twice daily (BID) on days 1-3, dexamethasone orally (PO) once daily (QD) on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2 of cycles 1 and 3, day 8 of cycles 2 and 4, and IV over 24 hours on day 1 of cycles 2 and 4, doxorubicin hydrochloride IV continuously on day 4, vincristine sulfate IV over 15 minutes on days 4 and 11, and cytarabine IT on day 7 of cycles 1 and 3, day 2 of cycles 2 and 4, and IV over 2 hours on days 2 and 3 of cycles 2 and 4. Patients may also receive ofatumumab IV or rituximab IV over 4-6 hours on days 1 and 11 of cycles 1 and 3, and days 1 and 8 of cycles 2 and 4 at the discretion of the treating physician. Patients may receive ofatumumab IV over 4-6 hours on day 2 of cycle 1. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients receiving ofatumumab who transition to the blinatumomab phase prior to completing 4 cycles receive ofatumumab IV over 4-6 hours on days 2, 8, and 5 until 8 doses are achieved.

BLINATUMOMAB PHASE (CYCLES 5-8): Patients receive blinatumomab IV continuously on weeks 1-4. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: At doctor's discretion, patients may receive maintenance therapy prior to completing 4 cycles of hyper-CVAD and/or 4 cycles of blinatumomab. Patients receive mercaptopurine PO thrice daily (TID), methotrexate PO every week, vincristine sulfate IV over 15 minutes every month, and prednisone PO on days 1-5. Cycles repeat every 6 weeks for 12 months in the absence of disease progression or unacceptable toxicity. Patients also receive blinatumomab IV after every 3 cycles of maintenance therapy for a total of about 15 cycles.

COHORT II:

INTENSIVE PHASE: Patients receive cyclophosphamide IV over 3 hours BID on days 1-3, mesna IV continuously over 24 hours on days 1-3, doxorubicin hydrochloride IV continuously over 24 hours, vincristine IV on days 4 and 11, dexamethasone IV or PO on days 1-4 and 11-14, ofatumumab IV on days 1, 2, and 11 of cycle 1 and 3 and day 1 and 8 of cycle 2, rituximab IV on days 1 and 11 of cycles 1 and 3 and day 1 of cycles 2 and 4, pegfilgrastim or filgrastim subcutaneously (SC) daily, methotrexate IT over 2 hours on day 2 of cycles 1 and 3 and day 8 of cycles 2 and 4, cytarabine IT over 2 hours on day 7 of cycle 1 and 3 and days 2 and 3 of cycles 2 and 4. Patients receive inotuzumab ozogamicin IV on days 1 and 8 of cycles 2 and 4. Treatment repeats every 3 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

BLINATUMOMAB AND INOTUZUMAB OZOGAMICIN PHASE (CYCLES 5-8): Patients receive blinatumomab IV continuously on weeks 1-4. Patients receive inotuzumab ozogamicin IV over 1 hour on days 5 and 11 or days 8 and 15 of cycles 6 and 8. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: At doctor's discretion, patients may receive maintenance therapy prior to completing 4 cycles of hyper-CVAD and/or 4 cycles of blinatumomab. Patients receive mercaptopurine PO thrice daily (TID) on cycles 1-3, 5-6, 9-11, and 13-15, methotrexate PO every week, vincristine sulfate IV on day 1 of every month, and prednisone PO on days 1-5. Cycles repeat every 6 weeks for 12 months in the absence of disease progression or unacceptable toxicity. Patients also receive blinatumomab IV after every 3 cycles of maintenance therapy for a total of about 15 cycles.

Patients also undergo collection of blood samples, and computed tomography (CT) and positron emission tomography (PET) scans at screening.

After completion of study treatment, patients are followed up 1 time each month for up to 24 months.