Asparaginase Erwinia Chrysanthemi With Chemotherapy for the Treatment of High-Risk Adults With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

This phase II trial tests the safety, side effects, and effectiveness of asparaginase Erwinia chrysanthemi during induction chemotherapy followed by consolidation chemotherapy in treating high-risk adults with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma. Asparaginase Erwinia chrysanthemi, a type of protein synthesis inhibitor, is a drug that is made up of the enzyme asparaginase, which comes from the bacterium Erwinia chrysanthemi, and is used with other drugs in people who cannot take asparaginase that comes from the bacterium E. coli. Asparaginase Erwinia chrysanthemi breaks down the amino acid asparagine and may stop the growth of cancer cells that need asparagine to grow. It may also kill cancer cells. Induction therapy, consisting of cytarabine, dexamethasone, vincristine, daunorubicin, methotrexate, and rituximab, is the first choice of treatment. Consolidation therapy, consisting of cyclophosphamide, cytarabine, vincristine, mercaptopurine, methotrexate and rituximab, is given after initial therapy to kill any remaining cancer cells. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill cancer cells. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Cytarabine and mercaptopurine stop cells from making DNA and may kill cancer cells. They are a type of antimetabolite. Daunorubicin blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. It is a type of anthracycline antibiotic and a type of topoisomerase inhibitor. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving asparaginase Erwinia chrysanthemi with induction chemotherapy followed by consolidation chemotherapy may be safe, tolerable, and/or effective in treating high-risk adults with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma.

PRIMARY OBJECTIVES:

1. To evaluate the safety and tolerability of asparaginase Erwinia chrysanthemi (asparaginase Erwinia chrysanthemi-recombinant-rywn [recombinant Erwinia asparaginase]; 25 mg/m² every 48 hours [hrs]) as first asparaginase during induction therapy through the assessment of type, frequency, severity, attribution, time course and duration of adverse events. (Safety Lead-in) II. To evaluate the proportion of patients with grade 3 or higher (G3+) hepatotoxicity that are at least possibly related to the study drug (recombinant Erwinia asparaginase) and not resolved to grade 1 or lower within 14 days of occurrence in the target patient population during induction. (Expansion)

SECONDARY OBJECTIVES:

1. To evaluate the safety and tolerability of recombinant Erwinia asparaginase (25 mg/m² every 48 hrs) as first asparaginase during induction therapy through the assessment of type, frequency, severity, attribution, and duration of adverse events (expansion cohort).

II. To evaluate composite complete remission (CR or CR with incomplete hematologic recovery [CRi]) rate after induction ± extended induction.

III. To evaluate CR rate after induction ± extended induction. IV. To evaluate minimal residual disease (MRD) negativity rate after induction ± extended induction.

1. To evaluate number of patients able to receive extended induction or post induction consolidation or salvage therapy within 42 days from initiating induction.

VI. To evaluate MRD negativity rate after consolidation for patients receiving the study drug.

VII. To evaluate the proportion of patients with G3+ hepatotoxicity that are at least possibly related to the study drug during induction.

VIII. To evaluate the proportion of patients maintaining adequate 48 hour nadir serum asparaginase activity (NSAA ≥ 0.1 IU/mL) post recombinant Erwinia asparaginase during induction +/- extended induction.

IX. To evaluate the duration of G3+ hepatotoxicity.

EXPLORATORY OBJECTIVES:

1. To evaluate the safety and tolerability of recombinant Erwinia asparaginase (at approved dosing) as first asparaginase during extended induction and consolidation therapy through the assessment of type, frequency, severity, attribution, time course and duration of adverse events.

II. To evaluate the proportion of patients maintaining adequate, either at 48 hours or 72 hrs, nadir serum asparaginase activity (NSAA ≥ 0.1 IU/mL) post recombinant Erwinia asparaginase during consolidation.

III. To evaluate the molecular profile by next-generation sequencing (NGS) and its association with MRD- response to recombinant Erwinia asparaginase based induction.

OUTLINE:

INDUCTION (CYCLE 1): Patients receive cytarabine intrathecally (IT) on day 1, dexamethasone orally (PO) twice daily (BID) on days 1-7 and 15-21, vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 5-30 minutes on days 1, 8, 15, and 22, asparaginase Erwinia chrysanthemi intramuscularly (IM) on days 4, 6, 8, 10, 12, 14, and 16, and methotrexate IT on days 8 and 29. Patients with CNS3 disease also receive methotrexate IT on days 15 and 22. CD20 positive patients also receive rituximab IV on day 8. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with M2 marrow (> 5% lymphoblasts) on day 29 proceed to Extended Induction Cycle 1A. All other patients proceed to Consolidation Cycle 2.

EXTENDED INDUCTION (CYCLE 1A): Patients receive dexamethasone PO BID on days 1-7, vincristine IV on days 1 and 8, daunorubicin IV over 5-30 minutes on day 1, and asparaginase Erwinia chrysanthemi IM on days 4, 6, 8, 10, 12, 14, and 16 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLE 2): Patients receive cyclophosphamide IV on days 1 and 29, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, vincristine IV on days 15, 22, 43, and 50, and methotrexate IT on days 1, 8, 15 and 22 (NOTE: Patients with CNS3 disease omit methotrexate on days 15 and 22). CD20 positive patients also receive rituximab IV on days 1 and 20. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit may also receive asparaginase Erwinia chrysanthemi IM every other day on days 15, 17, 19, 21, 23, 25, 27, 43, 45, 47, 49, 51, 53, and 55 or every Monday/Wednesday/Friday (if days 15 and 43 are Mondays) on days 15, 17, 19, 22, 24, 26, 43, 45, 47, 50, 52, and 54 at discretion of treating physician. Patients may receive 2 courses of every other day or Monday/Wednesday/Friday treatment in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo echocardiography at screening and blood sample collection, bone marrow aspiration and/or biopsy, lumbar puncture, and computed tomography (CT) and/or positron emission tomography (PET)/CT throughout the study.

After completion of study treatment, patients are followed up at 30 days.