Recombinant Erwinia Asparaginase, Dexamethasone and Venetoclax in Combination with Blinatumomab for the Treatment of Relapsed or Refractory CD19 Positive B-cell Acute Lymphoblastic Leukemia

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative
• Age between 12 and 55
• Eastern Cooperative Oncology Group (ECOG) ≤ 2 or Karnofsky performance status (KPS) ≥ 70
• Patients with relapsed or refractory (R/R) CD19 positive (+) B-cell acute lymphoblastic leukemia (B-ALL) according to World Health Organization (WHO) criteria * Greater than or equal to 5% blasts in the bone marrow * Participants aged 12 to 17 years are eligible only if they have documented ≥ second relapse, defined as relapse occurring after completion or failure of at least one salvage regimen following first relapse. Participants within this group in first relapse are not eligible
• White blood cell count less than 25 x 10^9/L prior to initiation of venetoclax. (within 14 days prior to day 1 of protocol therapy) Cytoreduction with hydroxyurea, steroid or a single dose of cyclophosphamide chemotherapy prior to treatment may be required
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to day 1 of protocol therapy) (unless has Gilbert’s disease or underlying leukemia, ≤ 3 x ULN)
• Prothrombin time (PT) ≤ 1.5 ULN (within 14 days prior to day 1 of protocol therapy)
• Partial thromboplastin time (PTT) ≤ 1.5 ULN (within 14 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN (within 14 days prior to day 1 of protocol therapy) (Unless it is related to underlying leukemia, then AST ≤ 5 x ULN)
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN (within 14 days prior to day 1 of protocol therapy) (Unless it is related to underlying leukemia, then ALT ≤ 5 x ULN)
• Creatinine clearance of ≥ 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 14 days prior to day 1 of protocol therapy)
• Left ventricular ejection fraction (LVEF) ≥ 50% (within 14 days prior to day 1 of protocol therapy) * Note: Echocardiogram to be performed within 42 days prior to day 1 of protocol therapy
• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (within 14 days prior to day 1 of protocol therapy) * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria

• Allogeneic hematopoietic cell transplantation (HCT) within 8 weeks prior to the start of protocol-specific therapy. Subjects must be off all immunosuppression for ≥ 2 weeks
• Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy with the exception of: intrathecal chemotherapy and/or low-dose maintenance therapy (e.g. vina alkaloids, mercaptopurine, methotrexate, or hydroxyurea etc). Patients who have discontinued the use of calcineurin inhibitors (CNIs) must have been off CNIs for at least 4 weeks
• Patients with unresolved toxicities (grade > 1) from prior therapies, including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery
• Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior to day 1 of protocol therapy
• Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John’s wort) within 3 days prior to initiation of and during study treatment
• Immunotherapy (e.g. rituximab) within 4 weeks before the start of protocol-specified therapy. Prior failed CD19-directed therapy such as prior blinatumomab or CD19-directed chimeric antigen receptor (CAR)-T cells will be allowed if treatment ended > 4 weeks prior to start of protocol-specific therapy and there is demonstrated continued CD19+ expression
• Must not have received or planning to receive live vaccine while being on study or 2 weeks before and after completion of treatment
• Patients with any prior intolerance leading to discontinuation of pegylated (PEG)-asparaginase due to grade 3 or more pancreatitis or central nervous system thrombosis requiring anticoagulant treatment attributed to the PEG-asparaginase
• Active ALL in the central nervous system (CNS): Presence of > 5 white blood cells (WBC) per cubic millimeter in the cerebrospinal fluid (CSF) with lymphoblasts present (confirmed by CSF analysis) and/or clinical signs of CNS leukemia. If CSF leukemia is present, subjects will need to receive intrathecal chemotherapy and have documented negative CSF prior to enrollment
• Active acute graft versus host disease (GVHD) of any grade at screening, and chronic GVHD requiring any systemic therapy at screening
• History of intracranial thrombosis or history of recurrent thrombosis or grade 3 and greater pulmonary embolism (except for catheter-related thrombosis)
• Participants with history of grade ≥ 3 pancreatitis
• History of alcohol overuse if deemed relevant in investigator’s opinion
• Known hypersensitivity to blinatumomab/ recombinant Erwinia asparaginase or to any component of the product formulation, otherwise prior treatment with single agent blinatumomab is allowed
• Uncontrolled active infection
• Clinically significant uncontrolled illness or cirrhosis
• Other active malignancy (except superficial skin cancers squamous cell carcinoma [SCC]/basal cell carcinoma [BCC], early-stage malignancies ductal carcinoma in-situ [DCIS] status post [s/p] excision or elevated prostate specific antigen [PSA])
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)