Venetoclax and Combination Chemotherapy in Treating Patients with Recurrent or Refractory B or T Cell Acute Lymphoblastic Leukemia

Inclusion Criteria

• PHASE IB: Patients with previously untreated acute lymphoblastic leukemia (B-cell or T-cell) * Bone marrow involvement with >= 20% lymphoblasts * Age >= 60 Years
• PHASE IB: Patients with relapsed or refractory acute lymphoblastic leukemia (B-cell or T-cell) defined as receiving one or more cytotoxic containing regimens and * Bone marrow involvement with >= 5% lymphoblasts * Age >= 18 Years
• PHASE IB: Eastern Cooperative Oncology Group (ECOG) performance status =< 2. ECOG 3 allowed after discussion with principal investigator (PI) if related to disease
• PHASE IB: Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert’s disease
• PHASE IB: Alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to disease involvement
• PHASE IB: Creatinine clearance > 50 mL/min (calculated according to institutional standards or using Cockcroft-Gault or Modification of Diet in Renal Disease [MDRD] formula)
• PHASE IB: Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy; men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
• PHASE IB: Patients or their legally authorized representative must provide written informed consent
• PHASE II: Patients with previously untreated acute leukemia with lymphoid lineage (B-cell, T-cell, mixed phenotype or bi-phenotypic) * Presence of >= 20% blasts with lymphoid differentiation on bone marrow aspirate, and/or bone marrow core biopsy, and/or peripheral blood. * Age >= 55 Years, or 50-54 years with body mass index (BMI) of >= 35 kg/m^2
• PHASE II: Eastern Cooperative Oncology Group (ECOG) performance status =< 2. ECOG 3 allowed after discussion with overall PI if related to disease
• PHASE II: Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert’s disease, unless clearly due to disease involvement and discussed with the overall PI
• PHASE II: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN, unless clearly due to disease involvement and discussed with the overall PI
• PHASE II: Creatinine clearance >= 50 mL/min (calculated according to Cockcroft-Gault formula)
• PHASE II: Patients or their legally authorized representative must provide written informed consent
• Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Women of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug

Exclusion Criteria

• Philadelphia (Ph)-positive ALL, Burkitt’s leukemia/lymphoma, or lymphoblastic lymphoma (without concurrent marrow involvement)
• Patient is pregnant or breastfeeding
• Patients with uncontrolled infection
• Known active hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
• Major surgery or radiation therapy within 4 weeks prior to the first study dose
• For Phase 1b, systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and/or steroids, or one dose of cytarabine) prior to starting therapy. For phase II, any prior systemic chemotherapy or radiotherapy for treatment of ALL is an exclusion with the exception of hydroxyurea, steroids, tretinoin (ATRA), vincristine (maximum 2 doses), and/or intra-thecal chemotherapy. No more than 2 weeks (14 days) of steroids is permitted
• Symptomatic central nervous system (CNS)/ leptomeningeal disease or spinal cord compression
• Patients with active heart disease (New York Heart Association [NYHA] class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)
• Patients with a cardiac ejection fraction (as measured by either Multi Gated Acquisition [MUGA] or echocardiogram [EKG]) < 40%
• History of another primary invasive malignancy except: a) malignancies that have definitively treated (i.e. completely resected, completed curative therapy), b) patients with multiple myeloma with undetectable disease (serum and urine paraprotein measurements and marrow assessments) for 1 year; c) patients with non-melanoma skin cancers or with carcinomas in situ, d) patients with prostate cancer or similar low grade malignancies (i.e. meningioma) under active surveillance that do not have a current indication for treatment, e) other cancers cases of prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. The treating investigator must review such cases with the overall principal investigator (PI) prior to confirming eligibility
• Concurrent use of warfarin (patient may transition to alternative anti-coagulation)
• Unable to discontinue cytochrome P450 3A (CYP3A) inhibitors during venetoclax ramp-up. It is recommended that strong CYP3A4 inhibitors be discontinued 7 days prior to starting venetoclax. Shorter intervals may be permissible after discussion with the overall PI
• Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax
• Current treatment with venetoclax (if venetoclax previously used for another indication, 60 or more days must have elapsed since last dose of venetoclax)
• Malabsorption syndrome or other conditions that preclude enteral route of administration
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study