Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL
Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL
This research study is studying a medication called Venetoclax and a chemotherapy regimen as
 a possible treatment for Acute Lymphoblastic Leukemia.

 The drugs involved in this study are:

 -  Venetoclax

 -  Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin,
 dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine
This research study is a Phase I clinical trial, which tests the safety of an investigational
 drug and drug combination and also tries to define the appropriate dose of the
 investigational drug and drug combination to use for further studies. "Investigational" means
 that the drug and drug combination is being studied.

 The FDA (the U.S. Food and Drug Administration) has not approved Venetoclax for this specific
 disease, but it has been approved for other uses.

 Venetoclax is an inhibitor of Bcl-2. Bcl-2 is critical for keeping cancer cells alive.

 By inhibiting Bcl-2, venetoclax promotes cancer cell death. This drug is currently being used
 in other clinical trials for people with certain types of leukemia, lymphoma, and multiple
 myeloma. There is some evidence from those and other laboratory trials that venetoclax may
 kill cancer cells and cause tumors to shrink.

 In this research study, the investigators are investigating how safe the combination of
 Venetoclax and standard chemotherapy is and how it affects this disease.. The participant
 will be given Venetoclax alone first and the standard chemotherapies will be given in
 combination. This study aims to provide information to help determine the dose of Venetoclax
 , in combination with standard chemotherapy, affects this disease the best and which dose is
 the safest.
Inclusion Criteria:

 -  Patients with previously untreated acute lymphoblastic leukemia (B-cell or T-cell)

 -  Bone marrow involvement with ≥20% lymphoblasts

 -  Age ≥ 60 Years

 OR

 -  Patients with relapsed or refractory acute lumphoblastic leukemia (B-cell or T-cell)
 defined as receiving one or more cytotoxic containing regimens

 -  Bone marrow involvement with ≥5% lymphoblasts

 -  Age ≥ 18 Years

 -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Refer to Appendix D)

 -  Adequate organ function

 -  Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients
 with Gilbert's disease

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN,
 unless clearly due to disease involvement

 -  Creatinine clearance >50 mL/min (calculated according to institutional standards
 or using Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula)

 -  Women of childbearing potential must have a negative serum or urine beta human
 chorionic gonadotropin (β-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

 -  Patients or their legally authorized representative must provide written informed
 consent

 Exclusion Criteria:

 -  Ph-positive ALL, Burkitt's leukemia/lymphoma, or lymphoblastic lymphoma

 -  Patient is pregnant or breastfeeding

 -  Patients with uncontrolled infection

 -  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

 -  Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the
 exception of hydroxyurea and/or dexamethasone, or one dose of cytarabine) prior to
 starting therapy

 -  Symptomatic or untreated 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 that has not been definitively treated
 or in remission for at least 2 years. Patients with non-melanoma skin cancers or with
 carcinomas in situ are eligible regardless of the time from diagnosis (including
 concomitant diagnoses)

 -  Concurrent use of warfarin

 -  Received Cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole,
 voriconazole, and clarithromycin) within 3 days of starting venetoclax; received
 strong CYP3A inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St.
 John's Wort) within 3 days of starting venetoclax

 -  Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
 prior to starting venetoclax

 -  Prior treatment with 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