Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL

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