A Phase Ib/II Study of the Combination of Venetoclax with Chemotherapy as Frontline Therapy in Older Patients with Acute Lymphoblastic Leukemia

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

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 lymphoblastic 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