Low-Intensity Chemotherapy and Venetoclax in Treating Patients With Relapsed or Refractory B- or T-Cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limited toxicities (DLTs) of
venetoclax in combination with low-intensity chemotherapy in patients with
relapsed/refractory acute lymphoblastic leukemia (ALL) (Phase I).

II. Evaluate the overall response rate (complete response [CR] + CR with inadequate count
recovery [CRi]) of the regimen after 2 cycles. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate other clinical efficacy endpoints (minimal residual disease [MRD] negativity,
duration of response [DOR], event-free survival [EFS] and overall survival [OS]).

II. Determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance
to the combination regimen.

OUTLINE: This is a phase I, dose-escalation study of venetoclax, followed by a phase II
study.

CHEMOTHERAPY AND VENETOCLAX:

COURSE 1: Patients receive venetoclax orally (PO) once daily (QD) on days 1-21, vincristine
intravenously (IV) over 15 minutes on days 7 and 17, cyclophosphamide IV twice daily (BID)
over 3 hours on days 7-9, and dexamethasone IV over 30 minutes or PO QD on days 7-10 and
17-20. Patients may also receive rituximab IV over 4-6 hours on days 7 and 17 per physician
discretion.

COURSES 2, 4, 6, and 8: Patients receive venetoclax PO QD on days 1-21, methotrexate IV over
24 hours on day 1, and cytarabine IV BID over 3 hours on days 2 and 3. Patients may also
receive rituximab IV over 4-6 hours on days 1 and 8 per physician discretion.

COURSES 3, 5, and 7: Patients receive venetoclax PO QD on days 1-21, cyclophosphamide IV BID
over 3 hours on days 1-3, vincristine IV over 15 minutes on days 1 and 11, and dexamethasone
IV over 30 minutes or PO QD on days 1-4 and 11-14. Patients may also receive rituximab IV
over 4-6 hours on days 1 and 11 per physician discretion.

T-CELL ALL: After the first 4 courses, patients receive nelarabine IV over 2 hours on days
1-5 and pegaspargase IV over 2 hours on day 5. Courses repeat every 28 days for 2 courses
(after couse 4 and 5) in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients may receive prednisone PO QD on days 1-5, vincristine IV over
15 minutes on day 1, and venetoclax, PO QD on days 1-21. Courses repeat every 28 days for 2
years in the absence of disease progression or unacceptable toxicity.

T-CELL ALL (MAINTENANCE THERAPY): After the first 5 courses of maintenance therapy, patients
who received nelarabine and pegaspargase will receive nelarabine IV QD over 2 hours on days
1-5 and pegaspargase IV over 2 hours on day 5 during maintenance courses 6 and 7 instead of
prednisone, vincristine, and venetoclax.

After completion of study treatment, patients are followed up for 30 days and then every 3
months thereafter.

Inclusion Criteria:

- Patients with relapsed/refractory B- or T-cell ALL

- Performance status =< 3 (Eastern Cooperative Oncology Group [ECOG] Scale)

- Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert's
syndrome

- Alanine aminotransferase (ALT) =< 3 x ULN

- Aspartate aminotransferase (AST) =< 3 x ULN

- Creatinine clearance >= 30 mL/min

- For females of childbearing potential, a negative pregnancy test must be documented
within 1 week of starting treatment

- Female and male patients who are fertile must agree to use an effective form of
contraception (birth control methods while on study, such as birth control pills or
injections, intrauterine devices [IUDs]), or double-barrier methods (for example, a
condom in combination with spermicide) with their sexual partners for 4 months after
the end of treatment

- Signed informed consent

Exclusion Criteria:

- Patients with Philadelphia chromosome-positive ALL or Burkitt leukemia

- Active serious infection not controlled by oral or intravenous antibiotics

- Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
squamous cell carcinoma) that in the investigator's opinion will shorten survival to
less than 1 year

- Known hepatitis B or C infection, or known seropositivity for human immunodeficiency
virus (HIV)

- Active Grade III-V cardiac failure as defined by the New York Heart Association
Criteria

- Patients with a cardiac ejection fraction (as measured by either multigated
acquisition [MUGA] or echocardiogram) < 40%

- Received 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 history of treatment with venetoclax

- Treatment with any investigational antileukemic agents or chemotherapy agents in the
last 7 days before study entry, unless full recovery from side effects has occurred or
patient has rapidly progressive disease judged to be life-threatening by the
investigator. Exception: Treatment with hydroxyurea and/or dexamethasone are allowed
prior to study treatment, without window of exclusion

- Pregnant and lactating women will not be eligible; women of childbearing potential
should have a negative pregnancy test prior to entering on the study and be willing to
practice methods of contraception. Women do not have childbearing potential if they
have had a hysterectomy or are postmenopausal without menses for 12 months. In
addition, men enrolled on this study should understand the risks to any sexual partner
of childbearing potential and should practice an effective method of birth control

- History of significant bleeding disorder unrelated to cancer, including: Diagnosed
congenital bleeding disorders (e.g., von Willebrand's disease); diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)