Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of venetoclax in combination with vincristine
liposomal (liposomal vincristine) in patients with relapsed or refractory T-cell and B-cell
acute lymphoblastic leukemia (ALL). (Phase I) II. Safety assessment and toxicity
characterization after treatment of venetoclax in combination with liposomal vincristine in
patients with relapsed or refractory T-cell and B-cell ALL. (Phase I) III. To determine the
preliminary efficacy of venetoclax in combination with liposomal vincristine to induce
complete remission (CR) by day 70 in patients with relapsed or refractory T-cell and B-cell
ALL. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival, overall survival and toxicity after the
combination treatment in patients with relapsed or refractory T-cell and B-cell ALL. (Phase
II)

TERTIARY OBJECTIVES:

I. To determine if genetic signature as determined by next generation sequencing can predict
response to combination. (Phase II) II. To determine if immunophenotype of ALL is associated
with response to combination. (Phase II) III. To determine if the BH3 profile is associated
with response to combination. (Phase II) IV. To determine if relative expression of BCL-2
measure by flow cytometry is associated with response to combination. (Phase II)

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

Patients receive venetoclax orally (PO) once daily (QD) on days 1-42 of course 1 and days
43-70 of course 2. Patients also receive vincristine liposomal intravenously (IV) weekly for
4 weeks starting on day 14 of course 1.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Inclusion Criteria:

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Relapsed or refractory ALL after
multi-agent chemotherapy (>= 5% marrow lymphoblasts, assessed by morphology and flow
cytometry; flow cytometry will be used to confirm immunophenotype and percentage of
blasts will be assessed by morphology)

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Eastern Cooperative Oncology Group
(ECOG) performance status 0-2

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Adequate liver function with aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) less than 3 X upper limit of
normal and total bilirubin less than 2 mg/dL within 7 days prior to first dose of
study agent

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Circulating white blood cell (WBC)
count must not be above 20 x10^9/L within 7 days prior to first dose of study agent

- Patients with WBC count above 20 x 10^9/L may be eligible if they start steroids
or hydroxyurea per institutional guidelines, but they must discontinue before day
1 of study drug

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Creatinine clearance of at least 50
mL/min within 7 days prior to first dose of study agent

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Women must not be pregnant or
breast-feeding

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): All females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Women of childbearing potential and
sexually active males must use an accepted and highly effective method of
contraception or to abstain from sexual intercourse for the duration of their
participation in the study and for 30 days after the last dose of venetoclax; should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she (or the participating partner) should inform the
treating physician immediately

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): No evidence of prior malignancy except
adequately treated non-melanoma skin cancer, in situ cervical carcinoma, or any
surgically- or radiation-cured malignancy continuously disease free for >= 5 years so
as not to interfere with interpretation of radiographic response

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): No evidence of isolated extramedullary
relapse (i.e., testicular or central nervous system [CNS])

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patient must not have Burkitt?s
lymphoma/leukemia based on the World Health Organization (WHO) criteria

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients must not have active central
nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of
lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for
active disease within the prior 28 days; previously treated CNS disease with
documented cleared CSF will be allowed

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patient will not be enrolled if they
received prior chemotherapy within 2 weeks before enrollment with the following
exceptions: to reduce the circulating lymphoblast count or palliation (i.e., steroids
or hydroxyurea) or for ALL maintenance (mercaptopurine, methotrexate, vincristine,
thioguanine, and/or tyrosine kinase inhibitors)

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patient may be enrolled with a prior
allogeneic hematopoietic stem cell transplant (HSCT) but the transplant date must be
at least 90 days before date of enrollment; patient must be off immunosuppression and
without active graft versus host disease (GVHD) prior to enrollment if previous HSCT

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patient cannot have poorly controlled
human immunodeficiency virus (HIV), or CD4 < 400; HIV positive patients are allowed on
this study if they have a CD4 count >= 400, and are on a stable antiviral regimen

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients with New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia may not be enrolled

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients with serious medical or
psychiatric illness that in the opinion of the primary investigator is likely to
interfere with study participation may not be enrolled

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients must not be participating in
any other clinical trial or taking any other experimental medications within 21 days
prior to registration

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients should not have received the
following within 7 days prior to the first dose of study drug:

- Steroid therapy for anti-neoplastic intent;

- Strong and moderate CYP3A inhibitors;

- Strong and moderate CYP3A inducers

- ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients must not have grade 3 or
higher peripheral neuropathy

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Relapsed or refractory ALL after multi-agent
chemotherapy (>= 5% marrow lymphoblasts, assessed by morphology and flow cytometry;
flow cytometry will be used to confirm immunophenotype and percentage of blasts will
be assessed by morphology)

- ELIGIBILITY CRITERIA - PHASE II (ARM D): ECOG performance status 0-2

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Adequate liver function with AST/ALT less
than 3 X upper limit of normal and total bilirubin less than 2 mg/dL within 7 days
prior to first dose of study agent

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Circulating WBC count must not be above 20
x10^9/L within 7 days prior to first dose of study agent

- Patients with WBC count above 20 x10^9/L may be eligible if they start steroids
or hydroxyurea per institutional guidelines, but they must discontinue before day
1 of study drug

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Creatinine clearance of at least 50 mL/min
within 7 days prior to first dose of study agent

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Women must not be pregnant or breast-feeding

- ELIGIBILITY CRITERIA - PHASE II (ARM D): All females of childbearing potential must
have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Women of childbearing potential and sexually
active males must use an accepted and highly effective method of contraception or to
abstain from sexual intercourse for the duration of their participation in the study
and for 30 days after the last dose of venetoclax; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
(or the participating partner) should inform the treating physician immediately

- ELIGIBILITY CRITERIA - PHASE II (ARM D): No evidence of prior malignancy except
adequately treated non-melanoma skin cancer, in situ cervical carcinoma, or any
surgically- or radiation-cured malignancy continuously disease free for >= 5 years so
as not to interfere with interpretation of radiographic response

- ELIGIBILITY CRITERIA - PHASE II (ARM D): No evidence of isolated extramedullary
relapse (i.e., testicular or CNS)

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patient must not have Burkitt?s
lymphoma/leukemia based on the WHO criteria

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients must not have active central nervous
system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts
in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active
disease within the prior 28 days; previously treated CNS disease with documented
cleared CSF will be allowed

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patient will not be enrolled if they received
prior chemotherapy within 2 weeks before enrollment with the following exceptions: to
reduce the circulating lymphoblast count or palliation (i.e., steroids or
hydroxyurea), for ALL maintenance (mercaptopurine, methotrexate, vincristine,
thioguanine, and/or tyrosine kinase inhibitors)

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patient may be enrolled with a prior
allogeneic hematopoietic stem cell transplant (HSCT) but the transplant date must be
at least 90 days before date of enrollment; patient must be off immunosuppression and
without active GVHD prior to enrollment if previous HSCT

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patient cannot have poorly controlled HIV, or
CD4 < 400; HIV positive patients are allowed on this study if they have a CD4 count >=
400, and are on a stable antiviral regimen

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients with NYHA class III or IV heart
failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
electrocardiographic evidence of acute ischemia may not be enrolled

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients with serious medical or psychiatric
illness that in the opinion of the primary investigator is likely to interfere with
study participation may not be enrolled

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients must not be participating in any
other clinical trial or taking any other experimental medications within 21 days prior
to registration

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients should not have received the
following within 7 days prior to the first dose of study drug:

- Steroid therapy for anti-neoplastic intent;

- Strong and moderate CYP3A inhibitors;

- Strong and moderate CYP3A inducers

- ELIGIBILITY CRITERIA - PHASE II (ARM D): Patients must not have grade 3 or higher
peripheral neuropathy