A Phase Ib/II Study of Venetoclax (ABT-199) in Combination with Liposomal Vincristine in Patients with Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia.

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