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

Inclusion Criteria:

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 0: Patient must be considered apotential candidate for the trial

• NOTE: Enrollment to Step 0 may occur prior to or following completion of theassessments to verify patient eligibility for Step 1 registration; bone marrowand/or peripheral blood specimens collected during Step 0 or prior to treatmenton Step 1 must be submitted for central review in order for the patient to beconsidered evaluable; results will not be reported to the site and will notimpact patient participation in the trial

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must have adiagnosis of:

• Relapsed or refractory B-cell or T-cell ALL after multi-agent chemotherapy

• Patients with < 5% blasts may enroll on trial in phase I portion provided thatminimal residual disease (MRD) is present at > 10^-3 as tested on an assay withminimum sensitivity of 10^-4 OR

• Relapsed lymphoblastic lymphoma

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Age >= 18 years

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Eastern Cooperative OncologyGroup (ECOG) performance status 0-2

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Adequate liver function withaspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than 3 x upperlimit of normal and total bilirubin less than 2 mg/dL within 10 days prior to firstdose of study agent

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Circulating white blood cell (WBC) count must not be above 25 x 10^9/L at the time of registration

• Patients with WBC count above 25 x 10^9/L are eligible if they have startedsteroids or hydroxyurea per institutional guidelines

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Glomerular filtration rate (GFR) of at least 40 mL/min within 7 days prior to first dose of study agent

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: All patients of childbearingpotential must have a blood test or urine study with a minimum sensitivity 25 IU/Lor equivalent units of human chorionic gonadotropin (HCG) within 2 weeks prior toregistration to rule out pregnancy

• A patient of childbearing potential is defined as anyone, regardless of sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has achieved menarche at some point, 2) has notundergone a hysterectomy or bilateral oophorectomy; or 3) has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months)

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must not expect toconceive or father children by using accepted and highly effective method(s) ofcontraception or by abstaining from sexual intercourse for the duration of theirparticipation in the study and for 30 days after the last dose of venetoclax

• Should a patient or a partner of a patient become pregnant or suspect they arepregnant while participating in the study, the treating physician should benotified immediately

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: No evidence of prior solidmalignancy except adequately treated non-melanoma skin cancer, in situ cervicalcarcinoma, or any surgically- or radiation-cured malignancy continuously diseasefree for >= 2 years so as not to interfere with interpretation of radiographicresponse

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients may be enrolledwith a prior allogeneic hematopoietic stem cell transplant (HSCT) but the transplantdate must be at least 90 days before date of registration to step 1; patient must beoff immunosuppression and without active graft versus host disease (GVHD) prior toregistration to step 1 if previous HSCT

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 0: Patient must be considered apotential candidate for the trial

• NOTE: Enrollment to Step 0 may occur prior to or following completion of theassessments to verify patient eligibility for Step 1 registration

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Relapsed or refractory B-cell orT-cell ALL, including lymphoblastic lymphoma, after at least one line ofchemotherapy

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Age >= 18 years

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: ECOG performance status 0-2

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Adequate liver function withAST/ALT less than 3 x upper limit of normal and total bilirubin less than 2 mg/dLwithin 10 days prior to first dose of study agent

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Circulating WBC count must not beabove 25 x 10^9/L at the time of registration to step 1

• Patients with WBC count above 25 x 10^9/L are eligible if they have startedsteroids or hydroxyurea per institutional guidelines

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: GFR of at least 40 mL/min within 7days prior to first dose of study agent

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: All patients of childbearingpotential must have a blood test or urine study with a minimum sensitivity 25 IU/Lor equivalent units of HCG within 2 weeks prior to registration to rule outpregnancy.

• A patient of childbearing potential is defined as anyone, regardless of sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has achieved menarche at some point, 2) has notundergone a hysterectomy or bilateral oophorectomy; or 3) has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months)

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not expect toconceive or father children by using accepted and highly effective method(s) ofcontraception or by abstaining from sexual intercourse for the duration of theirparticipation in the study and for 30 days after the last dose of venetoclax

• Should a patient or partner of a patient become pregnant or suspect she ispregnant while participating in this study, the treating physician should beinformed immediately

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients may be enrolled with aprior allogeneic hematopoietic stem cell transplant (HSCT) but the transplant datemust be at least 90 days before date of enrollment; patient must be offimmunosuppression and without active GVHD prior to enrollment if previous HSCT.Low-dose steroids (10mg or less) are allowed

Exclusion Criteria:

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients of childbearingpotential must not be pregnant or breast-feeding due to risk of fetal harm by thechemotherapeutic agents prescribed in this protocol

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients with isolatedtesticular or central nervous system (CNS) relapsed disease are not eligible

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must not haveBurkitt's lymphoma/leukemia based on the World Health Organization (WHO) criteria

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must not haveactive central nervous system (CNS) leukemia, as defined by unequivocal morphologicevidence of lymphoblasts in the cerebrospinal fluid (CSF) or the use of CNS-directedlocal treatment for active disease within the prior 28 days; prophylacticintrathecal chemotherapy is allowed; previously treated CNS disease with documentedclearance of the CSF will be allowed

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients will not beenrolled if they received prior chemotherapy within 2 weeks before registration tostep 1 with the following exceptions: to reduce the circulating lymphoblast count orpalliation or for ALL maintenance (mercaptopurine, methotrexate, vincristine,thioguanine, and/or tyrosine kinase inhibitors)

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients cannot have poorlycontrolled chronic viral infections including hepatitis B, C, or humanimmunodeficiency virus (HIV); HIV positive patients are allowed on this study ifthey have a CD4 count >= 400, and are on a stable antiviral regimen

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients with New York HeartAssociation (NYHA) class III or IV heart failure, uncontrolled angina, severeuncontrolled ventricular arrhythmias, or electrocardiographic evidence of acuteischemia may not be enrolled

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients with seriousmedical or psychiatric illness that in the opinion of the primary investigator islikely to interfere with study participation may not be enrolled

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must not be takingany other experimental medications within 21 days prior to registration. Clinicaltrial medications that are Food and Drug Administration (FDA) approved will beallowed within 14 days prior to registration

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients should not havereceived the following within 7 days prior to the first dose of study drug:

• Strong and moderate CYP3A inhibitors;

• Strong and moderate CYP3A inducers

• ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C) - STEP 1: Patients must not have grade 3 or higher peripheral neuropathy or history of grade 3 or higher peripheralneuropathy. Patients with familial demyelinating disease like Charcot-Marie-Toothdisease are also excluded

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients with prior venetoclaxtreatment for ALL will be excluded

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not be pregnant orbreast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribedin this protocol

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: No evidence of prior malignancyexcept adequately treated non-melanoma skin cancer, in situ cervical or breastcarcinoma, or chemotherapy-surgically- or radiation-cured malignancy continuouslydisease free for >= 2 years

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients with isolated testicularor CNS relapsed disease are not eligible

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not have Burkitt'slymphoma/leukemia based on the WHO criteria

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not have activecentral nervous system (CNS) leukemia, as defined by unequivocal morphologicevidence of lymphoblasts in the cerebrospinal fluid (CSF) or the use of CNS-directedlocal treatment for active disease within the prior 28 days; prophylacticintrathecal chemotherapy is allowed; previously treated CNS disease with documentedclearance of the CSF will be allowed and once cleared, prophylactic intrathecalchemotherapy can be continued

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patient will not be enrolled ifthey received prior chemotherapy within 2 weeks before enrollment with the followingexceptions: 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) - STEP 1: Patients cannot have poorlycontrolled chronic viral infections including hepatitis B, C, or HIV; HIV positivepatients with undetectable viral load are allowed

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients with NYHA class III or IVheart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, orelectrocardiographic evidence of acute ischemia may not be enrolled

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients with serious medical orpsychiatric illness that in the opinion of the primary investigator is likely tointerfere with study participation may not be enrolled

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not be participatingin any other clinical trial or taking any other experimental medications within 21days prior to registration

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not have receivedthe following within 7 days prior to the first dose of study drug or while on studytreatment:

• Strong and moderate CYP3A inhibitors;

• Strong and moderate CYP3A inducers

• ELIGIBILITY CRITERIA - PHASE II (ARM D) - STEP 1: Patients must not have grade 3 orhigher peripheral neuropathy or history of grade 3 peripheral neuropathy; patientswith familial demyelinating diseases like Charcot-Marie-Tooth disease also excluded