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

Status: Active

Description

This phase Ib / II clinical trial studies the side effects and best dose of venetoclax and how well it works when given together with vincristine liposomal in treating patients with T-cell or B-cell acute lymphoblastic leukemia that has come back (recurrent) or does not respond to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vincristine liposomal, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with vincristine liposomal may work better in treating patients with acute lymphoblastic leukemia compared to vincristine liposomal alone.

Eligibility Criteria

Inclusion Criteria

  • ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients must have a diagnosis of: * Relapsed or refractory B-cell or T-cell 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) * Patients with < 5% blasts may enroll on trial on phase I portion provided that minimal residual disease (MRD) is present at > 10^-3 as tested on an assay with minimum sensitivity of 10^-4; presence of MRD must be confirmed by Leukemia Translational Research Laboratory (LTRL) before starting step 1 OR * Relapsed lymphoblastic lymphoma
  • 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 at the time of registration * Patients with WBC count above 20 x 10^9/L may be eligible if they have started steroids or hydroxyurea per institutional guidelines
  • ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): 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): All females of childbearing potential must have a blood test or urine study with a minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG) 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): 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 registration to step 1; patient must be off immunosuppression and without active graft versus host disease (GVHD) prior to registration to step 1 if previous HSCT
  • ELIGIBILITY CRITERIA - PHASE II (ARM D): Relapsed or refractory B-cell or T-cell 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 at the time of registration to step 1 * Patients with WBC count above 20 x10^9/L are eligible if they have started steroids or hydroxyurea per institutional guidelines
  • ELIGIBILITY CRITERIA - PHASE II (ARM D): GFR of at least 40 mL/min within 7 days prior to first dose of study agent
  • ELIGIBILITY CRITERIA - PHASE II (ARM D): All females of childbearing potential must have a blood test or urine study with a minimum sensitivity 25 IU/L or equivalent units of HCG 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): 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

Exclusion Criteria

  • ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Women must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol
  • ELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients with isolated testicular or central nervous system (CNS) relapsed disease are not eligible
  • 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) or the use of CNS-directed local treatment for active disease within the prior 28 days; prophylactic intrathecal chemotherapy is allowed; previously treated CNS disease with documented clearance of the 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 registration to step 1 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 cannot have poorly controlled chronic viral infections including hepatitis B, C, or human immunodeficiency virus (HIV); 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: * 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; patients with familial demyelinating disease like Charcot-Marie-Tooth disease are also excluded
  • ELIGIBILITY CRITERIA - PHASE II (ARM D): Women must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol
  • 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): Patients with isolated testicular or CNS relapsed disease are not eligible
  • 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) or the 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 cannot have poorly controlled chronic viral infections including hepatitis B, C, or HIV; 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: * 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 history of grade 3 peripheral neuropathy; patients with familial demyelinating diseases like Charcot-Marie-Tooth disease also excluded

Locations & Contacts

Connecticut

New Haven
Yale University
Status: Active
Contact: Site Public Contact
Phone: 203-785-5702
Email: canceranswers@yale.edu

Illinois

Chicago
Northwestern University
Status: Active
Contact: Site Public Contact
Phone: 312-695-1301
Email: cancer@northwestern.edu

Minnesota

Rochester
Mayo Clinic
Status: Active
Contact: Site Public Contact
Phone: 855-776-0015

New Jersey

New Brunswick
Rutgers Cancer Institute of New Jersey
Status: Active
Contact: Site Public Contact
Phone: 732-235-8675

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592

Pennsylvania

Hershey
Penn State Milton S Hershey Medical Center
Status: Active
Contact: Site Public Contact
Phone: 717-531-3779
Email: CTO@hmc.psu.edu
Philadelphia
Thomas Jefferson University Hospital
Status: Active
Contact: Site Public Contact
Phone: 215-955-6084
University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 800-474-9892

Wisconsin

Milwaukee
Medical College of Wisconsin
Status: Active
Contact: Site Public Contact
Phone: 414-805-3666

Trial Objectives and Outline

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)

EXPLORATORY/CORRELATIVE 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 cycle 1 and days 43-70 of cycle 2. Patients also receive vincristine liposomal intravenously (IV) weekly for 4 weeks starting on day 15 of cycle 1.

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

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Neil David Palmisiano

Trial IDs

Primary ID EA9152
Secondary IDs NCI-2017-01158
Clinicaltrials.gov ID NCT03504644