Clinical Trials /

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

NCT03504644

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 or does not respond to treatment. 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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: EA9152
  • SECONDARY ID: NCI-2017-01158
  • SECONDARY ID: EA9152
  • SECONDARY ID: EA9152
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03504644

Conditions

  • B Acute Lymphoblastic Leukemia
  • Lymphoblasts 5 Percent or More of Bone Marrow Nucleated Cells
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Refractory Acute Lymphoblastic Leukemia
  • T Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaTreatment (venetoclax, vincristine liposomal)
Vincristine LiposomalLipid-Encapsulated Vincristine, Liposomal Vincristine, Onco TCS, Vincacine, VincaXome, Vincristine Liposome, Vincristine, LiposomalTreatment (venetoclax, vincristine liposomal)

Purpose

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 or does not respond to treatment. 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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (venetoclax, vincristine liposomal)ExperimentalPatients receive venetoclax PO QD on days 1-42 of course 1 and days 43-70 of course 2. Patients also receive vincristine liposomal IV weekly for 4 weeks starting on day 14 of course 1.
  • Venetoclax
  • Vincristine Liposomal

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of venetoclax (Phase I)
Time Frame:Up to 70 days
Safety Issue:
Description:Toxicities will be assessed and graded according to Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From study registration to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and the median PFS along with its corresponding 95% confidence interval will be reported.
Measure:Overall survival (OS)
Time Frame:From study registration to death from any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and the median OS along with its corresponding 95% confidence interval will be reported.
Measure:Rate of minimal residual disease
Time Frame:Up to 5 years
Safety Issue:
Description:95% confidence interval will be computed.
Measure:Change in intracellular BCL-2 expression
Time Frame:Baseline up to 5 years
Safety Issue:
Description:Will be assessed by flow cytometry and dichotomized into two groups by the median (low vs. high). Univariate Cox proportional hazards (PH) models will be used to evaluate the association of the BCL-2 expression at baseline and immunophenotype (B-cell and T-cell acute lymphoblastic leukemia) with OS and PFS, separately. Logistic regression models will be used to investigate the association of the BCL-2 expression at baseline and immunophenotype with response (CR/CRi/partial remission [PR] versus [vs.] others by 70 days). Multivariable Cox PH modelling and logistic regression modelling will also be used to adjust for the effect of covariates that are possibly associated with these efficacy outcomes

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ECOG-ACRIN Cancer Research Group

Last Updated

July 26, 2019