Clinical Trials /

Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia in the Post-Transplant Setting

NCT04128501

Description:

This phase II trial studies how well venetoclax and azacitidine work for the treatment of acute myeloid leukemia after stem cell transplantation. Venetoclax, a BCL-2 inhibitor, and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and azacitidine after a stem cell transplant may help control high risk leukemia and prevent it from coming back after the transplant.

Related Conditions:
  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Mixed Phenotype Acute Leukemia
  • T-Cell Acute Lymphoblastic Leukemia
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia in the Post-Transplant Setting
  • Official Title: A Phase II Study of Venetoclax in Combination With Azacitidine in the Post-Transplant Setting for AML, T Cell ALL, and Mixed Phenotype Acute Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2019-0353
  • SECONDARY ID: NCI-2019-06674
  • SECONDARY ID: 2019-0353
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04128501

Conditions

  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Blasts More Than 5 Percent of Bone Marrow Nucleated Cells
  • Minimal Residual Disease
  • Mixed Phenotype Acute Leukemia
  • T Acute Lymphoblastic Leukemia
  • Therapy-Related Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (azacitidine, venetoclax)

Purpose

This phase II trial studies how well venetoclax and azacitidine work for the treatment of acute myeloid leukemia after stem cell transplantation. Venetoclax, a BCL-2 inhibitor, and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and azacitidine after a stem cell transplant may help control high risk leukemia and prevent it from coming back after the transplant.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine relapse-free survival after the use of venetoclax in combination with
      azacitidine given as maintenance therapy or for eradication of minimal residual disease in
      patients with high risk acute myeloid leukemia (AML) after hematopoietic stem cell
      transplantation (HSCT).

      SECONDARY OBJECTIVES:

      I. To determine the safety and toxicity of venetoclax in combination with azacitidine (type,
      frequency, severity of adverse events [AEs] and relationship of adverse events [AEs] to
      venetoclax).

      II. To determine response duration, overall survival. III. To determine incidence of acute
      and chronic graft versus host disease (GVHD).

      IV. To perform matched pairs analysis to obtain bias corrected treatment comparisons of
      venetoclax + azacitidine (vidaza) (V+V) to standard therapy in the acute myeloid leukemia
      (AML) patients with no evidence of disease (AML D-) subgroup.

      EXPLORATORY OBJECTIVE:

      I. To investigate possible relationships between baseline protein and gene expression
      signatures/mutation profile and BH3 profiling in predicting relapse-free survival time to the
      combination.

      OUTLINE:

      Patients receiving venetoclax and azacitidine for maintenance after allogeneic stem cell
      transplantation, receive azacitidine subcutaneously (SC) on days 1-5 and venetoclax orally
      (PO) once daily (QD) on days 1-7. Patients receiving venetoclax and azacitidine for minimal
      residual disease after allogeneic stem cell transplant, receive azacitidine SC on days 1-7
      and venetoclax PO QD on days 1-14. Treatment repeats every 4-8 weeks for up to 12 cycles in
      the absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, venetoclax)ExperimentalPatients receiving venetoclax and azacitidine for maintenance after allogeneic stem cell transplantation, receive azacitidine SC on days 1-5 and venetoclax PO QD on days 1-7. Patients receiving venetoclax and azacitidine for minimal residual disease after allogeneic stem cell transplant, receive azacitidine SC on days 1-7 and venetoclax PO QD on days 1-14. Treatment repeats every 4-8 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Patients 18 to 75 years of age.

          -  Patients with AML who are in morphological remission after allogeneic stem cell
             transplantation with peripheral blood stem cell (PBSC)s or bone marrow if they had at
             least one of the following disease characteristics:

               -  Therapy related AML

               -  Cytogenetics and molecular features consistent with adverse risk group by
                  European LeukemiaNet classification for AML

               -  Primary induction failure defined as absence of complete remission after two
                  different lines of anti-leukemia therapy following diagnosis

               -  Presence of minimal residual disease by multi-color flow cytometry or
                  cytogenetics or molecular studies at the time of HSCT

               -  Presence of active disease defined as bone marrow blast count > 5% at the time of
                  HSCT

               -  Patients transplanted beyond first remission

          -  Patients with biphenotypic or bilineage leukemia (including a myeloid component) or
             mixed phenotype acute leukemia (MPAL) or T cell acute lymphoblastic leukemia who are
             in morphological remission after allogeneic stem cell transplantation with PBSCs or
             bone marrow

          -  The use of reduced intensity regimen with fludarabine/melphalan (100-140 mg/m^2) with
             or without total-body irradiation (TBI) with post-transplant cytoxan

          -  The use of myeloablative regimens including: sequential busulfan (area under curve
             [AUC] > 5000)/flurabine with post-transplant cytoxan or TBI/etoposide with any GVHD
             regimen

          -  Patients who are in remission with no detectable minimal residual disease after
             allogeneic stem cell transplant should have:

               -  Adequate engraftment within 14 days prior to starting study drug

               -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L without daily use of myeloid
                  growth factor

               -  Platelet >= 30 x 10^9/L without platelet transfusion within 1 week; and

               -  Be able to start the drug therapy between 42 to 100 days following HSCT

          -  Persistence or reappearance of minimal residual disease by flow cytometry or
             cytogenetic or molecular testing while being in morphological remission after
             allogeneic stem cell transplantation

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Serum creatinine =< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min
             as defined by the Cockcroft-Gault equation

          -  Serum bilirubin =< 1.5 x upper limit of normal (ULN)

          -  Aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x ULN

          -  Alkaline phosphatase =< 2.5 x UL

          -  Capable of understanding the investigational nature, potential risks and benefits of
             the study, and able to provide valid informed consent

          -  Negative serum or urine pregnancy test for women with reproductive potential. The only
             subjects who will be exempt from this criterion are postmenopausal women (defined as
             women who have been amenorrheic for > 12 months) or subjects who have been surgically
             sterilized or otherwise proven sterile

        Exclusion Criteria:

          -  Active acute GVHD grade II or higher

          -  Active chronic GVHD that is extensive

          -  Uncontrolled GVHD

          -  Concurrent use of systemic immune suppressive other than calcineurin inhibitors,
             mycophenolate mofetil (MMF) and sirolimus

          -  Active uncontrolled systemic fungal, bacterial or viral infection

          -  Active bleeding

          -  Symptomatic or uncontrolled arrhythmias

          -  Significant active cardiac disease within the previous 6 months, including: New York
             Heart Association (NYHA) class III or IV congestive heart failure. Unstable angina or
             angina requiring surgical or medical intervention, and/or myocardial infarction

          -  Known active viral infection with human immunodeficiency virus (HIV), hepatitis B
             virus (HBV) or hepatitis C virus (HCV)

          -  Prior history of malignancies, other than leukemia, unless the subject has been free
             of the disease for >= 1 year. However, subjects with the following history/concurrent
             conditions are allowed:

               -  Basal or squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  node, metastasis [TNM] clinical staging system)
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free survival (RFS) time
Time Frame:From the date of first administration of venetoclax + azacitidine (vidaza) (V+V), assessed up to 60 days after last V+V dose
Safety Issue:
Description:Summary statistics for RFS time will be computed for all patients and within each (disease status, disease type) subgroup. RFS time distributions will be estimated within each subgroup using the method of Kaplan and Meier.

Secondary Outcome Measures

Measure:Overall survival (OS) time
Time Frame:Up to 60 days after last V+V dose
Safety Issue:
Description:Summary statistics for OS time will be computed for all patients and within each (disease status, disease type) subgroup. OS time distributions will be estimated within each subgroup using the method of Kaplan and Meier.
Measure:Incidence of severe (grade 3 or 4) infection
Time Frame:Up to 60 days after last V+V dose
Safety Issue:
Description:Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Measure:Incidence of Acute and Chronic Graft-versus-host disease
Time Frame:Up to 60 days after last V+V dose
Safety Issue:
Description:Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Measure:Incidence of other inter-current adverse events during follow up
Time Frame:Up to 60 days after last V+V dose
Safety Issue:
Description:Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Measure:Incident of the Non-relapse mortality
Time Frame:Within 90 days from the start of V+V treatment
Safety Issue:
Description:Defined as death from any cause, within 90 days from the start of V+V treatment that is not preceded by disease recurrence. Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

January 31, 2020