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

Primary Purpose

Acute Bilineal Leukemia, Acute Biphenotypic Leukemia, Acute Myeloid Leukemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Azacitidine
Venetoclax
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Bilineal Leukemia

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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)

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (azacitidine, venetoclax)

Arm Description

Patients 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.

Outcomes

Primary Outcome Measures

Relapse-free survival (RFS) time
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

Overall survival (OS) time
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.
Incidence of severe (grade 3 or 4) infection
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Graft-versus-host disease
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Incidence of other inter-current adverse events during follow up
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Non-relapse mortality
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.

Full Information

First Posted
October 14, 2019
Last Updated
October 13, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04128501
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 Leukemia, and Mixed Phenotype Acute Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 5, 2020 (Actual)
Primary Completion Date
October 31, 2024 (Anticipated)
Study Completion Date
October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase II trial studies how well venetoclax and azacitidine work for the treatment of acute myeloid leukemia after stem cell transplantation. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as azacitidine, 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Bilineal Leukemia, Acute Biphenotypic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia, Therapy-Related Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
125 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (azacitidine, venetoclax)
Arm Type
Experimental
Arm Description
Patients 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.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Relapse-free survival (RFS) time
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.
Time Frame
From the date of first administration of venetoclax + azacitidine (vidaza) (V+V), assessed up to 60 days after last V+V dose
Secondary Outcome Measure Information:
Title
Overall survival (OS) time
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.
Time Frame
Up to 60 days after last V+V dose
Title
Incidence of severe (grade 3 or 4) infection
Description
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Time Frame
Up to 60 days after last V+V dose
Title
Graft-versus-host disease
Description
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Time Frame
Up to 60 days after last V+V dose
Title
Incidence of other inter-current adverse events during follow up
Description
Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
Time Frame
Up to 60 days after last V+V dose
Title
Non-relapse mortality
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.
Time Frame
Within 90 days from the start of V+V treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Betul Oran
Phone
713-792-8750
Email
boran@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Betul Oran
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Betul Oran
Phone
713-745-2820
Email
boran@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Betul Oran

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

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

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