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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04128501
Recruitment Status : Recruiting
First Posted : October 16, 2019
Last Update Posted : October 29, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE October 14, 2019
First Posted Date  ICMJE October 16, 2019
Last Update Posted Date October 29, 2020
Actual Study Start Date  ICMJE May 5, 2020
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 14, 2019)
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 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2019)
  • Overall survival (OS) time [ Time Frame: Up to 60 days after last V+V dose ]
    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 [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Incidence of Acute and Chronic Graft-versus-host disease [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Incidence of other inter-current adverse events during follow up [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Incident of the Non-relapse mortality [ Time Frame: Within 90 days from the start of V+V treatment ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 14, 2019)
  • Overall survival (OS) time [ Time Frame: Up to 60 days after last V+V dose ]
    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 [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Graft-versus-host disease [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Incidence of other inter-current adverse events during follow up [ Time Frame: Up to 60 days after last V+V dose ]
    Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models.
  • Non-relapse mortality [ Time Frame: Within 90 days from the start of V+V treatment ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia in the Post-Transplant Setting
Official Title  ICMJE 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
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, 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Azacitidine
    Given SC
    Other Names:
    • 5 AZC
    • 5-AC
    • 5-Azacytidine
    • 5-AZC
    • Azacytidine
    • Azacytidine, 5-
    • Ladakamycin
    • Mylosar
    • U-18496
    • Vidaza
  • Drug: Venetoclax
    Given PO
    Other Names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
    • Venclyxto
Study Arms  ICMJE Experimental: Treatment (azacitidine, venetoclax)
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.
Interventions:
  • Drug: Azacitidine
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 14, 2019)
125
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2022
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Betul Oran 713-792-8750 boran@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04128501
Other Study ID Numbers  ICMJE 2019-0353
NCI-2019-06674 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2019-0353 ( Other Identifier: M D Anderson Cancer Center )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Betul Oran M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP