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

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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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Relapse-free survival (RFS) time

Secondary Outcome

 Overall survival (OS) time

Condition

Acute Bilineal Leukemia

Intervention

Azacitidine

Study Arms / Comparison Groups

 Treatment (azacitidine, venetoclax)
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

125

Start Date

May 5, 2020

Completion Date

October 1, 2022

Primary Completion Date

October 1, 2022

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)
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Betul Oran, 713-792-8750, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04128501

Organization ID

2019-0353

Secondary IDs

NCI-2019-06674

Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Betul Oran, Principal Investigator, M.D. Anderson Cancer Center


Verification Date

May 2021