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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Bilineal Leukemia, Acute Biphenotypic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia, Therapy-Related Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (azacitidine, venetoclax)<br>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. | Drug: Azacitidine<br>* Given SC<br>* Other names: Vidaza;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the date of first administration of venetoclax + azacitidine (vidaza) (V+V), assessed up to 60 days after last V+V dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 60 days after last V+V dose | 
| Incidence of severe (grade 3 or 4) infection | Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models. | Up to 60 days after last V+V dose | 
| Graft-versus-host disease | Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models. | Up to 60 days after last V+V dose | 
| Incidence of other inter-current adverse events during follow up | Will be summarized, and relevant parameters will be estimated under appropriate Bayesian models. | Up to 60 days after last V+V dose | 
| 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. | Within 90 days from the start of V+V treatment |