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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04128501

Collaborator

(none)

125

Enrollment

Location

Arm

28.9

Anticipated Duration (Months)

4.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Bilineal Leukemia Acute Biphenotypic Leukemia Acute Myeloid Leukemia Mixed Phenotype Acute Leukemia T Acute Lymphoblastic Leukemia Therapy-Related Acute Myeloid Leukemia	Drug: Azacitidine Drug: Venetoclax	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

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:

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

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 Design

Study Type:

Interventional

Anticipated Enrollment :

125 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 5, 2020

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Azacitidine Given SC Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar Onureg U-18496 Vidaza Drug: Venetoclax Given PO Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta Venclyxto

Arm

Intervention/Treatment

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.

Drug: Azacitidine

Given SC

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

Onureg

U-18496

Vidaza

Drug: Venetoclax

Given PO

Other Names:

ABT-0199

ABT-199

ABT199

GDC-0199

RG7601

Venclexta

Venclyxto

Outcome Measures

Primary Outcome Measures

Relapse-free survival (RFS) time [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.

Secondary Outcome Measures

Overall survival (OS) time [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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)