- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04128501
Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia in the Post-Transplant Setting
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 Overview
Status
Conditions
Intervention / Treatment
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. This exploratory analysis will be done for the data from the entire study, accounting for the noted biological variables covariates, as well as disease status and whether or not the patient had AML, by fitting a Bayesian time-to-event regression model with RFS the outcome variable.
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
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Betul Oran
- Phone Number: 713-792-8750
- Email: boran@mdanderson.org
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- Recruiting
- M D Anderson Cancer Center
-
Contact:
- Betul Oran
- Phone Number: 713-745-2820
- Email: boran@mdanderson.org
-
Principal Investigator:
- Betul Oran
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Participants 18 to 75 years of age.
- English and non-English speaking patients are eligible.
Participants with AML who are in morphological remission after allogeneic stem cell transplantation with PBSCs 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 (see Appendix A.).
- 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.
- Participants transplanted beyond first remission.
- Participants with biphenotypic or bilineage leukemia (including a myeloid component) or mixed phenotype acute leukemia (MPAL) or who are in morphological remission after allogeneic stem cell transplantation with PBSCs or bone marrow.
- Participants with acute lymphoblastic leukemia; B cell or T cell in original, 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/m2) with or without TBI with post-transplant Cytoxan.
- The use of myeloablative regimens including: sequential busulfan (AUC at or greater than 4000)/fludarabine with post-transplant Cytoxan or total body irradiation (TBI)/etoposide with any graft versus host disease (GVHD) regimen.
- Participants on clinical trials investigating different conditioning regimens (with the above described backbone) with investigational agents will be allowed to enroll.
Participants who are in remission with no detectable minimal residual disease (MRD) after allogeneic stem cell transplant should have:
- Adequate engraftment within 14 days prior to starting study drug:
- Absolute neutrophil count (ANC) >/= 1.0 x 109/L without daily use of myeloid growth factor (G-CSF) for at least 7 days; and,
- Platelet >/= 30 x 109/L without platelet transfusion within 1 week
- Be able to start the drug therapy between 42 to 100 days following HSCT.
Persistence or reappearance of MRD by flow cytometry or cytogenetic or molecular testing while being in morphological remission after allogeneic stem cell transplantation.
a. When MRD is detected by flow cytometry, disease level at or above the sensitivity level of the test will be required.
- MRD level at or above 0.01% for B cell ALL and T cell ALL.
- MRD level at or above 0.1% for AML and mixed phenotype acute leukemia. b. When MRD is detected by cytogenetics, disease level at or above the sensitivity level of the test will be required.
- The limited of detection is about 0.25% for males and 0.44% for females. c. When MRD is detected by molecular testing, disease level at or above the sensitivity level of the test will be required.
- The limited of detection is 0.01%
- 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 participants who will be exempt from this criterion are postmenopausal women (defined as women who have been amenorrheic for > 12 months) or participants who have been surgically sterilized or otherwise proven sterile.
Exclusion Criteria:
- Active acute GVHD grade II or higher.
- Active chronic GVHD that is extensive (see Appendix C.).
- Uncontrolled GVHD (see Appendix C.).
- Concurrent use of systemic immune suppressive other than calcineurin inhibitors, sirolimus and steroids
- 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 see Appendix C.).
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, participants 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).
- Participants with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / 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.
|
Given PO
Other Names:
Given SC
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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
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.
|
Up to 60 days after last V+V dose
|
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.
|
Up to 60 days after last V+V dose
|
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.
|
Up to 60 days after last V+V dose
|
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.
|
Up to 60 days after last V+V dose
|
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.
|
Within 90 days from the start of V+V treatment
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Betul Oran, M.D. Anderson Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Hematologic Diseases
- Leukemia, Lymphoid
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Biphenotypic, Acute
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Venetoclax
- Azacitidine
Other Study ID Numbers
- 2019-0353 (Other Identifier: M D Anderson Cancer Center)
- NCI-2019-06674 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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