Venetoclax in Combination With Azacitidine (VEN/AZA) Followed by Donor Lymphocyte Infusion (DLI) for Patients With Very High-Risk Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Cell Transplant (HCT)

A Phase 1 Study of Venetoclax in Combination With Azacitidine (VEN/AZA) Followed by Donor Lymphocyte Infusion (DLI) for Patients With Very High-Risk Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Cell Transplant (HCT)

The purpose of this study is to see the effects of an investigational combination treatment of venetoclax, azacitidine, and donor lymphocyte infusion (DLI) in patients with high-risk AML receiving allogeneic hematopoietic cell transplantation, and to assess if the combination treatment is well tolerated and prevents disease relapse after transplant.

Study Overview

• Status: Suspended
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Venetoclax; Drug: Azacitidine; Biological: Donor Lymphocyte Infusion

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female patients between the ages of 18-75.
2. Patients with a histologic diagnosis of AML in morphological remission (<5% bone marrow (BM) blasts) prior to allogeneic hematopoietic cell transplantation and very high-risk for relapse defined as: (i) Presence of measurable residual disease (MRD) by multicolor flow cytometry (MFC) prior to transplant and receiving a reduced intensity conditioning (RIC) or nonmyeloablative (NMA) regimen (ii) Presence of MRD by MFC at day +30 post-transplant (iii) All patients with monosomal karyotype (MK) and those with 17p/tumor protein p53 (TP53) mutated disease irrespective of MRD status and intensity of conditioning regimen.

3. Adequate hematopoietic recovery after HCT, defined as:

   • Absolute neutrophil count (ANC) >= 1 x 10^9/L without daily use of myeloid growth factors
   • Platelet count >= 50 x 10^9/L without platelet transfusion within 1 week
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Serum creatinine =< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min
6. Serum bilirubin =< 1.5 x upper limit of normal (ULN)
7. Aspartate transaminase (AST) or alanine transaminase (ALT) =< 2.5 x ULN
8. Alkaline phosphatase =< 2.5 x UL
9. Negative serum or urine pregnancy test for women with reproductive potential.
10. A negative donor-specific antibody (DSA) assay (i.e., Micro-Flow Imaging (MFI) <m3000) for recipients of any mismatched graft (including haploidentical) HCT.

Exclusion Criteria:

1. Active disease (>5% blasts or any evidence of extra-medullary disease) at the time of transplantation or at day +30
2. Active acute graft-versus-host disease (aGVHD) requiring systemic IST or history of aGVHD grade III or higher.
3. Active chronic GVHD requiring systemic immunosuppressive therapy (IST).
4. Active uncontrolled systemic fungal, bacterial, or viral infection
5. Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
6. Significant active cardiac disease within the previous 6 months, including: New York Heart Association (NYHA) class III or IV congestive heart failure. Unstable angina, angina requiring surgical or medical intervention, and/or myocardial infarction.
7. History of any other malignancy within 2 years prior to study entry, except for: adequately treated in situ carcinoma of the cervix or carcinoma in situ of breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; myelodysplastic syndrome.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VEN/AZA Dose Escalation/De-Escalation Cohort; Participants in this group will begin Venetoclax and Azacitidine (VEN/AZA) combination therapy between day +42 and day +100 following hematopoietic cell transplant (HCT) infusion. VEN/AZA combination therapy will be administered for up to six (6) cycles, followed by up to six (6) additional cycles of Venetoclax monotherapy in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days. Participants may also receive donor lymphocyte infusions (DLI) at the discretion of the treating physician, if certain criteria are met. Participants will receive up to one year (12 cycles) of study therapy, followed by up to one year of follow-up. Total participation duration is up to two years.	Drug: Venetoclax; Venetoclax will be given orally (PO) at the assigned doses of 50 or 100 mg once daily for 7, 14 or 21 days starting at day 1 of each 28-day cycle, for up to 12 cycles.; Other Names: Venclexta; Venclyxto; Drug: Azacitidine; Azacitidine will be administered at a dose of 20mg/m^2 once daily subcutaneously (SC) or intravenously (IV) for five days (Days 1-5) of each 28-day cycle.; Other Names: Vidaza; Azadine; Biological: Donor Lymphocyte Infusion; Donor lymphocyte infusions (DLI) may be administered at the discretion of the treating physician, if certain criteria are met. Participants may receive up to three (3) infusions of donor lymphocytes (a type of white blood cell) at the following dose levels and study timepoints: DLI 1: 1x10^6 cluster of differentiation 3+ (CD3+) cells/kg, after cycle 3; DLI 2: 5x10^6 CD3+ cells/kg, after cycle 5, if there is persistent MRD; DLI 3: 1x10^7 CD3+ cells/kg, after cycle 7, if there is persistent MRD.
Experimental: VEN/AZA Expansion Cohort; Participants in this group will receive VEN/AZA therapy at the most appropriate dose determined in Part 1. Participants may also receive donor lymphocyte infusions (DLI) at the discretion of the treating physician, if certain criteria are met. Participants will receive up to one year (12 cycles) of study therapy, followed by up to one year of follow-up. Total participation duration is up to two years.	Drug: Venetoclax; Venetoclax will be given orally (PO) at the assigned doses of 50 or 100 mg once daily for 7, 14 or 21 days starting at day 1 of each 28-day cycle, for up to 12 cycles.; Other Names: Venclexta; Venclyxto; Drug: Azacitidine; Azacitidine will be administered at a dose of 20mg/m^2 once daily subcutaneously (SC) or intravenously (IV) for five days (Days 1-5) of each 28-day cycle.; Other Names: Vidaza; Azadine; Biological: Donor Lymphocyte Infusion; Donor lymphocyte infusions (DLI) may be administered at the discretion of the treating physician, if certain criteria are met. Participants may receive up to three (3) infusions of donor lymphocytes (a type of white blood cell) at the following dose levels and study timepoints: DLI 1: 1x10^6 cluster of differentiation 3+ (CD3+) cells/kg, after cycle 3; DLI 2: 5x10^6 CD3+ cells/kg, after cycle 5, if there is persistent MRD; DLI 3: 1x10^7 CD3+ cells/kg, after cycle 7, if there is persistent MRD.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D)	The RP2D of VEN/AZA therapy will be determined as the maximum tolerated dose of study treatment as assessed by treating physician using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Up to 13 months
Number of Participants Experiencing Treatment-Related Toxicity	The number of participants experiencing treatment-related toxicity. Toxicity is defined as including dose limiting toxicities (DLTs), serious adverse events (SAEs) and adverse events (AEs) in study participants after starting study therapy. Toxicity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion.	Up to 13 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-Free Survival (RFS)	Recurrence-free survival (RFS) is defined as the elapsed time measured in months between the treatment start date (Cycle 1 Day 1) and date of documented disease recurrence or death from any cause. Alive patients without recurrence will be censored at the date of last documentation of recurrence-free status.	Up to 24 months
Overall Survival (OS)	Overall survival (OS) is defined as the elapsed time measured in months between the treatment start date (Cycle 1 Day 1) and date of death from any cause. Alive patients will be censored at the date last known to be alive.	Up to 24 months
Proportion of Participants with Treatment-Related Mortality (TRM)	Treatment-related Mortality (TRM) is defined as the proportion of participants that died after starting study therapy, during the time of observation and in the absence of disease progression.	180 days
Number of Participants with acute GVHD After Allogeneic Hematopoietic Cell Transplant (HCT)	The number of participants with acute graft-versus-host disease (aGVHD) among study participants will be reported at +100 and +180 days post-allogeneic HCT.	Up to 180 days
Number of Participants with chronic GVHD After Allogeneic Hematopoietic Cell Transplant (HCT)	The number of participants with chronic graft-versus-host disease (cGVHD) among study participants will be reported at one (1) year post-allogeneic HCT.	1 year

Collaborators and Investigators

• Sponsor: Antonio M Jimenez Jimenez
• Collaborators: AbbVie
• Investigators: Principal Investigator: Antonio M Jimenez Jimenez, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: November 27, 2023
• First Submitted That Met QC Criteria: November 27, 2023
• First Posted (Actual): December 6, 2023

Study Record Updates

• Last Update Posted (Actual): August 6, 2025
• Last Update Submitted That Met QC Criteria: August 2, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Hematopoietic Cell Transplant (HCT)
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Venetoclax; Azacitidine
• Other Study ID Numbers: 20230190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No