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)

Antonio M Jimenez Jimenez

Status and phase: Not yet enrolling; Phase 1

Conditions: Acute Myeloid Leukemia

Treatments: Biological: Donor Lymphocyte Infusion; Drug: Venetoclax; Drug: Azacitidine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06158100

20230190

Details and patient eligibility

About

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.

Enrollment: 25 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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25 participants in 2 patient groups

VEN/AZA Dose Escalation/De-Escalation Cohort

Experimental group

Description:

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.

Treatment:

Drug: Azacitidine

Drug: Venetoclax

Biological: Donor Lymphocyte Infusion

VEN/AZA Expansion Cohort

Experimental group

Description:

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.

Treatment:

Drug: Azacitidine

Drug: Venetoclax

Biological: Donor Lymphocyte Infusion