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)

Acute Myeloid Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06158100
• Other study ID #: 20230190
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: July 31, 2024
• Est. completion date: July 31, 2029

Study information

• Verified date: May 2024
• Source: University of Miami
• Contact: Antonio M Jimenez Jimenez, MD
• Phone: (305)243-3379
• Email: amjimenez[@]med.miami.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 25
• Est. completion date: July 31, 2029
• Est. primary completion date: July 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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.
• 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.

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.

Locations

Country	Name	City	State
United States	University of Miami	Miami	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Antonio M Jimenez Jimenez	AbbVie

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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