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)
Overview
- Phase
- Phase 1
- Intervention
- Venetoclax
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Antonio M Jimenez Jimenez
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Recommended Phase 2 Dose (RP2D)
- Status
- Suspended
- Last Updated
- 8 months ago
Overview
Brief 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.
Investigators
Antonio M Jimenez Jimenez
Associate Professor of Clinical
University of Miami
Eligibility Criteria
Inclusion Criteria
- •Male and female patients between the ages of 18-
- •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.
- •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
- •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
- •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
Exclusion Criteria
- •Active disease (\>5% blasts or any evidence of extra-medullary disease) at the time of transplantation or at day +30
- •Active acute graft-versus-host disease (aGVHD) requiring systemic IST or history of aGVHD grade III or higher.
- •Active chronic GVHD requiring systemic immunosuppressive therapy (IST).
- •Active uncontrolled systemic fungal, bacterial, or viral infection
- •Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
- •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.
- •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.
Arms & Interventions
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.
Intervention: Venetoclax
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.
Intervention: Azacitidine
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.
Intervention: Donor Lymphocyte Infusion
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.
Intervention: Venetoclax
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.
Intervention: Azacitidine
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.
Intervention: Donor Lymphocyte Infusion
Outcomes
Primary Outcomes
Recommended Phase 2 Dose (RP2D)
Time Frame: Up to 13 months
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.
Number of Participants Experiencing Treatment-Related Toxicity
Time Frame: Up to 13 months
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.
Secondary Outcomes
- Recurrence-Free Survival (RFS)(Up to 24 months)
- Overall Survival (OS)(Up to 24 months)
- Proportion of Participants with Treatment-Related Mortality (TRM)(180 days)
- Number of Participants with acute GVHD After Allogeneic Hematopoietic Cell Transplant (HCT)(Up to 180 days)
- Number of Participants with chronic GVHD After Allogeneic Hematopoietic Cell Transplant (HCT)(1 year)