Acute Myeloid Leukemia
Conditions
Keywords
Hematopoietic Cell Transplant (HCT)
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.
Interventions
DRUGVenetoclax
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.
DRUGAzacitidine
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.
BIOLOGICALDonor 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.
Sponsors
AbbVie
Antonio M Jimenez Jimenez
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 dose escalation/de-escalation and dose expansion design.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants with Treatment-Related Mortality (TRM) | 180 days | 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. |
| Recurrence-Free Survival (RFS) | Up to 24 months | 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. |
| Number of Participants with chronic GVHD After Allogeneic Hematopoietic Cell Transplant (HCT) | 1 year | The number of participants with chronic graft-versus-host disease (cGVHD) among study participants will be reported at one (1) year post-allogeneic HCT. |
| Number of Participants with acute GVHD After Allogeneic Hematopoietic Cell Transplant (HCT) | Up to 180 days | 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. |
| Overall Survival (OS) | Up to 24 months | 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. |
Countries
United States
Outcome results
None listed