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)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Negative serum or urine pregnancy test for women with reproductive potential.
- •A negative donor-specific antibody (DSA) assay (i.e., Micro-Flow Imaging (MFI) <m3000) for recipients of any mismatched graft (including haploidentical) HCT.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Venetoclax (Drug)
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.
干预措施: Azacitidine (Drug)
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.
干预措施: Donor Lymphocyte Infusion (Biological)
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.
干预措施: Donor Lymphocyte Infusion (Biological)
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.
干预措施: Venetoclax (Drug)
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.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: 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
时间窗: 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.
次要结局
- 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)
研究者
Antonio M Jimenez Jimenez
Associate Professor of Clinical
University of Miami