Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 324
- 试验地点
- 1
- 主要终点
- 1-year progression free survival (PFS)
研究概览
简要总结
This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid leukemia or myelodysplastic syndrome who are undergoing stem cell transplant. Chemotherapy drugs, such as venetoclax, busulfan, cladribine, and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax to the current standard of care stem cell transplant regimen of busulfan, fludarabine, and cladribine may help to control high-risk acute myeloid leukemia or myelodysplastic syndrome.
详细描述
Phase 2 Portion
Primary Objective 1) To obtain preliminary evidence of efficacy as defined by 1-year progression free survival.
Secondary Objectives
To determine:
- Safety of this regimen as per NCI toxicity criteria
- Time to neutrophil and platelet engraftment
- Incidence of acute and chronic GVHD
- Relapse incidence
- Non-relapse mortality
- Overall survival
- Graft versus host disease-relapse free survival (GRFS)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible.
- •Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:
- •ELN17 adverse risk prognostic group irrespective of remission status (see Appendix 2)
- •Measurable residual disease positive (MRD +)
- •Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 3 for details.
- •AML secondary to MDS or MPD
- •Therapy-related AML.
- •Not in complete remission after one course of induction therapy
- •Patients with myelodysplastic syndrome or CMML and one of the following high-risk features:
- •Poor or Very poor cytogenetic risk group as per IPSS-R
- •Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1
- •Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
- •≥ 5% BM blasts at transplant
- •Therapy-related MDS
- •HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available
- •Subject must voluntarily sign an informed consent
- •Female subjects of childbearing potential must have negative results for pregnancy test
- •Adequate hepatic and renal function per local laboratory reference range as follows:
- •Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
- •Bilirubin <1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
- •Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
- •Age ≥ 18 and ≤ 65 years. English and non-English speaking patients are eligible.
- •Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features:
- •ELN22 adverse risk prognostic group irrespective of remission status (see Appendix
- •Measurable residual disease positive (MRD +) including MRD + any time after induction therapy.
- •Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 4 for details.
- •AML secondary to MDS or MPD
- •Therapy-related AML.
- •Not in complete remission after one course of induction therapy
- •Second or higher complete remission
- •Patients with myelodysplastic syndrome and one of the following high-risk features:
- •Poor or Very poor cytogenetic risk group as per IPSS-R
- •Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN11) or ASXL1 or RUNX1 or moderate high, or high, or very high-risk group as per IPSS-M
- •Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.
- •≥ 5% BM blasts at transplant
- •Therapy-related MDS
- •Patients with CMML
- •HLA-identical sibling or a minimum of 7/8 matched unrelated donor
- •Subject must voluntarily sign an informed consent
- •Female subjects of childbearing potential must have negative results for pregnancy test
- •Adequate hepatic and renal function per local laboratory reference range as follows:
- •Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
- •Bilirubin <1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
- •Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
排除标准
- •Subject is known to be positive for HIV.
- •Subject has cognitive impairments and/or is a prisoner.
- •Subject has acute promyelocytic leukemia
- •Subject has known active CNS involvement with AML.
- •Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
- •Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
- •Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
- •Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina;
- •Corrected DLCO < 50% or FEV1 <65%.
- •Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
- •grapefruit or grapefruit products
- •Seville oranges (including marmalade containing Seville oranges)
- •star fruit
- •Patients with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures.
- •Prior allogeneic stem cell transplantation.
研究组 & 干预措施
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Hematopoietic Cell Transplantation (Procedure)
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Thiotepa (Drug)
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Busulfan (Drug)
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Cladribine (Drug)
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Fludarabine Phosphate (Drug)
Treatment (venetoclax, busulfan, fludarabine, cladribine)
Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.
干预措施: Venetoclax (Drug)
结局指标
主要结局
1-year progression free survival (PFS)
时间窗: At 1 year post-transplant
The proportion of patients who are alive without disease relapse (PFS) at one year will be reported along with the corresponding 95% credible interval. Cox proportional hazards regression will be used to assess the association between PFS and clinical and treatment covariates of interest.
次要结局
- Overall survival (OS)(Up to 3 years post-transplant)
- Time to neutrophil engraftment(From the time of transplant up to 3 years)
- Graft-versus (vs.)-host disease-free, relapse-free survival (GRFS)(Up to 3 years post-transplant)
- Incidence of acute and chronic graft-vs.-host disease (GvHD)(Up to 3 years post-transplant)
- Incidence of relapse and non-relapse mortality(Up to 3 years post-transplant)
- Time to platelet engraftment(From the time of transplant up to 3 years)
- Incidence of adverse events(Up to 3 years post-transplant)