A Phase I/II Study of Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events
研究概览
简要总结
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL); however, human leukocyte antigen (HLA)-matched donor availability continues to be a major hurdle. Historically, HLA haploidentical donor hematopoietic cell transplantation (haplo-HCT) was associated with high incidences of graft rejection and excessive non-relapse mortality (NRM), but recent advances utilizing post-transplant cyclophosphamide (PT-Cy) have revolutionized haplo-HCT and the outcomes are now comparable to allo-HCT using more traditional HLA matched related and unrelated donors. However, graft-versus-host disease (GvHD) continues to be a problem and is associated with significant morbidity and mortality in allo-HCT patients including those who receive haplo-HCT on PT-Cy platform. The aim of this early phase study is to investigate the safety and overall efficacy of azacitidine in reducing the incidence and severity of GvHD when added to PT-Cy based haplo-HCT platform for patients with AML, ALL, or advanced MDS.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of acute leukemia (AML/ALL) or advanced MDS (INT-2 or high risk) in complete remission (CR/CRc/CRi) documented by bone marrow biopsy done within 30 days prior to the initiation of conditioning regimen.
- •Available HLA-haploidentical donor that meets the following criteria:
- •Immediate family member (sibling, offspring, or parent)
- •At least 18 years of age
- •HLA-haploidentical donor/recipient match by class I serologic typing at the A&B locus.
- •In the treating physician's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC
- •No active hepatitis (B, C), HTLV, and HIV infections
- •Not pregnant
- •Karnofsky performance status ≥ 70 %
- •Adequate organ function as defined below:
- •Total bilirubin ≤ 2.5 mg/dl (unless the patient has a history of Gilbert's syndrome)
- •AST(SGOT) and ALT(SGPT) ≤ 3.0 x IULN
- •Creatinine ≤ 2.0 x IULN OR estimated creatinine clearance ≥ 30 mL/min/1.73 m^2 by Cockcroft-Gault Formula
- •Oxygen saturation ≥ 90% on room air
- •LVEF ≥ 40%
- •FEV1 and FVC ≥ 50% predicted, corrected DLCO ≥ 40% predicted
- •At least 18 years of age at the time of study registration
- •Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)
排除标准
- •Recipients with donor sensitive antibodies (DSA), defined by 2000 or higher MFI against one or more class I or II antigens
- •Known HIV or active Hepatitis B or C infection
- •Underwent a previous related or unrelated allogeneic transplant
- •Known hypersensitivity to one or more of the study agents
- •Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of the conditioning regimen.
- •Pregnant and/or breastfeeding
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmias.
- •Presence of a readily available 6/6 matched sibling donor who is a candidate for donation
研究组 & 干预措施
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Fludarabine (Drug)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Fractionated total body irradiation (Radiation)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Busulfan (Drug)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Cyclophosphamide (Drug)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Single dose total body irradiation (Radiation)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Melphalan (Drug)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Granulocyte-colony stimulating factor (Drug)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Stem cell transplant (Procedure)
Arm 1: Azacitidine
-
Treating physician must choose from one of these conditioning regimens (will be given per standard of care)
-
fludarabine and fractionated total body irradiation (Flu/FrTBI)
-
fludarabine and busulfan (Flu/Bu4)
-
fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
-
fludarabine and melphalan (Flu/Mel)
-
reduced-intensity fludarabine and busulfan (Flu/Bu2)
-
G-CSF from Day -5 through Day -1 per standard of care
-
On Day 0, the allograft will be infused per standard of care.
-
Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
-
Cyclophosphamide on Days +3 and +4 post-transplant
干预措施: Azacitidine (Drug)
结局指标
主要结局
Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events
时间窗: Up to Day 35
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Maximum tolerated dose of azacitidine (Phase I only)
时间窗: Estimated to be 3-4 months (completion of all Phase I patients through Day 35)
Grade II-IV acute GvHD rate of azacitidine (Phase II only)
时间窗: Up to Day 100
次要结局
- Non-relapse mortality (NRM)(Up to Day 100)
- Event-free survival (EFS)(Up to 48 months)
- Overall survival (OS)(Up to 48 months)
- Disease-free survival (DFS)(Up to 48 months)
- Time to neutrophil engraftment(Up to 12 months)
- Time to platelet engraftment(Up to 12 months)
- Rate of acute GvHD(Up to Day 100)
- Rate of chronic GvHD(Day 100 through Day 365)