Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 17
- 主要终点
- Progression-free Survival
研究概览
简要总结
This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.
详细描述
PRIMARY OBJECTIVE:
I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age
SECONDARY OBJECTIVES:
I. To determine the safety and feasibility of using post-transplantation azacitidine.
II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.
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 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meets one of the following sets of criteria:
- •Myelodysplastic syndromes (MDS):
- •Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:
- •International prognostic scoring system (IPSS) risk >= intermediate-2
- •Refractory anemia with excess blasts by French-American-British (FAB) classification
- •High-risk cytogenetics (either complex or -7)
- •Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
- •Less than 75 years old
- •Acute myeloid leukemia (AML):
- •No FAB M3
- •No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
- •Patients with preceding MDS or treatment-related AML are eligible
- •Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation
- •Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:
- •Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
- •No extramedullary leukemia
- •No blasts in peripheral blood
- •Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy
- •Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
- •Age 60 to 74 years
- •Donors must meet the following criteria:
- •One of the following:
- •HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
- •Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
- •No syngeneic donors
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Calculated creatinine clearance ≥ 40 mL/min
- •Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
- •Aspartate aminotransferase (AST) < 3 times upper limit of normal
- •Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
- •Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •No uncontrolled diabetes mellitus or active serious infections
- •No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
- •No human immunodeficiency virus (HIV) infection or active hepatitis B or C
- •Prior azacitidine or decitabine allowed
- •No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
- •At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery
- •No more than 2 courses of consolidation therapy before transplantation (for patients with AML)
- •Any consolidation regimen that does not require transplantation can be used
- •No more than 6 months from documentation of morphologic CR to transplantation
排除标准
- 未提供
研究组 & 干预措施
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Anti-Thymocyte Globulin (Biological)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Azacitidine (Drug)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Busulfan (Drug)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Fludarabine Phosphate (Drug)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Methotrexate (Drug)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Pharmacological Study (Other)
Treatment (chemotherapy and transplant)
REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).
TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).
CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Progression-free Survival
时间窗: Up to 5 years
Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: * Reappearance of leukemia blast cells in peripheral blood and \> 5% blasts in marrow * If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow \>= 1 week later with \> 5% blasts * Development of extramedullary leukemia MDS progression is defined as * For patients with \<5% bone marrow blasts: ≥50% increase in blasts to \>5% blasts * For patients with 5-10% bone marrow blasts: ≥50% increase to \>10% blasts * Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate
次要结局
- 100-day Mortality(Up to 100 days post-treatment)
- Overall Survival (OS)(Up to 5 years)