A Phase 2 Single Arm Trial of HLA-Matched Transplants, CD34+ Enriched, T-Cell Depleted Peripheral Blood Stem Cells Isolated by CliniMACS System in the Treatment of Patients With AML in 1st or 2nd Morphologic Complete Remission (BMTCTN0303)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 15
- 主要终点
- Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint)
研究概览
简要总结
This study is a single arm Phase II, multicenter trial. It is designed to determine whether the anticipated endpoints for a T cell depleted transplant arm of a planned prospective randomized trial comparing T cell depleted and unmodified hematopoietic allografts are likely to be achieved in a multicenter study conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN or Network). The study population is patients with acute myeloid leukemia (AML) in first or second morphologic complete remission. The enrollment is 45 patients.
Based on published results of unmodified transplants from HLA-matched siblings applied to patients with AML in first or second morphologic complete remission, a significant improvement in results with a graft modified as specified in this protocol would be expected if disease-free survival (DFS) at 6 months was greater than 75%, the true incidence of transplant-related mortality at 1 year was less than 30%, and the DFS rate at 2 years was greater 70% for patients transplanted in first remission and less than 60% for patients transplanted in second remission. Additional secondary endpoints include the following: graft failure rate and incidences of acute grade II-IV and chronic graft-versus-host disease (GVHD). Additionally, the trial will have target specific doses of CD34+ progenitors and CD3+ T cells to be obtained following fractionation with the CliniMACS system. Based on the results of this trial, a Phase III trial comparing T cell depleted peripheral blood stem cell transplants (PBSCT) with unmanipulated bone marrow or unmanipulated PBSCT will be designed.
详细描述
BACKGROUND:
Allogeneic hematopoietic cell transplantation is an accepted therapy for AML. Transplants of unmodified HLA-matched related bone marrow or peripheral blood stem cells following conditioning with total body irradiation (TBI) and cyclophosphamide or VP-16 or busulfan and cyclophosphamide have led to sustained DFS rates of 45-60% for adults transplanted in first complete remission (CR1) and 40-53% for patients transplanted in second complete remission (CR2). In several single center and multicenter cooperative group prospective trials comparing HLA-matched allogeneic transplants to chemotherapy in the treatment of AML in CR1, DFS rates for the transplant arm were almost invariably superior; however, these advantages were statistically significant in only a minority of the cooperative group studies conducted. In each study, the risk of relapse was significantly lower for patients receiving allogeneic transplants. However, this advantage was counterbalanced by transplant-related mortality, principally reflecting infections complicating GVHD and its treatment.
DESIGN NARRATIVE:
Despite increased risks of infection, development of effective T cell depletion (TCD) techniques for prevention of GVHD and tolerable modifications of regimens for pre-transplant cytoreduction that secure consistent engraftment offer the potential for significant decreases in transplant-related mortality. Furthermore, the use of TCD transplants in the treatment of patients with AML is not associated with substantial increases in the incidence of relapse. Several single center trials indicate highly encouraging long-term results, particularly for patients with AML in CR1 or CR2. Although the number of cases in each single center series is limited, the consistency of the results suggests that the use of an effective technique for TCD together with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified grafts.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with AML with or without prior history of myelodysplastic syndrome based on the World Health Organization criteria at the following stages:
- •First morphologic complete remission (CR)
- •Second morphologic CR
- •If prior history of central nervous system (CNS) involvement, no evidence of active CNS leukemia during the pre-transplant evaluation (no evidence of leukemic blasts in cerebrospinal fluid)
- •First or second CR was achieved after no more than two cycles of induction (or re-induction for patients in second CR) chemotherapy
- •No more than 6 months elapsed from documentation of CR to transplant for patients in first CR, or 3 months for patients in second CR.
- •A 6/6 HLA antigen (A, B, DRB1)-compatible sibling donor; the match may be determined at serologic level for HLA-A and HLA-B loci; DRB1 must be matched at least at low-resolution using DNA typing techniques; HLA-C will be typed at the serologic level, but not included in the match algorithm
- •Karnofsky performance status greater than 70%
- •Life expectancy greater than 8 weeks
- •Diffusing capacity of the lung for carbon monoxide (DLCO) of at least 40% (corrected for hemoglobin) with no symptomatic pulmonary disease
- •Left ventricular ejection fraction (LVEF) by Multi Gated Acquisition Scan (MUGA) or echocardiogram greater than 40%
- •Serum creatinine greater than 2 mg/dL, bilirubin greater than 2 mg/dL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least 3 times the upper limit of normal at time of enrollment
- •Willingness of both the patient and the donor to participate
排除标准
- •M3-AML (acute promyelocytic leukemia) in first CR
- •Acute leukemia following blast transformation of prior chronic myelogenous leukemia (CML) or other myeloproliferative disease
- •M4Eo-AML with inv 16 in first CR
- •AML with t(8;21) in first CR
- •Participation in other clinical trials that involve investigational drugs or devices except with permission from the Medical Monitor
- •Evidence of active Hepatitis B or C infection or evidence of cirrhosis
- •HIV positive
- •Uncontrolled diabetes mellitus
- •If proven or probable invasive fungal infection, infection must be controlled; patients may be on prophylactic anti-fungal agents, but are not permitted to be on anti-fungal agents for therapeutic purposes (i.e., active treatment for disease)
- •Uncontrolled viral or bacterial infection (currently taking medication without clinical improvement)
- •Documented allergy to iron dextran or murine proteins
- •Pregnant or breastfeeding; women of childbearing age must avoid becoming pregnant while in the study
- •Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)
结局指标
主要结局
Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint)
时间窗: 6 months
The primary analysis will consist of estimating the 6-month DFS (from day of enrollment) probability based on the Kaplan-Meier product limit estimator. The 6-month DFS probability and confidence interval will be calculated. All registered patients will be considered for this analysis.
次要结局
- Platelet Engraftment(6 Months)
- Acute Graft Versus Host Disease (GVHD)(Day 100)
- Determination of Infusional Toxicity(28 day)
- Leukemia Relapse(Months 12 and 36)
- Graft Failure(Day 100)
- Chronic Graft Versus Host Disease (GVHD)(Year 2)
- Disease-free Survival (DFS)(Months 6, 12, and 36)
- Overall Survival(Months 12 and 36)
- CD34+ and CD3+ Cell Doses(Day 0)
- Neutrophil Engraftment(28 day)
- Transplant Related Mortality(Months 12, 24, and 36)
- Post-transplant Lymphoproliferative Disorder (PTLD)(Year 2)