Allogeneic Hematopoietic Cell Transplantation With HLA-matched Donors : a Phase II Randomized Study Comparing 2 Nonmyeloablative Conditionings
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 107
- 试验地点
- 11
- 主要终点
- Percentage of Participants With Grade II-IV Acute GVHD Between the 2 Groups
研究概览
简要总结
The present project aims at comparing two nonmyeloablative regimens currently used in 2 major HCT centers in the US for patients with HLA-matched related or unrelated donor: the one from the Seattle group consisting of 2 Gy TBI with fludarabine (90 mg/m²) versus the one from the Stanford group combining 8 Gy TLI with ATG.
详细描述
I. OBJECTIVES
The present project aims at comparing two nonmyeloablative regimens currently used in 2 major HCT centers in the US for patients with HLA-matched related or unrelated donor: the one from the Seattle group consisting of 2 Gy TBI with fludarabine (90 mg/m²) versus the one from the Stanford group combining 8 Gy TLI with ATG.
II. DESIGN OF THE STUDY
The study is a multicenter, randomized phase II study, comparing two conditioning regimens. Sixty patients with HLA-matched donors will be randomized between the TBI or the DLI regimen. There will be a stratification between centers. There will be a stopping rule for graft rejection > 15% at day 180 (in each group separately), and for nonrelapse mortality > 35% at day 180 (in each group separately). If the stopping rules are not triggered after 60 patients and no statistically significant differences are seen between the 2 arms in terms of acute GVHD, graft rejection and survival, a second cohort of 40 patients will be included.
III. TREATMENT PLAN
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Hematological malignancies confirmed histologically and not rapidly progressing:
- •AML in CR (defined as ≤ 5% marrow blasts and absence of blasts in the peripheral blood);
- •MDS with ≤ 5% marrow blasts and absence of blasts in the peripheral blood;
- •CML in CP;
- •MPS not in blast crisis and not with extensive marrow fibrosis,
- •ALL in CR;
- •Multiple myeloma not rapidly progressing;
- •Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);
- •Hodgkin's disease with chemosensitive disease.
- •Clinical situations
- •Theoretical indication for a standard allo-transplant, but not feasible because:
- •Age > 50 yrs;
- •Unacceptable end organ performance;
- •Patient's refusal.
- •Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
- •Other inclusion criteria
- •Male or female; fertile patients must use a reliable contraception method;
- •Age < 75 yrs;
- •Informed consent given by patient or his/her guardian if of minor age.
- •Related to the recipient (sibling, parent or child) or unrelated;
- •Male or female;
- •10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched;
- •Weight > 15 Kg (because of leukapheresis);
- •Fulfills criteria for allogeneic PBSC donation according to standard procedures;
- •Informed consent given by donor or his/her guardian if of minor age, as per donor center standard procedures.
排除标准
- •Any condition not fulfilling inclusion criteria;
- •HIV positive;
- •Non-hematological malignancy(ies) (except non-melanoma skin cancer) < 3 years before nonmyeloablative HCT.
- •Life expectancy severely limited by disease other than malignancy;
- •Administration of cytotoxic agent(s) for "cytoreduction" within three weeks prior to initiating the nonmyeloablative transplant conditioning (Exceptions are hydroxyurea and imatinib mesylate);
- •CNS involvement with disease refractory to intrathecal chemotherapy.
- •Terminal organ failure, except for renal failure (dialysis acceptable)
- •Uncontrolled infection;
- •Karnofsky Performance Score <70%;
- •Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment;
- •Patient is a female who is pregnant or breastfeeding;
- •Previous radiation therapy precluding the use of 2 Gy TBI or 8 Gy TLI;
- •Any condition not fulfilling inclusion criteria;
- •Unable to undergo leukapheresis because of poor vein access or other reasons.
研究组 & 干预措施
TLI + ATG
Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7.
干预措施: Conditioning regimen:TLI (8 Gy) + ATG (Drug)
TBI + fludarabine
Conditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells.
干预措施: Conditioning regimen: TBI + Fludarabine (Drug)
结局指标
主要结局
Percentage of Participants With Grade II-IV Acute GVHD Between the 2 Groups
时间窗: 180 days after HCT
Percentage of participants with aGVHD according grades: Grade I: rash skin \< 25 % area; bilirubin: 20-30 mg/ml; diarrhea: 500-1000 ml/day Grade II: rash skin 25-50 % area; bilirubin: 30-60 mg/ml; diarrhea: 10000-1500 ml/day Grade III:rash skin \> 50 % area; bilirubin: 60-150 mg/ml; diarrhea: \>1500 ml/day Grade IV: erythroderma; bilirubin: \> 150 mg/ml; diarrhea: \>2000 ml/day Grade IV is the worst grade Patients given a second allogeneic HCT were censured for GVHD analyses.
次要结局
- Number of Participants With Graft Rejection as Defined by Whole Blood and T Cell Chimerism(1 year after HCT)
- Percentage of Participants With Chronic GVHD in the 2 Groups(2 years after HCT)
- Incidences of Bacterial, Fungal and Viral Infections in the 2 Groups.(D100 after HCT)
- Percentage of Relapse Rate in the 2 Groups(1 year after HCT)
- Quality and Timing of Immunologic Reconstitution: Concentration of ATG Levels(Day 0, Day 3 and Day 10)
- Percentage of Non Relapse Mortality in the 2 Groups(1 year after HCT)
- Percentage of 4-year Progression Free Survival in the 2 Groups(4 year after HCT)
- Percentage of 5-year Progression Free Survival in the 2 Groups(5 year after HCT)
- Percentage of 4-year Overall Survival in the 2 Groups(4 year after HCT)
- Percentage of 5-year Overall Survival in the 2 Groups(5 year after HCT)