GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 47
- 试验地点
- 4
- 主要终点
- Methotrexate dose to be used in the phase 2 (Phase 1)
研究概览
简要总结
Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic strategy for many malignant and benign hematologic diseases. Haploidentical HCT has been increasingly used in patients lacking a HLA-matched donor due to its prompt availability, possibly lower cost and results comparable with other donor types. Graft-versus-host disease (GVHD) is the main cause of morbidity and mortality after HSCT, and prophylactic strategies are routinely used. In the context of haploidentical HCT, posttransplant cyclophosphamide plus cyclosporine and mycophenolate mofetil (MMF) is the most common platform used in Brazil. Data comparing MMF and methotrexate (MTX) as GVHD prophylaxes have proved controversial in other donor types, yet some large studies have showed that MTX is associated with lower risk of GVHD and improved long-term outcomes. Moreover, it is known that MMF is a potent inhibitor of natural killer (NK) cells, possibly interfering with the graft-versus-leukemia effect in haploidentical HCT. Given the possible advantages and the absence of consistent evidence regarding safety, efficacy and ideal dosage of MTX as GVHD prophylaxis in this setting, we propose a phase I / II study evaluating this drug in adult patients with hematologic malignancies undergoing haploidentical HCT with posttransplant cyclophosphamide.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 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
- 否
入选标准
- •Diagnosis of acute myeloid leukemia and chronic myeloid leukemia in complete morphologic remission, myelodysplastic syndrome with less than 10% in bone marrow or peripheral blood, Ph-negative acute lymphoblastic leukemia in complete morphologic remission, chemosensitive Hodgkin lymphoma or non-Hodgkin lymphoma in at least partial remission
- •Donor type: haploidentical related donor
- •Graft source: bone marrow or peripheral blood
- •Recipients of non-myeloblative or myeloablative intensity conditioning
- •Left Ventricle Ejection fraction > 40%
- •Estimated creatinine clearance > 40 mL/min
- •Adjusted DLCO ≥ 40% and FEV1 ≥ 40%
- •Total bilirubin < 2x ULN e ALT/AST < 2.5x ULN
排除标准
- •Prior allogeneic transplant
- •Ex-vivo graft manipulation (T-cell-depleted or CD34-selected grafts)
- •Use of alemtuzumab or anti-thymocyte globulin
- •KPS < 70%
- •Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
- •Pregnant or lactating women
- •Patients seropositive for human immunodeficiency virus (HIV) or active hepatitis B or C infection by PCR
- •Presence of fluid collection (ascites, pleural or pericardial effusion) that may interfere with methotrexate clearance or make methotrexate use contraindicated
- •Patients with a serious medical or psychiatric illness likely to interfere with participation in this study
研究组 & 干预措施
Experimental
GVHD prophylaxis will consist of high-dose PTCy (50 mg/kg i.v. on days +3 and +4) with mesna, cyclosporine (initiated on day +5) and methotrexate i.v (see doses on the right). Cyclosporine will be dosed with a target trough of 200 to 250 ng/mL and discontinued without taper at D+60 (if bone marrow graft) or until D+90 (is peripheral blood graft), unless acute GVHD is present. Filgrastim will be administered from day +5 until neutrophil recovery to ≥ 1,000/mcL for 3 days.
干预措施: Methotrexate Injectable Solution (Drug)
结局指标
主要结局
Methotrexate dose to be used in the phase 2 (Phase 1)
时间窗: Day 30
The methotrexate dose to be used in the subsequent phase 2 will be equal to or lower than the maximum tolerated dose (MTD). MTD will be considered exceeded if at least 2 out of 6 subjects on a certain dosing level develop dose-limiting toxicity (DLT). DLT consists of gastrointestinal tract perforation, mediastinitis, airway obstruction requiring orotracheal intubation, severe gastrointestinal bleeding (without evidence of GVHD), graft failure, or hyperbilirubinemia or increase in alanine transaminase \[ALT\] / aspartate transaminase \[AST\] levels \> 5x the upper limit of normal.
GVHD-free, relapse-free survival (Phase 2)
时间窗: Day 365
Relapse, grade 3-4 GVHD and 2014 NIH Chronic GVHD will be considered events, and non-relapse related mortality will be a competing event.
次要结局
- Overall survival(Day 365)
- Cumulative incidence of neutrophil and platelet engraftment(Day 30)
- Cumulative incidence of graft failure(Day 30)
- Cumulative incidence of grade II-IV acute GVHD(Day 100)
- Cumulative incidence of Chronic GVHD(Day 365)
- Change in 36-Item Short Form Health Survey (SF-36)(Baseline, Days 30, 90, 180, and 365)
- Cumulative incidence of grade III-IV acute GVHD(Day 100)
- Cumulative incidence of non-relapse/progression related mortality(Day 365)
- Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey(Baseline, Days 30, 90, 180, and 365)
- Frequency of Grade 3-5 adverse events(Day 30)
- Change in Natural Killer cell function [% activity](Days 30, 90, and 180)
- Change in lymphocyte subsets [absolute number/mcL](Days 30, 90, and 180)
- Cumulative incidence of CMV and EBV reactivation(Day 100)
- Change in bone marrow or peripheral blood donor chimerism [%](Days 30, 90, and 180)
- Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)(Days 12 and 19)