A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN #1203; Progress I)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 279
- 试验地点
- 30
- 主要终点
- Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS)
研究概览
简要总结
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.
详细描述
GVHD is a complication that can occur after a bone marrow or stem cell transplant. The transplant recipient's body is attacked by the newly introduced cells. Only about 40% of patients with acute GVHD have durable responses when treated with corticosteroid therapy. A strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an effective approach to improve survival after allogeneic transplantation.
GVHD incidence can be decreased with various treatment plans. Early transplants were done using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later shown to work better than methotrexate. Then doctors discovered that the combined use of cyclosporine and methotrexate worked even better than either agent alone. More recently, other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been conducted to compare available treatment combinations for related and unrelated donors. The combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis.
However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II clinical trial will compare each intervention arm with a Tac/MTX control.
This study will enroll people who have a cancer of the blood or lymph glands and a stem cell transplant is a treatment option. The study will take at least two years and will include 270 participants - 90 participants in each of three treatment groups. The purpose of this study is to compare three combinations of medications to see whether one or more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 years (patient is older than 18.0 and less than 76.0 years old)
- •Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow.
- •Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with chemosensitive disease at time of transplantation
- •Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)
- •Patients must have a related or unrelated peripheral blood stem cell donor as follows:
- •Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation.
- •Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and be medically cleared to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
- •Cardiac function: Ejection fraction at rest ≥ 45%
- •Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
- •Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
- •Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 1.5x the upper limit of normal.
- •Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post transplant (see Section 2.6.4 for definition of postmenopausal).
- •Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post transplant.
- •Signed informed consent
排除标准
- •Prior allogeneic transplant
- •Karnofsky Performance Score < 70%
- •Active central nervous system (CNS) involvement by malignant cells
- •Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
- •Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
- •Patients with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia)
- •Patients seropositive for the human immunodeficiency virus (HIV)
- •Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification tests (NAAT)
- •Patients with hypersensitivity to bortezomib, boron or mannitol
- •Patients with ≥ grade 2 sensory peripheral neuropathy
- •Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
- •Female patients who are lactating or pregnant
- •Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
- •Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
- •Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen.
- •Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI).
- •Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes (CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan metabolism during day -5 through day +
- •It is acceptable to use alternative non-interacting medications during this period, and then resume prior medications.
- •Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including Chronic myelomonocytic leukemia (CMML), with evidence of active myeloproliferative features or myelofibrosis in the background.
研究组 & 干预措施
Tacrolimus/Methotrexate/Maraviroc
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
干预措施: Maraviroc (Drug)
Tacrolimus/Methotrexate/Bortezomib
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
干预措施: Tacrolimus (ARM with Methotrexate) (Drug)
Tacrolimus/Methotrexate/Bortezomib
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
干预措施: Methotrexate (ARM with Bortezomib) (Drug)
Tacrolimus/Methotrexate/Bortezomib
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
干预措施: Bortezomib (Drug)
Tacrolimus/Methotrexate/Maraviroc
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
干预措施: Tacrolimus (ARM with Methotrexate) (Drug)
Tacrolimus/Methotrexate/Maraviroc
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
干预措施: Methotrexate (ARM with Maraviroc) (Drug)
Tacrolimus/MMF/Cyclophosphamide
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
干预措施: Tacrolimus (ARM with MMF and Cyclophosphamide) (Drug)
Tacrolimus/MMF/Cyclophosphamide
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
干预措施: Mycophenolate mofetil (Drug)
Tacrolimus/MMF/Cyclophosphamide
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS)
时间窗: 1 Year Post-transplant
GRFS is defined as being free of grade III-IV acute GVHD onset, chronic GVHD onset requiring systemic immunosuppressive therapy, disease relapse or progression, and death from any cause.
次要结局
- Percentage of Participants With Grade II-IV Acute GVHD(Day 180 Post-transplant)
- Percentage of Participants With Grade III-IV Acute GVHD(Day 180 Post-transplant)
- Percentage of Participants With Chronic GVHD(1 Year Post-transplant)
- Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy(1 Year Post-transplant)
- Percentage of Participants With Disease Relapse or Progression(1 Year Post-transplant)
- Percentage of Participants With Transplant-Related Mortality (TRM)(1 Year Post-transplant)
- Percentage of Participants With Disease-free Survival(1 Year Post-transplant)
- Percentage of Participants With GVHD-free Survival(1 Year Post-transplant)
- Percentage of Participants With Overall Survival(1 Year Post-transplant)
- Percentage of Participants With Neutrophil Recovery(Days 28 and 100 Post-transplant)
- Percentage of Participants With Platelet Recovery(Days 60 and 100 Post-transplant)
- Donor Cell Engraftment(Days 28 and 100 Post-transplant)
- Primary Cause of Death(1 Year Post-transplant)