Low Intensity Allogeneic Hematopoietic Stem Cell Transplantation Therapy of Metastatic Renal Cell Carcinoma Using Early and Multiple Donor Lymphocyte Infusions Consisting of Sirolimus-Generated Donor Th2 Cells
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR))
研究概览
简要总结
Background:
Low-dose chemotherapy is easier for the body to tolerate than typical high-dose chemotherapy and involves a shorter period of complete immune suppression.
Donor immune cells called lymphocytes, or T cells, fight residual tumor cells that might have remained in the recipients body after stem cell transplant, in what is called a graft-versus-tumor (GVT) effect.
The immune-suppressing drug sirolimus appears to help prevent graft-versus-host disease (GVHD), a side effect of stem cell transplant in which donated T cells sometimes attack healthy tissues, damaging organs such as the liver, intestines and skin.
Th2 cells are cells collected from the transplant donor and grown in a high concentration of sirolimus.
Objectives:
To determine whether stem cell transplantation using low-dose chemotherapy and sirolimus-generated Th2 cells can cause a remission of advanced kidney cancer.
Eligibility:
Patients between 18 and 75 years of age who have kidney cancer that has spread beyond the kidney and who have a tissue-matched sibling stem cell donor.
Design:
Patients undergo stem cell transplantation as follows:
- Low-intensity chemotherapy with pentostatin and cyclophosphamide over a 21-day period to reduce the level of the immune system to prepare for the transplant. Pentostatin is given through a vein (intravenous (IV)) on days 1, 8 and 15; cyclophosphamide tablets are taken by mouth for 21 consecutive days.
- Sirolimus tablets, taken by mouth, starting 2 days before the transplant and continuing until 60 days after the transplant.
- IV infusions of stem cells and Th2 cells.
Following the transplant, patients have the following procedures:
- Additional Th2 cell infusions on days 14 and 45 after the transplant.
- Follow-up visits at the National Institutes of Health (NIH) Clinical Center twice a week for the first 6 months after the transplant and then less frequently for at least 5 years to evaluate response to treatment and treatment side effects. Evaluations include a bone marrow aspirate and biopsy 1 month after transplant and periodic blood tests and imaging procedures (e.g., computed tomography (CT) or magnetic resonance imaging (MRI) scans).
详细描述
Background:
Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially effective treatment option for patients with metastatic renal cell carcinoma (RCC).
In a pilot clinical trial in refractory hematologic malignancy subjects, we have found that augmentation of a T cell-replete allograft with donor Th2 cells generated ex vivo in sirolimus (rapamycin; Th2.rapa cells) allows prompt donor engraftment after outpatient-intensity chemotherapy. This transplant approach has been associated with a low incidence of acute graft versus host disease (GVHD).
Based on these data, we seek to safely achieve objective clinical regression of metastatic RCC by the following new transplant approach. (1) The allograft will be administered after a low intensity, outpatient induction chemotherapy regimen consisting of pentostatin and cyclophosphamide. This regimen is intended to provide sufficient host immune T cell depletion, and as such, a conventional preparative regimen will not be administered. (2) To avoid mixed chimerism for rapid potentiation of graft-versus-tumor (GVT) effects, a growth colony stimulating factor (G-CSF) mobilized allograft will be augmented with donor lymphocyte infusion at day 14 post-transplant consisting of Th2.rapa cells.
Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Donors
A sibling who is 6/6 HLA --matched with the recipient. Donors undergo donor lymphocyte harvest and stem cell mobilization and harvest.
干预措施: Donor Lymphocyte Harvest (Procedure)
Donors
A sibling who is 6/6 HLA --matched with the recipient. Donors undergo donor lymphocyte harvest and stem cell mobilization and harvest.
干预措施: Donor Hematopoietic Stem Cell Harvest (Procedure)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Pentostatin (Drug)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Sirolimus (Drug)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Cyclophosphamide (Drug)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Allogeneic Hematopoietic Stem Cell Transplant (HSCT) (Procedure)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Th2 rapa cells (Procedure)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: Induction Therapy (Procedure)
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
干预措施: GVHD prophylaxis (Procedure)
结局指标
主要结局
Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR))
时间窗: 6 Months Post-Transplant (Day +100)
Response was assessed by computed tomography measurements and the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest LD recorded since the treatment started or the appearance of one or more new lesions.
次要结局
- Immune Depletion in Cluster of Differentiation 4 (CD4) Cells(Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen))
- Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen(During the 21-day PC regimen)
- Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells(Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen))
- Count of Patients With Grade II or Greater Acute Graft Versus Host Disease (GVHD) in First 100 Days Post-Transplant(100 days post transplant)
- Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen(During the 21-day PC regimen)
- Count of Patients With Late Acute Graft Versus Host Disease (GVHD) After Day 100 Post-Transplant(100 days post-transplant through 5 years post-transplant)
- Count of Patients With Chronic Graft Versus Host Disease (GVHD)(For the duration of post-transplant follow-up)
- Count of Participants With Adverse Events(50 months and 6 days)
- Immune Suppression(Cytokine analysis at baseline and within 24 hours of completion of the pentostatin/cyclophosphamide regimen)
- Engraftment Donor T Cell and Myeloid Cell Chimerism(Days 14, 28, 45, and 60 post transplant)
- Cluster of Differentiation 4 (CD4) T Cells Immune Reconstitution(Days 14, 60, and 100 post transplant)
- Cluster of Differentiation 8 (CD8)+ T Cells Immune Reconstitution(Days 14, 60, and 100 post transplant)
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th2 Transcription Factor GATA Binding Protein 3 (GATA-3)(Days 14, 60 and 100 post transplant)
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th1 Transcription Factor T-bet(Days 14, 60, and 100 post transplant)
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the T-reg Transcription Factor Forkhead Box P3 (FoxP3))(Days 14, 60, and 100 post transplant)
研究者
Daniel Fowler, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)