Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer
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|ClinicalTrials.gov Identifier: NCT00923845|
Recruitment Status : Completed
First Posted : June 18, 2009
Results First Posted : December 21, 2015
Last Update Posted : September 29, 2017
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.
To determine whether stem cell transplantation using low-dose chemotherapy and sirolimus-generated Th2 cells can cause a remission of advanced kidney cancer.
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.
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).
|Condition or disease||Intervention/treatment||Phase|
|Renal Cell Carcinoma Graft-Versus-Host Disease Engraftment Syndrome||Drug: Pentostatin Drug: Sirolimus Drug: Cyclophosphamide Procedure: Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Procedure: Th2 rapa cells Procedure: Donor Lymphocyte Harvest Procedure: Induction Therapy Procedure: GVHD prophylaxis Procedure: Donor Hematopoietic Stem Cell Harvest||Phase 2|
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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.
Primary objective: (1) Determine whether this new, low-intensity transplant approach can yield objective partial or complete remission of metastatic RCC, with the goal of ruling out a partial response (PR)/complete response (CR) rate of 20% in favor of a rate of 60%.
Secondary objectives: (1) Evaluate the safety and immune-depleting properties of the pentostatin/cyclophosphamide regimen; (2) Characterize the engraftment kinetics and GVHD profile of this new transplant approach; and (3) Characterize post-transplant immunity in study subjects, including cytokine phenotype, immune reconstitution, and potential anti-tumor effector mechanisms.
Adults (18 - 75 years) with metastatic RCC who have an eligible 6/6 human leukocyte antigen (HLA)-matched sibling donor.
Must have had one prior therapy with either sorafenib, sunitinib, or temsirolimus or any other Food and Drug Administration (FDA)-approved agent for therapy of metastatic renal cell carcinoma..
Life expectancy greater than or equal to 3 months, Karnofsky score greater than or equal to 80, relatively normal organ function, and absence of central nervous system (CNS) metastases.
Patients will receive a 21-day course of pentostatin (intravenous infusion on days 1, 8, and 15; 4 mg/m^2 per dose) and daily oral cyclophosphamide (200 mg per day).
Patients will receive a mobilized, T cell-replete allogeneic hematopoietic stem cell graft followed by a pre-emptive donor lymphocyte infusion with donor Th2 cells at day 14 post-transplant. GVHD prophylaxis will consist of a short-course of sirolimus plus maintenance therapy with cyclosporine A.
If greater than or equal to 2/5 partial or complete responses are observed within 6 months post-transplant, the therapy will be considered potentially promising, and will be expanded in a Simon two-stage design to evaluate a total of n = 14 subjects. If greater than or equal to 5/14 PR/CR are achieved, the therapy will be considered worthy of further investigation.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||March 1, 2008|
|Actual Primary Completion Date :||June 1, 2015|
|Actual Study Completion Date :||June 22, 2017|
A sibling who is 6/6 HLA --matched with the recipient. Donors undergo donor lymphocyte harvest and stem cell mobilization and harvest.
Procedure: Donor Lymphocyte Harvest
Procedure: Donor Hematopoietic Stem Cell Harvest
Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
Pentostatin: 2- 4mg/m^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15
Other Name: Nipent
Sirolimus: 4 mg by mouth (PO) on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-stem cell transplant (SCT))
Other Name: Rapamune
Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of hematopoietic stem cell transplant (HSCT)
Other Name: Cytoxan
Procedure: Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
Allogeneic Hematopoietic Stem Cell Transplant
Procedure: Th2 rapa cells
Th2 rapa cell Transplantation
Procedure: Induction Therapy
Pentostatin and cyclophosphamide (PC) conditioning regimen.
Procedure: GVHD prophylaxis
Short course of sirolimus plus maintenance therapy with sirolimus A.
- Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR)) [ Time Frame: 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.
- Count of Participants With Adverse Events [ Time Frame: 50 months and 6 days ]Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
- Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen [ Time Frame: During the 21-day PC regimen ]Absolute neutrophil count determination by complete blood count methodology (Absolute Neutrophil Count (ANC) < 500 Cells/µL).
- Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen [ Time Frame: During the 21-day PC regimen ]Occurrence of infection by Common Terminology Criteria for Adverse Events (CTCAE).
- Immune Depletion in Cluster of Differentiation 4 (CD4) Cells [ Time Frame: Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen) ]Reduction in cluster of differentiation 4 (CD4)+ T cells [change in median values and (range of values)].
- Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells [ Time Frame: Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen) ]Reduction in cluster of differentiation 8 (CD8)+ T cells [change in median values and (range of values)].
- Immune Suppression [ Time Frame: Cytokine analysis at baseline and within 24 hours of completion of the pentostatin/cyclophosphamide regimen ]Immune suppression is defined by the frequency of elimination of a pre-transplant T cell cytokine value.
- Engraftment Donor T Cell and Myeloid Cell Chimerism [ Time Frame: Days 14, 28, 45, and 60 post transplant ]Donor Genetic Elements by variable number tandem repeat-polymerase chain reaction (VNTR-PCR) Analysis.
- Count of Patients With Grade II or Greater Acute Graft Versus Host Disease (GVHD) in First 100 Days Post-Transplant [ Time Frame: 100 days post transplant ]Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD may include rash, diarrhea, and liver damage (i.e. rash Grading: <25% body surface area (BSA) = 1, rash 25-50% BSA = 2, generalized erythroderma = 3, and desquamation and bullae = 4); liver Grading: total bilirubin 2-3 mg/dl = 1, total bilirubin 3-6 mg/dl =2, total bilirubin 6-15 mg/dl =3, and total bilirubin >15 mg/dl = 4)).
- Count of Patients With Late Acute Graft Versus Host Disease (GVHD) After Day 100 Post-Transplant [ Time Frame: 100 days post-transplant through 5 years post-transplant ]Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD grading criteria. Acute GVHD may include rash, diarrhea, and liver damage (i.e. rash Grading: <25% body surface area (BSA) = 1, rash 25-50% BSA = 2, generalized erythroderma = 3, and desquamation and bullae = 4); liver Grading: total bilirubin 2-3 mg/dl = 1, total bilirubin 3-6 mg/dl =2, total bilirubin 6-15 mg/dl =3, and total bilirubin >15 mg/dl = 4)).
- Count of Patients With Chronic Graft Versus Host Disease (GVHD) [ Time Frame: For the duration of post-transplant follow-up ]Chronic GVHD was assessed by the 2005 Chronic GVHD Consensus Project. Chronic GVHS may include dryness of the mouth and eyes, weight loss, liver damage and lung damage leading to cough and shortness of breath (i.e. skin Grading: no symptoms = 0, <18% body surface area (BSA) = 1, 19-50% BSA = 2, and >50% BSA = 3); oral cavity Grading: no symptoms = 0, mild symptoms = 1, moderate symptoms =2 and severe symptoms =3)).
- Cluster of Differentiation 4 (CD4) T Cells Immune Reconstitution [ Time Frame: Days 14, 60, and 100 post transplant ]CD4 T Cells immune reconstitution is defined as distribution of CD4+ T cells subsets within naïve, central memory, effector memory, and effector memory-RA cells analyzed by flow cytometry.
- Cluster of Differentiation 8 (CD8)+ T Cells Immune Reconstitution [ Time Frame: Days 14, 60, and 100 post transplant ]CD8+ T Cells immune reconstitution is defined as distribution of CD8+ T cells subsets within naïve, central memory, effector memory, and effector memory-RA cells analyzed by flow cytometry.
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th2 Transcription Factor GATA Binding Protein 3 (GATA-3) [ Time Frame: Days 14, 60 and 100 post transplant ]Intra-cellular flow cytometry detection of GATA3 transcription factor.
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th1 Transcription Factor T-bet [ Time Frame: Days 14, 60, and 100 post transplant ]CD4+ T cells were analyzed by flow cytometry for intracellular detection of Tbet transcription factor.
- Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the T-reg Transcription Factor Forkhead Box P3 (FoxP3)) [ Time Frame: Days 14, 60, and 100 post transplant ]CD4+ T cells were analyzed by flow cytometry for intracellular expression of FoxP3.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00923845
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Daniel H Fowler, M.D.||National Cancer Institute (NCI)|