Low-Intensity Stem Cell Transplantation With Multiple Lymphocyte Infusions to Treat Advanced Kidney Cancer

Study Overview
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Brief Summary
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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).

Detailed Description
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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: 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. Eligibility: 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. Design: 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.

Official Title
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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

Conditions
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Renal Cell Carcinoma, Graft-Versus-Host Disease, Engraftment Syndrome

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Recipient Diagnosis of metastatic renal cell carcinoma, either clear cell type or non-clear cell type. The diagnosis must be confirmed by the Laboratory of Pathology of National Cancer Institute (NCI) or Hackensack (there will be no central pathology review). The consent process will include a discussion of the potential role of high-dose interleukin-2 (IL-2) therapy prior to protocol enrollment. High-dose IL-2 therapy is not widely available, but may be available on an NCI protocol (Dr. Yang) or through Dr. Alter for Hackensack patients. IL-2 therapy may also be administered by any other qualified physician; the Novartis web-site has a list of such physicians. For subjects who are deemed to be eligible for high-dose IL-2 and elect to receive this therapy, such subjects must have progressive disease post-IL-2 to enter this study; such subjects must also have received and have had progressive disease after therapy with one of the agents listed below. Subject must have progressive disease after therapy consisting of one of the following Food and Drug Administration (FDA)-approved agents: sorafenib, sunitinib, or temsirolimus. Patients 18 - 75 years of age. Subjects older than 75 will not be enrolled due to an increased rate of transplant-related complications. Must have consenting sibling matched at 6/6 human leukocyte antigen (HLA) antigens (A, B, DR). Patient or legal guardian must be able to give informed consent. All previous therapy must be completed at least 2 weeks prior to study entry. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less. Karnofsky performance status greater than or equal to 80%. Life expectancy of at least 3 months. Left ventricular ejection fraction greater than 40% (multi-gated acquisition scan (MUGA) or echo) within 28 days of enrollment. Carbon monoxide diffusing capacity (DLCO) greater than 50% of expected value (hemoglobin (Hb) corrected), obtained within 28 days of enrollment. Creatinine clearance greater than or equal to 40 ml/min. Creatinine clearance will be determined by testing of a 24 hour urine collection and simultaneous serum creatinine value. In previous studies, the creatine clearance of patients with metastatic renal cell cancer who underwent nephrectomy was 53 plus or minus 19. Serum total bilirubin less than 2.5 mg/dl, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of normal. ALT and AST values above these levels may be accepted (up to a maximum of 5 times the upper limit of normal), at the discretion of the principal investigator (PI) or study chairperson, if such elevations are thought to be due to liver involvement by malignancy. INCLUSION CRITERIA : Donor Sibling who is 6/6 HLA-matched with recipient. Ability to give informed consent. Age 18 years to 80 years. Donors older than 80 will not be eligible due to potentially increased complications from the donation procedure. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis. Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface antigen negative, and hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient. Donors with a history of hepatitis B or hepatitis C infections may be eligible. However, eligibility determination of such patients will require a hepatology consultation. The risk/benefit of the transplant and the possibility of transmitting hepatitis will be discussed with the patient and eligibility will then be determined by the principal investigator. A donor who is lactating must substitute formula feeding for her infant during the period of cytokine administration. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known. Limited clinical data suggest that administration of filgrastim or to neonates is not associated with adverse outcomes. EXCLUSION CRITERIA: Recipient Active infection that is not responding to antimicrobial therapy. Active central nervous system (CNS) involvement by malignancy. HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with concomitant positive hepatitis B surface antigen, patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with the patient and eligibility determined by the principal investigator and protocol chairperson. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C will be discussed with the patient and eligibility determined by the principal investigator and protocol chairperson. Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception from the time of study entry to at least one year post-transplant; effective methods include intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner s vasectomy, or barrier methods (condom, diaphragm, or cervical cap). Males on the protocol, and their partners of child-bearing potential, must also use an effective form of contraception at study entry and for one year post-transplant. The effects of the chemotherapy, the subsequent transplant, and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant; therefore, women should not breastfeed during the interval from study entry to one year post-transplant. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by principal investigator or study chairman). EXCLUSION CRITERIA: Donor History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. History of hypertension that is not controlled by medication, stroke, or severe heart disease. Individuals with symptomatic angina will be considered to have severe heart disease and will not be eligible to be a donor. No other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident). Patients with a history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-by-case basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient. Donors must not be pregnant. The effects of cytokine therapy on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception from the time of study entry until at least one year post-transplant. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Donors<br>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<br>* Apheresis<br>Procedure: Donor Hematopoietic Stem Cell Harvest<br>* Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.<br>|
| Other: Recipients<br>Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis. | Drug: Pentostatin<br>* Pentostatin: 2- 4mg/m^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15<br>* Other names: Nipent;Drug: Sirolimus<br>* Sirolimus: 4 mg by mouth (PO) on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-stem cell transplant (SCT))<br>* Other names: Rapamune;Drug: Cyclophosphamide<br>* Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of hematopoietic stem cell transplant (HSCT)<br>* Other names: Cytoxan;Procedure: Allogeneic Hematopoietic Stem Cell Transplant (HSCT)<br>* Allogeneic Hematopoietic Stem Cell Transplant<br>Procedure: Th2 rapa cells<br>* Th2 rapa cell Transplantation<br>Procedure: Induction Therapy<br>* Pentostatin and cyclophosphamide (PC) conditioning regimen.<br>Procedure: GVHD prophylaxis<br>* Short course of sirolimus plus maintenance therapy with sirolimus A.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Regression of Metastatic Renal Cell Carcinoma (Partial Response (PR)) or Complete Remission of Tumor (Complete Response (CR)) | 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. | 6 Months Post-Transplant (Day +100) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 50 months and 6 days | 
| Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen | Absolute neutrophil count determination by complete blood count methodology (Absolute Neutrophil Count (ANC) < 500 Cells/µL). | During the 21-day PC regimen | 
| Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen | Occurrence of infection by Common Terminology Criteria for Adverse Events (CTCAE). | During the 21-day PC regimen | 
| Immune Depletion in Cluster of Differentiation 4 (CD4) Cells | Reduction in cluster of differentiation 4 (CD4)+ T cells [change in median values and (range of values)]. | Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen) | 
| Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells | Reduction in cluster of differentiation 8 (CD8)+ T cells [change in median values and (range of values)]. | Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen) | 
| Immune Suppression | Immune suppression is defined by the frequency of elimination of a pre-transplant T cell cytokine value. | Cytokine analysis at baseline and within 24 hours of completion of the pentostatin/cyclophosphamide regimen | 
| Engraftment Donor T Cell and Myeloid Cell Chimerism | Donor Genetic Elements by variable number tandem repeat-polymerase chain reaction (VNTR-PCR) Analysis. | Days 14, 28, 45, and 60 post transplant | 
| Count of Patients With Grade II or Greater Acute Graft Versus Host Disease (GVHD) in First 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)). | 100 days post transplant | 
| Count of Patients With Late Acute Graft Versus Host Disease (GVHD) After Day 100 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)). | 100 days post-transplant through 5 years post-transplant | 
| Count of Patients With Chronic Graft Versus Host Disease (GVHD) | 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)). | For the duration of post-transplant follow-up | 
| Cluster of Differentiation 4 (CD4) T Cells Immune Reconstitution | 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. | Days 14, 60, and 100 post transplant | 
| Cluster of Differentiation 8 (CD8)+ T Cells Immune Reconstitution | 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. | 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) | Intra-cellular flow cytometry detection of GATA3 transcription factor. | Days 14, 60 and 100 post transplant | 
| Percentage of Cluster of Differentiation 4 (CD4)+ T Cells Expressing the Th1 Transcription Factor T-bet | CD4+ T cells were analyzed by flow cytometry for intracellular detection of Tbet transcription factor. | 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)) | CD4+ T cells were analyzed by flow cytometry for intracellular expression of FoxP3. | Days 14, 60, and 100 post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Renal Cell Carcinoma, Allogeneic Hematopoietic Stem Cell Transplant, Th2 Cells, Sirolimus, Pentostatin, Kidney Cancer, Renal Cell Carcinoma, Metastatic Renal Cell Cancer