This trial is active, not recruiting.

Conditions renal cell carcinoma, graft-versus-host disease, engraftment syndrome
Treatments pentostatin, sirolimus, cyclophosphamide, allogeneic hematopoietic stem cell transplant, th2 rapa cells
Phase phase 2
Targets mTOR, FKBP-12
Sponsor National Cancer Institute (NCI)
Start date March 2008
End date June 2015
Trial size 25 participants
Trial identifier NCT00923845, 08-C-0088, 080088, NCT00641485



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 recipient s 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 (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 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., CT or MRI scans).

United States No locations recruiting
Other countries No locations recruiting

Study Design

Endpoint classification efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Induction Therapy
Pentostatin: 2- 4mg/m2(CrCL based dosing) IV on days 1, 8, and 15
Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of HSCT
Alllogeneic cell Therapy
allogeneic hematopoietic stem cell transplant
Allogeneic Hematopoietic Stem Cell Transplant
th2 rapa cells
Th2 rapa cell Transplantation
GVHD Prophylaxis
Sirolimus: 4 mg PO on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-SCT)
th2 rapa cells
Th2 rapa cell Transplantation

Primary Outcomes

The frequency of subjects that achieve a partial remission of tumor (PR) or complete remission of tumor (CR)
time frame: 6 Months Post-Transplant

Secondary Outcomes

Immune depleting effect and immune supressive effects of pentostatin + cyclophosphamide
time frame: End of Treatment
Characterize the pattern of alloengraftment observed after this low-intensity transplant approach.
time frame: Ongoing
Evaluate any anti-tumor effector mechanism
time frame: Ongoing
To characterize the safety
time frame: End of Treatment

Eligibility Criteria

Male or female participants from 18 years up to 75 years old.

- 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 NCI or Hackensack (there will be no central pathology review). The consent process will include a discussion of the potential role of high-dose 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 FDA-approved agents: sorafenib, sunitib, 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 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% (MUGA or echo) within 28 days of enrollment. DLCO greater than 50% of expected value (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 ALT and 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 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 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 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).

Additional Information

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
Principal investigator Daniel H Fowler, M.D.
Description 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 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 GVT effects, a 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 PR/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 HLA-matched sibling donor. Must have had one prior therapy with either sorafenib, sunitib, or temsirolimus or any other 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 CNS metastases. Design: Patients will receive a 21-day course of pentostatin (intravenous infusion on days 1, 8, and 15; 4 mg/m2 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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2015.
Information provided to ClinicalTrials.gov by National Institutes of Health Clinical Center (CC).
Location data was received from the National Cancer Institute and was last updated in February 2017.