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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Daniel Fowler, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00923845
First received: June 17, 2009
Last updated: July 27, 2017
Last verified: July 2017
  Purpose

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).

Condition Intervention 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

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

Resource links provided by NLM:


Further study details as provided by Daniel Fowler, M.D., National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 25
Actual Study Start Date: March 1, 2008
Estimated Study Completion Date: August 25, 2017
Primary Completion Date: June 1, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Donors
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
Apheresis
Procedure: Donor Hematopoietic Stem Cell Harvest
Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.
Recipients
Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
Drug: Pentostatin
Pentostatin: 2- 4mg/m^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15
Other Name: Nipent
Drug: Sirolimus
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
Drug: Cyclophosphamide
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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).

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00923845

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Daniel H Fowler, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: Daniel Fowler, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00923845     History of Changes
Obsolete Identifiers: NCT00641485
Other Study ID Numbers: 080088
08-C-0088
Study First Received: June 17, 2009
Results First Received: November 16, 2015
Last Updated: July 27, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daniel Fowler, M.D., National Institutes of Health Clinical Center (CC):
Metastatic Renal Cell Carcinoma
Allogeneic Hematopoietic Stem Cell Transplant
Th2 Cells
Sirolimus
Pentostatin
Kidney Cancer
Renal Cell Carcinoma
Metastatic Renal Cell Cancer

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Graft vs Host Disease
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Immune System Diseases
Cyclophosphamide
Sirolimus
Everolimus
Pentostatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on September 20, 2017