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

NCT00923845 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 08008808-C-0088
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Renal Cell Carcinoma; Graft-Versus-Host Disease; Engraftment Syndrome

Keywords

Metastatic Renal Cell Carcinoma; Allogeneic Hematopoietic Stem Cell Transplant; Th2 Cells; Sirolimus; Pentostatin; Kidney Cancer; Renal Cell Carcinoma; Metastatic Renal Cell Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Count of Participants With Adverse Events

  50 months and 6 days

• Count of Patients Having Neutropenia Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen

  During the 21-day PC regimen

• Count of Patients Having an Infectious Complication Attributable to the Pentostatin and Cyclophosphamide (PC) Regimen

  During the 21-day PC regimen

• Immune Depletion in Cluster of Differentiation 4 (CD4) Cells

  Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)

• Immune Depletion in Cluster of Differentiation 8 (CD8)+ T Cells

  Baseline and day 21 (completion of the pentostatin/cyclophosphamide regimen)

Study Arms (2)

Donors

OTHER

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

Recipients

OTHER

Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.

Drug: Pentostatin; Drug: Sirolimus; Drug: Cyclophosphamide; Procedure: Allogeneic Hematopoietic Stem Cell Transplant (HSCT); Procedure: Th2 rapa cells; Procedure: Induction Therapy; Procedure: GVHD prophylaxis

Interventions

Pentostatin DRUG

Pentostatin: 2- 4mg/m\^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15

Also known as: Nipent

Recipients

Sirolimus DRUG

Sirolimus: 4 mg by mouth (PO) on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-stem cell transplant (SCT))

Also known as: Rapamune

Recipients

Cyclophosphamide DRUG

Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of hematopoietic stem cell transplant (HSCT)

Also known as: Cytoxan

Recipients

Allogeneic Hematopoietic Stem Cell Transplant (HSCT) PROCEDURE

Allogeneic Hematopoietic Stem Cell Transplant

Recipients

Th2 rapa cells PROCEDURE

Th2 rapa cell Transplantation

Recipients

Donor Lymphocyte Harvest PROCEDURE

Apheresis

Donors

Induction Therapy PROCEDURE

Pentostatin and cyclophosphamide (PC) conditioning regimen.

Recipients

GVHD prophylaxis PROCEDURE

Short course of sirolimus plus maintenance therapy with sirolimus A.

Recipients

Donor Hematopoietic Stem Cell Harvest PROCEDURE

Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.

Donors

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Sibling who is 6/6 HLA-matched with recipient.
• Ability to give informed consent.

You may not qualify if:

• 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).
• 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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma. Semin Oncol. 2006 Oct;33(5):527-33. doi: 10.1053/j.seminoncol.2006.06.010.

  PMID: 17045081 BACKGROUND

• Shuch BM, Lam JS, Belldegrun AS, Figlin RA. Prognostic factors in renal cell carcinoma. Semin Oncol. 2006 Oct;33(5):563-75. doi: 10.1053/j.seminoncol.2006.06.006.

  PMID: 17045085 BACKGROUND

• Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, De La Taille A, Tostain J, Artibani W, Abbou CC, Lobel B, Guille F, Chopin DK, Mulders PF, Wood CG, Swanson DA, Figlin RA, Belldegrun AS, Pantuck AJ. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005 Apr 20;23(12):2763-71. doi: 10.1200/JCO.2005.07.055.

  PMID: 15837991 BACKGROUND

• Mossoba ME, Halverson DC, Kurlander R, Schuver BB, Carpenter A, Hansen B, Steinberg SM, Ali SA, Tageja N, Hakim FT, Gea-Banacloche J, Sportes C, Hardy NM, Hickstein DD, Pavletic SZ, Khuu H, Sabatini M, Stroncek D, Levine BL, June CH, Mariotti J, Rixe O, Fojo AT, Bishop MR, Gress RE, Fowler DH. High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. Clin Cancer Res. 2015 Oct 1;21(19):4312-20. doi: 10.1158/1078-0432.CCR-15-0340. Epub 2015 Jun 12.

  PMID: 26071480 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Renal Cell; Graft vs Host Disease; Kidney Neoplasms

Interventions

Pentostatin; Sirolimus; Cyclophosphamide; Neoadjuvant Therapy

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Coformycin; Formycins; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Combined Modality Therapy; Therapeutics

Results Point of Contact

• Title: Dr. Daniel Fowler
• Organization: National Cancer Institute

fowlerda@mail.nih.gov

301-435-8641

Study Officials

• Daniel H Fowler, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: March 1, 2008
• Primary Completion: June 1, 2015
• Study Completion: June 22, 2017
• Last Updated: September 29, 2017
• Results First Posted: December 21, 2015

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)