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Vaccine Therapy With Tumor Specific Mutated VHL Peptides in Adult Cancer Patients With Renal Cell Carcinoma

Primary Purpose

Renal Cell Carcinoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
incomplete Freund's adjuvant
von Hippel-Lindau peptide vaccine
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring Immunotherapy, Kidney, Genes, Vaccine Therapy, Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must be 18 years of age or older. Histologic diagnosis of renal cell carcinoma. Tumor tissue availability for determination of Von Hippel-Lindau (VHL) mutation (paraffin block, or fresh tissue). Patients must carry a VHL mutation in their tumor. Patients must have metastatic disease for which no further chemotherapy or radiation options, which are known to increase survival, are available. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Expected survival more than 3 months. While measurable disease is preferable, it is not a necessity. The patient should not have received chemotherapy, radiation therapy, immunotherapy or steroids for at least 4 weeks prior to starting vaccination, and should have recovered from all acute toxicities of previous treatment. Patients must understand and sign an informed consent document that explains the neoplastic nature of his/her disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, and potential risks and toxicities. Exclusion Criteria: Any condition that does not fit with the inclusion criteria. Any of the following: White blood cells (WBC) less than 2000/mm(3); Platelets less than 100K/mm (3); Creatinine greater than 2.0 mg/dl; Serum Bilirubin greater than 2.0 mg/dl, Serum glutamic oxaloacetic transaminase (SGOT), or Serum glutamic pyruvic transaminase (SGPT) greater than 4x normal. Human Immunodeficiency virus (HIV) or active Hepatitis B or C (i.e. detectable Hepatitis B surface (HBS) Antigen or Heteroconjugate (HC) antibodies). Pregnant women or nursing mothers are ineligible. Women with reproductive potential must have negative urine pregnancy test. Women of reproductive potential must use adequate contraception. Patients with active ischemic heart disease (i.e. Class III or IV cardiac disease)-New York Heart Association), a recent history of myocardial infarction (within the last 6 months), history of congestive heart failure, ventricular arrhythmias or other arrhythmias requiring therapy, or any other medical conditions that the principal investigators sees to be unfit for such therapy. History of Central Nervous System (CNS) metastases. Patients with history of autoimmune disease e.g. (autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; systemic lupus erythematosus, Sjogren syndrome, or scleroderma; myasthenia grave's; Good pasture syndrome; Addison's disease, Hashimoto's thyroiditis, rheumatoid arthritis, multiple sclerosis, or active Graves' disease). If, in the opinion of the principal or associate investigators, it is not in the best medical interest of the patient to enter this study, the patient will be ineligible.

Sites / Locations

  • National Cancer Institute, National Institutes of Health

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Group A-VHL peptide and ISA-51 adjuvant

Arm Description

Patients are vaccinated with 1000 micrograms of the mutant Von Hipple-Lindau (VHL) peptide administered subcutaneously along with ISA-51 adjuvant (Montanide ISA-51 adjuvant, Incomplete Freund's adjuvant) and injected subcutaneously every four weeks for a total of four vaccinations.

Outcomes

Primary Outcome Measures

Percentage of Participants Who Generated an Immune Response
The immunological response was assessed by in-vitro T cell cytokine production enzyme-linked immunosorbent spot (ELISPOT). From each patients, post-vaccination peripheral blood mononuclear cells (PBMC) were compared to pre-vaccination as a baseline. A positive ELISPOT result for the patients was defined as a total number of experimental spots in the post-vaccination sample of more than twofold above the total spots in the pre-vaccination sample.

Secondary Outcome Measures

The Number of Participants With Adverse Events.
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Full Information

First Posted
November 3, 1999
Last Updated
July 16, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00001703
Brief Title
Vaccine Therapy With Tumor Specific Mutated VHL Peptides in Adult Cancer Patients With Renal Cell Carcinoma
Official Title
Vaccine Therapy With Tumor Specific Mutated VHL Peptides in Adult Cancer Patients With Renal Cell Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
July 2014
Overall Recruitment Status
Terminated
Why Stopped
Due to poor accrual and lack of peptide vaccine
Study Start Date
August 1998 (undefined)
Primary Completion Date
November 2008 (Actual)
Study Completion Date
November 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
About 27,000 new cases of renal cell carcinoma (RCC) are diagnosed every year in the United States. 11,000 of these cases will die from the disease. More than half of patients present with advanced or metastatic disease for which chemotherapy plays a very limited role. Therefore, development of another therapeutic approach is needed. Cancers in humans are commonly associated with mutations in dominant and recessive oncogenes. These genes produce mutated proteins that are unique to cancer cells. Von Hipple-Lindau (VHL) gene which is associated with the development of the VHL disease, has been recently mapped and cloned, and it is found to be mutated in 57% of sporadic renal cell carcinomas. Data in mice have shown the generation of major histocompatibility complex (MHC) restricted cytotoxic T lymphocyte (CTL) that are capable of detecting endogenous cytoplasmic peptide derived from mutated oncogenes. In addition, we have recently demonstrated, by conducting different phase I clinical trials in which we vaccinate cancer patients with mutated Ras or p53 peptides corresponding to the abnormality patients harbor in their tumors, that in some patients we can generate immunological responses represented by the generation of lymphocytes (CD4+ and/or CD8+). In the current study, we would like to extend our observations to test whether VHL tumor suppressor protein can be immunologically targeted by vaccination. We have identified specific epitopes along the amino acid sequence of the VHL protein, which represent known specific human leukocyte antigen (HLA) class-I binding motifs. These amino acids stretches in the VHL protein correspond to the area of the point mutation hot spots. Therefore, we propose to treat patients with sporadic RCC who carry VHL mutations in their tumors with corresponding mutant VHL peptide vaccination. This vaccination will be done either by using pulsed-autologous peripheral mononuclear cells with the peptides, or peptides administered subcutaneously alone or in combination with cytokines.
Detailed Description
About 27,000 new cases of renal cell carcinoma (RCC) are diagnosed every year in the United States. 11,000 of these cases will die from the disease. More than half of patients present with advanced or metastatic disease for which chemotherapy plays a very limited role. Therefore, development of another therapeutic approach is needed. Cancers in humans are commonly associated with mutations in dominant and recessive oncogenes. These genes produce mutated proteins that are unique to cancer cells. Von Hipple-Lindau gene, which is associated with the development of the VHL disease, has been recently mapped and cloned; it is found to be mutated in 57% of sporadic renal cell carcinomas. Data in mice have shown the generation of MHC restricted CTL that are capable of detecting endogenous cytoplasmic peptide derived from mutated oncogenes. In addition, we have recently demonstrated, by conducting different phase I clinical trials in which we vaccinate cancer patients with mutated Ras or p53 peptides corresponding to the abnormality patients harbor in their tumors, that in some patients we can generate immunological responses represented by the generation of lymphocytes (CD4+ and/or CD8+). In the current study, we would like to extend our observations to test whether VHL tumor suppressor protein can be immunologically targeted by vaccination. We have identified specific epitopes along the amino acid sequence of the VHL protein which represent known specific HLA class-I binding motifs. These amino acids stretches in the VHL protein correspond to the area of the point mutation hot spots. Therefore, this protocol treats patients with sporadic RCC who carry VHL mutations in their tumors with corresponding mutant VHL peptide vaccination.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma
Keywords
Immunotherapy, Kidney, Genes, Vaccine Therapy, Renal Cell Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A-VHL peptide and ISA-51 adjuvant
Arm Type
Experimental
Arm Description
Patients are vaccinated with 1000 micrograms of the mutant Von Hipple-Lindau (VHL) peptide administered subcutaneously along with ISA-51 adjuvant (Montanide ISA-51 adjuvant, Incomplete Freund's adjuvant) and injected subcutaneously every four weeks for a total of four vaccinations.
Intervention Type
Biological
Intervention Name(s)
incomplete Freund's adjuvant
Other Intervention Name(s)
ISA-51, Montanide ISA-51 adjuvant
Intervention Description
0.7 ml of ISA-51 (Montanide ISA-51 adjuvant, incomplete Freund's adjuvant) will be mixed with peptide alone and injected subcutaneously every four weeks for a total of four vaccinations.
Intervention Type
Biological
Intervention Name(s)
von Hippel-Lindau peptide vaccine
Intervention Description
1000 micrograms administered subcutaneously every four weeks for a total of four vaccinations.
Primary Outcome Measure Information:
Title
Percentage of Participants Who Generated an Immune Response
Description
The immunological response was assessed by in-vitro T cell cytokine production enzyme-linked immunosorbent spot (ELISPOT). From each patients, post-vaccination peripheral blood mononuclear cells (PBMC) were compared to pre-vaccination as a baseline. A positive ELISPOT result for the patients was defined as a total number of experimental spots in the post-vaccination sample of more than twofold above the total spots in the pre-vaccination sample.
Time Frame
30 months
Secondary Outcome Measure Information:
Title
The Number of Participants With Adverse Events.
Description
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame
88 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must be 18 years of age or older. Histologic diagnosis of renal cell carcinoma. Tumor tissue availability for determination of Von Hippel-Lindau (VHL) mutation (paraffin block, or fresh tissue). Patients must carry a VHL mutation in their tumor. Patients must have metastatic disease for which no further chemotherapy or radiation options, which are known to increase survival, are available. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Expected survival more than 3 months. While measurable disease is preferable, it is not a necessity. The patient should not have received chemotherapy, radiation therapy, immunotherapy or steroids for at least 4 weeks prior to starting vaccination, and should have recovered from all acute toxicities of previous treatment. Patients must understand and sign an informed consent document that explains the neoplastic nature of his/her disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, and potential risks and toxicities. Exclusion Criteria: Any condition that does not fit with the inclusion criteria. Any of the following: White blood cells (WBC) less than 2000/mm(3); Platelets less than 100K/mm (3); Creatinine greater than 2.0 mg/dl; Serum Bilirubin greater than 2.0 mg/dl, Serum glutamic oxaloacetic transaminase (SGOT), or Serum glutamic pyruvic transaminase (SGPT) greater than 4x normal. Human Immunodeficiency virus (HIV) or active Hepatitis B or C (i.e. detectable Hepatitis B surface (HBS) Antigen or Heteroconjugate (HC) antibodies). Pregnant women or nursing mothers are ineligible. Women with reproductive potential must have negative urine pregnancy test. Women of reproductive potential must use adequate contraception. Patients with active ischemic heart disease (i.e. Class III or IV cardiac disease)-New York Heart Association), a recent history of myocardial infarction (within the last 6 months), history of congestive heart failure, ventricular arrhythmias or other arrhythmias requiring therapy, or any other medical conditions that the principal investigators sees to be unfit for such therapy. History of Central Nervous System (CNS) metastases. Patients with history of autoimmune disease e.g. (autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; systemic lupus erythematosus, Sjogren syndrome, or scleroderma; myasthenia grave's; Good pasture syndrome; Addison's disease, Hashimoto's thyroiditis, rheumatoid arthritis, multiple sclerosis, or active Graves' disease). If, in the opinion of the principal or associate investigators, it is not in the best medical interest of the patient to enter this study, the patient will be ineligible.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Samir N Khleif, M.D.
Organizational Affiliation
National Cancer Institute, National Institutes of Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Cancer Institute, National Institutes of Health
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
1553577
Citation
Stahl M, Wilke HJ, Seeber S, Schmoll HJ. Cytokines and cytotoxic agents in renal cell carcinoma: a review. Semin Oncol. 1992 Apr;19(2 Suppl 4):70-9. No abstract available.
Results Reference
background
PubMed Identifier
7855621
Citation
Stadler WM, Vogelzang NJ. Low-dose interleukin-2 in the treatment of metastatic renal-cell carcinoma. Semin Oncol. 1995 Feb;22(1):67-73. No abstract available.
Results Reference
background
PubMed Identifier
7855620
Citation
Parkinson DR, Sznol M. High-dose interleukin-2 in the therapy of metastatic renal-cell carcinoma. Semin Oncol. 1995 Feb;22(1):61-6. No abstract available.
Results Reference
background
Links:
URL
http://ghr.nlm.nih.gov/
Description
Genetics Home Reference
URL
http://www.nlm.nih.gov/medlineplus/
Description
MedlinePlus
URL
http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp
Description
Drug Information
URL
http://www.clinicaltrials.gov/ct2/info/fdalinks
Description
U.S. FDA Resources

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Vaccine Therapy With Tumor Specific Mutated VHL Peptides in Adult Cancer Patients With Renal Cell Carcinoma

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