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

July 16, 2014 updated by: National Cancer Institute (NCI)

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

6

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Cancer Institute, National Institutes of Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A-VHL peptide and ISA-51 adjuvant
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.
Biological: incomplete Freund's adjuvant
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.
Other Names:
  • ISA-51
  • Montanide ISA-51 adjuvant
Biological: von Hippel-Lindau peptide vaccine
1000 micrograms administered subcutaneously every four weeks for a total of four vaccinations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Who Generated an Immune Response
Time Frame: 30 months
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.
30 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Number of Participants With Adverse Events.
Time Frame: 88 months
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
88 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Samir N Khleif, M.D., National Cancer Institute, National Institutes of Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 1998

Primary Completion (Actual)

November 1, 2008

Study Completion (Actual)

November 1, 2008

Study Registration Dates

First Submitted

November 3, 1999

First Submitted That Met QC Criteria

November 3, 1999

First Posted (Estimate)

November 4, 1999

Study Record Updates

Last Update Posted (Estimate)

July 25, 2014

Last Update Submitted That Met QC Criteria

July 16, 2014

Last Verified

July 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 980139
  • 98-C-0139 (Other Identifier: Clinical Center, National Institutes of Health)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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