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| Sponsor: | National Cancer Institute (NCI) |
|---|---|
| Information provided by: | National Institutes of Health Clinical Center (CC) |
| ClinicalTrials.gov Identifier: | NCT00001703 |
Purpose
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 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, 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.
| Condition | Intervention | Phase |
|---|---|---|
|
Renal Cell Carcinoma |
Biological: aldesleukin Biological: incomplete Freund's adjuvant Biological: sargramostim Biological: von Hippel-Lindau peptide vaccine |
Phase II |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Primary Purpose: Treatment |
| Official Title: | Vaccine Therapy With Tumor Specific Mutated VHL Peptides in Adult Cancer Patients With Renal Cell Carcinoma |
| Enrollment: | 6 |
| Study Start Date: | August 1998 |
| Study Completion Date: | November 2008 |
| Primary Completion Date: | November 2008 (Final data collection date for primary outcome measure) |
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Patients must be 18 years of age or older.
Histologic diagnosis of renal cell carcinoma.
Tumor tissue availability for determination of 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.
ECOG performance status of 0 or 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: 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, SGOT, or SGPT greater than 4x normal.
HIV or active Hepatitis B or C (i.e. detectable HBS Antigen or 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 VI cardiac disease - New York Heart Association), a recent history of myocardial infarction (within the last 6 months), history of congestive heart failure, ventricular arrythmias or other arrhythmias requiring therapy, or any other medical conditions that the principal investigator sees to be unfit for such therapy.
History of 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; Goodpasture 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.
Contacts and Locations More Information
| Responsible Party: | Samir N. Khleif, M.D./National Cancer Institute, National Institutes of Health |
| ClinicalTrials.gov Identifier: | NCT00001703 History of Changes |
| Obsolete Identifiers: | NCT00019526 |
| Other Study ID Numbers: | 980139, 98-C-0139 |
| Study First Received: | November 3, 1999 |
| Last Updated: | January 11, 2011 |
| Health Authority: | United States: Federal Government |
|
Immunotherapy Kidney Genes Vaccine Therapy Renal Cell Carcinoma |
|
Carcinoma Carcinoma, Renal Cell Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Adenocarcinoma Kidney Neoplasms Urologic Neoplasms Urogenital Neoplasms Neoplasms by Site Kidney Diseases Urologic Diseases |
Freund's Adjuvant Aldesleukin Adjuvants, Immunologic Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents |
