NCT00001703

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.

Trial Health

57
Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
6

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Aug 1998

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
terminated

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

August 1, 1998

Completed
1.3 years until next milestone

First Submitted

Initial submission to the registry

November 3, 1999

Completed
1 day until next milestone

First Posted

Study publicly available on registry

November 4, 1999

Completed
9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 1, 2008

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

November 1, 2008

Completed
3.6 years until next milestone

Results Posted

Study results publicly available

June 14, 2012

Completed
Last Updated

July 25, 2014

Status Verified

July 1, 2014

Enrollment Period

10.3 years

First QC Date

November 3, 1999

Results QC Date

May 17, 2011

Last Update Submit

July 16, 2014

Conditions

Renal Cell Carcinoma

Keywords

ImmunotherapyKidneyGenesVaccine TherapyRenal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

  • 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.

    30 months

Secondary Outcomes (1)

  • The Number of Participants With Adverse Events.

    88 months

Study Arms (1)

Group A-VHL peptide and ISA-51 adjuvant

EXPERIMENTAL

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 adjuvantBiological: von Hippel-Lindau peptide vaccine

Interventions

incomplete Freund's adjuvantBIOLOGICAL

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.

Also known as: ISA-51, Montanide ISA-51 adjuvant
Group A-VHL peptide and ISA-51 adjuvant
von Hippel-Lindau peptide vaccineBIOLOGICAL

1000 micrograms administered subcutaneously every four weeks for a total of four vaccinations.

Group A-VHL peptide and ISA-51 adjuvant

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

National Cancer Institute, National Institutes of Health

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

  • 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.

    PMID: 1553577BACKGROUND

  • 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.

    PMID: 7855621BACKGROUND

  • 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.

    PMID: 7855620BACKGROUND

Related Links

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

incomplete Freund's adjuvantmontanide ISA 51

Condition Hierarchy (Ancestors)

AdenocarcinomaCarcinomaNeoplasms, Glandular and EpithelialNeoplasms by Histologic TypeNeoplasmsKidney NeoplasmsUrologic NeoplasmsUrogenital NeoplasmsNeoplasms by SiteFemale Urogenital DiseasesFemale Urogenital Diseases and Pregnancy ComplicationsUrogenital DiseasesKidney DiseasesUrologic DiseasesMale Urogenital Diseases

Limitations and Caveats

Patients were enrolled to Arm A only due to poor accrual and the lack of peptide vaccine.

Results Point of Contact

Title
Samir N. Khleif, M.D.
Organization
National Cancer Institute, National Institutes of Health
khleifs@mail.nih.gov
301-496-0901

Study Officials

  • Samir N Khleif, M.D.

    National Cancer Institute, National Institutes of Health

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
NIH

Study Record Dates

First Submitted

November 3, 1999

First Posted

November 4, 1999

Study Start

August 1, 1998

Primary Completion

November 1, 2008

Study Completion

November 1, 2008

Last Updated

July 25, 2014

Results First Posted

June 14, 2012

Record last verified: 2014-07

Locations

US(1)