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Immunization of Patients With Renal Cancer Using HLA-A2 and HLA-A3-Binding Peptides From Fibroblast Growth Factors 5 (FGF-5)


Phase 2
16 Years
N/A
Not Enrolling
Both
Kidney Cancer

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Trial Information

Immunization of Patients With Renal Cancer Using HLA-A2 and HLA-A3-Binding Peptides From Fibroblast Growth Factors 5 (FGF-5)


Background:

Several preliminary clinical results in the treatment of cancer lend credence to the
hypothesis that augmented T-cell responses will improve IL-2 therapy. A peptide vaccine
derived from the melanoma/melanosomal antigen, GP100, when given with high-dose IL-2
resulted in a response rate over 30% in a small Phase II study. These results have led to
efforts to identify similar T-cells and tumor-associated antigens for IL-2 responsive tumors
such as renal cell cancer. Work in our laboratory generated a renal cancer-reactive T-cell
clone, raised from tumor-infiltrating lymphocytes (TIL) within a renal cell cancer (RCC)
metastasis undergoing spontaneous regression. This clone was HLA-A3 restricted and
recognized autologous tumor as well as a number of allogeneic RCC lines also expressing
HLA-A3. Expression cloning of the antigen recognized by this clone demonstrated that the
RCC-associated antigen being recognized was unmutated fibroblast growth factor 5 (FGF-5).
We concluded from numerous studies that FGF-5 was a tumor associated antigen over-expressed
by a majority of RCC and that it had several favorable characteristics as a target for
immunotherapy. At this point, having demonstrated in the laboratory that tumor-reactive
T-cells generated from patients with renal cancer can recognize naturally presented FGF-5 in
either the context of HLA-A2 or HLA-A3 via the minimal determinants 117-126:FGF-5
(MLSVLEIFAV) or FGF-5:172-176/217-220 (NTYASPRFK), respectively. With this study we plan to
determine if vaccination with these peptides can enhance the number of FGF-5-reactive
cytotoxic T lymphocytes (CTL) precursors in patients with renal cancer or affect the
anticipated response rate from high-dose IL-2.

Objectives:

The primary objective for patients with renal cell carcinoma will be to determine overall
response rates and toxicity of peptide vaccination with HLA-A2 and HLA-A3- binding peptides
from FGF-5 in HLA-appropriate patients, and to explore the effect of such vaccination on the
response rate to high-dose IL-2. The primary objective for patients who are receiving
vaccination in the adjuvant setting will be to evaluate the immunologic responses and
toxicity of FGF-5 peptide vaccination who are likely to receive repeat vaccination prior to
requiring IL-2. The secondary objective is to evaluate the immunologic responses to FGF-5
peptide vaccination.

Eligibility:

Patients who are HLA-A2+ or HLA-A3+, must be age greater than or equal to 16, and have an
expected survival greater than three months. For cohort A and B, patients must have
measurable metastatic renal cancer and FGF-5 tumor expression. For cohort C, patients are
required to have had a Stage III primary tumor (i.e. T3/T4 or N1/N2) excised within the last
6 months.) Patients in cohorts A and B must have tumor sites safely accessible for biopsy
or indications for resection of a site of tumor (e.g. an indicated nephrectomy or
symptomatic metastasis) and be willing to undergo biopsy, and have FGF-5 expression
determined by reverse transcription polymerase chain reaction (RT-PCR) and will only be
eligible if it is detectable. Patients must meet specific safety laboratory criteria. May
not have undergone other systemic therapies for their cancer in the past 3 weeks (6 weeks
for nitrosureas), not have any major medical illnesses, or require systemic steroid therapy.

Design:

Patients will first be divided into cohorts with measurable metastatic disease (Cohorts A
and B) or high-risk loco-regional disease (Cohort C). Patients with measurable metastatic
disease will then be separated into those who require immediate IL-2 therapy (Cohort B) or
those who do not (cohort A).

Cohort A will begin receiving vaccination with HLA-appropriate peptide emulsified in
Montanide ISA-51 or Montanide® (Registered Trademark) ISA 51 VG daily for four days every 3
weeks and will continue this for up to a year, or until tumor progression is documented. At
that point, those ineligible for high-dose IL-2 or who have had previous IL-2 as an
inpatient (considered high dose at doses greater than or equal to 600,000 IU/kg) will be
taken off of study, and those still eligible for IL-2 who have not yet received it, will
have high-dose intravenous bolus IL-2 (720,000 IU/kg/dose every 8 hours up to 12 doses)
added to their peptide vaccination regimen. Two cycles, separated by 10-14 days, will be
given during every two-month period (constitutes a course.). Patients in Cohort A crossing
over to vaccination plus IL-2 therapy, will receive peptide in MONTANIDE ISA-51 or
Montanide® (Registered Trademark) ISA 51 VG vaccination the day prior to starting an IL-2
cycle (instead of every 3 weeks, to accommodate the IL-2 regimen) and repeated daily for
three additional days (for a total of four days) during IL-2 administration.

Patients in Cohort B will begin with high-dose bolus IL-2 therapy in two cycles within every
two month period, with each cycle preceded by a peptide in MONTANIDE ISA-51 or Montanide®
(Registered Trademark) ISA 51 VG vaccine the day prior to starting each IL-2 cycle with
peptide in MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG repeated daily
for three additional days (for a total of four days) during IL-2 administration.

Patients in Cohort C will undergo the same HLA-appropriate vaccination with peptide and
MONTANIDE ISA-51 or Montanide® (Registered Trademark) ISA 51 VG daily for four days every 3
weeks and continue for up to 6 months or until disease relapse is documented. At the time
of relapse, eligible patients in Cohort C will receive treatment with high-dose bolus IL-2
and continuing peptide vaccination using the same schedule as specified for the Cohort A
crossover arm above.

For patients in cohort A on peptide vaccine alone, evaluation will be performed every 3
months during the first 6 months of therapy and if stable, every 3-6 months thereafter. For
cohorts A and B during peptide vaccine plus high-dose IL-2 therapy, evaluation will be
performed every 2 months while on IL-2, and every 3-6 months for stable patients off
therapy. For cohort C, evaluations will be performed every 3 months for the first year and
every 6-12 months thereafter.

The maximal accrual possible would be 210 patients (Cohort A with 80 patients, Cohort B with
66 patients and Cohort C with 64 patients), and maximal enrollment could take up to 5 years.

Inclusion Criteria


- INCLUSION CRITERIA

Patients will be screened for inclusion on this study while participating in the Surgery
Branch protocol 99-C-0128: Evaluation for the National Cancer Institute (NCI) Surgery
Branch Clinical Research Protocols

Patients with clear cell renal carcinoma must fall into one of the two following groups:

For cohort A and B, patients must have measurable metastatic renal cancer and fibroblast
growth factor 5 (FGF-5) tumor expression. For cohort C, patients are required to have had
a Stage III primary tumor (i.e. T3/T4 or N1/N2) excised within the last 6 months.

Patients must be greater than or equal to 16.

Expected survival must be greater than three months

Patients in cohorts A and B must have tumor sites safely accessible for biopsy or
indications for resection of a site of tumor (e.g. an indicated nephrectomy or symptomatic
metastasis) and have FGF-5 expression determined by RT-PCR (reverse transcription
polymerase chain reaction) and will only be eligible if it is detectable.

Must be human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+) or
HLA-A3+.

Serum creatinine of 2.0 mg/dl or less.

Bilirubin 1.6 mg/dl or less, except in patients with Gilbert's syndrome who must have a
total bilirubin less than 3.0 mg/dl.

White blood cell (WBC) 3000/mm or greater.

Platelet count 90,000mm^3 or greater.

Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less then three
times normal.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients of both genders must be willing to practice effective birth control during this
trial and for three months after active treatment on this trial.

Patients who have received previous low dose interleukin-2 (IL-2) (less than 600,000 IU/kg
Food and Drug Administration (FDA) approved dosing regimen) will be eligible.

For cohort A for each human leukocyte antigen (HLA) type, if there are no clinical
responses to vaccine alone in the first 12 patients enrolled, subsequent patients must be
eligible to receive high-dose IL-2.

Patients must be able to understand and sign the informed consent document.

Eligibility for administration of IL-2.

Patients must meet the following criteria to be eligible to receive IL-2:

Patients may not have active major medical illnesses such as cardiac ischemia, myocardial
infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

Patients with recent prolonged history of cigarette smoking or symptoms of respiratory
dysfunction must have a normal pulmonary function test as evidenced by a forced expiratory
volume in 1 second (FEV1) greater than 60% predicted.

Patients with electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia or
arrhythmias or age greater than 50 years will have a normal stress cardiac test (stress
thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram or other
stress test).

Patients must be willing to sign a durable power of attorney (DPA).

Serum creatinine of 2.0 mg/dl or less.

Total bilirubin 2.0 mg/dl or less, except in patients with Gilbert's syndrome who must
have a total bilirubin less than 3.0 mg/dl.

White blood cell (WBC) 3000/mm^3 or greater.

Platelet count 90,000 mm^3 or greater.

EXCLUSION CRITERIA:

Patients will be excluded:

Who are not willing or able to be biopsied.

Who are undergoing or have undergone in the past 3 weeks any other form of therapy for
their cancer, or have undergone nitrosurea therapy within the past 6 weeks. All patients
toxicities must have recovered to a grade 1 or less. Patients may have undergone minor
surgical procedures or local radiotherapy within the past 3 weeks as long as all
toxicities have recovered to a grade 1 or less.

Have active systemic infections, coagulation disorder, or other major medical illnesses of
the cardiovascular or respiratory symptoms or any known immunodeficiency disease (Immune
competence will be defined as lymphocyte count greater than 500 (grade 3 toxicity in
Common Toxicity Criteria (CTC) 3); white blood cell (WBC) 1000; and absence of
opportunistic infections).

Who require systemic steroid therapy.

Who are pregnant (because of possible side effects on the fetus) or who are breastfeeding,
or who are unwilling/unable to practice effective birth control.

Who are known to be positive for hepatitis BsAG, or human immunodeficiency virus (HIV)
antibody, or hepatitis C antibody (unless antigen negative), (because of possible immune
effects of these conditions).

Who have had a known allergic reaction to Incomplete Freund's Adjuvant (MONTANIDE ISA-51)
or hypersensitivity to any agent used on this protocol.

Who have a fresh tumor specimen with no evidence of FGF-5 expression on a technically
adequate RT-PCR assessment.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

Overall response is defined as the best response (e.g. complete response...) recorded from the start of treatment until disease progression/recurrence. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease is at least a 20% increase in the sum of LD of target lesions since the treatment started or the appearance of new lesion. Stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

Outcome Time Frame:

3 years and 9 months

Safety Issue:

No

Principal Investigator

James Yang, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

040259

NCT ID:

NCT00089778

Start Date:

August 2004

Completion Date:

November 2008

Related Keywords:

  • Kidney Cancer
  • Clinical Response
  • Toxicity
  • Immunologic Response
  • Adjuvant
  • IL-2
  • Renal Cancer
  • Carcinoma, Renal Cell
  • Kidney Neoplasms

Name

Location

National Cancer Institute (NCI)Bethesda, Maryland  20892