This study will evaluate whether it is safe and suitable to use an intraprostatic vaccine strategy, that is, vaccine administered into the prostate gland, for prostate cancer patients whose cancer has recurred following radiation therapy. A live virus vaccine known as vaccinia, to be given underneath the skin, will contain the genes for prostate-specific antigen (PSA) and other molecules. Researchers will look at the response of T-cells, or helper cells, in blood.

Prostate cancer is the most common cancer diagnosis in American males and the second leading cause of cancer death. One out of 11 men will develop clinically significant prostate cancer in his lifetime. It has been estimated that during 2004, more than 220,000 men in this country will be diagnosed with the disease, and 29,000 will die from it. About 30% to 40% of patients will not experience successful results from localized therapy from radiation or surgery. Depriving the body of androgen, a male sex hormone, has been the major therapy in beginning treatments of cancer that has spread. Although that treatment can lower the level of PSA, side effects are numerous. There are few other options for treatment.

Patients age 18 or older who have confirmed cases of prostate cancer, have had locally recurrent cancer proven through a biopsy, and whose life expectancy is equal to or greater than 6 months may be eligible for this study.

Patients will undergo the following procedures and tests:

- Medical history and physical examination, including measurement of height and weight.

- Blood tests, including complete blood count and other measurements.

- Additional tests for acute care, including electrolytes.

- Tests for the liver and minerals.

- Urinalysis and other studies of the urine.

A process called aphersis will also be conducted. It involves collection of the patient's blood, which is then separated into blood components, and the remaining blood is then transfused to the patient. A prostate biopsy will be encouraged, but it is an optional procedure for patients. A typical reaction in patients who have never received vaccinia or received it long ago includes a red swelling, followed by a blister after 5 to 6 days and then a boil 1/2 inches in diameter from 9 to 11 days after injection. There may be a large area of redness. A crusted scab usually forms by the second week and falls off by the third week, with a scar remaining, about 1/2 inch in diameter. Fever and a feeling of general illness may occur. Swollen and tender lymph glands may continue for months. Patients previously vaccinated with vaccinia typically experience, in 2 to 3 days, a small swelling that may enlarge to 1 to 2 inches across, a small blister after 5 to 7 days, and healing with little scarring within 2 to 3 weeks. For fever or aches, acetaminophen (Tylenol) can be used, but aspirin should be avoided. Patients will be given instructions about caring for the vaccination site, activities to avoid, and caution regarding contact with other people, to avoid spreading the virus. Patients will be monitored on the day of the vaccination and on days 29, 57, 85, and 113. They will come off the study after day 113 and will be followed up yearly according to guidelines set by the Food and Drug Administration, for up to 15 years.

Condition	Treatment or Intervention	Phase
Prostatic Neoplasms	Drug: Recombinant Vaccinia-PSA(L155)/TRICOM (PROSTVAC-V/TRICOM)  Drug: Recombinant Fowlpox-PSA(L155)/TRICOM (PROSTVAC-F/TRICOM)  Drug: Recombinant Fowlpox-GM-CSF	Phase I

Further Study Details: 

Expected Total Enrollment:  30

This trial is a collaborative effort of the Urologic Oncology Branch and the Laboratory of Tumor Immunology and Biology (LTIB) and involves the use of vaccine vectors and strategies pioneered at the LTIB. It is designed to evaluate the safety and feasibility of an intraprostatic vaccine strategy in prostate cancer patients with biopsy proven local recurrence of disease following radiation therapy. There are no standard treatment options for these patients with almost universally incurable disease. The vaccine strategy includes priming with subcutaneous (s.c.) recombinant vaccinia containing the genes for prostate specific antigen (PSA) and a triad of costimulatory molecules, B7-1, ICAM-1 and LFA-3 (designated TRICOM) (rV- PSA(L155)/TRICOM), with subsequent monthly boosts using intraprostatic injections of recombinant fowlpox-PSA(L155)/TRICOM (rF- PSA(L155)/TRICOM) with and without rF-GM-CSF. PSA(L155) is the human PSA gene with an HLA-A2 agonist epitope resulting from a single amino acid modification of PSA, which has been shown to enhance immunogenicity.

An important secondary objective of this trial is to evaluate the immunologic effects of the intraprostatic vaccine strategy alone versus simultaneous booster injections of intraprostatic and s.c. vaccine (cohorts 4 and 5). Immunological effects will be assessed on multiple levels. We plan to measure the PSA-specific T-cell response with immunoassay of peripheral blood before and after vaccination while an analysis of prostatic T-cell infiltrate will be assessed histologically.

This study utilizes a dose escalation Phase I design. The first two cohorts utilize a booster intraprostatic dose escalation of rF-PSA(L155)/TRICOM, while the third and fourth cohorts test the safety of dose escalations of rF-GM-CSF along with rF-PSA(L155)/TRICOM. The final cohort utilizes booster intraprostatic vaccine (rF-PSA(L155)/TRICOM and rF-GM-CSF) with simultaneous identical booster vaccine given s.c. Patients in all cohorts receive initial priming with rV- PSA(L155)/TRICOM and rF-GM-CSF s.c. The maximum accrual to the trial is 30, with 3-6 patients in each of the five cohorts. We project that we will complete accrual within 30 months.

Genders Eligible for Study:  Male

Criteria

INCLUSION CRITERIA:
A. Histopathological documentation of prostate cancer confirmed in the Laboratory of Pathology at: Warren Grant Magnuson Clinical Center, National Institutes of Health (NIH), the National Naval Medical Center, or Walter Reed Army Medical Center prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist's report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.
B. Must have biopsy proven, locally recurrent prostate cancer following local radiation as defined by the ASTRO consensus criteria as 3 consecutively rising PSA levels. The biopsy confirming local recurrence must be done at least 18 months after the completion of RT. Since this may also generate a systemic immune response, patients with minimal extraprostatic disease may be enrolled.
C. Agree to use adequate contraception prior to study entry and for at least 4 months following the last vaccine injection.
D. Life expectancy greater than or equal to 6 months.
E. ECOG performance status of 0 to 2.
F. Recovered from any acute toxicity related to prior therapy, including surgery, and radiation (treatment must have been completed at least 4 weeks prior to being eligible for the study).
G. Hematological eligibility parameters (within 16 days of starting therapy).
-Granulocyte count equal to or greater than 1,500/mm3
-Platelet count equal to or greater than 100,000/mm3
-Lymphocyte count equal to or greater than 500/mm3
-Hgb equal to or greater than 10 Gm/dL
H. Biochemical eligibility parameters (within 16 days of starting therapy):
-A 24-hour urine collection for baseline to measure creatinine clearance, protein and electrolytes. CrCl greater than 60, proteinuria less than 1000 milligrams per 24 hours, and no abnormal sediment. Serum creatinine within normal limits. For patients who are not able to obtain an accurate collection, a calculated creatinine clearance and urine analysis for protein may be used. Any abnormalities in the sediment or the presence of hematuria without a likely underlying cause should prompt the investigator to consider an evaluation by a nephrologist or urologist for evidence of underlying renal pathology. Patients may be eligible if the underlying cause of the abnormality is determined to be non-renal.
-Hepatic function: Bilirubin less than 1.5 mg/dl, AST and ALT less than 2.5 times upper limit of normal
-PT/PTT within the institution limits of normal
I. No other active malignancies within the past 12 months (with the exception of non-melanoma skin cancers or carcinoma in situ of the bladder) or life threatening illnesses.
J. Willing to travel to the NIH for follow-up visits.
K. 18 years of age or greater.
L. Vaccinia-naive or vaccinia immune.
M. Able to understand and sign informed consent.
N. Tested for HLA-A2; however, the results of this test will not affect entry into first 3 cohorts of this study. This test may be drawn by the patient's referring physician at the time of referral (see Screening Consent for HLA typing). Patients in cohorts 4 and 5 must be HLA-A2 positive. This consent will be mailed to the patient and discussed with patient. The signed consent will be signed with a non-family member witness and then mailed to the assigned research nurse at the NIH Clinical Center.
O. Concurrent hormonal therapy will be allowed.
EXCLUSION CRITERIA:
A. Patients should have no evidence of being immunocompromised as listed below.
-Human immunodeficiency virus positivity due to the potential for decreased tolerance and may be at risk for severe side effects
-Active autoimmune diseases such as, Addison's disease, Hashimoto's thyroiditis, or systemic lupus erythematous, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome active Grave's disease. Patients with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI tract will be allowed
-Hepatitis B or C positivity
-Concurrent use of systemic steroids, except for physiologic doses for systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Steroid eye drops are contraindicated for at least 2 weeks prior vaccinia vaccination and at least 4 weeks post vaccinia vaccination.
B. History of allergy or untoward reaction to prior vaccination with vaccinia virus or to any component of the vaccinia vaccine regimen.
C. Must be able to avoid close household contact (close household contacts are those who share housing or have close physical contact) for at least three weeks after recombinant vaccinia vaccination with: persons with active or a history of eczema or other eczematoid skin disorders; those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds) until condition resolves; pregnant or nursing women; children 3 years of age and under; and immunodeficient or immunosuppressed persons (by disease or therapy), including HIV infection. (see Appendix B)
D. Serious intercurrent medical illness which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis.
E. Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with ordinary physical activity (New York Heart Association class 2 or greater) are not eligible.
F. Patients who have objective evidence of congestive heart failure by physical exam or imaging are not eligible.
G. Patients with pulmonary disease that have fatigue or dyspnea with ordinary physical activity are not eligible.
H. Concurrent chemotherapy.
I. Clinically active brain metastasis, or with a history of seizures, encephalitis, or multiple sclerosis.
J. Serious hypersensitivity reaction to egg products.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050017; 05-C-0017
Record last reviewed:  December 14, 2004
Last Updated:  February 17, 2005
Record first received:  November 9, 2004
ClinicalTrials.gov Identifier:  NCT00096551
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08