A Phase I Feasibility Study of an Intraprostatic PSA-Based Vaccine in Men With Prostate Cancer With Local Failure Following Radiotherapy or Cryotherapy or Clinical Progression on Androgen Deprivation Therapy in the Absence of Local Definitive Therapy
A Phase I Feasibility Study of an Intraprostatic PSA-Based Vaccine in Men With Prostate Cancer With Local Failure Following Radiotherapy or Cryotherapy or Clinical Progression on Androgen Deprivation Therapy in the Absence of Local Definitive Therapy
Background:

 -  Pox viral vectors can induce a PSA-specific T-cell responses and clinical responses in
 patients with advanced prostate cancer.

 -  Intratumoral vaccines of recombinant fowlpox vectors appear to be more potent in
 inducing antitumor effects than the s.c. route of administration, especially when the
 recombinant rF-vector given intratumorally is preceded by a rV-recombinant given s.c.
 This may be due to:

 -  Making the tumor cell an antigen presenting cell via upregulation of both antigen
 (signal 1) and costimulatory molecules (signal 2).

 -  Making the tumor cell more susceptible to killing via upregulation of ICAM.

 -  The increased expression of perforin in peptide-specific T cells that came into contact
 with the TRICOM-infected targets.

 -  Potentially allowing the immune system to select for other tumor encoded antigens to
 generate a polyvalent immune response.

 Objectives:

 -  1: Safety and feasibility of an intraprostatic vaccine strategy.

 -  2: To assess the change in PSA-specific T-cell response as measured by ELISPOT assay.

 -  2: To evaluate T-cell infiltration histologically in patients who have pre- and
 post-vaccine prostate biopsies.

 Eligibility:

 -  Must have either a) biopsy proven, locally recurrent prostate cancer following local
 radiation as defined by the ASTRO consensus criteria as 3 consecutively rising PSA
 levels or b) have refused or not be candidates for local definitive therapy (surgery or
 radiation therapy) and have clinically progressive disease on androgen deprivation
 therapy (eg. three increases in PSA over nadir, separated by at least one week). For
 patients with previous RT, 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.

 -  Hepatic function: Bilirubin < 1.5 mg/dl, AST and ALT< 2.5 times upper limit of normal

 Design:

 -  Dose escalation Phase I design. Each cohort will consist of 3-6 patients, with cohorts 4
 & 5 restricted to include only HLA-A2 + patients; maximum accrual is 30

 -  Patients in all cohorts receive initial priming with rV- PSA(L155)/TRICOM and rF-GM-CSF
 s.c.

 -  The first two cohorts utilize a booster intraprostatic with dose escalation of
 rF-PSA(L155)/TRICOM.

 -  Third and fourth cohorts add dose escalations of rF-GM-CSF along with the highest dose
 of rF-PSA(L155)/TRICOM

 -  Last (5th) cohort u...
Background:

 -  Pox viral vectors can induce a PSA-specific T-cell responses and clinical responses in
 patients with advanced prostate cancer.

 -  Intratumoral vaccines of recombinant fowlpox vectors appear to be more potent in
 inducing antitumor effects than the s.c. route of administration, especially when the
 recombinant rF-vector given intratumorally is preceded by a rV-recombinant given s.c.
 This may be due to:

 -  Making the tumor cell an antigen presenting cell via upregulation of both antigen
 (signal 1) and costimulatory molecules (signal 2).

 -  Making the tumor cell more susceptible to killing via upregulation of ICAM.

 -  The increased expression of perforin in peptide-specific T cells that came into contact
 with the TRICOM-infected targets.

 -  Potentially allowing the immune system to select for other tumor encoded antigens to
 generate a polyvalent immune response.

 Objectives:

 -  1: Safety and feasibility of an intraprostatic vaccine strategy.

 -  2: To assess the change in PSA-specific T-cell response as measured by ELISPOT assay.

 -  2: To evaluate T-cell infiltration histologically in patients who have pre- and
 post-vaccine prostate biopsies.

 Eligibility:

 -  Must have either a) biopsy proven, locally recurrent prostate cancer following local
 radiation as defined by the ASTRO consensus criteria as 3 consecutively rising PSA
 levels or b) have refused or not be candidates for local definitive therapy (surgery or
 radiation therapy) and have clinically progressive disease on androgen deprivation
 therapy (eg. three increases in PSA over nadir, separated by at least one week). For
 patients with previous RT, 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.

 -  Hepatic function: Bilirubin less than 1.5 mg/dl, AST and ALT less than 2.5 times upper
 limit of normal.

 Design:

 -  Dose escalation Phase I design. Each cohort will consist of 3-6 patients; maximum
 accrual is 30

 -  Patients in all cohorts receive initial priming with rV- PSA(L155)/TRICOM and rF-GM-CSF
 s.c.

 -  The first two cohorts utilize a booster intraprostatic with dose escalation of
 rF-PSA(L155)/TRICOM.

 -  Third and fourth cohorts add dose escalations of rF-GM-CSF along with the highest dose
 of rF-PSA(L155)/TRICOM.

 -  Last (5th) cohort utilizes booster intraprostatic vaccine (rF-PSA(L155)/TRICOM and
 rF-GM-CSF) with simultaneous identical booster vaccine given s.c.
-  INCLUSION CRITERIA:

 A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
 Pathology at: NIH 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 either a) biopsy proven, locally recurrent prostate cancer following local
 radiation or cyrotherapy as defined by the ASTRO consensus criteria as 3 consecutively
 rising PSA levels or b) have refused or not be candidates for local definitive therapy
 (surgery or radiation therapy) and have clinically progressive disease on androgen
 deprivation therapy (e.g., three increases in PSA over nadir, separated by at least one
 week). For patients with previous RT, 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 (see Appendix A).

 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, see Appendix
 D).

 Granulocyte count greater than or equal to 1,500/mm3

 Platelet count greater than or equal to 100,000/mm3

 Lymphocyte count greater than or equal to 500/mm3

 Hgb greater than or equal to 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 60mL/min, proteinuria less than 1000 milligrams per 24
 hours, and no abnormal sediment. Serum creatinine not above normal limits OR creatinine
 clearance on a 24 hour urine collection of greater than 60 mL/min. 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 equal to 1.5 mg/dL or patients with Gilbert's syndrome, a
 total bilirubin less than or equal to 3.0 mg/dL, AST and ALT less than 2.5 times upper
 limit 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 this
 study. This test may be drawn by the patient's referring physician at the time of referral
 (see Screening Consent for HLA typing). 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.

 P. PT / PTT will be drawn prior to any invasive protocol related procedure (i.e., prostate
 biopsy or intraprostatic injection) and standard clinical guidelines followed.

 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.

 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.