A Phase II Study of PROSTVAC-V (Vaccinia)/TRICOM and PROSTVAC-F (Fowlpox)/TRICOM With GM-CSF in Patients With PSA Progression After Local Therapy for Prostate Cancer

Study Overview
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Brief Summary
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Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Biological therapies, such as GM-CSF, may stimulate the immune system in different ways and stop tumor cells from growing. Androgens can cause the growth of prostate cancer cells. Drugs, such as bicalutamide and goserelin, may stop the adrenal glands from making androgens in patients whose tumor cells continue to grow. Giving vaccine therapy together with GM-CSF and, when needed, androgen ablation may be a more effective treatment for prostate cancer. This phase II trial is studying how well giving vaccine therapy together with GM-CSF works in treating patients with prostate cancer that progressed after surgery and/or radiation therapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the effect of PROSTVAC-V/TRICOM (Vaccinia) on cycle 1 followed by PROSTVAC-F/TRICOM (Fowlpox) and GM-CSF on biochemical PSA progression at 6 months. II. To determine the change in PSA velocity pre-treatment to post-treatment. SECONDARY OBJECTIVES: I. To evaluate the percentage of patients experiencing a >50% decline in serum PSA repeated at 4 weeks. II. To evaluate tolerability and any toxicity related to treatment with PSA vaccine and GM-CSF. III. To determine the effect of GM-CSF on PSA immediately after treatment (day 4) compared to a delayed effect (day 15). IV. To determine the PSA nadir, and percentage of patients with undetectable PSA, treated with combined vaccine and androgen ablation therapy over 12 months. OUTLINE: This is a multicenter study. Patients receive vaccinia-PSA-TRICOM vaccine subcutaneously (SC) on day 1 and sargramostim (GM-CSF) SC on days 1-4 during weeks 1-4. Beginning in week 5, patients receive fowlpox-PSA-TRICOM vaccine SC on day 1 and GM-CSF SC on days 1-4. Treatment with fowlpox-PSA-TRICOM vaccine and GM-CSF repeats every 4 weeks for 3 courses (weeks 5-16). Beginning in week 17, patients receive fowlpox-PSA-TRICOM vaccine and GM-CSF as above every 12 weeks in the absence of clinical or biochemical disease progression or unacceptable toxicity. Patients with biochemical or clinical disease progression receive androgen ablation therapy comprising oral bicalutamide once daily for 1 month and goserelin SC once every 4 weeks in addition to fowlpox-PSA-TRICOM vaccine and GM-CSF. Treatment continues in the absence of further clinical or biochemical disease progression. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years. PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study within 6 months.

Official Title
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A Phase II Study of PROSTVAC-V (Vaccinia)/TRICOM and PROSTVAC-F (Fowlpox)/TRICOM With GM-CSF in Patients With PSA Progression After Local Therapy for Prostate Cancer

Conditions
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Recurrent Prostate Carcinoma, Stage I Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer, Stage III Prostate Cancer

Intervention / Treatment
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* Drug: Bicalutamide
* Drug: Goserelin Acetate
* Biological: Recombinant Fowlpox-PSA(L155)/TRICOM Vaccine
* Biological: Recombinant Vaccinia-TRICOM Vaccine
* Biological: Sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically proven prostate cancer and tumors limited to the prostate (including seminal vesical involvement, provided all visible disease was surgically removed) that have completed local therapy and have an elevated PSA after surgery or rising PSA after radiation therapy, as defined below; patients with lymph node involvement (D1) are not eligible Histologically confirmed diagnosis of prostate cancer Previous treatment with definitive surgery or radiation therapy or both No evidence of metastatic disease on physical exam, CT (MRI), and bone scan within 4 weeks prior to randomization Prior neoadjuvant/adjuvant hormonal or chemotherapy is allowed if it was last used >= 1 year prior to enrollment (no prior vaccine/immunotherapy for prostate cancer will be allowed) No therapy modulating testosterone levels (such as leuteinizing-hormone releasing-hormone agonists/antagonists and antiandrogens) is permitted within 1 year prior to enrollment; agents such as 5-reductase inhibitors, ketoconazole, megestrol acetate, systemic steroids, and herbal products are not permitted at any time during the period that the PSA values are being collected Hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL at the time of enrollment within 4 weeks prior to randomization There must be one PSA measurement (referred to as the baseline PSA) obtained within one week prior to registration; the baseline PSA value must be greater than 0.4 ng/mL (after prostatectomy) or greater than 1.5 ng/mL (after radiation therapy) All patients must have evidence of biochemical progression as determined by 3 PSA measurements (PSA1, PSA2, PSA3), each higher than the previous value, each obtained at least 4 weeks apart from the others with the most recent one (PSA3) being the baseline PSA; all of these PSA values must be obtained at the same reference lab; the earliest (PSA1) must be done within 6 months prior to registration. PSA doubling time (PSADT) must be less than 12 months, calculated using the following formula: PSADT in days = (0.693 (t))/(In (PSA3) - In (PSA2)) Where t = the number of days between PSA3 and PSA2 In = the natural log PSADT in months = PSADT in days divided by 30.4375 Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 1 Leukocytes >= 3000/mm^³ Granulocytes >= 1500/mm^3 Platelet count >= 100,000/mm^3 Serum creatinine within normal institutional limits or creatinine clearance >= 60 mL/min for patients with creatinine levels above institutional normal (a calculated clearance may be used); an initial urine analysis will be required with grade 0 proteinuria and no abnormal sediment; for any positive protein a 24 hour urine should be less than 1,000 mg per 24 hours and no indication of chronic renal disease Serum total bilirubin, and alkaline phosphatase within normal institutional limits SGOT (AST) and SGPT (ALT) =< 2.5 x institutional upper limit of normal Patients cannot have evidence of immunosuppression: Patients must be human immunodeficiency virus sero-negative due to the potential for severe reactions to vaccinia and the need for an intact immune system to respond to the immunization Patients must not have active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematous, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Grave's disease; patients with a history of autoimmunity that has required systemic immunosuppressive therapy or has impaired organ function including CNS, heart, lungs, kidneys, skin, and GI tract are ineligible; patients receiving replacement thyroid hormone would be eligible No concurrent use of systemic steroids, except for local (topical, nasal, or inhaled) steroid use; steroid eye drops are contraindicated for at least 2 weeks before vaccinia vaccination and at least 4 weeks post vaccinia vaccination Patients must be hepatitis B and hepatitis C negative Patients must have a normal PT/INR within 4 weeks prior to randomization Patients must not be receiving any other investigational agents or receiving concurrent anticancer therapy No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; because of the recently recognized risk of cardiac inflammation after vaccinia, patients with clinically significant cardiomyopathy are excluded; patients must have recovered from any intercurrent illness and any acute toxicity related to prior therapy (i.e., surgery and/or radiation) Patients must use a safe and effective method of contraception to prevent virus transmission; the potential risk to spermatogenesis and fetal development after paternal immunization with this vaccine is not known; patients must agree to avoid fathering a child and use a latex barrier with adequate contraception prior to study entry and for at least 4 months following the last vaccine injection All sites of disease must be evaluated within 4 weeks prior to registration Patients with significant allergy or hypersensitivity to eggs should be excluded; patients must not have a history of allergy or untoward reaction to prior vaccination with vaccinia virus or to any component of the vaccinia vaccine regimen Patients must not have active eczema, a history of eczema, atopic dermatitis, or Darier.s disease; other acute, chronic, or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herpes or other open rashes or wounds Patients must be able to avoid close contact with those who share housing or have close physical contact for at least three weeks after recombinant vaccinia vaccination with persons at increased risk including those with active or a history of eczema or atopic dermatitis, or Dariers disease; those with other acute, chronic or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herpes 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), which includes those infected with HIV until the condition resolves

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vaccine therapy)<br>Patients receive vaccinia-PSA-TRICOM vaccine SC on day 1 and sargramostim (GM-CSF) SC on days 1-4 during weeks 1-4. Beginning in week 5, patients receive fowlpox-PSA-TRICOM vaccine SC on day 1 and GM-CSF SC on days 1-4. Treatment with fowlpox-PSA-TRICOM vaccine and GM-CSF repeats every 4 weeks for 3 courses (weeks 5-16). Beginning in week 17, patients receive fowlpox-PSA-TRICOM vaccine and GM-CSF as above every 12 weeks in the absence of clinical or biochemical disease progression or unacceptable toxicity. Patients with biochemical or clinical disease progression receive androgen ablation therapy comprising oral bicalutamide once daily for 1 month and goserelin SC once every 4 weeks in addition to fowlpox-PSA-TRICOM vaccine and GM-CSF. Treatment continues in the absence of further clinical or biochemical disease progression. | Drug: Bicalutamide<br>* Given orally<br>* Other names: ICI 176334;Drug: Goserelin Acetate<br>* Given SC<br>* Other names: Zoladex;Biological: Recombinant Fowlpox-PSA(L155)/TRICOM Vaccine<br>* Given SC<br>* Other names: rFowlpox-PSA(L155)/TRICOM Vaccine;Biological: Recombinant Vaccinia-TRICOM Vaccine<br>* Given SC<br>* Other names: vaccinia-TRICOM vaccine;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Free of PSA Progression at 6 Months (Prior to the Start of Androgen Ablation) | For patients who achieved a > 50% decline in PSA, an increase in PSA value by 50% over the nadir, confirmed by a second PSA two weeks later is considered progressive disease. The PSA rise must be at least 5 ng/mL or back to pretreatment baseline, whichever is greater. Changes in PSA below 5 ng/mL will not be considered assessable for progression. For patients whose PSA has not decreased by 50%, an increase in PSA value > 50% of baseline (on trial) or nadir PSA, whichever is lower, confirmed by a repeat PSA two weeks later is considered progressive disease. The PSA must have risen by at least 5 ng/mL. | Assessed at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With PSA Response | PSA response is defined as complete biochemical response or partial response. Complete Response: A PSA < 0.2 ng/mL confirmed by a repeat PSA one month later is considered a complete biochemical response for patients with prior radical prostatectomy. A PSA < 1 ng/mL on three separate occasions taken at least one month apart is considered a complete biochemical response in patients with radiation therapy only. Partial Response: A reduction in PSA by > 50% from baseline, confirmed by repeat PSA 1 month later. | Assessed monthly during the first 24 weeks and then every 3 months for a maximum total of 24 months | 
| Difference Between Day 4 PSA Level and Day 15 PSA Level | PSA level was assessed on Day 4 and Day 15 of cycle 1, and a comparison between the two measurements was done. | Assessed at day 4 and day 15 of cycle 1 | 
| The Difference Between PSA Slopes Before and After Treatment | PSA slopes were assessed by multiple PSA values obtained prior to registration and during treatment. Only patients who completed at least 3 months of treatment were included in this analysis. The PSA slopes were calculated by a piecewise linear model using the three or four PSA values obtained prior to registration and PSA measurements obtained every 4 weeks for the first six months of treatment. Natural log transformed PSA levels were used in this analysis, and the difference between PSA slopes before and after treatment was calculated. | Assessed monthly during the first 24 weeks and then every 3 months for a maximum total of 24 months |