This study will evaluate, in two parts, the safety and effectiveness of vaccinations against prostate cancer in patients with disease that has recurred or metastasized (spread beyond the primary site) following standard treatment. The vaccine consists of three parts, or ingredients. Part 1 is derived from the vaccinia virus, which has been used for many years against smallpox. Part 2 is made from a related virus called fowlpox. Two kinds of human DNA are put inside some of the vaccinia and fowlpox viruses-one produces PSA protein, which is made by prostate cancer cells; the other produces various proteins called Tricom that enhance immune activity. Part 3 of the vaccine involves a protein called Sargramostin (also called granulocyte-macrophage colony stimulating factor, or GM-CSF), which boosts the immune system. An experimental form of Sargramostin, in which the human DNA for GM-CSF is put inside the fowlpox virus, is included in the regimen. Stage 1 of the study will examine the safety of the vaccine and Stage 2 will examine its ability to produce an immune response against tumor cells.

Patients 18 years of age or older with recurrent or metastatic prostate cancer may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood and urine tests, and imaging studies, including computed tomography (CT) of the chest, abdomen and pelvis. Candidates for Stage 2 will have a blood test to determine tissue type (human leukocyte antigen, or HLA) type. Only patients with HLA-A2 type may participate in Stage 2. Patients who are allergic to eggs may not participate in either part.

Part 1 - Safety Study

Patients in Part 1 receive different combinations and dosages of vaccines. The specific vaccine and dosage for an individual is determined by his or her time of entry in the study. The first group of 3 to 6 patients receive fowlpox vaccine; group 2 patients receive vaccinia and fowlpox; group 3, vaccinia, fowlpox and Sargramostin; group 4, vaccinia and fowlpox, and group 5, vaccinia and fowlpox. All vaccines are injected under the skin. Patients receiving the vaccinia and fowlpox vaccines have injections of one or the other once every 4 weeks for 3 months. Patients receiving Sargramostin in addition to fowlpox and vaccinia vaccines receive the Sargramostin injections daily for 4 days, starting with the day of each vaccine injection.

Part 2 - Immune Response Study

Patients in Part 2 are randomly assigned to one of four treatment groups, consisting of different combinations or doses of vaccines to test the effects of the vaccines on the immune system. The course of treatment is similar to that in Part 1. To obtain sufficient numbers of immune system cells to measure immune response, patients undergo lymphapheresis-a procedure for collecting lymphocytes (a type of white blood cell)-on days 1 and 85 of the study. For this procedure, whole blood is collected through a needle in an arm vein and circulated through a machine that separates it into its components. The lymphocytes are removed, and the rest of the blood is returned to the patient through the same needle. For patients who do not have good arm veins, lymphocytes are collected through a central line-a temporary catheter (plastic tube) that is placed in a large vein in the neck or under the collarbone. Patients whose disease remains stable and who tolerate the treatments well may continue to receive the vaccines every 12 weeks. Patients are monitored closely throughout treatment with monthly blood tests and with x-ray studies-including bone scans and CT scans of the abdomen and pelvis-every 85 days.

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

Further Study Details: 

Expected Total Enrollment:  62

There are two objectives of this trial. The first objective (Stage 1) is to evaluate the clinical safety of a prime/boost vaccine strategy: priming with a recombinant vaccinia containing the genes for prostate specific antigen (PSA) and a triad of costimulatory molecules (rV-PSA-(L155)-TRICOM) with subsequent monthly boosts using Fowlpox-PSA (L155)-TRICOM (rFOWLPOX-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM). PSA-L155 is the human PSA gene with an agonist epitope resulting from a single amino acid modification of a PSA HLA-A2 epitope. Patients must have prostate cancer with clinical progression as documented per PSA consensus criteria (1). Stage 1 will also evaluate the combination of these agents with recombinant GM-CSF (r-GM-CSF) as well as two doses of fowlpox-GM-CSF (rF-GM-CSF). This study will utilize a dose escalation Phase I design. Stage 1 will consist of five cohorts as shown in the schema. The first cohort utilizes a fixed dose of rFOWLPOX-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM) alone, while the second cohort will test the safety of rV-PSA (L155)-TRICOM as a priming vaccination followed by monthly boosting with rFOWLPOX-PSA (L155)-TRICOME (PROSTVAC-F/TRICOM). Cohorts three, four and five will provide safety data combining cohort two with rGM-CSF as well as two doses of rFGM-CSF respectively. The maximal tolerated dose (MTD) established in Stage 1 (cohorts 2-5) of this trial will be used in Stage 2 of the protocol.

Stage 2 will be conducted as a small, randomized pilot study to compare the immunologic effects of the above vaccine strategy alone, with recombinant GM-CSF, or with either of 2 doses of fowlpox-GM-CSF. Stage 2 will consist of 4 randomized arms of 8 patients each, all of whom are HLA-A2+. All four of these arms will be randomized against one another in order to minimize biases associated with patient selection and to enhance the ability to interpret the results of comparisons obtained. Patients enrolled on Stage 2 must have measurable metastatic disease without prior chemotherapy. Stage 2 will be conducted to determine if any of the strategies provides strongly convincing evidence of superiority of effect with respect to T-cell precursor frequency changes. The maximum accrual to the trial should be 62: up to 30 patients in Stage 1 (5 cohorts of up to 6 patients), and 32 patients in Stage 2 (4 arms of 8 patients apiece). It is expected that accrual to this trial can be completed within 2 years.

Genders Eligible for Study:  Male

Criteria

INCLUSION CRITERIA: Stage 1 Patients
Patients must have histopathological documentation of prostate cancer confirmed in the Laboratory of Pathology, CCR, NCI, or NNMC prior to starting this study. If no pathologic specimen is available to the NCI or NNMC, patients may enroll with a pathologist's report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.
Patients must have androgen insensitive metastatic prostate cancer. Progression must be documented by at least one of the following parameters.
a. All patients must have received standard of care (hormonal) treatment before entering the trial.
b. All patients will have received and progressed on hormonal therapy for metastatic prostate carcinoma.
c. All subjects must have objective evidence of metastasis or relapsing local disease to be eligible for this Phase I trial; therefore, they must have a rising PSA and at least one of the following: positive bone scan, palpable disease, or positive imaging studies, as defined below.
i. Two consecutively rising PSA levels, separated by at least 1 week, with at least one measurement that is 50% above the
nadir reached after the last therapeutic maneuver (as long as the last measurement is 5 ng/ml or greater), and
ii. At least one lesion consistent with metastatic cancer on Technetium (Tc)-99 whole body scintigraphy, and/or
iii. Soft-tissue metastases as measured by appropriate modalities (i.e., imaging, palpation).
Patients must have a life expectancy of more than 6 months.
Patients must have a performance status of 0 to 2 according to the ECOG criteria.
Patients must have 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). Patients who are responding to hormonal therapy are not eligible until evidence of disease progression.
Hematological eligibility parameters (within 16 days of starting therapy):
-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 to10 Gm/dL
Biochemical eligibility parameters (within 16 days of starting therapy):
a. A 24-hour urine collection for baseline to measure creatinine clearance, protein and electrolytes. CrCl greater than 60, less than 1000 milligrams per 24 hours, less than or equal to Grade 1 (NCI-CTC version 2.0) proteinuria, Grade 0 hematuria, and no abnormal sediment. Grade 0 creatinine. Patients must have serum creatinine within normal limits.
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 for evidence of underlying renal pathology. Patients may be eligible if the underlying cause of the abnormality is determined to be non-renal.
b. Hepatic function: Bilirubin less than 1.5 mg/dl, AST and ALT less than 2.5 times upper limit of normal.
c. Patients must be test negative for HIV, Hepatitis B and C.
Patients must not have other active malignancies within the past 2 years (with the exception of non-melanoma skin cancers or carcinoma in situ of the bladder) or life threatening illnesses.
Patients must be willing to travel to the NIH for follow-up visits.
Patients must be greater than or equal to 18 years of age.
All patients who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of allergy or untoward reaction to the vaccine. Since vaccinia immunoglobulin (VIG) is available from the CDC, prior vaccinia vaccination as a safety precaution is no longer required.
Patients must understand and sign informed consent that explains the neoplastic nature of their disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, potential risks and toxicities, and the voluntary nature of participation.
For Stage 2 of this study only, patients must not have received the following chemotherapeutic agents for cancer within 3 years of enrolling on study: docetaxel, paclitaxel, doxorubicin, cisplatinum, carboplatinum, mitoxantrone, estramustine, cyclophosphamide, irinotecan, topotecan. Patients must not have received prior PSA vaccine therapy.
Patients will tested for HLA-A2; however, the results of this test will not affect entry onto Stage 1 of this study. This test may be drawn by the patient's referring physician at the time of referral (see Appendix C, HLA-typing consent). This consent will be mailed to the patient and discussed with patient. The signed consent will be signed with a witness, then mailed to the assigned research nurse at the NIH Clinical Center. These patients must have measurable disease on CT, MRI, or bone scan.
The effects of the study agents used in this protocol on the developing human fetus are unknown. For this reason men must agree to use adequate contraception prior to study entry and for the duration of study participation.
INCLUSION CRITERIA: Stage 2 Patients
Patients must have histopathological documentation of prostate cancer confirmed in the Laboratory of Pathology, CCR, NCI, or NNMC prior to starting this study. If no pathologic specimen is available to the NCI or NNMC, patients may enroll with a pathologist's report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.
Patients must have androgen insensitive metastatic prostate cancer. Progression must be documented by at least one of the following parameters.
a. All patients must have received standard of care (hormonal) treatment before entering the trial.
b. All patients will have received and progressed on hormonal therapy for metastatic prostate carcinoma.
c. All subjects must have objective evidence of metastasis or relapsing local disease to be eligible for this Phase I trial; therefore, they must have a rising PSA and at least one of the following: positive bone scan, palpable disease, or positive imaging studies, as defined below.
i. Two consecutively rising PSA levels, separated by at least 1 week, with at least one measurement that is 50% above the
nadir reached after the last therapeutic maneuver (as long as the last measurement is 5 ng/ml or greater), and
ii. At least one lesion consistent with metastatic cancer on Technetium (Tc)-99 whole body scintigraphy, and/or
iii. Soft-tissue metastases as measured by appropriate modalities (i.e., imaging, palpation).
Patients must have a life expectancy of more than 6 months.
Patients must have a performance status of 0 to 2 according to the ECOG criteria.
Patients must have 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).
Hematological eligibility parameters (within 16 days of starting therapy):
-Granulocyte count greater than or equal to1,500/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
Biochemical eligibility parameters (within 16 days of starting therapy):
a. 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, less than or equal to Grade 1 (NCI-CTC version 2.0) proteinuria, Grade 0 hematuria, and no abnormal sediment. Grade 0 creatinine. Patients must have serum creatinine within normal limits.
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 for evidence of underlying renal pathology. Patients may be eligible if the underlying cause of the abnormality is determined to be non-renal.
b. Hepatic function: Bilirubin less than 1.5 mg/dl, AST and ALT less than 2.5 times upper limit of normal.
c. Patients must test negative for HIV, Hepatitis B and C.
Patients must not have other active malignancies within the past 2 years (with the exception of non-melanoma skin cancers or carcinoma in situ of the bladder) or life threatening illnesses.
Patients must be willing to travel to the NIH for follow-up visits.
Patients must be greater than or equal to 18 years of age.
All patients who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of allergy or untoward reaction to the vaccine. Since vaccinia immunoglobulin (VIG) is available from the CDC, prior vaccinia vaccination as a safety precaution is no longer required.
Patients must understand and sign informed consent that explains the neoplastic nature of their disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, potential risks and toxicities, and the voluntary nature of participation.
For Stage 2 of this study only, patients have not received the following chemotherapeutic agents for cancer within 3 years of enrolling on study: docetaxel, paclitaxel, doxorubicin, cisplatinum, carboplatinum, mitoxantrone, estramustine, cyclophosphamide, irinotecan, topotecan. Patients have not received prior PSA vaccine therapy.
All patients will tested for HLA-A2; however, for Stage 2 of this study patients must be HLA-A2+. This test may be drawn by the patient's referring physician at the time of referral (see Appendix C, HLA-typing consent). This consent will be mailed to the patient and discussed with patient. The signed consent will be signed with a witness, then mailed to the assigned research nurse at the NIH Clinical Center. These patients must have measurable disease on CT, MRI, or bone.
The effects of the study agents used in this protocol on the developing human fetus are unknown. For this reason men must agree to use adequate contraception prior to study entry and for the duration of study participation.
EXCLUSION CRITERIA: Stage 1 Patients
Prior splenectomy.
Concurrent steroid use, except topical steroids or inhaled steroid use.
The recombinant vaccinia vaccine should not be administered if the following apply to either recipients or, for at least 3 weeks after vaccination, their close household contacts: 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 under 5 years of age; and immunodeficient or immunosuppressed persons (by disease or therapy), including HIV infection. Close household contacts are those who share housing or have close physical contact.
Patients with known allergy to eggs.
Other serious intercurrent illness.
Patients with brain metastases.
Patients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Association class II-IV congestive heart failure.
Patients on antiandrogen therapy must undergo antiandrogen withdrawal for at least 4 weeks and still show evidence of a rising PSA. Following treatment with bicalutamide, patients must undergo withdrawal for at least 6 weeks and still show evidence of a rising PSA.
Patients with significant autoimmune disease that is active or potentially life threatening if activated.
Patients with clinically significant cardiomyopathy requiring treatment should be excluded from protocol eligibility at this time.
EXCLUSION CRITERIA: Stage 2 Patients
Prior splenectomy.
Concurrent steroid use, except topical steroids or inhaled steroid use.
The recombinant vaccinia vaccine should not be administered if the following apply to either recipients or, for at least 3 weeks after vaccination, their close household contacts: 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 under 5 years of age; and immunodeficient or immunosuppressed persons (by disease or therapy), including HIV infection. Close household contacts are those who share housing or have close physical contact.
Patients with known allergy to eggs.
Other serious intercurrent illness.
Patients with brain metastases.
Patients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Association class II-IV congestive heart failure.
Patients on antiandrogen therapy must undergo antiandrogen withdrawal for at least 4 weeks and still show evidence of a rising PSA. Following treatment with bicalutamide, patients must undergo withdrawal for at least 6 weeks and still show evidence of a rising PSA.
For Stage 2 patients only, prior treatments with vaccine expressing PSA are NOT eligible.
Patients with significant autoimmune disease that is active or potentially life threatening if activated.
Patients with clinically significant cardiomyopathy requiring treatment should be excluded from protocol eligibility at this time.

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

Study ID Numbers:  030176; 03-C-0176
Record last reviewed:  December 2, 2004
Last Updated:  April 6, 2005
Record first received:  May 7, 2003
ClinicalTrials.gov Identifier:  NCT00060528
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08