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.
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.
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.
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.
- 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.
1. All patients must have received standard of care (hormonal) treatment before entering
the trial.
2. All patients will have received and progressed on hormonal therapy for metastatic
prostate carcinoma.
3. 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):
1. 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.
2. Hepatic function: Bilirubin less than 1. 5 mg/dl, AST and ALT less than 2. 5 times upper
limit of normal.
3. 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.
1. All patients must have received standard of care (hormonal) treatment before entering
the trial.
2. All patients will have received and progressed on hormonal therapy for metastatic
prostate carcinoma.
3. 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):
1. 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.
2. Hepatic function: Bilirubin less than 1. 5 mg/dl, AST and ALT less than 2. 5 times upper
limit of normal.
3. 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 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.
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.
Correale P, Walmsley K, Nieroda C, Zaremba S, Zhu M, Schlom J, Tsang KY. In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen. J Natl Cancer Inst. 1997 Feb 19;89(4):293-300.
