Neoplasms, Prostate, Prostate Cancer, Prostatic Neoplasms
Conditions
Keywords
Surgery, Neoadjuvant, CD8 Cell Infiltrate Response, CD4 Cell Infiltrate Response, Vaccine
Brief summary
Background: \- Some men with prostate cancer have their prostate glands removed. The cancer can still come back. Researchers want to know if receiving a vaccine before prostate removal surgery can lead to less recurrence. Objective: \- To see if a vaccine and booster shots given to men with prostate cancer before surgery changes the immune cells in the prostate gland. Eligibility: \- Men age 18 and older who have prostate cancer that has not spread, and who want to have their prostate glands removed as treatment. Design: * Participants will be screened by their regular cancer care. They may have a small piece of prostate removed. * Participants must practice effective birth control before and during the study treatment and for 1 month after the last vaccine booster. * Participants will have a medical history, physical exam, and blood and liver tests. They will be asked about how they perform daily activities. * Participants will have a magnetic resonance imaging (MRI) scan of the prostate. The scanner is a metal cylinder in a strong magnetic field. Participants will lie on a table that slides in and out of the scanner. * Participants will be injected with the vaccine, most likely in the leg. They will be injected with the vaccine booster 3 times over several weeks. * At each booster visit, participants will have a medical history, physical exam, and blood and liver tests. * Participants will have another MRI. Then they will have surgery to remove their prostate. * Participants will have 2 follow-up visits during the year after surgery. They will have a medical history, physical exam, and blood test.
Detailed description
Background * Adenocarcinoma of the prostate is the most common cancer diagnosis in American males and follows lung cancer as the leading cause of cancer death. * Vaccine strategies represent a novel therapeutic approach in the treatment for prostate cancer. One potential target for a prostate cancer vaccine is prostatic specific antigen (PSA), due to its restricted expression on prostate cancer and normal prostatic epithelial cells. * A neoadjuvant approach may be of potential benefit providing prolonged protection via the patient s immune system against future recurrence. * PROSTVAC is a vaccine that induces strong immune responses, has shown promising evidence of activity in a randomized phase II study (8.5 month improvement in median overall survival) and is currently in phase III clinical testing. * This vaccine has been tested in locally recurrent prostate cancer with substantial inflammatory infiltrates within the prostate seen following subcutaneous and intraprostatic injection. Objectives -The primary objective is to evaluate the post vaccine immunologic cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) cell infiltrate response of a neoadjuvant vaccine strategy in prostatectomy specimens in patients who plan to undergo radical prostatectomy. Eligibility * Patients must have biopsy proven prostate cancer and are surgical candidates for radical prostatectomy * Must be of sufficient good health to be surgical candidates for radical prostatectomy and have elected radical prostatectomy for management of their prostate cancer * Granulocyte count is greater than or equal to 1,500/mm(3), Platelet is greater than or equal to 50,000/mm(3), hemoglobin (Hgb) is greater than or equal to 8 g/dL, Bilirubin \< 1.5mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5x upper limit of normal (ULN), Creatinine is less than or equal to 1.5 X ULN * Pre-intervention biopsy tissue must be available either from outside institution or repeat biopsy Design * This study will utilize rV-PSA(L155)-TRICOM (PROSTVAC-V) as a priming vaccination followed by monthly boosting with rF-PSA (L155)-TRICOM (PROSTVAC-F) for 3 months. * Patients will undergo radical prostatectomy after 4 months of treatment with PROSTVAC-V/F. * The maximum accrual to the trial will be 27 patients.
Interventions
BIOLOGICALPROSTVAC-V/TRICOM
A recombinant vaccinia virus vector vaccine containing the genes for human prostatic specific antigen (PSA) and three co-stimulatory molecules.
BIOLOGICALPROSTVAC-F/TRICOM
A recombinant fowlpox virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA 1. Patients must have histopathological documentation of adenocarcinoma of the prostate prior to starting this study and evaluable biopsy tissue (e.g., unstained slides or blocks) available for analysis. If evaluable tissue is not available, the patient must agree to undergo a pre-vaccination prostate biopsy on study as an alternative to having available tissue available. 2. Patients must be a surgical candidate for radical prostatectomy based on standard workup of prostatic specific antigen (PSA), biopsy results, and if necessary supplemental imaging. 3. Patients must have chosen radical prostatectomy as their definitive treatment of choice for management of their prostate cancer. 4. Patients must have a performance status of 0 to 1 according to the Eastern Cooperative Oncology Group (ECOG) criteria 5. No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of experimental therapy. Limited doses of systemic steroids to prevent intravenous (IV) contrast, allergic reaction or anaphylaxis (in patients who have known contrast allergies) are allowed. 6. Hematological eligibility parameters (within one month of starting therapy): * Granulocyte count greater than or equal to 1,500/mm(3) * Platelet count greater than or equal to 50,000/mm(3) * Hemoglobin (Hgb) greater than or equal to 8 g/dL 7. Biochemical eligibility parameters (within one month of starting therapy): 1. Hepatic function: Bilirubin \< 1.5 mg/dl (OR in patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0 mg/dL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 times upper limit of normal.-. Creatinine less than or equal to 1.5 X ULN 2. Creatinine less than or equal to 1.5 X ULN 3. Patients must be test negative for human immunodeficiency virus (HIV), Hepatitis B and C. 8. Patients must not have other active invasive malignancies within the past 2 years (with the exception of non-melanoma skin cancers) or life threatening illnesses. 9. Patients must be willing to travel to the study site for follow-up visits. 10. Patients must be greater or equal to18 years of age. 11. All patients who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of allergy to the vaccine. 12. 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. 13. 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 (abstinence,vasectomy, or female partner use of intrauterine device (IUD), hormonal \[birth control pills, injections, or implants\], tubal ligation) prior to study entry and for up to one month after the last vaccination.
Exclusion criteria
1. Prior splenectomy. 2. 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 (Close household contacts are those who share housing or have close physical contact): * 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 3 years of age * Patients should have no evidence, as listed below, of being immunocompromised: * HIV positivity due to the potential for decreased tolerance and risk for severe side effects. * Hepatitis B or C positivity. * Concurrent use of topical steroids (including steroid eye drops) or systemic steroids. This is to avoid immunosuppression which may lead to potential complications with vaccinia (priming vaccination). Nasal or inhaled steroid use is permitted. 3. Patients with known allergy to eggs. 4. Other serious intercurrent illness. 5. 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. 6. Patients with significant autoimmune disease that is active or potentially life threatening if activated. 7. Patients with clinically significant cardiomyopathy requiring treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates | Baseline (pre vaccination) and approximately week 10 | Immunologic CD4 and CD8 cell infiltrate response of a neoadjuvant prime/boost vaccine strategy in prostatectomy specimens. Prostate biopsy specimens are collected and stained for CD4 and CD8 cells. Quantification is reported as the number of stained cells per micron squared of surface area. Change will be noted by utilizing computer automated staining analysis. Density of cell infiltrate will be calculated and the pre and post vaccine values will be compared to determine response to vaccine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | Baseline (pre vaccination) and week 10 | Change in peripheral prostatic specific antigen (PSA)-specific T cells will be assessed by the enzyme-linked immunospot (ELISPOT) assay. A change of \>250 cluster of differentiation 4 (CD4) or cluster of differentiation 8 (CD8) cells producing cytokine or positive for cluster of differentiation 107a (CD107a) in response to PSA post vaccination relative to baseline will be considered evidence of an immunologic response to the vaccine. The number of subjects developing positive PSA-Specific T cell responses with vaccination will be reported. |
| Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining | Baseline (pre vaccination) and post surgery after last dose of vaccine, approximately week 10 | Prostate biopsy samples collected at baseline and at surgery after last dose of vaccine will be stained for analysis of immune cell infiltrate. Quantification will be reported as number of stained cells per micron squared of surface area. |
| Prostatic Specific Antigen (PSA) Changes Secondary to Vaccination | Baseline (pre vaccination) and approximately week 10 | A change in PSA secondary to vaccination is defined as an increase or decrease in PSA value beyond the baseline level. PSA levels of 4.0 ng/ml and lower are considered normal. |
| Magnetic Resonance Imaging (MRI) Changes Secondary to Vaccination | Baseline (pre vaccination) and approximately week 10 | MRI of the prostate was performed for changes in imaging characteristics of prostate cancer pre and post vaccination. MRI changes secondary to vaccination is defined as increase or decrease in the size of lesions from baseline (pre-vaccine) measurements. |
| Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | Date treatment consent signed to date off study, approximately 33 months and 5 days | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vaccine Plus Booster Shots PROSTVAC-V/TRICOM followed by PROSTVAC-F/ TRICOM boost monthly until radical prostatectomy or off therapy PROSTVAC
PROSTVAC-V/TRICOM: A recombinant vaccinia virus vector vaccine containing the genes for human prostatic specific antigen (PSA) and three co-stimulatory molecules.
PROSTVAC-F/TRICOM: A recombinant fowlpox virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules. | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Refused further treatment | 1 |
Baseline characteristics
| Characteristic | Vaccine Plus Booster Shots |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 64.24 years STANDARD_DEVIATION 6.62 |
| Baseline Prostatic Specific Antigen (PSA) | 9.66 ng/ml STANDARD_DEVIATION 10.45 |
| Largest Lesion Size at Baseline | 1.55 cm STANDARD_DEVIATION 0.92 |
| Magnetic Resonance Imaging (MRI) Prostate Volume at Baseline | 45.70 cc STANDARD_DEVIATION 17.24 |
| Number of Lesions on MRI at Baseline | 2.04 lesions STANDARD_DEVIATION 1.21 |
| Number of Participants with Gleason Score 6-10 at Baseline Gleason score 6-7 (3+4) | 11 Participants |
| Number of Participants with Gleason Score 6-10 at Baseline Gleason score 7 (4+3) | 8 Participants |
| Number of Participants with Gleason Score 6-10 at Baseline Gleason score 8-10 | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Mexican, Puerto Rican, Central or So. Amer. or Oth | 2 Participants |
| Race/Ethnicity, Customized Multi-racial | 1 Participants |
| Race/Ethnicity, Customized Not meeting definition for Hispanic or Latino | 25 Participants |
| Race/Ethnicity, Customized White | 23 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 1 / 27 |
Outcome results
Primary
Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates
Immunologic CD4 and CD8 cell infiltrate response of a neoadjuvant prime/boost vaccine strategy in prostatectomy specimens. Prostate biopsy specimens are collected and stained for CD4 and CD8 cells. Quantification is reported as the number of stained cells per micron squared of surface area. Change will be noted by utilizing computer automated staining analysis. Density of cell infiltrate will be calculated and the pre and post vaccine values will be compared to determine response to vaccine.
Time frame: Baseline (pre vaccination) and approximately week 10
Population: Only 26 participants had available tissue for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vaccine Plus Booster Shots | Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates | Median CD4 at baseline | 132.2 Cell/mm(2) |
| Vaccine Plus Booster Shots | Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates | Median CD4 at week 10 | 153.7 Cell/mm(2) |
| Vaccine Plus Booster Shots | Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates | Median CD8 at baseline | 105.1 Cell/mm(2) |
| Vaccine Plus Booster Shots | Changes From Baseline to After Surgery of Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Infiltrates | Median CD8 at week 10 | 140.5 Cell/mm(2) |
Secondary
Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses
Change in peripheral prostatic specific antigen (PSA)-specific T cells will be assessed by the enzyme-linked immunospot (ELISPOT) assay. A change of \>250 cluster of differentiation 4 (CD4) or cluster of differentiation 8 (CD8) cells producing cytokine or positive for cluster of differentiation 107a (CD107a) in response to PSA post vaccination relative to baseline will be considered evidence of an immunologic response to the vaccine. The number of subjects developing positive PSA-Specific T cell responses with vaccination will be reported.
Time frame: Baseline (pre vaccination) and week 10
Population: 25/27 pts analyzed because 2x10(6) viable cells are required to setup the stimulation assay for each antigen at each time point and one patient had no viable cells after thawing blood. One patient could not be analyzed due to an experimental error which was a clog in the flow cytometry that occurred during acquisition for the final assay readout.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD4 CD107a | 4 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD4 interferon gamma (IFNq) | 2 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD4 interleukin-2 (IL2) | 1 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD4 tumor necrosis factor (TNF) | 0 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD8 CD107a | 0 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD8 IFNq | 0 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD8 IL2 | 0 Participants |
| Vaccine Plus Booster Shots | Count of Participants With Change in Peripheral Prostatic Specific Antigen (PSA)-Specific T Cell Responses | CD8 TNF | 1 Participants |
Secondary
Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, approximately 33 months and 5 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccine Plus Booster Shots | Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 27 Participants |
Secondary
Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining
Prostate biopsy samples collected at baseline and at surgery after last dose of vaccine will be stained for analysis of immune cell infiltrate. Quantification will be reported as number of stained cells per micron squared of surface area.
Time frame: Baseline (pre vaccination) and post surgery after last dose of vaccine, approximately week 10
Population: Only 26 subjects had available tissue for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine Plus Booster Shots | Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining | CD4 at baseline | 199.8 Cell/mm(2) | Standard Deviation 195.3 |
| Vaccine Plus Booster Shots | Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining | CD4 at surgery after last dose of vaccine | 237.6 Cell/mm(2) | Standard Deviation 289.9 |
| Vaccine Plus Booster Shots | Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining | FOX-P3 at baseline | 16.93 Cell/mm(2) | Standard Deviation 29.3 |
| Vaccine Plus Booster Shots | Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4)+Forkhead Box P3 (FOX-P3) Staining | FOX-P3 at surgery after last dose of vaccine | 5.466 Cell/mm(2) | Standard Deviation 4.524 |
Secondary
Magnetic Resonance Imaging (MRI) Changes Secondary to Vaccination
MRI of the prostate was performed for changes in imaging characteristics of prostate cancer pre and post vaccination. MRI changes secondary to vaccination is defined as increase or decrease in the size of lesions from baseline (pre-vaccine) measurements.
Time frame: Baseline (pre vaccination) and approximately week 10
Population: 3 subjects did not have week 10 MRI performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine Plus Booster Shots | Magnetic Resonance Imaging (MRI) Changes Secondary to Vaccination | Largest lesion measurement at baseline | 1.58 cm | Standard Deviation 0.91 |
| Vaccine Plus Booster Shots | Magnetic Resonance Imaging (MRI) Changes Secondary to Vaccination | Largest lesion measurement at 10 weeks | 1.57 cm | Standard Deviation 0.94 |
Secondary
Prostatic Specific Antigen (PSA) Changes Secondary to Vaccination
A change in PSA secondary to vaccination is defined as an increase or decrease in PSA value beyond the baseline level. PSA levels of 4.0 ng/ml and lower are considered normal.
Time frame: Baseline (pre vaccination) and approximately week 10
Population: One subject came off-study prior to radical prostatectomy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine Plus Booster Shots | Prostatic Specific Antigen (PSA) Changes Secondary to Vaccination | PSA at Baseline | 8.94 ng/mL | Standard Deviation 9.96 |
| Vaccine Plus Booster Shots | Prostatic Specific Antigen (PSA) Changes Secondary to Vaccination | PSA at 10 Weeks | 10.18 ng/mL | Standard Deviation 15.45 |