PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer
- Conditions
- Prostate Cancer
- Interventions
- Registration Number
- NCT02933255
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
The immune system is the cells and organs in the body that recognize and fight infection and cancer. The prostate specific antigen (PSA)/TRICOM (PROSTVAC) vaccine might teach the immune system to find and kill certain prostate cancer cells. Nivolumab is a drug that allows the immune system to fight tumors. It might help PROSTVAC work better.
Objective:
To test the safety and effectiveness of the combination of PROSTVAC and nivolumab. To test this for people with castration resistant prostate cancer and then for other people with localized prostate cancer who are candidates for surgical removal of the prostate.
Eligibility:
Men ages 18 and older with prostate cancer
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Electrocardiogram
Bone scan
Computed tomography (CT) scan or magnetic resonance imaging (MRI)
Tumor sample. This may be from a previous procedure.
All participants will get a combination of the study drugs over 8 weeks. They will have 1 visit for the initial injection then 3 booster injection / nivolumab infusion visits. Blood will be tested at these visits.
Over the next 4 weeks, some participants will have:
An exam of the large intestine through the rectum.
CT and bone scans
Standard hormonal treatment
Option to continue treatment every 3 weeks if their disease does not get worse. They will have scans every 12 weeks.
Other participants will have surgery to remove the prostate in week 9.
Participants will have a safety visit about a month after their last treatment. This will include a physical exam, blood tests, and possibly scans.
If their cancer progresses, participants will leave the study and may enroll in a long-term follow-up study. They will be contacted once a year to ask about their cancer and treatment.
- Detailed Description
Background:
Immune checkpoint inhibitors interfere with the immune systems autoregulatory mechanisms, allowing for a potentially expanded and prolonged T-cell response with the possibility of greater antitumor effects.
Nivolumab is a fully human Immunoglobulin G4 (IgG4) monoclonal antibody that targets the programmed cell death protein 1 (PD-1) protein. Specifically, the antibody binds to the PD-1 receptor and blocks its interaction with programmed death-ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2), thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.
PROSTVAC (developed by the National Cancer Institute \[NCI\] and licensed to Bavarian Nordic Immunotherapeutics, Mountain View, California (CA) is a therapeutic cancer vaccine for prostate cancer. Early studies have demonstrated immunologic efficacy and suggested clinical benefit. A phase III trial has completed accrual.
A previous study combining the immune checkpoint inhibitor ipilimumab and PROSTVAC suggested greater efficacy than PROSTVAC alone. Additional studies have demonstrated the potential efficacy of immunologic combination therapy with the immune checkpoint inhibitor nivolumab.
This study will aim to evaluate the impact of the combination of PROSTVAC and the immune checkpoint inhibitor nivolumab on the tumor microenvironment focusing on immune cell infiltration as the primary endpoint.
United States (US)-MRI imaging technology will be employed to sample the tumor before treatment and after radical prostatectomy.
The findings from this study could serve as the basis for future studies with this combination in this population of participants and more advanced disease.
Objectives:
Safety (For castration resistant prostate cancer (CRPC) lead-in cohort)
Evaluate changes in T-cell infiltration in the tumor after neoadjuvant treatment with PROSTVAC and nivolumab, relative to changes seen in a phase 2 trial with PROSTVAC alone in the neoadjuvant setting- NCT02153918 (For the neoadjuvant cohort).
Eligibility:
Participants 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.
For the castration resistant lead in cohort, if histopathological documentation is unavailable, a rising prostate specific antigen (PSA) and a clinical course consistent with prostate cancer would be acceptable.
Participants must have a performance status of 0 to 1 according to the Eastern Cooperative Oncology Group (ECOG) criteria.
Hematological eligibility parameters (within 16 days of starting therapy):
Granulocyte count 1,500/mm\^3
Platelet count 100,000/mm\^3
Hemoglobin (Hgb) \>= 8 g/dL
Biochemical eligibility parameters (within 16 days of starting therapy):
Hepatic function: Bilirubin \< 1.5 mg/dl (OR in participants with Gilbert's syndrome, total bilirubin \<= 3.0 mg/dL), aspartate aminotransferase (AST) and alanine transaminase (ALT) \<= 2.5 times upper limit of normal.
Creatinine \<= 1.5 X ULN
Design:
The primary focus of this study will be to evaluate PROSTVAC and nivolumab in the neoadjuvant setting.
Lead-in cohort evaluating the safety and tolerability of this combination in the castration resistant setting (CRPC cohort)
Following this lead-in cohort in the CRPC setting, we will enroll a cohort in the neoadjuvant setting evaluating the combination of PROSTVAC and nivolumab.
The lead-in safety cohort will require 10 participants and the neoadjuvant cohort will require 17 evaluable participants. In order to allow for a small number of inevaluable participants, the accrual ceiling will be set to 29 participants.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 24
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Lead-in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort PROSTVAC-V/F Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-F on week 2, 4, and 8. Nivolumab will be administered on week 2, 4, 6, 8 and 10. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo restaging scans on week 12. If no progressive disease (PD), option to continue treatment with nivolumab every 2 weeks and PROSTVAC-F every 4 weeks until intolerance or progression. Option to extend nivolumab interval to 4 weeks for participants who remain on protocol beyond 1 year. Lead-in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort Nivolumab Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-F on week 2, 4, and 8. Nivolumab will be administered on week 2, 4, 6, 8 and 10. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo restaging scans on week 12. If no progressive disease (PD), option to continue treatment with nivolumab every 2 weeks and PROSTVAC-F every 4 weeks until intolerance or progression. Option to extend nivolumab interval to 4 weeks for participants who remain on protocol beyond 1 year. Neoadjuvant Cohort PROSTVAC-V/F Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-fowlpox (F) on 2, 4 and 8 weeks. Nivolumab will be administered on week 2, 4, and 8. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9. Neoadjuvant Cohort Prostatectomy Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-fowlpox (F) on 2, 4 and 8 weeks. Nivolumab will be administered on week 2, 4, and 8. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9. Neoadjuvant Cohort Biopsy Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-fowlpox (F) on 2, 4 and 8 weeks. Nivolumab will be administered on week 2, 4, and 8. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9. Lead-in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort Tylenol Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-F on week 2, 4, and 8. Nivolumab will be administered on week 2, 4, 6, 8 and 10. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo restaging scans on week 12. If no progressive disease (PD), option to continue treatment with nivolumab every 2 weeks and PROSTVAC-F every 4 weeks until intolerance or progression. Option to extend nivolumab interval to 4 weeks for participants who remain on protocol beyond 1 year. Neoadjuvant Cohort Nivolumab Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-fowlpox (F) on 2, 4 and 8 weeks. Nivolumab will be administered on week 2, 4, and 8. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9. Neoadjuvant Cohort Tylenol Prostate-specific antigen (PSA)-TRICOM vaccinia (PROSTVAC)-V on week 0 followed by booster injection called PROSTVAC-fowlpox (F) on 2, 4 and 8 weeks. Nivolumab will be administered on week 2, 4, and 8. When administered on the same day, the preferred order of administration is PROSTVAC first followed by nivolumab. Participants will undergo prostatectomy on week 9.
- Primary Outcome Measures
Name Time Method Number of Participants With Clinically Important Immune-related Adverse Events (for the Lead-In Cohort) From treatment start throughout study completion, an average of 1.4 years. Clinically important immune-related adverse events were defined as grade 3 or above inflammation requiring steroids or anti cytokine therapy or not resolving to grade 1 or less within 28 days. These immune-related adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse event.
Changes in T-cell Infiltration in the Tumor After Neoadjuvant Treatment (Only for the Neoadjuvant Cohort) From baseline to radical prostatectomy (approximately week 9) Changes in T-cell infiltration in the tumor after neoadjuvant treatment with PROSTVAC and nivolumab, is defined as difference in density of cytotoxic T lymphocytes (CD8 T) cells and clusters of differentiation 4 (CD4 T) cells infiltrate from baseline to post-treatment (radical prostatectomy performed at week 9), calculated utilizing computer automated staining analysis. The analysis was done per tissue compartment (normal region, intra-tumoral and invasive margin). We hypothesized an increase in T cell infiltration after treatment. Statistically significant changes in T-cell infiltration are those with p\<0.05; to 0.05. The changes are not statistically significant.
- Secondary Outcome Measures
Name Time Method Changes in Magnetic Resonance Imaging (MRI) Secondary to Immune Treatment (Only for Neoadjuvant Cohort) From baseline to closest date to prostatectomy, average on week 9. MRI of the prostate was performed to assess for changes in imaging characteristics of prostate cancer pre and post vaccination. MRI changes secondary to immune treatment is defined as increase or decrease in the size of lesions from baseline (pre-vaccine) measurements. Decrease from baseline to after treatment would represent a positive outcome.
Number of Participants With Peripheral Prostate-Specific Antigen (PSA)-Specific T Secondary To Immune Treatment Weeks 7-10 and 17-22 compared to baseline The number of participants who developed positive PSA-Specific T cell responses secondary to immune treatment will be reported. Peripheral prostatic specific antigen (PSA)-specific T cells at baseline and after therapy were assessed. PSA-specific T cells were those producing cytokine (Interferon gamma (IFNγ), Tumor Necrosis Factor Alpha (TNFα), Interleukin-2 (IL-2) or positive for the degranulation marker cluster of differentiation 107a (CD107a) following in vitro stimulation with PSA-15-mer peptides compared to a negative control peptide pool, measured by intracellular cytokine staining. A positive response will be defined as a \>2-fold increase in PSA-specific T cells after therapy compared to baseline.
Number of Participants With Clinically Important Immune-related Adverse Events (Only for Neoadjuvant Cohort) From baseline throughout study completion, an average of 20 weeks. Clinically important immune-related adverse events were defined as grade 3 or above inflammation requiring steroids or anti cytokine therapy or not resolving to grade 1 or less within 28 days. These immune-related adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe, grade 4 is life-threatening, and grade 5 is death related to adverse events.
Changes in Soluble Immune Mediating Factors (Soluble Cluster of Differentiation 27 (sCD27) in Sera Week 4, week 10, and week 20 after therapy compared to baseline Changes in soluble immune mediating factors were defined as differences in sCD27 concentration between pre- and post-treatment samples and were measured by enzyme-linked immunosorbent assay (ELISA) and Mesoscale Assay. P values were calculated using the Wilcoxon Signed Rank Test. We hypothesized an increase in sCD27 after treatment. Statistically significant changes in soluble analyzes are those with p\<0.05; to 0.05 means no statistically significant changes.
Changes in Soluble Immune Mediating Factors (Tumor Necrosis Factor Alpha (TNFα) and Interleukin 10 (IL-10) in Sera Week 4, week 10, and week 20 after therapy compared to baseline Changes in soluble immune mediating factors were defined as differences in TNFα, and IL-10 concentration between pre- and post-treatment samples and were measured by enzyme-linked immunosorbent assay (ELISA) and Mesoscale Assay. P values were calculated using the Wilcoxon Signed Rank Test. We hypothesized an increase in TNFα and IL-10 after treatment. Statistically significant changes in soluble analyzes are those with p\<0.05, p0.05 means the changes are not statistically significant.
Changes in Immune Cell Subsets in the Peripheral Blood Week 4 and week 10 after therapy compared to baseline. Peripheral blood samples were collected at baseline and after treatment start via apheresis and cryopreserved peripheral blood mononucleate cells (PBMCs) were analyzed through multicolor flow cytometry to assess cell subsets, i.e. cluster of differentiation 4 (CD4+) T cells, cytotoxic T cells (CD8+) T cells, Tregs, B cells, Natural Killer (NK) cells, NK-T cells, conventional Dendritic Cells (cDCs), plasmocytoid DCs (pDCs), myeloid-derived suppressor cells (MDSCs), and monocytes and refined subsets related to their maturation/function. P values were calculated using the Wilcoxon Signed Rank Test. Statistically significant changes in immune cell subsets are defined as those with p\<0.05 and \>50% of participants having a \>25% change in a given subset.
Changes in Circulating Tumor Cells (CTCs) Levels At baseline and at week 9 Blood samples will be collected at baseline and after treatment, and aliquoted onto slides and examined, cytokeratin-positive/lymphocyte common antigen (CD45)-negative cells with an intact nucleus and a malignancy-consistent morphology will be identified as CTCs, and their exact positions on the slides recorded.
Number of Participants With a Pathologic Complete Response (pCR) (Only for Neoadjuvant Cohort) From baseline and time of radical prostatectomy (average of week 9) Complete pathologic response is defined as the absence of detectable malignant cells in the prostatectomy specimen evaluated by standard histologic techniques.
Rate of Biochemical Recurrence After Prostatectomy (Only for Neoadjuvant Cohort) From time of prostatectomy through study completion, an average of 10 weeks Biochemical recurrence following radical prostatectomy is defined as at least two prostate-specific antigen (PSA) values that are 0.2 ng/mL or higher.
Best Overall Response for Participants With Measurable Disease (Only in the Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort) Baseline throughout study completion (average 1.4 years) The best overall response is the best response recorded from the start of the treatment until disease progression/ recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
Percent Change of Tumor Cells Expressing Programmed Death-ligand 1 (PDL-1) (for the Neo-adjuvant Cohort) Baseline (biopsy before first PROSTVAC administration) and at time of radical prostatectomy (on week 9) Changes in PD-L1 expression is defined as changes in density of cells positive for PDL1 and was analyzed by immunohistochemistry staining using the clone 22C3. Placenta tissue was used as a positive control. Previous studies have shown that high PDL1 expression is associated with poor clinical outcomes in prostate cancer participants. An increase of PDL1 after immunotherapy could indicate a resistance of the tumor to the treatment. Values can go from 0 to 100. 50% of Tumor cells is considered positive for PDL1. The sample will be considered positive if at least 1% or tumor cells express PDL1.
Number of Participants With Serologic Response From baseline throughout study completion, an average of 1.4 years. Best serologic response secondary to immune treatment was reported. Change in Prostate-specific Antigen (PSA) was used to identify serological responses among participants in the lead-in cohort. Complete Serological Response was defined as PSA level less than 0.2 ng/mL measured for 2 consecutive measurements at least 4 weeks apart. Partial Serological Response was defined as decline of PSA at least 50% measured for 2 consecutive measurements at least 4 weeks apart. Serological Progression: Serological progression will only be measured once PSA has risen above 4 ng/mL and this value must be 50% above the PSA level before commencing treatment. Increase in PSA more than 50% of nadir (lowest PSA on treatment). Values must be measured for 2 consecutive measurements at least 2 weeks apart. The date of the first increase will be recorded as progression. Stable disease: not meeting progressive disease (PD) criteria for ≥12 weeks from treatment start.
Changes in Apparent Diffusion Coefficient (ADC) Mapping, Secondary to Immune Treatment (Only for Neoadjuvant Cohort) From baseline to closest date to prostatectomy, average on week 9. Apparent diffusion coefficient (ADC) mapping in magnetic resonance imaging (MRI) is an indicator of tumor cell density. This outcome aims to capture any changes in ADC within the prostate tissue before and after the treatment administration. ADC changes secondary to immune treatment are defined as increase or decrease in ADC from baseline (pre-treatment) measurements. Low ADC values in tumors reflect areas of cell proliferation, and high ADC values reflects necrotic and acellular areas.
Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4+) and Forkhead Box P3 (FOX-P3) Staining (Only for Neoadjuvant Cohort) Baseline and at time of prostatectomy (approximately week 9) Intraprostatic Treg cell infiltration was measured by computer automated staining analysis pre and post treatment. Quantification will be reported as number of stained cells per mm\^2 of tissue.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States