PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

Phase I/II Study of PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02933255
• Other study ID #: 170007
• Secondary ID: 17-C-0007
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 18, 2017
• Est. completion date: December 1, 2023

Study information

• Verified date: May 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: December 1, 2023
• Est. primary completion date: June 20, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 120 Years

Eligibility

• INCLUSION CRITERIA:

For the neoadjuvant cohort, 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. For the castration-resistant prostate cancer (CRPC) 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.

• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of PROSTVAC in combination with nivolumab, ipilimumab or both in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Participants must not have other active invasive malignancies within the past 2 years (with the exception, of non-melanoma skin cancers) (for CRPC cohort only).

• Participants must be willing to travel to the study site for follow-up visits

• All participants who have received prior vaccination with vaccinia virus (for smallpox immunization) must not have a history of serious adverse reaction to the vaccine.

• The effects of PROSTVAC in combination nivolumab, ipilimumab or both on the developing human fetus are unknown. For this reason, men must agree to use adequate contraception (abstinence, vasectomy) or female partner must use (intrauterine device (IUD), hormonal [birth control, pills, injections, or implants], tubal ligation] prior to study entry and for up to 7 months after the last dose.

• Participants 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.

• Participants must have normal organ and marrow function as defined below:

• hemoglobin greater than or equal to 8 g/dL

• granulocytes greater than or equal to 1,500/mcL

• platelets greater than or equal to 100,000/mcL

• total bilirubin < 1.5 mg/dL (or less than or equal to 3.0 mg/dL in patients with Gilbert syndrome)

• Aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase (SGOT)(SGOT)/alanine transaminase (ALT)serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5 X institutional upper limit of normal

• creatinine less than or equal to 1.5 X ULN

• For the lead in cohort:

• Castrate testosterone level (<50ng/dl or 1.7nmol /L)

• Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone:

• Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR

• PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (Prostate Cancer Clinical Trials Working Group (PCWG2) PSA eligibility criteria). If participants had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal.

• Participants must agree to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy

• For all neoadjuvant cohorts:

• Participants must be a surgical candidate for radical prostatectomy based on standard workup of PSA, biopsy results, and if necessary supplemental imaging.

• Participants must have chosen radical prostatectomy as their definitive treatment of choice for management of their prostate cancer.

• 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.

EXCLUSION CRITERIA:

• Prior splenectomy.

• 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

• Participants should have no evidence, as listed below, of being immunocompromised:

• Human immunodeficiency virus (HIV) positivity due to the potential for decreased tolerance and risk for severe side effects.

• Hepatitis B or C positivity.

• Concurrent use of systemic steroids or steroid eye drops. This is to avoid immunosuppression which may lead to potential complications with vaccinia (priming vaccination). Nasal, topical, or inhaled steroid use is permitted.

• Participants with known allergy to eggs or to compounds with a similar chemical or biologic composition to PROSTVAC, ipilimumab or nivolumab.

• No prior immune checkpoint inhibitors (e.g., anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4), anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PDL1) are allowed.

• Other serious intercurrent illness.

• Participants 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.

• Participants with significant autoimmune disease that is active or potentially life threatening if activated.

• Participants with clinically significant cardiomyopathy requiring treatment.

• Participants with ongoing toxicities related to prior therapies targeting T cell coregulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody are excluded

• No transfusion of blood or blood products within 2 weeks and no granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 2 weeks prior to initiations of experimental therapy.

• Contraindication to biopsy or prostatectomy (for sequential neoadjuvant cohorts only):

• Bleeding disorders

• Artificial heart valve

• Prothrombin time (PT)/partial thromboplastin time (PTT) greater than or equal to 1.5 in participants not taking anticoagulation. Participants on anticoagulation (e.g., enoxaparin, oral anticoagulants) are eligible regardless of PT/PTT. Prior to biopsy, anticoagulation will be held per standard practice.

• For participants with localized prostate cancer contraindication to magnetic resonance imaging (MRI):

• Participants weighing >136 kilograms (weight limit for the scanner tables)

• Allergy to magnetic resonance (MR) contrast agent

• Participants with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic devices

• History of radiation proctitis (for lead-in CRPC cohort only)

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Biological:
• PROSTVAC-V/F
PROSTVAC-V (vaccinia) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 2x10^8 infectious units. PROSTVAC-F (fowlpox) will be administered subcutaneously in an extremity (e.g., thigh) at a dose of 1x10^9 infectious units.

Drug:
• Nivolumab
Nivolumab is to be administered as a flat dose over approximately 30-minutes via intravenous (IV) infusion.

Procedure:
• Prostatectomy
Participants in the neoadjuvant cohort will undergo a radical prostatectomy in week 9. (If surgery is scheduled earlier than 9 weeks after initial dosing, the 6 and 8 week dosing may be skipped, and surgery may be done as early as week 5.)
• Biopsy
A baseline biopsy is performed for participants in the neoadjuvant cohort that do not have a previous collection of biopsy material.

Drug:
• Tylenol
Participants who experience aches or fever after vaccination may take Tylenol as directed.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for 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.	First study intervention, Study Day 1, to 30 days after participant received last study drug administration. Approximately 1.4 years for the metastatic castration-resistant prostate cancer cohort, and an average of 20 weeks for the neoadjuvant cohort.
Primary	Number of Participants With Clinically Important Immune-related Adverse Events (for the Lead-In Cohort)	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.	From treatment start throughout study completion, an average of 1.4 years.
Primary	Changes in T-cell Infiltration in the Tumor After Neoadjuvant Treatment (Only for the Neoadjuvant Cohort)	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.	From baseline to radical prostatectomy (approximately week 9)
Secondary	Number of Participants With Clinically Important Immune-related Adverse Events (Only for Neoadjuvant Cohort)	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.	From baseline throughout study completion, an average of 20 weeks.
Secondary	Changes in Soluble Immune Mediating Factors (Soluble Cluster of Differentiation 27 (sCD27) in Sera	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.	Week 4, week 10, and week 20 after therapy compared to baseline
Secondary	Changes in Soluble Immune Mediating Factors (Tumor Necrosis Factor Alpha (TNFa) and Interleukin 10 (IL-10) in Sera	Changes in soluble immune mediating factors were defined as differences in TNFa, 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 TNFa 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.	Week 4, week 10, and week 20 after therapy compared to baseline
Secondary	Percent Change of Tumor Cells Expressing Programmed Death-ligand 1 (PDL-1) (for the Neo-adjuvant Cohort)	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.	Baseline (biopsy before first PROSTVAC administration) and at time of radical prostatectomy (on week 9)
Secondary	Changes in Immune Cell Subsets in the Peripheral Blood	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.	Week 4 and week 10 after therapy compared to baseline.
Secondary	Changes in Circulating Tumor Cells (CTCs) Levels	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.	At baseline and at week 9
Secondary	Number of Participants With a Pathologic Complete Response (pCR) (Only for Neoadjuvant Cohort)	Complete pathologic response is defined as the absence of detectable malignant cells in the prostatectomy specimen evaluated by standard histologic techniques.	From baseline and time of radical prostatectomy (average of week 9)
Secondary	Number of Participants With Serologic Response	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.	From baseline throughout study completion, an average of 1.4 years.
Secondary	Rate of Biochemical Recurrence After Prostatectomy (Only for Neoadjuvant Cohort)	Biochemical recurrence following radical prostatectomy is defined as at least two prostate-specific antigen (PSA) values that are 0.2 ng/mL or higher.	From time of prostatectomy through study completion, an average of 10 weeks
Secondary	Changes in Magnetic Resonance Imaging (MRI) Secondary to Immune Treatment (Only for Neoadjuvant Cohort)	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.	From baseline to closest date to prostatectomy, average on week 9.
Secondary	Changes in Apparent Diffusion Coefficient (ADC) Mapping, Secondary to Immune Treatment (Only for Neoadjuvant Cohort)	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.	From baseline to closest date to prostatectomy, average on week 9.
Secondary	Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4+) and Forkhead Box P3 (FOX-P3) Staining (Only for Neoadjuvant Cohort)	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.	Baseline and at time of prostatectomy (approximately week 9)
Secondary	Number of Participants With Peripheral Prostate-Specific Antigen (PSA)-Specific T Secondary To Immune Treatment	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 (IFN?), Tumor Necrosis Factor Alpha (TNFa), 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.	Weeks 7-10 and 17-22 compared to baseline
Secondary	Best Overall Response for Participants With Measurable Disease (Only in the Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort)	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.	Baseline throughout study completion (average 1.4 years)

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