Clinical trial NCT02933255: PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer
Official title: Phase I/II Study of PROSTVAC in Combination With Nivolumab in Men With Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Prostate Cancer
Keywords: Safety
Neoadjuvant
Prostatectomy
Immunotherapy
Vaccine
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2016-10-14
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: * 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)

Primary outcomes:
measure: Number of Participants With Clinically Important Immune-related Adverse Events (for the Lead-In Cohort)
timeFrame: From treatment start throughout study completion, an average of 1.4 years.
measure: Changes in T-cell Infiltration in the Tumor After Neoadjuvant Treatment (Only for the Neoadjuvant Cohort)
timeFrame: From baseline to radical prostatectomy (approximately week 9)
Secondary outcomes:
measure: Number of Participants With Clinically Important Immune-related Adverse Events (Only for Neoadjuvant Cohort)
timeFrame: From baseline throughout study completion, an average of 20 weeks.
measure: Changes in Soluble Immune Mediating Factors (Soluble Cluster of Differentiation 27 (sCD27) in Sera
timeFrame: Week 4, week 10, and week 20 after therapy compared to baseline
measure: Changes in Soluble Immune Mediating Factors (Tumor Necrosis Factor Alpha (TNFα) and Interleukin 10 (IL-10) in Sera
timeFrame: Week 4, week 10, and week 20 after therapy compared to baseline
measure: Percent Change of Tumor Cells Expressing Programmed Death-ligand 1 (PDL-1) (for the Neo-adjuvant Cohort)
timeFrame: Baseline (biopsy before first PROSTVAC administration) and at time of radical prostatectomy (on week 9)
measure: Changes in Immune Cell Subsets in the Peripheral Blood
timeFrame: Week 4 and week 10 after therapy compared to baseline.
measure: Changes in Circulating Tumor Cells (CTCs) Levels
timeFrame: At baseline and at week 9
measure: Number of Participants With a Pathologic Complete Response (pCR) (Only for Neoadjuvant Cohort)
timeFrame: From baseline and time of radical prostatectomy (average of week 9)
measure: Number of Participants With Serologic Response
timeFrame: From baseline throughout study completion, an average of 1.4 years.
measure: Rate of Biochemical Recurrence After Prostatectomy (Only for Neoadjuvant Cohort)
timeFrame: From time of prostatectomy through study completion, an average of 10 weeks
measure: Changes in Magnetic Resonance Imaging (MRI) Secondary to Immune Treatment (Only for Neoadjuvant Cohort)
timeFrame: From baseline to closest date to prostatectomy, average on week 9.
measure: Changes in Apparent Diffusion Coefficient (ADC) Mapping, Secondary to Immune Treatment (Only for Neoadjuvant Cohort)
timeFrame: From baseline to closest date to prostatectomy, average on week 9.
measure: Intraprostatic Treg Cell Infiltration With Cluster of Differentiation 4 (CD4+) and Forkhead Box P3 (FOX-P3) Staining (Only for Neoadjuvant Cohort)
timeFrame: Baseline and at time of prostatectomy (approximately week 9)
measure: Number of Participants With Peripheral Prostate-Specific Antigen (PSA)-Specific T Secondary To Immune Treatment
timeFrame: Weeks 7-10 and 17-22 compared to baseline
measure: Best Overall Response for Participants With Measurable Disease (Only in the Metastatic Castration-Resistant Prostate Cancer (mCRPC) Cohort)
timeFrame: Baseline throughout study completion (average 1.4 years)
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: 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.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: James L Gulley, M.D.
role: PRINCIPAL_INVESTIGATOR
References: