VAccination in Early and ADvanced Prostate caNCEr

Study Overview
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Brief Summary
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This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses (ChAdOx1- chimpanzee adenovirus Ox1 and MVA - modified vaccinia Ankara) that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells. This vaccine will be used in combination with the immunotherapy drug called nivolumab which is an anti-PD-1 (Programmed Death protein-1) monoclonal antibody. This is a molecule that releases the brakes on the immune system and helps the immune system to kill cancer cells more efficiently. Nivolumab as a monotherapy was approved for treatment of several tumour types but not for the prostate cancer. This study will evaluate the safety and efficacy of ChAdOx1-MVA 5T4 vaccine in combination with nivolumab in low and intermediate risk prostate cancer patients who have elected to have their prostate removed and in patients with advanced metastatic prostate cancer.

Official Title
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Phase I/II Open Label Non-randomised Safety and Efficacy Study of the Viral Vectored ChAd-MVA 5T4 Vaccine in Combination With PD-1 Checkpoint Blockade in Low- or Intermediate-risk Localized or Locally Advanced Prostate Cancer and Advanced Metastatic Prostate Cancer

Conditions
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Intermediate Risk Prostate Cancer, Castration-resistant Prostate Cancer

Intervention / Treatment
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* Biological: ChAdOx1-MVA 5T4 vaccine
* Drug: Nivolumab Infusion [Opdivo]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all participants: Histologically confirmed adenocarcinoma of the prostate cancer Any antineoplastic therapy must have been completed a minimum of 28 days prior to enrolment Systemic antimicrobial therapy must have been completed a minimum of 7 days prior to enrolment An archival specimen of tumour tissue should be available Baseline laboratory parameters must meet the following criteria: Haemoglobin ≥ 80 g/L, White cell count ≥ 2.0 x10^9/L, Neutrophils ≥ 1.5 x10^9/L, Lymphocytes ≥ 0.5 x10^9/L, Platelets ≥ 100 x10^9/L, Creatinine Clearance ≥ 40 ml/min by Cockcroft Gault formulation, Total Bilirubin ≤ 1.5 ULN, Alanine Aminotransferase ≤ 1.5 ULN, Amylase ≤ 1.5 ULN For surgical cohort: Clinically localised or locally advanced disease deemed operable by the treating consultant urological surgeon i.e.: Gleason score ≤ 7, local tumour stage ≤T3c and deemed operable, no evidence of metastases (Nx/N0 and Mx/M0), no evidence of high grade Gleason 5 disease, PSA ≤ 20 ng/ml Scheduled for and considered fit for radical prostatectomy For advanced metastatic cohort: Evidence of at least one distant metastasis based on MRI, CT, PET or bone scintigraphy Established on and suitable to continue with androgen deprivation therapy (ADT) using any luteinizing hormone releasing hormone (LHRH) agonist On treatment with anti-androgen therapy using either abiraterone (Zytiga®) or enzalutamide (Xtandi®) and demonstrating evidence of disease progression at the time of enrolment Suitable to continue therapy with either abiraterone or enzalutamide at the time of enrolment at discretion of their managing clinician Patients who have received chemotherapy following progression on androgen-targeting therapies are eligible Satisfactory functional status defined as ECOG Performance Status ≤ 1 Exclusion Criteria: For all participants: Any prior diagnosis or clinical suspicion of autoimmune disease History of allergic disease or reaction likely to be exacerbated by any component of the vaccine, e.g. egg products Other prior malignancy with an estimated ≥ 30% chance of relapse within 2 years Participation in another research study involving an investigational product or investigational surgical procedure in the 30 days preceding enrolment, or planned use during the study period Any prior exposure to checkpoint inhibitor drugs including anti-PD-1, anti-PD-L1, or anti-CTLA-4 monoclonal antibodies or any prior treatment with investigational vaccines Administration of immunoglobulins and/or any blood products within the one month preceding the planned administration of the study drugs Seropositive for hepatitis B surface antigen (HBsAg) Seropositive for hepatitis C virus (antibodies to HCV) Any confirmed or suspected immunocompromised state Any history of hereditary angioedema, acquired angioedema, or idiopathic angioedema History of anaphylaxis in relation to vaccination or any clinically significant allergic disease likely to be exacerbated by any component of the vaccine or checkpoint inhibitor preparations For advanced metastatic cohort: The treating oncologist estimates a subject's life expectancy to be ≤ 6 months Any active, previously treated, or suspected intracranial or leptomeningeal metastases

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermediate risk prostate cancer<br>ChAdOx1.5T4 on week 0 followed by booster injection of MVA.5T4 and nivolumab infusion on week 1. Patients will undergo radical prostatectomy on week 6. | Biological: ChAdOx1-MVA 5T4 vaccine<br>* ChAdOx1.5T4 will be administered intramuscularly in an extremity (e.g. thigh) at a dose of 2.5 x10^10 virus particles followed by MVA.5T4 administered via the same route at the dose of 2x10^8 plaque forming units<br>Drug: Nivolumab Infusion [Opdivo]<br>* Nivolumab is to be administered as a flat dose of 480 mg over approximately 60-minutes via IV infusion<br>* Other names: anti-PD-1 monoclonal antibody;|
| Experimental: Advanced metastatic prostate cancer<br>ChAdOx1.5T4 on week 0 followed by booster injections of MVA.5T4 on week 4, ChAdOx1.5T4 on week 12 and MVA.5T4 on week 16. Nivolumab infusions are to be administered on week 4, 8 and 12. | Biological: ChAdOx1-MVA 5T4 vaccine<br>* ChAdOx1.5T4 will be administered intramuscularly in an extremity (e.g. thigh) at a dose of 2.5 x10^10 virus particles followed by MVA.5T4 administered via the same route at the dose of 2x10^8 plaque forming units<br>Drug: Nivolumab Infusion [Opdivo]<br>* Nivolumab is to be administered as a flat dose of 480 mg over approximately 60-minutes via IV infusion<br>* Other names: anti-PD-1 monoclonal antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - incidence of treatment-related adverse events. | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | From baseline to 12 months | 
| Efficacy - measure composite response rate defined as one of the following: 1) change in circulating tumour DNA, 2) change in serum PSA | Number of participants with 50% or more change in ctDNA or PSA concentration in the blood from baseline to 12 months post treatment | From baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate immune responses to the vaccine antigen in the periphery | Number of participants with peripheral 5T4-specific T cell responses secondary to treatment | From baseline to 12 months | 
| Evaluate immune cell subsets in the prostate secondary to treatment (for surgical cohort) | Number of participants with intraprostatic infiltration of CD3+CD8+ T cells secondary to treatment | From baseline to radical prostatectomy, an expected average of 6 weeks | 
| Evaluate progression-free survival following study treatment (for advanced metastatic cancer cohort) | Number of participants experiencing progression-free survival at 6 and 12 months post treatment | 6-12 months | 
| Evaluate overall survival following study treatment (for advanced metastatic cancer cohort) | Number of participants experiencing overall survival at 6 and 12 months post treatment | 6-12 months |