Vaccination in Prostate Cancer (VANCE)

A Randomized Phase I Study to Determine the Safety and Immunogenicity of ChAd-MVA Vaccination Compared to MVA Alone With and Without Low Dose Cyclophosphamide in Low and Intermediate Risk Localised Prostate Cancer

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" and "MVA") 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 is a first-in-human study to evaluate the safety and immunogenicity of ChAdOx1.5T4-MVA.5T4 vaccination regime. It is evaluated in neo-adjuvant setting in low and intermediate risk localised prostate cancer patients who have either decided to have their prostate removed or are stable on active surveillance.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Biological: ChAdOx1.5T4; Biological: MVA.5T4; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Oxford, United Kingdom, OX3 7DQ
    • University of Oxford
  • Sheffield, United Kingdom, S10 2IF
    • Royal Hallamshire Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria(Radical Prostatectomy patients):

• Males aged 18 years and older
• Histologically confirmed prostate cancer diagnosed on biopsy within 6 months

• Clinically localised, low or intermediate risk prostate cancer, i.e.:

  • Gleason score ≤ 7
  • Local tumour stage ≤T2c
  • No evidence of metastases (Nx/N0 and Mx/M0)
  • PSA ≤ 20 ng/ml
• Scheduled for and considered fit for radical prostatectomy
• Absence of any indication to perform urgent surgery that would not allow administration of the vaccine during the 12 week period prior to radical prostatectomy
• No invasive treatment for prostatic disease within the last 2 years
• Subject is free of clinically apparent/active autoimmune disease (no prior confirmed diagnosis or treatment for autoimmune disease including Systemic Lupus Erythematosis, Grave's Disease, Hashimoto's Thyroiditis, Multiple Sclerosis, and Insulin Dependent Diabetes Mellitus). Note subjects with Non-Insulin Dependent Diabetes Mellitus can be included.
• Subject has adequate bone marrow function as defined by an Absolute Lymphocyte Count (ALC) ≥ 500/µL, Absolute Neutrophil Count (ANC) >1200/µL, Platelet Count >100,000/µL.
• Subject must practice a reliable form of contraception (barrier or vasectomy) while they are being treated with vaccines and another effective method of birth control must also be used by their partner

Inclusion Criteria (Active Surveillance patients)

• Males aged 18 and older
• Histologically confirmed prostate cancer diagnosed on biopsy within 6 months

• Clinically localised, low or intermediate risk prostate cancer, i.e.:

  • Gleason score ≤ 7
  • Local tumour stage ≤T2c
  • No evidence of metastases (Nx/N0 and Mx/M0)
  • PSA ≤ 20 ng/ml
• Stable disease on Active Surveillance for a minimum of 12 months previously
• Suitable to remain on Active Surveillance at time of last clinical assessment
• No invasive treatment for prostatic disease within the last 2 years
• Subject is free of clinically apparent/active autoimmune disease (no prior confirmed diagnosis or treatment for autoimmune disease including Systemic Lupus Erythematosis, Grave's Disease, Hashimoto's Thyroiditis, Multiple Sclerosis, and Insulin Dependent Diabetes Mellitus). Note subjects with Non-Insulin Dependent Diabetes Mellitus can be included.
• Subject has adequate bone marrow function as defined by an Absolute Lymphocyte Count (ALC) ≥ 500/µL, Absolute Neutrophil Count (ANC) >1200/µL, Platelet Count >100,000/µL.
• Subject must practice a reliable form of contraception (barrier or vasectomy) while they are being treated with vaccines and another effective method of birth control must also be used by their partner

Exclusion Criteria:

• Diagnosis of any cancer other than prostate cancer within the last 5 years (except basal cell carcinoma)
• Any suspicion of metastatic cancer
• Any Gleason grade 5 component in the prostatic biopsies
• Participation in another research study involving an investigational product in the 30 days preceding enrolment, or planned use during the study period
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate
• Seropositive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) or HIV
• Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled/topical steroids are allowed)
• Platelet count >400,000/μL; Monocytes >80,000/μL; Hemoglobin <11g/dL
• Known allergy to neomycin
• History of allergic response to previous vaccinia vaccinations
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. egg products
• History of hypersensitivity and haemorrhagic cystitis
• Any history of anaphylaxis
• Suspected or known current injecting drug or alcohol abuse (as defined by an alcohol intake of greater than 42 units per week)
• History of a serious psychiatric condition or other circumstance s that may be associated with not understanding or complying with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CHAMVA standard regime; ChAdOx1.5T4 prime followed by two boost of MVA.5T4 vaccine at 4 week intervals until radical prostatectomy	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4
Experimental: CHAMVA+CTX standard regime; One week of low dose cyclophosphamide pre-conditioning before each vaccination. ChAdOx1.5T4 prime followed by two boost of MVA.5T4 at 4 week intervals until radical prostatectomy.	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4; Drug: Cyclophosphamide; Metronomic cyclophosphamide (50mg bd); Other Names: CTX, CY, Cytoxan
Active Comparator: MVA standard regime; Three MVA.5T4 vaccinations at 4 week intervals until radical prostatectomy	Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4
Active Comparator: MVA+CTX standard regime; One week of low dose cyclophosphamide pre-conditioning before each vaccination.Three MVA.5T4 vaccinations at 4 week intervals until radical prostatectomy	Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4; Drug: Cyclophosphamide; Metronomic cyclophosphamide (50mg bd); Other Names: CTX, CY, Cytoxan
Experimental: CHAMVA accelerated regime; ChAdOx1.5T4 prime followed by one boost of MVA.5T4 one week later until radical prostatectomy.	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4
Experimental: CHAMVA+CTX accelerated regime; One week of low dose cyclophosphamide pre-conditioning before each vaccination. ChAdOx1.5T4 prime followed by one boost of MVA.5T4 one week later until radical prostatectomy.	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4; Drug: Cyclophosphamide; Metronomic cyclophosphamide (50mg bd); Other Names: CTX, CY, Cytoxan
Experimental: CHAMVA accelerated regime AS; ChAdOx1.5T4 prime followed by one boost of MVA.5T4 one week later. Patients continue on active surveillance.	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4
Experimental: CHAMVA+CTX accelerated regime AS; One week of low dose cyclophosphamide pre-conditioning before each vaccination. ChAdOx1.5T4 prime followed by one boost of MVA.5T4 one week later. Patients continue on active surveillance.	Biological: ChAdOx1.5T4; A recombinant simian adenovirus encoding human tumour-associated antigen 5T4; Biological: MVA.5T4; A recombinant replication deficient Modified Vaccinia Ankara virus encoding human tumour-associated antigen 5T4; Drug: Cyclophosphamide; Metronomic cyclophosphamide (50mg bd); Other Names: CTX, CY, Cytoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaccine safety and immunogenicity	Development or increase in anti-5T4 cellular and humoral responses in patients treated with CHAMVA or CHAMVA + CTX	Up to 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular and humoral immune response with CHAMVA	Development or increase in anti-5T4 cellular and humoral responses in patients treated with the CHAMVA vaccination regimes	Up to 52 weeks
Cellular and humoral immune response with MVA	Development or increase in anti-5T4 cellular and humoral response in patients treated with the MVA vaccination regimes.	Up to 52 weeks
PSA level change secondary to vaccination	PSA level decrease in patients treated with CHAMVA or MVA vaccination at week 4,8 or 12.	Participants will be followed for the duration of the study, up to 52 weeks
MRI or Gleason score change secondary to vaccination	Reduction of tumour burden or Gleason score at weeks 4, 8 or 12.	Participants will be followed for the duration of the study, up to 52 weeks
Regulatory T-cell response	Change in the frequency of regulatory T-cells measured in blood or tumour samples from patients treated with metronomic cyclophosphamide compared to patients not receiving cyclophosphamide	Participants will be followed for the duration of the study, up to 52 weeks

Collaborators and Investigators

• Sponsor: University of Oxford
• Investigators: Study Chair: Freddie Hamdy, Oxford University Hospitals NHS Trust

Publications and helpful links

General Publications

• Cappuccini F, Bryant R, Pollock E, Carter L, Verrill C, Hollidge J, Poulton I, Baker M, Mitton C, Baines A, Meier A, Schmidt G, Harrop R, Protheroe A, MacPherson R, Kennish S, Morgan S, Vigano S, Romero PJ, Evans T, Catto J, Hamdy F, Hill AVS, Redchenko I. Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial. J Immunother Cancer. 2020 Jun;8(1):e000928. doi: 10.1136/jitc-2020-000928.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): May 15, 2018
• Study Completion (Actual): May 15, 2019

Study Registration Dates

• First Submitted: March 10, 2015
• First Submitted That Met QC Criteria: March 16, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: February 7, 2020
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: VANCE01