Clinical Trial Results:
Phase II open label 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
Summary
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EudraCT number |
2017-001992-22 |
Trial protocol |
GB |
Global end of trial date |
20 May 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Aug 2023
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First version publication date |
04 Aug 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ADVANCE
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03815942 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
RGEA, University of Oxford
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Sponsor organisation address |
Churchill hospital, Old Road, Headington, Oxford, United Kingdom, OX3 7LE
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Public contact |
Adrian Hill, The Jenner Institute, University of Oxford, +44 1865617610, adrian.hill@ndm.ox.ac.uk
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Scientific contact |
Adrian Hill, The Jenner Institute, University of Oxford, +44 1865617610, adrian.hill@ndm.ox.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 May 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 May 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
20 May 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To assess the safety and efficacy of ChAd-MVA 5T4 vaccination in combination with checkpoint inhibitor nivolumab when administered to early stage and advanced metastatic prostate cancer patients.
Low- or intermediate-risk localised or locally advanced prostate cancer patients:
• To assess safety of the viral vectored ChAd-MVA 5T4 vaccine when administered in combination with anti-PD-1 mAb
• To determine whether ChAd-MVA 5T4 vaccine in combination with anti-PD-1 will impact on the serum level of PSA
Metastatic prostate cancer patients
• To assess safety of the viral vectored ChAd-MVA 5T4 vaccine when administered in combination with anti-PD-1 mAb
• To assess efficacy of the viral vectored ChAd-MVA 5T4 vaccine when administered in combination with anti-PD-1 mAb as measured by composite response rate defined as one of the following:
o reduction of circulating tumour DNA
o serum PSA decrease
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Protection of trial subjects |
All patients will sign and date the informed consent form before any study-specific procedures are performed. The information sheet will be made available to the patient at least 24 hours prior to the screening visit. The patient will be fully informed of all aspects of the trial, the potential risks and their obligations. The following general principles will be emphasised:
• Participation in the study is entirely voluntary
• Refusal to participate involves no penalty or loss of medical benefits
• The patient may withdraw from the study at any time
• The patient is free to ask questions at any time to allow him or her to understand the purpose of the study and the procedures involved
• The study involves research of an investigational vaccine and checkpoint inhibitor
• The study involves delaying the patient’s surgery by approximately 2 months
• There may be no direct benefit for participating
The aims of the study and all tests to be carried out will be explained. The patient will be given the opportunity to ask about details of the study, and will then have time to consider whether or not to participate. If they do decide to participate, they will sign and date the consent form, which will also be signed and dated by the investigator. One copy will be given to the partiicpant, one copy will be placed in the study file, and the original will be placed in their medical notes.
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Background therapy |
- | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
01 Oct 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 23
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Worldwide total number of subjects |
23
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
2
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From 65 to 84 years |
21
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were recruited into one of two cohorts within the study: those with operable localised or locally advanced prostate cancer who are planned to undergo radical prostatectomy, or those with metastatic prostate cancer who demonstrate disease progression on therapy with second generation anti-androgens (enzalutamide or abiraterone). | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
The subjects were men over 18 years old. 2 groups Radical prostatectomy: Men with low- or intermediate-risk advanced prostate cancer and deemed operable and fit to undergo radical prostatectomy (0 recruited) Metastatic prostate cancer: men with metastatic prostate cancer with demonstrated disease progression following anti-androgen treatment (23) | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Whole trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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Group 2 | ||||||||||||||||||||||||
Arm description |
Participants with Metastatic Prostate Cancer | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ChAdOx1.5T4 vaccine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Injection , Intramuscular use
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Dosage and administration details |
ChAdOx1.5T4 vaccine is is an unlicensed medicinal product manufactured by by the University of Oxford Clinical Biomanufacturing Facility (CBF), Churchill Hospital, Oxford. It is formulated in formulation buffer at a nominal concentration of 1.1x1011 vp/mL.
The formulation buffer consists of 10mM Histidine, 7.5% sucrose, 35mM NaCI, 1mM MgCl2, 0.1% PS80, 0.1mM EDTA, 0.5% EtOH, pH 6.6. The fill volume is 0.5-1.0 mL.
The dose of ChAdOx1.5T4 used in this study is 2.5x1010 vp.
The vaccine was allowed to thaw to room temperature and were administered by intramuscular injection within 1 hour of removal from the freezer. The preferred site for vaccination was the vastus lateralis muscle of the thigh but the deltoid muscle of the arm was an acceptable alternative.
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Investigational medicinal product name |
MVA.5T4 vaccine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Injection , Intramuscular use
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Dosage and administration details |
MVA.5T4 vaccine is an unlicensed medicinal product that has not been administered to humans before.
It has been manufactured under Good Manufacturing Practice conditions by IDT Biologika GmbH, Germany.
MVA.5T4 was supplied as a frozen liquid formulation in 10mM Tris buffer 140 mM NaCl, pH 7.7 in 2.0 mL clear glass vials. The formulation titre is 2x109 pfu/ml, the final drug product titre is 1x109pfu/ml. The fill volume is 0.55 mL.
The vaccine was allowed to thaw to room temperature and administered by intramuscular injection within 1 hour of removal from the freezer. The preferred site for vaccination was the vastus lateralis muscle of the thigh but the deltoid muscle of the arm was an acceptable alternative. It was planned to use a different thigh (arm) for each of the two MVA.5T4 immunisations.
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Investigational medicinal product name |
Immune checkpoint inhibitor nivolumab
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Investigational medicinal product code |
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Other name |
Opdivo®
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Nivolumab 480mg, was prepared from 10mg/ml concentrate, diluted into sodium chloride 9mg/mL (0.9%) solution for injection and administered intravenously in a volume of 100ml to a final concentration of 4.8mg/ml. Preparation and handling adopted strict aseptic technique.
In line with the manufacturer’s instructions, nivolumab was administered intravenously over a period of 60 minutes using a volumetric pump, an infusion set and an in-line, sterile, nonpyrogenic, low protein binding filter of pore size of 0.2μm to 1.2μm. After administration the line was flushed with sodium chloride 9 mg/mL (0.9%) solution for injection.
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Baseline characteristics reporting groups
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Reporting group title |
Group 2
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Reporting group description |
Participants with Metastatic Prostate Cancer | ||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Group 2
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The participant must satisfy all the following criteria to be eligible for the study:
- Histologically confirmed adenocarcinoma of the prostate cancer. Note, any Gleason grade or primary tumour staging at diagnosis is permitted.
- 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. LHRH agonist therapy may include goserelin (Zoladex®), leuprorelin acetate (Prostap®) or any other licenced product in this class.
- On treatment with anti-androgen therapy using either abiraterone (Zytiga®) or enzalutamide (Xtandi®) and demonstrating evidence of disease progression at the time of enrolment, defined according Prostate Cancer Working Group 3 Criteria as either:
• PSA progression as defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screeni
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End points reporting groups
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Reporting group title |
Group 2
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Reporting group description |
Participants with Metastatic Prostate Cancer | ||
Subject analysis set title |
Group 2
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The participant must satisfy all the following criteria to be eligible for the study:
- Histologically confirmed adenocarcinoma of the prostate cancer. Note, any Gleason grade or primary tumour staging at diagnosis is permitted.
- 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. LHRH agonist therapy may include goserelin (Zoladex®), leuprorelin acetate (Prostap®) or any other licenced product in this class.
- On treatment with anti-androgen therapy using either abiraterone (Zytiga®) or enzalutamide (Xtandi®) and demonstrating evidence of disease progression at the time of enrolment, defined according Prostate Cancer Working Group 3 Criteria as either:
• PSA progression as defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screeni
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End point title |
Completed the study [1] | ||||||||||||||||||||||||||||||||||||
End point description |
Those participants who completed the full study
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End point type |
Primary
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End point timeframe |
Week 48
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the confidential nature of this information, we have not provided this analysis at this time. The scientific paper can be uploaded following publication if required. |
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No statistical analyses for this end point |
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End point title |
Received Vaccination / Infusions [2] | ||||||||||||||||||||||||||||||
End point description |
How many had the dose(s) administered at each stage
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End point type |
Primary
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End point timeframe |
Progression of vaccinations / infusions through the trial
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the confidential nature of this information, we have not provided this analysis at this time. The scientific paper can be uploaded following publication if required. |
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
From Enrolment until End of Study
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Adverse event reporting additional description |
ADV-00118011
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26
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Reporting groups
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Reporting group title |
Group 2
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Reporting group description |
All of the participants in the trial (metastatic prostate cancer) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Due to the confidential nature of this information, we have not provided this analysis at this time. The scientific paper can be uploaded following publication if required. |
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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08 Jun 2016 |
SA001 was REC-Only and included changes to the Protocol, the Participant Information Sheets (PIS RP and PIS mPCa), ICF(RP), Diary Cards and GP letter and provision of the new Investigator’s Brochure for MVA.5T4 IMP.
The changes to the Protocol were: 1) Removal of one recruiting site 2) Addition of one recruiting site 3) For radical prostatectomy patients (RP) reduction of the following: a) number of nivolimab infusions, b) intervals between study treatments, c) surgery delay, d) number of study visits, e) follow-up period. 4) for metastatic prostate cancer patients (mPCa): modification of the vaccines and nivolumab dosing regimes and clarification of study endpoints 5) New information regarding the MVA.5T4 vaccine.
The PIS RP was changed to reflect the changes above.
The PIS mPCa was changed to reflect the changes above.
The ICF RP was changed to reflect the reduction of nivolumab infusions.
The changes to the GP Letter reflected the reduction in follow-up period for RP participants.
The Diary Cards were changed to reflect the changes in dosing regimens.
New Investigator’s Brochure for MVA.5T4
The HRA schedule of events was changed to reflect the changes in the vaccines and nivolumab dosing regimens.
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05 Sep 2018 |
SA002 was submitted to the REC and the MHRA and modified the study protocol and extended the shelf-life of the study IMP ChADOx1.5T4 to 15Jul2019 on the basis of stability test results.
The changes to the protocol were 1) Removal of 3 recruiting sites 2) Addition of 1 recruiting site 3) Addition of Principal Investigator 4) Reduction in sample size from 60 to 36 participants 5) For Metastatic Prostate Cancer participants: a) removal of the control arm receiving Nivolumab only b) removal of randomisation c) reduction of the follow-up period to 12 months and reduction of the number of study visits
ADVANCE Protocol Version 3.0, 03Sep2018 was submitted.
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29 Nov 2018 |
SA003 was submitted to the REC and the MHRA and modified the study protocol.
The changes in the protocol were in Appendix 1 (Schedule of events): 1) No collection of blood samples for exploratory biochemistry for Group 2 (mPCA) 2) Significant reduction in number of blood samples for ctDNA quantification but increase in blood volume 3) Small increase in blood volume for exploratory immunology at several timepoint
ADVANCE Protocol Version 4.0, 19Nov2018 was submitted.
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19 Feb 2019 |
SA004 was submitted to the REC and the MHRA and modified the study protocol.
The changes to the protocol were: 1) Two sites and their respective Principal Investigators were removed 2) Treatment with abiraterone and enzalutamide were discontinued after enrolment to the study 3) Participant confidentiality section was modified to comply with GDPR and Data Protection Act 4) Changes to the Schedule of events: a) Timeframe for phone call increased to 2+3 days b) Blood sample for HLA typing collected at visit 2 instead of 3 c) Timepoints for ctDNA and CTC modified to remove collection at week 48 and add collection at weeks 4, 8 and 12 for cdctDNA and week 8 for CTC sample.
ADVANCE Protocol Version 5.0, 15Feb2019 was submitted.
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16 Oct 2019 |
SA006 was submitted to the REC and the MHRA and constituted a temporary halt of the study following the identification of a potentially serious breach. |
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19 Nov 2019 |
SA007 was submitted to the REC and the MHRA and requested the re-start of the trial following the implementation of measures to rectify the situation. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
No participants were recruited to Group 1 (Radical prostatectomy group) |