AdUP: AdNRGM; VDEPT + GMCSF in locally recurrent prostate cancer

ISRCTN	ISRCTN06254734
DOI	https://doi.org/10.1186/ISRCTN06254734
EudraCT/CTIS number	2007-700341-13
IRAS number	45807
ClinicalTrials.gov number	NCT04374240
Secondary identifying numbers	13599

Submission date: 28/02/2013
Registration date: 28/02/2013
Last edited: 02/06/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/cancer-help/trials/trials-search/a-trial-looking-biological-therapy-treat-prostate-cancer-come-back-after-radiotherapy-hormone-therapy-adup

Study website

Contact information

Dr Ann Pope
Scientific

Cancer Research UK Clinical Trials Unit
Institute for Cancer Studies
Edgbaston
Birmingham
B15 2TT
United Kingdom

Email	AdUP@trials.bham.ac.uk

Study information

Study design	Non-randomised interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	AdUP: A Phase I Clinical Trial of a replication defective type 5 adenovirus vector expressing nitroreductase and GMCSF (AdNRGM) given via trans-perineal, template-guided, intra-prostatic injection, followed by intravenous CB1954, in patients with locally relapsed hormone-refractory Prostate Cancer
Study acronym	AdUP
Study objectives	The main purpose of this trial is to determine the safety and tolerability of a gene therapy strategy for the treatment of locally relapsed prostate cancer. The gene therapy is based on the intraprostatic injection of a viral vector (AdNRGM) carrying a gene called GMCSF which is able to induce a strong immune response against the prostate cancer, and a gene called NTR which is able to convert an inactive compound called CB1954 (prodrug) to a powerful anti-cancer drug. To ensure coverage of the whole prostate the vector will be administered by multiple stereotactically-guided intraprostatic injections. 48 hours after the injection of the viral vector, the prodrug CB1954 will be administered intravenously. It is expected that the combination of the immune response induced by the GMCSF and the activation of the prodrug C1954 operated by NTR within the tumour tissue will result in the death of a significant number of prostate cancer cells.
Ethics approval(s)	Oxford A, 07/12/2012, ref: 12_SC_0660
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	Current interventions as of 12/07/2016: This is an open-label, non-randomised, phase I, sequential group trial which will explore the safety and tolerability of ascending doses of replication defective adenovirus type 5 vector expressing nitroreductase and GMCSF (AdNRGM), in combination with CB1954. Five groups of three patients each will be treated with escalating doses of AdNRGM (1010, 3x1010, 1011, 3x1011, 1012 vp) followed 2 days later by intravenous CB1954 at a fixed dose (24mg/m2). The AdNRGM is given via trans-perineal, template-guided, intra-prostatic injection. Patients will be monitored on days 1, 2 and 5-7 following AdNRGM administration, with telephone contact on days 3 and 4; then seen at weeks 2, 3 and 4, then monthly for 12 months or until PSA progression. Previous interventions: AdNRGM Administration, Template-guided prostate brachytherapy CB1954 Infusion, Infusion of 24 mg/m2
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	Intraprostatic injection of a viral vector (AdNRGM)
Primary outcome measure	Current primary outcome measures as of 26/07/2016: 1. Safety and tolerability of escalating doses of AdNRGM, followed by iv CB1954 determined by assessing local effects on tumour etc. and number of participants with treatment related adverse events by CTCAE v4.0 (Time Frame: 12 months) 1.1. Safety will be assessed in terms of local effects on the tumour, the prostate gland and the lower urinary tract as well as in terms of systemic effects. The data will be summarised descriptively 1.2. Adverse events and side effects will be determined as changes of the relevant clinical parameters as well as changes of haematological and clinical biochemistry data Previous primary outcome measures: Toxicity; timepoint(s): up to end of Month 11 visit
Secondary outcome measures	Current secondary outcome measures as of 26/07/2016: 1. PSA levels and PSA kinetics following treatment with AdNRGM and CB1954 (time frame: 12 months). Changes in the level and kinetics of the serum PSA will be measured to provide an indication of changes in tumour burden, growth rate and possible anti-tumour activity of the treatment. Other pre-specified outcome measures: 2. Evidence for local tumour destruction, and immune infiltration, in tumour biopsies taken after the treatment (time frame: 12 months). Treatment-induced immune responses will be assessed by measurement of T cell responses to prostate cancer antigens in blood samples collected at baseline and at intervals (2, 3, 4, and 8 weeks) following treatment. 3. Changes in cellular immune response to prostate cancer antigens following treatment with AdNRGM and CB1954 (time frame: 12 months). Evidence of tumour destruction and immune infiltration will be assessed by looking at patterns of tissue damage, residual tumour tissue and immune cell infiltrates detected by immunohistochemistry in post-treatment prostate biopsies Previous secondary outcome measures: PSA level and kinetics; timepoint(s): Up to end of Month 11
Overall study start date	15/03/2013
Completion date	31/07/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Male
Target number of participants	UK Sample Size: 15
Total final enrolment	18
Key inclusion criteria	1. Patients who present with biopsy proven local recurrence of prostate cancer following radical radiotherapy and a rising PSA while on androgen suppression with LHRH agonist therapy or after bilateral orchidectomy. A rising PSA is defined as 3 consecutive increases (measured by the same laboratory) over a minimum period of 6 weeks, with timepoints separated by at least 15 days. If the patient is on LHRH agonist therapy, this therapy should be continued. 2. Life expectancy greater than 3 months 3. Aged at least 18 years 4. Written informed consent 5. WHO performance status of 0-1 (Appendix 2) 6. PSA value = 4 and = 25 ng/ml at study entry 7. Adequate hepatic function (i.e. bilirubin, AST, ALT all < 1.5 x upper limit of normal for Institution) 8. Normal renal function (<1.25 x upper normal limit for the Institution) 9. Adequate haematological function (i.e. haemoglobin > 10g/dl, WCC > 3x109/l, platelets > 150x109/l) and normal clotting (INR and APTT <1.2) 10. Patients must agree not to father a child within 12 months following AdNRGM administration, and must practice a barrier method of contraception starting from the time of AdNRGM administration for at least 12 months 11. No known immunoincompetence
Key exclusion criteria	1. Patients with a prostate or tumour which is deemed clinically unsuitable for transperineal templateguided injection 2. Patients who have previously been treated with prostate brachytherapy 3. Patients who have received chemotherapy, radiotherapy or immunotherapy within 28 days of study entry 4. Acute active infection (viral, bacterial, or fungal) which requires specific therapy 5. Chronic hepatitis B or C infection, HIV positive patients (patients will be tested for HBV/HCV, but not HIV) 6. Concurrent severe medical illnesses incompatible with the treatment including psychiatric pathology likely to affect protocol compliance 7. Tumours of other organs or tissues still active or treated radically less that 3 years before (except that successfully treated, nonmetastatic skin cancers are not an exclusion criterion) 8. Concurrent corticosteroids, or any medication known to have significant immunosuppressive action 9. Patients unable to travel for regular hospital assessments 10. Evidence of adenovirus infection and/or shedding at prescreening
Date of first enrolment	15/03/2013
Date of final enrolment	05/08/2019

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom

Sponsor information

University of Birmingham (UK)
University/education

Edgbaston
Birmingham
B15 2TT
England
United Kingdom

Email	adup@trials.bham.ac.uk
Website	http://www.birmingham.ac.uk
"ROR"	https://ror.org/03angcq70

Funders

Funder type

Charity

Cancer Research UK (UK); Grant Codes: C198/A9699
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Medical Research Council (MRC) (UK)
Government organisation / National government

Alternative name(s): Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location: United Kingdom

Results and Publications

Intention to publish date	01/09/2023
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Publish protocol & planned publication of results in a high-impact peer-reviewed journal.
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon request. Scientifically sound proposals from appropriately qualified Research Groups will be considered for data sharing. Requests should be made by returning a completed Data Sharing Request Form and curriculum vitae of the lead applicant and statistician to newbusiness@trials.bham.ac.uk. The Data Sharing Request Form captures information on the specific requirements of the research, the statistical analysis plan, and the intended publication schedule. The request will be reviewed independently by the Cancer Research UK Clinical Trials Unit (CRCTU) Directors at University of Birmingham in discussion with the Chief Investigator and Trial Management Group. In making their decision the Director’s Committee will consider the scientific validity of the request, the qualifications of the Research Group, the views of the Chief Investigator and Trial Management Group, consent arrangements, the practicality of anonymizing the requested data and contractual obligations. Where the CRCTU Directors and appropriate Trial Committees are supportive of the request, and where not already obtained, consent for data transfer will be sought from the Sponsor of the trial before notifying the applicant of the outcome of their request. It is anticipated that applicants will be notified of a decision within 3 months of receipt of the original request.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results	version 1.0	01/06/2023	02/06/2023	No	No

Additional files

ISRCTN06254734_BasicResults_v1.0_01Jun23.pdf

Editorial Notes

02/06/2023: The following changes were made to the study record:
1. Basic results uploaded.
2. Institute for Cancer Studies was removed and University Hospitals Birmingham NHS Foundation Trust was added as a study participating centre.
3. The intention to publish date was changed from 01/09/2022 to 01/09/2023.
15/06/2022: The following changes have been made:
1. The IRAS number has been added.
2. The NCT code has been added.
3. The trial website has been added.
4. The overall trial end date has been changed from 31/12/2020 to 31/07/2021.
5. The trial setting has been changed from 'Other' to 'Hospitals'.
6. The intention to publish date has been changed from 31/12/2021 to 01/09/2022.
7. The IPD sharing statement has been added.
10/09/2019: The following changes were made to the trial record:
1. The total final enrolment was added.
2. The recruitment end date was changed from 20/08/2019 to 05/08/2019.
13/06/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/02/2019 to 20/08/2019.
2. The overall end date was changed from 01/02/2019 to 31/12/2020.
3. The intention to publish date was added.
4. The publication and dissemination plan was added.
06/12/2017: Dr Ann Pope replaced Dr Laura Crack as the primary study contact.
12/07/2016: the overall trial end date and recruitment end date were changed from 31/01/2014 to 01/02/2019.