Contact information
Type
Scientific
Primary contact
Dr Ann Pope
ORCID ID
Contact details
Cancer Research UK Clinical Trials Unit
Institute for Cancer Studies
Edgbaston
Birmingham
B15 2TT
United Kingdom
-
AdUP@trials.bham.ac.uk
Additional identifiers
EudraCT number
2007-700341-13
ClinicalTrials.gov number
Protocol/serial number
13599
Study information
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
Acronym
AdUP
Study hypothesis
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
Oxford A, 07/12/2012, ref: 12_SC_0660
Study design
Non-randomised interventional; Design type: Treatment
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Other
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
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
Phase
Phase I
Drug names
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 trial start date
15/03/2013
Overall trial end date
01/02/2019
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Male
Target number of participants
UK Sample Size: 15
Participant 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
Recruitment start date
15/03/2013
Recruitment end date
01/02/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Institute for Cancer Studies
Birmingham
B15 2TT
United Kingdom
Sponsor information
Organisation
University of Birmingham (UK)
Sponsor details
Edgbaston
Birmingham
B15 2TT
United Kingdom
-
adup@trials.bham.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Cancer Research UK (UK); Grant Codes: C198/A9699
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
Funder name
Medical Research Council (MRC) (UK)
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
To be confirmed at a later date
Intention to publish date
Participant level data
Available on request
Basic results (scientific)
Publication list