A Clinical Trial of AdNRGM Plus CB1954 in Prostate Cancer

NCT04374240 | Completed Phase 1

• 3 other identifiers: RG_06-226ISRCTN062547342007-007041-13
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label, non-randomised, phase I, sequential group trial which will explore the safety and tolerability of ascending doses of AdNRGM, in combination with CB1954. Five groups of 3 patients each will be treated with escalating doses of AdNRGM (10\^10, 3x10\^10, 10\^11, 3x10\^11, 10\^12 vp) followed 2 days later by intravenous CB1954 at a fixed dose (24mg/m\^2). To ensure the coverage of the whole prostate the vector will be delivered by multiple, template-guided trans-perineal injections using an adaptation of standard prostate brachytherapy technique. Dose escalation will be dependent on safety and tolerability; at each dose-level, if dose-limiting toxicity (DLT) is seen in one patient, the cohort will be expanded to a maximum of 6 patients. If DLT is then observed in a second patient at that dose, no further patients will be recruited and the previous (lower) dose-level will be defined as the maximum tolerated dose (MTD). If DLT is seen in 0/3 or just 1/6 patients, dose escalation may continue.

Conditions

Prostate Cancer

Keywords

adenovirus

Outcome Measures

Primary Outcomes (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

  * 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. * 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.

  12 months

Secondary Outcomes (1)

• Measuring PSA levels following treatment with AdNRGM and CB1954

  12 months

Other Outcomes (2)

• To assess the evidence for local tumour destruction, and immune infiltration, in tumour biopsies taken after the treatment

  8 weeks post treatment

• To investigate changes in cellular immune response to prostate cancer antigens following treatment with AdNRGM and CB1954

  12 months

Study Arms (1)

AdNRGM followed on day 2 by CB1954

EXPERIMENTAL

The proposed dose levels for AdNRGM are 10\^10, 3x10\^10, 10\^11, 3x10\^11, 10\^12 vp while the prodrug CB1954 will be given at a standard dose of 24 mg/m\^2

Genetic: AdNRGM

Interventions

AdNRGM GENETIC

AdNRGM is an E1-E3 deleted, replication deficient type 5 adenovirus which contains the E. coli NTR gene regulated by the CMV promoter, an internal ribosomal entry site (IRES) and the human GMCSF gene. CB1954 \[5-(aziridin-1-yl)-2,4-dinitrobenzamide\]

Also known as: CB1954

AdNRGM followed on day 2 by CB1954

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who present with biopsy-proven local recurrence of prostate cancer following radical radiotherapy and a rising PSA with or without androgen suppression with antiandrogens or LHRH agonist/antagonist therapy or after bilateral orchidectomy. A rising PSA is defined as 2 increases over 3 or 4 readings over a minimum period of 6 weeks, with time-points separated by at least 2 weeks. If the patient is on antiandrogens or LHRH agonist/antagonist therapy, this therapy should be continued.
• Life expectancy greater than 3 months.
• Aged at least 18 years.
• Written informed consent.
• World Health Organisation (WHO) performance status of 0-1.
• PSA value ≥ 2 and ≤ 100 ng/ml at study entry.
• Adequate hepatic function (i.e. bilirubin, AST, ALT all \< 1.5 x upper limit of normal for Institution).
• Normal renal function (\<1.25 x upper normal limit for the Institution).
• Adequate haematological function (i.e. haemoglobin \> 10g/dl, WCC \> 3x109/l, platelets \> 150x10\^9/l) and normal clotting (INR and APTT \<1.2).
• Patients must agree not to father a child within 12 months following AdNRGM administration, and must use at least two methods of contraception, one of which is barrier, starting from the time of AdNRGM administration for at least 12 months.
• No known immuno-incompetence.

You may not qualify if:

• Patients with a prostate or abnormal focus which is deemed clinically unsuitable for trans-perineal template-guided injection.
• Patients who have previously been treated with prostate brachytherapy.
• Patients who have previously been treated with AdNRGM and CB1954; or who have been administered any other human adenovirus type 5 vector within the last 5 years.
• Patients who have received chemotherapy, radiotherapy or immunotherapy within 28 days of study entry.
• Acute active infection (viral, bacterial, or fungal) which requires specific therapy.
• Chronic hepatitis B or C infection, HIV positive patients. (Patients will be tested for HBV/HCV, but not HIV).
• Concurrent severe medical illnesses incompatible with the treatment including psychiatric pathology likely to affect protocol compliance.
• Concurrent corticosteroids, or any medication known to have significant immunosuppressive action.
• Patients unable to travel for regular hospital assessments.
• Evidence of adenovirus infection and/or shedding at baseline.
• Clinical judgement by the Investigator that the patient should not participate in the study.

Sponsors & Collaborators

• University of Birmingham: lead
• Janssen, LP: collaborator
• Department of Health, United Kingdom: collaborator
• Medical Research Council: collaborator

Study Sites (1)

Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust

Birmingham, West Midlands, B15 2GW, United Kingdom

Location

Related Publications (1)

• Patel P, Young JG, Mautner V, Ashdown D, Bonney S, Pineda RG, Collins SI, Searle PF, Hull D, Peers E, Chester J, Wallace DM, Doherty A, Leung H, Young LS, James ND. A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Mol Ther. 2009 Jul;17(7):1292-9. doi: 10.1038/mt.2009.80. Epub 2009 Apr 14.

  PMID: 19367257 BACKGROUND

Related Links

• Trial Website

MeSH Terms

Conditions

Prostatic Neoplasms; Adenoviridae Infections

Interventions

tretazicar

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; DNA Virus Infections; Virus Diseases; Infections

Study Officials

• Prashant Patel, FRCS Ed

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: AdNRGM plus CB1954

Study Record Dates

• First Submitted: March 1, 2016
• First Posted: May 5, 2020
• Study Start: March 19, 2013
• Primary Completion: August 1, 2021
• Study Completion: August 1, 2021
• Last Updated: November 3, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)