Phase I Trial of Replicative Defective Type 5 Adenovirus Vector Expressing Nitroreductase & GMCSF Given Via Trans-perineal Template-guided Intra-prostatic Injection Followed by iv CB1954 in Locally Relapsed Prostate Cancer Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
Background and Rationale:
Locally relapsed prostate cancer presents an attractive target for gene therapy because the tumour remains localised to the prostate or to the surrounding tissue for a long phase of the disease. Also the delivery of gene therapy vectors to the prostate is straightforward using either ultrasound-guided, trans-rectal injection or adapting methods developed for brachytherapy, to deliver multiple, template-guided trans-perineal injections to achieve saturation coverage of the prostate. Several gene therapy and gene-immunotherapy strategies have been tested in patients with locally relapsed or metastatic prostate cancer, including Virus Directed Enzyme Prodrug Therapy (VDEPT), Conditionally Replicating Adenoviruses (CRAds) and GMCSF based immune stimulation. These treatments were well tolerated and showed some evidence of anti-tumour activity.
The nitroreductase/CB1954 VDEPT system:
The nitroreductase/CB1954 system employs E. coli nitroreductase (NTR) as the prodrug activating enzyme, and CB1954 as the prodrug to be activated. To exploit this system a an E1-E3 deleted, replication-defective human adenovirus (Ad5) designated CTL102 which contains the NTR gene under the control of the cytomegalovirus (CMV) promoter was previously generated. CTL102 was able to infect cancer cells and to induce NTR expression in vitro, in addition NTR expressing cells are sensitised to CB1954. Experiments carried out in animal models demonstrated that NTR expression could be detected in prostate cancer xenografts injected with CTL102 and that growth of the xenografts was inhibited by intratumoural injection of CTL102 followed 2 days later by intra peritoneal administration of CB1954.
CB1954 prodrug conversion and clinical development:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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.
- •Tumours of other organs or tissues of high malignant potential still active or treated radically less than 3 years before (except that successfully treated, non-metastatic skin cancers or non-muscle invasive bladder cancers are not an exclusion criterion).
- •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.
研究组 & 干预措施
AdNRGM followed on day 2 by CB1954
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
干预措施: AdNRGM (Genetic)
结局指标
主要结局
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
时间窗: 12 months
* 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.
次要结局
- Measuring PSA levels following treatment with AdNRGM and CB1954(12 months)