Intravesical Instillation Therapy With Bacillus Calmette-Guérin (BCG) and Sequential BCG and Electromotive Mitomycin-C (EMDA-MCC) in Patients With High-risk Non-muscle-invasive Bladder Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 7
- 主要终点
- Bladder cancer recurrence rate
研究概览
简要总结
Disease recurrence and progression is a major issue in high risk non-muscle-invasive bladder cancer (NMIBC).
The current study compares two adjuvant instillation therapies in the treatment of high risk NMIBC. After resection of the tumour(s), patients will receive either traditional regimen of Bacillus Calmette-Guérin (BCG) instillations or combination treatment consisting of sequential BCG-instillations and mitomycin C instillations administered with electromotive drug administration (EMDA) device.
详细描述
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease. The patients with NMIBC may be categorized in three risk groups according to the risk of recurrence and progression characterized by the disease. The treatment of high risk NMIBC includes a transurethral resection of the tumour(s), which is followed by an adjuvant instillation therapy, aiming to reduce the risk of recurrence and progression. Intravesical bacillus Calmette-Guérin (BCG) treatment is been the most effective single agent against NMIBC, and it is referred to as the gold standard in the treatment of high risk disease.
BCG is a solution of live, attenuated mycobacterium bovis bacteria, which is administered intravesically in an outpatient clinic. BCG activates an immunological reaction in the bladder wall, which leads to antitumour effect by activation of macrophages, T-cells, and natural killer (NK) cells. BCG treatment comprises an induction period, which includes six weekly instillations. This is followed by maintenance period including monthly or repeated series of three weekly instillations up to 1-3 years.
Other instillation therapies include intravesically administered chemotherapy. Mitomycin C (MMC) is the most used chemotherapeutic agent. MMC provides a better tolerated side effect profile, but is less effective against high risk NMIBC than BCG, when MMC is used as a single agent. Combinations of BCG- and MMC treatment has also been described with various results. The rationale for combining BCG and MMC is to enhance the absorption of BCG as MMC might cause disruption of bladder mucosa, which makes the mucosa more permeable thus enhancing the absorption of BCG. However, it is also hypothesized, that BCG may also work synergistic in favor of MMC.
The absorption and effect of MMC may be enhanced with electromotive drug administration (EMDA) device. After instillation of MMC, an electric field is conducted in the bladder with EMDA device via catheter and electrodes, which are placed in the bladder and lower abdomen skin. Electric field creates movement of sodium ions and water into the bladder wall, which creates electro-osmotic drag of MMC molecules. In a laboratory setting, EMDA-MMC instillation results in 4-7 times greater concentration of MMC in the deeper layers of the bladder wall than passively administered MMC instillation. EMDA-MMC treatment may also be combined with BCG treatment administering BCG and EMDA-MMC instillations sequentially. Results from a prospective randomized trial suggested, that sequential EMDA-MMC and BCG treatment might be even more effective against NMIBC than BCG therapy alone in terms of recurrence, progression and overall survival.
The current study is a prospective, open label, phase III randomized study allocating patients with high risk NMIBC to receive adjuvant instillation therapy either as traditional BCG treatment, or sequential BCG- and EMDA-MMC treatment. The aim of the study is to compare effectiveness and tolerability of the two treatment regimens in preventing recurrence and progression of high risk NMIBC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically proven non-muscle-invasive tumour types confined to the urinary bladder
- •Carcinoma in situ with or without a papillary tumour(s)
- •Ta tumour(s) of high-grade
- •Any T1 tumour(s)
- •Written informed consent is required from every eligible patient
- •Second resection performed in case of T1 tumour
- •Adequate physical and mental condition to participate in the study (as judged by treating physician
排除标准
- •Ta low grade tumour(s)
- •Muscle invasive (pT≥2) tumors
- •Urothelial cancer involving the prostatic urethra or upper urinary tract
- •Non-urothelial bladder cancer.
- •Prior BCG failure (If the patient has previously been successfully treated with BCG, and duration from the last instillation is >12 months, participation may be considered, if bladder preserving is chosen)
- •Prior or concurrent immunotherapy
- •Any medication or condition considered as contraindication to BCG or MMC (as judged by the treating physician)
- •Urethral stricture, stone disease, chronic urinary tract infection or any other urological condition that may comprise study participation (as judged by the treating physician)
- •Known allergy to MMC or BCG
- •Age < 18 years
- •Pregnancy or lactating patient
- •Other untreated or unstable malignancy in risk of recurrence/progression (as judged by the treating physician)
- •Cardiac pacemaker
- •Expected survival time less than one year
- •Expected poor compliance
研究组 & 干预措施
Group A
BCG instillation therapy with induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG
Dosage of Bacillus of Calmette-Guerin (BCG) is dependent on the preferred brand of BCG by the participating institution. Either 2 x 10^8 - 3 x 10^9 for BCG-MEDAC, 2-8 x 10^8 colony forming unit for OncoTICE or, 81mg for ImmuCYST and TheraCys. The investigators will nominate which BCG brand is used.
干预措施: BCG instillation therapy (Drug)
Group B
Sequential BCG and EMDA mitomycin C treatment with nine weekly instillations of BCG, BCG, EMDA-MMC x3 followed by nine monthly instillations of EMDA-MMC, EMDA-MMC, BCG x3
Dosage of Bacillus of Calmette-Guerin (BCG) is dependent on the preferred brand of BCG by the participating institution. Either 2 x 10^8 - 3 x 10^9 for BCG-MEDAC, 2-8 x 10^8 colony forming unit for OncoTICE or, 81mg for ImmuCYST and TheraCys. The investigators will nominate which BCG brand is used.
Mitomycin C dosage is 40 mg of MMC with 960 mg of excipient sodium chloride dissolved in 100 ml sterile water
干预措施: Sequential BCG and EMDA mitomycin C (Drug)
结局指标
主要结局
Bladder cancer recurrence rate
时间窗: 2 years
Any bladder cancer recurrence at 2 years
次要结局
- Progression of bladder cancer(2 years)
- Adverse effects(2 years)
- Mortality(2 years)
- NMIBC24 quality of life questionnaire (QLQ) score(2 years)