Clinical trial NCT03664869: Electromotive Mitomycin-C (EMDA-MMC) in Preventing Recurrences in High-risk Non-muscle-invasive Bladder Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Bladder Cancer
Keywords: bladder cancer
recurrence
BCG
mitomycin C
electromotive drug administration
Lead sponsor: Turku University Hospital
Sponsor class: OTHER_GOV
Collaborators: name: Finnbladder
First posted: 2018-09-11
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Bladder cancer recurrence rate
timeFrame: 2 years
Secondary outcomes:
measure: Progression of bladder cancer
timeFrame: 2 years
measure: Mortality
timeFrame: 2 years
measure: NMIBC24 quality of life questionnaire (QLQ) score
timeFrame: 2 years
measure: Adverse effects
timeFrame: 2 years
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: HYKS Peijas Hospital
city: Jyväskylä
country: Finland
facility: Jyväskylä Central Hospital
city: Lahti
country: Finland
facility: Päijät-Häme Central hospital
city: Mikkeli
country: Finland
facility: Mikkeli Central Hospital
city: Seinäjoki
country: Finland
facility: Seinäjoki Central Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
Study officials:
affiliation: Turku University Hospital, Hospital District of Southwest Finland
name: Peter J Boström, MD, PhD
role: STUDY_DIRECTOR
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