Electromotive Mitomycin-C (EMDA-MMC) in Preventing Recurrences in High-risk Non-muscle-invasive Bladder Cancer (FB10)

March 31, 2021 updated by: Turku University Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Finland
      • Helsinki, Finland, 00029
        • Recruiting
        • HYKS Peijas Hospital
        • Contact:
        • Principal Investigator:
          • Riikka Järvinen, MD, PhD
      • Jyväskylä, Finland, 40620
        • Recruiting
        • Jyväskylä Central Hospital
        • Contact:
        • Principal Investigator:
          • Heikki Seikkula, MD, PhD
      • Lahti, Finland, 15850
        • Recruiting
        • Päijät-Häme Central hospital
        • Contact:
        • Principal Investigator:
          • Taina Isotalo, Md, PhD
      • Mikkeli, Finland, 50100
        • Recruiting
        • Mikkeli Central Hospital
        • Contact:
        • Principal Investigator:
          • Niilo Hendolin, MD
      • Seinäjoki, Finland, 60220
        • Recruiting
        • Seinäjoki Central Hospital
        • Contact:
        • Principal Investigator:
          • Timo Marttila, MD
      • Tampere, Finland, 33521
        • Recruiting
        • Tampere University Hospital
        • Contact:
        • Principal Investigator:
          • Dimitri Pogodin-Hannolainen, MD
      • Turku, Finland, 20521
        • Recruiting
        • Turku University Hospital
        • Contact:
        • Principal Investigator:
          • Pertti T Nurminen, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 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.
Drug: BCG instillation therapy
Induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG
Other Names:
  • OncoTICE
  • BCG
  • BCG-MEDAC
  • ImmuCyst
  • TheraCys
Experimental: 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
Drug: Sequential BCG and EMDA mitomycin C

Induction period includes nine weekly instillations of sequential BCG and EMDA-MMC instillations applied as three cycles of BCG, BCG and EMDA-MMC. Induction period is followed by maintenance period of nine monthly instillations of sequential EMDA-MMC and BCG applied with three cycles of EMDA-MMC, EMDA-MMC and BCG.

BCG instillation is performed as a standard instillation.

Mitomycin C is administered with electromotive drug administration (EMDA) device (Instillation: 40 mg mitomycin C with 960 mg of excipient sodium chloride dissolved in 100 ml sterile water, EMDA settings: current rise rate 30-50 microamperes per second, max 25 milliamperes, treatment duration 30 min)

Other Names:
  • Sequential BCG and EMDA-MMC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bladder cancer recurrence rate
Time Frame: 2 years
Any bladder cancer recurrence at 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression of bladder cancer
Time Frame: 2 years
Progression of bladder cancer in terms of T-category compared to the last resected tumour prior to randomisation
2 years
Mortality
Time Frame: 2 years
Death due bladder cancer or other reasons
2 years
NMIBC24 quality of life questionnaire (QLQ) score
Time Frame: 2 years
Side-effects related to the treatment measured with EORTC QLQ-NMIBC24
2 years
Adverse effects
Time Frame: 2 years
Complications or adverse events related to bladder cancer or the treatment
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Turku University Hospital

Collaborators

Finnbladder

Investigators

  • Study Director: Peter J Boström, MD, PhD, Turku University Hospital, Hospital District of Southwest Finland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 26, 2018

Primary Completion (Anticipated)

November 1, 2025

Study Completion (Anticipated)

November 1, 2025

Study Registration Dates

First Submitted

September 6, 2018

First Submitted That Met QC Criteria

September 6, 2018

First Posted (Actual)

September 11, 2018

Study Record Updates

Last Update Posted (Actual)

April 1, 2021

Last Update Submitted That Met QC Criteria

March 31, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Finnbladder-10

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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