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Bladder CancerPhase 3FB10NCT03664869

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

A Phase 3 study testing BCG instillation therapy and Sequential BCG and EMDA mitomycin C in people with Bladder Cancer, run by Turku University Hospital at 7 sites in Finland.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Bladder Cancer
What is being tested?
BCG instillation therapy and Sequential BCG and EMDA mitomycin C
Could I receive a placebo?
No, everyone receives an active treatment
How many people
300 participants
Where
7 sitesFinland
Study dates
26 Oct 2018to 1 Nov 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 15Show fewer
  • 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

Trial locations and contacts

7 sites in 1 country.

Pertti T Nurminen, MD contact

+358 2 3135922

pertti.nurminen@tyks.fi

Riikka Järvinen, MD, PhD contact

+358 50 427 1015

riikka.jarvinen@hus.fi

7 sites in 1 country

Finland7 sites, 7 recruiting

  • HYKS Peijas Hospital

    Helsinki, 00029

    Riikka Järvinen, MD, PhD, +358 50 4271015, riikka.jarvinen@hus.fi

    Riikka Järvinen, MD, PhD

    Recruiting

  • Jyväskylä Central Hospital

    Jyväskylä, 40620

    Heikki Seikkula, MD, PhD, +358 14 269 1811, heikki.seikkula@ksshp.fi

    Heikki Seikkula, MD, PhD

    Recruiting

  • Päijät-Häme Central hospital

    Lahti, 15850

    Taina Isotalo, MD, PhD, +358 3 819 11, taina.isotalo@phsotey.fi

    Taina Isotalo, Md, PhD

    Recruiting

  • Mikkeli Central Hospital

    Mikkeli, 50100

    Niilo Hendolin, MD, +358 1 53 511, niilo.hendolin@essote.fi

    Niilo Hendolin, MD

    Recruiting

  • Seinäjoki Central Hospital

    Seinäjoki, 60220

    Timo Marttila, MD, +358 6 415 4111, timo.marttila@epshp.fi

    Timo Marttila, MD

    Recruiting

  • Tampere University Hospital

    Tampere, 33521

    Dimitri Pogodin-Hannolainen, MD, +358 3 311 611, dimitri.pogodin-hannolainen@pshp.fi

    Dimitri Pogodin-Hannolainen, MD

    Recruiting

  • Turku University Hospital

    Turku, 20521

    Pertti T Nurminen, MD, +358 2 3135922, pertti.nurminen@tyks.fi

    Pertti T Nurminen, MD

    Recruiting

Other trials in Finland

About this study

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

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.

Read the 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.

Conditions
Bladder Cancer
Being tested
BCG instillation therapy, Sequential BCG and EMDA mitomycin C
Keywords
bladder cancer, recurrence, BCG, mitomycin C, electromotive drug administration
Medical subject headings
Urinary Bladder Neoplasms, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BCG instillation therapyDrug

    Also called BCG, BCG-MEDAC, OncoTICE, ImmuCyst

    Induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG

  • Sequential BCG and EMDA mitomycin CDrug

    Also called Sequential BCG and EMDA-MMC

    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)

Study groups in NCT03664869
Study groupRoleWhat they receive
Group AActive comparatorBCG 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.
Receives: Drug: BCG instillation therapy
Group BExperimentalSequential 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
Receives: Drug: Sequential BCG and EMDA mitomycin C

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Bladder cancer recurrence rate

    Any bladder cancer recurrence at 2 years

    Measured: 2 years

Secondary outcomes (4)

  1. Progression of bladder cancer

    Progression of bladder cancer in terms of T-category compared to the last resected tumour prior to randomisation

    Measured: 2 years

  2. Mortality

    Death due bladder cancer or other reasons

    Measured: 2 years

  3. NMIBC24 quality of life questionnaire (QLQ) score

    Side-effects related to the treatment measured with EORTC QLQ-NMIBC24

    Measured: 2 years

  4. Adverse effects

    Complications or adverse events related to bladder cancer or the treatment

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Sep 2018
  2. Study start26 Oct 2018
  3. Primary completion1 Nov 2025 (estimated)
  4. Study completion1 Nov 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
300 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03664869
Sponsor's protocol ID
Finnbladder-10
Acronym
FB10
Status last verified
Mar 2021
First submitted
6 Sep 2018
Last updated
1 Apr 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP. Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev Urol. 2008 Winter;10(1):31-43.

    PubMed 18470273

  • Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006 Mar;49(3):466-5; discussion 475-7. doi: 10.1016/j.eururo.2005.12.031. Epub 2006 Jan 17.

    PubMed 16442208

  • Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BWG, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017 Mar;71(3):447-461. doi: 10.1016/j.eururo.2016.05.041. Epub 2016 Jun 17.

    PubMed 27324428

  • Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF. Radio-immunoassay detection of interferon-gamma in urine after intravesical Evans BCG therapy. J Urol. 1990 Nov;144(5):1248-51. doi: 10.1016/s0022-5347(17)39713-6.

    PubMed 2122008

  • Luo Y, Knudson MJ. Mycobacterium bovis bacillus Calmette-Guerin-induced macrophage cytotoxicity against bladder cancer cells. Clin Dev Immunol. 2010;2010:357591. doi: 10.1155/2010/357591. Epub 2010 Sep 1.

    PubMed 20862387

  • Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff TL, Bohle A. NK cells are essential for effective BCG immunotherapy. Int J Cancer. 2001 Jun 1;92(5):697-702. doi: 10.1002/1097-0215(20010601)92:53.0.co;2-z.

    PubMed 11340575

  • Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976 Aug;116(2):180-3. doi: 10.1016/s0022-5347(17)58737-6.

    PubMed 820877

  • Pan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with non-muscle invasive bladder cancer? An update and cumulative meta-analysis. Front Med. 2014 Jun;8(2):241-9. doi: 10.1007/s11684-014-0328-0. Epub 2014 May 8.

    PubMed 24810644

  • Malmstrom PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, Solsona E, Di Stasi SM, Witjes JA. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009 Aug;56(2):247-56. doi: 10.1016/j.eururo.2009.04.038. Epub 2009 Apr 24.

    PubMed 19409692

  • Chou R, Selph S, Buckley DI, Fu R, Griffin JC, Grusing S, Gore JL. Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. J Urol. 2017 May;197(5):1189-1199. doi: 10.1016/j.juro.2016.12.090. Epub 2016 Dec 24.

    PubMed 28027868

  • Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. doi: 10.1016/S0022-5347(05)64273-5.

    PubMed 12394686

  • Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology. 2004 Apr;63(4):682-6; discussion 686-7. doi: 10.1016/j.urology.2003.11.049.

    PubMed 15072879

  • Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9.

    PubMed 10737480

  • Di Stasi SM, Giannantoni A, Massoud R, Dolci S, Navarra P, Vespasiani G, Stephen RL. Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies. Cancer Res. 1999 Oct 1;59(19):4912-8.

    PubMed 10519404

  • Rajala P, Kaasinen E, Rintala E, Jauhiainen K, Nurmi M, Alfthan O, Lahde M. Cytostatic effect of different strains of Bacillus Calmette-Guerin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol Res. 1992;20(3):215-7. doi: 10.1007/BF00299720.

    PubMed 1615583

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing BCG instillation therapy and Sequential BCG and EMDA mitomycin C in people with Bladder Cancer, run by Turku University Hospital at 7 sites in Finland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Pertti T Nurminen, MD (+358 2 3135922, pertti.nurminen@tyks.fi), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Bladder cancer recurrence rate (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03664869, which also lists 21 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2021.

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