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

NCT03664869 | Unknown Phase 3 DMC

• 1 other identifier: Finnbladder-10
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 7

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.

Conditions

Bladder Cancer

Keywords

bladder cancer; recurrence; BCG; mitomycin C; electromotive drug administration

Outcome Measures

Primary Outcomes (1)

• Bladder cancer recurrence rate

  Any bladder cancer recurrence at 2 years

  2 years

Secondary Outcomes (4)

• Progression of bladder cancer

  2 years

• Mortality

  2 years

• NMIBC24 quality of life questionnaire (QLQ) score

  2 years

• Adverse effects

  2 years

Study Arms (2)

Group A

ACTIVE COMPARATOR

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

Group B

EXPERIMENTAL

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

Interventions

BCG instillation therapy DRUG

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

Also known as: BCG, BCG-MEDAC, OncoTICE, ImmuCyst, TheraCys

Group A

Sequential BCG and EMDA mitomycin C DRUG

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)

Also known as: Sequential BCG and EMDA-MMC

Group B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Turku University Hospital: lead
• Finnbladder: collaborator

Study Sites (7)

HYKS Peijas Hospital

Helsinki, 00029, Finland

RECRUITING

Jyväskylä Central Hospital

Jyväskylä, 40620, Finland

RECRUITING

Päijät-Häme Central hospital

Lahti, 15850, Finland

RECRUITING

Mikkeli Central Hospital

Mikkeli, 50100, Finland

RECRUITING

Seinäjoki Central Hospital

Seinäjoki, 60220, Finland

RECRUITING

Tampere University Hospital

Tampere, 33521, Finland

RECRUITING

Turku University Hospital

Turku, 20521, Finland

RECRUITING

Related Publications (21)

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• 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.

  PMID: 27324428 BACKGROUND

• 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.

  PMID: 2122008 BACKGROUND

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  PMID: 20862387 BACKGROUND

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• 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.

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• 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.

  PMID: 19409692 BACKGROUND

• 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.

  PMID: 28027868 BACKGROUND

• 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.

  PMID: 12394686 BACKGROUND

• 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.

  PMID: 15072879 BACKGROUND

• 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.

  PMID: 10737480 BACKGROUND

• 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.

  PMID: 10519404 BACKGROUND

• 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.

  PMID: 1615583 BACKGROUND

• Oosterlinck W, Kirkali Z, Sylvester R, da Silva FC, Busch C, Algaba F, Collette S, Bono A. Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guerin and with bacillus Calmette-Guerin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993). Eur Urol. 2011 Mar;59(3):438-46. doi: 10.1016/j.eururo.2010.11.038. Epub 2010 Dec 7.

  PMID: 21156335 BACKGROUND

• Kaasinen E, Wijkstrom H, Malmstrom PU, Hellsten S, Duchek M, Mestad O, Rintala E; Nordic Urothelial Cancer Group. Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study. Eur Urol. 2003 Jun;43(6):637-45. doi: 10.1016/s0302-2838(03)00140-4.

  PMID: 12767365 BACKGROUND

• Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo JA, Alonso JM, Astobieta A, Unda M, Martinez-Pineiro L, Rabadan M, Ojea A, Rodriguez-Molina J, Beardo P, Muntanola P, Gomez M, Montesinos M, Martinez Pineiro JA; Members of Club Urologico Espanol de Tratamiento Oncologico. Sequential combination of mitomycin C plus bacillus Calmette-Guerin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015 Mar;67(3):508-16. doi: 10.1016/j.eururo.2014.09.026. Epub 2014 Oct 6.

  PMID: 25301758 BACKGROUND

• Di Stasi SM, Giannantoni A, Stephen RL, Capelli G, Navarra P, Massoud R, Vespasiani G. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol. 2003 Sep;170(3):777-82. doi: 10.1097/01.ju.0000080568.91703.18.

  PMID: 12913696 BACKGROUND

• Di Stasi SM, Giannantoni A, Giurioli A, Valenti M, Zampa G, Storti L, Attisani F, De Carolis A, Capelli G, Vespasiani G, Stephen RL. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006 Jan;7(1):43-51. doi: 10.1016/S1470-2045(05)70472-1.

  PMID: 16389183 RESULT

• Gan C, Amery S, Chatterton K, Khan MS, Thomas K, O'Brien T. Sequential bacillus Calmette-Guerin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in High Risk Nonmuscle Invasive Bladder Cancer: 2-Year Outcomes. J Urol. 2016 Jun;195(6):1697-703. doi: 10.1016/j.juro.2016.01.103. Epub 2016 Feb 2.

  PMID: 26845426 RESULT

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Recurrence

Interventions

BCG Vaccine; BCG Connaught

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Peter J Boström, MD, PhD

  Turku University Hospital, Hospital District of Southwest Finland

  STUDY DIRECTOR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2018
• First Posted: September 11, 2018
• Study Start: October 26, 2018
• Primary Completion: November 1, 2025
• Study Completion: November 1, 2025
• Last Updated: April 1, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

FI (7)