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

Bladder Cancer Clinical Trial

— FB10  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03664869
• Other study ID #: Finnbladder-10
• Status: Recruiting
• Phase: Phase 3
• Start date: October 26, 2018
• Est. completion date: November 1, 2025

Study information

• Verified date: March 2021
• Source: Turku University Hospital
• Contact: Pertti T Nurminen, MD
• Phone: +358 2 3135922
• Email: pertti.nurminen[@]tyks.fi
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: November 1, 2025
• Est. primary completion date: November 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Drug:
• BCG instillation therapy
Induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG
• 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)

Locations

Country	Name	City	State
Finland	HYKS Peijas Hospital	Helsinki
Finland	Jyväskylä Central Hospital	Jyväskylä
Finland	Päijät-Häme Central hospital	Lahti
Finland	Mikkeli Central Hospital	Mikkeli
Finland	Seinäjoki Central Hospital	Seinäjoki
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku

Sponsors (2)

Lead Sponsor	Collaborator
Turku University Hospital	Finnbladder

Country where clinical trial is conducted

Finland, 

References & Publications (21)

Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt 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. — View Citation

Böhle A, Bock PR. Intravesical bacille Calmette-Guérin 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. — View Citation

Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff TL, Böhle A. NK cells are essential for effective BCG immunotherapy. Int J Cancer. 2001 Jun 1;92(5):697-702. — View Citation

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. — View Citation

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 control — View Citation

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. — View Citation

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. — View Citation

Gan C, Amery S, Chatterton K, Khan MS, Thomas K, O'Brien T. Sequential bacillus Calmette-Guérin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in High Risk Nonmuscle Invasive Bladder Cancer: 2-Year Outcomes. J Urol. — View Citation

Kaasinen E, Wijkström H, Malmström 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. — View Citation

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. — View Citation

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

Malmström 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-Guérin 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. — View Citation

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. — View Citation

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-Guérin and with bacillus Calmette-Guérin 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. — View Citation

Pan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guérin 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. — View Citation

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. — View Citation

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. — View Citation

Rajala P, Kaasinen E, Rintala E, Jauhiainen K, Nurmi M, Alfthan O, Lähde M. Cytostatic effect of different strains of Bacillus Calmette-Guérin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol Res. 1992;20(3):215-7. — View Citation

Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo JA, Alonso JM, Astobieta A, Unda M, Martinez-Piñeiro L, Rabadan M, Ojea A, Rodriguez-Molina J, Beardo P, Muntañola P, Gomez M, Montesinos M, Martinez Piñeiro JA; Members of Club Urológico Español de Tratamiento Oncológico. Sequential combination of mitomycin C plus bacillus Calmette-Guérin (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. — View Citation

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. — View Citation

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. Epub 2006 Jan 17. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bladder cancer recurrence rate	Any bladder cancer recurrence at 2 years	2 years
Secondary	Progression of bladder cancer	Progression of bladder cancer in terms of T-category compared to the last resected tumour prior to randomisation	2 years
Secondary	Mortality	Death due bladder cancer or other reasons	2 years
Secondary	NMIBC24 quality of life questionnaire (QLQ) score	Side-effects related to the treatment measured with EORTC QLQ-NMIBC24	2 years
Secondary	Adverse effects	Complications or adverse events related to bladder cancer or the treatment	2 years