Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer

NCT01442519 | Completed Phase 3 DMC

• 1 other identifier: UTV-119-1993
• Study Type: interventional
• Target: 212
• Locations: 1 country
• Sites: 1

Brief Summary

Intravesical treatment for superficial bladder cancer has been used for the past 4-5 decades. Intravesical chemotherapy is beneficial in terms of recurrence and time to recurrence in grade 1-2 stage Ta tumours, usually non-invasive. Intravesical chemotherapy has negligible effect on disease progression in high-risk superficial bladder cancer-ie, grade 3, stage T1, and carcinoma in situ. However, BCG as induction and maintenance treatment effectively delays progression. Electromotive mitomycin increases tissue uptake compared with that of passive diffusion. Electromotive mitomycin has emerged as an alternative or complementary treatment to BCG. The rationale for combining anticancer drugs is based on the need to increase efficacy and reduce emergence of resistant malignant cells. This approach is not frequently applied to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. Studies have addressed concurrent use of mitomycin and BCG, and assigned two roles to mitomycin: antitumor action and tissue-scarifying (ie, surface-modifying) effect that enables BCG to attach more efficiently to the urothelium. The investigators therefore aimed to assess whether induction of inflammation by use of BCG before mitomycin treatment makes the bladder mucosa more permeable and thus enables mitomycin to reach the target more easily. This randomised trial to compare the efficacy of sequential BCG and electromotive mitomycin with that of the current standard of BCG alone for patients with high-risk superficial bladder cancer. After transurethral resection and multiple biopsies patients with stage pT1 bladder cancer are randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks; or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were intention to treat.

Conditions

Bladder Cancer

Keywords

non-muscle invasive urothelial bladder cancer; intravesical therapy; BCG; mitomycin; electromotive drug administration; Bladder Cancer Stage 0, Without Cancer in Situ

Outcome Measures

Primary Outcomes (1)

• Disease-free interval

  The primary endpoint is disease-free interval for patients without carcinoma in situ and for patients with carcinoma in situ who are disease-free after treatment-ie, time from randomisation to first cystoscopy noting recurrence. Patients with carcinoma in situ who did not have complete response after 3 months of treatment are regarded as having recurrence with no follow-up.

  From date of randomization until the date of first documented recurrence, assessed up to 120 months

Secondary Outcomes (3)

• Time to progression

  From date of randomization until the date of documented progression, assessed up to 120 months.

• Overall survival

  From date of randomization until the date of death for any cause, assessed up to 120 months.

• Disease-specific survival

  From date of randomization until the date of death for bladder cancer, assessed up to 120 months.

Study Arms (2)

Intravesical BCG alone

ACTIVE COMPARATOR

Biological: bacillus Calmette-Guerin

Intravesical sequential BCG and EMDA MMC

EXPERIMENTAL

Drug: electromotive mitomycin

Interventions

bacillus Calmette-Guerin BIOLOGICAL

The BCG instillation consisted of 81 mg wet weight (10•2±9•0\_108 colony-forming units) BCG Connaught substrain (ImmuCyst®, Alfa Wassermann SpA, Bologna, Italy). Lyophilised (ie, freeze-dried) BCG is suspended in 50 mL bacteriostatic-free solution of 0•9% sodium chloride. After draining of the bladder, the suspension is infused intravesically through a Foley catheter. The solution is retained in the bladder for 120 min, followed by emptying of the bladder and removal of the catheter. The BCG-alone group is assigned one course of intravesical treatment per week for 6 weeks. Patients in the BCG-alone group who are disease-free 3 months after treatment are scheduled to receive monthly infusions of BCG for 10 months

Also known as: IMMUCYST, Alpha Wassermann, Bologna, Italy

Intravesical BCG alone

electromotive mitomycin DRUG

BCG instillation of 81 mg BCG Connaught-substrain, suspended in 50 mL bacteriostatic-free saline solution, retained for 120 min. Electromotive instillation: 40 mg mitomycin in 100 mL water infused intravesically and retained in the bladder for 30 min, while 20 mA for 30 min pulsed electric current is given externally. Patients assigned sequential BCG and EMDA MMC are assigned 1 course of treatment/week for 9 weeks: one cycle consisted of two BCG infusions and one mitomycin infusion (three cycles in total). Patients in the BCG-and-mitomycin group who are disease-free 3 months after treatment are scheduled to receive one infusion a month for 9 months: three cycles of mitomycin, mitomycin, and BCG (ie, six infusions of MMC and three of BCG).

Also known as: IMMUCYST, Alpha Wassermann, Bologna, Italy, MITOMYCIN C 40 mg, Kyowa Italiana Farmaceutici

Intravesical sequential BCG and EMDA MMC

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• adequate bone-marrow reserve (ie, white-blood-cell count ≥4000 x106 cells/L and platelet count ≥120 x 109/L)
• normal renal function (ie, serum creatinine ≤123•76 μmol/L)
• normal liver function (ie, serum glutamic-oxaloacetic transaminase ≤42 U/L, serum glutamic-pyruvic transaminase ≤48 U/L, and total bilirubin ≤22•23 μmol/L)
• Karnofsky performance status between 50 and 100.

You may not qualify if:

• previous treatment with BCG or electromotive mitomycin
• treatment with any other intravesical cytostatic agent within the past 6 months
• concomitant urothelial tumours of the upper urinary tract;
• previous muscle-invasive (ie, stage T2 or higher) transitional-cell - carcinoma of the bladder
• bladder capacity less than 2 L
• untreated urinary-tract infection
• severe systemic infection (ie, sepsis)
• urethral strictures that would prevent endoscopic procedures and repeated catheterisation
• disease of upper urinary tract (eg, vesicoureteral reflux or urinary-tract stones) that would make multiple transurethral procedures a risk
• previous radiotherapy to the pelvis
• other concurrent chemotherapy
• treatment with radiotherapy-response or biological-response modifiers;
• history of tuberculosis
• other malignant diseases within 5 years of trial registration (except for basal-cell carcinoma)
• pregnancy or nursing

Sponsors & Collaborators

• University of Rome Tor Vergata: lead
• University of L'Aquila: collaborator

Study Sites (1)

Dept. of Surgery/Urology, Tor Vergata University

Rome, RM, 00133, Italy

Location

Related Publications (1)

• 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

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

BCG Vaccine; BCG Connaught; Mitomycin

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

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Mitomycins; Indolequinones; Quinones; Organic Chemicals; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Savino M Di Stasi, MD, PhD

  Tor Vergata University, Rome, Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 29, 2011
• First Posted: September 28, 2011
• Study Start: January 1, 1994
• Primary Completion: June 1, 2002
• Study Completion: June 1, 2002
• Last Updated: September 28, 2011

Record last verified: 2011-09

Locations

IT (1)