Hyperthermia and Mitomycin C, Bacillus Calmette-Guerin, or Standard Therapy as Second-Line Therapy in Treating Patients With Recurrent Bladder Cancer

Bladder Cancer Clinical Trial

Official title:

HYMN: A Randomized Controlled Phase III Trial Comparing Hyperthermia Plus Mitomycin to a Second Course of Bacillus Calmette-Guerin or Standard Therapy in Patients With Recurrence of Non-Muscle Invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guerin Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01094964
• Other study ID #: CRC-TU-BL3010-HYMN
• Secondary ID: CDR0000668528ISR
• Status: Recruiting
• Phase: Phase 3
• First received: March 26, 2010
• Last updated: August 9, 2013
• Start date: October 2009

Study information

• Verified date: March 2010
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Hyperthermia therapy kills tumor cells by heating them to several degrees above normal body temperature. Drugs used in chemotherapy, such as mitomycin C and epirubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapies, such as bacillus calmette-guerin (BCG) and interferon alfa, may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether giving hyperthermia together with mitomycin C is more effective than giving BCG or standard therapy as second-line therapy in treating patients with recurrent bladder cancer.

PURPOSE: This randomized phase III trial is studying how well hyperthermia given together with mitomycin C works compared with BCG or standard therapy as second-line therapy in treating patients with recurrent bladder cancer.

Description:

OBJECTIVES:

Primary

• To determine whether hyperthermia in combination with mitomycin C versus bacillus Calmette-Guerin (BCG) or standard therapy as second-line therapy is effective in patients with recurrent non-muscle invasive bladder cancer following induction or maintenance therapy with BCG.

• To compare disease-free survival time in all patients.

• To compare complete response rate at 3 months in patients with carcinoma in situ.

Secondary

• To compare progression-free survival, overall survival, safety and tolerability of treatments, quality of life, cost, and cost-effectiveness in these patients.

• To assess biomarkers of response to standard and investigational treatment.

OUTLINE: This is a multicenter study. Patients are stratified according to presence of carcinoma in situ (yes vs no), prior bacillus Calmette-Guérin (BCG) therapy (induction vs maintenance), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I (experimental): Patients receive intravesical mitomycin C over two 30-minute instillations per session, and bladder hyperthermia (42 +/-2°C) is delivered in combination with each instillation. The suspension is maintained in the bladder for up to 2 hours. Treatment repeats once a week for 6 weeks followed by a 6-week rest period. Patients who are disease-free proceed to maintenance therapy consisting of one instillation of mitomycin C with bladder hyperthermia every 6 weeks for 1 year and then once every 8 weeks for 1 year. Patients who are disease-free at 24 months may continue treatment at the discretion of the clinician.

• Arm II (control): Patients receive 1 of the following treatment regimens depending on prior BCG treatment.

• Second course of BCG therapy (patients who failed previous induction BCG):

Patients receive intravesical BCG (1 instillation) once a week for 6 weeks. The suspension is maintained in the bladder for up to 2 hours. Patients then receive maintenance therapy consisting of BCG once a week for 3 weeks in months 3, 6, 12, 18, and 24. Patients who are disease-free at 24 months may continue treatment at the discretion of the clinician.

• Standard therapy (patients who failed previous maintenance BCG): Patients receive standard therapy for BCG failure as defined by their treating centers. Standard therapy may include intravesical BCG alone, intravesical mitomycin C alone, intravesical epirubicin hydrochloride alone, or intravesical BCG in combination with interferon alpha.

All patients undergo cystoscopic surveillance with or without a biopsy every 3 months for 2 years. Urine, blood, and tissue samples are collected periodically for biomarker laboratory studies. Patients complete quality of life questionnaires (EORTC QLQ-BLS24, QLQ-C30, and EQ5D) at baseline, at 12 weeks, and at 6, 9, and 12 months.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 242
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of non-muscle invasive bladder cancer

• Recurrent disease after undergoing induction or maintenance therapy with bacillus Calmette-Guérin (BCG), meeting any 1 of the following criteria:

• Stage Ta or T1 disease (grade 2 or 3)

• Carcinoma in situ with stage Ta or T1 disease (grade 1, 2, or 3)

• Carcinoma in situ alone

• Has undergone a second resection of all T1 disease to exclude muscle invasive disease

• No urothelial cell carcinoma (UCC) = T2

• No recurrence of grade 1 UCC following BCG induction therapy

• No UCC involving the prostatic urethra or upper urinary tract

PATIENT CHARACTERISTICS:

• WHO performance status 0-4

• WBC = 3.0 x 10^9/L

• Absolute neutrophil count = 1.5 x 10^9/L

• Hemoglobin = 10 g/dL

• Platelet count = 100 x 10^9/L

• Serum creatinine < 1.5 times upper limit of normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Normal kidneys and ureters on imaging CT scan within the past 12 months

• Available for long-term follow-up with a life expectancy of the duration of the trial

• Must be fit and willing to undergo a full or partial cystectomy

• No known or suspected reduced bladder capacity (< 250 mL)

• No significant bleeding disorder

• No other malignancy within the past 5 years except nonmelanomatous skin cancer cured by excision, adequately treated carcinoma in situ of the cervix, or DCIS/LCIS of the breast

• No known allergy to mitomycin or bacillus Calmette-Guérin (BCG), or previously withdrawn from BCG treatment due to a related adverse event (e.g., systemic infection)

• No active or intractable urinary tract infection

• No urethral stricture or any situation impeding the insertion of a 20F catheter

• No bladder diverticula > 1 cm

• No significant urinary incontinence

• No concurrent implanted electronic devices (e.g., cardiac pacemakers) or metallic implants within the pelvis, lower torso, spine, hip, or upper femur

• No immunocompromised state for any reason

PRIOR CONCURRENT THERAPY:

• At least 6 months since prior intravesical chemotherapy, except for single instillation post-transurethral resection

• No prior pelvic irradiation

• No prior hyperthermia in combination with intravesical mitomycin

• Concurrent participation in other studies allowed

• No current or long-term use of corticosteroids

• No concurrent chemotherapy

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Biological:
• BCG solution

• recombinant interferon alfa

Drug:
• epirubicin hydrochloride

• mitomycin C

Other:
• laboratory biomarker analysis

Procedure:
• hyperthermia treatment

• quality-of-life assessment

Locations

Country	Name	City	State
United Kingdom	Basingstoke and North Hampshire NHS Foundation Trust	Basingstoke	England
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	University College of London Hospitals	London	England
United Kingdom	South Manchester University Hospital	Manchester	England
United Kingdom	James Cook University Hospital	Middlesbrough	England

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Research Campaign Clinical Trials Centre

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free survival time			No
Primary	Complete response rate at 3 months in patients with carcinoma in situ			No
Secondary	Recurrence-free survival time			No
Secondary	Progression-free survival time			No
Secondary	Overall survival time			No
Secondary	Disease-specific survival time			No
Secondary	Safety and tolerability			Yes
Secondary	Quality of Life			No
Secondary	Cost effectiveness			No
Secondary	Biomarkers of response to standard and investigational treatment			No