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
18 Years
N/A
Both
Bladder Cancer
Trial Information
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
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
Inclusion Criteria
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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Disease-free survival time
Safety Issue:
No
Principal Investigator
John Kelly, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University College London Hospitals
Authority:
Unspecified
Study ID:
CDR0000668528
NCT ID:
NCT01094964
Start Date:
October 2009
Completion Date:
Related Keywords:
- Bladder Cancer
- recurrent bladder cancer
- stage 0 bladder cancer
- stage I bladder cancer
- adenocarcinoma of the bladder
- squamous cell carcinoma of the bladder
- Urinary Bladder Neoplasms
- Fever
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