Clinical trial NCT01094964: Hyperthermia and Mitomycin C, Bacillus Calmette-Guerin, or Standard Therapy as Second-Line Therapy in Treating Patients With Recurrent Bladder Cancer
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bladder Cancer
Keywords: recurrent bladder cancer
stage 0 bladder cancer
stage I bladder cancer
adenocarcinoma of the bladder
squamous cell carcinoma of the bladder
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-03-29
Enrollment: 242
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility 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

Primary outcomes:
measure: Disease-free survival time
measure: Complete response rate at 3 months in patients with carcinoma in situ
Secondary outcomes:
measure: Recurrence-free survival time
measure: Progression-free survival time
measure: Overall survival time
measure: Disease-specific survival time
measure: Safety and tolerability
measure: Quality of Life
measure: Cost effectiveness
measure: Biomarkers of response to standard and investigational treatment
Other outcomes:
Locations:
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire NHS Foundation Trust
state: England
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: University College of London Hospitals
state: England
city: Manchester
country: United Kingdom
facility: South Manchester University Hospital
state: England
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: England
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
Study officials:
affiliation: University College London Hospitals
name: John Kelly, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tan WS, Panchal A, Buckley L, Devall AJ, Loubiere LS, Pope AM, Feneley MR, Cresswell J, Issa R, Mostafid H, Madaan S, Bhatt R, McGrath J, Sangar V, Griffiths TRL, Page T, Hodgson D, Datta SN, Billingham LJ, Kelly JD. Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guerin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guerin Therapy (HYMN): A Phase III, Open-label, Randomised Controlled Trial. Eur Urol. 2019 Jan;75(1):63-71. doi: 10.1016/j.eururo.2018.09.005. Epub 2018 Sep 28.