Clinical trial NCT02948543: Adding Mitomycin to BCG as Adjuvant Intravesical Therapy for High-risk Non-Muscle-invasive Bladder Cancer
Official title: Adding Mitomycin to Bacillus of Calmette-Guerin (BCG) as Adjuvant Intravesical Therapy for High-risk, Non-Muscle-invasive Bladder Cancer: a Randomised Phase 3 Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bladder Cancer
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Cancer Australia
First posted: 2016-10-28
Enrollment: 501
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Open label, randomised phase 3 trial of the addition of Mitomycin to BCG as adjuvant intravesical therapy for high-risk, non-muscle-invasive bladder cancer. The study aim is to compare disease-free survival between treatment arms: BCG alone versus Mitomycin in addition to BCG.

Detailed description: PROTOCOL SYNOPSIS

Background:

Instillation of Bacillus of Calmette-Guerin (BCG) into the urinary bladder (intravesical administration) improves rates of disease recurrence and progression after transurethral resection (TUR) of high risk, non-muscle-invasive bladder cancer (NMIBC), but over 30% of people still develop recurrent transitional cell carcinoma (TCC) despite optimal therapy with adjuvant intravesical BCG. Our meta-analysis, including a recent randomised phase 2 trial, suggests that outcomes might be improved further by using an adjuvant intravesical regimen that includes both Mitomycin (MM) and BCG. These promising findings require corroboration in a definitive, large scale, randomised phase 3 trial using standard techniques for intravesical administration.

General Aim:

To determine the efficacy and safety of MM in addition to BCG in patients with NMIBC.

Design:

Open label, randomised, stratified, 2-arm multicentre phase 3 clinical trial. Population: The target population is adults with resected, high-risk NMIBC (high grade Ta or any grade T1) suitable for intravesical chemotherapy treatment. Key eligibility criteria include: prior transurethral resection of all visible tumour, adequate organ function, and ECOG performance status 0-2.

Study Treatments:

Arm A: Intravesical BCG Alone (standard): Induction (weekly x 6), followed by Maintenance (monthly x 10); or Arm B: Intravesical BCG + MM (experimental): Induction (weekly x 9), followed by Maintenance (monthly x 9).

Statistical Considerations:

A sample size of 500 (followed until 213 events are observed) provides 85% power to detect a 10% improvement in disease free survival (DFS) rate at 2 years from 70% on BCG alone to 80% on BCG and MM (hazard ratio 0.63) at a significance level of 0.05, allowing for 10% non-compliance.

Eligibility criteria: Inclusion Criteria:

1. Males or females with confirmed high grade pTa or stage pT1 (any grade) non-muscle invasive bladder cancer on initial or re-resection histology (concurrent carcinoma in situ is allowed).
2. Age \>= 18 yrs
3. No macroscopically visible disease at cystoscopy within 8 weeks prior to randomisation. This may be either the initial Transurethral Resection of the Bladder Tumour (TURBT) at which the primary tumour was completely resected, or a planned second cystoscopy and/or re-resection done within 8 weeks of the initial TURBT.
4. ECOG Performance Status of 0-2
5. Adequate bone marrow, renal and liver function confirmed by pre-randomisation blood tests.
6. Study treatment both planned and able to start within 4 weeks of randomisation
7. Has completed the HRQL questionnaires or is unable to complete them because of literacy, insufficient English or limited vision
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of all required assessments
9. Signed, written informed consent

Exclusion Criteria:

1. Contraindications or hypersensitivity to investigational products, BCG and Mitomycin
2. Prior treatment with any other intravesical agent including BCG or Mitomycin (excludes single doses given post TURBT)
3. Current or past transitional cell carcinoma (TCC) of the upper urinary tract
4. Prior muscle-invasive (stage T2 or higher) transitional-cell carcinoma of the bladder
5. Bladder dysfunction precluding intravesical therapy eg. Severe urinary incontinence or overactive or spastic bladder
6. Life expectancy \< 3 months
7. Congenital or acquired immune deficiencies, whether due to a concurrent disease (e.g. acquired immune deficiency syndrome (AIDS), leukaemia, lymphoma) or immunosuppressive therapy (e.g. corticosteroids), or cancer therapy (cytotoxic drugs, radiation)
8. Prior radiotherapy of the pelvis
9. Prior or current treatment with radiotherapy-response or biological-response modifiers
10. Clinical evidence of existing active tuberculosis
11. History of another malignancy within 5 years prior to registration. Patients with non-melanomatous carcinoma of the skin are eligible for this study.
12. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
13. Pregnancy, lactation, or inadequate contraception. Women must be post menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Primary outcomes:
measure: Disease free survival (death or recurrence)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Activity (Clear cystoscopy at 3 months)
timeFrame: At 3 months after patient randomised
measure: Time to recurrence (recurrence)
timeFrame: Up to 5 years
measure: Time to progression (disease progression)
timeFrame: Up to 5 years
measure: Safety (Adverse events graded according to CTC AE V4.0)
timeFrame: Measured before day 1 of each instillation during treatment.
measure: Health-Related Quality of Life
timeFrame: Up to 5 years from the date of randomisation
measure: Overall survival time (death from any cause)
timeFrame: Up to 5 years
measure: Treatment Completion
timeFrame: Measured at end of study treatment (12 months after patient randomized).
measure: Marginal resource use
timeFrame: 5 years after last patient randomized (or date last patient has died, whichever sooner).
Other outcomes:
measure: Exploratory Tissue Biomarker Investigation
timeFrame: Baseline
Locations:
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Miranda
country: Australia
facility: Southside Cancer Care Centre
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: GenesisCare
state: New South Wales
city: Tweed Heads
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Wahroonga
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Redcliffe
country: Australia
facility: Redcliffe Hospital
state: Queensland
city: Footscray
country: Australia
facility: Footscray Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health - Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital - City Campus
state: Victoria
city: Richmond
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital - City Campus
Study officials:
affiliation: Fiona Stanley Hospital
name: Dickon Hayne
role: STUDY_CHAIR
References: