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Trial registered on ANZCTR


Registration number
ACTRN12613000513718
Ethics application status
Approved
Date submitted
1/05/2013
Date registered
8/05/2013
Date last updated
15/08/2019
Date data sharing statement initially provided
15/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Adding mitomycin C to Bacillus of Calmette-Guerin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: a randomised phase 3 trial.
Scientific title
In patients with high-risk, non–muscle-invasive bladder cancer, is adding mitomycin C to BCG for adjuvant intravesical therapy as good as or better than BCG alone for disease free survival?
Secondary ID [1] 282428 0
Nil
Universal Trial Number (UTN)
U1111-1142-5602
Trial acronym
BCG+MMC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
bladder cancer 289036 0
Condition category
Condition code
Cancer 289376 289376 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Experimental Treatment (Arm B):
Intravesical Bacillus of Calmette-Guerin (BCG) + Mitomycin (MMC).
Induction (weekly x 9); and followed by Maintenance (monthly x 9) beginning 3 months after randomisation.

Dosage of BCG dependent on preferred brand of BCG by participating institution. Either 2-8 x 10^8 CFU for OncoTICE or, 81mg for ImmuCYST and TheraCys. Prior to treatment commencement, investigators should nominate which BCG brand will be used. The same brand of BCG must be used for all treatment administered to an individual participant throughout the study.

Dosage of MMC fixed at 40mg per instillation.
Intervention code [1] 287074 0
Treatment: Drugs
Comparator / control treatment
Standard Treatment (Arm A):
Intravesical Bacillus of Calmette-Guerin (BCG).
Induction (weekly x 6); and followed by Maintenance (monthly x 10) beginning 3 months after randomisation.

Dosage of BCG dependent on preferred brand of BCG by participating institution. Either 2-8 x 10^8 CFU for OncoTICE or, 81mg for ImmuCYST and TheraCys. Prior to treatment commencement, investigators should nominate which BCG brand will be used. The same brand of BCG must be used for all treatment administered to an individual participant throughout the study.
Control group
Active

Outcomes
Primary outcome [1] 289481 0
Disease free survival (death or progression)
Timepoint [1] 289481 0
Measured from the date of randomisation until the date after randomisation that disease recurrence is first evident (or until the date last known to be alive and without disease recurrence).
Assessed via cystoscopy
Secondary outcome [1] 302575 0
Activity (Clear cystoscopy at 3 months)
Timepoint [1] 302575 0
At 3 months after patient randomized.
Assessed via cystoscopy and biopsy.
Secondary outcome [2] 302576 0
Time to recurrence (recurrence)
Timepoint [2] 302576 0
Measured from the date of randomisation until the first date recurrence is detected. Disease recurrence is defined as evidence on cystoscopy or biopsy of Ta or T1-4 disease, or if there is evidence of metastatic disease.
Assessed via cystoscopy.
Secondary outcome [3] 302577 0
Time to progression (disease progression)
Timepoint [3] 302577 0
Measured from the date of randomisation until the first date progression is detected. Disease progression is defined as evidence of disease that is of a higher grade or a higher stage than at baseline.
Assessed via cystoscopy.
Secondary outcome [4] 302578 0
Safety (Adverse events graded according to CTC AE V4.0)
Timepoint [4] 302578 0
Measured before day 1 of each instillation during treatment.
Secondary outcome [5] 302579 0
Health-Related Quality of Life
Timepoint [5] 302579 0
5 years after last patient randomized (or date last patient has died, whichever sooner).

Assessed using EORTC QLQ-BLS24 and QLQ-C30 Forms, and the AUA, I-PSS Form.
Secondary outcome [6] 302580 0
Feasibility (Compliance with intravesical therapy)
Timepoint [6] 302580 0
Measured at end of study treatment (12 months after patient randomized)
Secondary outcome [7] 302581 0
Overall survival time (death from any cause)
Timepoint [7] 302581 0
5 years after last patient randomized (or date last patient has died, whichever sooner)
Secondary outcome [8] 302582 0
Marginal resource use
Timepoint [8] 302582 0
5 years after last patient randomized (or date last patient has died, whichever sooner).

Assessed via a specifically designed resource utilisation form (collecting information such as number, type and duration of visits).

Secondary outcome [9] 302668 0
Biomarkers and disease-free survival, time to recurrence and time to progression.
Timepoint [9] 302668 0
5 years after last patient randomized (or date last patient has died, whichever sooner).

Assessed via analysis of tissue assays.

Eligibility
Key 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 function
6. Adequate renal function
7. Adequate liver function
8. Study treatment both planned and able to start within 4 weeks of randomisation
9. Has completed the HRQL questionnaires or is unable to complete them because of literacy, insufficient English or limited vision
10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of all required assessments
11. Signed, written informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications or hypersensitivity to investigational products, BCG and Mitomycin C
2. Prior treatment with any other intravesical agent including BCG or Mitomycin C (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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants must meet all eligibility criteria before being randomised and before starting study treatment. Treatment should be planned to start within 28 days after randomisation.

Registration and randomisation will be performed in one transaction via central system and should be done according to the instructions in the Study Manual.

Once the randomisation process has been completed, the subject will be assigned a treatment arm, and written confirmation of randomisation will be provided to the site.

Participants may only be randomised once in this trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Open label, multi-centre, two-stage, phase III trial with central randomisation, dynamically balanced for T-stage, presence of carcinoma in situ (Cis), and centre.
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A sample size of 500 provides 85% power to detect a 10% improvement in DFS rate at 2 years from 70% on BCG alone to 80% on BCG and MMC (hazard ratio 0.63) at a significance level of 0.05, allowing for 10% non-compliance. Accrual will take place over 54 months and follow-up on all patients will continue until death or 5 years follow up has been completed for each patient.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 2825 0
The Alfred - Prahran
Recruitment hospital [2] 4164 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 4165 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 4166 0
Western Hospital - Footscray
Recruitment hospital [5] 4167 0
Frankston Hospital - Frankston
Recruitment hospital [6] 4168 0
Northern Cancer Institute - St Leonards
Recruitment hospital [7] 4169 0
Concord Repatriation Hospital - Concord
Recruitment hospital [8] 4170 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [9] 4171 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [10] 4172 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [11] 8895 0
Epworth Richmond - Richmond
Recruitment hospital [12] 8896 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 17142 0
2145 - Westmead
Recruitment postcode(s) [2] 17141 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 287199 0
Government body
Name [1] 287199 0
Cancer Australia
Address [1] 287199 0
PO Box 1201
Dickson
ACT 2602
Country [1] 287199 0
Australia
Funding source category [2] 303560 0
Government body
Name [2] 303560 0
NHMRC (National Health and Medical Research Council)
Address [2] 303560 0
GPO Box 1421
Canberra ACT 2601
Country [2] 303560 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 285962 0
Other Collaborative groups
Name [1] 285962 0
Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Address [1] 285962 0
Level 6, 119 – 143 Missenden Road, Camperdown NSW 2050
Country [1] 285962 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289192 0
Sydney Local Health District Ethics Review Committee (RPAH zone)
Ethics committee address [1] 289192 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 289192 0
Australia
Date submitted for ethics approval [1] 289192 0
03/06/2013
Approval date [1] 289192 0
05/07/2013
Ethics approval number [1] 289192 0
X13-0191
Ethics committee name [2] 293336 0
South Metropolitan Health Service (SMHS) Human Research and Ethics Committee (HREC)
Ethics committee address [2] 293336 0
Level 2, Southern Research Facility (Perkins building)
Fiona Stanley Hospital, 11 Robin Warren Drive
MURDOCH WA 6150
Ethics committee country [2] 293336 0
Australia
Date submitted for ethics approval [2] 293336 0
Approval date [2] 293336 0
16/09/2013
Ethics approval number [2] 293336 0
13/75
Ethics committee name [3] 293623 0
The Alfred Hospital Ethics Committee
Ethics committee address [3] 293623 0
OFFICE OF ETHICS & RESEARCH GOVERNANCE
Ground Floor
Linay Pavilion
The Alfred
Prahran VIC 3181
Ethics committee country [3] 293623 0
Australia
Date submitted for ethics approval [3] 293623 0
Approval date [3] 293623 0
03/03/2014
Ethics approval number [3] 293623 0
536/13

Summary
Brief summary
Summary
The purpose of this study is to determine the effect of adding mitomycin C (a chemotherapy drug) to best current treatment in patients with high-risk non-muscle invasive bladder cancer.

Who is it for?
You may be eligible to join this study if you are at least 18 years of age and have been diagnosed with non-muscle invasive bladder cancer. You should have undergone transurethral resection of the bladder tumour (TURBT) within 8 weeks prior to enrolment with no visible disease remaining.

Trial details
Non-muscle invasive bladder cancer is common, causes substantial suffering, and requires radical removal or irradiation of the bladder within 5 years in over 30% of people with high risk tumours despite best current treatment. Recent preliminary studies show promising results from adding mitomycin C, a chemotherapy drug, to best current treatment with BCG.

Participants in this trial will be randomly (by chance) allocated to one of two groups. Participants in one group will receive the current standard treatment. This involves direct instillation of the drug, Bacillus of Calmette-Guerin (BCG) into the bladder weekly for 6 weeks, and then monthly for 10 months. Participants in the other group with receive BCG and the chemotherapy drug, mitomycin C, via instillation into the bladder weekly for 9 weeks, and then monthly for 9 months.

Participants will be regularly assessed for up to 5 years in order to determine the effects of adding mitomycin C on cure rates, survival, side effects, and quality of life.
Trial website
http://www.anzup.org.au/content.aspx?page=trials-bcgmmc
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39718 0
Prof Dickon Hayne
Address 39718 0
School of Surgery, University of Western Australia (M704)
35 Stirling Highway CRAWLEY WA 6009
Country 39718 0
Australia
Phone 39718 0
+61 8 6151 1130
Fax 39718 0
Email 39718 0
dickon.hayne@uwa.edu.au
Contact person for public queries
Name 39719 0
Mr BCG+MMC Trial Coordinator
Address 39719 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 39719 0
Australia
Phone 39719 0
+61 2 9562 5000
Fax 39719 0
Email 39719 0
bcgmmc@ctc.usyd.edu.au
Contact person for scientific queries
Name 39720 0
Prof Dickon Hayne
Address 39720 0
School of Surgery, University of Western Australia (M704)
35 Stirling Highway CRAWLEY WA 6009
Country 39720 0
Australia
Phone 39720 0
+61 8 6151 1130
Fax 39720 0
Email 39720 0
dickon.hayne@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results