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Adding Mitomycin to BCG as Adjuvant Intravesical Therapy for High-risk Non-Muscle-invasive Bladder Cancer (BCG+MM)

Primary Purpose

Bladder Cancer

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Bacillus of Calmette-Guerin (BCG)
Mitomycin (MM)
Sponsored by
University of Sydney
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bladder Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Concord Repatriation General Hospital
  • Nepean Hospital
  • Southside Cancer Care Centre
  • John Hunter Hospital
  • GenesisCare
  • The Tweed Hospital
  • Sydney Adventist Hospital
  • Westmead Hospital
  • Redcliffe Hospital
  • Footscray Hospital
  • Frankston Hospital
  • Austin Health - Austin Hospital
  • The Alfred Hospital
  • Royal Melbourne Hospital - City Campus
  • Epworth Healthcare
  • Fiona Stanley Hospital
  • Nottingham City Hospital - City Campus

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Treatment (Arm B):Intravesical BCG + MM

Treatment (Arm A): Intravesical BCG

Arm Description

Induction (weekly x 9); and followed by Maintenance (monthly x 9) beginning 3 months after randomisation. Dosage of Bacillus of Calmette-Guerin (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 Mitomycin (MM) fixed at 40mg per instillation.

Induction (weekly x 6); and followed by Maintenance (monthly x 10) beginning 3 months after randomisation. Dosage of Bacillus of Calmette-Guerin (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.

Outcomes

Primary Outcome Measures

Disease free survival (death or recurrence)
Measured from the date of randomisation until the date of disease recurrence, upper tract disease is first evident, or the date of death, or until the date last known to be alive and without disease recurrence. Assessed via cystoscopy.

Secondary Outcome Measures

Activity (Clear cystoscopy at 3 months)
Treatment activity is defined as a negative cystoscopy & biopsy at nominal week 12 (i.e. after induction therapy, but prior to the commencement of maintenance therapy). Assessed via cystoscopy and biopsy.
Time to recurrence (recurrence)
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.
Time to progression (disease progression)
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.
Safety (Adverse events graded according to CTC AE V4.0)
The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events after each treatment cycle.
Health-Related Quality of Life
Health related quality life is a composite outcome aggregated to arrive at one reported value to ensure multiple aspects of the participants life are adequately assessed and measured. The following questionnaires will be used; the 24-item EORTC Bladder Symptoms Quality of Life module (QLM-BLS24); the EORTC Core Quality of Life Questionnaire (QLQ-C30); and the International Prostate Symptom Score (I-PSS).
Overall survival time (death from any cause)
Overall survival is defined as the interval from the date of randomisation to the date of death from any cause or the date last known to be alive.
Treatment Completion
Treatment completion is defined as having received 75% or more of the planned numbers of induction and maintenance doses.
Marginal resource use
Assessed via a specifically designed resource utilisation form (collecting information such as number, type and duration of visits).

Full Information

First Posted
August 1, 2016
Last Updated
June 14, 2023
Sponsor
University of Sydney
Collaborators
Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Cancer Australia
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1. Study Identification

Unique Protocol Identification Number
NCT02948543
Brief Title
Adding Mitomycin to BCG as Adjuvant Intravesical Therapy for High-risk Non-Muscle-invasive Bladder Cancer
Acronym
BCG+MM
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

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 2013 (undefined)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Sydney
Collaborators
Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Cancer Australia

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bladder Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
501 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (Arm B):Intravesical BCG + MM
Arm Type
Experimental
Arm Description
Induction (weekly x 9); and followed by Maintenance (monthly x 9) beginning 3 months after randomisation. Dosage of Bacillus of Calmette-Guerin (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 Mitomycin (MM) fixed at 40mg per instillation.
Arm Title
Treatment (Arm A): Intravesical BCG
Arm Type
Other
Arm Description
Induction (weekly x 6); and followed by Maintenance (monthly x 10) beginning 3 months after randomisation. Dosage of Bacillus of Calmette-Guerin (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.
Intervention Type
Biological
Intervention Name(s)
Bacillus of Calmette-Guerin (BCG)
Other Intervention Name(s)
OncoTICE, ImmuCYST, TheraCys
Intervention Description
A strain of tubercle bacillus which modifies biologic response.
Intervention Type
Drug
Intervention Name(s)
Mitomycin (MM)
Intervention Description
An antibiotic produced by a soil actinomycete which inhibits DNA synthesis.
Primary Outcome Measure Information:
Title
Disease free survival (death or recurrence)
Description
Measured from the date of randomisation until the date of disease recurrence, upper tract disease is first evident, or the date of death, or until the date last known to be alive and without disease recurrence. Assessed via cystoscopy.
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Activity (Clear cystoscopy at 3 months)
Description
Treatment activity is defined as a negative cystoscopy & biopsy at nominal week 12 (i.e. after induction therapy, but prior to the commencement of maintenance therapy). Assessed via cystoscopy and biopsy.
Time Frame
At 3 months after patient randomised
Title
Time to recurrence (recurrence)
Description
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.
Time Frame
Up to 5 years
Title
Time to progression (disease progression)
Description
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.
Time Frame
Up to 5 years
Title
Safety (Adverse events graded according to CTC AE V4.0)
Description
The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events after each treatment cycle.
Time Frame
Measured before day 1 of each instillation during treatment.
Title
Health-Related Quality of Life
Description
Health related quality life is a composite outcome aggregated to arrive at one reported value to ensure multiple aspects of the participants life are adequately assessed and measured. The following questionnaires will be used; the 24-item EORTC Bladder Symptoms Quality of Life module (QLM-BLS24); the EORTC Core Quality of Life Questionnaire (QLQ-C30); and the International Prostate Symptom Score (I-PSS).
Time Frame
Up to 5 years from the date of randomisation
Title
Overall survival time (death from any cause)
Description
Overall survival is defined as the interval from the date of randomisation to the date of death from any cause or the date last known to be alive.
Time Frame
Up to 5 years
Title
Treatment Completion
Description
Treatment completion is defined as having received 75% or more of the planned numbers of induction and maintenance doses.
Time Frame
Measured at end of study treatment (12 months after patient randomized).
Title
Marginal resource use
Description
Assessed via a specifically designed resource utilisation form (collecting information such as number, type and duration of visits).
Time Frame
5 years after last patient randomized (or date last patient has died, whichever sooner).
Other Pre-specified Outcome Measures:
Title
Exploratory Tissue Biomarker Investigation
Description
Optional donation of formalin-fixed paraffin embedded (FFPE) tumour tissue for future biological or translational sub-studies. These future studies may include investigations of how BCG + MM may work in people with Non-Muscle-invasive Bladder Cancer as well as studies that may help to understand the pathogenic course of this cancer and related diseases.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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). Age >= 18 yrs 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. ECOG Performance Status of 0-2 Adequate bone marrow, renal and liver function confirmed by pre-randomisation blood tests. Study treatment both planned and able to start within 4 weeks of randomisation Has completed the HRQL questionnaires or is unable to complete them because of literacy, insufficient English or limited vision Willing and able to comply with all study requirements, including treatment, timing and/or nature of all required assessments Signed, written informed consent Exclusion Criteria: Contraindications or hypersensitivity to investigational products, BCG and Mitomycin Prior treatment with any other intravesical agent including BCG or Mitomycin (excludes single doses given post TURBT) Current or past transitional cell carcinoma (TCC) of the upper urinary tract Prior muscle-invasive (stage T2 or higher) transitional-cell carcinoma of the bladder Bladder dysfunction precluding intravesical therapy eg. Severe urinary incontinence or overactive or spastic bladder Life expectancy < 3 months 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) Prior radiotherapy of the pelvis Prior or current treatment with radiotherapy-response or biological-response modifiers Clinical evidence of existing active tuberculosis History of another malignancy within 5 years prior to registration. Patients with non-melanomatous carcinoma of the skin are eligible for this study. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dickon Hayne
Organizational Affiliation
Fiona Stanley Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Concord Repatriation General Hospital
City
Concord
State/Province
New South Wales
ZIP/Postal Code
2139
Country
Australia
Facility Name
Nepean Hospital
City
Kingswood
State/Province
New South Wales
ZIP/Postal Code
2747
Country
Australia
Facility Name
Southside Cancer Care Centre
City
Miranda
State/Province
New South Wales
ZIP/Postal Code
2228
Country
Australia
Facility Name
John Hunter Hospital
City
New Lambton Heights
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
GenesisCare
City
St Leonards
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Facility Name
The Tweed Hospital
City
Tweed Heads
State/Province
New South Wales
ZIP/Postal Code
2485
Country
Australia
Facility Name
Sydney Adventist Hospital
City
Wahroonga
State/Province
New South Wales
ZIP/Postal Code
2076
Country
Australia
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Redcliffe Hospital
City
Redcliffe
State/Province
Queensland
ZIP/Postal Code
4020
Country
Australia
Facility Name
Footscray Hospital
City
Footscray
State/Province
Victoria
ZIP/Postal Code
3011
Country
Australia
Facility Name
Frankston Hospital
City
Frankston
State/Province
Victoria
ZIP/Postal Code
3199
Country
Australia
Facility Name
Austin Health - Austin Hospital
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Facility Name
The Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Facility Name
Royal Melbourne Hospital - City Campus
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Epworth Healthcare
City
Richmond
State/Province
Victoria
ZIP/Postal Code
3121
Country
Australia
Facility Name
Fiona Stanley Hospital
City
Murdoch
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
Nottingham City Hospital - City Campus
City
Nottingham
ZIP/Postal Code
NG7 2UH
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Adding Mitomycin to BCG as Adjuvant Intravesical Therapy for High-risk Non-Muscle-invasive Bladder Cancer

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