Adding Mitomycin C to Bacillus of Calmette-Guerin (BCG) as Adjuvant Intravesical Therapy for High-risk, Non-Muscle-invasive Bladder Cancer (BCG+MMC)

• ClinicalTrials.gov Identifier: NCT02948543
• Recruitment Status: Unknown
• First Posted: October 28, 2016
• Last Update Posted: May 9, 2018
• Sponsor: University of Sydney
• Collaborators: Australian and New Zealand Urogenital and Prostate Cancer Trials Group; Cancer Australia
• Information provided by (Responsible Party): University of Sydney

Study Description

Brief Summary:

Open label, randomised phase 3 trial of the addition of Mitomycin C 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 Mitomyicn C in addition to BCG.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer	Biological: Bacillus of Calmette-Guerin (BCG); Drug: Mitomycin C (MMC)	Phase 3

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 recur despite optimal therapy with adjuvant intravesical BCG. The 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 C (MMC) 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 MMC 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 + MMC (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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Study Start Date: July 2013
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (Arm B):Intravesical BCG + MMC; 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 (MMC) fixed at 40mg per instillation.	Biological: Bacillus of Calmette-Guerin (BCG); A strain of tubercle bacillus which modifies biologic response.; Other Names: OncoTICE; ImmuCYST; TheraCys; Drug: Mitomycin C (MMC); An antibiotic produced by a soil actinomycete which inhibits DNA synthesis.
Treatment (Arm A): Intravesical BCG; 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.	Biological: Bacillus of Calmette-Guerin (BCG); A strain of tubercle bacillus which modifies biologic response.; Other Names: OncoTICE; ImmuCYST; TheraCys

Outcome Measures

Primary Outcome Measures :

1. Disease free survival (death or recurrence) [ Time Frame: Up to 5 years ]

Secondary Outcome Measures :

1. Activity (Clear cystoscopy at 3 months) [ Time Frame: At 3 months after patient randomised ]
2. Time to recurrence (recurrence) [ Time Frame: Up to 5 years ]
3. Time to progression (disease progression) [ Time Frame: Up to 5 years ]
4. Safety (Adverse events graded according to CTC AE V4.0) [ Time Frame: Measured before day 1 of each instillation during treatment. ]
5. Health-Related Quality of Life [ Time Frame: Up to 5 years ]
   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).
6. Overall survival time (death from any cause) [ Time Frame: Up to 5 years ]
7. Treatment Completion [ Time Frame: Measured at end of study treatment (12 months after patient randomized). ]
   Treatment completion is defined as having received 75% or more of the planned numbers of induction and maintenance doses.
8. Marginal resource use [ Time Frame: 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).

Other Outcome Measures:

1. Exploratory Tissue Biomarker Investigation [ Time Frame: Baseline ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

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.

Contacts and Locations

Contacts

Contact: BCG+MMC Trial Coordinator; +61 2 9562 5000; bcgmmc@ctc.usyd.edu.au

Locations

Australia, New South Wales

Concord Repatriation General Hospital; Recruiting

Concord, New South Wales, Australia, 2139

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Andrew Mitterdorfer

Northern Cancer Institute, St Leonards; Recruiting

St Leonards, New South Wales, Australia, 2065

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Laurence Krieger

The Tweed Hospital; Recruiting

Tweed Heads, New South Wales, Australia, 2485

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Ehtesham Abdi

Sydney Adventist Hospital; Recruiting

Wahroonga, New South Wales, Australia, 2076

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Gavin Marx

Australia, Victoria

Footscray Hospital; Recruiting

Footscray, Victoria, Australia, 3011

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Conrad Bishop

Frankston Hospital; Recruiting

Frankston, Victoria, Australia, 3199

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Emma Beardsley

Austin Health - Austin Hospital; Recruiting

Heidelberg, Victoria, Australia, 3084

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Shomik Sengupta

The Alfred Hospital; Recruiting

Melbourne, Victoria, Australia, 3004

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Jeremy Grummet

Royal Melbourne Hospital - City Campus; Recruiting

Parkville, Victoria, Australia, 3050

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Paul Anderson

Australia, Western Australia

Fiona Stanley Hospital; Recruiting

Murdoch, Western Australia, Australia, 6150

Contact bcgmmc@ctc.usyd.edu.au

Principal Investigator: Dickon Hayne

Sponsors and Collaborators

University of Sydney

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Cancer Australia

Investigators

• Study Chair: Dickon Hayne; Fiona Stanley Hospital

More Information

• Responsible Party: University of Sydney
• ClinicalTrials.gov Identifier: NCT02948543
• Other Study ID Numbers: ANZUP 1301; 12613000513718 ( Registry Identifier: Australian New Zealand Clinical Trials Registry (ANZCTR) )
• First Posted: October 28, 2016
• Last Update Posted: May 9, 2018
• Last Verified: May 2018

Additional relevant MeSH terms:

Urinary Bladder Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Mitomycins; Mitomycin; Antibiotics, Antineoplastic; Antineoplastic Agents; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors