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

Bladder Cancer Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02948543
• Other study ID #: ANZUP 1301
• Secondary ID: 12613000513718
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 2013
• Est. completion date: December 2024

Study information

• Verified date: June 2023
• Source: University of Sydney
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 501
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Biological:
• Bacillus of Calmette-Guerin (BCG)
A strain of tubercle bacillus which modifies biologic response.

Drug:
• Mitomycin (MM)
An antibiotic produced by a soil actinomycete which inhibits DNA synthesis.

Locations

Country	Name	City	State
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Footscray Hospital	Footscray	Victoria
Australia	Frankston Hospital	Frankston	Victoria
Australia	Austin Health - Austin Hospital	Heidelberg	Victoria
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Southside Cancer Care Centre	Miranda	New South Wales
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Royal Melbourne Hospital - City Campus	Parkville	Victoria
Australia	Redcliffe Hospital	Redcliffe	Queensland
Australia	Epworth Healthcare	Richmond	Victoria
Australia	GenesisCare	St Leonards	New South Wales
Australia	The Tweed Hospital	Tweed Heads	New South Wales
Australia	Sydney Adventist Hospital	Wahroonga	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
United Kingdom	Nottingham City Hospital - City Campus	Nottingham

Sponsors (3)

Lead Sponsor	Collaborator
University of Sydney	Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Cancer Australia

Countries where clinical trial is conducted

Australia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Tissue Biomarker Investigation	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.	Baseline
Primary	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.	Up to 5 years
Secondary	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.	At 3 months after patient randomised
Secondary	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.	Up to 5 years
Secondary	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.	Up to 5 years
Secondary	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.	Measured before day 1 of each instillation during treatment.
Secondary	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).	Up to 5 years from the date of randomisation
Secondary	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.	Up to 5 years
Secondary	Treatment Completion	Treatment completion is defined as having received 75% or more of the planned numbers of induction and maintenance doses.	Measured at end of study treatment (12 months after patient randomized).
Secondary	Marginal resource use	Assessed via a specifically designed resource utilisation form (collecting information such as number, type and duration of visits).	5 years after last patient randomized (or date last patient has died, whichever sooner).