BCG + MMC: Adding Mitomycin C to BCG in High-risk, Non-muscle-invasive Bladder Cancer

BCG + MMC: Adding Mitomycin C to BCG as Adjuvant Intravesical Therapy for High-risk, Non-muscle-invasive Bladder Cancer: a Randomised Phase 3 Trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Transitional Cell Carcinoma; Transurethral Resection
• Intervention / Treatment: Biological: Bacillus Calmette-Guerin Vaccine Intravesical; Drug: Mitomycin

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG51PB
    • Nottingham University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 either be the initial 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. Is willing to complete 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 MM
2. Prior treatment with any other intravesical agent including BCG or MM (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 e.g. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Standard Intravesical BCG; Standard intravesical BCG therapy given as per usual standard of care	Biological: Bacillus Calmette-Guerin Vaccine Intravesical; BCG (Oncotice) is administered intravesically as per usual standard of care
Experimental: Arm B: Experimental BCG + MM; Combination therapy with BCG and MM, given on specific protocol sessions	Biological: Bacillus Calmette-Guerin Vaccine Intravesical; BCG (Oncotice) is administered intravesically as per usual standard of care; Drug: Mitomycin; MMC is administered intravesically as per usual standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	Death, disease free survival, or evidence of transitional cell carcinoma (TCC)	5 years follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Activity	Clear cystoscopy at 3 months	3 months
Time to Recurrence	Recurrence of TCC bladder	5 years follow up
Time to Progression	Recurrence of Higher Grade or Stage	5 years follow up
Safety and adverse events	Adverse Events Graded According to CTC AE V4.03	During treatment phase of the trial (typically 12 months)
Health-Related Quality of Life	QLQ-BLS24. Individual internationally-validated (but subjective) symptom score questionnaire that gives an overall QOL assesment, that can be tracked throughout follow up. They do not use SI units of measurement.	5 years follow up
Health-Related Quality of Life	QLQ-C30. Individual internationally-validated (but subjective) symptom score questionnaire that gives an overall QOL assesment, that can be tracked throughout follow up. They do not use SI units of measurement.	5 years follow up
Health-Related Quality of Life	I-PSS. Individual internationally-validated (but subjective) symptom score questionnaire that gives an overall QOL assesment, that can be tracked throughout follow up. They do not use SI units of measurement.	5 years follow up
Overall Survival Time	Death from any Cause	5 years follow up
Feasibility as a future standard of care	Compliance with intravesical therapy, measured in percent (%) of planned intravesical therapies actually given	During treatment phase of the trial, typically 1 year
Marginal Resource Use	Number of GP visits, Number of outpatient and emergency department visits, number of inpatient admissions and number of days admitted	5 years follow up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To consider future exploratory biomarker studies as potential prognostic biomarkers or predictive biomarkers of treatment	Future (as yet unidentified) biomarker expression could be measured and then statistical association of those biomarkers with primary outcome meaures assessed.	5 years follow up

Collaborators and Investigators

• Sponsor: Nottingham University Hospitals NHS Trust
• Collaborators: University of Sydney; Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Investigators: Study Director: Dickon Hayne, PhD, The University of Western Australia

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2020
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 29, 2023
• First Submitted That Met QC Criteria: June 12, 2024
• First Posted (Actual): June 17, 2024

Study Record Updates

• Last Update Posted (Actual): June 17, 2024
• Last Update Submitted That Met QC Criteria: June 12, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Non-Muscle Invasive Bladder Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Alkylating Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; BCG Vaccine; Mitomycins; Mitomycin
• Other Study ID Numbers: 18UR004

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No