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

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

INTRODUCTION

  • Org Study ID: ANZUP 1301
  • Secondary ID: 12613000513718
  • NTC ID: NCT02948543
  • Sponsor: University of Sydney

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.

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.

  • Overall Status
    Unknown status
  • Start Date
    July 2013
  • Phase
    Phase 3
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Disease free survival (death or recurrence)

Primary Outcome 1 - Timeframe: Up to 5 years

CONDITION

  • Bladder Cancer

ELIGIBILITY

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 function

- Adequate renal function

- Adequate liver function

- 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 C

- Prior treatment with any other intravesical agent including BCG or Mitomycin C (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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Dickon Hayne

Role: Study Chair

Affiliation: Fiona Stanley Hospital

Overall Contact

Name: Dickon Hayne

Phone: +61 2 9562 5000

Email: bcgmmc@ctc.usyd.edu.au

LOCATION

Facility Status Contact

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