Investigating Bladder Chemotherapy Instead of Surgery for Low Risk Bladder Cancer

Study Overview
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Brief Summary
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Patients diagnosed with low risk non-muscle invasive bladder cancer (NMIBC) are at risk of frequent low grade recurrence, which usually necessitates surgical intervention under general anaesthetic. This multicentre study aims to establish the short term efficacy of chemoresection using chemotherapy within the bladder for the treatment of NMIBC. Should the levels of complete response following chemoresection meet predefined criteria, a larger phase III trial would be developed to assess longer term disease related endpoints, with the aim of standardising management of recurrent low risk NMIBC and potentially removing the need for over a thousand patients each year to undergo surgery.

Detailed Description
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CALIBER is a two stage phase II, multicentre, randomised controlled trial (RCT). A control group has been included to provide prospective data about surgical management and outcomes and assess feasibility of recruitment to a randomised study. Stage 1: 80 patients will be recruited with treatment allocated 2:1 by randomisation between chemoresection and surgical management. Stage 2: If the stop/go activity criteria at the end of stage 1 indicate that recruitment should continue, 9 additional participants will be recruited, all of whom will receive chemoresection. Patients assigned to the chemoresection group will receive 4 once weekly intravesical instillations of 40mg Mitomycin C (MMC) as outpatients. This treatment will be delivered via catheter under local anaesthetic. Patients assigned to the surgical management group will receive the standard surgical management in use at their hospital for treatment of recurrence which may include a single post-operative installation of 40mg MMC within 24 hours. All participants will be followed up at 3 weeks from the start of treatment (ie at time of final MMC instillation for chemoresection group) and each will receive a cystoscopy three months from the end of treatment to assess response, in accordance with European Association of Urology (EAU) guidelines. Subsequent cystoscopic follow up will take place 12 months after treatment if recurrence-free at 3 months and then annually.

Official Title
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CALIBER - A Phase II Randomised Feasibility Study of Chemoresection and Surgical Management in Low Risk Non Muscle Invasive Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Mitomycin C
* Procedure: Surgical Management


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent NMIBC recurrence following original diagnosis of low risk NMIBC (defined as Ta G1 or Ta G2 (Ta low grade) with a risk of recurrence score of ≤6 using EORTC risk tables Histologically confirmed Transitional-cell carcinoma (TCC) at original diagnosis Aged 16 or over Satisfactory pre-treatment haematology values and serum creatinine < 1.5 x Upper Limit of Normal (ULN) Negative pregnancy test for women of child-bearing potential Exclusion Criteria: Any history of: grade 3/high grade or ≥T1 transitional cell carcinoma, concomitant carcinoma in situ, more than 7 tumours at one diagnosis or more than 1 recurrence per year since initial diagnosis or in the past five years, whichever is shorter Any history of histologically confirmed non-TCC bladder cancer Trial entry recurrence identified within 11.5 months of the date of the original diagnosis Any prior treatment of the trial entry recurrence (including biopsy) Previous MMC chemotherapy other than a single instillation at diagnostic surgery Known allergy to MMC Carcinoma involving the prostatic urethra or upper urinary tract (participants should have had imaging of the upper urinary tract within 2 years prior to randomisation) Known or suspected reduced bladder capacity (<100ml) Significant bleeding disorder Female patients who are breast-feeding or are of childbearing potential and unwilling or unable to use adequate non-hormonal contraception. Male patients should also use contraception if sexually active. Active or intractable urinary tract infection Urethral stricture or anything impeding the insertion of a catheter Large narrow neck diverticula Significant urinary incontinence Any other conditions that in the Principal Investigator's opinion would contraindicate protocol treatment Unable or unwilling to comply with study procedures or follow up schedule

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoresection<br>4 once weekly outpatient intravesical instillations 40mg Mitomycin C | Drug: Mitomycin C<br>* Patients assigned to the chemoresection group will receive 4 once weekly intravesical instillations of 40mg MMC as outpatients.<br>* Other names: MMC;|
| Other: Surgical Management<br>Surgical management according to local practice | Procedure: Surgical Management<br>* Patients in this group should be treated according to local practice. Surgical interventions may include transurethral resection (TUR) or ablation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate with chemoresection | Defined as an absence of any tumour following chemoresection and will be assessed visually at 3 month check cystoscopy by patients' urologists. A biopsy of the tumour bed would take place to confirm visual assessment of complete response. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment compliance in chemoresection group | Patients who receive 4 MMC instillations with no more than 14 days between each instillation will be described as fully compliant. | Duration of treatment (3 weeks) | 
| Salvage surgery rates | Assessing trans-urethral resection and biopsy rates following initial treatment in both treatment groups | 3 years | 
| Progression-free survival | Defined as time from randomisation to the first of muscle invasive bladder recurrence, recurrence in the pelvic nodes, distant metastatic recurrence or death from any cause. | 3 years | 
| Toxicity (NCI Common Toxicity Criteria for Adverse Effects (CTCAE) V4 and Clavien Dindo grade (in surgical group)) | Measuring side effects of both treatments using clinician reported toxicity scales | up to 12 months | 
| European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and Superficial Bladder Cancer (BLS24) questionnaire | Assessing side effects and impact of both treatments on patient reported quality of life. | up to 12 months | 
| Health service utilisation | Assessed using prospective data collection of health resource usage. | up to 12 months | 
| Recurrence free interval | Time from end of treatment to first relapse, in patients confirmed recurrence free at 3 months | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonmuscle invasive bladder cancer (NMIBC), Mitomycin C, Chemoresection