Investigating Bladder Chemotherapy Instead of Surgery for Low Risk Bladder Cancer (CALIBER)

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

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.

Study Overview

• Status: Unknown
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Mitomycin C; Procedure: Surgical Management

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW1 2BU
    • University College Hospital
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital
  • Manchester, United Kingdom, M20 2LR
    • Withington Hospital
  • Cheshire
    • Macclesfield, Cheshire, United Kingdom, SK10 3BL
      • Macclesfield District General Hospital
  • Cleveland
    • Middlesbrough, Cleveland, United Kingdom, TS4 3BW
      • James Cook University Hospital
  • Cumbria
    • Whitehaven, Cumbria, United Kingdom, CA28 8JG
      • West Cumberland Hospital
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Plymouth, Devon, United Kingdom, PL6 8DH
      • Derriford Hospital
  • Dorset
    • Bournemouth, Dorset, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Dorchester, Dorset, United Kingdom, DT1 2JY
      • Dorset County Hospital
  • England
    • Carlisle, England, United Kingdom, CA2 7HY
      • Cumberland Infirmary
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 5ET
      • Broomfield Hospital
    • Harlow, Essex, United Kingdom, CM20 1QX
      • Princess Alexandra Hospital
  • Gloucestershire
    • Cheltenham, Gloucestershire, United Kingdom, GL53 7AN
      • Cheltenham General Hospital
    • Gloucester, Gloucestershire, United Kingdom, GL1 3NN
      • Gloucestershire Royal Hospital
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, OL1 2JH
      • Royal Oldham Hospital
  • Hampshire
    • Basingstoke, Hampshire, United Kingdom, RG24 9NA
      • Basingstoke And North Hampshire Hospital
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Southampton General Hospital
  • Herefordshire
    • Hereford, Herefordshire, United Kingdom, HR1 2ER
      • Hereford County Hospital
  • Kent
    • Dartford, Kent, United Kingdom, DA2 8DA
      • Darent Valley Hospital
    • Gillingham, Kent, United Kingdom, ME7 5NY
      • Medway Maritime Hospital
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Royal Preston Hospital
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE5 4PW
      • Leicester General Hospital
  • Middlesex
    • Harrow, Middlesex, United Kingdom, HA1 3UJ
      • Northwick Park Hospital
  • Oxfordshire
    • Headington, Oxfordshire, United Kingdom, OX3 7LE
      • Churchill Hospital
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Royal Hallamshire Hospital
  • Suffolk
    • Ipswich, Suffolk, United Kingdom, IP4 5PD
      • Ipswich Hospital
  • Surrey
    • Croydon, Surrey, United Kingdom, CR7 7YE
      • Croydon University Hospital
    • Guildford, Surrey, United Kingdom, GU2 7XX
      • Royal Surrey County Hospital
  • Tyne And Wear
    • Newcastle upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN
      • Freeman Hospital
  • West Midlands
    • Wolverhampton, West Midlands, United Kingdom, WV10 0QP
      • New Cross Hospital
  • West Sussex
    • Chichester, West Sussex, United Kingdom, PO19 6SE
      • St Richard's Hospital
    • Worthing, West Sussex, United Kingdom, BN11 2DH
      • Worthing Hospital
  • West Yorkshire
    • Wakefield, West Yorkshire, United Kingdom, WF1 4DG
      • Pinderfields General Hospital
  • Worcestershire
    • Kidderminster, Worcestershire, United Kingdom, DY11 6RJ
      • Kidderminster Hospital
    • Redditch, Worcestershire, United Kingdom, B98 7UB
      • Alexandra Hospital
    • Worcester, Worcestershire, United Kingdom, WR5 1DD
      • Worcester Royal Hospital
  • Yorkshire
    • Leeds, Yorkshire, United Kingdom, LS9 7TF
      • St James's University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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
Experimental: Chemoresection; 4 once weekly outpatient intravesical instillations 40mg Mitomycin C	Drug: Mitomycin C; Patients assigned to the chemoresection group will receive 4 once weekly intravesical instillations of 40mg MMC as outpatients.; Other Names: MMC
Other: Surgical Management; Surgical management according to local practice	Procedure: Surgical Management; Patients in this group should be treated according to local practice. Surgical interventions may include transurethral resection (TUR) or ablation.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institute of Cancer Research, United Kingdom
• Collaborators: National Institute for Health Research, United Kingdom
• Investigators: Principal Investigator: Hugh Mostafid, Royal Surrey County Hospital NHS Foundation Trust

Publications and helpful links

General Publications

• Mostafid AH, Porta N, Cresswell J, Griffiths TRL, Kelly JD, Penegar SR, Davenport K, McGrath JS, Campain N, Cooke P, Masood S, Knowles MA, Feber A, Knight A, Catto JWF, Lewis R, Hall E. CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin-C vs surgical management in low-risk non-muscle-invasive bladder cancer. BJU Int. 2020 Jun;125(6):817-826. doi: 10.1111/bju.15038. Epub 2020 Apr 3.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): January 1, 2018
• Study Completion (Anticipated): September 1, 2020

Study Registration Dates

• First Submitted: February 19, 2014
• First Submitted That Met QC Criteria: February 21, 2014
• First Posted (Estimate): February 25, 2014

Study Record Updates

• Last Update Posted (Actual): March 19, 2020
• Last Update Submitted That Met QC Criteria: March 17, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Mitomycin C; Nonmuscle invasive bladder cancer (NMIBC); Chemoresection
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin
• Other Study ID Numbers: ICR-CTSU/2013/10041; 2013-005095-18 (EudraCT Number)