Clinical Trial Results:
A phase II randomised feasibility study of chemoresection and surgical management in low risk non muscle invasive bladder cancer.
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Summary
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EudraCT number |
2013-005095-18 |
Trial protocol |
GB |
Global end of trial date |
21 Feb 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Feb 2023
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First version publication date |
01 Feb 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ICR-CTSU/2013/10041
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Additional study identifiers
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ISRCTN number |
ISRCTN24855462 | ||
US NCT number |
NCT02070120 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
NIHR Reference Number: PB-PG-0712-28112, Sponsor Identifier Number: CCR4134 | ||
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Sponsors
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Sponsor organisation name |
Institute of Cancer Research
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Sponsor organisation address |
15 Cotswold Road, Sutton, United Kingdom, SM2 5NG
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Public contact |
Steven Penegar, Institute of Cancer Research, 44 02087224238, caliber-icrctsu@icr.ac.uk
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Scientific contact |
Steven Penegar, Institute of Cancer Research, 44 02087224238, caliber-icrctsu@icr.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Jul 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Oct 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Feb 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Can chemotherapy in the bladder (chemoresection) enable the avoidance of surgery for those diagnosed with a recurrence of low risk non-muscle invasive bladder cancer?
CALIBER is a two stage phase II, multicentre, randomised (2:1) non-comparative trial (RCT) powered to demonstrate that chemoablation will achieve at least 60% complete response (CR) at 3 months under a Simon 2-stage design (p0=0.45, p1=0.60, alpha=0.10). A control group was included in stage1 to provide prospective data about surgical management and outcomes and assess feasibility of recruitment to a randomised study.
Trial did not met its pre-sopecified threshold at Stage 1 (at least 26 CR/51pts needed ), and the IDMC advised that the trial should stop for futility.
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Protection of trial subjects |
For trial entry and optional tissue donation, patients were given a verbal explanation, discussion and written information.
The Principal Investigator at each site was responsible for ensuring written informed consent was obtained for each patient.
Eligible patients were given as much time as they needed to consider and come to a decision about entering the trial, prior to giving consent for registration.
The patient information sheet, described fully which parties would have access to their identifiable personal information and patients were asked to
give consent to this.
The trial was overseen by an Independent Data Monitoring Committee, who reviewed the accumulating trial data and could recommend stopping the trial if there was any cause for concern about patient safety and if this were the case the patient's oncologist would be notified.
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Background therapy |
Bladder cancer is the ninth most common cancer worldwide, and most frequently presents as non-muscle-invasive bladder cancer (NMIBC). Approximately 50% of patients with bladder cancer have low-risk NMIBC, with a 0.8–6% risk of progression to muscle-invasive disease or bladder cancer death within 5 years and a relatively high rate of local recurrence, 46–62%. Half of recurrences occur within the first year of follow-up. The discomfort and inconvenience of managing NMIBC recurrence, combined with cost, are the key issues for patients and healthcare providers managing low-risk NMIBC. Guidelines recommend annual cystoscopy for 5 years for low-risk NMIBC. Treatments for local recurrence include transurethral resection and cystodiathermy under general anaesthesia, laser ablation under local anaesthesia and watchful waiting. This variety reflects the indolent nature of low-risk NMIBC and lack of high-quality evidence about the optimal management. | ||
Evidence for comparator |
Several small studies have demonstrated promising results for intravesical chemotherapy alone (chemoablation) as an alternative to surgical management for NMIBC. The optimal schedule and its effectiveness in achieving a complete response in low-risk NMIBC are unclear. Reviews of chemoablation (including >1200 patients with varying risk and different chemotherapy regimens) suggest the complete response rate is ~50%, with the therapeutic effect sustained for at least 2 years. These data suggest chemoablation may be a viable treatment for low-risk NMIBC. Surgical intervention is the standard of care within this patient population. | ||
Actual start date of recruitment |
01 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 82
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Worldwide total number of subjects |
82
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
62
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85 years and over |
6
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Recruitment
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Recruitment details |
Between February 2015 and August 2017 82 patients with visual diagnosis of recurrent low risk NMIBC were enrolled from 24 UK hospitals (54 chemoablation, 28 surgical management). | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Patients that met the eligibility criteria were recruited into the study. Eligible patients had previously diagnosed, histologically confirmed, low risk NMIBC with visual diagnosis of recurrence. Patients were over 16, with an EORTC risk of recurrence score ≤6 with no history of high grade/≥T1 or non-urothelial transitional cell carcinoma. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Chemoablation | |||||||||||||||||||||
Arm description |
Chemoablation participants received four once weekly intravesical instillations of 40mg mitomycin-C (MMC) as outpatients, in accordance with local policy. No dose reductions were permitted. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
mitomycin C
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Investigational medicinal product code |
ATC Code: L01D
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravesical use
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Dosage and administration details |
Four once weekly intravesical instillations of 40mg mitomycin-C (MMC) as outpatients, in accordance with local policy.
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Arm title
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Surgical Management | |||||||||||||||||||||
Arm description |
Participants assigned to surgical management had the local standard technique for treatment of recurrence; a single instillation of 40mg MMC within 24 hours post-operatively was permitted. | |||||||||||||||||||||
Arm type |
Surgery | |||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Chemoablation
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Reporting group description |
Chemoablation participants received four once weekly intravesical instillations of 40mg mitomycin-C (MMC) as outpatients, in accordance with local policy. No dose reductions were permitted. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Surgical Management
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Reporting group description |
Participants assigned to surgical management had the local standard technique for treatment of recurrence; a single instillation of 40mg MMC within 24 hours post-operatively was permitted. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Chemoablation
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Reporting group description |
Chemoablation participants received four once weekly intravesical instillations of 40mg mitomycin-C (MMC) as outpatients, in accordance with local policy. No dose reductions were permitted. | ||
Reporting group title |
Surgical Management
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Reporting group description |
Participants assigned to surgical management had the local standard technique for treatment of recurrence; a single instillation of 40mg MMC within 24 hours post-operatively was permitted. | ||
Subject analysis set title |
Evaluable population - chemoablation
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
This population includes all randomised patients with 3 months assessment available and who have received their allocated treatment regardless of whether they were later found to be ineligible or a protocol violator.
Because the primary endpoint is non-comparative, the patients in the chemoablation group define the chemoablation population as defined in the SAP v1.0.
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Subject analysis set title |
Evaluable population - surgery
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
This population includes all randomised patients with 3 months assessment available and who have received their allocated treatment regardless of whether they were later found to be ineligible or a protocol violator.
Because the primary endpoint is non-comparative, the patients in the chemoablation group define the chemoablation population as defined in the SAP v1.0.
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End point title |
Complete response [1] | ||||||||
End point description |
Complete response (CR) to chemoablation 3 months post-treatment, defined as an absence of any tumour following chemoablation. Response will be assessed visually at check cystoscopy by patients’ urologists and a biopsy of the tumour bed will take place to confirm visual assessment of CR.
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End point type |
Primary
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End point timeframe |
3 months post-treatment
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: CALIBER is a two stage phase II, multicentre, randomised (2:1) non-comparative trial (RCT) powered to demonstrate that chemoablation will achieve at least 60% complete response (CR) at 3 months under a Simon 2-stage design. A control group was included in stage1 to provide prospective data about surgical management and outcomes and assess feasibility of recruitment to a randomised study. Trial did not met its pre-specified threshold at Stage 1 (at least 26 CR needed ) and stopped accrual. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Treatment compliance in the chemoablation group | ||||||||||
End point description |
Patients who receive 4 MMC instillations with no more than 14 days between each instillation will be described as fully compliant
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End point type |
Secondary
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End point timeframe |
While on treatment
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| No statistical analyses for this end point | |||||||||||
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End point title |
Time to recurrence | ||||||||||||
End point description |
Time to recurrence: defined as time from end of treatment to first occurrence of subsequent disease (local or distant recurrence or death due to bladder cancer) by response status (with and without CR) at 3 months
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End point type |
Secondary
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End point timeframe |
Proportion free to subsequent recurrence at 12 months
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Statistical analysis title |
Comparison time to recurrence | ||||||||||||
Comparison groups |
Evaluable population - chemoablation v Evaluable population - surgery
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.089 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.44
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.17 | ||||||||||||
upper limit |
1.15 | ||||||||||||
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End point title |
Subsequent TURBT /biopsy rate | ||||||||||||
End point description |
Subsequent TURBT /biopsy rate by response status (with and without CR) at 3 months
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End point type |
Secondary
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End point timeframe |
3 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Progression free survival | ||||||||||||
End point description |
Time to progression is 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
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End point type |
Secondary
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End point timeframe |
12 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline in EORTC QLQ-C30 Global Health | ||||||||||||
End point description |
High score represents high quality of life
Positive change from baseline represents improvement.
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End point type |
Secondary
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End point timeframe |
Six months
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Statistical analysis title |
Difference in change from baseline | ||||||||||||
Statistical analysis description |
Treatment effect chemoablation vs surgery and its 99% confidence intervals are obtained from an analysis of covariance (ANCOVA) model, using change from baseline as the outcome measure and adjusting treatment effect for baseline score on the same subscale. A p-value of <0.01 will be deemed statistically significant to acknowledge that some adjustment be made for multiple testing
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Comparison groups |
Evaluable population - chemoablation v Evaluable population - surgery
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
-5.8
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Confidence interval |
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99% | ||||||||||||
sides |
2-sided
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lower limit |
-17.9 | ||||||||||||
upper limit |
6.3 | ||||||||||||
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End point title |
Change from baseline in EORTC QLQ-NMIBC24 Urinary Symptoms | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 months
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Statistical analysis title |
Diffewrence in mean change form baseline | ||||||||||||
Statistical analysis description |
Treatment effect chemoablation vs surgery and its 99% confidence intervals are obtained from an analysis of covariance (ANCOVA) model, using change from baseline as the outcome measure and adjusting treatment effect for baseline score on the same subscale. A p-value of <0.01 will be deemed statistically significant to acknowledge that some adjustment be made for multiple testing
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Comparison groups |
Evaluable population - chemoablation v Evaluable population - surgery
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-4.5
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Confidence interval |
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level |
99% | ||||||||||||
sides |
2-sided
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lower limit |
-12 | ||||||||||||
upper limit |
3 | ||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From randomisation until 3 months after treatment
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Adverse event reporting additional description |
Treatment-emergent adverse events are reported; these are defined as an event not present prior to the initiation of trial treatment or an event already present that worsens at end of treatment or at 3 month follow-up.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
pre-specified+Meddra | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Safety population - chemoablation
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Reporting group description |
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Reporting group title |
Safety population - surgery
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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26 Jan 2016 |
Inclusion of 2004 WHO classification of low grade tumour for sites where grade is no longer reported using 1973 WHO classification.
Clarification of the time period over which patients’ prior recurrence rate should be calculated. This has been limited to five years where lengthy disease history is present to ensure that these patients’ most recent recurrence rate is used to calculate risk of further recurrence.
Clarification that patients with any history of non-TCC bladder cancer should be excluded.
Clarification that patients are excluded if the trial entry recurrence is within 11.5 months of the original diagnosed tumour. Trial entry tumours seen within this period would have an ineligible recurrence rate of >1 recurrence per year. 11.5 months (rather than 12) has been used as a cut off to account for variation in patients’ annual follow up visits.
Removal of exclusion criterion following Trial Management Group review. This criterion was deemed not relevant as the primary endpoint is local tumour response at three months post treatment.
Detail of the collection of additional translational samples within the CALIBER-T sub study following funding by Cancer Research UK. |
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03 Mar 2016 |
Change in eligibility criteria. The criteria was clarified to state that patients with a history of intermediate/high risk NMIBC features were excluded from CALIBER. |
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02 Nov 2016 |
Change in eligibility criteria.
The criteria was widened to include patients with a risk of recurrence score of 6 (previously 5).
Clarification that patients presenting with any stage of transitional cell carcinoma greater than Ta would be ineligible.
Patients are eligible with visually diagnosed recurrent low risk NMIBC at outpatient cystoscopy.
Clarification that any residual/recurrent tumour found at cystoscopy at 3 months post treatment may be treated by biopsy and cystodiathermy where clinically appropriate.
Clarification that complete response would be evaluated in relation to patients in the chemoresection treatment group.
Clarification that further investigation would be demonstrated if adequate activity was assessed in the chemoresection group. |
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23 Jun 2017 |
Change of trial design and accrual target.
In order to complete recruitment within a reasonable timeframe, whilst also providing an estimate of the control rate with chemoresection, revisions are proposed such that the power of the trial is reduced from 90% to 85% and the significance level increased from 5% to 10%. Stage 1 will complete as originally planned. If the stop/go activity criteria at the end of stage 1 indicate that recruitment should continue, the second stage will recruit 9 additional chemoresection patients. As the trial is non-comparative and patient acceptance of randomisation has been demonstrated during stage 1 (acceptance rate of 56% to March 2017 reported on screening) the surgical management control group will be dropped following completion of stage 1. The overall target sample size (including stage 1 controls and a 5% allowance for drop outs) will therefore be amended to 89 patients (from 174). |
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29 Sep 2017 |
Notification of closure to recruitment. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The trial was not powered for direct comparison of response rate between randomised groups. The population reflects a group of patients with intermediate, rather than low-risk NMIBC. There was relatively poor compliance with the biopsy at 3 months. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32124514 |
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