Clinical Trial Results:
A Phase II Trial of Vinflunine chemotherapy in locally advanced and metastatic carcinoma of the penis
Summary
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EudraCT number |
2012-002592-34 |
Trial protocol |
GB |
Global end of trial date |
06 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Nov 2019
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First version publication date |
27 Nov 2019
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Other versions |
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/2012/10036
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02057913 | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
Sponsor Identification Number: CCR3858, ICRCTSU protocol number: ICR-CTSU/2012/10036, CRUK reference number: CRUK/12/021, Main REC reference: 13/LO/0822, MHRA CTA number: 2213810018/001{001 | ||
Sponsors
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Sponsor organisation name |
The 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 |
Stephanie Burnett, The Institute of Cancer Research, +44 02087224261, vincap-icrctsu@icr.ac.uk
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Scientific contact |
Stephanie Burnett, The Institute of Cancer Research, +44 02087224261, vincap-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 |
01 Nov 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Nov 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Nov 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The principal research objective of the VinCaP study is to determine the clinical benefit (complete response + partial response + stable disease) and toxicity of vinflunine chemotherapy in patients with inoperable (locally advanced or metastatic) cancer of the penis and thus determine whether this regimen warrants further research.
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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.
Laxatives and dietary measures (including oral hydration) were recommended from day 1 to day 5 or 7 after each vinflunine administration in order to prevent constipation. Anti-emetics were given according to local hospital policy.
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 |
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Evidence for comparator |
Platinum-based combination chemotherapy has been in common use for the treatment of squamous carcinoma of the penis since 1990. Phase II trials of cisplatin-based regimens have reported response rates around 30% (Di Lorenzo et al, 2012), and it is not clear that there is any survival benefit accruing to such treatment. This suggests that complex chemotherapy may be justified in the neoadjuvant setting, but the relatively low response rates and high toxicity rates mean that such an approach has substantially less value for patients with metastatic disease. Vinca alkaloids have been a component of treatment regimens for penis cancer since the mid-1970s, even though evidence for single-agent activity is lacking (Williams et al, 1974). Vinflunine is a third-generation vinca alkaloid approved by the European Medicines Agency for use as a second-line treatment in patients with urothelial carcinoma resistant to first-line platinum-containing chemotherapy (EMA; Pizzocaro et al, 2010). Doses of older vinca alkaloids such as vincristine are limited by sensory neuropathy and constipation. Vinflunine has been shown to be tolerable in this regard. It is anticipated that single-agent use of vinflunine in penis cancer will be associated with a favourable toxicity profile combined with the potential to produce meaningful clinical response. | ||
Actual start date of recruitment |
25 Jun 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: 25
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Worldwide total number of subjects |
25
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EEA total number of subjects |
25
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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) |
9
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From 65 to 84 years |
16
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85 years and over |
0
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Recruitment
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Recruitment details |
Twenty-five patients were recruited from eight UK centres between June 2014 and May 2017. | ||||||||||||||||
Pre-assignment
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Screening details |
Patients that met the eligibility criteria were recruited into the study. | ||||||||||||||||
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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||
Arms
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Arm title
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Vinflunine Chemotherapy | ||||||||||||||||
Arm description |
The Vinflunine chemotherapy regimen consists of vinflunine 320mg/m2 day 1 with a cycle of 21 days, four cycles to be given in total. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Vinflunine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
IV vinflunine 320mg/m2 day 1 with a cycle of 21 days, four cycles to be given prior to formal re-staging. Patients judged to have stable disease, partial remission or complete remission and who are fit to do so will then be able to continue on treatment until disease progression or until toxicity supervenes or until treatment is discontinued on clinician’s advice or on patient preference.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention to treat population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This population includes all patients enrolled into the study regardless of whether they are later found to be ineligible, a protocol violator, never treated or evaluated. Patients for whom the primary endpoint cannot be evaluated will be treated as non-responders.
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Subject analysis set title |
Evaluable population
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This population contains all enrolled patients for whom the primary endpoint can be evaluated. A patient is considered not evaluable if:
1. The patient received <1 cycle of study vinflunine chemotherapy for one of the following reasons:
Death from any cause
Withdrawal from trial due to progressive disease
Withdrawal from trial for a reason unrelated to drug or disease(e.g. patient preference, administrative reasons), regardless of the number of cycles of chemotherapy.
Or
2. Disease cannot be measured at the end of study treatment for one of the following reasons:
Death from causes other than penile cancer
Withdrawal from trial for a reason unrelated to drug or disease(e.g. patient preference, administrative reasons), regardless of the number of cycles of chemotherapy
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Subject analysis set title |
Measureable population
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients who had a scan at 12 weeks or discontinued prior to 12 weeks due to progression. Patients who discontinued prior to 12 weeks for non-disease related reasons were excluded from this analysis.
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End points reporting groups
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Reporting group title |
Vinflunine Chemotherapy
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Reporting group description |
The Vinflunine chemotherapy regimen consists of vinflunine 320mg/m2 day 1 with a cycle of 21 days, four cycles to be given in total. | ||
Subject analysis set title |
Intention to treat population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This population includes all patients enrolled into the study regardless of whether they are later found to be ineligible, a protocol violator, never treated or evaluated. Patients for whom the primary endpoint cannot be evaluated will be treated as non-responders.
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Subject analysis set title |
Evaluable population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
This population contains all enrolled patients for whom the primary endpoint can be evaluated. A patient is considered not evaluable if:
1. The patient received <1 cycle of study vinflunine chemotherapy for one of the following reasons:
Death from any cause
Withdrawal from trial due to progressive disease
Withdrawal from trial for a reason unrelated to drug or disease(e.g. patient preference, administrative reasons), regardless of the number of cycles of chemotherapy.
Or
2. Disease cannot be measured at the end of study treatment for one of the following reasons:
Death from causes other than penile cancer
Withdrawal from trial for a reason unrelated to drug or disease(e.g. patient preference, administrative reasons), regardless of the number of cycles of chemotherapy
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Subject analysis set title |
Measureable population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Patients who had a scan at 12 weeks or discontinued prior to 12 weeks due to progression. Patients who discontinued prior to 12 weeks for non-disease related reasons were excluded from this analysis.
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End point title |
Clinical Benefit [1] | |||||||||||||||
End point description |
The clinical benefit rate is defined as the proportion of patients having achieved partial remission, complete remission or stable disease according to RECIST criteria (v1.1) on imaging and/ or bi-dimensional clinical measurements (of skin disease) performed after 4 cycles (approximately 11-12 weeks from Day 1 of first cycle).
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End point type |
Primary
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End point timeframe |
4 weeks from the date of commencement of the final cycle of chemotherapy
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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: This is a single arm study and no comparative analysis was performed, however the system expects at least 2 groups to be identified. All methods and options specified in the analysis section apply to statistical methods and summary measures to report and compare at least 2 independent groups, which is not the case in this single arm trial. There is no way of reporting one group inference and summary values without triggering an error or reporting inaccurate information. |
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No statistical analyses for this end point |
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End point title |
Objective response rate | ||||||||||||||||||||
End point description |
Defined as the proportion of patients having achieved partial or complete remission.
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End point type |
Secondary
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End point timeframe |
4 weeks from the date of commencement of the final cycle of chemotherapy
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No statistical analyses for this end point |
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End point title |
Progression-free survival | ||||||||||||
End point description |
Defined as time from registration until the first of clinically or radiologically documented disease progression, or death from any cause death. Kaplan-Meier curves will be drawn and estimates of median progression-free survival estimates with their 95% CI will be presented along with the proportion of patients, alive and progression free, at 6 and 12 months respectively.
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End point type |
Secondary
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End point timeframe |
Progression free survival at 12 months
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No statistical analyses for this end point |
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End point title |
Overall survival | ||||||||||||
End point description |
Kaplan-Meier curves will be drawn and estimates of median overall survival estimates with their 95% CI will be presented along with the proportion of patients alive, at 6 and 12 months respectively.
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End point type |
Secondary
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End point timeframe |
Overall survival will be defined as the time from registration until death from any cause. Patients alive at time of analysis will be censored at date last seen. Patients lost to follow-up will be censored at date last seen.
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No statistical analyses for this end point |
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End point title |
Treatment compliance | ||||||||||||||||||||||||||||||||||||
End point description |
An investigation of treatment compliance of the study treatment will involve a summary of the frequency of dose reductions and delays together with their reasons. The proportion of planned doses delivered will be summarised with a 95% CI.
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End point type |
Secondary
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End point timeframe |
Treatment duration
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From trial entry to 30 days after last dose of trial treatment
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Adverse event reporting additional description |
AE data for patients who received at least 1 dose of experimental treatment.
In the non-serious adverse events section we report all serious and non-serious adverse events reported with grade 3 or 4 according to the CTCAE grading, that were present in more than 5% of patients.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14
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Reporting groups
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Reporting group title |
Safety population
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Reporting group description |
Patients who received at least 1 dose of experimental treatment. In the non-serious adverse events section we report all adverse events reported at any grade according to the CTCAE grading, that were present in more than 5% of patients. Worst grade per patient is included for each event. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Nov 2013 |
Removal of toxicity, bowel toxicity and adverse event monitoring assessments at the primary endpoint visit as this was a duplicated assessment (already performed at cycle 4 toxicity).
• Change to liver function criteria. Added to inclusion criteria, removed from exclusion criteria.
Liver function: Patients must have (with or without the presence of liver metastases):
o A prothrombin time >70% NV (normal value) AND
o Bilirubin <1.5xULN AND
o Transaminases <2.5xULN AND
o GGT <5xULN
• Changes to Primary Endpoint Assessment visit.
o Adverse events and toxicity assessment removed
o Bowel toxicity monitoring removed.
• Clarification that patients who father a child during the course of treatment must be reported as a SAE. SAEs are defined as events that occur after the commencement of study treatment and up to 30 days following the last dose of study drug.
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04 Mar 2015 |
Inclusion criteria revised to ensure that patients have GFR ≥ 60ml/min. GFR to be assessed according to local practice (recommended technique of eGFR using the MDRD formula (see Appendix 2). Where GFR is 55-60ml/min please contact the trials unit for a decision to be made on patient inclusion by the Chief Investigator OR Clinical Co-ordinator. The Trial Management Group (TMG) reviewed discussed the inclusion criteria that GFR should be ≥60ml/min. The TMG and Trial Steering Committee agreed to amend the inclusion criterion to consider patients for the trial with GFR 55-60ml/min as long as all other eligibility criteria are met. The decision to include such a patient must be discussed with the Chief Investigator and/or the Clinical Coordinator.
Previous safety concerns raised by Pierre Fabre (drug company for Vinflunine), about inclusion of patients with a lower GFR, in relation to renal function, originate from use of Vinflunine in bladder cancer patients where disturbance of renal function would be expected; the TMG and TSC agreed that this safety concern is not applicable to this patient group. This amendment was also supported by the pharmaceutical company, Pierre-Fabre.
Added requirement to forward SAEs and SARs to the pharmaceutical company, Pierre-Fabre.
Change to ICR professional address in affiliations for all ICR staff: Sutton, Surrey to London to comply with new institutional guidance. |
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25 Jun 2015 |
Change to the liver function criteria in line with the SmPC. Liver function parameters updated to allow patients on trial with transaminases <5xULN only in the presence of liver metastases. This accurately reflects the parameters outlined in the summary of product characteristics (SmPC). The trial management group discussed and agreed to this update on the basis that the protocol should fall in line with the SmPC recommendations for patients with hepatic impairment:
Liver function: Patients must have (with or without the presence of liver metastases):
o A prothrombin time >70% NV (normal value) AND
o Bilirubin <1.5xULN AND
o Transaminases <2.5xULN (<5xULN only in the case of liver metastases) AND
o GGT <5xULN
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04 May 2016 |
• Change to the liver function criteria - Specifying AST and/or ALT to be consistent with the wording in section 8.3 of the protocol
• Changes to the exclusion criteria:
o Patients who are sexually active and unwilling to use effective contraception (if they are not already surgically sterile). New exclusion criterion linked with new section – lifestyle guidelines: Update to the protocol to provide a definition of effective contraception.
o Other malignancy (other than Squamous Cell Carcinoma or Basal Cell Carcinoma of non-penile skin) that has required surgical or non-surgical treatment in the last 2 years. Change from 5 to 2 years. The 5 year window was an arbitrary timeframe and two years was felt to be a more reasonable period
• If a patient’s performance status deteriorates to PS2, the decision to continue to treat the patient should be made by the local treating clinician. Where possible, discussion with the either the Chief Investigator or Clinical Co-ordinator is encouraged before the next cycle of vinflunine is administered.
• Drug Dose Reduction Schedule - If any of the criteria for a dose reduction or delay are met, for example a grade 3 toxicity (considered severe or life threatening), but in the opinion of the treating clinician the event does not indicate a need to dose reduce at the expense of the patient deriving benefit from vinflunine, the case should be discussed with either the Chief Investigator or Clinical Co-ordinator prior to the start of the next cycle of treatment.
• correction that IDMC, not TMG are responsible for reviewing evaluability of patients. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
None reported |