Clinical Trial Results:
An early phase trial of topical tropomyosin kinase (TRK) inhibitor as a treatment for inherited CYLD defective skin tumours
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Summary
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EudraCT number |
2014-001342-21 |
Trial protocol |
GB |
Global end of trial date |
19 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Aug 2018
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First version publication date |
22 Aug 2018
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Other versions |
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Summary report(s) |
TRAC Cohort 1 Summary attachment |
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 |
NCTUTRK1(6840)
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Additional study identifiers
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ISRCTN number |
ISRCTN75715723 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
The Newcastle upon Tyne Hospitals NHS Foundation Trust
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Sponsor organisation address |
Level 1, Regent Point, Regent Point Road, Newcastle upon Tyne, United Kingdom, NE3 3HD
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Public contact |
Neil Rajan, Newcastle University, 0191 2418813, neil.rajan@ncl.ac.uk
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Scientific contact |
Neil Rajan, Newcastle University, 0191 2418813, neil.rajan@ncl.ac.uk
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Sponsor organisation name |
The Newcastle upon Tyne Hospitals NHS Foundation Trust
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Sponsor organisation address |
Level 1 Regent Point, Regent Point Road, Newcastle upon Tyne, United Kingdom, NE3 3HD
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Public contact |
Dr Neil Rajan, Newcastle University, 0191 241 8813,
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Scientific contact |
Dr Neil Rajan, Newcastle University, 0191 241 8813, neil.rajan@newcastle.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 |
23 Nov 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Sep 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Sep 2016
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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 for Cohort 1 was to find out whether CT327 (an ointment with a drug called a TRK inhibitor in it) is a safe treatment for patients with CYLD defective tumours (lumps). The results for Cohort 1 are in the summary attachment.
The principal research objective for Cohort 2 was to investigate whether CYLD defective tumours (lumps) respond to CT327.
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Protection of trial subjects |
The trial involved an independent data monitoring committee to provide overall supervision for the trial on behalf of the Trial Sponsor and Trial Funder and to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
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Background therapy |
No Background therapy used by all subjects. | ||
Evidence for comparator |
There are no known effective medical alternatives to treat this condition. | ||
Actual start date of recruitment |
09 Mar 2015
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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: 15
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Worldwide total number of subjects |
15
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EEA total number of subjects |
15
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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) |
11
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
CYLD mutation carrier patients known to the clinical genetics and dermatology department in Newcastle will be reviewed by the clinical team to verify that they meet the trial inclusion criteria. Patients were either approached during a routine outpatient appointment or written to and invited to attend a clinical appointment to discuss the trial. | ||||||||||
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Pre-assignment
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Screening details |
Inclusion criteria was checked and patients were assessed to ensure they had an appropriate tumour scheduled for routine excision, which was not ulcerated. Once written informed consent was obtained patients would undergo the trial specific screening which was a urine based pregnancy test for Female patients of child bearing age. | ||||||||||
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Period 1
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Period 1 title |
Cohort 2 (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||
Roles blinded |
Subject, Investigator, Monitor, Assessor | ||||||||||
Blinding implementation details |
Randomisation was at the per patient level randomising active and placebo treatments to left or right sided application. Patients and investigators were blinded to the treatment allocation. Those responsible for tumour volume measurements, histology assessments and molecular analysis were also blinded. Participants randomised to arm A received active treatment on the 5 tumours on the left hand side of the body whereas participants randomised to Arm B received active treatment on the right side.
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Arms
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Arm title
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Cohort 2: Arm A and Arm B | ||||||||||
Arm description |
In cohort 2, active and placebo trial medication was provided at baseline and visit 4 to supply enough ointment for the 12 week period. Active medication contained CT327 at 0.5%w/w. Each participant pack of active medication or placebo was presented as a 20g glass jar. Tumours on one half of the body with active CT327 and the other half of the body with placebo according to the randomisation allocation for a 12 week period. Participants randomised to arm A received active treatment on the 5 tumours located on the left hand side. The 5 tumours on the right hand side received placebo treatment. Participants randomised to Arm B received active treatment on the 5 tumours located on the right hand side of the body. The 5 tumours on the left hand side received placebo treatment. The Investigator, study team and trial management team were blinded to which side the participants received active treatment vs placebo treatment. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Pegcantratinib 0.5% w/v
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Investigational medicinal product code |
CT327 (0.5%w/v)
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Other name |
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Pharmaceutical forms |
Ointment
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Routes of administration |
Epicutaneous use
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Dosage and administration details |
Patients were allocated both active and placebo treatments to be applied randomly to tumours on their left or right side (Group1: L=active; R=placebo, Group 2: L=placebo; R=active). In cohort 2 active and placebo trial medication were provided at baseline and visit 4 to supply enough ointment for the 12 week period. Active medication contained CT327 at 0.5%w/w. Each participant pack of active medication or placebo was presented as a 20g glass jar. The dose consisted of one application (1 standardised spatula) in the evening to each tumour as directed at the first visit by the research nurse/doctor. Patients recorded the application of treatment in a patient diary. All participants were treating tumours on one half of the body with active CT327 and the other half of the body with placebo according to the randomisation allocation for a 12 week period.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 2
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Reporting group description |
The trial is split into two phases namely a phase 1b (cohort 1) which aims to determine the safety profile of CT327, and a phase 2a (cohort 2) that will investigate if CYLD defective tumours respond to CT327. Cohort 2 is a Phase 2a is a randomised double blind single site trial where the primary objective is to establish if CYLD defective tumours respond to CT327. The primary outcome will be the proportion of tumours responding to treatment by 12 weeks in both actively treated lesions and placebo treated lesions. Secondary outcome measures will be change in tumour volume, adverse events, compliance, confirmation of the definition of response, patient reported quality of life according to EQ5D and DLQI, acceptability of treatment and a trial specific pain measure. To achieve the 150 tumours required 15 were recruited into Phase 2a. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 2: Arm A and Arm B
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Reporting group description |
In cohort 2, active and placebo trial medication was provided at baseline and visit 4 to supply enough ointment for the 12 week period. Active medication contained CT327 at 0.5%w/w. Each participant pack of active medication or placebo was presented as a 20g glass jar. Tumours on one half of the body with active CT327 and the other half of the body with placebo according to the randomisation allocation for a 12 week period. Participants randomised to arm A received active treatment on the 5 tumours located on the left hand side. The 5 tumours on the right hand side received placebo treatment. Participants randomised to Arm B received active treatment on the 5 tumours located on the right hand side of the body. The 5 tumours on the left hand side received placebo treatment. The Investigator, study team and trial management team were blinded to which side the participants received active treatment vs placebo treatment. | ||
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End point title |
Proportion of tumours responding to treatment [1] | ||||||||||||||||||||||||
End point description |
Cohort 2- Participants randomised to Arm A receiving active treatment on the 5 tumours located on the left hand side of the body. The 5 tumours on the right hand side of the body received placebo treatment.
Please note the number reported in the endpoint table below is a percentage value.
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End point type |
Primary
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End point timeframe |
12 weeks
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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: No additional statistical analysis performed |
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Attachments |
Table 1-4 Tumour size at baseline Table 6 Tumour response according to WHO RECIST |
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| Notes [2] - 10 tumours from each participant were used for this trial. Therefore 140 tumours from 14 patients. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Sensitivity analysis of response [3] | ||||||||||||||||||||||||
End point description |
The primary analysis has been repeated without the inclusion of 1007, who was found to have applied treatment ointment to the wrong tumours.
Please note the number reported in the endpoint table below is a percentage value.
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End point type |
Primary
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End point timeframe |
Tumour response at 12 weeks
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| Notes [3] - 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: No additional statistical analysis performed |
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Attachments |
Table 7 WHO RECIST excluding 1007 Table 13 Sensitivity analysis of response endpoint |
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| Notes [4] - 130 tumours from 13 participants were analysed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Tumour-level change [5] | ||||||||||||||
End point description |
Tumour measurements have been reported descriptively as mean (standard deviation), median and IQR at baseline, 4 weeks and 12 weeks by treatment received and overall.
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End point type |
Primary
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End point timeframe |
Tumour level change from baseline to 12 week tumour measurement.
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| Notes [5] - 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: No additional statistical analysis performed |
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Attachments |
Table 5 Tumour level change endpoint |
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| Notes [6] - 140 tumours were measured from 14 participants. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Assessment of acceptability of trial treatment | ||||||||||||||||||||||||||||||||||
End point description |
Patients completed questions 1-5 of the patient treatment questionnaire. This was used to determine the acceptability of the treatment. The questionnaire was completed at the final visit, at the end of treatment by 14 participants.
The Patient Treatment Questionnaire has been analysed descriptively reporting the number of patients answering each response level in each question. Question 5 is reported as the percentage of patients who were able to correctly identify which side had been allocated the treatment ointment. Comments left in the text box are listed.
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End point type |
Secondary
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End point timeframe |
End of treatment (EOT) visit
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Attachments |
Table 8 & 9 Treatment questionnaire and compliance |
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| Notes [7] - 14 participants answered 5 questions using the patient treatment questionnaire. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
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End point title |
Patient reported Quality of Life - EQ-5D-5L | ||||||||||||||
End point description |
EQ-5D-3L was collected at the baseline visit. The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no Descriptive problems, some problems, extreme problems. A variable is derived to describe the unique health of each participant this state is defined by combining 1 level from each of the 5 dimensions. Detailed descriptions regarding calculation of scores can be found in the user guide found at http://www.euroqol.org.
Health states determined by the EQ-5D are reported as numbers of patients responding to each dimension.
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End point type |
Secondary
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End point timeframe |
EQ-5D-3L was collected at the baseline visit.
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Attachments |
Table 10 EQ-5D-5L at baseline visit |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Patient reported quality of life - DLQI | ||||||||||||||||
End point description |
The Dermatology Life Quality Index (DLQI) questionnaire is designed for use in adults, i.e. patients over the age of 16 and is a patient reported questionnaire. It is collected at the baseline visit. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The DLQI can also be expressed as a percentage of the maximum possible score of 30. Detailed description of the calculation of the DLQI can be found in the instructions for use on the Cardiff University website. http://www.cardiff.ac.uk/dermatology/quality-of-life.
To obtain a total DLQI score the responses are scored as follows with a total score being a maximum of 30:
Very much scored 3
A lot scored 2
A little scored 1
Not at all scored 0
Not relevant scored 0
Question unanswered scored 0
Question 7: “prevented work or studying” scored 3
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End point type |
Secondary
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End point timeframe |
Dermatology Life Quality Index (DLQI) was completed at the baseline visit.
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Attachments |
Table 11 & 12 DLQI scores |
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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 |
In cohort 2 adverse events were reported for 16 weeks. AE Reporting commenced from the start date participant received CT327 and placebo treatment at baseline to 4 weeks after end of treatment.
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Adverse event reporting additional description |
14 adverse events were reported in 8 participants, all were reported as mild.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
verbatim | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Cohort 2
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Reporting group description |
Adverse events were recorded by clinical staff on a three-point scale of severity (mild, moderate or severe) and also by causality (relationship to treatment as categorised on a six point scale), as described in the protocol. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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18 Dec 2014 |
Removal of kit number, subject number and randomisation number from IMP label. |
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24 Jun 2015 |
Addition of a pain assessment at week 0, 4 and 12. |
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24 Mar 2016 |
Updates to the reference safety information (RSI) in the investigator brochure and protocol. |
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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. | |||
| None reported | |||
