Clinical Trial Results:
A phase II, open label, preoperative study to assess the efficacy of the novel steroid sulfatase inhibitor Irosustat in postmenopausal women with early oestrogen receptor positive breast cancer.
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Summary
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EudraCT number |
2011-005240-10 |
Trial protocol |
GB |
Global end of trial date |
26 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Mar 2016
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First version publication date |
23 Mar 2016
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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 |
C/24/2011
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01662726 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Ipsen Study Protocol Number: X-52-58064-011 | ||
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Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
Room 215 Level 2, Medical School Building Norfolk Place, London, United Kingdom, W2 1PG
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Public contact |
Professor Carlo Palmieri , University of Liverpool , 0044 151 706 3616, C.Palmieri@liverpool.ac.uk
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Scientific contact |
Professor Carlo Palmieri , University of Liverpool , 0044 151 706 3616, C.Palmieri@liverpool.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 |
28 Jan 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Nov 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Nov 2014
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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 |
This study will use 3’-deoxy-3’-[18F]Fluorothymidine Positron Emission Tomography (FLT-PET) to assess the ability of a novel endocrine treatment for breast cancer, Irosustat, to slow down cancer cell growth.
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Protection of trial subjects |
At protocol conception three main areas of risk were identified as requiring specific inclusion/exclusion criteria and/or monitoring throughout the study:
1. Known adverse events: Muscoskeletal side effects, renal toxicity and cardiac toxicity were identified from previous studies as requiring specific inclusion/exclusion criteria and monitoring throughout the study. These were addressed in the study protocol, and patients were fully-informed of the known adverse events associated with Irosustat.
2. Possible drug interactions: Advice was provided in the protocol as potential for Irosustat to induce drug-drug interactions through inhibition or induction of CYP450 isoenzymes. The protocol included details of medications that were not permitted whilst on study treatment, and medications for which caution and additional monitoring should be applied if administered in conjunction with Irosustat.
3. Radiation Exposure: The total amount of radiation received in this study was equivalent to the total amount of natural background radioactivity that one would have received over the past seven and a half years by being resident in the UK. These exposures are considered very unlikely to put the patients’ health at risk.
An independent, combined Trial Steering Committee/Data Monitoring Committee was convened to oversee the trial.
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Background therapy |
There were no protocol-specified background therapies. Concomitant medications could be prescribed at the treating physicians discretion, with the exception of prohibited medications described in the study protocol. Concomitant medications (and the reason for the medication) were recorded in the study database from consent until the patient's last study visit. | ||
Evidence for comparator |
Not applicable - this was a single arm study. | ||
Actual start date of recruitment |
07 Nov 2012
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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: 10
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Worldwide total number of subjects |
10
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EEA total number of subjects |
10
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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) |
5
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Three UK sites were opened to recruitment, three of these enrolled patients to the study. The first site opened to recruitment on 14/08/2012 and the first patient consent was on 07/11/2012. The study terminated on 26/11/12, after 13 patients had been enrolled. | ||||||||||
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Pre-assignment
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Screening details |
15 patients were consented to the trial. 2 were found to be ineligible and 13 were enrolled into the trial. Of these 13, three did not start trial intervention ( 2 FLT PET scan failure; 1 Adverse Event) | ||||||||||
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Pre-assignment period milestones
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Number of subjects started |
15 [1] | ||||||||||
Intermediate milestone: Number of subjects |
Confirmed Eligibilty: 13
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Number of subjects completed |
10 | ||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
FLT PET Scan Failure: 2 | ||||||||||
Reason: Number of subjects |
Adverse event, non-fatal: 1 | ||||||||||
Reason: Number of subjects |
Ineligible: 2 | ||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 15 were consented and screened for the study. 2 patients were found to be ineligible during screening and 1 patient suffered an AE during screening and was withdrawn. |
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not Applicable
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Arms
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Arm title
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Interventional Arm | ||||||||||
Arm description |
- | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Irosustat
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
40mg once daily.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
As per the Statistical Analysis Plan, only patients who received at least one dose of study drug are included in the analysis. Patients who were enrolled on the study, but did not start study treatment (N=3; withdrawal (1), day 1 scan failure (2)) are not included. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention to treat – evaluable for safety
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Intention to treat – evaluable for safety
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Subject analysis set title |
Per protocol analysis – evaluable for safety & efficacy
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Per protocol analysis – evaluable for safety & efficacy
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End points reporting groups
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Reporting group title |
Interventional Arm
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Reporting group description |
- | ||
Subject analysis set title |
Intention to treat – evaluable for safety
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Intention to treat – evaluable for safety
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Subject analysis set title |
Per protocol analysis – evaluable for safety & efficacy
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per protocol analysis – evaluable for safety & efficacy
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End point title |
Changes in FLT uptake - SUV [1] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Changes in FLT uptake between Day 1 and Day 14 FLT-PET scan
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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 study is a one arm design. Therefore the statistical analysis does not have more than one comparison arm. The EudraCT system would not allow statistical analysis details to be completed without defining a second comparison arm, however, this does not exist for this data set. Therefore we are unable to add statistical analysis details due to operational errors with the database. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Changes in FLT uptake - SUVmax [2] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Changes in FLT uptake between Day 1 and Day 14 FLT-PET scan
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| Notes [2] - 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 study is a one arm design. Therefore the statistical analysis does not have more than one comparison arm. The EudraCT system would not allow statistical analysis details to be completed without defining a second comparison arm, however, this does not exist for this data set. Therefore we are unable to add statistical analysis details due to operational errors with the database. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Changes in FLT uptake - Ki [3] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Changes in FLT uptake between Day 1 and Day 14 FLT-PET scan
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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: This study is a one arm design. Therefore the statistical analysis does not have more than one comparison arm. The EudraCT system would not allow statistical analysis details to be completed without defining a second comparison arm, however, this does not exist for this data set. Therefore we are unable to add statistical analysis details due to operational errors with the database. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Circulating Steroid Hormone Levels - Oestradiol | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: Oestradiol Chart.pdf) |
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| Notes [4] - Results for Safety Follow-up only include 5 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels - Oestrone | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: Oesterone.pdf) |
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| Notes [5] - Results for Safety Follow-up only include 5 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels - Oestrone Sulphate | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow
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Attachments |
Untitled (Filename: Oesterone Sulphate.pdf) |
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| Notes [6] - Results for Day 7 only include 7 patients. Results for Safety Follow-up only include 5 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels – Dehydroepiandrosterone (DHEAS) | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow
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Attachments |
Untitled (Filename: DHEAS.pdf) |
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| Notes [7] - Results for Day 7, Day 14 and Safety Follow-up only include 5 patients. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels – Dehydroepiandrosterone (DHEA) | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: DHEA.pdf) |
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| Notes [8] - Results for Day 1 only include 7 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels - Testosterone | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: Testosterone.pdf) |
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| Notes [9] - Results from Day 14 only include 3 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels - Oesterone Sulphate / Oestrone ratio | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat.
Ratio of Oesterone Sulphate / Oestrone results.
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: Oesterone Sulphate to Oesterone Ratio.pdf) |
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| Notes [10] - Results for Safety Follow Up only include 5 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels - DHEAS / DHEA Ratio | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat.
Ratio of the DHEAS / DHEA results.
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: DHEAS to DHEA Ratio.pdf) |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Circulating Steroid Hormone Levels – Androstenedione | ||||||||||||||||
End point description |
To assess the pharmacodynamic profile of Irusostat
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End point type |
Secondary
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End point timeframe |
Samples were collected at Day 1, Day 7, Day 14 and Safety Follow-up
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Attachments |
Untitled (Filename: Androstenedione.pdf) |
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| Notes [11] - Results for Day 1 only include 7 patients Results for Safety Follow-up only include 5 patients |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Changes in Ki67 proliferation marker | ||||||||
End point description |
To assess the effect of Irosustat on breast tumour proliferation.
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End point type |
Other pre-specified
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End point timeframe |
Ki67 was measured pre-treatment from patients diagnostic biopsies and post treatment from patients surgical samples.
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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 |
Adverse Events were collected from the time a patient signed informed consent until the end of follow-up. AEs were followed-up according to local practice until the event has stabilised or resolved, or until the last follow-up visit, whichever was sooner
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Adverse event reporting additional description |
AEs were reviewed at every patient visit.
Disease progression was not classed as an AE.
AEs we assessed for severity (NCI CTCAE v4.03) and causality by the local PI; the CI provided an assessment for SAEs. All AEs were recorded in the study EDC system.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
Intention to Treat
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Reporting group description |
All patients who had at least one dose of IMP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Nov 2012 |
• End of trial definition amended to last patient, last data capture to bring it in line with latest guidance by the NRES.
• Eligibility criteria: Decreased tumour size from ≥20mm to 15≥mm by either mammography, ultrasound examination or magnetic resonance imaging. This is the minimum tumour size that can be captured by a PET Scan for the purposes of this study.
• Safety follow up visit amended to take place 7 days after the last administration of Irosustat instead of 30 days ( in line with the half-life of Irosustat).
• Updated SAE reporting process
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05 Nov 2013 |
• Removal of STS analysis: As a result of a reduction in funding funds are no longer available to carry out STS Analysis.
• Increase to blood sample volume collected during PET Scans: The total amount of venous blood taken during each FLT-PET scan and analysed for the relative contribution of FLT and its metabolite FLT-glucuronide was amended to include the amount of blood taken, but discarded, after the line has been flushed.
• The screening period for all assessments was changed from 21 to 35 days to allow patients whose pathology results are delayed to be included in the study.
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14 Jul 2014 |
• Duration of collection of AEs: Protocol amended so that any unresolved AEs at the time of the safety follow up visit that are considered to be related to the IMP can be followed up and recorded in the database until resolution or until termination of the study. Any new AEs that occur after the safety follow up visit and that are considered to be related to the IMP should also be recorded in the database and followed up until resolution or the termination of the study.
• Removal of requirement to fast prior to scan
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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. | |||
| Defining response as decreases of ≥20% in SUV and ≥30% in Ki, we observed responses in 1 (12.5% (95%CI 2-47%, p=0.001)) and 3 (43% (95%CI 16-75%, p=<0.001) patients respectively. | |||
