Clinical Trial Results:
Phase II trial of Linsitinib (anti-IGF-1R/IR) in patients with relapsed and/or refractory Ewing Sarcoma
Summary
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EudraCT number |
2012-000616-28 |
Trial protocol |
GB IT NL |
Global end of trial date |
03 Oct 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jun 2017
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First version publication date |
28 Jun 2017
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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 |
OCTO_038
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02546544 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Oxford
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Sponsor organisation address |
Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
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Public contact |
Joint Research Office, University of Oxford, ctrg@admin.ox.ac.uk
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Scientific contact |
Joint Research Office, University of Oxford, ctrg@admin.ox.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 |
06 Dec 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
15 Jul 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Oct 2016
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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 |
To determine the effect of the trial drug (linsitinib) on the patient’s tumours in terms of changes in biomarker and PET scans.
To establish the safety of the trial drug (linsitinib) in Ewing sarcoma at the dose and treatment schedule being used in the trial.
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Protection of trial subjects |
The trial was reviewed and approved by an appropriately constituted, independent Research Ethics Committee (REC) or equivalent for the non-UK countries (IRB etc.). Approval to conduct the study was obtained from the relevant Competent Authority in each participating country prior to initiating the study. In the UK the study was conducted under a Medicines and Healthcare products Regulatory Agency (MHRA) Clinical Trial Authorisation (CTA). The sponsor and investigators ensured that the trial was run in compliance with the European Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP) and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product under the European Union Clinical Trials Directive.
The trial design formally built in early stopping rules for treatment futility and/or toxicity to reduce the number of patients receiving an ineffective and/or toxic treatment.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Apr 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: 8
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Germany: 2
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Worldwide total number of subjects |
16
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EEA total number of subjects |
16
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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) |
16
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited from April 2014 until March 2016 at specialist cancer hospitals across Europe | ||||||||||||||||
Pre-assignment
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Screening details |
29 patients were assessed for eligibility. 13 patients were excluded: seven did not meet the inclusion criteria, five declined to participate and one passed away prior to starting screening. | ||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
Arms
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Arm title
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Linsitinib | ||||||||||||||||
Arm description |
Linsitinib | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Linsitinib
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Investigational medicinal product code |
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Other name |
ASP7487, OSI-906
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg.
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Baseline characteristics reporting groups
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Reporting group title |
Linsitinib
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Reporting group description |
Linsitinib | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Linsitinib
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Reporting group description |
Linsitinib |
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End point title |
To determine the pharmacodynamic effect of Linsitinib in the tumour (FDG uptake (SUV) responses in ES tumours using functional imaging 18FDG-PET-CT) evaluated using PERCIST. [1] | |||||||||
End point description |
Pharmacodynamic FDG uptake (SUV) responses in ES tumours using functional imaging 18FDG-PET-CT and repeat post treatment biopsies to establish biomarker responses in tumour biopsies. Response measured by PERCIST using SULpeak.
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End point type |
Primary
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End point timeframe |
Pre- and Post- dose responses following 1 cycle (21 days) of 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: This is a co primary endpoint. The proportion of patients with a partial or complete metabolic response according to PERCIST was used. The analysis was done using a Bayesian model. 1/16 patients satisfied this endpoint and thus the treatment was deemed to be ineffective according to the model. |
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No statistical analyses for this end point |
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End point title |
To evaluate the safety of Linsitinib [2] | ||||||||||
End point description |
A patient is defined as having a toxic event if they experienced at least one grade 3 adverse event (CTCAE v4.0 grade)
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End point type |
Primary
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End point timeframe |
Following 6 cycles of treatment (up to 6 months)
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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 is a co primary endpoint. The proportion of patients with at least one adverse event of grade 3 or higher was used. The analysis was done using a Bayesian model. 5/16 patients satisfied this endpoint and thus the treatment was deemed to have a greater than acceptable toxicity level according to the model. |
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No statistical analyses for this end point |
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End point title |
Clinical outcome (PFS) | ||||||||
End point description |
To determine the clinical outcome through assessment of
- Progression free survival; where length of survival is defined in whole days as the time from entry into the study until Ewing sarcoma progression or death from any cause.
Note that the upper end the of confidence interval was undefined.
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End point type |
Secondary
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End point timeframe |
Duration of study (up to 18 months)
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No statistical analyses for this end point |
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End point title |
Radiological Response as Measured by EORTC 1.0 | |||||||
End point description |
Radiological Response as Measured by EORTC 1.0. This methodology used SUVmax to measure change in glucose uptake in the tumour. Evaluated on site reported data.
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End point type |
Secondary
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End point timeframe |
Measured cycle 1 day 15
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No statistical analyses for this end point |
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End point title |
Clinical outcome (DSS) | ||||||||
End point description |
To determine the clinical outcome through assessment of
- Disease specific survival; where length of survival is defined in whole days as the time from entry into the study until death from Ewing sarcoma.
Note that the upper end the of confidence interval was undefined.
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End point type |
Secondary
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End point timeframe |
Duration of study (up to 18 months)
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No statistical analyses for this end point |
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End point title |
Radiological response measured by RECIST | ||||||||||||
End point description |
Radiological response measured using RECIST version 1.1
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End point type |
Secondary
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End point timeframe |
cycle 1 day 15
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Screening
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 1 Day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 1 day 15
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 1 day 17
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 2 day 3
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 3 day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 3 day 3
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
Cycle 4 day 1
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib) | ||||||||
End point description |
Plasma concentrations of linsitinib
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End point type |
Secondary
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End point timeframe |
End of treatment visit
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No statistical analyses for this end point |
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End point title |
Radiological response measured by RECIST | ||||||||||||
End point description |
Radiological response measured using RECIST version 1.1
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End point type |
Secondary
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End point timeframe |
Cycle 3 day 3
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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 baseline until 28 days post treatment.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Linsitinib
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Reporting group description |
Linsitinib | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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09 Feb 2014 |
Changes to the protocol and PIS to reflect updated information in the Investigator Brochure for Linsitinib. |
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24 Sep 2014 |
Amendments to the protocol schedule of events for PET CT and biopsy. This was done to ensure repeat biopsies could be obtained in the event of progressive disease.
Submission of updated investigational medicinal product dossier. Submission of updated Investigator Brochure. |
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09 Apr 2015 |
Amend eligibility criteria.
Amend the protocol to say that all patients who discontinue study treatment in the event of >= grade 3 ECG QTc prolongation must be monitored by continuous ECG until resolution or stabilisation. This change was requested by a country level ethics board. |
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23 Nov 2015 |
Amend statistical design in protocol to reflect final SAP. Improvements to the design identified and implemented to reduce the type I and type II error rates increase the likelihood of stopping early in the event of a very effective, ineffective or toxic drug whilst using the same number of participants.
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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 halted early due to a pre-planned stopping rule. This led to a small number of subjects to analyse. |