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    Clinical Trial Results:
    Phase II trial of Linsitinib (anti-IGF-1R/IR) in patients with relapsed and/or refractory Ewing Sarcoma

    Summary
    EudraCT number
    2012-000616-28
    Trial protocol
    GB   IT   NL  
    Global end of trial date
    03 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2017
    First version publication date
    28 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO_038
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02546544
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX3 7LE
    Public contact
    Joint Research Office, University of Oxford, ctrg@admin.ox.ac.uk
    Scientific contact
    Joint Research Office, University of Oxford, ctrg@admin.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    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.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Germany: 2
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited from April 2014 until March 2016 at specialist cancer hospitals across Europe

    Pre-assignment
    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
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Linsitinib
    Arm description
    Linsitinib
    Arm type
    Experimental

    Investigational medicinal product name
    Linsitinib
    Investigational medicinal product code
    Other name
    ASP7487, OSI-906
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    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.

    Number of subjects in period 1
    Linsitinib
    Started
    16
    Received allocated intervention
    16
    Completed
    0
    Not completed
    16
         Disease Progression
    14
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Linsitinib
    Reporting group description
    Linsitinib

    Reporting group values
    Linsitinib Total
    Number of subjects
    16 16
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    16 16
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    13 13
    Region of Enrollment
    Units: Subjects
        United Kingdom
    8 8
        Italy
    4 4
        Netherlands
    2 2
        Germany
    2 2
    WHO performance status
    Units: Subjects
        WHO PS 0
    5 5
        WHO PS 1
    7 7
        WHO PS 2
    4 4
    Histology
    Units: Subjects
        Ewing Sarcoma
    16 16
    Primary site
    Units: Subjects
        Chest wall
    4 4
        Extra-osseous site
    2 2
        Lower extremity
    3 3
        Pelvis
    5 5
        Spine
    1 1
        Upper extremity
    1 1
    Disease stage at screening
    Units: Subjects
        Metastatic
    16 16
    Number of lines of previous treatment
    Units: Subjects
        Second line
    1 1
        Third line
    1 1
        > third line
    14 14
    Prior radiotherapy
    Units: Subjects
        Yes
    13 13
        No
    3 3
    Prior chemotherapy
    Units: Subjects
        Yes
    16 16
    Prior surgery
    Units: Subjects
        Yes
    14 14
        No
    2 2
    Site of Metastases - Bone
    Units: Subjects
        Yes
    3 3
        No
    13 13
    Sites of Metastases - Lung
    Units: Subjects
        Yes
    11 11
        No
    5 5
    Site of Metastases - Bone, Other
    Units: Subjects
        Yes
    8 8
        No
    8 8
    Time since most recent relapse/progression (days)
    Units: days
        median (inter-quartile range (Q1-Q3))
    18 (12 to 39) -

    End points

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    End points reporting groups
    Reporting group title
    Linsitinib
    Reporting group description
    Linsitinib

    Primary: 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.

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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.
    End point type
    Primary
    End point timeframe
    Pre- and Post- dose responses following 1 cycle (21 days) of treatment
    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.
    End point values
    Number of subjects analysed
    Units: subjects
        Positive metabolic response
        Stable metabolic response
        Progressive metabolic response
        Not measurable at Baseline
        Not assessable - liver
        No repeat scan available
    No statistical analyses for this end point

    Primary: To evaluate the safety of Linsitinib

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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)
    End point type
    Primary
    End point timeframe
    Following 6 cycles of treatment (up to 6 months)
    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.
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: subjects
        Experienced a toxic event
    5
        Did not experienced a toxic event
    11
    No statistical analyses for this end point

    Secondary: Clinical outcome (PFS)

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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.
    End point type
    Secondary
    End point timeframe
    Duration of study (up to 18 months)
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: months
        median (confidence interval 95%)
    1.28 (0.66 to 999)
    No statistical analyses for this end point

    Secondary: Radiological Response as Measured by EORTC 1.0

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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.
    End point type
    Secondary
    End point timeframe
    Measured cycle 1 day 15
    End point values
    Number of subjects analysed
    Units: subjects
        Positive metabolic response
        Stable metabolic disease
        Progressive metabolic disease
        No paired scan
    No statistical analyses for this end point

    Secondary: Clinical outcome (DSS)

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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.
    End point type
    Secondary
    End point timeframe
    Duration of study (up to 18 months)
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: Months
        median (confidence interval 95%)
    7.13 (2.56 to 999)
    No statistical analyses for this end point

    Secondary: Radiological response measured by RECIST

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    End point title
    Radiological response measured by RECIST
    End point description
    Radiological response measured using RECIST version 1.1
    End point type
    Secondary
    End point timeframe
    cycle 1 day 15
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: subjects
        Stable disease
    7
        Progressive disease
    7
        No paired scan
    2
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    Linsitinib
    Number of subjects analysed
    15
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    4790 (286 to 7538)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 15
    End point values
    Linsitinib
    Number of subjects analysed
    6
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    2163 (1090 to 3206)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 17
    End point values
    Linsitinib
    Number of subjects analysed
    11
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    4977 (144 to 9628)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 2 day 3
    End point values
    Linsitinib
    Number of subjects analysed
    2
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    3409 (1534 to 5284)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 1
    End point values
    Linsitinib
    Number of subjects analysed
    6
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    6791 (849 to 8478)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 3
    End point values
    Linsitinib
    Number of subjects analysed
    5
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    1964 (417 to 14080)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    Cycle 4 day 1
    End point values
    Linsitinib
    Number of subjects analysed
    1
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    3591 (3591 to 3591)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)

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    End point title
    Pharmacokinetics assays of following linsitinib treatment (Plasma concentrations of linsitinib)
    End point description
    Plasma concentrations of linsitinib
    End point type
    Secondary
    End point timeframe
    End of treatment visit
    End point values
    Linsitinib
    Number of subjects analysed
    5
    Units: Concentration of Linsitinib (ng/ml)
        median (full range (min-max))
    1 (1 to 1432)
    No statistical analyses for this end point

    Secondary: Radiological response measured by RECIST

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    End point title
    Radiological response measured by RECIST
    End point description
    Radiological response measured using RECIST version 1.1
    End point type
    Secondary
    End point timeframe
    Cycle 3 day 3
    End point values
    Linsitinib
    Number of subjects analysed
    16
    Units: Patients
        Stable disease
    2
        Progressive disease
    4
        No paired scan
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from baseline until 28 days post treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Linsitinib
    Reporting group description
    Linsitinib

    Serious adverse events
    Linsitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 16 (18.75%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Linsitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    General disorders and administration site conditions
    Chest discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 16 (25.00%)
         occurrences all number
    4
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Spinal cord injury
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Investigations
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Electrocardiogram QT prolonged
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 16 (37.50%)
         occurrences all number
    11
    Haemoglobin decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Lymphocyte count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Platelet count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    3
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    3
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Renal and urinary disorders
    Pollakiuria
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Flank pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Hypokalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Hypomagnesaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Infections and infestations
    Pharyngitis streptococcal
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2014
    Changes to the protocol and PIS to reflect updated information in the Investigator Brochure for Linsitinib.
    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.
    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.
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    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.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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