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    Summary
    EudraCT Number:2012-000616-28
    Sponsor's Protocol Code Number:OCTO_038
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-000616-28
    A.3Full title of the trial
    Phase II trial of Linsitinib (anti-IGFR/IR) in patients with relapsed and/or refractory Ewing Sarcoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma
    A.3.2Name or abbreviated title of the trial where available
    LINES: Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma
    A.4.1Sponsor's protocol code numberOCTO_038
    A.5.4Other Identifiers
    Name:EORTCNumber:1225
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Oxford
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Oxford
    B.5.2Functional name of contact pointPortfolio Lead Early Phase Med Onc
    B.5.3 Address:
    B.5.3.1Street AddressCTO, Dept of Oncology, Uni of Oxford, ORCRB
    B.5.3.2Town/ cityOld Road Campus, Oxford
    B.5.3.3Post codeOX3 7DQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441865 227162
    B.5.5Fax number+441865 227199
    B.5.6E-maileurosarc@octo-oxford.org.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLinsitinib
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlinsitinib
    D.3.9.1CAS number 867160-71-2
    D.3.9.2Current sponsor codelinsitinib
    D.3.9.3Other descriptive nameASP7487, OSI–906
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed and/or refractory Ewing sarcoma
    E.1.1.1Medical condition in easily understood language
    Advanced Ewing sarcoma (bone cancer)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10015560
    E.1.2Term Ewing's sarcoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial
    To assess whether the trial drug improves the time to progression (progression free survival).
    To assess whether the trial drug improves life span of patients (disease specific survival).
    To assess whether the trial drug has an effect on patients tumour using CT scans.
    To further understand what the body does to the trial drug.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological or cytological confirmed original (no new biopsy required) diagnosis of Ewing sarcoma, preferably with EWSR in situ hybridisation break apart probe.
    2. First, second or any relapse or refractory disease to conventional treatment.
    3. Current disease state for which there either is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
    4. Has recovered from prior chemotherapy-related toxicity to ≤ grade 2.
    5. Male or female, Age ≥ 18 and ≤70 years.
    6. Life expectancy of at least 4 months.
    7. WHO performance score of 0-2.
    8. Must be able to take oral medication.
    9. Is willing and able to comply with the protocol for the duration of the study, and scheduled visits and examinations, including biopsies and PET-CT scans.
    10. Written (signed and dated) informed consent.
    11. Tumour at biopsy accessible site; in the case of lung metastases, accessible with VATS procedure.
    12. Tumour progression documented with imaging in the 3 months prior to study entry.
    13. At least one measurable lesion on CT scan performed in past 14 days of minimum size 1 cm and 18 FDG uptake positive
    14. Cardiac Ejection Fraction (Echocardiogram) ≥45%.
    15. Fasting glucose ≤ 150 mg/dL (8.3 mmol/L) with no history of diabetes mellitus. Concurrent use of non-insulinotropic anti-hyperglycemic therapy is permitted if the dose has been stable for ≥ 4 weeks at the time of enrolment.
    16. Haematological and biochemical indices within the specified ranges.
    E.4Principal exclusion criteria
    1. Females: Pregnant or breast-feeding, or of childbearing potential unless effective methods of contraception are used. Males: Unless effective methods of contraception are used.
    2. Significant active cardiac disease including: History (within last 6 months) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea).
    3. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded; uncontrolled high blood pressure (no greater than 2 SD above the mean for age for SBP and DBP), unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, or serious cardiac arrhythmias.
    4. Mean QTcF interval ≥ 450 msec based on analysis of screening visit ECGs;
    5. Use of drugs that have a known risk of causing Torsades de Pointes (TdP) within 14 days prior to registration.
    6. Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine within 7 days prior to registration. Linsitinib is primarily metabolized by CYP1A2 and inhibitors/inducers of CYP1A2 could alter the pharmacokinetics of linsitinib. Other less potent CYP1A2 inhibitors/inducers are not excluded.
    7. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
    8. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions.
    9. History of cerebrovascular accident (CVA) within 6 months prior to entry that resulted in ongoing neurologic instability.
    10. Patients with symptomatic brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
    11. Major surgery within 4 weeks prior to study treatment.
    12. Prior anti- IGF-1R treatment.
    13. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment.
    14. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
    E.5 End points
    E.5.1Primary end point(s)
    As this trial utilises Bayensian analysis there are 2 primary endpoints:
    1. Pharmacodynamic effects of linsitinib in the tumour measured by
    (a) FDG update (SUV) responses
    (b) Biomarker responses in tumour biopsies.
    2. Safety: Adverse events and laboratory abnormalities.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Pharmacodynamic endpoints will be measured as follows:
    (a) FDG-PET - baseline and cycle 1 day 17
    (b) Biopsies - baseline and cycle 2 day 3
    2. Safety data will be collected during cycles 1-6.
    E.5.2Secondary end point(s)
    1. Progression free survival
    2. Disease specific survival
    3. Objective responses (RECIST)
    4. Pharmacokinetic assays
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Time of progression.
    2. Time of death or censored for at time last known alive for patient still alive at the end of the trial.
    3. Baseline, cycle 1, 3 & 6.
    4. Cycles 1-6
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 39
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients can continue on trial treatment for as long as they are getting clinical benefit. Subsequently, patients will receive the appropriate treatment under the care of their specialist.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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