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    The EU Clinical Trials Register currently displays   44347   clinical trials with a EudraCT protocol, of which   7375   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2014-004407-71
    Sponsor's Protocol Code Number:IB2014-03
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-01-14
    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 ConcernedFrance - ANSM
    A.2EudraCT number2014-004407-71
    A.3Full title of the trial
    A Phase II study of XL 184 (Cabozantinib) in treating patients with relapsed Osteosarcomas and Ewing Sarcomas.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II study of XL 184 (Cabozantinib) in treating patients with relapsed Osteosarcomas and Ewing Sarcomas.
    A.3.2Name or abbreviated title of the trial where available
    CABONE
    A.4.1Sponsor's protocol code numberIB2014-03
    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 SponsorInstitut Bergonié
    B.1.3.4CountryFrance
    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 supportINCa (INSTITUT NATIONAL DU CANCER)
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportInstitut Bergonié
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationINSTITUT BERGONIE
    B.5.2Functional name of contact pointDeputy General Manager
    B.5.3 Address:
    B.5.3.1Street Address229, COURS DE L'ARGONNE - CS 61283
    B.5.3.2Town/ cityBORDEAUX
    B.5.3.3Post code33076
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)556333301
    B.5.5Fax number+33(0)556333330
    B.5.6E-mailc.fillatreau@bordeaux.unicancer.fr
    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 Yes
    D.2.1.1.1Trade name Cometriq
    D.2.1.1.2Name of the Marketing Authorisation holder TMC Pharma Services Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namecabozantinib
    D.3.2Product code XL 184
    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 INNcabozantinib
    D.3.9.1CAS number 849217-68-1
    D.3.9.2Current sponsor codeXL-184
    D.3.9.3Other descriptive nameCABOZANTINIB
    D.3.9.4EV Substance CodeSUB93452
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 60
    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
    Patients aged 12 years or older with unresectable locally advanced or metastatic osteosarcoma or Ewing sarcoma
    E.1.1.1Medical condition in easily understood language
    Relapsed Osteosarcomas and Ewing Sarcomas
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10031291
    E.1.2Term Osteosarcoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10015563
    E.1.2Term Ewing's sarcoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the antitumor activity of cabozantinib in terms of :
    •Osteosarcoma: 6-month non-progression (Complete response, partial response and stable disease) and 6-month objective response (Complete response, partial response) rates (composite endpoint) as per the Response Evaluation Criteria in Solid Tumors, Revised RECIST v1.1.
    •Ewing sarcoma: 6-month objective response as per the revised RECIST v1.1.
    E.2.2Secondary objectives of the trial
    •Ewing sarcoma only: 6-month non-progression rate
    Both strata:
    •Best overall response (as per the revised RECIST v1.1);
    •1- and 2-year progression-free survival;
    •1- and 2-year overall survival;
    •Cabozantinib safety;
    •To assess the ability of metabolic tumor response as measured by FDG-PET at the end of one cycle of treatment to predict PFS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional study, Version 1.0 of 2014/10/10.
    The objective is to determine and compare tumor expression of MET, phospho-MET and circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib.
    E.3Principal inclusion criteria
    1. Patients must have histologically confirmed diagnosis of osteosarcoma or Ewing sarcoma by central review, except if the diagnosis was already confirmed by the RRePS (Réseau de Référence en Pathologie des Sarcomes et des Tissus Mous et des Viscères) network.
    2. Relapsed disease after standard chemotherapy.
    3. Patients must have measurable disease (outside any previously irradiated field) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as > 10 mm with spiral CT scan.
    4. Age ≥12 years.
    5. ECOG performance status ≤1 (see Appendix A).
    6. Life expectancy of greater than 3 months.
    7. Patients must have normal organ and marrow function as defined below:
    - absolute neutrophil count ≥1,500/mcL
    - platelets ≥100,000/mcL
    - total bilirubin ≤1.5 × ULN
    - AST(SGOT)/ALT(SGPT) ≤3.0 × institutional upper limit of normal
    - creatinin ≤1.5 × ULN OR creatinine clearance ≥50 mL/min/1.73 m² for patients with creatinine levels above institutional normal (Cockcroft formula, see Appendix I).
    - hemoglobin ≥9 g/dL
    - serum albumin ≥2.8g/dL
    - lipase <2.0 × ULN and no radiologic or clinical evidence of pancreatitis
    - urine protein/creatinine, ratio (UPCR) ≤1
    - serum phosphorus, calcium, magnesium, and potassium ≥ LLN
    8. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.
    9. The effects of Cabozantinib on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (see below) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Cabozantinib administration.
    Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
    10. Metastatic or unresectable locally advanced.
    11. Documented disease progression (as per RECIST v1.1) before study entry. For patients with osteosarcoma, this progression will be confirmed by central review on the basis of two CT scan or MRI obtained at less than 6 months in the period of 12 months prior to inclusion.
    12. Ability to understand and the willingness to sign a written informed consent document.
    13. In accordance with French Regulatory Authorities: Patients with French Social Security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code).
    E.4Principal exclusion criteria
    1.cytotoxic chemotherapy or biologic agents within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment
    2.Prior treatment with Cabozantinib
    3.Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
    4.Small molecule kinase inhibitor within 14 days before the first dose of study treatment
    5.Any other type of investigational agent within 28 days before the first dose of study treatment
    6.Subject has not recovered to baseline or CTCAE ≤Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs
    7.Primary brain tumor
    8.Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 2 weeks before the first dose of study treatment
    9.Subject has PT/INR or PTT test ≥1.3 x the laboratory ULN within 7 days before the first dose of study treatment
    10.Subject requires concomitant treatment, in therapeutic doses, with anticoagulants, or antiplatelet agents.Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted
    11.Subject requires chronic concomitant treatment of strong CYP3A4 inducers
    12.Subject has experienced any of the following:•clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment•hemoptysis of ≥0.5 teaspoon or any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
    13.Subject has radiographic evidence of cavitating pulmonary lesion(s)
    14.Subject has tumor in contact with, invading or encasing any major blood vessels
    15.Subject has evidence of tumor invading the GI tract, or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
    16.Subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions
    1.Cardiovascular disorders including:a)Congestive heart failure : New York Heart Association Class III or Class IV
    b)Concurrent uncontrolled hypertension despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
    c)History of congenital long QT syndrome
    d)Any of the following within 6 months before the first dose of study treatment:•unstable angina pectoris•clinically-significant cardiac arrhythmias•stroke•myocardial infarction•thromboembolic event requiring therapeutic anticoagulation
    2.Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including
    a)Any of the following within 28 days before the first dose of study treatment
    •intra-abdominal tumor/metastases invading GI mucosa•any evidence of active peptic ulcer disease•any evidence of inflammatory bowel disease diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis•malabsorption syndrome
    b)Any of the following within 6 months before the first dose of study treatment:•abdominal fistula•gastrointestinal perforation•bowel or gastric outlet obstruction•intra-abdominal abscess.
    3.Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy
    4.Other clinically significant disorders•infection requiring systemic treatment within 28 days before the first dose of study treatment•serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment•history of organ transplant•hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment•history of major surgery:Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery
    17.Subject unable to swallow tablets
    18.Corrected QT interval calculated by the Cridericia formula >500 ms within 28 days before treatment
    19.Subject unable or unwilling to abide by the study protocol
    20.Another malignancy which required systemic treatment within 2 years of the start of study treatment
    21.History of allergic reactions attributed to compounds of similar chemical or biologic composition to Cabozantinib
    22.Pregnant women
    23.HIV-positive patients on combination antiretroviral therapy
    24.Participation to a study involving a medical or therapeutic intervention in the last 30 days
    25.Prior participation in this study
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy will be evaluated based on 6-month non-progression and 6-month objective response (composite primary endpoint) for osteosarcoma and 6-month objective response rate (ORR - primary endpoint) for Ewing sarcoma.
    Primary endpoint efficacy analyses will be based on radiological data reviewed by an independent expert radiologist.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months after the beginning of treatment
    E.5.2Secondary end point(s)
    Secondary endpoints include 6-month ORR for Ewing sarcoma, as well as for both strata: best overall response, 1- and 2-year PFS, and 1- and 2-year OS.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6-month ORR : 6 months after the beginning of treatment
    Best overall response : assessed as long as patients is under treatment
    1-year PFS and 1-year OS : assessed one year post treatment initiation
    2-year PFS and 2-year OS : assessed two yearrs post treatment initiation.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    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 years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Adolescents (12-17 years)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
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