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    Summary
    EudraCT Number:2013-003402-40
    Sponsor's Protocol Code Number:XL184-401
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-04-13
    Trial 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 ConcernedCroatia - MIZ
    A.2EudraCT number2013-003402-40
    A.3Full title of the trial
    A Randomized, Double-blind Study To Evaluate the Efficacy and Safety of Cabozantinib (XL184) at 60 mg/Day Compared to 140 mg/Day in Progressive, Metastatic Medullary Thyroid Cancer Patients
    Randomizirano dvostruko slijepo ispitivanje za procjenu učinkovitosti i sigurnosti kabozantiniba (XL184) u dozi od 60 mg na dan u usporedbi s dozom od 140 mg na dan u ispitanika s progresivnim metastatskim medularnim karcinomom štitnjače
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of two different doses of cabozantinib in progressive, metastatic medullary thyroid cancer
    Ispitivanje dviju različitih doza kabozantiniba u progresivnom, metastatskom karcinomu štitnjače
    A.3.2Name or abbreviated title of the trial where available
    EXAMINER
    A.4.1Sponsor's protocol code numberXL184-401
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01896479
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1147-2723
    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 SponsorExelixis, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportExelixis, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationExelixis, Inc.
    B.5.2Functional name of contact pointExelixis Medical Affairs
    B.5.3 Address:
    B.5.3.1Street Address1851 Harbor Bay Parkway
    B.5.3.2Town/ cityAlameda CA
    B.5.3.3Post code94502
    B.5.3.4CountryUnited States
    B.5.4Telephone number18883935494
    B.5.6E-maildruginfo@exelixis.com
    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 CABOMETYX
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 20 mg
    D.3.2Product code XL184
    D.3.4Pharmaceutical form Film-coated 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 1140909-48-3
    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 typeequal
    D.3.10.3Concentration number20
    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.IMP: 2
    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 CABOMETYX
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 60 mg
    D.3.2Product code XL184
    D.3.4Pharmaceutical form Film-coated 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 1140909-48-3
    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 typeequal
    D.3.10.3Concentration number60
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/08/610
    D.3 Description of the IMP
    D.3.1Product nameCabozantinib 20 mg
    D.3.2Product code XL184
    D.3.4Pharmaceutical form Capsule, hard
    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 1140909-48-3
    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 typeequal
    D.3.10.3Concentration number20
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation number EU/3/08/610
    D.3 Description of the IMP
    D.3.1Product nameCabozantinib 80 mg
    D.3.2Product code XL184
    D.3.4Pharmaceutical form Capsule, hard
    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 INNCaboozantinib
    D.3.9.1CAS number 1140909-48-3
    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 typeequal
    D.3.10.3Concentration number80
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Progressive Metastatic Medullary Thyroid Cancer
    Progresivni Metastatski Medularni karcinom štitnjače
    E.1.1.1Medical condition in easily understood language
    Medullary thyroid cancer, a rare type of thyroid cancer, that has spread to other parts of the body
    Medularni karcinom štitnjače, rijetka vrsta raka štitnjače, koja se proširila na druge dijelove tijela
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10027105
    E.1.2Term Medullary thyroid cancer
    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
    The objective of this study is to evaluate the efficacy of oral cabozantinib at a daily dose of 60 mg compared with 140 mg in subjects with progressive metastatic medullary thyroid cancer.
    Cilj ovog ispitivanja je procjena učinkovitosti oralnog kabozantiniba u dnevnoj dozi od 60 mg u odnosu na dozu od 140 mg u ispitanika s progresivnim metastatskim medularnim karcinomom štitnjače.
    E.2.2Secondary objectives of the trial
    Not applicable
    Nije primjenjivo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject has a histologically confirmed diagnosis of MTC.
    2. Availability of tumor tissue for shipment to the central laboratory according to prior determination of RET mutation status:
    a. For subjects lacking evidence of a RET or RAS mutation, a recent tumor tissue sample will be required. Tissue shall come from a progressive tumor location, preferably from the most recently progressed metastatic site if feasible. If a recent tumor sample is not available, a tumor biopsy will be obtained during screening.
    b. Subjects with documentation of a RET or RAS mutation found in tumor tissue will not be required to submit a recent tumor tissue sample; however, the report demonstrating the subject’s RET or RAS mutation must be reviewed and approved by the sponsor prior to subject randomization.
    c. For subjects with documentation of a hereditary RET mutation, a tumor sample will not be required. Review and approval of the RET mutation report by the sponsor is required prior to randomization of the subject.
    3. The subject has MTC that is metastatic as determined by the investigator based upon computerized tomography (CT), magnetic resonance imaging (MRI), bone scan, PET scan, or X-ray taken within 28 days before randomization.
    4. The subject has disease that is measurable per RECIST 1.1 as determined by the investigator based upon CT or MRI images taken within 28 days before randomization.
    5. The subject has documented progressive disease (PD) on CT, MRI, PET scan, bone scan, or X-ray as determined by the investigator per RECIST 1.1 on qualifying images taken within 4 months prior to randomization as compared to previous images taken within 14 months before the qualifying screening images.
    a. PET scan can only be used to establish PD by the presence of new lesions (not to document increases in target or non-target lesions).
    b. Bone scan or x-ray, can only be used to establish PD by the presence of new lesions in bone (not to document increases in target or non-target lesions).
    6. The subject has recovered to baseline or CTCAE v4.0 ≤ Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
    7. The subject is ≥ 18 years old on the day of consent.
    8. The subject has an ECOG (Eastern Cooperative Oncology Group) status ≤ 1 at screening
    9. The subject has adequate organ and marrow function, based upon the following laboratory criteria from assessments performed within 28 days before randomization
    a. Absolute neutrophil count (ANC) ≥ 1500/mm3
    b. Platelets ≥ 100,000/mm3
    c. Hemoglobin ≥ 9 g/dL
    d. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert’s disease, total bilirubin ≤ 3.0 mg/dL.
    e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x ULN
    f. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (using the Cockcroft-Gault equation: CrCl (mL/min) = (140 – age) x wt (kg) / (serum creatinine [mg/dL] x 72); for females multiply by 0.85
    g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g
    h. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test results at screening ≤ 1.3 x the laboratory ULN
    10. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
    11. Sexually active fertile subjects and their partners must agree to use medically
    accepted methods of contraception (defined in Appendix E) during the course of the
    study and for 4 months after the last dose of study treatment.
    12. 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, or ovarian suppression or other reasons.
    E.4Principal exclusion criteria
    1. The subject has previously received cabozantinib
    2. The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 28 days or five half-lives of the compound or active metabolites, whichever is shorter before randomization or at any time after the date of the qualifying images used to document PD for eligibility
    3. The subject has received prior systemic anti-tumor therapy within 28 days of randomization or at any time after the date of the qualifying images used to document PD for eligibility
    4. The subject has received any other type of investigational agent within 28 days before randomization or at any time after the date of the qualifying images used to document PD for eligibility
    5. The subject has received radiation therapy within 28 days or radionuclide treatment within 42 days of randomization. Subject is ineligible if there are any clinically relevant ongoing complications from prior radiation therapy
    6. The subject has untreated and/or active central nervous system (CNS) metastasis. Must have completed radiation therapy ≥ 28 days prior to randomization and stable without corticosteroids or anti-convulsant treatment for ≥ 10 days
    7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors
    8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
    a. Cardiovascular disorders incl.
    i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
    ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
    iii. Stroke, myocardial infarction, or other ischemic event within 6 months before randomization
    iv. Thromboembolic event within 3 months before randomization.
    b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
    i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
    ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
    Note: Complete healing must be confirmed prior to randomization, including radiographic evidence of complete resolution of abdominal abscess
    c. Major surgery within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery must have occurred at least 7 days before randomization. Subjects with clinically relevant complications from prior surgery are not eligible
    d. Cavitating pulmonary lesion(s) or endobronchial disease
    e. Lesion invading a major blood vessel
    f. Clinically significant bleeding risk including the following within 3 months of randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
    g. Other clinically significant disorders such as:
    i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness
    ii. Serious non-healing wound/ulcer/bone fracture
    iii. Malabsorption syndrome
    iv. Uncompensated/symptomatic hypothyroidism
    v. History of solid organ transplantation
    9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization. Note: If the QTcF is >500 ms in the first ECG, a total of three ECGs should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
    10. The subject is unable to swallow multiple tablets or capsules
    11. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation
    12. The subject is pregnant or breastfeeding
    13. The subject has had a diagnosis of another malignancy within 2 years before randomization, except for superficial scan cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS) per RECIST 1.1 per independent radiology review
    Preživljenje bez pogoršanja bolesti prema kriterijima RECIST 1.1 prema neovisnoj radiološkoj procjeni.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At screening and every 12 weeks (± 5 days) after randomization. Assessments should continue regardless of whether study treatment is given, reduced, or discontinued through the earlier of 12 weeks after radiographic progression per RECIST 1.1 as determined by the investigator (ie, one additional assessment after investigator-determined progression), or the date of initiation of subsequent systemic anti-cancer therapy.
    Prilikom probira svakih 12 tjedana (± 5 dana) nakon randomizacije. Procjene se trebaju nastaviti bez obzira na to da li se ispitivani lijek primjenjuje, da li je doza smanjena ili da li je primjena prekinuta do 12 tjedana nakon radiološki potvrđenog pogoršanja bolesti prema kriterijima RECIST 1.1 prema utvrđenju ispitivača (odnosno, jedne dodatne procjene nakon napretka bolesti prema utvrđenju ispitivača) ili do datuma početka sljedeće sistemske antikarcinomske terapije.
    E.5.2Secondary end point(s)
    •Objective response rate (ORR) per RECIST 1.1 per independent radiology review
    •Safety and tolerability of cabozantinib as assessed by AEs including hemorrhage, gastrointestinal and non-gastrointestinal fistulas, gastrointestinal perforation, hypertension, diarrhea, oral mucositis/stomatitits, and PPE, changes in laboratory parameters, and frequency of dose modifications
    •Pharmacokinetics (PK) of Cabozantinib
    •Biochemical response to cabozantinib as assessed by the plasma tumor markers including calcitonin (CTN) and carcinoembryonic antigen (CEA)
    •Pharmacodynamic effects of cabozantinib on plasma biomarkers of cabozantinib target pathway inhibition and bone turnover
    •Correlation of germline and somatic genetic alterations to tumor response or resistance, cabozantinib exposure, and/or toxicity.
    •objektivna stopa odgovora prema kriterijima RECIST 1.1 prema neovisnoj radiološkoj procjeni.
    •sigurnost i podnošljivost kabozantiniba procjenjivane prema štetnim događajima poput krvarenja, gastrointestinalnih i negastrointestinalnih fistula, gastrointestinalnih perforacija, povišenja krvnog tlaka, proljeva, oralnog mukozitisa ili stomatitisa, sindroma palmarno-plantarne eritrodisestezije, promjena u laboratorijskim parametrima i učestalosti promjena doza
    •farmakokinetika kabozantiniba
    •biokemijski odgovor na kabozantinib procjenjivan tumorskim biljezima u plazmi uključujući kalcitonin i karcinoembrionalni antigen
    •farmakodinamički učinci kabozantiniba na plazmatske biološke biljege kabozantinibove inhibicije ciljane putanje i koštanu pregradnju
    •korelacija germinativne linije i somatskih genetskih promjena na odgovor ili rezistenciju tumora, izloženost kabozantinibu i/ili toksičnost.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At scheduled visits.
    U zakazanim posjetima.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    Kabozantinib (XL184) 140 mg / dan
    Cabozantinib (XL184) 140 mg/Day
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Canada
    Croatia
    France
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    Poland
    Romania
    Russian Federation
    Spain
    Sweden
    Turkey
    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
    Zadnji posjet posljednjeg ispitanika
    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 days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 139
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 250
    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)
    Standard of care or other treatment options deemed appropriate by the physician.
    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 Decision2017-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-19
    P. End of Trial
    P.End of Trial StatusOngoing
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