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    Summary
    EudraCT Number:2007-000147-98
    Sponsor's Protocol Code Number:20060159
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2007-05-16
    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 number2007-000147-98
    A.3Full title of the trial
    A Randomized, Double Blinded, Multi-Center Study 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination with AMG 386 or Placebo in Subjects with Metastatic Clear Cell Carcinoma of the Kidney
    A.4.1Sponsor's protocol code number20060159
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmgen 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameAMG 386
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMG 386
    D.3.9.2Current sponsor codeAMG 386
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Information not present in EudraCT
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 Nexavar
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Healthcare AG, D-51368 Leverkusen
    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/3/04/207
    D.3 Description of the IMP
    D.3.1Product namesorafenib
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNSorafenib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination with AMG 386 or Placebo in Subjects with Metastatic Clear Cell Carcinoma of the Kidney
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10050513
    E.1.2Term Metastatic renal cell carcinoma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the clinical benefit as measured by progression free survival (PFS) of subjects receiving AMG 386 (either 3mg/kg or 10mg/kg IV QW) in combination with sorafenib (400mg PO BID) compared to subjects receiving sorafenib (400mg PO BID) plus placebo.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of the combination regimen of AMG 386 and sorafenib.
    To estimate the clinical benefit (by parameters other than PFS) of subjects receiving AMG 386 (either 3 mg/kg or 10 mg/kg IV QW) in combination with sorafenib (400 mg PO BID) compared to the subjects receiving sorafenib (400 mg PO BID) plus placebo
    To evaluate the pharmacokinetics (pK) of AMG 386 and sorafenib when used in combination.
    To determine the incidence of occurrence of anti-AMG386 antibody formation.
    To evaluate patient reported outcomes (PRO) using the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15) and EQ-5D.
    To evaluate the clinical benefit of subjects receiving AMG 386 10.0 mg/kg QW in combination with sorafenib after treatment failure with sorafenib plus placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Disease Related:

    • Subjects must have a histologically confirmed metastatic RCC with a clear cell
    component
    • Low or intermediate risk according to the Memorial Sloan Kettering Cancer Center
    (MSKCC) prognostic risk classification defined as between 0 and 2 of the following risk factors:
    - Karnofsky performance status < 80%
    - Serum lactate dehydrogenase > 1.5 x upper limit of normal (ULN)
    - Serum hemoglobin < lower limit of normal (LLN) for their institutions
    - Serum Calcium (corrected) > 10 mg/dL
    - Time from diagnosis of RCC to first systemic treatment < 1 year
    • Measurable disease with at least one unidimensionally measurable lesion per RECIST guidelines with modifications.

    Demographic:

    • Men or women≥ 18 years old

    Laboratory:

    • Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days of randomization:
    • Hematological function, as follows:
    - Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L
    - Platelet count ≥ 100 x 10e9/L
    - Hemoglobin≥9 g/dL
    • Renal function, as follows:
    - Creatinine ≤ 2.0 x ULN
    - Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample
    • Amylase ≤ 1.5 x ULN
    • Lipase ≤ 1.5 x ULN
    • Hepatic function, as follows:
    - Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN)
    - Alanine aminotransferase (ALT) ≤ 2.5 x ULN (if liver metastases are present, ≤ 5 x ULN)
    - Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver metastases are present, ≤ 5 x ULN)
    - Bilirubin≤ 2.0 x ULN
    • Hemostatic function, as follows:
    - INR≤ 1.5
    - Partial thromboplastin time (PTT) within normal limits

    General:

    • Able to tolerate infusions and self-administer oral medications
    • Competent to comprehend, sign, and date an institutional review board (IRB) -approved informed consent form
    • ECOG of 0 or 1
    • Subject plans to begin protocol directed therapy within 7 days of randomization
    E.4Principal exclusion criteria
    Disease Related:

    • Primary tumor in situ
    - Subjects must have their primary tumor resected to be eligible for this study
    • Known history of central nervous system metastases. An MRI or CT scan of the brain will be performed within 21 days of randomization.
    • History of arterial or venous thrombosis within 6 months prior to randomization
    • History of bleeding diathesis or clinically significant bleeding within 14 days of
    randomization
    • Previous treatment (excluding surgery and palliative radiotherapy) for advanced or
    metastatic renal cell carcinoma
    • Focal radiation therapy for palliation of pain from bony metastases within 14 days of randomization.
    • Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to randomization

    Medications:

    • Currently or previously treated with AMG 706, bevacizumab or small molecule inhibitors of VEGF including, but not limited to, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AEE-788, BAY 43-9006 (sorafenib)
    • Currently or previously treated with AMG 386, or other molecules that inhibit the
    angiopoietins or Tie2 receptor including but not limited to, AZD-5180, XL-820, CEP
    11981/SSR-106462, BSF-466,895, CGI-1842, LOC-590, XL-184, or CP-8681596
    • Concomitant or use within 30 days prior to randomization of any strong inducer of
    CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin,
    carbamazepine, phenobarbital and dexamethasone

    General Medical:

    • Myocardial infarction, cerebrovascular accident, transient ischemic attack, percutaneous transluminal coronary angioplasty/stent, congestive heart failure, grade 2 or greater peripheral vascular disease, arrhythmias not controlled by outpatient medication, or unstable angina within 1 year prior to randomization
    • Major surgery within 30 days before randomization or still recovering from prior surgery
    • History of allergic reactions to bacterially produced proteins
    • Pregnant (i.e., positive beta-human chorionic gonadotropin test) or is breast feeding
    • Prior malignancy (other than thyroid cancer, in situ cervical cancer, or nonmelanomatous cancer of the skin treated with curative intent and without evidence of disease for ≥ 3 years before randomization)
    • Central venous catheter placement (including tunneled catheters and port-o-caths) within 7 days of randomization
    • Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic >150 mmHg. Anti-hypertensive medications are permitted.
    • Known active or ongoing infection within 14 days before randomization
    • Subject known to have tested positive for HIV
    • Subject known to have chronic hepatitis
    • Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
    • History of pulmonary hemorrhage or gross hemoptysis (1/2 teaspoon or more of bright red blood) within 6 months before randomization
    • Concurrent or prior (within 1 week before randomization) anticoagulation therapy,
    excluding Aspirin. The concurrent use of low molecular weight heparin or low dose
    warfarin (ie, ≤ 1 mg daily) for prophylaxis against central venous catheter thrombosis is acceptable

    Other:

    • Other investigational procedures are excluded
    • Subject not consenting to the use of highly effective contraceptive, e.g. double barrier method (i.e. condom plus diaphragm) precautions during the course of the study and for 6 months after administration of the last study medication
    • Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s)
    • Any disorder that compromises the ability of the subject to give written informed consent and/or comply with the study procedures
    • Subject has known sensitivity to any of the products to be administered during dosing.
    • Subject has previously been randomized onto this study
    • Subject will not be available for follow-up assessment
    • Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint:

    Progression-free survival (PFS): time from randomization date to date of disease progression per the modified RECIST criteria or death. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.

    Secondary Endpoints:

    Objective Response Rate (ORR): The incidence of either a confirmed complete response (CR) or partial response (PR) per modified RECIST criteria (responder). A confirmed CR requires two consecutive assessments of CR at least 28 days apart. A confirmed PR requires two assessments at least 28 days apart of PR or CR. All subjects that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
    Duration of response (DOR): (calculated only for those subjects with an objective response) time from first confirmed objective response to disease progression per the modified RECIST criteria.
    Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
    Change in continuous measures of tumor burden
    Time-adjusted area under the curve (AUC) for the FACT-Kidney Cancer Symptom Index (FKSI-
    15) scale score from baseline through disease progression with imputation for missing data.
    Incidence of AEs and significant laboratory changes
    Incidence of the occurrence of anti-AMG 386 antibody formation

    Tertiary Endpoints:

    Overall survival: time from randomization date to date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
    Time to progression (TTP): time from randomization date to date of disease progression per the modified RECIST criteria. Subjects not meeting criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
    Time to response: time from randomization date to date of first objective response for confirmed responders. Non-responders by the analysis data cutoff date with a best response of SD will be censored at their last assessment of SD, and subjects with a best response of PD will be censored at the maximum observed time to a first confirmed response among all responders.
    AMG 386 pharmacokinetic parameters
    Time-adjusted AUC for the EuroQol EQ-5D Index Score from baseline through disease
    progression with imputation for missing data.
    Time-adjusted AUC for the EuroQol Visual Analog Scale EQ-5D VAS score from baseline through disease progression with imputation for missing data.
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 Yes
    E.8.1.7.1Other trial design description
    Subjects in Arm C have option to go to sorafenib + open label AMG 386 following disease progression.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    sorafenib
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    The end of study is when all subjects have completed the treatment period or long-term follow-up (maximum 48 months from the date the last subject was randomized), whichever is later.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    E.8.9.2In all countries concerned by the trial months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 150
    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 Decision2007-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-07-26
    P. End of Trial
    P.End of Trial StatusOngoing
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