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    Summary
    EudraCT Number:2008-006212-38
    Sponsor's Protocol Code Number:20080580
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-14
    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 ConcernedGermany - BfArM
    A.2EudraCT number2008-006212-38
    A.3Full title of the trial
    Phase 2, Open-label Single-Arm, Multi-Center Study to Evaluate the Efficacy and Safety of AMG 386 and Sorafenib as First Line Therapy for Subjects with Advanced or Inoperable Hepatocellular Carcinoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Effectiveness and Safety of AMG 386 and Sorafenib to Treat Advanced or Inoperable Hepatocellular Cancer
    A.3.2Name or abbreviated title of the trial where available
    Not applicable
    A.4.1Sponsor's protocol code number20080580
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00872014
    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 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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ Medical Info - Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.o. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post code(CH-)6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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 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.3.2Product code AMG 386
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeAMG 386
    D.3.9.3Other descriptive nameN/A
    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 No
    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) 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 Yes
    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 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.3.2Product code AMG 386
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeAMG 386
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) 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 Yes
    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
    advanced or inoperable hepatocellular carcinoma
    E.1.1.1Medical condition in easily understood language
    advanced or inoperable hepatocellular carcinoma (a cancer of the liver)
    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 LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of AMG 386 in combination with sorafenib as measured by the progression-free survival rate (PFS) at 4 months in subjects with advanced or inoperable hepatocellular carcinoma (HCC).
    E.2.2Secondary objectives of the trial
    • To evaluate the safety and tolerability of AMG 386 in combination with sorafenib in subjects with advanced or inoperable hepatocellular carcinoma and Child Pugh A liver function score
    • To estimate the efficacy (as measured by objective response rate [ORR], disease control rate [DCR], time to progression [TTP], progression free survival [PFS], and overall survival [OS]) of AMG 386 10 mg/kg or 15 mg/kg IV QW in combination with sorafenib 400 mg PO BID in subjects with advanced or inoperable hepatocellular carcinoma
    • To evaluate the pharmacokinetics (PK) of AMG 386 and sorafenib when used in combination (only in a sub-group of subjects at selected sites outside of Europe for sorafenib)
    • To determine the incidence of occurrence of anti-AMG386 antibody formation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Disease Related
    • Subjects must have histologically confirmed advanced or inoperable HCC. Biopsy by fine needle aspirate (FNA) is not preferred over a core biopsy but acceptable
    • Child-Pugh liver function class A (see Appendix G)
    • Measurable disease with at least one unidimensionally measurable lesion per RECIST criteria 1.0 with modifications (see Appendix E).
    Demographic
    • Men or women ≥ 18 years old
    • Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
    • Subjects of child-bearing potential and sexually active must consent to the use of an accepted and effective non-hormonal method of contraception (ie, double barrier method [eg, condom plus diaphragm]) from signing the informed consent through 6 months following last administration of study drug
    Laboratory
    Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to enrollment:
    o Hematological function, as follows:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelet count ≥ 60 x 109/L
    • Hemoglobin ≥ 8.5 g/dL
    o Renal function, as follows:
    • Creatinine clearance > 40 mL/min per 24-hour urine collection or
    calculated according to the Cockcroft-Gault formula

    (140-age) x actual body weight (kg) ( x 0.85 for
    CrCl (mL/min) 72 x serum creatinine (mg/dL) females)

    Or

    CrCl (140-age) x actual body weight (kg) ( x 0.85 for
    (mL/min) 0.8136 x serum creatinine (umol/L) females)

    Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or
    ≤1+ on dipstick, unless quantitative protein is < 1000 mg in a
    24 hour urine sample
    o Hepatic function, as follows:
    • Total bilirubin ≤ 2.0 mg/dL
    o Hemostatic function, as follows:
    • International Normalized Ratio (INR) ≤ 2.2
    General
    • Able to tolerate infusions and self-administer oral medications
    • Competent to comprehend, sign, and date an institutional review board (IRB)/Independent Ethics Committee (IEC) -approved informed consent form
    • Life expectancy ≥ 3 months (per investigator opinion)
    • Subject plans to begin protocol directed therapy within 7 days of enrollment
    E.4Principal exclusion criteria
    Disease Related
    • Subject is eligible for liver transplant per investigator’s discretion
    • Any previous systemic chemotherapy for HCC (chemotherapy or targeted therapies)
    • Previous surgical resections are allowed if ≥ 30 days elapsed prior to enrollment
    • Locoregional therapies (eg, TACE) are allowed if ≥ 30 days elapsed prior to enrollment provided that subjects either have a target lesion which has not been subjected to local therapy and/or the target lesions(s) within the field of the local therapy has shown an increase of ≥ 20% in size
    • History of arterial or venous thromboembolism within 12 months prior to enrollment
    o Subjects with portal vein thrombosis are eligible for this study
    except those with main portal vein thrombosis defined as the part of
    the portal vein between the inferior vena cava and the first
    bifurcation into the left and right vein
    • History of clinically significant bleeding within 6 months prior to enrollment (including pulmonary hemorrhage, gastroesophageal varices or gross hemoptysis (≥ 1/2 teaspoon or 2.5 mL of bright red blood)
    • Known history of central nervous system metastases. An MRI or CT scan of the brain or head will be performed within 28 days prior to enrollment.
    • Patients with fibrolamellar hepatocellular carcinoma
    • Radiation therapy ≤ 14 days prior to enrollment. Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to enrollment
    Medications
    • Currently or previously treated with sorafenib or other small molecule inhibitors of VEGF including, but not limited to AMG 706 (motesanib), SU11248 (sunitinib), PTK787 (vatalanib), AZD 2171 (cediranib), AEE-788
    • Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
    • Concomitant or use within 30 days prior to enrollment of any strong inducer of CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital and dexamethasone. Dexamethasone as bolus injection or premedication is allowed.
    • Concomitant anti-viral therapy is allowed with the exception of interferon alfa or pegylated interferon alfa therapy
    • Current or within 30 days prior to enrollment treatment with immune modulators such as systemic cyclosporine and tacrolimus
    • Enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trials, or currently receiving other investigational treatments
    General Medical
    • Known ongoing pancreatitis
    • Clinically significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
    • Major surgery within 4 weeks before enrollment or still recovering from prior surgery
    • History of allergic reactions to bacterially produced proteins
    • Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding
    • Exclude subjects with a history of prior malignancy (see protocol)
    • Minor surgical procedures, except placement of tunneled central venous access device (except PICC or peripherally inserted central catheter), or fine needle aspiration within 7 days prior to enrollment
    • Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic > 150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted.
    • Known active or ongoing infection (except uncomplicated urinary tract infection [UTI]) within 14 days before enrollment
    • Subject known positive test(s) for human immunodeficiency virus (HIV) infection,
    • Anticoagulation therapy must be stopped 1 week prior to enrollment except:
    - aspirin and anti-platelet agents
    - low dose warfarin or derivatives (e.g. coumarin) (ie. ≤ 1mg daily)
    • Non-healing wound, ulcer (including gastrointestinal) or fracture
    Other
    • Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
    • Other investigational procedures are excluded.
    • 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)
    The primary endpoint is progression-free survival (PFS) rate at 4 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of efficacy and safety will occur after the last subject enrolled has been followed for at least 4 months. The primary analysis of efficacy may occur at different times in cohorts A and B and will be performed separately for the 2 cohorts. The final analysis will occur after all the subjects have completed the long-term follow-up.
    E.5.2Secondary end point(s)
    • Incidence of adverse events and significant laboratory abnormalities
    • Objective response rate (ORR)
    • Disease Control Rate (DCR)
    • Progression Free Survival (PFS)
    • Overall Survival (OS)
    • Time to progression (TTP)
    • Pharmacokinetic (PK) parameters (Cmax and Cmin) for AMG 386 when used in combination with sorafenib
    • Pharmacokinetic (PK) parameter (Cmin) for sorafenib when used in combination with AMG 386 in a sub-group of subjects at selected sites outside of Europe
    • Incidence of the occurrence of anti-AMG 386 antibody formation
    E.5.2.1Timepoint(s) of evaluation of this end point
    The primary analysis of efficacy and safety will occur after the last subject enrolled has been followed for at least 4 months. The primary analysis of efficacy may occur at different times in cohorts A and B and will be performed separately for the 2 cohorts. The final analysis will occur after all the subjects have completed the long-term follow-up.
    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 No
    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 Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Historical comparator data
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    France
    Germany
    United States
    E.8.7Trial has a data monitoring committee No
    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 safety follow-up or long-term follow-up (maximum 48 months from the date the last subject was enrolled), 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 months9
    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 months9
    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: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 60
    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 Decision2009-07-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-09-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-21
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