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    Summary
    EudraCT Number:2013-000311-25
    Sponsor's Protocol Code Number:BAY86-9766/16553
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-07-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2013-000311-25
    A.3Full title of the trial
    A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY 86-9766) in patients with RAS mutant Hepatocellular Carcinoma (HCC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Refametinib given to patients with unresectable or metastatic HCC carrying a RAS mutation
    A.3.2Name or abbreviated title of the trial where available
    Refametinib in RAS mutant HCC
    A.4.1Sponsor's protocol code numberBAY86-9766/16553
    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 SponsorBayer Healthcare AG
    B.1.3.4CountryGermany
    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 supportBayer Healthcare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer Healthcare AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCPT Team / Ref: "EU CTR"/ Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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 nameRefametinib
    D.3.2Product code BAY 86-9766, Capsule 10 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 nameRefametinib
    D.3.2Product code BAY 86-9766, Capsule 20 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    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: 3
    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 nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 50 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 30 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 5
    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 nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 20 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    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.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
    KRAS or NRAS mutant unresectable or metastatic Hepatocellular carcinoma (HCC)
    E.1.1.1Medical condition in easily understood language
    RAS mutant unresectable or metastatic Hepatocellular carcinoma (HCC)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of refametinib in patients with KRAS or NRAS mutant unresectable or metastatic HCC.
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate the safety of refametinib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. Additional objectives are the analysis of biomarkers, pharmacokinetics (PK), and patient reported outcomes (PRO, stage 2 only).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligibility criteria for RAS mutation testing:
    •Ability to understand and willingness to sign written informed consent (IC). Signed informed consent from (ICF) for RAS mutation testing has to be obtained before any study specific procedure.
    •Unresectable or metastatic HCC, confirmed either by histology or clinically according to the American Association for the Study of Liver Disease (AASLD) criteria for cirrhotic patients. For non-cirrhotic patients, histological confirmation is mandatory.
    •Male or female ≥18 years of age.
    •ECOG performance state 0 or 1.
    •Life expectancy of at least 12 weeks.
    •No prior use of targeted agents, experimental therapy or systemic anticancer treatment (except sorafenib and/or cytotoxic chemotherapy).
    •No previous treatment with refametinib.

    Criteria for study treatment eligibility:
    •Ability to understand and willingness to sign written IC. Signed ICF for study treatment eligibility has to be obtained before any study specific procedure.
    •Patient must harbor KRAS or NRAS mutation based on BEAMing plasma test.
    •Patients must have at least one uni-dimensional measurable lesion by CT or MR according to RECIST 1.1 and mRECIST (specified in Section 14.4) which is either naïve (not previously treated by local therapy such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) or previously treated and has progressed until baseline (both, measureable lesion and/or progressed lesion have to be confirmed by central image review of baseline and progression scan).
    •Patients who have received local therapy such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation are eligible. Previously treated lesions are only selected as target lesions when they have progressed (to be confirmed by central image review of an initial set of scans taken after the local treatment and another showing progression. At least 8 weeks are needed between the scans). Local therapy has to be completed at least 4 weeks prior to the baseline scan.
    •Resolution of all acute toxic effects of any prior local therapy to Common Toxicity Criteria for Adverse Events (CTCAE 4.03) grade ≤1.
    •ECOG performance status of 0 or 1.
    •Liver function status of Child-Pugh Class A.
    •The following laboratory criteria must be met:
    Platelet count ≥ 60 x 109/L
    Hemoglobin ≥ 8.5 g/dL
    Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    Total bilirubin ≤ 3.0 mg/dL
    Alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN)
    Aspartate aminotransferase (AST) ≤ 5 x ULN
    Albumin ≥ 2.8 g/dL
    Amylase and lipase ≤ 1.5 x ULN
    Serum creatinine ≤ 1.5 x ULN
    Prothrombin time-international normalized ratio (PT-INR) ≤2.3, or PT ≤ 6 seconds above control.
    •Patient has within normal range cardiac function confirmed by the enrolling clinical institute as measured by echocardiogram or multiple gated acquisition (MUGA) scan.
    •Patients who are therapeutically anti-coagulated with an agent such as warfarin or heparin are allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable (within Child Pugh class A threshold) based on a measurement at pre-dose, as defined by the local standard of care.
    E.4Principal exclusion criteria
    •Any Cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Staging: Ta, Tis and T1).
    •Patients who are eligible for surgery, liver transplantation, ablation or transarterial chemoembolization for HCC.
    •Renal failure requiring hemo- or peritoneal dialysis.
    •History of cardiac disease
    -Congestive heart failure New York Heart Association (NYHA) > class 2.
    -Unstable angina (angina symptoms at rest, new-onset angina i.e. within the last 3 months) or myocardial infarction (MI) within the past 6 months prior to start of screening.
    -Cardiac arrhythmias requiring anti-arrhythmic therapy.
    •Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management).
    •Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B is allowed if no active replication (defined as abnormal ALT >2xULN associated with HBV DNA >20,000 IU/mL ) is present (45). Hepatitis C is allowed if no antiviral treatment is required.
    •Known human immunodeficiency virus (HIV) infection.
    •Known history of, or symptomatic metastatic brain or meningeal tumors (head CT or MR at Screening to confirm the absence of central nervous system [CNS] disease if patient had symptoms suggestive or consistent with CNS disease).
    •History of interstitial lung disease (ILD).
    •History of hepatic encephalopathy.
    •Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days prior to start of screening.
    •Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months prior to start of screening.
    •History of organ allograft, cornea transplantation will be allowed.
    •Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
    •Known or suspected hypersensitivity to any of the study drugs, study drug classes, or components in the formulation given during the course of this study.
    •Patients unable to take oral medication, requiring intravenous alimentation, who had malabsorption syndrome or any other conditions affecting GI absorption, or who have active peptic ulcer disease.
    •Any condition that was unstable or which could jeopardize the safety of the patient and his/her compliance in the study.
    •Pregnant or lactating women.
    •Uncontrolled ascites (defined as not easily controlled with diuretic treatment).
    •History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
    •Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR.
    •Non-healing wound, ulcer, or bone fracture.
    •Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention: beta blockers or endoscopic treatment. Assessment of esophageal varices should be performed by endoscopy within 6 months prior to start of study treatment and within 12 months for patients in whom conventional medical intervention for known esophageal varices is already in place.
    •Patients with seizure disorder requiring medication.
    Excluded previous therapies and medications:
    •Radiotherapy within 4 weeks prior to start of screening. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of PD if this is the only site of disease.
    •Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, hormonal therapy and experimental or approved therapies during this trial or within 30 days prior to start of screening, except prior therapy with sorafenib as detailed in the current protocol.
    •Sorafenib treatment within 2 weeks of signing ICF.
    •Any drug (except sorafenib) that targets angiogenesis, especially vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR).
    •Tyrosine-kinase inhibitors (except sorafenib).
    •Major surgery or significant traumatic injury within 4 weeks prior to start of screening.
    •Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte colony-stimulating factor (GM-CSF), within 3 weeks prior to start of screening (these may be used in the management of acute toxicity such as febrile neutropenia or CTCAE 4.03 grade 3-4 neutropenia at the discretion of the investigator; however they may not be substituted for a required dose reduction).
    •Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should be stopped 2 weeks before start of screening
    •Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before start of screeningt and thereafter).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable, for both stages of this study, is the central radiological assessment of ORR [confirmed complete response (CR) plus partial response (PR)] according to mRECIST. ORR is defined as the proportion of patients with the best tumor response (confirmed PR or CR) that is achieved during the study.
    Radiologic tumor assessments (central image review and investigator's assessment) will be done at Screening and then every 6 weeks during treatment. A further radiologic tumor assessment will be done within 14 days after last study medications intake, not needed if the previous tumor evaluation was performed within 4 weeks. In case of clinical progression, every effort should be made to provide radiological images for central image review to confirm the progression radiologically.

    Analysis will be performed separately for each stage. The analysis of the primary efficacy variable of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment. At that timepoint, an exploratory analysis of all other safety and efficacy variables will be performed. If the study is not continued into Stage 2, the final analysis of Stage 1 will be performed 12 months after the last Stage 1 patient's first treatment.

    The primary analysis of the primary efficacy variable of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment. At that time point, an exploratory analysis of all other safety and efficacy variables will be performed.

    Efficacy variables will be analyzed for both the FAS and the PPS. At Stage 1 and Stage 2, the analysis based on the FAS, full-analysis set (all patients assigned to study treatment) will be considered primary.

    As Stage 1 is exploratory, there will be no statistical testing at the end of Stage 1; all analyses will be descriptive only.

    ORR will be tested at Stage 2 against the null hypothesis that the true ORR is less than or equal to 0.45 at a one-sided type-1 error level of 0.025. A point estimate and the 95% confidence intervals for ORR will be calculated.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will be performed for both stages approximately 12 weeks after the last patient started study treatment.
    E.5.2Secondary end point(s)
    Overall response rate (ORR) by investigator's assessment according to mRECIST and RECIST 1.1
    Overall response rate (ORR) confirmed according to RECIST (Version 1.1)
    Disease control rate (DCR), central and investigator's assessment
    Overall survival (OS)
    Time to radiographic tumor progression (TTP), central and investigator's assessment
    Duration of Response (DOR), central and investigator's assessment
    Time to objective response (CR or PR), central and investigator's assessment
    Change in tumor size, central and investigator's assessment
    Best overall response, central and investigator's assessment
    Progression-free survival (PFS), central and investigator's assessment
    Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep)
    Biomarker analysis
    PK analysis
    Patient Reported Outcome (PRO) / Health Related Quality of Life (HRQoL) at Stage 2 only
    Safety

    Secondary efficacy variables will be evaluated and presented by means of descriptive statistics. Time-to-event variables will be displayed by Kaplan-Meier estimates and corresponding graphs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    An exploratory analysis of all other safety and efficacy variables of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment.
    An exploratory analysis of all other safety and efficacy variables of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment.
    The final analysis of all secondary efficacy and safety variables, and an additional exploratory analysis of the primary efficacy variable will be performed when the median time to radiological tumor progression can be determined (i.e. when the majority of patients have experienced progression).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    China
    Czech Republic
    France
    Germany
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    New Zealand
    Philippines
    Russian Federation
    Singapore
    Spain
    Switzerland
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    Vietnam
    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
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
    The primary completion date for this study according to the Food and Drug Administration (FDA) Amendment Act is specified in a separate document (not part of this Clinical Study Protocol CSP).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    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: 1590
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1060
    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 795
    F.4.2.2In the whole clinical trial 2650
    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)
    Post-study therapy will be at the discretion of the investigator.
    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 Decision2013-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-10-08
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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