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    Summary
    EudraCT Number:2016-001604-28
    Sponsor's Protocol Code Number:EMR200095-006
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-12
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2016-001604-28
    A.3Full title of the trial
    A Phase Ib/II Multicenter, Randomized, Open Label Trial to Compare Tepotinib(MSC2156119J) Combined with Gefitinib Versus Chemotherapy as Second-line Treatment in Subjects with MET Positive, Locally Advanced or Metastatic Non-small
    Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tepotinib with Gefitinib in Subjects with Locally Advanced or Metastatic NSCLC (INSIGHT)
    A.3.2Name or abbreviated title of the trial where available
    INSIGHT
    A.4.1Sponsor's protocol code numberEMR200095-006
    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 SponsorMerck KGaA
    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 supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 6151 72 5200
    B.5.5Fax number+49 6151 72 2000
    B.5.6E-mailservice@merckgroup.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 nameTepotinib
    D.3.2Product code MSC2156119J
    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 INNtepotinib
    D.3.9.2Current sponsor codeMSC2156119J
    D.3.9.3Other descriptive nameMSC2156119J
    D.3.9.4EV Substance CodeSUB177092
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtepotinib
    D.3.9.2Current sponsor codeMSC2156119J
    D.3.9.3Other descriptive nameMSC2156119J
    D.3.9.4EV Substance CodeSUB177092
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 IRESSA 250 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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.3.4Pharmaceutical 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 INNgefitinib
    D.3.9.1CAS number 184475-35-2
    D.3.9.3Other descriptive nameGEFITINIB
    D.3.9.4EV Substance CodeSUB20637
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 ALIMTA 500 mg powder for concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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.3.4Pharmaceutical form Powder for concentrate 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 INNpemetrexed
    D.3.9.1CAS number 150399-23-8
    D.3.9.3Other descriptive namePEMETREXED DISODIUM
    D.3.9.4EV Substance CodeSUB03669MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Cisplatin 1 mg/ml Sterile Concentrate
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intraabdominal use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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 Carboplatin 10 mg/ml Intravenous Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical 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 INNcarboplatin
    D.3.9.1CAS number 41575-94-4
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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
    Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)
    E.1.1.1Medical condition in easily understood language
    Lung Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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
    Phase Ib
     To determine the RP2D of tepotinib when used in combination with gefitinib (at the approved standard dose of 250 mg) when administered orally once daily over a 21-day cycle in subjects with MET+ advanced NSCLC.
    Phase II
    To evaluate whether the efficacy in terms of progression free survival (PFS) of
    second-line tepotinib in combination with gefitinib is superior to
    pemetrexed+cisplatin/carboplatin in subjects with T790M negative, MET+ locally
    advanced or metastatic NSCLC harboring an EGFR mutation and having acquired
    resistance to first-line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or
    afatinib
    E.2.2Secondary objectives of the trial
    Phase Ib
    To characterize the PK of tepotinib when given in combination with gefitinib
    To characterize the PK of gefitinib when given in combination with tepotinib
    To assess the safety and tolerability of tepotinib in combination with gefitinib
    To evaluate preliminary antitumor activity of tepotinib in combination with gefitinib
    Phase II
    To evaluate the safety and tolerability of tepotinib in comb with gefitinib
    To evaluate the efficacy of tepotinib in combination with gefitinib in T790M negative, MET+ subjects
    To evaluate the antitumor activity of tepotinib in combination with gefitinib in T790M positive, MET+ subjects in a separate single-arm cohort (mainland China sites only)
    To assess patient-reported outcomes (PROs) with respect to quality of life (QoL), as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and time-to-symptom progression (TTSP), as measured by Lung Cancer Symptom Scale (LCSS)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenomics Substudy:
    The Pharmacogenomic Analysis Set will include all subjects who have provided the blood
    sample for PGx gene analysis and who have given consent for the PGx analyses.
    PGx analyses will be performed on genetic variations of genes such as UGT that may be
    involved in the PK, safety and efficacy of tepotinib in combination with gefitinib. In addition,
    analyses of other genetic variants that may influence the safety and efficacy of tepotinib in
    combination with gefitinib may be explored. The results of these exploratory PGx analyses will
    be provided in a separate report.
    E.3Principal inclusion criteria
    Phase Ib
    a) Histologically or cytologically confirmed advanced NSCLC, regardless of histology subtype, which failed on gefitinib for reasons other than toxicity or compliance;
    b) Availability of a fresh or archived pretreatment tumor biopsy (excluding fine needle aspiration and cytology samples). For subjects who have had at least 1 prior anticancer treatment, a biopsy obtained between failure of the most recent anticancer treatment and enrollment is mandatory;
    c) MET+ status, as determined by the central laboratory, i.e. c-Met overexpression as determined by immunohistochemistry (IHC) (i.e., IHC 2+ or IHC 3+);
    d) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
    Phase II
    a) Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology);
    b) Activating mutation of the EGFR receptor (documented, or as determined by the central laboratory);
    c) Acquired resistance on first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib;
    d) EGFR T790M status (as determined by the central laboratory, using a validated PCR test);
    T790M negative status for the randomized part T790M positive status for the single-arm cohort (mainland China sites only)
    e) Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory;
    f) MET+ status, as determined by the central laboratory, i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH;
    g) ECOG PS of 0 or 1.

    E.4Principal exclusion criteria
    Phase Ib .Subjects are not eligible for Phase Ib if they fulfill any of the following exclusion criteria:
    Cancer Related
    1.Symptomatic metastasis of brain and/or CNS, uncontrolled with antiepileptics and requiring steroids, unless treated and stable without steroids for at least 10 days within 4 weeks prior to the first dose of trial treatment;
    2.Any unresolved toxicity more than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) Grade 2 from previous anticancer therapy;
    3.Estimated life expectancy < 3 months;
    4.Need for transfusion within 14 days prior to the first dose of trial treatment;
    5.Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment.
    Laboratory Values and Organ Function
    1.Inadequate hematological function:Hemoglobin < 8.5 g/dLNeutrophils < 1.5 × 109/LPlatelets < 100 × 109/L
    2.Inadequate liver function:Total bilirubin > 1.5 × upper limit of normal (ULN)Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × ULN;
    For subjects with liver metastases:Total bilirubin > 1.5 × ULNAST/ALT > 5 × ULN
    3.Known pre-existing interstitial lung disease
    4.Inadequate renal function:
    6.Renal impairment as evidenced by serum creatinine  1.5 × ULN, or creatinine clearance (CrCl) < 60 mL/min calculated by the Cockcroft-Gault formula (24 hour CrCl might be requested by the investigator for confirmation, if calculated CrCl is < 60 mL/min. In such case, subjects with 24 hour CrCl < 60 mL/min should be excluded
    5.Subjects who have ongoing medical history of acute pancreatitis and/or chronic pancreatitis, with concomitant elevated lipase and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the diagnosis (subjects in mainland China only)
    General
    1.Impaired cardiac function
    Left ventricular ejection fraction (LVEF) < 45% defined by echocardiography (a screening LVEF assessment without history of congestive heart failure [CHF] is not required)
    Serious arrhythmia
    Unstable angina pectoris
    CHF New York Heart Association (NYHA) III and IV (Appendix E)
    Myocardial infarction within the last 12 months prior to trial entry
    Signs of pericardial effusion
    2.Hypertension uncontrolled by standard therapies (not stabilized to <150/90 mmHg)
    3.Contraindication to the administration of gefitinib
    4.Medical history of liver fibrosis/cirrhosis
    5.Past or current history of neoplasm other than NSCLC, except for curatively treated non melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years;
    6.Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product
    7.Major surgery within 28 days prior to Day 1 of trial treatment
    8.Known human immunodeficiency virus positivity
    9.Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of investigators
    10.Female subjects who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy until the end of study. A highly effective method of contraception is defined as those, alone or in combination, that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. This requirement begins 2 weeks before receiving the first trial treatment and ends 3 months after receiving the last treatment
    11.Known hypersensitivity to any of the trial treatment ingredients
    12.Legal incapacity or limited legal capacity
    13.Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial
    14.Participation in another interventional clinical trial (except those subjects who were solely involved in other trials where the investigation product was gefitinib, erlotinib, icotinib, or afatinib) within the 30 days prior to randomization/first dose
    Phase II
    Subjects are not eligible for Phase II if they fulfill any Phase Ib exclusion criteria listed above. Additional exclusion criteria, listed below, apply to Phase II only.
    General
    Any contraindication to the administration of either pemetrexed+cisplatin or pemetrexed+carboplatin
    Cancer Related
    1.Prior systemic anticancer treatment with eg. chemotherapy or any other agents excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo]adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed)
    2.Prior treatment with other agents targeting the HGF/c-Met pathway
    E.5 End points
    E.5.1Primary end point(s)
    1- Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT)
    2- Phase 1b: Percentage of subjects with adverse events (AEs)
    3- Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment
    E.5.1.1Timepoint(s) of evaluation of this end point
    1- Up to Day 21 of Cycle 1
    2- Baseline up to Day 30 after the last dose of study treatment
    3- Up to 8 months
    E.5.2Secondary end point(s)
    1. Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments
    2. Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment
    3. Overall Survival (OS) Time
    4. Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria
    5. Percentage of subjects with disease control according to RECIST version 1.1 criteria
    6. Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t)
    7. Percentage of subject with treatment emergent adverse events (TEAEs), treatment related TEAEs, SAEs, treatment related SAEs, TEAEs with toxicity >= 3, treatment related TEAEs >= 3, and TEAEs leading to permanent treatment discontinuation
    8. Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau)
    9. Phase 1b: Maximum Observed Plasma Concentration (Cmax)
    10. Phase 1b: Average Plasma Concentration (Cavg)
    11. Phase 1b: Minimum Concentration (Cmin)
    12. Phase 1b:Time to Maximum Concentration (Tmax)
    13. Phase 1b: Area Under the Curve From Time Zero to Infinity (AUC 0-inf)
    14. Phase 1b: Apparent Body Clearance of the drug from Plasma (CL/F)
    15. Phase 1b: Apparent Volume of Distribution (Vz/F)
    16. Phase 1b: Volume of Distribution at Steady State (Vss/F)
    17. Phase 1b: Apparent Terminal Rate Constant (λ z)
    18. Phase 1b: Apparent Terminal Half-Life (t1/2)
    19. Percentage of subjects with death with reasons within 30 (±3) days after the last dose of study drug
    20. Percentage of subjects with abnormalities in safety laboratory tests as graded by NCI-CTCAE (Version 4.0)
    21. Percentage of subjects with abnormalities incl. vital signs, 12-lead ECG changes, physical examination, body weight, and Eastern Cooperative Oncology Group (ECOG) PS.
    22. Health related quality of life (HRQoL)
    23. Time-to-Symptom Progression (TTSP) measured by Lung Cancer Symptom Scale (LCSS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- Time from randomiz. to death or up to 8 mo whichever occur first
    2- Time from 1st drug adm. to death or up to 8 mo whichever occur 1st
    3- Time from random. to death or up to 10 mo whichever occur 1st
    4- endpoint number 7 and 8: Every 6 wks until Wk 72 and every 12 weeks after Wk 72 til radiol. documented PD, death, end of trial, or starting a new treatment, whichever occurs first
    5- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1
    6- 0 up to D 30 after the last dose 7 to 18- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1
    19- 30 days after the last dose
    20, and 21- 0 up to Day30 after the last dose
    22 and 23- D 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until PD, and end of treatment
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    to determine the recomended Phase II dose
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    pemetrexed + cisplatin/carboplatin
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Bulgaria
    Canada
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Netherlands
    Romania
    Singapore
    Slovakia
    Spain
    Taiwan
    United States
    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 the trial is defined as the time point in Phase II when death has been reported for two thirds of the subjects
    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 years3
    E.8.9.2In all countries concerned by the trial months6
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 112
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 184
    F.4.2.2In the whole clinical trial 192
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-08-11
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