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    Summary
    EudraCT Number:2015-002646-31
    Sponsor's Protocol Code Number:CL1-49076-003
    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:2017-07-03
    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 number2015-002646-31
    A.3Full title of the trial
    Phase I/II study of oral administration of S 49076 given in combination with gefitinib in patients with EGFR mutated advanced non-small-cell lung cancer who have progressed after treatment with EGFR tyrosine kinase inhibitor.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I/II study to evaluate safety and activity of oral administration of S 49076 in combination with gefitinib in adult patients with EGFR mutated advanced non-small cell lung cancer who have progressed while on treatment with EGFR tyrosine kinase inhibitor (TKI) therapy.
    A.4.1Sponsor's protocol code numberCL1-49076-003
    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 SponsorInstitut de Recherche International Servier
    B.1.3.4CountryFrance
    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 supportADIR
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut de Recherche International SERVIER
    B.5.2Functional name of contact pointClinical Study Department
    B.5.3 Address:
    B.5.3.1Street Address50 rue Carnot
    B.5.3.2Town/ citySuresnes
    B.5.3.3Post code92284
    B.5.3.4CountryFrance
    B.5.4Telephone number+33155724366
    B.5.5Fax number+33155725412
    B.5.6E-mailclinicaltrials@servier.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.3.2Product code S49076
    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.3.9.2Current sponsor codeS49076
    D.3.9.3Other descriptive nameS49076
    D.3.9.4EV Substance CodeSUB130475
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    E.1.1.1Medical condition in easily understood language
    EGFR mutated advanced non-small cell lung cancer becoming resistant to EGFR TKI therapy.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025054
    E.1.2Term Lung cancer non-small cell stage IIIB
    E.1.2System Organ Class 100000015840
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025055
    E.1.2Term Lung cancer non-small cell stage IV
    E.1.2System Organ Class 100000015841
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I: -Determine the safety profile and tolerability of S 49076 given in combination with a fixed dose of gefitinib by assessment of DLT (assessed during cycle 1) and the adverse event profile (assessed at each study visit).
    -Establish the RP2D of S 49076 given in combination with a fixed dose of gefitinib.
    Phase II: -Evaluate the objective response rate (ORR) according to RECIST v1.1, in 3 subgroups of patients with locally advanced or metastatic NSCLC and treated with S 49076 and gefitinib defined according to the mechanism of acquired resistance to EGFR tyrosine kinase inhibitor (TKI):
    • Subgroup 1: Moderate to high level of MET amplification and/or high level of MET overexpression
    • Subgroup 2: Moderate level of AXL overexpression
    • Subgroup 3: High level of AXL overexpression.
    An interim analysis will be performed in each subgroup to stop the recruitment early for futility if it is clear that the association S 49076 and gefitinib is unlikely to show the expected benefit.
    E.2.2Secondary objectives of the trial
    Phase I:-Evaluate the PK profile of S 49076 and gefitinib in combination. -Evaluate the response to S 49076 and gefitinib in 3 subgroups of patients with MET and/or AXL dysregulation using archived tumour or newly performed biopsy. -Measure tumour response to S 49076 in combination with gefitinib by using RECIST v1.1.
    Phase II:-Evaluate the survival rate at 6 months, the progression-free survival, the response duration, the Clinical Benefit Rate in the 3 subgroups of patients. Clinical benefit rate is defined as the proportion of patients who have confirmed Complete Response or Partial Response as best response, or who experience Stable Disease lasting at least 6 months in the 3 subgroups of patients. -Characterize the safety and tolerability of the combination in assessing incidence of adverse events according to CTCAE V4.0. -Collect additional information on the PK profile of S 49076 in combination with gefitinib.
    -Evaluate the biomarkers potentially predictive of response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Male or female patient aged ≥ 18 years old or legal age of the majority in the country.
    -Histologically or cytologically confirmed stage IIIB/IV NSCLC ( locally advanced or metastatic, non-eligible for radical chemoradiotherapy or surgery with curative intention).
    -Progression will have occurred on single agent EGFR TKI treatment (erlotinib, gefitinib, icotinib, afatinib,dacomitinib) in the 1st line setting or in the 2nd line (after a first line of chemotherapy).
    -Patients must meet definition of acquired resistance based on the modified Jackman criteria.
    -Patients must have measurable tumour disease according to RECIST v1.1. (with at least one measurable lesion).
    -Estimated life expectancy > 12 weeks.
    -Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
    E.4Principal exclusion criteria
    -Foreseeable poor compliance to the study procedures.
    -Legally incapacitated person under guardianship or trusteeship.
    -Pregnant or breast-feeding women.
    -Unable to undergo CT scans or MRI.
    -Patients who have received more than 1 line of chemotherapy and more than 1 line of erlotinib, gefitinib, icotinib ,afatinib or dacotinimib.
    -Blood transfusion within 2 weeks prior to the inclusion.
    -Major surgery within 4 weeks prior to the inclusion
    -Prior radiotherapy within 4 weeks prior to the inclusion (within 1 week for palliative radiotherapy at localised lesions)
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - DLTs of S 49076 when given in combination with gefitinib.
    - Safety tolerance profile of the combination S 49076 / gefitinib.
    Phase II:
    - Objective Response Rate (ORR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I:
    - DLTs: D1 Cycle 2.
    - Safety tolerance profile: All visits
    Phase II:
    - Objective Response Rate (ORR): Screening visit, D1 Cycle 3 and withdrawal visit.
    E.5.2Secondary end point(s)
    Phase I:
    1-PK parameters of S 49076 and gefitinib in combination.
    2-Biomarkers predictive of response using archived tumours or newly performed biopsy.
    3-Tumour response of S 49076 in combination with gefitinib by using RECIST v1.1.
    Phase II:
    I.Activity:
    1-Survival rate.
    2-Progression Free Survival (PFS).
    3-Clinical Benefit Rate (CBR).
    4-Response duration.
    II.Safety tolerance profile.
    III.PK parameters of S 49076 in combination with gefitinib.
    IV.Biomarkers predictive of response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I:
    1-:D1, D2 and D15 of cycle 1 and D1 of cycle 2.
    2-:Prescreening
    3-:Screening visit, D1 Cycle 3 and withdrawal visit.
    Phase II:
    I.1-:-at 6 months.
    2-:will be calculated from the date of first drug intake until the date of progression or death due to any cause, whichever occurs first.
    3-:will be calculated as the proportion of patients with a confirmed CR or PR or a SD with duration of at least 6 months according to RECIST v1.1.
    4-:will be calculated among patients with confirmed response from the time that measurement criteria are first met for response until the date of progression or death due to any cause.
    II.: All visits
    III.: D1, D2 and D15 of cycle 1, and D1 of cycle 2.
    IV.: At Prescreening and at D1 of cycle 1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    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
    Canada
    China
    Germany
    Hungary
    Italy
    Japan
    Korea, Republic of
    Philippines
    Russian Federation
    Singapore
    Spain
    Taiwan
    Thailand
    United Kingdom
    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
    Last visit of last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    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: 114
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 57
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 171
    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)
    After discontinuation of the study drug and its associated agent, the participant will receive another treatment and/or have access to other appropriate care by her doctor, which will be at the investigator's discretion.
    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 Decision2017-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-07
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