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    Summary
    EudraCT Number:2015-002646-31
    Sponsor's Protocol Code Number:CL1-49076-003
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-10-05
    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 ConcernedSpain - AEMPS
    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.
    Estudio de fase I/II con S49076 oral administrado en combinación con gefitinib en pacientes con cáncer de pulmón de células no pequeñas avanzado con mutación del EGFR que han progresado tras tratamiento con un inhibidor de la tirosina kinasa del EGFR
    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.
    Estudio de fase I/II para evaluar la seguridad y actividad de la adiministración oral de S49076 en combinación con gefitinib en pacientes adultos con cáncer de pulmón de células no pequeñas avanzado que han progresado durante la terapia con un tratamiento con un inhibidor de la tirosina kinasa del EGFR
    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 SponsorLaboratorios Servier S. L.
    B.1.3.4CountrySpain
    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 supportLaboratorios Servier S.L.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLaboratios Servier S.L.
    B.5.2Functional name of contact pointDpto. Investigación y Desarrollo
    B.5.3 Address:
    B.5.3.1Street AddressAv. de los Madroños 33
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28043
    B.5.3.4CountrySpain
    B.5.4Telephone number+34917489014
    B.5.5Fax number+34913003249
    B.5.6E-mailitziar.fernandezgonzalez@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.3.8INN - Proposed INNNA
    D.3.9.1CAS number NA
    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
    Cáncer de pulmón de células no pequeñas localmente avanzado o metástasico
    E.1.1.1Medical condition in easily understood language
    EGFR mutated advanced non-small cell lung cancer becoming resistant to EGFR TKI therapy.
    cancer de pulmon de células no pequeñas que ha mostrado resistenncia tras la terapia con un inhibidor de la tirosina kinasa del EGFR
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10025054
    E.1.2Term Lung cancer non-small cell stage IIIB
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10025055
    E.1.2Term Lung cancer non-small cell stage IV
    E.1.2System Organ Class 100000004864
    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 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.
    ­Fase I:Determinar el perfil de seguridad y tolerabilidad de S 49076 administrado junto con una dosis fija de gefitinib mediante la evaluación de TLD (evaluada en C1) y el perfil de AEs (evaluado en cada visita de estudio).
    -­Establecer la DRF2 de S 49076 administrada junto con una dosis fija de gefitinib.
    Fase II:­Determinar la tasa de respuesta objetiva según los crit. RECIST v1.1 en 3 subgrupos de pctes con CPCNP localmente avanzado o metastásico y tratados con S 49076 y gefitinib definida en función del mecanismo de resistencia adquirida al ITK del EGFR .
    ?Subgrupo 1: Nivel de moderado a alto de la amplificación y/o sobreexpresión de MET
    ?Subgrupo 2: Nivel moderado de sobreexpresión de AXL
    ?Subgrupo 3: Nivel alto de sobreexpresión de AXL.
    Se realizará un análisis intermedio en cada subgrupo para interrumpir la inclusión prematuramente por intrascendencia si resulta evidente que es poco probable que la asociación de S 49076 con gefitinib muestre el beneficio esperado.
    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.
    Fase I:­-Evaluar el perfil PK)de S 49076 y gefitinib combinados-Evaluar la rpta a S49076 y gefitinib en 3 subgrupos de pacientes con alteración de la regulación de MET y/o AXL utilizando tumores almacenados o biopsias recién realizadas.Medir la rpta del tumor a S49076 combinado con gefitinib usando los criterios RECIST v1.1.
    Fase II:­Evaluar la tasa de supervivencia a 6 meses la supervivencia libre de progresión, la duración de la respuesta y la tasa de beneficio clínico en los 3 subgrupos de pacientes. La tasa de beneficio clínico se define como la proporción de pctes que presentan rpta completa confirmada o respuesta parcial como mejor rpta o que presenten enfermedad estable durante al menos 6 meses en los 3 subgrup.
    ­Caracterizar la seguridad y tolerabilidad de la combinación evaluando la incidencia de AEs según los CTCAE V4.0.
    ­Obtener información adicional sobre el perfil PK de S49076 combinado con gefitinib.
    ­Evaluar los biomarcadores potencialmente predictivos de rpta.
    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) 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
    Paciente masculino o femenino de ³ 18 años de edad, o edad de mayoría legal en ese país.
    CPCNP en etapa IIIB/IV confirmado histológica o citológicamente (localmente avanzado o metastásico, no subsidiario de quimioradioterapia radical o cirugía con intención curativa).
    La progresión se habrá producido durante el tratamiento con un ITK del EGFR en monoterapia (erlotinib, gefitinib, icotinib, afatinib) en primera o segunda línea (después de una primera línea de quimioterapia).
    Los pacientes deben cumplir la definición de resistencia adquirida en base a los criterios de Jackman
    Los pacientes deben tener enfermedad tumoral medible según los criterios RECIST v1.1 (con al menos una lesión medible).
    Esperanza de vida estimada > 12 semanas.
    Estado de rendimiento del paciente ECOG ? 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 or afatinib.
    -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.
    Previsión de incumplimiento de los procedimientos del estudio.
    Persona incapacitada legalmente bajo tutela o fideicomiso.
    Mujeres embarazadas o en periodo de lactancia.
    Imposibilidad de someterse a TAC o RM.
    Pacientes que han recibido más de 1 línea de quimioterapia y más de 1 línea de erlotinib, gefitinib, icotinib o afatinib.
    Transfusión de sangre en las 2 semanas anteriores a la inclusión.
    Cirugía mayor en las 4 semanas anteriores a la inclusión.
    Radioterapia previa en las 4 semanas anteriores a la inclusión.
    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)
    Fase I:
    ­-TLDs de S 49076 combinado con gefitinib.
    ­-Perfil de seguridad y tolerancia de la combinación S 49076/gefitinib

    Fase II:
    -Tasa de respuesta objetiva (TRO)
    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.
    FaseI:
    - TLDs: D1 ciclo 2.
    - Perfil de seguridad y tolerancia : todas las visitas
    Fase II:
    -Tasa de respuesta objetiva (TRO): visita de Screening , D1 ciclo 3 y visita de salida
    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.
    Fase I:
    ­1.Parámetros PK de S 49076 junto con gefitinib.
    ­2.Biomarcadores predictivos de respuesta usando tumores almacenados o en biopsia recién realizada.
    ­3.Respuesta tumoral a S 49076 en combinación con gefitinib mediante RECIST v1.1
    Fase II:
    ­I.Actividad:
    1.Tasa de supervivencia
    2.Supervivencia libre de progresión (SLP)
    3.?Tasa de Beneficio Clínico (TBC)
    4.Duración de la respuesta
    II.­Perfil de seguridad y tolerancia
    III.­Parámetros PK de S 49076 en combinación con gefitinib.
    ­IV.Biomarcadores predictivos de respuesta
    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-:D1 of each cycle.
    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.: D1 of each cycle.
    Fase I:
    1-:D1, D2 y D15 del ciclo1 y D1 del ciclo2.
    2-:D1 de cada ciclo.
    3-:Visita de Screening , D1 Ciclo 3 y vista de salida
    Fase II:
    1-:-a los 6 meses.
    2.se calculará desde la primera toma de la medicación del estudio hasta la fecha de la progresión o muerte por cualquier causa, lo que suceda primero.
    3.se calculará como la propoción de pacientes con una RC confirmada, una RP o una EE de al menos 6 meses de duración de acuerdo con RECIST v1.1.
    4.Se calculará entre los pacientes con respuesta confirmada desde el momento en que los criterios de medición se cumplen por primera vez para la respuesta y hasta la fecha de progresión o de muerte por cualquier causa.
    II.: en todas las visitas
    III.: D1, D2 yD15 del ciclo1, y D1 del ciclo 2.
    IV.: D1 de cada ciclo.
    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 Yes
    E.7.1.3.1Other trial type description
    to determine the Recommended Phase II Dose
    Determinar la dosis recomendada para la Fase II
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    China
    Germany
    Hong Kong
    Hungary
    Italy
    Korea, Republic of
    Malaysia
    Philippines
    Poland
    Singapore
    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 years3
    E.8.9.1In the Member State concerned months4
    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 months4
    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: 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 state85
    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 Decision2015-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-11-07
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