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    Summary
    EudraCT Number:2016-000621-39
    Sponsor's Protocol Code Number:Sym004-11
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-09
    Trial 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 number2016-000621-39
    A.3Full title of the trial
    An Open-label, Multicenter, Phase 2 Trial Investigating Sym004 in Patients with Metastatic Colorectal Cancer and Acquired Resistance to Anti-EGFR Monoclonal Antibodies and Documented Mutation of Extra Cellular Domain of EGFR (ECD-EGFR)
    Estudio abierto, multicéntrico, de fase 2 que investiga Sym004 en pacientes con cáncer colorrectal metastásico, con resistencia adquirida a anticuerpos monoclonales anti-EGFR y con mutación documentada del dominio extracelular del EGFR (ECD-EGFR)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Sym004 in Metastatic Colorectal Cancer and ECD-EGFR Patients
    Sym004 en pacientes con cáncer colorrectal metastásico y ECD-EGFR .
    A.4.1Sponsor's protocol code numberSym004-11
    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 SponsorSymphogen A/S
    B.1.3.4CountryDenmark
    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 supportSymphogen A/S
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSymphogen A/S
    B.5.2Functional name of contact pointIvan Horak
    B.5.3 Address:
    B.5.3.1Street AddressPederstrupvej 93
    B.5.3.2Town/ cityBallerup
    B.5.3.3Post code2750
    B.5.3.4CountryDenmark
    B.5.4Telephone number45 20552604
    B.5.6E-mailidh@symphogen.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 nameSym004
    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 INNFutuximab
    D.3.9.1CAS number 1310460-85-5
    D.3.9.2Current sponsor code992DS
    D.3.9.3Other descriptive nameSYM004
    D.3.9.4EV Substance CodeSUB177082
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNModotuximab
    D.3.9.1CAS number 1310460-86-6
    D.3.9.2Current sponsor code1024DS
    D.3.9.3Other descriptive nameSYM004
    D.3.9.4EV Substance CodeSUB177082
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Colorectal Cancer and Acquired Resistance to Anti-EGFR Monoclonal Antibodies and Documented Mutation of Extra Cellular Doman of EGFR
    Cáncer colorrectal metastásico y resistencia adquirida a anticuerpos monoclonales anti-EGFR y con mutación documentada del dominio extracelular del EGFR (ECD-EGFR)
    E.1.1.1Medical condition in easily understood language
    Metastatic Colorectal Cancer
    Cáncer colorrectal metastásico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    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
    To assess the efficacy of the weekly dosing regimen (9 mg/kg loading dose followed by 6 mg/kg/week dose) of Sym004 in terms of overall response rate (ORR) in patients with mCRC harboring ECD-EGFR mutations
    evaluar la eficacia de la pauta posológica semanal (dosis de carga de 9 mg/kg seguida de dosis semanal de 6 mg/kg) de Sym004 en cuanto a la tasa de respuesta general (TRG) en pacientes con cáncer colorrectal metastásico (CCRm) que presentan mutaciones del dominio extracelular del receptor del factor de crecimiento epidérmico (ECD-EGFR)
    E.2.2Secondary objectives of the trial
    • To assess efficacy in terms of duration of response (DOR), progression-free survival (PFS), time-to-treatment failure (TTF), and overall survival (OS)
    • To determine the safety profile of the weekly dosing regimen
    • To evaluate the dose intensity for the weekly dosing regimen
    • To evaluate pharmacokinetics and immunogenicity of Sym004
    • Evaluar la eficacia en cuanto a la duración de la respuesta (DR), la supervivencia sin progresión (SSP), el tiempo hasta el fracaso del tratamiento (TFT) y la supervivencia general (SG)
    • Determinar el perfil de seguridad de la pauta posológica semanal
    • Evaluar la intensidad de la dosis de la pauta posológica semanal
    • Evaluar la farmacocinética (FC) y la inmunogenicidad de Sym004
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent obtained before undergoing any study-related activities
    • Male or female, at least 18 years of age
    • Histologically or cytologically confirmed locally advanced or metastatic CRC that is documented to be without KRAS or NRAS gene mutations (i.e. tumors must express the KRAS and NRAS wild type (WT) exon 2, 3, and 4)
    • Identification of any ECD-EGFR mutation in blood sample
    • Failure of or intolerance to all of the following
    a. Fluorouracil (5-FU)
    b. Oxaliplatin
    c. Irinotecan
    • Previous treatment with bevacizumab and/or ziv-aflibercept is allowed, but not mandatory.
    • “Acquired resistance” to marketed anti-EGFR mAbs
    a. Response while on previous treatment with marketed anti-EGFR mAb, defined as
    i. Partial response (PR) or complete response (CR) and/or
    ii. Stable disease (SD) for more than 16 weeks
    b. Documented progressive disease (PD) during or within 3 calendar months after cessation of previous anti-EGFR mAb treatment
    • No more than 3 calendar months from last dose of previous anti-EGFR mAb to time of consent
    • Measurable disease defined as one or more target lesions according to RECIST 1.1
    • Life expectancy of at least 3 months
    • ECOG PS ≤ 1
    • Consentimiento informado por escrito otorgado antes de realizar cualquier actividad relacionada con el estudio.
    • Edad mínima de 18 años, ya se trate de un hombre o una mujer.
    • Confirmación histológica o citológica de CCR localmente avanzado o metastásico que haya sido documentado sin mutaciones del gen KRAS o NRAS (es decir, los tumores deben expresar el gen KRAS o NRAS de tipo natural [wild type, WT], exones 2, 3 y 4)
    • Identificación de cualquier mutación ECD-EGFR en la muestra de sangre
    • Fracaso de todos estos medicamentos o intolerancia a ellos:
    a. Fluorouracilo (5-FU)
    b. Oxaliplatino
    c. Irinotecán
    • Se permite un tratamiento previo con bevacizumab o ziv-aflibercept, pero no es obligatorio.
    • “Resistencia adquirida” a los ACM anti-EGFR comercializados
    a. En un tratamiento anterior con ACM anti-EGFR comercializados, respuesta definida como:
    i. Respuesta parcial (RP) o respuesta completa (RC), o
    ii. Enfermedad estable (EE) durante más de 16 semanas
    b. Enfermedad progresiva (EP) documentada durante 3 meses naturales o en un plazo de 3 meses tras la interrupción de un tratamiento previo con ACM anti-EGFR.
    • No más de 3 meses naturales transcurridos desde la última dosis del tratamiento previo con ACM anti-EGFR hasta el momento del consentimiento
    • Enfermedad medible definida como una o más lesiones diana según los RECIST 1.1
    • Expectativa de vida de, por lo menos, 3 meses.
    • EG ECOG ≤ 1
    E.4Principal exclusion criteria
    • Intake of any investigational drug or any anticancer therapy in the 28 days (or 5 half-lives for noncytotoxics, whichever is shorter) before the first dose of IMP
    • Previous treatment with Sym004, TAS-102 (trifluridine and tipiracil [Lonsurf®]) and/or regorafenib [Stivarga®]
    • Patients who in the opinion of the Investigator would benefit more from regorafenib or Lonsurf® treatment (except where regorafenib or Lonsurf® are not reimbursed in the country)
    • Diarrhea Common Terminology Criteria for Adverse Events (CTCAE) Grade >1 at Screening (Step 1)
    • Skin rash CTCAE Grade >1 from previous anti-EGFR therapy at Screening (Step 1)
    • Magnesium <0.9 mg/dL
    • Abnormal organ or bone marrow function
    • Administración de cualquier tratamiento antineoplásico o cualquier fármaco en investigación durante los 28 días anteriores a la primera dosis del PEI (o 5 semividas para los no citotóxicos, lo que ocurra antes).
    • Tratamiento previo con Sym004, TAS-102 (trifluridina y tipiracilo [Lonsurf®]) o regorafenib [Stivarga®]
    • Pacientes que, según la opinión del investigador, se beneficiarían más con un tratamiento con regorafenib o Lonsurf® (excepto en el caso en que no se reembolse el coste de regorafenib o Lonsurf® en el país)
    • Grado de diarrea según los Criterios terminológicos comunes para acontecimientos adversos (Common Terminology Criteria for Adverse Events, CTCAE) > 1 en la selección (paso 1)
    • Grado de erupción cutánea según CTCAA > 1 en tratamiento anti-EGFR previo en la selección (paso 1)
    • Magnesio < 0,9 mg/dl
    • Función anómala de la médula ósea o de algún órgano
    E.5 End points
    E.5.1Primary end point(s)
    Documented best overall response (OR), assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on Investigator assessment.
    la mejor respuesta general (RG) documentada, evaluada por los Criterios de evaluación de respuesta en tumores sólidos (Response Evaluation Criteria in Solid Tumors, RECIST) v1.1 según la evaluación del investigador
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response (CR, PR, PD, or SD) will initially be evaluated per RECIST v1.1 by the Investigator. All scans from responders from Stage 1 of the trial will be subject for central evaluation at the timepoint of the futility assessment and all the rest will be evaluated at the end of the trial
    Respuesta (RC,RP,EP o EE) será incialmente evaluado por RECIST por el Investigador. Todos los escaners
    E.5.2Secondary end point(s)
    • DOR, which is defined as time from first documentation of tumor response (complete response [CR] or partial response [PR]) to disease progression
    • PFS, which is defined as the duration from the first dose of Sym004 until first event, where an event can be a progression (radiological confirmation or clinical progression) or death due to any cause, where death will only be considered as an event if it occurs within 12 weeks after last tumor response assessment without progression
    • TTF, which is defined as time from the first dose until discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death
    • OS, which is defined as the time from the first dose to the date of death. If a patient has not died, his survival time will be censored at the last date he was known to be alive
    • Pharmacokinetic (PK) parameters for Sym004 describing systemic exposure, half-life, clearance, and volume of distribution
    E.5.2.1Timepoint(s) of evaluation of this end point
    DOR is defined as time from first documentation of tumor response to disease progression
    PFS is defined as the duration from the first dose of Sym004 until first event, where an event can be a progression or death due to any cause, where death will only be considered as an event if it occurs within 12 weeks after last tumor response assessment without progression
    TTF is defined as time from the first dose until discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death
    OS is defined as the time from the first dose to the date of death. If a patient has not died, his survival time will be censored at the last date he was known to be alive
    PK - throughout study until end of treatment visit
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenicidad
    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 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 EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the complete trial is defined as last patient’s last visit (End-of-Trial Visit) or until last patient on treatment has completed 52 weeks on treatment, whichever is earlier.
    El final del ensayo completado se define como la última visita del último paciente (visita final del ensayo) o hasta que el último paciente haya completado 52 semanas de tratamiento, cualquierea que sea antes.
    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 months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months5
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 48
    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 a patient has discontinued Sym004 or has withdrawn early, usual treatment will be administered, if required, in accordance with the trial site’s standard of care and generally accepted medical practice and depending on the patient’s individual medical needs.
    Después de que un paciente ha dejado Sym004 o se ha retirado temprano, se administrará tratamiento habitual, si es necesario, de acuerdo con el estándar del centro de ensayo de atención y la práctica médica generalmente aceptada y en función de las necesidades médicas de cada paciente.
    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 Decision2016-11-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-29
    P. End of Trial
    P.End of Trial StatusCompleted
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