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    Summary
    EudraCT Number:2016-000621-39
    Sponsor's Protocol Code Number:Sym004-11
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-20
    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 ConcernedItaly - Italian Medicines Agency
    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)
    Sperimentazione di fase 2, in aperto, multicentrica volta a valutare Sym004 nei pazienti con carcinoma colorettale metastatico e resistenza acquisita agli anticorpi monoclonali anti-EGFR e mutazione documentata del dominio extracellulare (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 in pazienti con carcinoma colorettale metastatico e ECD-EGFR
    A.3.2Name or abbreviated title of the trial where available
    Sym004 in Metastatic Colorectal Cancer and ECD-EGFR Patients
    Sym004 in pazienti con carcinoma colorettale metastatico e 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 number004520552604
    B.5.5Fax number004520552604
    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.3.9.4EV 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
    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.3.9.4EV 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
    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
    Carcinoma colorettale metastatico e resistenza acquisita agli anticorpi monoclonali anti-recettore del fattore di crescita dell¿epidermide (EGFR) e mutazione documentata del dominio extracellulare (Extra Cellular Domain) di EGFR (ECD-EGFR)
    E.1.1.1Medical condition in easily understood language
    Metastatic Colorectal Cancer
    Carcinoma colorettale metastatico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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
    Valutare l¿efficacia del regime di somministrazione settimanale (una dose di carico da 9 mg/kg seguita da una dose settimanale da 6 mg/kg) di Sym004 in termini di tasso di risposta complessiva (ORR) in pazienti affetti da cancro colorettale metastatico (mCRC) che presenta mutazioni del dominio extracellulare del recettore del fattore di crescita dell¿epidermide (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
    ¿ Valutare l¿efficacia in termini di durata della risposta (DOR), sopravvivenza libera da progressione (PFS), tempo al fallimento del trattamento (TTF) e sopravvivenza complessiva (OS)
    ¿ Determinare il profilo di sicurezza del regime di somministrazione settimanale
    ¿ Valutare l¿intensit¿ della dose per il regime di somministrazione settimanale
    ¿ Valutare la farmacocinetica (PK) e l¿immunogenicit¿
    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
    • Consenso informato scritto ottenuto prima di intraprendere qualsiasi attività correlata allo studio
    • Soggetti di sesso maschile o femminile, di almeno 18 anni d’età
    • CRC localmente avanzato o metastatico, istologicamente o citologicamente confermato, privo, in maniera documentabile, di mutazioni dei geni KRAS o NRAS (in altre parole, i tumori devono presentare gli esoni 2, 3 e 4 di KRAS e NRAS wild type [WT])
    • Identificazione di qualsiasi mutazione di ECD-EGFR nel campione di sangue
    • Fallimento di o intolleranza ai seguenti trattamenti:
    a. Fluorouracile (5-FU)
    b. Oxaliplatino
    c. Irinotecan
    • È consentito, ma non obbligatorio, un precedente trattamento con bevacizumab e/o ziv-aflibercept
    • “Resistenza acquisita” ai mAb anti-EGFR commercializzati
    a. Risposta nel corso di precedenti trattamenti con mAb anti-EGFR commercializzati, definita come:
    i. Risposta parziale (RP) oppure risposta completa (RC) e/o
    ii. Malattia stabile (SD) per oltre 16 settimane
    b. Malattia progressiva (PD) documentata durante o entro i 3 mesi successivi all’interruzione di un precedente trattamento con mAb anti-EGFR
    • Non più di 3 mesi dall’ultima dose del precedente trattamento con mAb anti-EGFR fino al momento del consenso
    • Malattia misurabile, definita come una o più lesioni target in base ai RECIST 1.1
    • Aspettativa di vita di almeno 3 mesi
    • PS 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
    • Assunzione di qualsiasi farmaco sperimentale o terapia antitumorale nei 28 giorni (o 5 emivite per i non citotossici, a seconda di quale periodo sia più breve) precedenti alla prima dose di IMP
    • Precedente trattamento con Sym004, TAS-102 (trifluridina e tipiracil [Lonsurf®]) e/o regorafenib [Stivarga®]
    • Pazienti che, a giudizio dello sperimentatore, trarrebbero maggiori benefici dal trattamento con regorafenib o Lonsurf® (ad eccezione dei Paesi nei quali regorafenib o Lonsurf® non è rimborsato)
    • Diarrea di Grado >1 secondo i Criteri terminologici comuni per gli eventi avversi (CTCAE) allo Screening (Fase 1)
    • Eruzione cutanea di Grado >1 secondo i CTCAE da precedente terapia anti-EGFR allo Screening (Fase 1)
    • Magnesio <0,9 mg/dl
    • Funzionamento anomalo di un organo o del midollo osseo
    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.
    Migliore risposta complessiva (OR) documentata, valutata dallo sperimentatore in base ai criteri di valutazione della risposta nei tumori solidi (RECIST) v1.1
    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
    Le risposte (CR, PR, PD, or SD) verranno inizialmente valutate dallo sperimentatore per RESIST v1.1. Tutte le scansioni dei responders dallo Stage 1 dello studio saranno soggette a valutazione centrale al tempo del " futility assessment" e il resto delle scansioni verranno valutate alla fine dello studio.
    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
    ¿ DOR, definito come il tempo dalla prima documentazione di risposta tumorale (CR o PR) alla progressione di malattia
    ¿ PFS, definita come la durata dalla prima dose di Sym004 fino al primo evento, dove un evento pu¿ essere progressione (conferma radiologica o progressione clinica) o morte dovuta a qualsiasi causa - morte verr¿ considerata come un evento se occorre entro 12 settimane dopo l'ultima risposta tumorale senza progressione
    ¿ TTF, definita come il tempo dalla prima dose fino all'interruzione del trattamento per qualsiasi motivo, inclusi progressione di malattia, tossicit¿ del trattamento, e morte
    ¿ OS, definita come il tempo dalla prima dose di farmaco alla data della morte. Se il paziente non ¿ deceduto, il suo tempo di sopravvivenza sar¿ censurato in occasione dell'ultima data in cui era noto essere vivo
    ¿ Parametri PK per Sym004 che descrivono esposizione sistemica, emivita, clearance e volume di distribuzione
    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
    DOR definito come il tempo dalla prima documentazione di risposta tumorale alla progressione di malattia
    PFS, definita come la durata dalla prima dose di Sym004 fino al primo evento, dove un evento pu¿ essere progressione (conferma radiologica o progressione clinica) o morte dovuta a qualsiasi causa - morte verr¿ considerata come un evento se occorre entro 12 settimane dopo l'ultima risposta tumorale senza progressione
    TTF definita come il tempo dalla prima dose fino all'interruzione del trattamento per qualsiasi motivo, inclusi progressione di malattia, tossicit¿ del trattamento, e morte
    OS definita come il tempo dalla prima dose di farmaco alla data della morte. Se il paziente non ¿ deceduto, il suo tempo di sopravvivenza sar¿ censurato in occasione dell'ultima data in cui era noto esse
    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
    Immunogenicit¿
    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.8.2.4Number of treatment arms in the trial1
    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 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 Information not present in EudraCT
    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.
    la conclusione della sperimemtazione ¿ definita come LVLP oppure come completamento delle 52 settimane di trattamento dell'ultimo paziente, se anteriore al LPLV.
    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.
    Dopo che un paziente ha interrotto Sym004 o si ¿ ritirato precocemente dallo studio, sar¿ somministrato il trattamento di normale pratica clinica previsto dal centro e a seconda di individuali esigenze mediche del paziente.
    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 Decision2016-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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