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    Summary
    EudraCT Number:2015-004849-11
    Sponsor's Protocol Code Number:AIO-KRK-0116
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-07-04
    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 ConcernedGermany - PEI
    A.2EudraCT number2015-004849-11
    A.3Full title of the trial
    Randomised study to investigate FOLFOXIRI plus cetuximab or FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutated metastatic colorectal cancer (FIRE-4.5)
    Randomisierte Studie zur Untersuchung von FOLFOXIRI plus Cetuximab oder FOLFOXIRI plus Bevacizumab als Erstlinientherapie des BRAF mutierten metastasierten kolorektalen Karzinoms
    (FIRE-4.5)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomised study to investigate FOLFOXIRI plus Cetuximab or FOLFOXIRI plus bevacizumab as first-line treatment of BRAF-mutated metastatic colorectal cancer (FIRE 4.5)
    Randomisierte Studie zur Untersuchung von FOLFOXIRI plus Cetuximab oder FOLFOXIRI plus Bevacizumab als Erstlinientherapie des BRAF mutierten metastasierten kolorektalen Karzinoms
    (FIRE-4.5)
    A.3.2Name or abbreviated title of the trial where available
    FIRE 4.5
    FIRE 4.5
    A.4.1Sponsor's protocol code numberAIO-KRK-0116
    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 SponsorUniversity Clinic od Munich-Großhadern (represented by the medical management)
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Healthcare KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Ludwig-Maximilians-Univ. München, Klinikum Großhadern
    B.5.2Functional name of contact pointstudy secretariat
    B.5.3 Address:
    B.5.3.1Street AddressMarchionistr. 15
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number004989440072208
    B.5.5Fax number004989440075256
    B.5.6E-mailMatthias.Wolff@med.uni-muenchen.de
    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 Yes
    D.2.1.1.1Trade name Erbitux (100 mg)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe 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 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 INNCETUXIMAB
    D.3.9.1CAS number 205923-56-4
    D.3.9.4EV Substance CodeSUB01178MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal IgG1 antibody
    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.2.1.2Country 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 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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 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 Yes
    D.3.11.13.1Other medicinal product typehumanised monoclonal anti-VEGF antibody
    D.IMP: 3
    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 Erbitux (500mg)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe 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 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 INNCETUXIMAB
    D.3.9.1CAS number 205923-56-4
    D.3.9.4EV Substance CodeSUB01178MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal IgG1 antibody
    D.IMP: 4
    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.2.1.2Country 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 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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 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 Yes
    D.3.11.13.1Other medicinal product typehumanised monoclonal anti-VEGF antibody
    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.2.1.2Country 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.3.1Product nameIrinotecan
    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
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIRINOTECAN
    D.3.9.1CAS number 97682-44-5
    D.3.9.4EV Substance CodeSUB08295MIG
    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: 6
    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.2.1.2Country 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.3.1Product name5-Fluorouracil
    D.3.4Pharmaceutical form Solution for injection
    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.3.9.1CAS number 51-21-8
    D.3.9.3Other descriptive nameFLUOROURACIL
    D.3.9.4EV Substance CodeSUB07721MIG
    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: 7
    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.2.1.2Country 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.3.1Product nameFolinic acid
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravascular use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameFOLINIC ACID
    D.3.9.4EV Substance CodeSUB13910MIG
    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: 8
    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.2.1.2Country 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.3.1Product nameOxaliplatin
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNOXALIPLATIN
    D.3.9.1CAS number 61825-94-3
    D.3.9.4EV Substance CodeSUB09490MIG
    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
    Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer, mCRC), primarily non-resectable or surgery refused by the patient;
    RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis); BRAF-mutated (V600E) tumour (proven in the primary tumour or metastasis)
    Histologisch gesichertes Adenokarzinom des Kolons oder Rektums im UICC Stadium IV mit Metastasen (metastasiertes kolorektales Karzinom [mKRK]), Metastasen primär nicht resektabel oder Patient lehnt Operation ab; RAS - Wildtyp-Status (KRAS und NRAS Exone 2,3,4) des Tumors (nachgewiesen in Primärtumor oder Metastase); BRAF mutierter (V600E) Tumor (nachgewiesen in Primärtumor oder Metastase)
    E.1.1.1Medical condition in easily understood language
    BRAF-mutated metastatic colerectal cancer, RAS-wildtyp
    BRAF-mutiertes, metastasiertes Kolorektales Karzinom, RAS-Wildtyp
    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 compare the objective response rate (ORR) according to RECIST 1.1 of treatment with FOLFOXIRI plus cetuximab versus treatment with FOLFOXIRI plus bevacizumab in BRAF-mutated patients.
    Vergleich der Ansprechrate (ORR) nach RECIST 1.1 der Behandlung mit FOLFOXIRI plus Cetuximab gegenüber der Behandlung mit FOLFOXIRI plus Bevacizumab bei BRAF-mutierten Patienten.
    E.2.2Secondary objectives of the trial
    • Investigation of progression-free survival (PFS) from randomisation
    • Investigation of overall survival (OS) from randomisation
    • Investigation of early tumour shrinkage (ETS) and depth of response (DpR)
    • Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
    • Investigation of prospective analysis of tumour marker level evolution (CEA and CA 19-9)
    • Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment
    • Investigation of the sequence of therapy after 1st-line treatment and its impact on OS
    • Untersuchung des progressionsfreien Überlebens (PFS) ab Randomisation
    • Untersuchung des Gesamtüberlebens (OS) ab Randomisation
    • Untersuchung der frühen Tumorreduktion („early tumor shrinkage [ETS]“) und der Tumoransprechtiefe („depth of response [DpR]“)
    • Untersuchung von molekularen Biomarkern zur Prädiktion von Sensitivität und sekundärer Resistenz einer anti-EGFR Therapie mit Cetuximab (inklusive Tumorbiopsien und Flüssigbiopsien aus Blutproben)
    • Untersuchung der prospektiven Analyse des Tumormarkerverlaufs (CEA und CA 19-9)
    • Erfassung der Sicherheit und Verträglichkeit (NCI-CTCAE Version 4.03 Kriterien) der Therapie
    • Untersuchung der Reihenfolge von Therapielinien nach der Erstlinientherapie und deren Einfluss auf das Gesamtüberleben
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer, mCRC), primarily non-resectable or surgery refused by the patient
    • RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis)
    • BRAF V600E mutation-positive tumour (proven in the primary tumour or metastasis)
    • Age ≥18 years
    • ECOG performance status 0-1
    • Patients suitable for chemotherapy administration
    • Patient's written declaration of consent obtained
    • Estimated life expectancy > 3 months
    • Presence of at least one measurable reference lesion according to the RECIST 1.1 – criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation)
    • Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. Molecular profiling of blood samples is optionally performed.
    • Females of childbearing potential (FCBP) and men must agree to use effective contraceptive measures (Pearl index <1) for the duration of the study treatment and for at least 6 months after last administration of the study medication. A female subject will be considered to be of child-bearing potential unless she is ≥ 50 years of age as well as has had a natural menopause for at least 2 years or has been surgically sterilised
    • Adequate bone marrow function:
    • Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
    • Thrombocytes ≥ 100 x 109/L,
    • Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
    • Adequate hepatic function:
    - Serum bilirubin ≤ 1.5 x upper limit of normal (ULN),
    - ALAT and ASAT ≤ 2.5 x ULN (in case of hepatic metastases, ALAT and ASAT ≤ 5 x ULN)
    • INR < 1.5 and aPTT < 1.5 x ULN (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range for at least 2 weeks.
    • Adequate renal function:
    ▫ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50ml/min.
    • Adequate cardiac function: ECG and echocardiogram with a LVEF of ≥55%
    • No previous chemotherapy for metastatic disease (prior radiotherapy of metastasis/metastases without application of chemotherapy permitted provided that no radiated metastasis is selected as target lesion). Patients with need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFOX, FOLFIRI or FOLFOXIRI prior to randomisation (Cycle 0).
    • Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy ≥3 months
    • Any relevant toxicities of previous treatments must have subsided to grade 0
    • Histologisch gesichertes Adenokarzinom des Kolons oder Rektums im UICC Stadium IV mit Metastasen (metastasiertes kolorektales Karzinom [mKRK]), Metastasen primär nicht resektabel oder Patient lehnt Operation ab
    • RAS - Wildtyp-Status (KRAS und NRAS Exone 2,3,4) des Tumors (nachgewiesen in Primärtumor oder Metastase)
    • BRAF-V600E Mutation-positiver Tumor (nachgewiesen in Primärtumor oder Metastase)
    • Alter ≥18 Jahre
    • ECOG Performance Status 0-1
    • Patient ist für die Applikation einer Chemotherapie geeignet
    • Schriftliche Einverständniserklärung des Patienten
    • Geschätzte Lebenserwartung > 3 Monate
    • Vorliegen mindestens einer messbaren Referenzläsion entsprechend der RECIST 1.1 –Kriterien (Röntgen Thorax in zwei Ebenen oder CT Thorax und CT Abdomen 4 Wochen oder weniger vor Randomisation)
    • Primärtumorgewebe vorhanden und Einwilligung des Patienten in Aufbewahrung, molekulare und genetische Charakterisierung des Tumormaterials. Fakultativ erfolgt molekulare Charakterisierung von Blutproben.
    • Gebärfähige Frauen und Männer müssen einverstanden sein für die Dauer der Studienbehandlung und für mindestens 6 Monate nach letzter Gabe der Studienmedikation effektive kontrazeptive Maßnahmen (Pearl- Index <1) anzuwenden.
    Eine Frau wird als gebärfähig betrachtet sofern sie nicht mindestens 50 Jahre alt ist und sich außerdem seit mindestens 2 Jahren naturbedingt in der Menopause befindet oder aber chirurgisch sterilisiert worden ist.
    • Adäquate Knochenmarksfunktion:
    ▫ Leukozyten ≥ 3,0 x 109/L mit Neutrophilen ≥ 1,5 x 109/L
    ▫ Thrombozyten ≥ 100 x 109/L,
    ▫ Hämoglobin ≥ 5,6 mmol/L (entspr. 9 g/dL)
    • Adäquate Leberfunktion:
    ▫ Serumbilirubin ≤ 1,5 x obere Normwertgrenze (ULN)
    ▫ ALAT und ASAT ≤ 2,5 x ULN (bei Vorliegen von Lebermetastasen ALAT und ASAT ≤ 5 x ULN)
     INR < 1,5 und aPTT < 1,5 x ULN (Patienten ohne Antikoagulation). Therapeutische Antikoagulation ist erlaubt, wenn INR und aPTT für mindestens 2 Wochen stabil im therapeutischen Bereich liegen.
    • Adäquate Nierenfunktion:
    ▫ Serumkreatinin ≤ 1,5 x ULN oder Kreatinin Clearance (berechnet nach Cockroft und Gault) ≥ 50 ml/min
    • adäquate Herzfunktion: EKG und Echokardiogramm mit einer LVEF von ≥ 55%
    • Keine vorangegangene Chemotherapie für eine metastasierte Erkrankung (vorausgegangene Bestrahlung einer Metastase/von Metastasen ohne Gabe einer Chemotherapie ist erlaubt vorausgesetzt, dass keine bestrahlte Metastase als Target Läsion ausgewählt wird). Patienten, die eine sofortige
    Behandlung benötigen (hohe Tumorlast, Symptome) dürfen einen Zyklus FOLFOX, FOLFIRI oder FOLFOXIRI vor der Randomisierung erhalten (Zyklus 0).
    • Zeit zur letzten Gabe einer ggf. vorangegangenen neoadjuvanten/adjuvanten Chemotherapie oder Radiochemotherapie ≥3 Monate
    • Relevante Toxizitäten vorheriger Therapien müssen abgeklungen sein (auf Grad 0).
    E.4Principal exclusion criteria
    • Grade III or IV heart failure (NYHA classification)
    • Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before randomisation
    • Pregnancy (absence of pregnancy has to be ascertained by a beta hCG test) or breast feeding
    • Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
    • Additional cancer treatment (chemotherapy, radiation, immune therapy or hormone treatment) during the study treatment. Treatments that are conducted as part of an anthroposophical or homeopathic treatment approach, e.g. mistletoe therapy, do not represent an exclusion criterion.
    • Previous chemotherapy for the colorectal cancer with exception of chemotherapy or radiochemotherapy given as neoadjuvant or adjuvant treatment with curative intent, completed ≥3 months before randomisation
    Further exception:
    Patients with metastatic disease and need of immediate treatment (high tumour load, symptoms) may have received one cycle of FOLFOX, FOLFIRI or FOLFOXIRI prior to randomisation (Cycle 0).
    • Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest, or simultaneous participation in another clinical study while taking part in the study
    • Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, cetuximab, irinotecan, bevacizumab, oxaliplatin and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances
    • Known hypersensitivity to CHO (Chinese hamster ovary cells) - cell products or other recombinant human or humanised antibodies
    • Patients with confirmed cerebral metastases. In case of clinical suspicion of brain metastases, a cranial CT or MRI must be performed to rule out brain metastases before study inclusion.
    • History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea.
    • Symptomatic peritoneal carcinosis
    • Severe, non-healing wounds, ulcers or bone fractures
    • Patients with active infection (including confirmed HIV and/or HBV/HCV infection). In case of clinical suspicion of the presence of HIV or HBV/HCV infection, the latter should be ruled out before study inclusion.
    • Requirement for immunisation with live vaccine including attenuated live vaccine from at least 4 weeks before start of study treatment until 6 months after the administration of the last study medication.
    • Uncontrolled hypertension
    • Marked proteinuria (nephrotic syndrome)
    • Arterial thromboembolism or severe haemorrhage within 6 months prior to randomisation (with the exception of tumour bleeding before tumour resection surgery)
    • Haemorrhagic diathesis or tendency towards thrombosis
    • Known complete DPD deficiency (specific screening according to the recommendations of the SmPC in effect for 5-FU or capecitabine, respectively; patients with a known complete DPD deficiency must be excluded; patients with a known partial DPD deficiency may be included at the
    discretion of the investigator)
    • Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
    • Treatment with nucleoside analogues including sorivudine or brivudine within 28 days before study enrollment or requirement for concomitant antiviral treatment with sorivudine or brivudine or analogues
    • History of a second malignancy during the 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
    • Known history of alcohol or drug abuse
    • A significant concomitant disease, in particular chronic hepatic or renal disease, chronic inflammatory or autoimmune diseases, ruling out the patient's participation in the study according to investigator’s judgement.
    • Absent or restricted legal capacity
    • Herzinsuffizienz Grad III oder IV (NYHA-Klassifikation)
    • Myokardinfarkt, instabile Angina pectoris, Ballonangioplastie (PTCA) mit oder ohne Stenting innerhalb der letzten 12 Monate vor Randomisation
    • Schwangerschaft (Ausschluss durch beta-hCG-Test sicherzustellen) oder Stillen
    • Medizinische oder psychologische Beeinträchtigungen, die mit eingeschränkter Einwilligungsfähigkeit einhergehen oder die Durchführung der Studie nicht erlauben
    • Zusätzliche Krebstherapie (Chemotherapie, Bestrahlung, Immuntherapie oder Hormonbehandlung) während der Studientherapie. Therapien welche im Rahmen eines anthroposophischen oder homöopathischen Heilansatzes durchgeführt werden z.B. Misteltherapie stellen kein Ausschlusskriterium dar.
    • Vorherige Chemotherapie des kolorektalen Karzinoms mit Ausnahme einer Chemotherapie oder Radiochemotherapie, die als neoadjuvante oder adjuvante Therapie im Rahmen mit kurativer Behandlungsintension gegeben wurde und die ≥ 3 Monate vor Randomisierung beendet wurde.
    Weitere Ausnahme:
    Patienten mit metastasierter Erkrankung, die eine sofortige Therapie benötigen (hohe Tumorlast, Symptome) dürfen einen Zyklus FOLFOX, FOLFIRI oder FOLFOXIRI vor der Randomisierung erhalten (Zyklus 0).
    • Teilnahme an einer klinischen Studie oder experimentelle medikamentöse Behandlung innerhalb von 30 Tagen vor Studieneinschluss oder innerhalb eines Zeitraums von 5 Halbwertszeiten der in einer klinischen Studie oder bei einer experimentellen medikamentösen Behandlung verabreichten Substanzen vor Studieneinschluss, je nachdem welcher Zeitraum länger ist oder gleichzeitige Teilnahme an einer anderen klinischen Studie während der Studienteilnahme
    • Bekannte Hypersensitivität oder allergische Reaktion gegen eine der folgenden Substanzen: 5-Fluorouracil, Folinsäure Cetuximab, Irinotecan, Bevacizumab, Oxaliplatin und chemisch verwandte Substanzen und/oder Überempfindlichkeit gegen einen der sonstigen Bestandteile einer der genannten Substanzen
    • Bekannte Überempfindlichkeit gegen CHO (Ovarialzellen des chinesischen Hamsters) -Zellprodukte oder andere rekombinante humane oder humanisierte Antikörper
    • Patienten mit bekannten Hirnmetastasen. Bei klinischem Verdacht auf Hirnmetastasen muss vor Studieneinschluss ein kraniales CT oder MRI zum Ausschluss von Hirnmetastasen erfolgen.
    • Akuter oder subakuter Darmverschluss oder chronisch-entzündliche Darmerkrankung in der Anamnese oder chronische Diarrhoe
    • Symptomatische Peritonealkarzinose
    • Schwere, nicht heilende Wunden, Ulcera oder Knochenfrakturen
    • Patienten mit aktiver Infektion (einschließlich bekannter HIV und/oder HBV/HCV-Infektion). Bei klinischem Verdacht auf Vorliegen einer Infektion mit HIV oder HBV/HCV sollte diese ausgeschlossen werden vor Studieneinschluss.
    • Erfordernis für Impfung mit Lebendimpfstoff einschließlich attenuierten Lebendimpfstoffen von mindestens 4 Wochen vor dem Start der Studienbehandlung bis 6 Monate nach der letzten Verabreichung der Studienmedikation
    • Unkontrollierte Hypertonie
    • Ausgeprägte Proteinurie (nephrotisches Syndrom)
    • Arterielle Thromboembolien oder schwere Blutungen innerhalb von 6 Monaten vor Randomisaton (Ausnahme Tumorblutung vor der Tumorresektionsoperation)
    • Hämorrhagische Diathese oder Thromboseneigung
    • Bekannter kompletter DPD-Mangel (Spezifisches Screening gemäß der Empfehlungen der gültigen Fachinformation für 5-FU bzw. Capecitabin; Patienten mit einem bekannten vollständigen DPD Mangel sind von der Studienteilnahme ausgeschlossen, Patienten mit einem bekannten partiellen DPD-Mangel dürfen nach Entscheidung des Prüfarztes eingeschlossen werden.)
    • Bekannter Glukuronidierungsdefekt (Gilbert-Meulengracht-Syndrom) (spezielles Screening nicht erforderlich)
    • Behandlung mit Sorivudin oder Brivudin innerhalb von 28 Tagen vor Studienbeginn oder Erfordernis einer gleichzeitigen antiviralen Behandlung mit Sorivudin, Brivudin oder Analoga
    • Zweitmalignom in der Anamnese während der letzten 5 Jahre vor Studieneinschluss oder während der Studienteilnahme, mit Ausnahme eines Basalioms, Spinalioms oder eines in-situ-Karzinoms der Cervix uteri, soweit diese kurativ behandelt wurden.
    • Bekannter Alkohol- oder Drogenabusus
    • Eine signifikante Begleiterkrankung, insbesondere eine chronische Leber- oder Nierenerkrankung, eine chronisch entzündliche Erkrankung oder Autoimmunerkrankungen, welche nach Ansicht des Prüfarztes die Teilnahme des Patienten an der Studie ausschließen
    • Fehlende oder eingeschränkte juristische Geschäftsfähigkeit
    E.5 End points
    E.5.1Primary end point(s)
    To compare the objective response rate (ORR) according to RECIST 1.1 of treatment with FOLFOXIRI plus cetuximab versus treatment with FOLFOXIRI plus bevacizumab in BRAF-mutated patients.
    Vergleich der Ansprechrate (ORR) nach RECIST 1.1 der Behandlung mit FOLFOXIRI plus Cetuximab gegenüber der Behandlung mit FOLFOXIRI plus Bevacizumab bei BRAF-mutierten Patienten.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Restaging according to RECIST 1.1 will be performed after treatment week 8, 16, 24 and every 12 treatment weeks thereafter.
    Eine Tumorevaluierung gemäß RECIST 1.1 wird nach Behandlungswoche 8, 16, 24 und dann alle 12 Wochen durchgeführt.
    E.5.2Secondary end point(s)
    • Investigation of progression-free survival (PFS) from randomisation
    • Investigation of overall survival (OS) from randomisation
    • Investigation of early tumour shrinkage (ETS) and depth of response (DpR)
    • Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
    • Investigation of prospective analysis of tumour marker evolution (CEA and CA 19-9)
    • Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment
    • Investigation of the sequence of therapy after 1st-line treatment and its impact on OS
    • Untersuchung des progressionsfreien Überlebens (PFS) ab Randomisation
    • Untersuchung des Gesamtüberlebens (OS) ab Randomisation
    • Untersuchung der frühen Tumorreduktion („early tumor shrinkage [ETS]“) und der Tumoransprechtiefe („depth of response [DpR]“)
    • Untersuchung von molekularen Biomarkern zur Prädiktion von Sensitivität und sekundärer Resistenz einer anti-EGFR Therapie mit Cetuximab (inklusive Tumorbiopsien und Flüssigbiopsien aus Blutproben)
    • Untersuchung der prospektiven Analyse des Tumormarkerverlaufs (CEA und CA 19-9)
    • Erfassung der Sicherheit und Verträglichkeit (NCI-CTCAE Version 4.03 Kriterien) der Therapie
    • Untersuchung der Reihenfolge von Therapielinien nach der Erstlinientherapie und deren Einfluss auf das Gesamtüberleben
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PFS, ETS and DpR will be analysed according to RECIST 1.1. Restaging will be performed after treatment week 8, 16, 24 and every 12 weeks thereafter
    - OS will be evaluated in a continously manner, after study treatment every 3 months for up to 2.5 years after last study treatment
    - tumor markers will be evaluated after treatment week 8, 16, 26, thereafter every 12 weeks, at end of treatment and every 3 months in Follow Up but only untill progression occurs
    - safety and tolerability will be evaluated in a continously manner
    - molecular biomarkers will be evaluated before study treatment, after 8 weeks of treatment, after termination of study and on progression
    - PFS, ETS und DpR werden gemäß den RECIST 1.1 Kriterien nach 8, 16, 24 und in Folge alle 12 Behandlungswochen untersucht
    - OS wird kontinuierlich untersucht und im Nachbeobachtungszeitraum alle 3 Monate für längsten 2,5 Jahre nach Ende der Studienbehanldung erhoben
    - Die Tumormarker werden nach 8, 16, 24 und in Folge alle 12 Behandlungswochen, sowie zm Therapieende und zum Zeitpunkt der Progression erhoben
    - Sicherheit und Tolerabilität werden kontinuierlich während der Studientherapie untersucht
    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 No
    E.6.7Pharmacodynamic No
    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) 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 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 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 Yes
    E.8.2.3.1Comparator description
    FOLFOXIRI+Cetuximab // FOLFOXIRI+Bevacizumab
    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 concerned140
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA150
    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
    LVLS
    Letzter Besuch des letzten Patienten im Follow-Up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    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.1.3Elderly (>=65 years) Yes
    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 state108
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 108
    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)
    A maintenance therapy with either cetuximab in combination with Irinotecan or 5-FU/ Folinic acid (FUFA) or bevacizumab in combination with FUFA or capecitabine , dependent on the study treatment arm, is recommended but not part of the study treatment. The investigator is responsible for further treatment decisions.
    Im Anschluss an die Studienbehandlung wird eine Erhaltungstherapie in Form entweder mit Cetuximab in Kombination mit 5-FU/ Folinsäure (FUFA) oder Irinotecan bzw. Bevacizumab in Kombination mit FUFA oder Capecitabine empfohlen, abhängig davon, in welchem Arm der Patient in der Studie behandelt wurde. Die Entscheidung über die weitere Behandlung liegt jedoch beim Prüfarzt.
    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 Decision2016-09-27
    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 StatusOngoing
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