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    Summary
    EudraCT Number:2014-003787-21
    Sponsor's Protocol Code Number:FIRE-4
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-24
    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 ConcernedAustria - BASG
    A.2EudraCT number2014-003787-21
    A.3Full title of the trial
    Randomised study of the efficacy of cetuximab rechallenge in patients with metastatic colorectal cancer (RAS wild-type) responding to first-line treatment with FOLFIRI plus cetuximab
    Randomisierte Studie zur Wirksamkeit einer Cetuximab-Reexposition bei Patienten mit metastasiertem kolorektalem Karzinom (RAS Wildtyp), welche auf eine Erstlinien-Behandlung mit FOLFIRI plus Cetuximab ein Ansprechen zeigten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomised study of the efficacy of cetuximab rechallenge in patients with metastatic colorectal cancer (RAS wild-type) responding to first-line treatment with FOLFIRI plus cetuximab
    Randomisierte Studie zur Wirksamkeit einer Cetuximab-Reexposition bei Patienten mit metastasiertem kolorektalem Karzinom (RAS Wildtyp), welche auf eine Erstlinien-Behandlung mit FOLFIRI plus Cetuximab ein Ansprechen zeigten
    A.3.2Name or abbreviated title of the trial where available
    AIO KRK-0114/FIRE-4
    A.4.1Sponsor's protocol code numberFIRE-4
    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 SponsorKlinikum der Ludwig-Maximilians-Univ. Münch , Klinikum Großhadern (vertreten durch die kaufmännische Direktion)
    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 Serono GmbH
    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 pointStudiensekretariat
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistr. 15
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number0049894400 72208
    B.5.5Fax number0049894400 75256
    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.2.1.2Country which granted the Marketing AuthorisationAustria
    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 HYDROCHLORIDE
    D.3.9.3Other descriptive nameIRINOTECAN HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB02772MIG
    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: 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 AuthorisationAustria
    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 Concentrate for solution for injection/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 INNFOLINIC ACID
    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: 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.2.1.2Country which granted the Marketing AuthorisationAustria
    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.3.8INN - Proposed INNFLUOROURACIL
    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: 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.2.1.1.1Trade name Erbitux
    D.2.1.1.2Name of the Marketing Authorisation holderMerck KGaA
    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/l milligram(s)/litre
    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: 5
    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.3.1Product nameCapecitabine
    D.3.4Pharmaceutical form Film-coated 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 INNCAPECITABINE
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    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 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 Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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/l milligram(s)/litre
    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.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 (metastatic colorectal cancer), primarily non-resectable or with surgery refused by the patient
    Histologisch gesichertes Adenokarzinom des Kolons oder Rektums im UICC Stadium IV (metastasiertes kolorektales Karzinom), primär nicht resektabel oder Patient lehnt Operation ab
    E.1.1.1Medical condition in easily understood language
    metastatic colorectal cancer
    metastasiertes kolorektales Karzinom
    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
    Prospective investigation of overall survival from randomisation to third-line treatment (OS3) under cetuximab rechallenge versus an anti-EGFR-free treatment in patients that have responded to first-line treatment with cetuximab in combination with FOLFIRI or FOLFOX or FOLFOXIRI with CR or PR of any duration or SD ≥ 6 months.
    Prospektive Untersuchung des Gesamtüberlebens ab Randomisation in Drittlinientherapie (OS3) unter einer Cetuximab-Reexposition gegenüber einer anti-EGFR freien Therapie bei Patienten, welche auf eine Erstlinientherapie mit Cetuximab in Kombination mit FOLFIRI oder FOLFOX oder FOLFOXIRI mit CR oder PR ohne festgelegte Mindestdauer oder SD ≥ 6 Monate angesprochen haben.
    E.2.2Secondary objectives of the trial
    • Response rate ORR1, 2 and 3 (assessment of ORR 1 and ORR 2 only if the patient was already included in part 1 of the study)
    • Progression-free survival PFS1, 2 and 3 (assessment of PFS 1 and PFS 2 only if the patient was already included in part 1 of the study)
    • Overall survival (OS1) from randomisation to first-line treatment (assessment only if the patient was already included in part 1 of the study)
    • Investigation of early tumour shrinkage and depth of response during first-line and third-line treatment.
    • Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance to an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
    • Prospective validation of a biomarker score (AREG/EREG)
    • Prospective analysis of tumour marker level evolution (CEA and CA 19-9)
    • Recording of the safety and tolerance (NCI-CTCAE version 4.03 criteria) of the first-line and third-line treatment
    • Ansprechrate ORR1, 2 und 3 (Evaluation von ORR1 und ORR2 nur dann, wenn der Studieneinschluss bereits im Teil 1 der Studie erfolgte)
    • Progressions-freie Zeit PFS1, 2 und 3 (Evaluation von PFS1 und PFS2 nur dann, wenn der Studieneinschluss bereits im Teil 1 der Studie erfolgte)
    • Gesamtüberleben (OS1) ab Randomisation in Erstlinientherapie (nur dann, wenn der Studieneinschluss bereits im Teil 1 der Studie erfolgte)
    • Untersuchung der frühen Tumorreduktion („early tumor shrinkage“) und der Remissionstiefe in Erst- und Drittlinientherapie
    • Untersuchung von molekularen Biomarkern zur Prädiktion von Sensitivität und sekundärer Resistenz einer anti-EGFR Therapie mit Cetuximab (inkl. Tumorbiopsien und Flüssigbiopsien aus Blutproben)
    • Prospektive Validierung eines Biomarker Scores (AREG/EREG)
    • Prospektive Analyse des Tumormarkerverlaufs (CEA und CA 19-9)
    • Erfassung der Sicherheit und Verträglichkeit (NCI-CTCAE Version 4.03 Kriterien) der Erstlinien- und Drittlinientherapie
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Criteria for inclusion in the study:
    • Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer), metastases primarily non-resectable or surgery refused by the patient
    • RAS wild-type tumour status (KRAS and NRAS exon 2, 3, 4), proven in the primary tumour or metastasis prior to each randomisation time point.
    Only for inclusion in part 2: If a repeated tumour biopsy is infeasible or poses an unacceptable risk to the patient as assessed by the investigator, RAS wild-type tumour status determined in liquid biopsy in Laboratory for Immunological Molecular Biology, Universitätsklinikum Knappschafts-krankenhaus Bochum GmbH permitted.
    • Age ≥18
    • 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 tumour material (patients directly included in part 2 of the study in whom primary tumour material is no longer available may be included in the study). Molecular profiling of blood samples is optionally performed.
    • Females of childbearing potential (FCBPs) and men must agree to use highly effective contraceptive measures (Pearl index <1) or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject) for the duration of the study treatment and for at least 6 months after last administration of study medication. A woman will be considered as being of childbearing potential unless she is at least 50 years old and moreover has gone through 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 the presence 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:
    - Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min
    • Adequate cardiac function: ECG and echocardiogram with a LVEF of ≥ 55%

    Inclusion criteria - only applicable for Part 1:
    • No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumour load, symptoms) may have received one application of FOLFIRI prior to study entry.
    • Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumour in curative treatment intention ≥ 6 months
    • Any relevant toxicities of prior treatments must have resolved.

    Additional inclusion criteria only applicable for Part 2:
    • Prior first-line treatment of the metastatic colorectal cancer with cetuximab in combination with FOLFIRI or FOLFOX or FOLFOXIRI; data available for the duration of treatment and the response within the context of first-line treatment
    • Within the maintenance arms, re-induction of the primary treatment strategy with irinotecan + cetuximab is allowed as part of first-line strategy. In this context, 2nd-line treatment is defined as the introduction of a new agent that was not part of the 1st-line therapy.
    • Proof of a RAS wild-type tumour (KRAS and NRAS exons 2, 3, 4) in a biopsy of the primary tumour (or any metastasis)
    or liquid biopsy (RAS wild-type status in liquid biopsy as determined in Laboratory for Immunological Molecular Biology, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH), within 4 weeks before randomisation
    • CT examinations with evidence of response (partial response [PR] or complete response [CR]) or alternatively stable disease (SD) ≥ 6 months according to RECIST Version 1.1 criteria as best response within the context of the first-line treatment with cetuximab in combination with FOLFIRI or FOLFOX or FOLFOXIRI
    Note for clarification: CR and PR as best response do not require duration of response for ≥ 6 months, this is only required in case of SD as best response.
    • Last administration of any anti EGFR substance ≥ 4 months before randomisation 2
    • At least one documented progression during first-line and second-line treatment
    Kriterien zum Einschluss in die Studie
    • Histologisch gesichertes Adenokarzinom des Kolons oder Rektums im UICC Stadium IV mit Metastasen (metastasiertes kolorektales Karzinom), 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 vor jedem Randomisationszeitpunkt.
    Nur vor Einschluss in Teil 2: Falls eine erneute Tumorbiopsie nach Einschätzung des Prüfarztes nicht durchführbar ist oder den Patienten einem nicht akzeptablen Risiko aussetzen würde, so darf der in der Flüssigbiopsie im Immunologischen Molekularbiologischen Labor des Universitätsklinikum Knappschaftskrankenhauses Bochum GmbH bestimmte RAS Wildtyp-Status herangezogen werden.
    • 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 (Patienten, die direkt in Teil 2 der Studie eingeschlossen werden, bei denen kein primäres Tumormaterial mehr vorhanden ist, dürfen in die Studie aufgenommen werden). 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 hochwirksame kontrazeptive Maßnahmen (Pearl- Index <1) anzuwenden oder vollständige Enthaltsamkeit von jedem heterosexuellen Geschlechtsverkehr zu praktizieren (tatsächliche Enthaltsamkeit ist akzeptabel wenn diese mit dem bevorzugten und üblichen Lebensstil der Patientin/des Patienten im Einklang steht).
    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 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
    - ALAT und ASAT ≤ 2,5 x obere Normwertgrenze (bei Vorliegen von Lebermetastasen ALAT und ASAT ≤ 5 x obere Normwertgrenze)
    • INR < 1,5 und aPTT < 1,5 x obere Normwertgrenze (Patienten ohne Antikoagulation). Therapeutische Antikoagulation ist erlaubt, wenn INR und aPTT für mindestens 2 Wochen stabil im therapeutischen Bereich liegen.
    • Adäquate Nierenfunktion:
    - Kreatinin Clearance (berechnet nach Cockroft und Gault) ≥ 50 mL/min
    • adäquate Herzfunktion: EKG und Echokardiogram mit einer LVEF von ≥ 55%

    Einschlusskriterium nur für Teil 1:
    • Keine vorangegangene Chemotherapie für eine metastasierte Erkrankung. Bei Patienten mit hohem Therapiedruck (große Tumorlast, Symptome) darf maximal eine FOLFIRI Gabe vor Studieneingang erfolgt sein.
    • Zeit zur letzten Gabe einer vorangegangenen neoadjuvanten oder adjuvanten Chemotherapie oder einer vorangegangenen Radiochemotherapie des Primärtumors in kurativer Behandlungsintention ≥ 6 Monate
    • Relevante Toxizitäten vorheriger Therapien müssen abgeklungen sein

    Zusätzliche Einschlusskriterien nur für Teil 2:
    • Stattgehabte Erstlinientherapie des metastasierten kolorektalen Karzinoms mit Cetxuximab in Kombination mit FOLFIRI oder FOLFOX oder FOLFOXIRI; Daten zur Therapiedauer und zum Response im Rahmen der Erstlinientherapie sind verfügbar
    • Innerhalb der Studienarme mit Erhaltungstherapie ist eine Re-induktion der primären Behandlungsstrategie mit Irinotecan und Cetuximab als Teil der Erstlinienstrategie zulässig. In diesem Kontext wird die Zweitlinientherapie definiert als die Einführung einer neuen Substanz, die nicht Bestandteil der Erstlinientherapie war.
    • Nachweis eines RAS-Wildtyp Tumors (KRAS und NRAS Exone 2, 3 und 4) in einer Tumorbiopsie (oder Metastase) oder Flüssigbiopsie (RAS-Wildtyp in Flüssigbiopsie, bestimmt im Immunologischen Molekularbiologischen Labor des Universitätsklinikum Knappschaftskrankenhauses Bochum GmbH) ,innerhalb von 4 Wochen vor Randomisation
    • CT Untersuchungen mit dem Nachweis eines Ansprechen (partielle [PR] oder komplette Remission [CR]) oder alternativ stabile Erkrankung (SD) ≥ 6 Monate nach RECIST Version 1.1 Kriterien als bestes Ansprechen im Rahmen der Erstlinientherapie mit Cetuximab in Kombination mit FOLFIRI oder FOLFOX oder FOLFOXIRI
    • Seit der letzten Gabe einer anti-EGFR Substanz müssen mindestens 4 Monate vergangen sein.
    • Unter Erst- und Zweitlinientherapie muss zumindest einmal eine dokumentierte Progression erfolgt sein.
    E.4Principal exclusion criteria
    • Proof of a RAS mutation (KRAS or NRAS, exons 2, 3, 4 in the tumour (proven in the primary tumour or metastasis) or liquid biopsy (permitted only prior to Part 2) or absence of testing for RAS mutation
    • Primarily resectable metastases and the patient wishes for resection
    • ≥ Grade II heart failure (NYHA classification)
    • Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident/stroke within the past 12 months before randomisation 1 or before randomisation 2, unstable angina pectoris, serious cardiac arrhythmia according to investigator’s judgement requiring medication.
    • Pre-existing pulmonary fibrosis or immune pneumonitis
    • Pregnancy (absence of pregnancy to be ascertained by a negative 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, immunotherapy or hormone treatment) during the study treatment in first-line and third-line treatment (treatments that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy do not represent an exclusion criterion)
    • Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study (exclusion criterion solely for part 1)
    • Toxicity > Grade 1 that has not yet resolved, attributed to a previous treatment or measure for treatment of the mCRC.
    • However, alopecia (all grades) and oxaliplatin-induced neurotoxicity ≤ Grade 2 are acceptable (exclusion criterion only for part 2).
    • 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 study while taking part in the study
    • Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, capecitabine, cetuximab, irinotecan, bevacizumab and chemically related substances and/or hypersensitivity to any of the components in the formulations of the aforementioned substances, including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥ 3.
    • Known hypersensitivity to Chinese hamster ovary cell (CHO) – cellular products or other recombinant human or humanized monoclonal antibodies
    • Patients with known brain metastases. In case of clinical suspicion of brain metastasis a cranial CT or MRI must be performed to rule out brain metastasis before study inclusion.
    • History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhea
    • Symptomatic peritoneal carcinosis
    • Severe, non-healing wounds, ulcers or bone fractures
    • Patients with active infection requiring systemic therapy
    • Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
    • Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required).
    • Requirement for immunisation with live vaccine under the study treatment.
    • Haemorrhagic diathesis or known thrombophilia
    • Known DPD deficiency (specific screening not required)
    • Known glucuronidation eficiency (Gilbert's syndrome) (specific screening not required)
    • History of a second primary malignancy during the past 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
    • Any other severe acute or chronic concomitant disease or medical condition including psychiatric conditions (including recent i.e. within the past year or active suicidal ideation or behavior) or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    • Absent or restricted legal capacity
    • Nachweis einer RAS-Mutation (KRAS oder NRAS, Exone 2, 3 und 4 im Tumor (nachgewiesen in Primärtumor oder Metastase) oder Flüssigbiopsie (erlaubt nur vor Teil 2) oder fehlende Untersuchung auf RAS-Mutation
    • Primär resektable Metastasen und Patient wünscht Resektion
    • Herzinsuffizienz ≥ Grad II (NYHA-Klassifikation)
    • Myokardinfarkt, Ballonangioplastie (PTCA) mit und ohne Stenting, oder zerebraler Insult/Schlaganfall innerhalb der letzten 12 Monaten vor Randomisierung 1 oder vor Randomisierung 2, instabile Angina pectoris; schwere Herzrhythmusstörung nach Einschätzung des Prüfarztes, die eine medikamentöse Behandlung erfordert.
    • Vorbestehende Lungenfibrose oder immunvermittelte Pneumonitis
    • Schwangerschaft (Ausschluss durch negativen 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 in der Erstlinien- und Drittlinientherapie (Therapien welche im Rahmen eines anthroposophischen oder homöopathischen Heilansatzes durchgeführt werden, wie z.B. Misteltherapie, stellen kein Ausschlusskriterium dar)
    • Vorangegangene Chemotherapie des kolorektalen Karzinoms mit Ausnahme einer adjuvanten Therapie, die mindestens 6 Monate vor Studieneintritt beendet wurde (Ausschlusskriterium nur für Teil 1)
    • Noch nicht abgeklungene Toxizität > Grad 1, welche auf eine frühere Therapie oder Maßnahme zur Behandlung des mCRC zurückgeführt wird. Hiervon ausgenommen sind Haarausfall (alle Grade) und eine durch Oxaliplatin bedingte Neurotoxizität ≤ Grad 2 (Ausschlusskriterium nur für Teil 2)
    • 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, Capecitabin, Cetuximab, Irinotecan, Bevacizumab und chemisch verwandte Substanzen und/oder Überempfindlichkeit gegen einen der sonstigen Bestandteile einer der genannten Substanzen, einschließlich bekannter
    • Hypersensitivität auf monoklonale Antikörper mit NCI CTCAE Grad ≥ 3
    • 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, entzündliche Darmerkrankung, immunvermittelte Kolitis oder chronische Diarrhoe in der Anamnese
    • Symptomatische Peritonealkarzinose
    • Schwere, nicht heilende Wunden, Ulcera oder Knochenfrakturen
    • Patienten mit aktiver Infektion, die systemische Behandlung benötigen.
    • Anamnestisch positiv getestet auf HIV oder bekannte AIDS-Erkrankung. Aktive oder chronische Hepatitis B-Virus (HBV) oder Hepatitis C-Virus (HCV) Infektion (positives HBs Antigen oder HCV RNA falls der Screening-Test auf anti-HCV Antikörper positiv ausfällt; serologische Testing erforderlich).
    • Erfordernis für Impfung mit Lebendimpfstoff unter der Studientherapie
    • Hämorrhagische Diathese oder Thromboseneigung Bekannter DPD-Mangel (spezielles Screening nicht erforderlich)
    • Bekannter Glukuronidierungsdefekt (Gilbert-Meulengracht-Syndrom) (spezielles Screening nicht erforderlich)
    • 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
    • Jede schwere akute oder chronische Begleiterkrankung oder Gesundheitsstörung einschließlich psychiatrischer Erkrankungen (einschließlich in letzter Zeit [innerhalb des letzten Jahres aufgetreten] oder aktiver Suizidgedanken oder Suizidverhalten) oder Laborabnormalitäten, welche für den Patienten das Risiko, das mit der Studienteilnahme oder der Gabe der Studienmedikation verbunden ist, erhöhen könnten oder die Interpretation von Studienergebnissen stören könnten oder, nach Einschätzung des Prüfarztes, den Patienten für einen Studieneinschluss ungeeignet erscheinen lassen.
    • Fehlende oder eingeschränkte juristische Geschäftsfähigkeit
    E.5 End points
    E.5.1Primary end point(s)
    Randomisation 1:
    Overall survival from randomisation to third-line treatment
    Randomisation 1:
    Gesamtüberleben ab Randomisation in Drittlinientherapie
    E.5.1.1Timepoint(s) of evaluation of this end point
    The anlaysis of the primary endpoint (OS3) is event driven and will be performed when 196 events have occurred. At this point, entry to part 2 will be closed.
    Die Analyse des primären Endpunkts (OS3) erfolgt ereignisbezogen und wird durchgeführt sobald 196 Ereignisse eingetreten sind. Zu diesem Zeitpunkt wird Einschluss 2 geschlossen.
    E.5.2Secondary end point(s)
    Randomisation 1:
    Time to first progression (PFS1)
    Randomisation 1:
    Zeit bis zur ersten Progression (PFS1)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The anlaysis of the secondary endpoint (PFS1) will be performed when 359 events have occurred or to final analysis.
    Die Anlayse des sekundären Endpunkts (PFS1) wird durchgeführt sobald 359 Ereignisse eingetreten sind oder zur Endauswertung.
    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 Yes
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned12
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 670
    F.4.2.2In the whole clinical trial 670
    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)
    None
    keine
    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 Decision2016-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-15
    P. End of Trial
    P.End of Trial StatusOngoing
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