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    Summary
    EudraCT Number:2012-002138-35
    Sponsor's Protocol Code Number:CLGX818X2103
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-09-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-002138-35
    A.3Full title of the trial
    A phase Ib/II multi-center, open-label, dose escalation study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in patients with BRAF mutant metastatic colorectal cancer
    Studio di Fase Ib/II, multicentrico, in aperto, di incremento della dose con LGX818 e cetuximab o LGX818, BYL719 e cetuximab in pazienti con carcinoma colorettale metastatico con mutazione BRAF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in BRAF mutant metastatic colorectal cancer
    Studio con LGX818 e cetuximab o LGX818, BYL719 e cetuximab nel carcinoma colorettale metastatico con mutazione BRAF
    A.4.1Sponsor's protocol code numberCLGX818X2103
    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 SponsorARRAY BIOPHARMA INC.
    B.1.3.4CountryUnited States
    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 supportArray Biopharma Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation Array BioPharma Inc.
    B.5.2Functional name of contact pointMargaret Vargo
    B.5.3 Address:
    B.5.3.1Street Address3200 Walnut Street
    B.5.3.2Town/ cityBoulder
    B.5.3.3Post codeCO 80301
    B.5.3.4CountryUnited States
    B.5.4Telephone number0013033861485
    B.5.5Fax number0013033861252
    B.5.6E-mailmargie.vargo@arraybiopharma.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 nameBYL719
    D.3.2Product code BYL719
    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 INNBYL719
    D.3.9.1CAS number 1217486-61-7
    D.3.9.2Current sponsor codeBYL719
    D.3.9.3Other descriptive nameBYL719
    D.3.9.4EV Substance CodeSUB31405
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 nameBYL719
    D.3.2Product code BYL719
    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 INNBYL719
    D.3.9.1CAS number 1217486-61-7
    D.3.9.2Current sponsor codeBYL719
    D.3.9.3Other descriptive nameBYL719
    D.3.9.4EV Substance CodeSUB31405
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 nameBYL719
    D.3.2Product code BYL719
    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 INNBYL719
    D.3.9.1CAS number 1217486-61-7
    D.3.9.2Current sponsor codeBYL719
    D.3.9.3Other descriptive nameBYL719
    D.3.9.4EV Substance CodeSUB31405
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 - 1 FLACONCINO DI SOLUZIONE PER INFUSIONE DA 50 ML
    D.2.1.1.2Name of the Marketing Authorisation holderMERCK KGAA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameErbitux
    D.3.2Product code Erbitux
    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.3.9.2Current sponsor codeCETUXIMAB
    D.3.9.3Other descriptive nameCETUXIMAB
    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 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.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 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 nameLGX818
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INNLGX818
    D.3.9.1CAS number 1269440-17-6
    D.3.9.2Current sponsor codeLGX818
    D.3.9.3Other descriptive nameLGX818
    D.3.9.4EV Substance CodeSUB32790
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 nameLGX818
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INN LGX818
    D.3.9.2Current sponsor code LGX818
    D.3.9.3Other descriptive nameLGX818
    D.3.9.4EV Substance CodeSUB32790
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 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 nameLGX818
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INNLGX818
    D.3.9.2Current sponsor codeLGX818
    D.3.9.3Other descriptive nameLGX818
    D.3.9.4EV Substance CodeSUB32790
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 nameLGX818
    D.3.2Product code LGX818
    D.3.4Pharmaceutical form Capsule, hard
    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 INNLGX818
    D.3.9.2Current sponsor codeLGX818
    D.3.9.3Other descriptive nameLGX818
    D.3.9.4EV Substance CodeSUB32790
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    BRAF mutant metastatic colorectal cancer
    pazienti con carcinoma colorettale metastatico con mutazione BRAF
    E.1.1.1Medical condition in easily understood language
    BRAF mutant metastatic colorectal cancer
    carcinoma colorettale metastatico con mutazione BRAF
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10010035
    E.1.2Term Colorectal cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10010034
    E.1.2Term Colorectal cancer stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10010030
    E.1.2Term Colorectal cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Phase Ib: To estimate the maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of LGX818 in combination with cetuximab ± BYL719 as measured by
    incidence of dose-limiting toxicities.
    2. Phase II: To compare the efficacy of the dual (LGX818, cetuximab) and triple (LGX818, BYL719, cetuximab) combinations as measured by progression free survival
    1. Fase Ib: Valutare la massima dose tollerata (MTD) e/o la dose raccomandata per la Fase II (RP2D) di LGX818 somministrato in associazione a cetuximab ± BYL719 mediante la determinazione dell’incidenza di tossicità limitanti la dose.
    2. Fase II: confrontare l’efficacia della duplice associazione (LGX818, cetuximab) e della triplice associazione (LGX818, BYL719, cetuximab) mediante la determinazione della sopravvivenza libera da progressione.
    E.2.2Secondary objectives of the trial
    1. To characterize the safety and tolerability of LGX818 in combination with cetuximab ± BYL719 as assessed by the incidence and severity of adverse events.
    2. To determine the single dose and multiple dose pharmacokinetic profile of LGX818 in combination with cetuximab ± BYL719 as measured by plasma concentration.
    3. To assess anti-tumor activity of LGX818 in combination with cetuximab ± BYL719 as measured by overall response rate, duration of response, time to response, progression free survival and overall survival.
    4. Phase II: To assess gene alterations/expression relevant to the RAF/MEK/ERK and EGFR/PI3K/AKT pathways in tumor tissue as measured by baseline molecular status of potential predictive markers of tumor response or resistance
    1. Caratterizzare la sicurezza d’impiego e la tollerabilità di LGX818 in associazione a cetuximab ± BYL719 mediante la determinazione dell’incidenza e della gravità degli effetti collaterali.
    2. Determinare il profilo farmacocinetico di dosi singole e dosi ripetute di LGX818 in associazione a cetuximab ± BYL719 mediante la determinazione della concentrazione plasmatica.
    3. Valutare l’attività antitumorale di LGX818 in associazione a cetuximab ± BYL719 mediante la determinazione del tasso di risposta complessivo, durata della risposta, tempo alla risposta, sopravvivenza libera da progressione e sopravvivenza globale.
    4. Fase II: Valutare l’alterazione/espressione genica rilevante per le vie RAF/MEK/ERK ed EGFR/PI3K/AKT nel tessuto tumorale, determinate dallo status molecolare basale dei possibili indicatori biologici predittivi della risposta tumorale o della resistenza.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria:
    1. Age ≥ 18 years at the beginning of the administration of treatment (Phase Ib) or at the time of randomization (Phase II).
    2. Histological or cytological proof of metastatic colorectal cancer (mCRC)
    3. Progression after at least one prior standard of care regimen or be intolerant to irinotecan based regimens. Phase Ib only: Exception will be given to patients for whom, in the opinion of the investigator, no effective approved therapy is available
    4. Written documentation of KRAS wild-type and BRAF V600E mutation, or any other BRAF V600 mutation. Patients with written documentation of other BRAF mutations may be considered for participation in phase Ib after consultation with the Sponsor’s clinical study team
    5. Phase II only: fresh tumor biopsy at baseline
    6. Evidence of measurable disease, as determined by RECIST v1.1.
    Note: Lesions in areas of prior radiotherapy or other locoregional therapies (e.g., percutaneous ablation) should not be considered measurable, unless lesion progression has been documented since the therapy.
    7. Life expectancy ≥ 3 months
    8. ECOG performance status ≤ 1
    9. Negative serum pregnancy test within 72 hours prior to the first dose of study treatment in all women of childbearing potential
    10. Able to understand and voluntarily sign the informed consent form, and ability to comply with the study visit schedule and other protocol requirements. Written informed consent must be obtained prior to screen procedures.
    I pazienti eleggibili all’inclusione nel presente studio devono soddisfare tutti i criteri seguenti:
    1. Pazienti di età ≥18 anni all’inizio della somministrazione del trattamento (Fase Ib) o al momento della randomizzazione (Fase II).
    2. Conferma istologica o citologica di carcinoma colorettale metastatico (mCRC).
    3. Progressione dopo almeno un regime di terapia standard precedente o intolleranza a regimi a base di irinotecan. Solo Fase Ib: saranno ammesse eccezioni nei pazienti nei quali, secondo l’opinione dello sperimentatore, non sono disponibili terapie efficaci approvate.
    4. Documentazione scritta di KRAS wild-type e mutazione BRAF V600E o qualsiasi altra mutazione BRAF V600. I pazienti con documentazione scritta di altre mutazioni BRAF possono essere considerati per la partecipazione alla Fase Ib dopo aver consultato il clinical study team dello sponsor.
    5. Solo Fase II: biopsia di tessuto tumorale fresco al basale.
    6. Evidenza di malattia misurabile, determinata in base a RECIST v1.1.
    Nota: Le lesioni in aree precedentemente sottoposte a radioterapia o ad altre terapie loco regionali (ad es: ablazione percutanea) non devono essere considerate misurabili, a meno che non sia stata documentata la progressione della lesione dal momento della terapia.
    7. Aspettativa di vita > 3 mesi.
    8. ECOG performance status ≤ 1.
    9. Test di gravidanza sul siero negativo eseguito nelle 72 ore precedenti la somministrazione della prima dose del trattamento in studio in tutte le donne potenzialmente fertili.
    10. Pazienti in grado di comprendere e disposti a firmare il modulo di consenso informato e capaci di aderire allo schema delle visite dello studio e agli altri requisiti del protocollo. Il consenso informato scritto deve essere ottenuto prima di qualsiasi procedura di screening.
    E.4Principal exclusion criteria
    1. Phase II only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors
    2. Phase II only: previous treatment with RAF-inhibitors, PI3K-inhibitors, and/or MEKinhibitors
    3. Symptomatic or untreated leptomeningeal disease
    4. Symptomatic brain metastasis.
    5. Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting glucose ≥ 140 mg/dL / 7.8 mmol/L, history of clinically significant gestational diabetes mellitus or documented steroid-induced diabetes mellitus. Phase Ib only: Exception will be given for patients assigned to dual combination treatment of LGX818 and cetuximab.
    6. Known acute or chronic pancreatitis
    7. Clinically significant cardiac disease including any of the following:
    •Congestive heart failure requiring treatment (NYHA grade ≥ 2), LVEF < 45% as determined by MUGA scan or ECHO, or uncontrolled hypertension
    •History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
    •Clinically significant resting bradycardia
    •Unstable angina pectoris ≤ 3 months prior to starting study drug
    •Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting study drug
    •QTcF > 480 msec
    8. Patients with any of the following laboratory values at Screening/baseline:
    •Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]
    •Platelets < 100,000/mm3 [100 x 109/L]
    •Hemoglobin < 9.0 g/dL
    •Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN
    •Serum total bilirubin >1.5 x ULN, except for patients with Gilbert’s syndrome, who may be included if total bilirubin is ≤ 3.0 x ULN and direct bilirubin is ≤ 1.5 x ULN
    •AST/SGOT and/or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
    9. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/BYL719
    10. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
    11. Pregnant or nursing (lactating) women.
    Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 3 months after study drug discontinuation. Post-menopausal women are allowed to participate in this study.
    12. Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping treatment and should not father a child in this period.
    13. History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.
    14. Patients who have received radiation therapy (that includes > 30% of the bone marrow reserve), chemotherapy, biological therapy (e.g., antibodies) within ≤ 4 weeks (6 weeks for nitrosourea, mitomycin-C), or who have been treated with continuous or intermittent small molecule therapeutics or investigational agents within 5 half-lives of the agent (or ≤ 4 weeks when half-life is unknown) prior to starting study drug or who have not recovered from the side effects of such therapy (except alopecia).
    15. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery
    16. Known human immunodeficiency virus (HIV) infection
    17. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
    18. Patients receiving treatment with medications that are known to be strong CYP3A4 inhibitors and cannot be discontinued 7 days prior to the start of LGX818 treatment and for the duration of the study or patients receiving therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants and cannot be discontinued for the duration of BYL719 treatment.
    1. Solo Fase II: trattamento precedente con cetuximab, panitumumab e/o altri inibitori di EGFR.
    2. Solo Fase II: trattamento precedente con inibitori di RAF, inibitori di PI3K e/o inibitori di MEK.
    3. Malattia leptomeningea sintomatica o non trattata.
    4. Metastasi cerebrali sintomatiche.
    5. Pazienti con diabete mellito che necessita di terapia insulinica e/o segni clinici o glicemia a digiuno > 140 mg/dL / 7,8 mmol/L, anamnesi positiva per diabete mellito gestazionale o diabete mellito indotto da steroidi documentato. Solo Fase Ib: saranno ammesse eccezioni nei pazienti assegnati al trattamento con la duplice associazione di LGX818 e cetuximab.
    6. Pancreatite acuta o cronica nota.
    7. Patologia cardiaca clinicamente rilevante comprendente una qualsiasi delle condizioni seguenti:
    •Insufficienza cardiaca congestizia che richiede trattamento (Classe NYHA ≥ 2), LVEF < 45% determinata mediante angioscintigrafia cardiaca (MUGA) o ecocardiografia o ipertensione arteriosa non controllata
    •Evidenza pregressa o attuale di aritmia ventricolare clinicamente significativa o fibrillazione atriale
    •Bradicardia a riposo clinicamente significativa
    •Angina pectoris instabile <3 mesi prima dell’inizio della somministrazione del trattamento in studio
    •Infarto miocardico acuto (IMA) <3 mesi prima dell’inizio del trattamento in studio
    •QTcF > 480 msec
    8. I pazienti devono presentare uno qualsiasi dei seguenti valori di laboratorio allo/al screening/basale:
    •Conta neutrofila assoluta (ANC) < 1,500/m3 [1,5 x 109/L]
    •Piastrine < 100.000/mm3 [100 x 109/L]
    •Emoglobina < 9,0 g/dL
    •Creatinina sierica > 1,5 x ULN oppure clearance della creatinina calcolata o misurata direttamente < 50 % LLN
    •Bilirubina sierica > 1,5 x ULN, a eccezione di pazienti con sindrome di Gilbert che possono essere inclusi se la bilirubina totale è > 3,0 x ULN e la bilirubina diretta è < 1,5 x ULN
    •AST/SGOT e/o ALT/SGPT > 2,5 x ULN o > 5 x ULN in presenza di metastasi epatiche
    9. Compromissione della funzionalità gastrointestinale (GI) o gastropatie che possono alterare significativamente l’assorbimento di LGX818/BYL719 per via orale
    10. Neoplasia concomitante o precedente. Eccezioni: carcinoma cutaneo a cellule basali o a cellule squamose adeguatamente trattato, carcinoma in situ della cervice uterina trattato e senza evidenza di recidiva per almeno 3 anni prima dell’ingresso nello studio o altro tumore solido sottoposto a trattamento curativo e senza evidenza di recidiva per almeno 3 anni prima dell’ingresso nello studio.
    11. Donne in gravidanza e allattamento.
    Le donne potenzialmente fertili non possono partecipare al presente studio A MENO CHE non utilizzino un metodo contraccettivo di efficacia elevata per l’intera durata dello studio e nei 3 mesi successivi alla sospensione del trattamento in studio. Le donne in post-menopausa possono partecipare al presente studio.
    12. I pazienti sessualmente attivi devono utilizzare un preservativo durante i rapporti sessuali mentre stanno assumendo il trattamento in studio e per 3 mesi dopo il termine del trattamento e non devono concepire un figlio nello stesso periodo di tempo.
    13. Anamnesi positiva per evento tromboembolico o cerebrovascolare entro gli ultimi 6 mesi, compresi attacco ischemico transitorio, ictus cerebrovascolare, trombosi venosa profonda o embolia polmonare.
    14. Pazienti sottoposti a radioterapia (che comprende > 30% della riserva del midollo osseo), chemioterapia, terapia con agenti biologici (ad es: anticorpi) entro ≤ 4 settimane (6 settimane per nitrosurea, mitomicina-C) o terapia continuativa o intermittente con molecole piccole o qualsiasi altro farmaco sperimentale entro un periodo di 5 emivite del farmaco (o < 4 settimane se l’emivita non è nota) prima dell’inizio del trattamento in studio o che non hanno presentato guarigione dagli effetti collaterali di tale terapia (a eccezione di alopecia).
    15. Pazienti sottoposti a intervento chirurgico maggiore entro le ultime 2 settimane prima dell’inizio del trattamento in studio che non hanno presentato guarigione dagli effetti collaterali di tale procedura.
    16. Pazienti con infezione da virus dell’HIV.
    17. Qualsiasi condizione clinica grave, acuta o cronica o disturbo psichiatrico o alterazione dei valori degli esami di laboratorio che possa aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del trattamento in studio o che possa
    interferire con l’interpretazione dei risultati dello studio e, secondo l’opinione dello sperimentatore, renda il paziente non idoneo allo studio.
    18. Pazienti che ricevono il trattamento con farmaci noti per essere forti inibitori del
    CYP3A4 e che non possono essere sospesi 7 giorni prima dell’inizio del trattamento con LGX818 per la durata dello studio o pazienti che ricevono dosi terapeutiche di warfarin sodio (Coumadin®) o qualsiasi altro anticoagulante derivato coumarinico e che non può essere sospeso per la durata del trattamento con BYL719.
    E.5 End points
    E.5.1Primary end point(s)
    Phase Ib : incidence rate of dose-limiting toxicities
    Phase II : Progression Free Survival
    Fase Ib : incidenza di tossicità limitanti la dose
    Fase II : sopravvivenza libera da progressione
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase Ib: 1.5 years
    Phase II : 2.5 years
    Fase Ib: 1.5 anni
    Fase II : 2.5 anni
    E.5.2Secondary end point(s)
    1- Incidence and severity of adverse events
    2- Plasma concentration
    3- Phase Ib/II:
    a) Overall response rate
    b) Duration of response
    c) Time to response
    d) Overall survival
    Ph Ib : Progression free survival
    Ph II : Overall survival
    4- 2.5 years
    1- incidenza e gravità degli effetti collaterali
    2- concentrazione plasmatica
    3- Fase Ib/II:
    a) tasso di risposta complessivo
    b) durata della risposta
    c) tempo alla risposta
    d) sopravvivenza globale
    Fase Ib: sopravvivenza libera da progressione
    Fase II: sopravvivenza globale
    4- 2.5 anni
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- 2.5 years
    2- 1.5 years
    3- Phase Ib/II:
    a) 2.5 years
    b) 2.5 years
    c) baseline, 2 years
    d) 3 years
    Phase Ib: 1.5 years
    Phase II: 3 years
    4- Baseline molecular status of potential predictive markers of tumor response or resistance
    1- 2.5 anni
    2- 1.5 anni
    3- Fase Ib/II:
    a) 2.5 anni
    b) 2.5 anni
    c) basale, 2 anni
    d) 3 anni
    Fase Ib: 1.5 anni
    Fase II: 3 anni
    4- status molecolare basale dei possibili indicatori biologici predittivi della risposta tumorale o della resistenza
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation study with LGX818/Cetuximab and then dose escalation with LGX818/BYL719/Cetuximab
    Studio di incremento della dose con LGX818/Cetuximab e poi incremento con LGX818/BYL719/Cetuximab
    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) 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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    United States
    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 study will be upon completion of the follow-up period of the last patient. This will occur when either all the patients in each arm of phase II are deceased, every patient in phase II has completed the study phase completion disposition and has been followed for at least 18 months for overall survival after initiation of treatment, or have been lost to follow-up or withdrew consent, whichever occurs first.
    La conclusione dello studio avverrà al termine del periodo di follow-up dell’ultimo paziente. Ciò si verificherà quando tutti i pazienti in ogni braccio della fase II sono deceduti, ogni paziente della fase II ha completato la fase di completamento dello studio
    ed è stato seguito per almeno 18 mesi per la sopravvivenza globale dopo l’inizio del trattamento, o quando sono andati perduti al follow-up o hanno ritirato il consenso, a seconda di quale situazione si verifica prima.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 125
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 113
    F.4.2.2In the whole clinical trial 162
    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)
    as per clinical practice
    secondo pratica clinica
    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 Decision2013-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-17
    P. End of Trial
    P.End of Trial StatusCompleted
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