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    Summary
    EudraCT Number:2017-004059-22
    Sponsor's Protocol Code Number:CL3-95005-006
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-13
    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 number2017-004059-22
    A.3Full title of the trial
    An open-label, randomised, phase III Study cOmparing trifLuridine/tipiracil (S 95005) in combination with bevacizumab to capecitabine in combination with bevacizumab in firST-line treatment of patients with metastatIC colorectal cancer who are not candidatE for intensive therapy (SOLSTICE study)
    Studio in aperto, randomizzato, di fase III, di confronto tra trifluridina/tipiracile (S 95005) in combinazione con bevacizumab rispetto al capecitabina in combinazione con bevacizumab in trattamento di prima linea per pazienti con tumore del colon retto metastatico non candidabili alla terapia intensiva.
    Studio SOLSTICE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase III study in first-line treatment of patients with metastatic colorectal cancer who are not candidate for intensive therapy
    Studio di fase III per trattamento in prima linea di pazienti con tumore metastatico del colon retto non candidabili alla terapia intensiva
    A.3.2Name or abbreviated title of the trial where available
    SOLSTICE
    SOLSTICE
    A.4.1Sponsor's protocol code numberCL3-95005-006
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1206-3198
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 SponsorINSTITUT DE RECHERCHES INTERNATIONALES SERVIER
    B.1.3.4CountryFrance
    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 supportA.D.I.R.
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto di Ricerca SERVIER s.r.l.
    B.5.2Functional name of contact pointProject Manager: Chiara PERTICA
    B.5.3 Address:
    B.5.3.1Street AddressVia Luca Passi, 85
    B.5.3.2Town/ cityROMA
    B.5.3.3Post code00166
    B.5.3.4CountryItaly
    B.5.4Telephone number003906669081
    B.5.5Fax number00390666908738
    B.5.6E-mailinfoirs@servier.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 Yes
    D.2.1.1.1Trade name LONSURF - 15 MG/6,14 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER AL/AL - 20 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderLES LABORATOIRES SERVIER
    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 nameLONSURF
    D.3.2Product code S95005
    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 INNTRIFLURIDINA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameTRIFLURIDINA
    D.3.9.4EV Substance CodeSUB11291MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTIPIRACIL HYDROCHLORIDE
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameTIPIRACIL HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB174132
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.2.1.1.1Trade name LONSURF - 20 MG/8,19 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER AL/AL - 20 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderLES LABORATOIRES SERVIER
    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 nameLONSURF
    D.3.2Product code S95005
    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 INNTRIFLURIDINA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameTRIFLURIDINA
    D.3.9.4EV Substance CodeSUB11291MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTIPIRACIL HYDROCHLORIDE
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameTIPIRACIL HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB174132
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number9
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.2.1.1.1Trade name AVASTIN - 1 FLACONCINO DA 400 MG DI CONCENTRATO PER SOLUZIONE PER INFUSIONE
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION GmbH
    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 nameAVASTIN
    D.3.2Product code na
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameBEVACIZUMAB
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 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 AVASTIN - 1 FLACONCINO DA 100 MG DI CONCENTRATO PER SOLUZIONE PER INFUSIONE
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION GmbH
    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 nameAVASTIN
    D.3.2Product code NA
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameBEVACIZUMAB
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.2.1.1.1Trade name XELODA - 150 MG 60 COMPRESSE FILMRIVESTITE IN BLISTER USO ORALE
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION GmbH
    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 nameXELODA
    D.3.2Product code NA
    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 INNCAPECITABINA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameCAPECITABINA
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.2.1.1.1Trade name XELODA - 500 MG 120 COMPRESSE FILMRIVESTITE IN BLISTER USO ORALE
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION GmbH
    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 nameCAPECITABINA
    D.3.2Product code NA
    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 INNCAPECITABINA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameCAPECITABINA
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Metastatic colorectal cancer
    Tumore del colon retto metastatico
    E.1.1.1Medical condition in easily understood language
    Colorectal cancer
    Tumore del colon retto
    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 PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    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
    To demonstrate the superiority of S 95005 in combination with bevacizumab over capecitabine in combination with bevacizumab in terms of progression-free survival (PFS) based on Investigator assessment in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy.
    Dimostrare la superiorit¿ di S 95005 combinato con bevacizumab verso capecitabina combinata con bevacizumab in termini di Sopravivvenza libera da progressione (PFS) in base a giudizio dello sperimentatore, sul trattamento di prima linea in pazienti con tumore del colon retto metastatico non operabile non candidabili alla terapia intensiva.
    E.2.2Secondary objectives of the trial
    To confirm clinical benefit for treatment through an evaluation of Overall survival (OS), Overall response rate (ORR), Disease control rate (DCR), Duration of response (DoR), Time to treatment failure (TTF) and to compare the safety and the impact on quality of life of S 95005 in combination with bevacizumab to capecitabine in combination with bevacizumab in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy.
    confermare il beneficio clinico del trattamento tramite valutazione di: Sopravivvenza globale (OS),Tasso di risposta globale (ORR), Tasso di controllo della malattia (DCR), Durata della risposta (DoR), Durata fino al fallimento del trattamento (TTF)
    Sicurezza e impatto sulla qualit¿ della vita di S95005 in comb. con Bevacizumab verso capecitabina in combinazione con Bevacizumab, sul trattamento di prima linea in pazienti con tumore del colon retto metastatico non operabile non candidabili alla terapia intensiva.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male or female participant aged =18 years old at the time of ICF signature (or legal age depending on local country regulation).
    - Has definitive histologically confirmed adenocarcinoma of the colon or rectum.
    - Has at least one measurable metastatic lesion.
    - RAS status based on local biological assessment of tumour biopsy must be available.
    - Patient is not a candidate for standard full dose combination chemotherapy with irinotecan or oxaliplatin according to investigator’s judgment and decision taken during a multidisciplinary meeting (if organised in the centre).
    Reasons for non-eligibility to these standard treatments could be, but are not limited to, age, performance status, low tumour burden, comorbidities or non-clinical reasons.
    - Patient is not a candidate for curative resection of metastatic lesions according to investigator’s judgment and decision taken during a multidisciplinary meeting (if organised in the centre).
    - No previous systemic anticancer therapy for unresectable metastatic colorectal cancer. Previous adjuvant or neoadjuvant chemotherapy is allowed only if the patient has been disease free for at least 6 months after the completion of the chemotherapy.
    - Ability to swallow oral medication.
    - Estimated life expectancy =12 weeks.
    - ECOG (Eastern Cooperative Oncology Group) performance status =2.
    - Adequate haematological, renal, hepatic and coagulation function.
    - Women of childbearing potential must have been tested negative in a serum pregnancy test. Within the frame of this study, female participants of childbearing potential and male participants with partners of childbearing potential must use an highly effective method of birth control as well as their partners lasting at least 6 months after the last dose of IMP. Women using hormonal contraceptive must also use a barrier method.
    - Written informed consent obtained.
    -Uomo o donna di età =18 anni al momento di firma del consenso informato
    - Adenocarcinoma del colon o retto confermato istologicamente
    - Presenza di almeno una lesione misurabile metastatica
    - Lo stato di RAS deve essere disponibile su base di analisi bioptica effettuata localmente
    - Pazienti non candidabili ad una chemioterapia standard di combinazione con irinotecan ed oxaliplatino secondo giudizio clinico e in condivisione con il team multidisciplinare, (se disponibile nel centro) I motivi che rendono il partecipante non candidabile possono essere dovuti all’età, al performance status, basso carico tumorale, a comorbidità o motivi non clinici e non solo.
    -Pazienti non candidabili a resezione curative delle lesioni metastatiche, secondo l’opinione dell’investigatore e in condivisione con il team multidisciplinare, se disponibile nel centro
    -Nessuna terapia antitumorale sistemica per il tumore colorettale metastatico non operabile. La chemioterapia precedente adiuvante o neoadiuvante è consentita solo se il partecipante è valutato libero da malattia da almeno sei mesi dalla fine della chemioterapia
    - Capacità di assumere la terapia per bocca.
    - Aspettativa di vita =12 settimane
    - ECOG (Eastern Cooperative Oncology Group) performance status =2.
    - Adeguata funzionalità ematologica, renale, epatica e della coagulazione
    -le donne potenzialmente fertili, devono aver un test sierico di gravidanza negativo. Le donne potenzialmente fertili e gli uomini con partner potenzialmente fertili, devono usare un metodo di contraccezione altamente efficace, così come le partner, per almeno 6 mesi dopo l’ultima assunzione di terapia sperimentale. Le donne potenzialmente fertili devono usare, oltre ad un metodo contraccettivo ormonale, anche u metodo barriera
    - Ottenimento del consenso informato scritto.
    E.4Principal exclusion criteria
    - Unlikely to cooperate in the study.
    - Pregnancy, breastfeeding or possibility of becoming pregnant during the study.
    - Participation in another interventional study, major surgery, drainage for ascites, pleural effusion or pericardial fluid, previous radiotherapy, within the specified timeframes prior to the randomisation.
    - Patients who have not recovered from clinically relevant non-hematologic CTCAE grade = 3 toxicity of previous anticancer therapy prior to the randomisation.
    - Symptomatic central nervous system metastases.
    - Has certain serious illness or serious medical condition(s) described in the protocol.
    - Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
    - Other malignancies excluding malignancies that are in remission for more than 5 years, cervix carcinoma-in-situ deemed cured by adequate treatment or basal cell carcinoma.
    - Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic setting or at a chronic low dose (=20mg/day prednisone equivalent)).
    - Criteria related to S 95005 administration:
    Has previously received S 95005.
    History of allergic reactions attributed to compounds of similar composition to S 95005 or any of its excipients.
    Any contraindication present in the SmPC of trifluridine/tipiracil,
    - Criteria related to bevacizumab administration:
    History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients.
    History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
    Serious non-healing wound, non-healing ulcer or non-healing bone fracture.
    Deep venous thromboembolic event within 4 weeks prior to randomisation,
    Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other haemorrhage/bleeding event CTCAE grade = 3 within 4 weeks prior to randomisation.
    Any contraindication present in the SmPC of bevacizumab.
    - Criteria related to capecitabine administration:
    History of allergic reactions or hypersensitivity to capecitabine or any of its excipients or fluorouracil.
    History of severe and unexpected reaction to fluoropyrimidine therapy.
    Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.
    Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 weeks prior to the randomisation.
    Any contraindication present in the SmPC of capecitabine.
    Scarsa probabilità di collaborare durante lo studio.
    Partecipante incinta, in allattamento o con possibilità di rimanere incinta durante lo studio
    Partecipazione ad altro studio interventistico, intervento chirurgico importante, drenaggio per asciti, effusione pleurica o di fluido pericardico, radioterapia precedente nei tempi specificati prima della randomizzazione.
    Partecipante che non si sia ripreso da tossicità clinicam. significativa di tipo non ematologico (CTCAE grado = 3) per terapia antitumorale precedente somministrata prima della randomizzazione.
    Metastasi sistema nervoso centrale sintomatiche
    Partecipante in condizioni di malattia grave od in condizioni mediche gravi come descritto nel protocollo.
    Problemi ereditari di intolleranza al galattosio, deficienza da Lapp lattasi o malassorbimento galattosio-glucosio
    Altri tumori, esclusi quelli in remissione da più di 5 anni, carcinoma della cervice in situ giudicati curati da trattamento adeguato o carcinoma delle cellule basali.
    Trattamento con terapia immunosoppressiva sistemica (eccetto steroidi in schema profilattico o a dosi
    croniche basse: =20mg/die prednisone equivalente).
    Criteri correlati all’assunzione di S 95005
    - Partecipante che abbia già assunto S95005 in precedenza.
    - Storia di reazioni allergiche provocate da composti di composizione simile a S95005 oppure a qualunque suo eccipiente.
    - Qualunque controindicazione presente nel foglietto illustrativo di trifluridina/tipiracile
    Criteri correlati all’assunzione di bevacizumab
    Storia di reazioni allergiche o ipersensitività a bevacizumab oppure a qualunque suo eccipiente.
    Storia di ipersensitività ai prodotti di cellule Chinese Hamster Ovary (CHO) o di altri anticorpi ricombinanti umani o umanizzati.
    Ferite gravi che non guariscono, ulcere o fratture delle ossa che non guariscono.
    Evento venoso tromboembolici profondo nelle 4 settimane precedenti la randomizzazione.
    Coagulopatia nota che aumenta il rischio di sanguinamento, diatesi emorragica. Qualsiasi altro tipo di emorragia/sanguinamento di grado CTCAE = 3 nelle 4 settimane precedenti la randomizzazione.
    Qualunque controindicazione presente nel foglietto illustrativo di bevacizumab.
    Criteri correlati all’assunzione di capecitabina
    - Storia di reazioni allergiche o ipersensitività a capecitabina oppure a qualunque suo eccipiente o al fluorouracile.
    - Storia di reazioni severe o inaspettate alla terapia con fluoropirimidina.
    - Mancanza assoluta e nota di attività di di-idropirimidine deidrogenasi (DPD)
    - Trattamenti con sorivudina o suoi analoghi chimici, tipo la brivudina, nelle 4 settimane precendenti la randomizzazione
    Qualunque controindicazione presente nel foglietto illustrativo di capecitabina.


    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) based on investigator judgement
    Sopravvivenza libera da progressione (PFS) secondo giudizio dell’investigatore
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumour assessments at baseline, every 8 weeks from C1D1 until
    radiological progression is documented and at the withdrawal visit if not
    done in the previous 8 weeks

    Valutazione del tumore alla baseline, ogni 8 settimane da C1D1 fino a progressione radiologica documentata ed alla visita di withdrawal se non eseguita nelle 8 settimane precedenti.
    E.5.2Secondary end point(s)
    Overall survival (OS)
    Overall response rate (ORR)
    Disease control rate (DCR)
    Duration of response (DoR)
    Time to treatment failure (TTF)
    Safety and tolerability assessed by incidence of adverse events (AE),
    laboratory tests, physical examination and performance status (ECOG),
    vital signs, 12-leads ECG parameters
    Quality of life (QoL)
    Tasso di Sopravvivenza (OS)
    Tasso di Risposta Totale (ORR)
    Tasso di controllo della Malattia(DCR)
    Durata della Risposta (DoR)
    Tempo al fallimento del trattamento(TTF)
    Sicurezza e Tollerabilit¿ valutate sulla base dell¿incidenza di eventi avversi
    Test di Laboratorio, esame fisico e Stato di performance
    segni vitali, ECG a 12 derivazioni
    Questionari Qualit¿ della Vita
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR, DCR, DoR, TTF: at baseline, every 8 weeks from C1D1 until
    radiological progression, and at withdrawal visit if not done in the
    previous 8 weeks.
    OS: survival status obtained at 8 week intervals until patient death or
    end of the study.
    AE: all over the study
    Laboratory tests, physical examination, ECOG, vital signs:
    Within 4 days prior to randomisation,
    At pre-dose of C1D1,
    At C1D15 (not for coagulation, physical examination and ECOG),
    Beginning with cycle 2, prior to start of study treatment in every cycle,
    Only for haematology and vital signs: At CxD15 (experimental arm only)
    prior to bevacizumab injection, Withdrawal visit.
    - ECG: within 28 days prior to randomisation and at withdrawal visit.
    - QoL: at baseline, every 6 weeks and at withdrawal visit.

    ORR, DCR, DoR, TTF: visita basale, ogni 8 settimane da C1D1 a progressione radiologica, visita di withdrawal se non eseguito nelle 8 settimane precedenti. OS: stato di sopravvivenza intervalli di 8 settimane fino morte del paziente o fine studio
    Eventi avversi: tutta la durata dello studio
    Test Laboratorio, esame fisico, ECOG, segni vitali: nelle 4 sett. precedenti la randomizz. Al pre-dose di C1D1, al C1D15 (escluso coagulazione, esame fisico ed ECOG). Ad inizio C2, prima inizio trattamento ad ogni ciclo.
    Ematologia e segni vitali: CxD15 (solo per braccio sperimentale) prima iniezione di bevacizumab, visita di withdrawal.
    ECG: entro 28 gg. precedenti la randomizz. e alla visita di withdrawal
    Qualit¿ della vita: ogni 6 sett. e alla visita di withdrawal
    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 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA144
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Bulgaria
    Croatia
    Denmark
    Estonia
    France
    Germany
    Ireland
    Italy
    Jamaica
    Lithuania
    Netherlands
    Poland
    Portugal
    Slovakia
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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
    End of Trial will occur 24 months after the first IMP intake of the last patient randomized and is defined as the date of the last follow-up of the last participant (including a contact phone), or the date of the last contact attempt if the last patient is declared lost to follow-up.
    La fine dello studio si realizzer¿ 24 mesi dalla prima assunzione di trattamento sperimentale dell¿ultimo paziente randomizzato ed ¿ definita come la data dell¿ultimo follow up dell¿ultimo partecipante (anche solo un contatto telefonico) o la data dell¿ultimo tentativo di contattare l¿ultimo paziente, se questo fosse perso al follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 213
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 641
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 727
    F.4.2.2In the whole clinical trial 854
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the discontinuation of the IMPs, patient¿s treatment is left to the physician¿s discretion.
    After completion of the study, patients currently being treated will be offered the option to continue the treatment(s) outside of the study.
    Dopo l¿interruzione della terapia, la scelta del trattamento ¿ lasciata al giudizio del clinico.
    Dopo il completamento dello studio, il paziente potr¿ continuare la terapia al di fuori dello studio
    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 Decision2018-04-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-01
    P. End of Trial
    P.End of Trial StatusOngoing
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