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    Summary
    EudraCT Number:2020-000158-88
    Sponsor's Protocol Code Number:2019-013-GLOB1
    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:2020-10-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-000158-88
    A.3Full title of the trial
    A Global, Multi Center, Randomized, Placebo-Controlled Phase 3 Trial to Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to Placebo Plus Best Supportive Care in Patients with Refractory Metastatic Colorectal Cancer (FRESCO-2)
    “Studio clinico di fase 3, internazionale , multicentrico, randomizzato, controllato con placebo, per confrontare l'efficacia e la sicurezza di fruquintinib più la migliore terapia di supporto rispetto a placebo più la migliore terapia di supporto in pazienti affetti da tumore metastatico refrattario del colon-retto (FRESCO-2)”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 study of fruquintinib in patients with refractory metastatic colorectal cancer
    Studio di fase 3 di fruquintinib in pazienti affetti da tumore metastatico refrattario del colon-retto
    A.3.2Name or abbreviated title of the trial where available
    Refer to the protocol
    Fare riferimento al protocollo
    A.4.1Sponsor's protocol code number2019-013-GLOB1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04322539
    A.5.4Other Identifiers
    Name:INDNumber:131038
    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 SponsorHutchison MediPharma Limited
    B.1.3.4CountryChina
    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 supportHutchison MediPharma Limited
    B.4.2CountryChina
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHutchison MediPharma Limited
    B.5.2Functional name of contact pointAlberto Fernandez
    B.5.3 Address:
    B.5.3.1Street Address25A Vreeland Road, Suite 304
    B.5.3.2Town/ cityFlorham Park
    B.5.3.3Post codeNJ 07932
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12012180368
    B.5.6E-mailFresco2@hmplglobal.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 nameFruquintinib
    D.3.2Product code [HMPL-013]
    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.3.9.1CAS number 1194506-26-7
    D.3.9.2Current sponsor codeFRUQUINTINIB
    D.3.9.3Other descriptive nameHM5006462, HMPL-013 (or 013 as abbreviation)
    D.3.9.4EV Substance CodeSUB198242
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 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 nameFruquintinib
    D.3.2Product code [HMPL-013]
    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.3.9.1CAS number 1194506-26-7
    D.3.9.2Current sponsor codeFRUQUINTINIB
    D.3.9.3Other descriptive nameHM5006462, HMPL-013 (or 013 as abbreviation)
    D.3.9.4EV Substance CodeSUB198242
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Refractory metastatic colorectal cancer
    Tumore metastatico refrattario del colon-retto
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC.
    Valutare la sopravvivenza complessiva di fruquintinib più BSC rispetto a placebo più BSC in soggetti con mCRC refrattario.
    E.2.2Secondary objectives of the trial
    • To evaluate progression-free survival (PFS) of fruquintinib plus BSC compared to placebo plus BSC
    • To evaluate the objective response rate (ORR), disease control rate (DCR), and duration of response (DoR)
    • To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus BSC
    • To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with refractory mCRC
    • To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib and M11 plasma concentrations
    • To evaluate the relationship between fruquintinib exposure and endpoints for efficacy and safety
    • To evaluate quality of life (QoL) as assessed by using QLQ-C30: cancer-specific; and EQ-5D-5L questionnaires
    • To assess resource utilization
    • Valutare la sopravvivenza libera da progressione (PFS) di fruquintinib più BSC rispetto a placebo più BSC
    • Valutare il tasso di risposta obiettiva (ORR), il tasso di controllo della malattia (DCR) e la durata della risposta (DoR)
    • Valutare la sicurezza e la tollerabilità di fruquintinib più BSC rispetto a placebo più BSC
    • Caratterizzare l’esposizione PK di fruquintinib e del metabolita M11 in soggetti con mCRC refrattario
    • Valutare l’effetto di fruquintinib sulla ripolarizzazione cardiaca, come rilevato in base alle variazioni negli intervalli QTc all’elettrocardiogramma (ECG), nonché la potenziale relazione con le concentrazioni plasmatiche di fruquintinib e M11
    • Valutare la relazione tra l’esposizione a fruquintinib e gli endpoint di efficacia e sicurezza
    • Analizzare la qualità della vita (QoL) valutata utilizzando il Questionario per misurare la qualità della vita QLQ-C30 specifico per il tumore e il questionario EQ-5D-5L
    • Valutare il consumo di risorse
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provide written informed consent;
    2. Age =18 years;
    3. Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented;
    4. Subjects must have progressed on or been intolerant to treatment with either
    trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wildtype,
    an anti-EGFR therapy.
    5. Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject’s country unless the patient is ineligible for treatment with a checkpoint inhibitor;
    6. Subjects who received oxaliplatin in the adjuvant setting must have progressed within 6 months of completion of adjuvant therapy;
    7. Body weight =40kg;
    8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;
    9. Have measurable disease according to RECIST Version1.1 (RECIST v1.1), assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST v1.1, unless there has been documented progression of those lesions.
    10. Expected survival >12 weeks;
    11. For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation together with a barrier method (eg, diaphragm, always containing
    a spermicide), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or sexual abstinence. Oral contraception should always be combined with an additional contraceptive method (ie, barrier method) because of a potential interaction with the study drug. The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
    12. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild type, an anti-EGFR therapy. Subjects with a documented BRAFV600E mutation must have been treated with a BRAF inhibitor if approved and available in the subject’s country, unless the subject is ineligible for treatment with a BRAF inhibitor. Subjects must be ECOG performance status 0 or 1, and have measurable disease per RECIST v1.1
    1.Consenso informato scritto.
    2.Età =18 anni.
    3.Documentazione istologica e/o citologica di adenocarcinoma metastatico del colon-retto. Lo stato di RAS, BRAF e dell’instabilità dei microsatelliti (MSI-H)/riparazione dei mismatch (dMMR) deve essere documentato.
    4.Progressione o intolleranza al trattamento con trifluridina/tipiracil (TAS-102) o regorafenib. I soggetti sono considerati intolleranti a TAS-102 o regorafenib qualora abbiano ricevuto almeno una dose di uno dei due agenti e abbiano interrotto la terapia per motivi diversi dalla progressione della malattia. Sono ammessi i soggetti che sono stati trattati sia con TAS-102 sia con regorafenib. Inoltre, i soggetti devono essere stati precedentemente trattati con terapie standard approvate: chemioterapia a base di fluoropirimidina, oxaliplatino e irinotecan, una terapia biologica anti-VEGF e, se wild-type per RAS, una terapia anti-EGFR.
    5.I soggetti con tumori che presentano elevata instabilità dei microsatelliti (MSI-H) o deficit del sistema di riparazione dei mismatch (dMMR) devono essere stati trattati con inibitori del checkpoint immunitario, se approvati e disponibili nel Paese del soggetto, tranne se il paziente non è idoneo al trattamento con un inibitore del checkpoint.
    6.I soggetti che hanno ricevuto oxaliplatino nell’ambito del trattamento adiuvante devono aver manifestato progressione entro 6 mesi dal completamento della terapia adiuvante.
    7.Peso corporeo =40 kg.
    8.Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) di 0-1.
    9.Malattia misurabile secondo i criteri RECIST Versione 1.1 (RECIST v1.1), valutata localmente. I tumori trattati con radioterapia non sono misurabili secondo i criteri RECIST v.1.1, salvo in caso di progressione documentata delle lesioni irradiate.
    10.Sopravvivenza attesa >12 settimane.
    11.Per i soggetti di sesso femminile in età fertile e i soggetti di sesso maschile con partner in età fertile, consenso a utilizzare uno o più metodi contraccettivi altamente efficaci, che comportino un basso tasso di insuccesso (<1% all’anno) se utilizzati regolarmente e correttamente, a partire dal periodo di screening, per tutta la durata del periodo dello studio e per 90 giorni dopo l’assunzione dell’ultima dose di farmaco sperimentale. Tali metodi includono: contraccezione ormonale orale (combinazione di estrogeno e progesterone o solo progesterone) associata a inibizione dell’ovulazione insieme a un metodo barriera (per es., diaframma, sempre contenente uno spermicida), dispositivo intrauterino (IUD), sistema intrauterino a rilascio di ormoni (IUS), legatura bilaterale delle tube, partner vasectomizzato o astinenza sessuale. La contraccezione orale deve sempre essere combinata con un metodo contraccettivo aggiuntivo (ovvero, metodo barriera) alla luce di una possibile interazione con il farmaco sperimentale. Gli stessi criteri si applicano ai soggetti di sesso maschile coinvolti in questa sperimentazione clinica la cui partner sia in età fertile; tali soggetti dovranno sempre utilizzare un preservativo.
    12. I soggetti devono anche essere stati precedentemente trattati con terapie standard approvate: chemioterapia a base di fluoropirimidina, oxaliplatino e irinotecan, una terapia biologica anti-VEGF e, se wild type per mutazioni in RAS, una terapia anti-EGFR. I soggetti con una mutazione BRAFV600E documentata devono essere stati trattati con un inibitore BRAF se approvato e disponibile nel paese del soggetto, a meno che il soggetto non sia idoneo per il trattamento con un inibitore BRAF. I soggetti devono avere lo stato di performance ECOG 0 o 1 e presentare una malattia definibile secondo RECIST v1.1
    E.4Principal exclusion criteria
    1. Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
    2. Serum total bilirubin >1.5 × the upper limit of normal (ULN). Subjects with Gilbert syndrome, bilirubin <2 X ULN, and normal aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are eligible;
    3. ALT or AST >2.5 × ULN in subjects without hepatic metastases; ALT or AST >5 × ULN in subjects with hepatic metastases; 4. Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation.5. Urine dipstick protein =2+ or 24-hour urine protein =1.0 g/24-h. Subjects with greater than 1+ proteinuria on urinalysis must undergo a 24-hour urine collection. 6. Uncontrolled hypertension, defined as: systolic blood pressure =140 mm Hg and/or diastolic blood pressure =90 mm Hg despite optimal medical management; 7. International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes; 8. History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;9. History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;10. History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening. 11. Stroke and/or transient ischemic attack within 12 months prior to screening; 12. Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram; 13. Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.14. Concomitant medications with a known risk of causing QT prolongation and/or torsades de pointes.15. Systemic anti-neoplastic therapies (except for those described in Exclusion Criterion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy; 16. Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug; For the complete list of exclusion criteria please refer to the protocol.
    1.Conta assoluta dei neutrofili (ANC) <1,5×109/l, conta piastrinica <100×109/l o emoglobina <9,0 g/dl. Il ricorso a trasfusioni di sangue entro 1 settimana prima dell’arruolamento per aumentare la probabilità che il soggetto risulti idoneo non è consentito.
    2.Bilirubina sierica totale >1,5 × il limite superiore della norma (ULN). I soggetti con sindrome di Gilbert, bilirubina <2 × l’ULN e aspartato aminotransferasi (AST)/alanina aminotransferasi (ALT) nella norma sono considerati idonei.
    3.ALT o AST >2,5 × l’ULN in soggetti senza metastasi epatiche; ALT o AST >5 × l’ULN in soggetti con metastasi epatiche. 4.Creatinina sierica >1,5 × l’ULN o clearance della creatinina <60 ml/min. La clearance della creatinina può essere misurata in una raccolta delle urine delle 24 ore oppure stimata mediante equazione di Cockroft-Gault. 5.Proteine urinarie al test su striscia reattiva =2+ o proteine nelle urine delle 24 ore =1,0 g/24 h. I soggetti con proteinuria superiore a 1+ all’analisi delle urine devono sottoporsi a una raccolta delle urine delle 24 ore. 6.Ipertensione non controllata, definita come pressione sanguigna sistolica =140 mmHg e/o pressione sanguigna diastolica =90 mmHg malgrado una gestione medica ottimale. 7.Rapporto internazionale normalizzato (INR) >1,5 × l’ULN o tempo di tromboplastina parziale attivata (aPTT) >1,5 × l’ULN, salvo il caso di trattamento anticoagulante profilattico attuale o in programma. 8.Ulcera gastrica/duodenale o colite ulcerosa anamnestica o attiva, emorragia attiva da tumore gastrointestinale non sottoposto a resezione, anamnesi di perforazione o fistole; oppure qualsiasi altra condizione che, a giudizio dello sperimentatore, possa esitare in emorragia o perforazione gastrointestinale entro i 6 mesi precedenti lo screening. 9.Anamnesi o presenza di emorragia in qualsiasi altra sede (per es., emottisi o ematemesi) entro 2 mesi prima dello screening. 10.Anamnesi di evento tromboembolico, comprese trombosi venosa profonda (TVP), embolia polmonare (EP) o embolia arteriosa, entro 6 mesi prima dello screening. 11.Ictus e/o attacco ischemico transitorio entro 12 mesi prima dello screening.12.Malattia cardiovascolare clinicamente significativa, tra cui, a titolo puramente esemplificativo, infarto miocardico acuto o chirurgia di bypass delle arterie coronarie entro 6 mesi prima dell’arruolamento, angina pectoris grave o instabile, insufficienza cardiaca congestizia in classe III/IV secondo la classificazione della New York Heart Association (Associazione dei cardiologi di New York), aritmie ventricolari con necessità di trattamento o frazione di eiezione ventricolare sinistra (FEVS) <50% in base all’ecocardiogramma.13.Intervallo QT medio corretto utilizzando il metodo di Fridericia (QTcF) >480 msec o eventuali fattori che aumentano il rischio di prolungamento del QTc o il rischio di eventi aritmici, quali ad esempio ipokaliemia, sindrome del QT lungo congenita, anamnesi familiare di sindrome del QT lungo o morte improvvisa inspiegata sotto i 40 anni di età in un parente di primo grado.14.Farmaci concomitanti con rischio noto di causare prolungamento del QT e/o torsades de pointes 15.Terapie antineoplastiche sistemiche (eccetto quelle descritte nel criterio di esclusione 18) o qualsiasi terapia sperimentale entro 4 settimane prima della prima dose di farmaco sperimentale, comprese chemioterapia, radioterapia con intento radicale, ormonoterapia, terapia biologica e immunoterapia.16.Terapie mirate sistemiche della classe delle piccole molecole (per es., inibitori tirosin-chinasici) entro 5 emivite o 4 settimane (a seconda di quale sia il periodo più breve) prima della prima dose di farmaco sperimentale.
    Per la lista completa dei criteri di esclusione si prega di fare riferimento al protocollo
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS)
    Sopravvivenza Globale
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint of the study is overall survival, defined as the time (months) from date of randomization to death from any cause. Subjects without report of death at the time of analysis will be censored at the date last known alive.
    L'endpoint primario dello studio è la sopravvivenza globale, definita come il tempo (mesi) dalla data della randomizzazione alla morte per qualsiasi causa. I soggetti per cui non è stato riportato un evento di morte al momento dell'analisi, verranno censurati facendo riferimento alla data dell'ultimo contatto
    E.5.2Secondary end point(s)
    - Progression-free survival (PFS)
    - Objective response rate (ORR)
    - Disease control rate (DCR)
    - Duration of response (DoR)
    - Safety including TEAEs, SAEs, deaths, ECG’s, and clinical laboratory abnormalities;
    - Observed plasma concentrations, estimated population PK and exposure parameters of fruquintinib and M11;
    - QTc interval and plasma concentrations of fruquintinib and M11 at specified time points;
    - Parameters describing exposure-response with efficacy (eg, OS) and safety (eg, AEs) endpoints;
    - Changes in health status (QLQ-C30: cancerspecific; and EQ-5D-5L);
    - Resource utilization including all concomitant medications, days in hospital.
    - Sopravvivenza libera da progressione
    - Tasso di risposta obiettiva
    - Tasso di controllo della malattia
    - Durata della risposta
    - Sicurezza inclusi TEAE, SAE, decessi, ECG e anomalie cliniche di laboratorio;
    - Concentrazioni plasmatiche osservate, stima del profilo farmacocinetico (PK) della popolazione e parametri di esposizione di fruquintinib e M11;
    - intervallo QTc e concentrazioni plasmatiche di fruquintinib e M11 in punti temporali specifici;
    - Parametri che descrivono gli endpoint di risposta all'esposizione di efficacia (ad es. spravvivenza globale OS) e sicurezza (ad es. Eventi avversi);
    - Cambiamenti nello stato di salute (QLQ-C30: specifico per il cancro; e EQ-5D-5L);
    - Utilizzo delle risorse, compresi tutte le terapie concomitanti, giorni in ospedale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PFS is defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator or death from any cause.
    - Objective response rate is defined as the proportion of subjects achieving a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator.
    - Disease control rate is defined as proportion of subjects achieving a best overall response of confirmed CR, PR, or SD, per RECIST v1.1, as determined by the investigator.
    Refer to the protocol for additional timepoints.
    -PFS è definito come il tempo (mesi) dalla randomizzazione fino alla prima documentazione radiografica della progressione obiettiva valutata dallo sperimentatore o dalla morte per qualsiasi causa.
    -Il tasso di risposta obiettiva è definito come percentuale di soggetti che ottengono la migliore risposta globale di risposta completa confermata (CR) o risposta parziale (PR), secondo i criteri RECIST v1.1, determinati dallo sperimentatore.
    -Il tasso di controllo della malattia è definito come percentuale di soggetti che ottengono la migliore risposta globale di CR, PR o di Malattia Stabile (SD) confermate, secondo i criteri RECIST v1.1, determinati dallo sperimentatore.
    Fare riferimento al protocollo per ulteriori punti temporali.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    Qualità della vita
    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 Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    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
    France
    Germany
    Hungary
    Italy
    Japan
    Spain
    United Kingdom
    United States
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 322
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state46
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 390
    F.4.2.2In the whole clinical trial 522
    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)
    Subjects who are still on study treatment at the time of study completion may continue to receive study treatment if they are experiencing clinical benefit and no undue risks.
    Continued access will apply to this study only if at least 1subject is still on study treatment when study completion occurs. The sponsor will notify investigators when the continued access period begins.
    I soggetti che sono ancora in trattamento di studio al momento del completamento dello studio possono continuare a ricevere il trattamento di studio se presentano benefici clinici e nessun rischio inutile
    L'accesso continuato si applicherà a questo studio solo se almeno 1 soggetto sarà ancora in trattamento quando si verificherà il completamento dello studio. Lo sponsor notificherà agli sperimentatori l'inizio del periodo di accesso continuato.
    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 Decision2020-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
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