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    Summary
    EudraCT Number:2020-006118-19
    Sponsor's Protocol Code Number:2020-012-00EU1
    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:2021-06-08
    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 number2020-006118-19
    A.3Full title of the trial
    An Open-Label Phase 2 Study of Surufatinib in Patients with Neuroendocrine Tumours in Europe
    Studio in aperto di fase 2 su surufatinib in pazienti europei affetti da tumori neuroendocrini
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label Phase 2 Study of Surufatinib in Patients with Neuroendocrine Tumours in Europe
    Studio in aperto di fase 2 su surufatinib in pazienti europei affetti da tumori neuroendocrini
    A.3.2Name or abbreviated title of the trial where available
    2020-012-00EU1
    2020-012-00EU1
    A.4.1Sponsor's protocol code number2020-012-00EU1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04579679
    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.1.3.4CountryUnited 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 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 pointNick Lawn
    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+19738262891
    B.5.6E-maileunet@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 Yes
    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 nameFexofenadine
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form 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 INNFEXOFENADINA CLORIDRATO
    D.3.9.1CAS number 83799-24-0
    D.3.9.2Current sponsor codeFexofenadine
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.2.1.2Country 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 nameMidazolam
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Oromucosal/laryngopharyngeal solution
    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 INNMIDAZOLAM CLORIDRATO
    D.3.9.1CAS number 59467-70-8
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2500
    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 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 nameSurufatinib
    D.3.2Product code [HMPL-012]
    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 INNSURUFATINIB
    D.3.9.1CAS number 1308672-74-3
    D.3.9.2Current sponsor codeHMPL-012
    D.3.9.4EV Substance CodeSUB194701
    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 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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing 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 nameRosuvastatin
    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 INNROSUVASTATINA SALE DI CALCIO
    D.3.9.1CAS number 287714-41-4
    D.3.9.2Current sponsor codeRosuvastatin
    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 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
    Neuroendocrine Tumours
    Tumori neuroendocrini
    E.1.1.1Medical condition in easily understood language
    Neuroendocrine Tumours
    Tumori neuroendocrini
    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 10052399
    E.1.2Term Neuroendocrine tumour
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the anti-tumour activity of surufatinib in patients with low-to intermediate-grade (Grade 1 or Grade 2), well differentiated NET
    Valutare l’attività antitumorale di surufatinib in pazienti con NET ben differenziati, di grado basso-intermedio (grado 1 o grado 2)
    E.2.2Secondary objectives of the trial
    - To characterise the PK of surufatinib in patients with NET
    - To evaluate the effect of surufatinib on cardiac repolarisation, as detected by
    changes in ECG QTc, and the potential relationship with surufatinib plasma
    concentrations
    - To further characterise the antitumour activity of surufatinib in patients with NET
    - Cohort D only: To evaluate the effects of repeat dosing of surufatinib on the
    single-dose PK of CYP3A4, P-gp, and BCRP) substrates in patients with NET
    - To evaluate the safety and tolerability of surufatinib in patients with NET
    - Caratterizzare la farmacocinetica (PK) di surufatinib in pazienti con NET
    - Valutare l’effetto di surufatinib sulla ripolarizzazione cardiaca, come rilevato in base alle variazioni negli intervalli QT corretti (QTc) all’elettrocardiogramma (ECG), nonché la potenziale relazione con le concentrazioni plasmatiche di surufatinib
    - Caratterizzare ulteriormente l’attività antitumorale di surufatinib in pazienti con NET
    - (Solo Coorte D): valutare gli effetti della somministrazione ripetuta di surufatinib sulla PK a dose singola dei substrati del citocromo P450 (CYP)3A4, della glicoproteina-P (P-gp) e della proteina di resistenza del carcinoma mammario (BCRP) in
    pazienti con NET
    -Valutare la sicurezza e la tollerabilità di surufatinib in pazienti con NET
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Cohort D (Drug-Drug Interaction [DDI] Sub-Study): The primary objective of this cohort is to investigate the potential DDI between surufatinib and a drug cocktail containing selective probes of CYP3A4 (midazolam), P-gp (fexofenadine), and BCRP (rosuvastatin) substrates.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Coorte D (Drug-Drug Interaction [DDI] Sub-Study): l'obiettivo primario di questa coorte è di indagare la potenziale interazione tra farmaci (DDI) tra surufatinib e il cocktail di farmaci contenenti substrati selettivi di CYP3A4 (midazolam), P-gp (Fexofenadina) e BCRP (rosuvastatina)
    E.3Principal inclusion criteria
    1. Has histologically or cytologically documented, locally advanced, or metastatic NET and has progressed on at least 1 prior line of therapy, but no more than 3 therapies:
    a. Cohort A: NET of lung origin
    b. Cohort B: NET of small bowel origin
    c. Cohort C: NET of non-small bowel, non-pancreas, and non-lung origin
    d. Cohort D (DDI substudy): NET of any origin
    2. Has radiologic evidence of progressive tumour within 12 months of study enrolment
    3. Is willing and able to provide informed consent
    4. Is =18 years of age
    5. Has measurable lesions according to RECIST Version 1.1
    6. Has absolute neutrophil count of = 1.5×109/L, platelet count of = 100×109/L, and haemoglobin = 9 g/dL
    7. Has serum total bilirubin <1.5 times the upper limit of normal (ULN)
    8. Has proteinuria <2+ by urinalysis, or 24-hour urine collection =1 g of protein, or urine protein: urine-creatinine ratio =1.9
    9. Has alanine aminotransferase (ALT), AST, or alkaline phosphatase levels = 2.5 times the ULN
    a. Patients with known liver metastases may have ALT, AST, and ALP = 3× the ULN 10. Has serum creatinine <1.5 times ULN or creatinine clearance = 60 mL/min
    11. International normalised ratio (INR) >1.5 or activated partial thromboplastin time (aPTT) >1.5×ULN
    12. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    13. Female patients of childbearing potential and male patients with partners of childbearing potential agree 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) or highly effective non-oral hormonal contraception (e.g., Depo-Provera and Implanon) associated with inhibition of ovulation together with a barrier method (e.g., diaphragm, always containing a spermicide), intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, or sexual abstinence in line with the preferred and usual lifestyle of the subject. Oral and non-oral hormonal contraception should always be combined with an additional contraceptive method (i.e., barrier method) because of a potential interaction with the study drug. The same criteria are applicable to male patients involved in this clinical study if they have a partner of childbirth potential, and male patients must always use a condom.
    1.Ha NET documentata istologicamente o citologicamente, localmente avanzata o metastatica e ha registrato progressi su almeno 1 linea di terapia precedente, ma non più di 3 terapie:
    a. coorte A: NET di origine polmonare
    b. Coorte B: NET di intestino tenue
    c. coorte C: NET di origine non intestinale, non infettiva e non polmonare
    d. coorte D (sottostudio DDI): NET di qualsiasi origine
    2. Ha evidenza radiologica di tumore progressivo entro 12 mesi dall'arruolamento allo studio
    3. E’ disposto e in grado di fornire il consenso informato
    4. Ha = 18 anni
    5. Presenta lesioni misurabili secondo la versione 1.1 del RECIST
    6. Conta dei neutrofili in assoluto = 1,5 109/L, conta delle piastrine di = 100 109/L ed emoglobina = 9 g/dL
    7. Ha una bilirubina totale sierica pari a 1,5 volte il limite superiore della normale (ULN)
    8. Ha proteinuria <2+ mediante analisi delle urine, o raccolta di urina 24 ore =1 g di
    proteine, o proteine delle urine: rapporto urina-creatinina =1.9
    9. Ha alanina aminotransferasi (ALT), AST o fosfatasi alcalina livelli = 2,5 volte l'ULNa. I pazienti con metastasi epatiche note possono avere ALT, AST e ALP=3 l'ULN
    10. Ha creatinina nel siero 1,5 volte ULN o clearance creatinina =60mL/min
    11. Rapporto normalizzato internazionale (INR) >1,5 o parziale attivato tempo di
    tromboplastina (aPTT) > 1,5 ULN
    12. Prestazioni del gruppo oncologico cooperativo orientale (ECOG) stato di 0 o 1
    13. Le pazienti in età fertile e i pazienti di sesso maschile con partner in età fertile accettano di utilizzare una forma (o forme) di contraccezione altamente efficace che si traduce in un basso tasso di fallimento (1% all'anno) se usata in modo coerente e corretto, a partire dal periodo di screening, per tutto il periodo di studio e per 90 giorni dopo l'assunzione dell'ultima dose di farmaco in esame. Tali metodi comprendono la contraccezione ormonale orale (solo estrogeni/progestogeni combinati o progestogeni) o contraccezione ormonale non orale altamente efficace (ad esempio, Depo-Provera e Implanon) associato con inibizione dell'ovulazione insieme con un metodo di barriera (ad
    esempio, diaframma, sempre contenente uno spermicida), dispositivo intrauterino, ormone intrauterino-sistema di rilascio, legatura tubarica bilaterale, partner vasectomizzato o astinenza sessuale in linea con lo stile di vita preferito e usuale del soggetto. Contraccezione ormonale orale e non orale dovrebbe sempre essere combinato con un
    metodo contraccettivo (cioè metodo barriera) a causa di una potenziale interazione con il farmaco in esame. Gli stessi criteri sono applicabili ai pazienti di sesso maschile coinvolti in questo studio clinico se hanno un partner di potenziale di parto, e i pazienti di sesso maschile devono sempre utilizzare un preservativo.
    E.4Principal exclusion criteria
    1. Has an AE due to previous anti-tumour therapy that has not recovered to =CTCAE Grade 1, except alopecia and peripheral neurotoxicity with = CTCAE Grade 2 caused by platinum chemotherapy
    2. Major surgery within previous 4 weeks or radiation therapy within 2 weeks prior to the start of treatment. Prior palliative radiotherapy for metastatic lesions is permitted if there is at least one measurable lesion that has not been irradiated.
    3. Prior VEGF/VEGFR-targeted therapy
    4. Has uncontrollable hypertension, defined as systolic blood pressure =140 mmHg and/or diastolic blood pressure =90 mmHg, despite antihypertensive medication
    5. PT/INR >1.5 or activated partial thromboplastin time (aPTT) >1.5×ULN. For patients on Coumadin or coumadin-like products, please refer to Section 7.3.3)
    6. Has gastrointestinal disease or condition within 6 months prior to first dose that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumour with active bleeding, or other gastrointestinal conditions that
    could, in the investigators judgment, result in bleeding or perforation
    7. Has a history or presence of a serious haemorrhage (>30 mL within 3 months) or haemoptysis (>5 mL blood within 4 weeks) within 6 months of first dose of study drug
    8. Has clinically significant cardiovascular disease, including, but not limited to, acute myocardial infarction within 6 months prior to enrolment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure =2 according to the New York Heart Association classification, ventricular arrhythmia that needs drug treatment, and left ventricular ejection fraction (LVEF) <50%
    9. Has a mean corrected QT interval by Fridericia (QTcF) =480 ms
    10. Has brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease (SD) for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded
    11. Has a high risk of bleeding at screening due to tumour invasion into major vessels, such as pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by investigators
    12. Has arterial thrombosis or deep venous thrombosis within 6 months prior to first dosing, or thromboembolic events (including stroke and/or transient ischaemic attack) within 6 months prior to first dose of study drug
    13. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose of surufatinib
    14. For Cohort D, use of medications that are known substrates, inhibitors, or inducers of CYP3A or substrates of P-gp or BCRP within 3 weeks before the first dose of the drug cocktail
    15. Prior history of other cancer except those treated with curative intent for in situ non-melanoma skin cancer, breast, or cervical cancer, or those treated with curative intent and no evidence of disease in the last 5 years prior to enrolment in the study
    16. Has a clinically meaningful ongoing infection
    17. Has clinical symptoms consistent with pancreatitis
    18. Has a history of allergies to any ingredient of surufatinib or its capsule shell,
    including tartrazine (E 102)
    1. Ha una AE dovuta a una precedente terapia antitumorale che non si è ripresa =grado 1 della CTCAE, tranne l'alopecia e la neurotossicità periferica con = CTCAE Grado 2 causato da chemioterapia al platino
    2. Interventi chirurgici gravi nelle 4 settimane precedenti o radioterapia entro 2 settimane prima dell'inizio del trattamento. Radioterapia palliativa precedente per lesioni metastatiche sono ammesse se esiste almeno una lesione misurabile che non è stato irradiata.
    3. Terapia preventiva mirata alla VEGF/VEGFR
    4. Ha ipertensione incontrollabile, definita come pressione sanguigna sistolica =140 mmHg e/o pressione sanguigna diastolica =90 mmHg, nonostante terapia antiipertensiva
    5. PT/INR >1,5 o tempo di tromboplastina parziale attivato (aPTT) >1,5 ULN. Per i pazienti con Coumadin o prodotti simili, consultare la Sezione 7.3.3)
    6. Ha una malattia o una condizione gastrointestinale nei 6 mesi precedenti la prima dose che i medici sospettano possa influire sull'assorbimento dei farmaci, tra cui: ma non solo, ulcere gastriche e duodenali attive, colite ulcerosa e altre malattie digestive, tumore gastrointestinale con attivo sanguinamento, o altre condizioni gastrointestinali che potrebbero, nel giudizio dei medici, provocare sanguinamento o perforazione
    7. Ha una storia o presenza di una grave emorragia (>30 mL in 3mesi) o emopoiesi (>5 mL di sangue in 4 settimane) entro 6 mesi della prima dose del farmaco in esame
    8. Ha malattie cardiovascolari clinicamente significative, tra cui, ma non limitato a, infarto miocardico acuto nei 6 mesi precedenti arruolamento, grave/instabile angina pectoris o bypass coronarico, insufficienza cardiaca congestizia =2 secondo Classificazione NYHA, aritmia ventricolare che ha bisogno di trattamento farmacologico e
    frazione di espulsione ventricolare sinistra (LVEF) <50%
    9. Ha un intervallo QT medio corretto di Fridericia (Qtcf) =480 ms
    10. Ha metastasi cerebrali e/o compressione del midollo spinale non trattate con chirurgia e/o radioterapia, e senza evidenza di imaging clinico di malattia stabile (SD) per 14 giorni o più; pazienti che richiedono steroidi entro 4 settimane prima dell'inizio del trattamento di studio sarà escluso
    11. Ha un alto rischio di sanguinamento allo screening a causa di invasione del tumore in vasi principali, come l'arteria polmonare, la vena cava superiore, o la vena cava inferiore, come determinato dai medici
    12. Ha trombosi arteriosa o trombosi venosa profonda entro 6 mesi prima della prima somministrazione o eventi tromboembolici (compresi ictus e/o attacco ischemico transitorio) nei 6 mesi precedenti la prima dose del farmaco in studio
    13. Uso di forti induttori o inibitori di CYP3A4 nelle due settimane precedenti la prima dose di surufatinib
    14. Per la coorte D, uso di farmaci che sono substrati noti, inibitori o induttori di CYP3A o substrati di P-gp o BCRP entro 3 settimane prima della prima dose del cocktail di farmaci
    15. Storia precedente di altri tumori, ad eccezione di quelli trattati con intento curativo per il cancro della pelle in situ non melanoma, al seno o al collo dell'utero, o trattati con intento curativo e senza evidenza di malattia negli ultimi 5 anni prima dell’arruolamento allo studio
    16. Ha un'infezione clinicamente significativa in corso
    17. Presenta sintomi clinici compatibili con la pancreatite
    18. Ha una storia di allergie a qualsiasi ingrediente del surufatinib o al rivestimento della capsula, compresa la tartrazina (E 102)
    E.5 End points
    E.5.1Primary end point(s)
    Disease Control Rate (DCR)
    Tasso di controllo della malattia
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 mesi
    E.5.2Secondary end point(s)
    - Observed plasma concentrations, estimated population PK, and exposure parameters of surufatinib
    - QTc and plasma concentrations of surufatinib at specified time points
    - Additional efficacy endpoints
    • Objective Response Rate (ORR)
    • Time to Response (TTR)
    • Duration of Response (DoR)
    • Progressive-Free Survival (PFS)
    - Cohort D only: Exposure parameters of CYP3A4, P-gp, and BCRP
    substrates
    - Safety assessments include:
    • Frequency and severity of AEs
    • Physical examination findings
    • Vital signs
    • Laboratory tests
    • ECG
    • Echocardiograms/MUGA
    - Concentrazioni plasmatiche osservate, PK di popolazione stimata e parametri di esposizione di surufatinib
    - QTc e concentrazioni plasmatiche di surufatinib in corrispondenza di specifici time point
    - Tasso di risposta obiettiva, tempo alla risposta, durata della risposta e Progressive-Free Survival PFS
    - Solo coorte D: Parametri di esposizione dei substrati di CYP3A4, P-gp e BCRP
    - Le valutazioni di sicurezza includono:
    - Frequenza e gravità degli eventi avversi
    - Risultati dell’esame obiettivo
    - Segni vitali
    - Test di laboratorio
    - ECG
    - MUGA (Ecocardiogramma/scansione con acquisizione a gate multipli)
    E.5.2.1Timepoint(s) of evaluation of this end point
    PK Plasma Sampling: Day (-1 & -2) & at specific timepoints as per Schedule of Events (SOE)
    ECG for QTc Evaluation: At pre & post-dose on Cycle 1 Day 1 and Cycle 1 Day 15 (+1 week) at specific time points given in SOE
    ORR: Time to attain best overall response or CR or PR per RECIST Version 1.1
    TTR: Time between the start date of study drug until first documented response (CR or PR) according to RECIST Version 1.1
    DoR: Timepoint at which the objective response reaches CR or PR, whichever comes first, until the occurrence of PD or death
    PFS: Time from the start of study drug to date of objective disease progression as defined by RECIST Version 1.1 or death, whichever comes first.
    Echocardiogram/MUGA: At screening, Every 12 weeks (±7 days) after the first dose
    AEs, SAEs: Screening, EOT
    Campionamento PK del plasma : Giorno (-1&-2) & a specifici intervalli secondo SOE; ECG per valutazione delle Qtc: pre/ post-dose nel Ciclo 1 Giorno 1 e Ciclo 1 Giorno 15 (+1 sett ad intervalli specifici indicati nella SOE ORR: Tempo per raggiungere la migliore risposta generale o CR o PR per RECIST V1.1; TTR: tempo che intercorre tra la data di inizio dello studio e la prima risposta documentata (CR o PR) secondo RECIST v1.1 DoR: Periodo di tempo entro il quale la risposta raggiunge CR o PR, a seconda di quale sia la prima, fino a PD o morte; PFS: Tempo da inizio farmaco di studio fino a progressione malattia come definita da RECIST V1.1 o morte, a seconda di quale si verifica prima. ECG/MUGA: Allo screening, Ogni 12 settimane ( 7 giorni) dopo la prima dose; AEs, SAEs: Screening, EOT
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability, Drug-drug interaction (DDI)
    Tollerabilità, Interazione tra farmaci (DDI)
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Aperto
    Open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    France
    Germany
    Italy
    Norway
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    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 months6
    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: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 38
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 63
    F.4.2.2In the whole clinical trial 76
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Nessuno
    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 Decision2021-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-24
    P. End of Trial
    P.End of Trial StatusOngoing
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