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    Summary
    EudraCT Number:2020-004163-12
    Sponsor's Protocol Code Number:2020-012-GLOB1
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-07-27
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-004163-12
    A.3Full title of the trial
    An Open-Label Phase Ib/II Study of Surufatinib in Combination with Tislelizumab in Subjects With Advanced Solid Tumors
    Estudio abierto de fase Ib/II del surufatinib en combinación con tislelizumab en
    sujetos con tumores sólidos avanzados
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Surufatinib in Combination With Tislelizumab in Advanced Solid Tumors
    Surufatinib en combinación con tislelizumab en tumores sólidos avanzados
    A.4.1Sponsor's protocol code number2020-012-GLOB1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04579757
    A.5.4Other Identifiers
    Name:INDNumber:124522
    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, Florham Park
    B.5.3.2Town/ cityNJ
    B.5.3.3Post code07932
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1973826 2891
    B.5.6E-mailnickl@hutch-med.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 nameSurufatinib
    D.3.2Product code HMPL-012
    D.3.4Pharmaceutical form Capsule
    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.3.9.3Other descriptive nameSulfatinib
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTislelizumab
    D.3.2Product code BGB-A317
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTISLELIZUMAB
    D.3.9.1CAS number 1858168-59-8
    D.3.9.2Current sponsor codeBGB-A317
    D.3.9.3Other descriptive nameBGB-A317, BGN1, JHL2108
    D.3.9.4EV Substance CodeSUB193656
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Advanced Solid Tumors
    Tumores sólidos avanzados
    E.1.1.1Medical condition in easily understood language
    Tumours
    Tumores
    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 10061451
    E.1.2Term Colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10059514
    E.1.2Term Small cell lung cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10017758
    E.1.2Term Gastric cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10075333
    E.1.2Term Soft tissue sarcoma
    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
    Part 1
    To evaluate the safety and tolerability of surufatinib, thereby determining the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab.

    Part 2
    To evaluate the objective response rate (ORR) as assessed by the investigator in patients with advanced solid tumors when treated with surufatinib in combination with tislelizumab according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    Parte 1:
    Evaluar la seguridad y tolerabilidad del surufatinib y determinar la DRF2 y/o la dosis máxima tolerada (DMT) de surufatinib en combinación con tislelizumab.

    Parte 2:
    Evaluar la tasa de respuesta objetiva (TRO) evaluada por el investigador en pacientes con tumores sólidos avanzados cuando reciben tratamiento con surufatinib en combinación con tislelizumab de acuerdo con los criterios RECIST v1.1.
    E.2.2Secondary objectives of the trial
    Part 1
    • To evaluate the antitumor activity in patients with advanced solid tumors when treated with surufatinib in combination with tislelizumab according to RECIST v1.1
    • To characterize the pharmacokinetics (PK) and immunogenicity of tislelizumab and surufatinib in combination

    Part 2
    • To evaluate further anticancer effects of surufatinib in combination with tislelizumab
    • To characterize the safety and tolerability of surufatinib in combination with tislelizumab
    • To characterize the PK and immunogenicity of tislelizumab and
    surufatinib in combination
    Parte 1:
    - Evaluar la actividad antitumoral en pacientes con tumores sólidos avanzados cuando reciben
    tratamiento con surufatinib en combinación con tislelizumab de acuerdo con los criterios RECIST v1.1.

    - Caracterizar la farmacocinética (FC) y la inmunogenicidad del tislelizumab y el surufatinib en combinación.

    Parte 2:
    - Evaluar otros efectos antineoplásicos del surufatinib en combinación con tislelizumab

    - Caracterizar la seguridad y tolerabilidad del surufatinib en combinación con tislelizumab

    - Caracterizar la FC y la inmunogenicidad del tislelizumab y el surufatinib en combinación
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines
    2. ≥18 years of age
    3. Part 1: have evaluable lesions (according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1])
    Part 2: have measurable lesions (according to RECIST v1.1)
    4. Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL
    5. Serum total bilirubin (TBIL) <1.5 times the upper limit of normal (ULN)
    6. Proteinuria <2+ by urinalysis; if proteinuria ≥2+, proteinuria <1 g by 24-hour urinary protein test is required
    7. Patients without liver metastases: must have alanine aminotransferase (ALT) and/or AST levels ≤2.5 times the ULN. Patients with liver metastases: must have ALT and AST levels ≤5 times the ULN
    8. Creatinine clearance ≥45 mL/min
    9. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless the patient is currently receiving anticoagulants for prophylactic purposes.
    10. Have a performance status of 0 or 1 on the ECOG scale
    11. 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 when used consistently and correctly.
    Dose Escalation:
    12. Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type that has progressed on or are intolerant of standard therapies and for which no curative therapy exists.
    Dose Expansion:
    13. Histologically or cytologically documented, locally advanced or metastatic.
    a. Cohort A: adenocarcinoma of the colon or rectum that is microsatellite stable. Patients must have progressed on, or had discontinued due to intolerable toxicity to, at least 3 prior regimens of standard therapy. Treatment progression is defined as disease progression during or within 3 months after the last dose of standard therapy. Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment. Patients must have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and, if RAS wild-type, an anti-epidermal growth factor receptor antibody therapy
    a. Cohort B: progressive, low, or intermediate grade (Grade 1 or Grade 2) NETs of thoracic (B1) or GEP (B2) origins. Patients must have radiological documentation of progression of disease in the last 6 months prior to the initiation of study treatment and must have progressed on at least 1 line of standard therapy for metastatic disease.
    i. For NETs originating from the thorax,
    A. Grade 1 is defined as <2 mitoses/10 high-power field (HPF) and no necrosis.
    B. Grade 2 is defined as 2-10/10 HPF and/or foci of necrosis.
    ii. For NETs originating from GEP,
    A. Grade 1 is defined as <2 mitoses/10 HPF and/or <3% Ki-67 index.
    B. Grade 2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index
    iii. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade is used to assign classification.
    iv. Patients who have functioning NETs and have been on a stable dose of an SSA for a minimum of 2 months prior to the first dose of study treatment for control of their secretory symptoms will be eligible.
    b. Cohort C: SCLC that has progressed on standard first line chemotherapy treatment.
    c. Cohort D: Adenocarcinoma of the stomach or gastroesophageal junction and have progressed on at least 2 prior lines of therapy. Must be microsatellite stable and have tumor stain for PD-L1 by combined positive score ≥5%.
    d. Cohort E: ASPS (E1) or UPS (E2). Patients must have radiological documentation of disease progression in the last 3 months prior to the initiation of study treatment and have progressed on at least 1 line of standard therapy or refused standard frontline cytotoxic chemotherapy.
    14. Patients in dose expansion: must be able to provide a minimum of 10 unstained slides for central confirmation of PD-L1 expression and microsatellite stability testing. In the event archived tumor samples are not available for testing, patients may opt for a core needle biopsy prior to beginning protocol therapy if medically feasible.

    Please refer to protocol for full list of inclusion criteria.
    1. Estar dispuesto y ser capaz de proporcionar un consentimiento informado firmado por el paciente del estudio o por un representante legalmente aceptable
    2. ≥18 años de edad
    3. Parte 1: tener lesiones evaluables (según los Criterios de Evaluación de la Respuesta en Tumores Sólidos versión 1.1 [RECIST v1.1])
    Parte 2: tener lesiones medibles (según RECIST v1.1)
    4. Recuento absoluto de neutrófilos (ANC) de ≥1,5×109/L, recuento de plaquetas de ≥100×109/L y hemoglobina ≥9 g/dL
    5. Bilirrubina total sérica (TBIL) <1,5 veces el límite superior de la normalidad (ULN)
    6. Proteinuria <2+ por análisis de orina; si la proteinuria es ≥2+, se requiere una proteinuria <1 g por análisis de proteínas en orina de 24 horas
    7. Pacientes sin metástasis hepáticas: tener niveles de alanina aminotransferasa (ALT) y/o AST ≤2,5 veces el ULN. Pacientes con metástasis hepáticas: tener niveles de ALT y AST ≤5 veces el ULN
    8. Aclaramiento de creatinina ≥45 mL/min.
    9. Coeficiente internacional normalizado (INR) ≤1,5 × ULN y tiempo de tromboplastina parcial activado (aPTT) ≤1,5 × ULN, a menos que el paciente esté recibiendo actualmente anticoagulantes con fines profilácticos.
    10. Tener un estado de rendimiento de 0 o 1 en la escala ECOG
    11. Pacientes mujeres en edad fértil y pacientes varones con parejas en edad fértil: aceptan utilizar una(s) forma(s) anticonceptiva(s) altamente efectiva(s) que resulte(n) en una baja tasa de fracaso cuando se utiliza(n) consistente(s) y correctamente.
    Aumento de la dosis:
    12. Enfermedad maligna sólida localmente avanzada o metastásica de cualquier tipo, documentada histológica o citológicamente, que haya progresado o sea intolerante a las terapias estándar y para la que no exista una terapia curativa.
    Ampliación de dosis:
    13. Enfermedad sólida localmente avanzada o metastásica, histológicamente o citológicamente documentada.
    a. Cohorte A: adenocarcinoma de colon o recto estable en cuanto a microsatélites. Los pacientes deben haber progresado con al menos 3 regímenes previos de terapia estándar o haberlos suspendido por toxicidad intolerable. La progresión del tratamiento se define como la progresión de la enfermedad durante o dentro de los 3 meses siguientes a la última dosis de la terapia estándar. La terapia previa podía incluir quimioterapia adyuvante si el tumor había reaparecido en los 6 meses siguientes a la última administración del tratamiento. Los pacientes deben haber sido tratados previamente con quimioterapia a base de fluoropirimidina, oxaliplatino e irinotecán; una terapia biológica anti-VEGF; y, si son de tipo RAS salvaje, una terapia de anticuerpos contra el receptor del factor de crecimiento epidérmico
    a. Cohorte B: TNE progresivos, de grado bajo o intermedio (Grado 1 o Grado 2) de origen torácico (B1) o GEP (B2). Los pacientes deben tener documentación radiológica de progresión de la enfermedad en los últimos 6 meses antes del inicio del tratamiento del estudio y deben haber progresado con al menos 1 línea de terapia estándar para la enfermedad metastásica.
    i. Para los TNE de origen torácico,
    A. El grado 1 se define como <2 mitosis/10 campos de alta potencia (HPF) y sin necrosis.
    B. El grado 2 se define como 2-10/10 HPF y/o focos de necrosis.
    ii. Para las NET que se originan en el GEP,
    A. El grado 1 se define como <2 mitosis/10 HPF y/o <3% de índice Ki-67.
    B. El grado 2 se define como 2-20/10 HPF y/o 3-20% de índice Ki-67
    iii. Si la proporción mitótica y el índice Ki-67 corresponden a un grado diferente, se utiliza el grado más alto para asignar la clasificación.
    iv. Serán elegibles los pacientes que tengan NETs funcionantes y que hayan estado con una dosis estable de un SSA durante un mínimo de 2 meses antes de la primera dosis de tratamiento del estudio para el control de sus síntomas secretores.
    b. Cohorte C: CPM que ha progresado con el tratamiento estándar de quimioterapia de primera línea.
    c. Cohorte D: Adenocarcinoma de estómago o de la unión gastroesofágica y que haya progresado con al menos 2 líneas de tratamiento previas. Deben ser microsatélites estables y tener tinción tumoral para PD-L1 por puntuación positiva combinada ≥5%.
    d. Cohorte E: ASPS (E1) o UPS (E2). Los pacientes deben tener documentación radiológica de progresión de la enfermedad en los últimos 3 meses antes del inicio del tratamiento del estudio y haber progresado con al menos 1 línea de terapia estándar o haber rechazado la quimioterapia citotóxica estándar de primera línea.
    14. Pacientes en expansión de dosis: deben poder proporcionar un mínimo de 10 portaobjetos sin teñir para la confirmación central de la expresión de PD-L1 y la prueba de estabilidad de microsatélites. En el caso de que las muestras tumorales archivadas no estén disponibles para las pruebas, los pacientes pueden optar por una biopsia con aguja gruesa antes de comenzar la terapia del protocolo si es médicamente factible.

    Consulte el protocolo para ver la lista completa de criterios de inclusión.
    E.4Principal exclusion criteria
    1. AEs due to previous antitumor therapy has not recovered to CTCAE ≤Grade 1, except alopecia and peripheral neurotoxicity with CTCAE ≤Grade 2
    2. Part 2 patients with CRC (Cohort A), NETs (Cohort B), and STS (Cohort E): previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway
    Note: Patients in the Part 1 and patients in Part 2 Cohorts C and D (SCLC and GC) may have received previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, CTLA-4 antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway;
    3. Previous treatment with surufatinib
    4. Uncontrollable hypertension, defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg
    5. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal
    conditions that may cause bleeding or perforation by investigator's discretion
    6. History or presence of a serious hemorrhage (>30 mL within 3 months), hemoptysis (>5 mL blood within 4 weeks), or life-threatening thromboembolic event within 6 months
    7. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure according to the New York Heart Association classification ≥2, ventricular arrhythmias which need drug treatment, or left ventricular ejection fraction (LVEF) <50%
    8. QT interval corrected by the method of Fredericia (QTcF) ≥480 milliseconds
    9. Other malignant tumors within 5 years prior to screening (except cured basal-cell carcinoma or squamous carcinoma at skin and cervical carcinoma in situ)
    10. Antitumor therapy received within 2 weeks or 5 half-lives, whichever is shorter, prior to the initiation of the investigational treatment, including, but not limited to, chemotherapy, radical radiotherapy, targeted therapy, immunotherapy, hepatic embolization, cryoablation, and radiofrequency ablation
    11. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the study treatment
    12. Strong inducers or inhibitors of Cytochrome P450, family 3, subfamily A (CYP3A) taken within two weeks prior to the first study treatment
    13. Any clinically significant active infection, including, but not limited to, known human immunodeficiency virus (HIV) infection
    14. Known history of active viral hepatitis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with hepatitis c virus (HCV) infection who are currently on treatment
    are eligible if they have an undetectable HCV viral load. Patients with an unknown history of viral hepatitis must be screened for HBV with HBs antigen; HBc antibody and HBS antibody; and HBV-DNA, if indicated and for HCV with HCV antibody.
    a. Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for >2 weeks before the first dose of study treatment.
    b. Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody.
    15. Brain metastases and/or leptomeningeal disease 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.
    16. Used corticosteroids (prednisone or other steroids with equivalent efficacy at a dose of >10 mg/day) or other immunosuppressants for systemic therapy within 2 weeks before the first drug administration. Nasal spray, inhaled, or other topical steroids are allowed (ie, ≤10 mg/day of prednisone or other glucocorticoids at an equivalent dose)
    17. For patients with NETs: administration of SSAs in the absence of secretory symptoms discontinued at least 4 weeks before the first dose of study treatment;
    18. Active autoimmune diseases or history of autoimmune diseases that may relapse.
    19. Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the duration of the study
    20. Major surgeries within 60 days prior to first dosing
    21. Uncontrollable malignant pleural effusion, ascites, or pericardial effusion.
    Please refer to protocol for complete list of exclusion criteria.
    1. EA debidos a la terapia antitumoral previa no recuperados hasta el CTCAE ≤Grado 1, excepto la alopecia y la neurotoxicidad periférica con CTCAE ≤Grado 2. 2. Pacientes Parte 2 con CCR (Cohorte A), NETs (Cohorte B) y STS (Cohorte E): tratamiento previo con anticuerpos anti-PD-1, anti-PD-L1/L2, anticuerpo anti-célula T asociada a linfocitos citotóxicos-4 (CTLA-4) o cualquier otro anticuerpo que actúe sobre la vía costimulatoria de las células T o sobre el punto control; 3. Tratamiento previo con surufatinib; 4.Hipertensión incontrolable, definida como presión arterial (PA) sistólica ≥140 mmHg y/o PA diastólica ≥90mmHg; 5. Enfermedad o afección gastrointestinal que puede afectar a la absorción del fármaco, como úlceras gástricas y duodenales activas, colitis ulcerosa y otras enfermedades digestivas, tumor gastrointestinal con hemorragia activa u otras
    condiciones que puedan causar hemorragia o perforación a criterio del investigador; 6.Antecedentes o presencia de una hemorragia grave (>30 mL en un plazo de 3 meses), hemoptisis (>5 mL de sangre en un plazo de 4 semanas), o evento tromboembólico potencialmente mortal en un plazo de 6 meses;7. Enfermedad cardiovascular clínicamente significativa como infarto agudo de miocardio en los 6 meses anteriores a la inscripción, angina de pecho grave/inestable o injerto de derivación arterial coronaria, insuficiencia cardíaca congestiva según la clasificación de la New York Heart Association ≥2, arritmias ventriculares que necesiten tratamiento farmacológico, o fracción de eyección del ventrículo izquierdo (FEVI) <50%.;8. Intervalo QT corregido por el método de Fredericia (QTcF) ≥480 milisegundos; 9. Otros tumores malignos en los 5 años anteriores al cribado (excepto carcinoma basocelular curado o carcinoma escamoso en la piel y carcinoma cervical in situ); 10. Terapia antitumoral recibida en un plazo de 2 semanas o 5 vidas medias, lo que sea más corto, antes del inicio del tratamiento en investigación como quimioterapia, radioterapia radical, terapia dirigida, inmunoterapia, embolización hepática, crioablación y ablación por radiofrecuencia; 11. Radioterapia paliativa para una lesión de metástasis ósea en las 2 semanas anteriores al inicio del tratamiento del estudio; 12. Inductores o inhibidores potentes del citocromo P450, familia 3, subfamilia A (CYP3A) tomados en las dos semanas anteriores al primer tratamiento del estudio; 13. Cualquier infección activa clínicamente significativa, incluida, entre otras, la infección conocida por el virus de la inmunodeficiencia humana (VIH); 14. Antecedentes conocidos de hepatitis viral activa. En el caso de los pacientes con evidencia de infección crónica por el virus de la hepatitis B (VHB), la carga viral del VHB debe ser indetectable con la terapia supresora, si está indicada. Pacientes con infección por hepatitis c (VHC) actualmente en tratamiento son elegibles si tienen una carga viral del VHC indetectable. Pacientes con antecedentes desconocidos de hepatitis vírica deben someterse a pruebas de detección del VHB con antígeno HBs; anticuerpos HBc y HBS; y ADN-VHB, si está indicado, y del VHC con anticuerpos VHC. a. Pacientes con HBsAg detectable o ADN del VHB detectable deben ser tratados según las pautas de tratamiento. Pacientes que reciban antivirales en el momento de la selección deberán haber sido tratados durante más de 2 semanas antes de la primera dosis del tratamiento del estudio. b. Pacientes con prueba de anticuerpos del VHC negativa en la selección o prueba de anticuerpos del VHC positiva seguida de prueba de ARN del VHC negativa son elegibles. La prueba de ARN del VHC se realizará únicamente a pacientes que den positivo en la prueba de anticuerpos del VHC; 15. Metástasis cerebrales y/o enfermedad leptomeníngea y/o compresión de la médula espinal no tratadas con cirugía y/o radioterapia y sin evidencia clínica por imagen de enfermedad estable (SD) durante 14 días o más. Se excluirán los pacientes que requieran esteroides en las 4 semanas anteriores al inicio del tratamiento del estudio; 16. Haber utilizado corticosteroides (prednisona u otros esteroides de eficacia equivalente a una dosis de >10 mg/día) u otros inmunosupresores para el tratamiento sistémico en las 2 semanas anteriores a la primera administración del fármaco. Se permite el uso de aerosoles nasales, inhalados u otros esteroides tópicos (es decir, ≤10 mg/día de prednisona u otros glucocorticoides a una dosis equivalente); 17. Pacientes con NETs: administración de SSAs en ausencia de síntomas secretores se suspende al menos 4 semanas antes de la primera dosis del tratamiento del estudio; Enfermedades autoinmunes activas o antecedentes de enfermedades autoinmunes que puedan recaer; Cualquier vacuna viva o viva atenuada dentro de las 4 semanas anteriores a la primera dosis o prevista para la duración del studio; Cirugías mayores dentro de 60 días anteriores a la primera dosis. Consulte el protocolo para ver la lista completa de criterios de exclusión.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    Safety including dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events (AEs) leading to discontinuation, ECGs, clinical laboratory abnormalities, and vital signs

    Part 2
    Objective Response Rate (ORR) at 12 weeks
    Parte 1
    Seguridad, incluyendo toxicidad limitante de la dosis (TLD), acontecimientos adversos surgidos durante el tratamiento (AAST), acontecimientos adversos graves (AAG), acontecimientos adversos (AA) causantes de la interrupción, electrocardiogramas (ECG), anomalías analíticas clínicas y constantes vitals

    Parte2
    TRO a las 12 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1: as stated in endpoint and for part 2: ORR at 12 weeks
    Parte 1: tal y como se indica en el criterio de valoración y para la parte 2: TRO a las 12 semanas
    E.5.2Secondary end point(s)
    Part 1
    ORR, progression-free survival (PFS), disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), time to response (TTR)
    • Concentrations of surufatinib in plasma and tislelizumab in serum
    • Incidence of antidrug antibodies (ADA) to tislelizumab

    Part 2
    PFS, DCR, CBR, DoR, TTR
    Safety including TEAEs, SAEs, AEs leading to discontinuation, electrocardiograms (ECGs), clinical laboratory abnormalities, and study drug discontinuation due to AEs
    • Concentrations of surufatinib in plasma and tislelizumab in serum
    • Incidence of ADA to tislelizumab
    Parte 1
    - TRO, supervivencia sin progresión (SSP), tasa de control de la enfermedad (TCE), tasa de beneficio clínico (TBC), duración de la respuesta (DR), tiempo hasta la respuesta (TR)
    - Concentraciones de surufatinib en plasma y tislelizumab en suero
    - Incidencia de anticuerpos antifármaco (AAF) contra el tislelizumab

    Parte 2
    - SSP, TCE, TBC, DR, TR
    - Seguridad, incluyendo AAST, AAG, AA causantes de la interrupción, electrocardiogramas (ECG), anomalías analíticas clínicas e interrupción del fármaco del estudio debido a AA
    - Concentraciones de surufatinib en plasma y tislelizumab en suero
    - Incidencia de AAF contra el tislelizumab
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the study assessments in the protocol
    Por favor consultar las evaluciones del estudio en el protocol.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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, biomarkers assessments
    Tolerabilidad, evalución de biomarcadores
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    1b
    1b
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Italy
    Spain
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the last visit of the last patient in the study.
    El fin del estudio se define como la última visita del último paciente del estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 43
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 107
    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)
    If a patient discontinues for any reason other than PD, they will continue to be followed for efficacy until disease progression, withdrawal of consent, new anticancer therapy, lost to follow up, or death.
    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 Decision2021-11-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-26
    P. End of Trial
    P.End of Trial StatusOngoing
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