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    Summary
    EudraCT Number:2017-005076-26
    Sponsor's Protocol Code Number:SGNTV-001
    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:2018-11-23
    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 number2017-005076-26
    A.3Full title of the trial
    Open Label Phase 2 Study of Tisotumab Vedotin for Locally Advanced or Metastatic Disease in Solid Tumors
    Estudio de fase 2, abierto, de tisotumab vedotina en tumores sólidos con enfermedad localmente avanzada o metastásica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open Label Phase 2 Study of Tisotumab Vedotin for Locally Advanced or Metastatic Disease in Solid Tumors
    Estudio de fase 2, abierto, de tisotumab vedotina en tumores sólidos con enfermedad localmente avanzada o metastásica
    A.4.1Sponsor's protocol code numberSGNTV-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03485209
    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 SponsorSeattle Genetics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSeattle Genetics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSeattle Genetics Trial Information Support
    B.5.2Functional name of contact pointSeattle Genetics Trial Information
    B.5.3 Address:
    B.5.3.1Street Address21823 30th Drive SE
    B.5.3.2Town/ cityBothell
    B.5.3.3Post codeWA 98021
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1866 333 7436
    B.5.6E-mailclinicaltrials@seagen.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 nameTisotumab vedotin
    D.3.2Product code HuMax-TF-ADC
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTISOTUMAB VEDOTIN
    D.3.9.2Current sponsor codeHuMax-TF-ADC
    D.3.9.4EV Substance CodeSUB192227
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    Locally Advanced or Metastatic Disease in Solid Tumors
    Tumores sólidos con enfermedad localmente avanzada o metastásica
    E.1.1.1Medical condition in easily understood language
    Locally Advanced or Metastatic Disease in Solid Tumors
    Tumores sólidos con enfermedad localmente avanzada o metastásica
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    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 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10059515
    E.1.2Term Non-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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066490
    E.1.2Term Progression of non-small cell lung 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 LLT
    E.1.2Classification code 10033599
    E.1.2Term Pancreatic adenocarcinoma 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10033600
    E.1.2Term Pancreatic adenocarcinoma non-resectable
    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 LLT
    E.1.2Classification code 10051971
    E.1.2Term Pancreatic adenocarcinoma
    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 10059326
    E.1.2Term Pancreatic carcinoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10033610
    E.1.2Term Pancreatic carcinoma 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10033609
    E.1.2Term Pancreatic carcinoma
    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 LLT
    E.1.2Classification code 10059333
    E.1.2Term Pancreatic carcinoma stage IVA
    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 LLT
    E.1.2Classification code 10059335
    E.1.2Term Pancreatic carcinoma stage IVB
    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 LLT
    E.1.2Classification code 10033604
    E.1.2Term Pancreatic 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 LLT
    E.1.2Classification code 10033605
    E.1.2Term Pancreatic 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10033606
    E.1.2Term Pancreatic cancer non-resectable
    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 10061902
    E.1.2Term Pancreatic neoplasm
    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 10071536
    E.1.2Term Head and neck cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10071537
    E.1.2Term Head and neck cancer stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10071540
    E.1.2Term Head and neck 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10010035
    E.1.2Term Colorectal cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic 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 20.0
    E.1.2Level HLT
    E.1.2Classification code 10010023
    E.1.2Term Colorectal neoplasms malignant
    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 10052360
    E.1.2Term Colorectal adenocarcinoma
    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 10061873
    E.1.2Term Non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    This study will evaluate the antitumor activity, safety, and pharmacokinetics (PK) of tisotumab vedotin in patients with locally advanced or metastatic tumors.
    Este estudio va a evaluar la actividad antitumoral, la seguridad y la farmacocinética de tisotumab vedotina en pacientes con tumores localmente avanzados o metastásicos.
    E.2.2Secondary objectives of the trial
    - Evaluate the safety and tolerability of tisotumab vedotin
    - Evaluate preliminary antitumor activity of tisotumab vedotin
    - Evaluate stability and control of disease
    - Evaluate durability of response in patients who respond to tisotumab vedotin
    - Evaluate the timing of responses
    - Evaluate progression-free survival (PFS) of patients treated with tisotumab vedotin
    - Evaluate survival of patients treated with tisotumab vedotin
    - Assess pharmacokinetics of tisotumab vedotin
    - Assess immunogenicity of tisotumab vedotin
    - Evaluar la seguridad y la tolerabilidad de tisotumab vedotina
    - Efectuar una evaluación preliminar de la actividad antitumoral de tisotumab vedotina
    - Evaluar la estabilidad y el control de la enfermedad
    - Evaluar la persistencia de la respuesta en los pacientes que respondan a tisotumab vedotina
    - Evaluar el momento de presentación de las respuestas
    - Evaluar la supervivencia sin progresión de los pacientes tratados con tisotumab vedotina
    - Evaluar la supervivencia de los pacientes tratados con tisotumab vedotina
    - Evaluar la farmacocinética de tisotumab vedotina
    - Evaluar la inmunogenia de tisotumab vedotina
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Relapsed, locally-advanced or metastatic colorectal or pancreatic cancer, squamous NSCLC, or SCCHN that has failed prior lines of systemic treatment as specified and which are not candidates for standard therapy.
    ● Colorectal Cancer: Patients with colorectal cancer must have experienced disease progression on or after their most recent systemic therapy for non-operable metastatic disease. Isolated increase in carcinoembryonic antigen (CEA) will not qualify for study entry. Patients must have received prior therapy with each of the following agents, if eligible: a fluoropyrimidine, oxaliplatin, irinotecan, and/or bevacizumab. Patients with known/previously-tested RAS wild-type tumors and/or known/previously-tested MSI-H tumors could have received cetuximab or panitumumab and CPI, if eligible. Patients should have received no more than 3 systemic regimens in the metastatic setting.
    ● NSCLC: Patients with NSCLC must have histologically or cytologically-documented squamous cell NSCLC and must have experienced disease progression on or after their most recent systemic therapy for locally advanced or metastatic disease. Patients must have received prior therapy with a platinum-based regimen, a tyrosine kinase inhibitor (TKI;
    ALK, ROS-1 gene rearrangement or EGFR mutation), and a CPI if eligible for such therapy. Patients should have received no more than 2 systemic regimens in the locally advanced or metastatic setting.
    ● Exocrine pancreatic adenocarcinoma: Patients with exocrine pancreatic adenocarcinoma must have biopsy proven, histologically confirmed diagnosis of exocrine pancreatic adenocarcinoma and must have experienced disease progression on or after their most recent systemic therapy for locally advanced or metastatic disease. Isolated increase in CA 19-9 or CEA will not qualify for study entry. Patients must have received prior therapy with a gemcitabine-based or 5FU-based regimen if eligible for such therapy. Patients should have received no more than 1 systemic regimen in the unresectable or metastatic setting.
    ● SCCHN: Patients with SCCHN must have experienced disease progression on or after their most recent systemic therapy for recurrent or metastatic disease. Patients must not have tumors involving or adjacent to major blood vessels or a history of radiation involving major blood vessels in the radiation field. Patients must have received prior therapy with a platinum-based regimen and/or a CPI if eligible for such therapy. Patients eligible to receive anti-EGFR therapy must have received anti-EGFR therapy prior to study entry. Patients should have received no more than 2 systemic regimens in the recurrent/metastatic setting.
    2. Measureable disease according to RECIST v1.1 as assessed by the investigator.
    ● A minimum of one non-nodal lesion ≥10 mm in the longest diameter from a non-irradiated area. If target lesion(s) are located within previously irradiated area only, the patient can be enrolled only if there has been demonstrated progression in the “in field” lesion and upon approval of the sponsor’s medical monitor.
    ● Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area.
    3. Age 18 years or older.
    4. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
    5. The following baseline laboratory data:
    ● absolute neutrophil count (ANC) ≥1500/μL assessed at least 2 weeks after growth factor support, if applicable.
    ● platelet count ≥100 x 109/L assessed at least 2 weeks after transfusion with blood products.
    ● hemoglobin ≥5.6 mmol/L (9.0 g/dL) assessed at least 2 weeks after transfusion with blood products and/or growth factor support.
    ● serum bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤2 x ULN in patients diagnosed with Gilbert’s syndrome.
    ● estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable.
    ● alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN. (If liver tumor/metastases are present, then <5 x ULN is allowed).
    6. Acceptable coagulation status.
    7. Life expectancy of at least 3 months.

    Other inclusion Criteria can be found in the Protocol.
    1. Cáncer colorrectal o de páncreas, cáncer de pulmón no microcítico epidermoide o carcinoma epidermoide de cabeza y cuello, localmente avanzado o metastásico, en recidiva, tras fracaso de líneas previas de tratamiento sistémico según se señala y sin indicación del tratamiento estándar.
    ● Cáncer colorrectal: Los pacientes deben haber presentado progresión de la enfermedad durante o después de su tratamiento sistémico más reciente por enfermedad metastásica inoperable. La elevación aislada del antígeno carcinoembrionario no justifica la entrada en el estudio. Los pacientes deben haber recibido tratamiento previo con cada uno de los siguientes agentes, si estuviera indicado: una fluoropirimidina, oxaliplatino, irinotecán y/o bevacizumab. Los pacientes con tumores portadores de RAS de tipo natural conocido/analizado previamente y/o con tumores portadores de MSI-H conocido/analizado previamente podrán haber recibido cetuximab o panitumumab y un inhibidor de los puntos de control inmunitario, si estuviera indicado. Los pacientes no deberán recibido más de 3 regímenes sistémicos por enfermedad metastásica.
    ● Cáncer de pulmón no microcítico: Los pacientes deben disponer de confirmación histológica o citológica del carcinoma de pulmón no microcítico epidermoide y haber presentado progresión de la enfermedad durante o después de su tratamiento sistémico más reciente por enfermedad localmente avanzada o metastásica. Los pacientes deben haber recibido tratamiento previo con un régimen que incluyera un derivado del platino, un inhibidor de tirosina quinasa (TKI; reordenamiento del gen ROS-1, ALK o mutación EGFR),y un inhibidor de los puntos de control inmunitario, si estuviera indicado. Los pacientes no deberán recibido más de 2 regímenes sistémicos por enfermedad localmente avanzada o metastásica.
    ● Adenocarcinoma de páncreas exocrino: Los pacientes deben presentar diagnóstico histológico de adenocarcinoma de páncreas exocrino confirmado por biopsia y haber presentado progresión de la enfermedad durante o después de su tratamiento sistémico más reciente por enfermedad localmente avanzada o metastásica. La elevación aislada de CA 19-9 o CEA no justifica la entrada en el estudio. Los pacientes deben haber recibido tratamiento previo con un régimen a base de gemcitabina o 5FU, si estuviera indicado. Los pacientes no deberán recibido más de un régimen sistémico por enfermedad no resecable o metastásica.
    ● Carcinoma epidermoide de cabeza y cuello: Los pacientes deben haber presentado progresión de la enfermedad durante o después de su tratamiento sistémico más reciente por recidiva o enfermedad metastásica. Los pacientes no deben presentar tumores que afecten o rodeen vasos sanguíneos importantes ni antecedentes de radioterapia que incluya vasos importantes en el campo de irradiación. Los pacientes deben haber recibido tratamiento previo con un régimen que incluyera un derivado del platino y/o un inhibidor de los puntos de control inmunitario, si estuviera indicado. Los pacientes en los que esté indicado un tratamiento anti-EGFR deberán haber recibido dicho tratamiento antes de la entrada en el estudio. Los pacientes no deberán recibido más de 2 regímenes sistémicos por recidiva o enfermedad metastásica.
    2. Enfermedad medible según los RECIST v1.1, en su evaluación por el investigador.
    ● Como mínimo una lesión no ganglionar ≥10 mm en su diámetro mayor en una zona no irradiada. Si la lesión o lesiones diana se encuentran únicamente en una zona irradiada con anterioridad, solo se podrá incluir al paciente en el estudio si se ha demostrado progresión en la lesión situada en el campo de irradiación y con la aprobación previa del monitor médico del promotor.
    ● Lesión ganglionar ≥15 mm en su diámetro menor en una zona no irradiada.
    3. Edad igual o superior a 18 años.
    4. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
    5. Los siguientes valores de laboratorio en el momento basal:
    ● cifra absoluta de neutrófilos ≥1500/μl, determinada como mínimo 2 semanas después de la administración de factores de crecimiento, si procede.
    ● cifra de plaquetas ≥100 x 109/l, determinada como mínimo 2 semanas después de la transfusión de hemoderivados.
    ● hemoglobina ≥5,6 mmol/l (9,0 g/dl), determinada como mínimo 2 semanas después de la transfusión de hemoderivados y/o de la administración de factores de crecimiento.
    ● bilirrubina sérica ≤1,5 x límite superior de la normalidad o bilirrubina directa ≤2 x límite superior de la normalidad en los pacientes diagnosticados de síndrome de Gilbert.
    ● tasa de filtración glomerular estimada ≥60 ml/min/1,73 m2 mediante la ecuación del estudio MDRD (Modification of Diet in Renal Disease), según proceda.
    ● alanina-aminotransferasa (ALT) y aspartato-aminotransferasa (AST) ≤2,5 x límite superior de la normalidad (En caso de tumor/metástasis en hígado, se permite <5 x límite superior de la normalidad).
    Véanse en el protocolo los demás criterios de inclusión.
    E.4Principal exclusion criteria
    1. Patients with primary neuroendocrine or sarcomatoid histologies.
    2. Hematological: Known past or current coagulation defects leading to an increased risk of bleeding; diffuse alveolar hemorrhage from vasculitis; known bleeding diathesis; ongoing major bleeding; trauma with increased risk of life-threatening bleeding or history of severe head trauma or intracranial surgery within 8 weeks of trial entry.
    3. Cardiovascular: Clinically significant cardiac disease including unstable angina, acute myocardial infarction 6 months prior to screening; any medical history of congestive heart failure (Grade III or IV as classified by the New York Heart Association, see Appendix G), any medical history of decreased cardiac ejection fraction of <45%.
    4. Ophthalmological: Active ocular surface disease at baseline. An ocular evaluation is to be confirmed by an ophthalmologist at screening. Patients with any prior episode of cicatricial conjunctivitis or Steven Johnson syndrome (as evaluated by the investigator) are ineligible.
    5. History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
    6. Lesions adjacent to or involving critical anatomical sites, including major blood vessels, mediastinum, and leptomeningeal disease.
    7. Inflammatory bowel disease including Crohn’s disease and colitis ulcerosa.
    8. Ongoing, acute or chronic inflammatory skin disease.
    9. Uncontrolled tumor-related pain
    10. Inflammatory lung disease, including moderate and severe asthma and chronic obstructive pulmonary disease, requiring chronic medical therapy
    11. Medications or treatment regimens:
    ● For patients with SCCHN or NSCLC, therapeutic anti-coagulation is not permitted. For patients with colorectal or pancreatic cancers, therapeutic anti-coagulation therapy is permitted IF the patient is no longer being actively titrated for anti-coagulation. For oral anticoagulation therapy, colorectal and pancreatic patients must be on steady doses for at least 4 weeks prior to the first dose of study drug.
    ● Chronic prophylactic treatment with ASA (e.g., aspirin) in combination with other anti-coagulation therapy is prohibited.
    ● Cumulative dose of corticosteroid ≥150 mg (prednisone or equivalent doses of corticosteroids) within 2 weeks of the first tisotumab vedotin administration is prohibited.
    12. Surgery/procedures: Major surgical procedure (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 4 weeks or excisional biopsy within 7 days prior to the first study drug administration. Patients who have planned major surgery during the treatment period must be excluded from the trial.
    13. Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
    14. Peripheral neuropathy Grade ≥2.
    15. Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parental hydration and/or nutrition.
    16. Prior therapy:
    ● Any prior treatment with MMAE-derived drugs.
    ● Radiotherapy within 21 days prior to the first administration of study drug. Patients must have recovered from all radiation-related toxicities. At least 42 days must have elapsed from the last administration of chemo-radiotherapy.
    ● Small molecules, chemotherapy, immunotherapy, biologics, experimental agents, or any other antitumor therapy within 21 days prior to the first administration of study drug. If underlying disease is progressing on treatment, patients may enroll within 21 days upon approval of the sponsor’s medical monitor. Patients must have recovered from all related toxicities.
    17. Any uncontrolled Grade 3 or higher (per the NCI CTCAE v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of tisotumab vedotin. Routine antimicrobial prophylaxis is permitted.
    18. Known seropositivity of human immunodeficiency virus; known medical history of hepatitis B or C infection.
    ● Note: No testing for human immunodeficiency virus, Hepatitis B, or Hepatitis C is required unless mandated by local health authorities.

    Other exclusion Criteria can be found in the Protocol.
    1. Pacientes con histología principal de tipo neuroendocrino o sarcomatoide.
    2. Trastornos hematológicos: Antecedentes o diagnostico actual de coagulopatía que aumente el riesgo de hemorragia; hemorragia alveolar difusa por vasculitis; diátesis hemorrágica conocida; hemorragia activa importante; traumatismo con aumento del riesgo de hemorragia potencialmente mortal o antecedentes de traumatismo craneoencefálico severo o de cirugía intracraneal en el plazo de las 8 semanas previas a la entrada en el ensayo.
    3. Trastornos cardiovasculares: Cardiopatía de importancia clínica, como angina inestable, infarto agudo de miocardio 6 meses antes de la selección; antecedentes de insuficiencia cardiaca congestiva (de grado III o IV de la clasificación de la New York Heart Association; véase el Apéndice G), antecedentes de fracción de eyección cardiaca <45%.
    4. Trastornos oftalmológicos: Enfermedades de la superficie ocular en el momento basal. El oftalmólogo deberá confirmar dicha evaluación ocular en la selección. No podrán participar en el estudio los pacientes con antecedentes de conjuntivitis cicatricial o de síndrome de Stevens-Johnson (según la evaluación del investigador).
    5. Antecedentes de otra neoplasia maligna en los 3 años anteriores a la primera dosis del fármaco del estudio, o signos de enfermedad residual de una neoplasia maligna diagnosticada previamente. Se exceptúan las neoplasias malignas con mínimo riesgo de metástasis o de muerte (esto es, supervivencia global a los 5 años ≥90%), como el carcinoma in situ del cuello uterino, el carcinoma cutáneo no melanómico, el cáncer de próstata localizado, el carcinoma ductal in situ o el cáncer uterino en estadio I, adecuadamente tratados.
    6. Lesiones adyacentes o que afecten a estructuras anatómicas fundamentales, por ejemplo, vasos sanguíneos importantes, mediastino o leptomeninges.
    7. Enfermedad inflamatoria intestinal, como enfermedad de Crohn y colitis ulcerosa.
    8. Enfermedad inflamatoria de la piel, aguda o crónica, en curso.
    9. Dolor oncológico no controlado.
    10. Neumopatía inflamatoria, como asma moderada o severa y enfermedad pulmonar obstructiva crónica, que precise tratamiento médico prolongado.
    11. Medicamentos o pautas de tratamiento:
    ● En los pacientes con carcinoma epidermoide de cabeza y cuello o con cáncer de pulmón no microcítico, no se permite la anticoagulación terapéutica. En los pacientes con cáncer colorrectal o de páncreas, se permite la anticoagulación terapéutica SI el paciente ya no se encuentra en proceso de ajuste de la dosis del anticoagulante. En caso de tratamiento con anticoagulantes orales, los pacientes con cáncer colorrectal o de páncreas deberán hallarse con dosis estables desde por lo menos 4 semanas antes de la primera dosis del fármaco del estudio.
    ● Se prohíbe el tratamiento profiláctico de larga duración con ácido acetilsalicílico en combinación con otro anticoagulante.
    ● Se prohíbe el tratamiento corticosteroideo con una dosis acumulada ≥150 mg (de prednisona o dosis equivalente de corticosteroides) en el plazo de las 2 semanas anteriores a la primera administración de tisotumab vedotina.
    12. Intervenciones quirúrgicas: Intervención quirúrgica mayor (definida como la que precisa que el paciente permanezca hospitalizado durante un mínimo de 48 horas) en el plazo de las 4 semanas anteriores a la primera administración del fármaco del estudio o biopsia por escisión en el plazo de los 7 días previos a dicha administración. Se excluirá del ensayo a los pacientes con intervenciones quirúrgicas mayores programadas durante el periodo de tratamiento.
    13. Recepción de una vacuna de gérmenes vivos en el plazo de los 30 días anteriores a la primera administración del tratamiento del ensayo. Como ejemplos de vacunas de gérmenes vivos pueden citarse las vacunas contra el sarampión, parotiditis, rubéola, varicela-zóster, fiebre amarilla, rabia, tuberculosis (BCG) y fiebre tifoidea. Las vacunas antigripales estacionales inyectables suelen ser vacunas inactivadas, que sí se permiten; en cambio, las vacunas antigripales intranasales (por ejemplo, FluMist®) se elaboran con virus vivos atenuados, por lo que no se permiten.
    14. Neuropatía periférica de grado ≥2.
    15. Pacientes con manifestaciones clínicas de obstrucción gastrointestinal y que requieran hidratación y/o nutrición parenteral.
    16. Tratamiento previo:
    ● Cualquier tratamiento previo con fármacos derivados de la monometilauristatina E (MMAE).
    ● Radioterapia en el plazo de los 21 días anteriores a la primera administración del fármaco del estudio. Los pacientes deberán haberse recuperado de todos los efectos secundarios de la radioterapia.
    Tendrá que haber transcurrido un mínimo de 42 días desde la última administración de quimiorradioterapia.
    Véanse en el protocolo los demás criterios de exclusión.
    E.5 End points
    E.5.1Primary end point(s)
    Investigator-determined confirmed ORR as measured by RECIST v1.1
    Tasa de respuesta objetiva confirmada según los RECIST v1.1, a juicio del investigador
    E.5.1.1Timepoint(s) of evaluation of this end point
    According to protocol.
    De acuerdo con el protocolo.
    E.5.2Secondary end point(s)
    - Safety and tolerability of tisotumab vedotin, as measured by type, incidence, severity, seriousness, and relatedness of AEs
    - Investigator-determined confirmed and unconfirmed ORR as measured by RECIST v 1.1
    - Investigator-determined disease control rate (DCR) as measured by RECIST v1.1
    - Investigator- determined duration of response (DOR) as measured by RECIST v1.1
    - Investigator- determined time to response (TTR) as measured by RECIST v1.1
    - Investigator- determined PFS as measured by RECIST v1.1
    - Overall survival (OS)
    - Selected PK parameters for tisotumab vedotin and MMAE
    - Incidence of anti-therapeutic antibodies (ATAs) to tisotumab vedotin
    - Seguridad y tolerabilidad de tisotumab vedotina, en su determinación por el tipo, la incidencia, la severidad, la gravedad y la relación con el tratamiento de los acontecimientos adversos
    - Tasa de respuesta objetiva confirmada y no confirmada según los RECIST v1.1, a juicio del investigador
    - Tasa de control de la enfermedad según los RECIST v1.1, a juicio del investigador
    - Duración de la respuesta según los RECIST v1.1, a juicio del investigador
    - Tiempo hasta la respuesta según los RECIST v1.1, a juicio del investigador
    - Supervivencia sin progresión según los RECIST v1.1, a juicio del investigador
    - Supervivencia global
    - Parámetros farmacocinéticos seleccionados de tisotumab vedotina y MMAE
    - Incidencia de anticuerpos antifármaco contra tisotumab vedotina
    E.5.2.1Timepoint(s) of evaluation of this end point
    According to protocol.
    De acuerdo con el protocolo.
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Canada
    France
    Germany
    Italy
    Spain
    United Kingdom
    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
    LVLS
    última visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    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: 133
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 67
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The patient or the patient’s legally authorized representative must provide written informed consent.
    El paciente o su representante legal deberán otorgar su consentimiento informado por escrito.
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 93
    F.4.2.2In the whole clinical trial 200
    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
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-14
    P. End of Trial
    P.End of Trial StatusOngoing
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