E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic Disease in Solid Tumors |
Tumores sólidos con enfermedad localmente avanzada o metastásica |
|
E.1.1.1 | Medical condition in easily understood language |
Locally Advanced or Metastatic Disease in Solid Tumors |
Tumores sólidos con enfermedad localmente avanzada o metastásica |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066490 |
E.1.2 | Term | Progression of non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033599 |
E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033600 |
E.1.2 | Term | Pancreatic adenocarcinoma non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051971 |
E.1.2 | Term | Pancreatic adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059326 |
E.1.2 | Term | Pancreatic carcinoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033610 |
E.1.2 | Term | Pancreatic carcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033609 |
E.1.2 | Term | Pancreatic carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059333 |
E.1.2 | Term | Pancreatic carcinoma stage IVA |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059335 |
E.1.2 | Term | Pancreatic carcinoma stage IVB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033604 |
E.1.2 | Term | Pancreatic cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033605 |
E.1.2 | Term | Pancreatic cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033606 |
E.1.2 | Term | Pancreatic cancer non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061902 |
E.1.2 | Term | Pancreatic neoplasm |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071536 |
E.1.2 | Term | Head and neck cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071537 |
E.1.2 | Term | Head and neck cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071540 |
E.1.2 | Term | Head and neck cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010035 |
E.1.2 | Term | Colorectal cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10010023 |
E.1.2 | Term | Colorectal neoplasms malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052360 |
E.1.2 | Term | Colorectal adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
According to protocol. |
De acuerdo con el protocolo. |
|
E.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |