| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (hereafter collectively referred to as platinum-resistant ovarian cancer and abbreviated as PROC) |
| Pacientes con cáncer ovárico epitelial, cáncer peritoneal primario o cáncer de trompas de Falopio (en adelante denominados en conjunto como cáncer ovárico resistente al platino y abreviado como CORP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the ovary |
| Cáncer de Ovario |
|
| 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 | 10033128 |
| E.1.2 | Term | Ovarian 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 | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080244 |
| E.1.2 | Term | Peritoneal cancer index |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| 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 |
(Safety run-in) Evaluate safety and tolerability of a dose-dense regimen of tisotumab vedotin
(Phase 2) Evaluate antitumor activity of tisotumab vedotin |
(Periodo de preinclusión de seguridad) Evaluar la seguridad y la tolerabilidad de una pauta de dosis densas de tisotumab vedotina
(Fase 2) Evaluar la actividad antitumoral de tisotumab vedotina |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the safety and tolerability of tisotumab vedotin
Evaluate preliminary antitumor activity of tisotumab vedotin
Evaluate antitumor activity of tisotumab vedotin
Evaluate durability of response in patients who respond to tisotumab vedotin
Evaluate stability and control of disease
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
Evaluar la actividad antitumoral preliminar de tisotumab vedotina
Evaluar la actividad antitumoral de tisotumab vedotina
Evaluar la durabilidad de la respuesta en pacientes que responden a tisotumab vedotina
Evaluar la estabilidad y el control de la enfermedad
Evaluar el momento de presentación de las respuestas
Evaluar la supervivencia sin progresión (SSP) en pacientes tratadas con tisotumab vedotina
Evaluar la supervivencia en pacientes tratadas con tisotumab vedotina
Evaluar la farmacocinética de tisotumab vedotina
Evaluar la inmunogenicidad de tisotumab vedotina |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologic documentation of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (excluding carcinosarcoma, mucinous, and low grade serous histologies), hereafter referred to as “ovarian cancer”.
2. Safety run-in patients only: Platinum-resistant ovarian cancer (PROC), which is defined as having progressed or relapsed within 6 months after previous platinum-containing chemotherapy and for which single agent chemotherapy is appropriate. Progression or relapse must be documented radiographically using RECIST v1.1 criteria. The patient may have received up to 5 prior systemic treatment regimens for ovarian cancer.
a. Subjects may or may not have received bevacizumab for treatment of ovarian cancer.
3. Phase 2 patients only: PROC. The patient must have received at most 1 prior cytotoxic chemotherapy regimen in the PROC setting. Patients eligible to receive a PARP inhibitor may have received such therapy; PARP inhibitors are not considered cytotoxic chemotherapy regimens for the purposes of this study.
a. If eligible, patients must have received previous treatment with a bevacizumab-containing regimen for ovarian cancer. Prior bevacizumab may have been given at any line of treatment.
4. Measurable disease according to RECIST v1.1 as assessed by the investigator, defined as:
a. 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.
OR
b. Lymph node lesion ≥15 mm in the shortest diameter from a non-irradiated area.
5. Age 18 years or older.
6. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (see Appendix E for conversion of performance status using Karnofsky and Lansky scales, if applicable).
7. 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.
● 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) ≥50 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).
8. Acceptable coagulation status:
● INR ≤1.2 without anticoagulation therapy.
● aPTT ≤1.25 ULN.
9. Life expectancy of at least 3 months. |
1.Documentación histológica de cáncer de ovario epitelial, cáncer peritoneal primario o cáncer de las trompas de Falopio (excepto histologías mucinosas y serosas de bajo grado y carcinosarcoma), en lo sucesivo denominado "cáncer de ovario".
2.Solo para pacientes de preinclusión de seguridad: cáncer de ovario resistente al platino (CORP), que se define como cáncer que ha progresado o presentado una recaída en los 6 meses posteriores a la quimioterapia con platino y para el que es adecuada la quimioterapia con un solo agente. La progresión o recaída debe documentarse radiológicamente según los criterios de RECIST v1.1. La paciente puede haber recibido hasta 5 pautas de tratamiento sistémico previas para el cáncer de ovario.
a.Las pacientes pueden o no haber recibido bevacizumab para el tratamiento del cáncer de ovario
3.Solo pacientes de la Fase 2: CORP. La paciente debe haber recibido como mucho 1 pauta de quimioterapia citotóxica anterior para el CORP. Las pacientes aptos para recibir un inhibidor de la PARP pueden haber recibido dicha terapia; los inhibidores de la PARP no se consideran pautas de quimioterapia citotóxica a efectos de este estudio.
a.Si son elegibles, las pacientes deben haber recibido un tratamiento previo con una pauta que contuviera bevacizumab para el cáncer de ovario. El bevacizumab anterior se puede haber administrado en cualquier línea de tratamiento
4.Enfermedad medible conforme a RECIST v1.1 según el criterio del investigador, definida como:
a.Mínimo de una lesión no ganglionar ≥10 mm en el diámetro más largo en un área no irradiada. Si las lesiones diana se encuentran solo en un área irradiada con anterioridad, la paciente únicamente puede inscribirse si se ha demostrado una progresión en la lesión situada en el campo de irradiación y con la aprobación del monitor médico del promotor, o
b.Lesión del ganglio linfático ≥15 mm en el diámetro más corto en un área no irradiada
5.Tener 18 años o más
6.Puntuación de 0 o 1 del estado funcional según el Eastern Cooperative Oncology Group (ECOG) (véase el Apéndice E para la conversión del estado funcional utilizando las escalas de Karnofsky y Lansky, si corresponde)
7.Los siguientes datos analíticos basales:
●Recuento absoluto de neutrófilos (RAN) ≥1500/μL determinado como mínimo 2 semanas después de la administración de factores de crecimiento, si procede
●Recuento de plaquetas ≥100 x 109/L determinado 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
●Bilirrubina sérica ≤1.5 x límite superior de la normalidad (LSN) o bilirrubina directa ≤2 x LSN en pacientes diagnosticadas con síndrome de Gilbert
●Tasa de filtración glomerular estimada (TFGe) ≥50 mL/min/1.73 m2 mediante la ecuación del estudio de Modificación de la dieta en la enfermedad renal (MDRD) según corresponda
●Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) ≤2.5 × LSN. (Si hay presencia de tumor/metástasis hepáticas, se permite <5 x LSN)
8.Estado de coagulación aceptable:
●RIN ≤1.2 sin tratamiento anticoagulante.
●TTPa ≤1.25 LSN.
9.Esperanza de vida de al menos 3 meses |
|
| E.4 | Principal exclusion criteria |
1.Primary platinum-refractory disease, defined as disease progression within 2 months of completion of first line platinum-based therapy.
2. Patients with clinical symptoms or signs of gastrointestinal obstruction within the past 6 months or who currently require parenteral nutrition.
3.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.
4. Cardiovascular: Clinically significant cardiac disease including uncontrolled hypertension (systolic BP >150 mmHg or diastolic BP >90 mmHg), unstable angina, acute myocardial infarction within 6 months prior to screening, serious cardiac arrhythmia requiring medication (not including asymptomatic atrial fibrillation with controlled ventricular rate); any medical history of congestive heart failure (Class II or higher as classified by the New York Heart Association, see Appendix H), or any medical history of decreased cardiac ejection fraction of <45%.
5. 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 Stevens Johnson syndrome (as evaluated by the investigator) are ineligible. Cataract is not considered active ocular surface disease for this study.
6.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, ductal carcinoma in situ, or stage I uterine cancer.
7.Inflammatory bowel disease including Crohn’s disease and ulcerative colitis
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.Grade 3 or higher pulmonary disease unrelated to underlying malignancy
12.Patients with significant peripheral vascular disease
13.Uncontrolled pleural or pericardial effusions |
1. Enfermedad primaria refractaria al platino, definida como progresión de la enfermedad en los 2 meses posteriores a la finalización del tratamiento de primera línea basado en platino.
2. Pacientes con signos o síntomas clínicos de obstrucción gastrointestinal en los últimos 6 meses o que actualmente requieren nutrición parenteral.
3. Trastornos hematológicos: antecedentes o diagnostico actual de coagulopatía que aumente el riesgo de hemorragia; hemorragia alveolar difusa por vasculitis; diátesis hemorrágica conocida; sangrado mayor en curso; 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.
4. Trastornos cardiovasculares: cardiopatía de importancia clínica que incluye hipertensión no controlada (TA sistólica >150 mmHg o diastólica >90 mmHg), angina inestable, infarto agudo de miocardio 6 meses antes de la selección, arritmia cardíaca grave que requiere medicación (salvo fibrilación auricular asintomática con respuesta ventricular controlada); antecedentes de insuficiencia cardiaca congestiva (de clase II o superior en la clasificación de New York Heart Association, véase el Apéndice H) o antecedentes de disminución de la fracción de eyección cardíaca <45 %.
5. Trastornos oftalmológicos: enfermedades de la superficie ocular en el período basal. El oftalmólogo deberá confirmar dicha evaluación ocular en la selección. No podrán participar en el estudio pacientes con antecedentes de conjuntivitis cicatricial o de síndrome de Stevens-Johnson (según la evaluación del investigador). En este estudio, las cataratas no se consideran enfermedad activa de la superficie ocular.
6. 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 del útero, el carcinoma cutáneo no melanómico, el carcinoma ductal in situ o el cáncer uterino en estadio I, adecuadamente tratados.
7. Enfermedad intestinal inflamatoria, incluidas la enfermedad de Crohn y la colitis ulcerosa
8. Enfermedad inflamatoria de la piel, aguda o crónica, en curso.
9. Dolor no controlado relacionado con el tumor
10. Neumopatía inflamatoria, como asma moderada o grave y enfermedad pulmonar obstructiva crónica que precise tratamiento médico prolongado
11. Neumopatía de grado 3 o superior no relacionada con la neoplasia maligna subyacente
12. Pacientes con enfermedad vascular periférica significativa.
13. Derrame pleural o pericárdico no controlado. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
(Safety run-in) Evaluate safety and tolerability of a dose-dense regimen of tisotumab vedotin
(Phase 2) Evaluate antitumor activity of tisotumab vedotin |
(Periodo de preinclusión de seguridad) Evaluar la seguridad y la tolerabilidad de una pauta de dosis densas de tisotumab vedotina
(Fase 2) Evaluar la actividad antitumoral de tisotumab vedotina |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and tolerability will be assessed at every visit and via phone calls as needed between visits. |
| La seguridad y la tolerabilidad se evaluarán en cada visita y mediante llamadas telefónicas entre visitas, según sea necesario. |
|
| E.5.2 | Secondary end point(s) |
| The confirmed and unconfirmed ORR according to RECIST v1.1, CA-125 response rate, combined RECIST/CA-125 overall response rate, and the DCR will be estimated and the 95% CIs will be calculated. |
| Se calculará la TRO confirmada y no confirmada según RECIST v1.1, la tasa de respuesta CA-125, la tasa de respuesta general combinada RECIST/CA-125 y la DdR, y se calculará el IC del 95 %. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Radiographic tumor assessments |
| Evaluaciones radiológicas de tumores |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Belgium |
| Denmark |
| Ireland |
| Italy |
| Spain |
| 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
|
| The date the patient met criteria for study discontinuation and the reason for study discontinuation will be recorded. |
| Se recogerá la fecha en la que la paciente cumplió los criterios para la interrupción del estudio y el motivo para la interrupción del mismo |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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