E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic urothelial cancer |
Cáncer urotelial localmente avanzado o metastásico |
|
E.1.1.1 | Medical condition in easily understood language |
Locally Advanced (inoperable) or metastatic urothelial (bladder) cancer |
Cáncer urotelial (vejiga) localmente avanzado (inoperable) o metastásico |
|
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 | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
1. To assess the safety and tolerability of investigational treatments 2. To evaluate objective response rate (ORR) of each investigational treatment arm as assessed by BICR per RECIST 1.1 |
1. Evaluar la seguridad y la tolerabilidad de varios tratamientos en investigación 2. Determinar la tasa de respuestas objetivas (TRO) en cada grupo de tratamiento en investigación, evaluada mediante una RCIE conforme a los criterios RECIST 1.1. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the duration of response (DOR) of each investigational treatment arm as assessed by BICR per RECIST 1.1 |
1. Determinar la duración de la respuesta (DR) en cada grupo de tratamiento en investigación, evaluada mediante una RCIE conforme a los criterios RECIST 1.1. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has a histologically or cytologically confirmed diagnosis of locally advanced/unresectable or mUC of the renal pelvis, ureter (upper urinary tract), bladder, or urethra. Participants with nonurothelial tumors, including pure squamous cell carcinoma, pure adenocarcinoma including urachal adenocarcinomas, neuroendocrine tumors, and mesenchymal tumors, are not eligible. 2. Has measurable disease as assessed by the site and verified by BICR according to RECIST 1.1. 3. Has PD-1/L1 refractory locally advanced or mUC as evidenced by: EITHER disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb for locally advanced/unresectable or mUC administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. In these participants, anti-PD-1/L1 mAb treatment is defined by meeting ALL of the following criteria: a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. b. Has demonstrated radiographic disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb by investigator assessment. c. Disease progression has been documented radiographically by the investigator within 12 weeks from the last dose of anti-PD-1/L1 mAb. OR Has experienced disease recurrence while on treatment or after treatment with an anti-PD-1/L1 mAb for MIUC administered as monotherapy. In these participants, anti-PD-1/L1 mAb treatment is defined by meeting ALL of the following criteria: a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. b. Has demonstrated radiographic disease recurrence while on treatment with an anti-PD-1/L1 mAb or within 6 months from treatment completion by investigator assessment. 4. Participants who received an anti-PD-1/L1 mAb for the treatment of locally advanced/unresectable or mUC must have demonstrated disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb based on investigator assessment. If available, scans before treatment with an anti-PD-1/L1 or showing nadir during treatment with an anti-PD-1/L1 mAb and scans that document radiographic disease progression within 12 weeks (84 days) from the last dose of an anti-PD-1/L1 mAb should be submitted to the iCRO. Participants who received an anti-PD-1/L1 mAb for the treatment of MIUC must have demonstrated disease recurrence while on treatment or within 6 months from treatment completion based on investigator assessment. If available, scan before treatment with an anti-PD-1/L1 mAb and scan that documents radiographic recurrence should be submitted to the iCRO. 5. Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable. 6. Has an ECOG performance status of 0 to 1 (as assessed within 7 days of the first dose of study intervention). 7. Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). 8. Has adequate organ function. Specimens must be collected within 7 days before the start of study intervention. 9. Participants are male or female, ≥18 years of age at the time of providing documented informed consent. 10. Male participants are eligible to participate if they agree to follow the contraception requirements for the investigational treatment arm to which they are assigned. • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed. 11. Female participants are eligible to participate if they agree to follow the contraception requirements for the investigational treatment arm to which they are assigned. 12. The participant (or legally acceptable representative) has provided documented informed consent for the study. |
1. Diagnóstico confirmado histológica o citológicamente de CU localmente avanzado/irresecable o metastásico de pelvis renal, uréter (vías urinarias altas), vejiga o uretra. No podrán participar pacientes con tumores no uroteliales, como carcinoma epidermoide puro, adenocarcinoma puro, incluidos adenocarcinomas de uraco, tumores neuroendocrinos y tumores mesenquimatosos. 2.Presencia de enfermedad mensurable, evaluada por el centro y verificada mediante una RCIE conforme a los criterios RECIST 1.1. 3.Presencia de CU localmente avanzado o metastásico resistente a inhibidores de PD-1/L1, demostrado por: Progresión de la enfermedad durante o después del tratamiento con un AcM anti-PD-1/L1 para el CU localmente avanzado/irresecable o metastásico administrado en monoterapia o en combinación con otros inhibidores de puntos de control inmunológico u otros tratamientos.En estos participantes, el tto. con AcM anti-PD-1/L1 se define por el cumplimiento de TODOS los criterios siguientes: a. Recepción de al menos 2 dosis de un AcM anti-PD-1/L1 aprobado b. Progresión radiológica de la enfermedad demostrada durante o después del tto. con un AcM anti-PD-1/L1 según la evaluación del investigador c. Documentación radiológica por el investigador de la progresión de la enfermedad en las 12 semanas siguientes a la última dosis de un AcM anti-PD-1/L1 O Recidiva de la enfermedad durante o después del tto. con un AcM anti-PD-1/L1 para el CU-MI (carcinoma urotelial musculo-invasivo) administrado en monoterapia. En estos participantes, el tto. con AcM anti-PD-1/L1 se define por el cumplimiento de TODOS los criterios siguientes: a. Recepción de al menos 2 dosis de un AcM anti-PD-1/L1 aprobado b. Recidiva radiológica de la enfermedad demostrada durante el tto. con un AcM anti-PD-1/L1 o en los 6 meses siguientes a la finalización del tto. según la evaluación del investigador. 4. Los participantes que hayan recibido un AcM anti-PD-1/L1 para el tto. del CU localmente avanzado/irresecable o metastásico deberán haber mostrado progresión de la enfermedad durante o después del tto. con un AcM anti-PD-1/L1 según la evaluación del investigador. Si están disponibles, deberán enviarse a la iCRO estudios de imagen previos al tto. con un AcM anti-PD-1/L1 o que muestren el nadir durante el tto. con un AcM anti-PD-1/L1 y los estudios de imagen que documenten la progresión radiológica de la enfermedad en las 12 semanas (84 días) siguientes a la última dosis de un AcM anti-PD-1/L1. Los participantes que hayan recibido un AcM anti-PD-1/L1 para el tto. de un CU-MI deberán haber presentado recidiva de la enfermedad durante el tto. o en los 6 meses siguientes a su finalización según la evaluación del investigador. Si está disponible, se enviará a la iCRO un estudio de imagen antes del tto. con un AcM anti-PD-1/L1 y otro que documente la recidiva radiológica. 5. Los participantes deberán proporcionar una muestra de tejido tumoral de archivo o de una biopsia reciente,con aguja gruesa o por escisión,de una lesión tumoral que demuestre CU, no irradiada previamente y que sea adecuada para la evaluación de biomarcadores. Es preferible una biopsia reciente, pero no será obligatoria si se dispone de tejido de archivo evaluable. 6. Estado funcional del ECOG de 0 o 1 (evaluado en los 7 días previos a la primera dosis de la intervención del estudio). 7. Resolución de los efectos tóxicos del tratamiento previo más reciente hasta un grado 1 o inferior (excepto la alopecia). 8. Función orgánica adecuada. Las muestras se obtendrán en los 7 días previos al comienzo de la intervención del estudio. 9. Participantes de cualquier sexo con una edad mínima de 18 años en el momento de otorgar el consentimiento informado documentado. 10. Los varones podrán participar si se comprometen a seguir los requisitos de anticoncepción correspondientes al grupo de tto. en investigación al que sean asignados • El uso de anticonceptivos por los varones deberá cumplir la normativa local sobre métodos anticonceptivos para participantes en estudios clínicos. Si los requisitos de anticoncepción de la ficha técnica local de cualquiera de las intervenciones del estudio son más estrictos que los requisitos anteriores, deberán seguirse los requisitos de la ficha técnica local. 11. Las mujeres podrán participar si se comprometen a cumplir los requisitos de anticoncepción correspondientes al grupo de tto. en investigación al que hayan sido asignadas. 12. El participante (o su representante legal) ha otorgado su consentimiento informado documentado para el estudio. |
|
E.4 | Principal exclusion criteria |
1. Has a known additional nonurothelial malignancy that is progressing or has required active treatment within 3 years prior to study randomization/allocation. 2. Has known active CNS metastases and/or carcinomatous meningitis. 3. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with pembrolizumab or other investigational agents being evaluated within this study. 4. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization/allocation. 5. Has an active infection requiring systemic therapy. 6. Has received prior radiotherapy within 2 weeks of first dose of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. 7. Has had major surgery (<3 weeks before first dose of study intervention). 8. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. 9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. 10. Has known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 11. Has known history of hepatitis B (defined as HBsAg reactive) or known hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 12. Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 13. Has had an allogeneic tissue/solid organ transplant. |
1. Presencia de otra neoplasia maligna no urotelial conocida que está en progresión o ha necesitado tratamiento activo en los 3 años previos a la aleatorización/asignación del estudio. 2. Metástasis activas en el SNC o meningitis carcinomatosa conocidas. 3. Hipersensibilidad conocida a los principios activos o a cualquiera de sus excipientes, incluida una reacción de hipersensibilidad de importancia clínica previa al tratamiento con pembrolizumab u otros fármacos en investigación que se evalúen en este estudio. 4. Recepción de un tratamiento antineoplásico sistémico previo, incluidos fármacos en investigación, en las 4 semanas previas a la aleatorización/asignación. 5. Presencia de una infección activa con necesidad de tratamiento sistémico. 6. Recepción de radioterapia en las 2 semanas previas a la primera dosis de la intervención del estudio. Los participantes deberán haberse recuperado de toda toxicidad relacionada con la radioterapia, no precisar corticoides y no haber sufrido neumonitis por radiación. 7. Antecedentes de una intervención de cirugía mayor (menos de 3 semanas antes de la primera dosis de la intervención del estudio). 8. Recepción de una vacuna de microorganismos vivos o atenuados en los 30 días previos a la primera dosis de la intervención del estudio. Se permite la administración de vacunas inactivadas. 9. Participación actual o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las 4 semanas previas a la administración de la primera dosis de la intervención del estudio. 10. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH; anticuerpos contra el VIH 1/2). 11. Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección por el virus de la hepatitis C (detección de ARN del virus de la hepatitis C [VHC] [cualitativo]). 12. Antecedentes o datos actuales de cualquier proceso, tratamiento o anomalía analítica que, en opinión del investigador responsable del tratamiento, podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o hacer que la participación no sea lo más conveniente para el posible participante. 13. Recepción de un alotrasplante de órgano sólido o tejidos. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Percentage of Participants Who Experienced At Least One Adverse Event (AE) 2. Percentage of Participants Who Discontinued Study Treatment Due to an AE 3. Objective Response Rate (ORR) |
1. Porcentaje de participantes que experimentaron al menos un Acontecimiento adverso (AA). 2. Porcentaje de participantes que suspendieron el tratamiento del estudio debido a un AA 3. Tasa de respuestas objetivas (TRO) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5 years 2. Up to approximately 5 years 3. Up to approximately 2 years |
1. Hasta aproximadamente 5 años 2. Hasta aproximadamente 5 años 3. Hasta aproximadamente 2 años |
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E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) |
1. Duración de la respuesta (DR) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 2 years |
1. Hasta aproximadamente 2 años |
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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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration of the investigational agents in the specified population |
Primera administración de los fármacos en investigación en la población especificada |
|
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 | Yes |
E.8.1.7.1 | Other trial design description |
Diseño adaptativo de ramas |
rolling-arm, adaptive design |
|
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
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 |
Australia |
Canada |
Israel |
Korea, Republic of |
Taiwan |
United States |
France |
Netherlands |
Spain |
Italy |
Denmark |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |