| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer |
| Cáncer colorrectal metastásico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
| Cáncer colorrectal 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 | 21.0 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| 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) |
|
| 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 |
| To compare the efficacy of the relatlimab-nivolumab FDC to investigator’s choice standard of care therapy (regorafenib or TAS-102) in participants with late-line metastatic colorectal cancer, including all randomized participants and randomized participants with PD-L1 CPS ≥ 1, respectively |
| Comparar la eficacia de la CDF de relatlimab-nivolumab con el tratamiento de referencia elegido por el investigador (regorafenib o TAS-102) en participantes con cáncer colorrectal metastásico con líneas de tratamiento posteriores, incluidos todos los participantes aleatorizados y los participantes aleatorizados con puntuación positiva combinada (combined positive score, CPS) de PD-L1 ≥1, respectivamente |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the antitumor activity based on ORR by BICR of the relatlimab-nivolumab FDC to investigator’s choice standard of care therapy (regorafenib or TAS-102) in participants with late-line metastatic colorectal cancer, including all randomized participants and randomized participants with PD-L1 CPS ≥1
- To compare the antitumor efficacy based on PFS by BICR of the relatlimab-nivolumab FDC to investigator’s choice standard of care therapy (regorafenib or TAS-102) in participants with late-line metastatic colorectal cancer, including all randomized participants and randomized participants with PD-L1 CPS ≥ 1
- To compare deterioration free survival (DeFS) of the relatlimab + nivolumab FDC to investigator’s choice standard of care therapy (regorafenib or TAS- 102) in participants with late-line metastatic colorectal cancer, including all randomized participants and randomized participants with PD-L1 CPS ≥ 1
Please refer to the protocol for a full list of secondary objectives |
-Comparar la actividad antitumoral basada en la TRO según RCIE de la CDF de relatlimab-nivolumab con el tratamiento de referencia elegido por el investigador (regorafenib o TAS-102) en participantes con cáncer colorrectal metastásico con líneas de tratamiento posteriores, incluidos todos los participantes aleatorizados y los participantes aleatorizados con CPS de PD-L1 ≥1
-Comparar la eficacia antitumoral basada en la SSP según RCIE de la CDF de relatlimab-nivolumab con el tratamiento de referencia elegido por el investigador (regorafenib o TAS-102) en participantes con cáncer colorrectal metastásico con líneas de tratamiento posteriores, incluidos todos los participantes aleatorizados y los participantes aleatorizados con CPS de PD-L1 ≥1
Para más información consultar la lista completa de los objetivos secundarios |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Histologically confirmed previously treated CRC with adenocarcinoma histology with metastatic or recurrent unresectable disease at study entry.
- Participants must have:
a)progressed during or within approximately 3 months following the last administration of approved standard therapies (at least 1, but not more than 4 prior lines of therapies), which must include a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF therapy, and anti-EGFR therapy (if KRAS wild-type), if approved in the respective country, or;
b)been intolerant to prior systemic chemotherapy regimens if there is documented evidence of clinically significant intolerance despite adequate supportive measures.
- Participants must have sufficient tumor tissue & evaluable PD-L1 expression to meet the study requirements. Participants with indeterminate PD-L1 results will be stratified with those participants assessed to be PD-L1 negative by CPS.
- Participants must have historically or locally confirmed tumor MSS/pMMR status to enroll in this study.
- KRAS mutation status must be documented based on available historical or local testing results as part of medical history prior to study enrollment.
- Participants must have measurable disease per RECIST v1.1. Participants with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately.
Please refer to the protocol for a full list of inclusion criteria. |
-Cáncer colorrectal previamente tratado y confirmado histológicamente con histología de adenocarcinoma y enfermedad irresecable metastásica o recurrente al entrar en el estudio.
-Los participantes:
a) deben haber experimentado progresión de la enfermedad durante o en el plazo aproximado de 3 meses tras la última administración de tratamientos estándar aprobados (al menos 1, pero no más de 4 líneas anteriores de tratamiento), que deben incluir un tratamiento con fluoropirimidina, oxaliplatino, irinotecán, un tratamiento contra el factor de crecimiento del endotelio vascular (VEGF) y un tratamiento contra el receptor del factor de crecimiento epidérmico (EGFR) (si el gen KRAS es de tipo natural), si están aprobados en el país.
b) ser intolerantes a pautas de quimioterapia sistémica anteriores son aptos si hay indicios documentados de intolerancia clínicamente significativa a pesar de las medidas sintomáticas adecuadas.
-Los participantes deben tener suficiente tejido tumoral y expresión de PD-L1 evaluable para cumplir los requisitos del estudio. Los participantes con resultados indeterminados de PD-L1 serán estratificados con aquellos participantes evaluados como negativos para PD-L1 por el CPS.
-Los participantes con estado de estabilidad microsatelital (MSS)/reparación de errores de emparejamiento competente (pMMR) del tumor confirmado históricamente o localmente son aptos para inscribirse en este estudio.
-El estado de mutación de KRAS debe documentarse basándose en los resultados de las pruebas locales o históricas disponibles como parte de los antecedentes médicos antes de la inscripción en el estudio.
-Los participantes deben tener enfermedad cuantificable según los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) v. 1.1. Los participantes con lesiones en un campo irradiado previamente como único lugar de enfermedad cuantificable podrán inscribirse siempre que las lesiones hayan mostrado una progresión clara y puedan medirse con precisión.
Para más información consultar en el protocolo la lista completa de los criterios de inclusión. |
|
| E.4 | Principal exclusion criteria |
- Prior treatment with either an immunotherapy (anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or with regorafenib or with TAS-102.
- Untreated CNS metastases. Participants are eligible if CNS metastases have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment)
- Participants with history of refractory hypertension not controlled with anti-hypertensive therapy, myocarditis (regardless of etiology), uncontrolled arrhythmias, acute coronary syndrome within 6 months prior to dosing, Class II congestive heart failure (as per the New York Heart Association Functional Classification), interstitial lung disease/pneumonitis or an active, known or suspected autoimmune disease.
- In the case of prior SARS-CoV-2 infection, acute symptoms must have completely resolved and based on investigator assessment in consultation with the clinical trial physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
Please refer to the protocol for a full list of exclusion criteria. |
- Tratamiento previo con inmunoterapia (anti-LAG-3, anti-PD-1, anti-PD-L1 o anticuerpo anti-CTLA-4, o cualquier otro anticuerpo o fármaco dirigido específicamente a la coestimulación de linfocitos T o las vías de punto de control), con regorafenib o con TAS-102.
- Metástasis en el sistema nervioso central (SNC) sin tratar. Los participantes son aptos si se han tratado metástasis en el SNC y han retornado neurológicamente a los valores iniciales (excepto signos o síntomas residuales relacionados con el tratamiento del SNC).
- Participantes con antecedentes de hipertensión resistente no controlada con terapia antihipertensiva, miocarditis (independientemente de la etiología), arritmias no controladas, síndrome coronario agudo en los 6 meses anteriores a la administración de la dosis, insuficiencia cardíaca congestiva de clase II (según la definición de la Asociación de Cardiología de Nueva York), neumopatía intersticial/neumonitis o con presencia o sospecha de enfermedad autoinmunitaria activa.
- En el caso de infección previa por el coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2), los síntomas agudos deben haberse resuelto por completo y, según la evaluación del investigador con el asesoramiento del médico del ensayo clínico, no hay secuelas que pongan al participante bajo un mayor riesgo de recibir tratamiento en investigación.
Para más información consultar en el protocolo la lista completa de los criterios de exclusión. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Overall Survival (OS) in randomized participants with PD-L1 CPS (combined positive score;) ≥ 1
- OS in all randomized participants |
- SG en participantes aleatorizados con CPS de PD-L1 ≥1
- SG en todos los participantes aleatorizados |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Until death, up to 5 years after last Participant randomized |
| Hasta la muerte, hasta 5 años después del último participante aleatorizado |
|
| E.5.2 | Secondary end point(s) |
1/ ORR (objective response rate) by BICR (blinded independent central review) per RECIST v1.1 in randomized participants with PD-L1 CPS ≥ 1 and all randomized participants, respectively
2/ PFS (progression-free survival) by BICR per RECIST v1.1 in randomized participants with PD-L1 CPS≥ 1 and all randomized participants, respectively
3/ DoR (duration of response;) by BICR per RECIST v1.1 in responders with PD-L1 CPS ≥ 1 and all responders, respectively
4/ Rate of AEs (adverse events), SAEs (serious adverse events), select AEs and IMAEs (immune-mediated adverse events), AEs leading to discontinuation and abnormalities in specific clinical laboratory assessments
5/ Deterioration free survival-quality of life (DeFS-QoL), which is defined as time until definitive deterioration in the EORTC QLQ-C30 global health status/QoL scale score or death, whichever is earlier in randomized participants with PD-L1 CPS ≥ 1 and all randomized participants, respectively
6/ Deterioration free survival-physical function (DeFS-PF), which is defined as time until definitive deterioration in the EORTC QLQ-C30 physical function scale score or death, whichever is earlier in randomized participants with PD-L1 CPS ≥ 1 and all randomized participants, Respectively |
1/ TRO mediante RCIE según los criterios RECIST v1.1 en participantes aleatorizados con CPS de PD-L1 ≥1 y todos los participantes aleatorizados, respectivamente
2/ SSP mediante RCIE según los criterios RECIST v1.1 en participantes aleatorizados con CPS de PD-L1 ≥1 y todos los participantes aleatorizados, respectivamente
3/ DR mediante RCIE según los criterios RECIST v1.1 en pacientes que responden al tratamiento con CPS de PD-L1 ≥1 y todos los pacientes que responden al tratamiento, respectivamente
4/ Tasa de AA, AAG, AA seleccionados y AAmsi, AA que provocan la interrupción y anomalías en evaluaciones analíticas clínicas específicas
5/ Supervivencia sin deterioro-Calidad de vida (SSD-CdV), que se define como el tiempo hasta el deterioro definitivo en la puntuación de la escala del estado de salud global/CdV del QLQ-C30 de la EORTC o la muerte, lo que ocurra primero en los participantes aleatorizados con CPS de PD-L1 ≥1 y en todos los participantes aleatorizados, respectivamente
6/Supervivencia sin deterioro-Función física (SSD-FF), que se define como el tiempo hasta el deterioro definitivo en la puntuación de la escala de función física del QLQ-C30 de la EORTC o la muerte, lo que ocurra primero en los participantes aleatorizados con CPS de PD-L1 ≥1 y en todos los participantes aleatorizados, respectivamente |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3: Tumor assessments should continue until disease progression or death or withdrawal of consent, whichever is earlier, up to 5 years after last participant randomized
4/ up to 5 years after last participant was randomized
5, 6: Until death, up to 5 years after last participant randomized |
1, 2, 3: Las evaluaciones del tumor deben continuar hasta la progresión de la enfermedad o la muerte o la retirada del consentimiento, lo que ocurra antes, hasta 5 años después de que el último participante haya sido aleatorizado
4/ hasta 5 años después del último participante aleatorizado
5, 6: Hasta la muerte, hasta 5 años después del último participante aleatorizado |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Chile |
| China |
| Japan |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Poland |
| Sweden |
| United Kingdom |
| Netherlands |
| Spain |
| Switzerland |
|
| 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
|
End of trial is defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last participant.
A participant is considered to have completed the study if he/she has completed all survival follow-up visits up to 5 years. |
El final del ensayo se define como la última visita o procedimiento programado que aparece en el Programa de Actividades para el último participante.
Se considera que un participante ha completado el estudio si ha realizado todas las visitas de seguimiento de supervivencia hasta los 5 años. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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