E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Colorectal Cancer |
Tumore metastatico del colon-retto |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic Colorectal Cancer |
Tumore metastatico del colon-retto |
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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) |
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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) |
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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 |
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 |
Confrontare l’efficacia della FDC di relatlimab-nivolumab rispetto alla terapia standard di cura scelta dallo sperimentatore (regorafenib o TAS-102) in partecipanti con tumore metastatico del colon-rettoin linea di trattamento più avanzata, inclusi tutti i partecipanti randomizzati e i partecipanti randomizzati con PD-L1 CPS ≥ 1, rispettivamente |
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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 |
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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 (see next slide for details). - 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 CA224-123_Protocol_original version_12Nov2021 for the full list of inclusion criteria. |
- Tumore del colon-retto precedentemente trattato confermato istologicamente con istologia di adenocarcinoma con malattia metastatica o ricorrente non resecabile all’ingresso nello studio. a) Tumore del colon-retto precedentemente trattato confermato istologicamente con istologia di adenocarcinoma con malattia metastatica o ricorrente non resecabile all’ingresso nello studio. b) I partecipanti che erano risultati intolleranti a precedenti regimi chemioterapici sistemici sono idonei se vi sono evidenze documentate di intolleranza clinicamente significativa nonostante adeguate misure di supporto. - I partecipanti devono presentare risultati valutabili dell’espressione di PD-L1 provenienti dal laboratorio centrale durante il periodo di screening prima della randomizzazione. - Solo i partecipanti con stato tumorale di stabilità ai microsatelliti/riparazione del mismatch competente (MSS/pMMR) del tumore confermato secondo i test standard locali sono idonei all’arruolamento in questo studio. - Lo stato della mutazione KRAS deve essere documentato in base ai risultati dei test anamnestici o locali disponibili nell’ambito dell’anamnesi medica prima dell’arruolamento nello studio. - I partecipanti devono avere una malattia misurabile secondo i Criteri di valutazione della risposta sui tumori solidi (RECIST) v1.1. I partecipanti con lesioni in un campo precedentemente irradiato come unico sito di malattia misurabile potranno arruolarsi a condizione che la/le lesione/i abbia/abbiano dimostrato una progressione chiara e misurabile con precisione.
Far riferimento al Protocollo: CA224-123_Protocol_original version_12Nov2021 per la lista completa dei criteri di inclusione.
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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 CA224-123_Protocol_original version_12Nov2021 for the full list of exclusion criteria. |
- Precedente trattamento con immunoterapia (anticorpi anti-LAG-3, anti-PD-1, anti-PD-L1 o anti-CTLA-4 o qualsiasi altro anticorpo o farmaco specificamente mirato alla co-stimolazione delle cellule T o dei pathway di checkpoint), con regorafenib o con TAS-102. - Metastasi al sistema nervoso centrale (SNC) non trattate. I partecipanti sono idonei se le metastasi nell’SNC sono state trattate e i partecipanti sono tornati neurologicamente al basale (ad eccezione dei segni o sintomi residui correlati al trattamento dell’SNC). - Ipertensione refrattaria al trattamento che non possa essere controllata mediante terapia antipertensiva, miocardite (, a prescindere dall’eziologia), aritmie clinicamente significative non controllate, sindromi coronariche acute nei 6 mesi precedenti la somministrazione, anamnesi o evidenza di attuale insufficienza cardiaca congestizia di classe ≥II, secondo la definizione della New York Heart Association, anamnesi di malattia polmonare interstiziale o polmonite, partecipanti con una malattia autoimmune attiva, nota o sospetta.
Far riferimento al Protocollo: CA224-123_Protocol_original version_12Nov2021 per la lista completa dei criteri di esclusione.
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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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Until death, up to 5 years after last Participant randomized
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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 |
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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 |
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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 | 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 | 8 |
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 |
France |
Poland |
Sweden |
United Kingdom |
Netherlands |
Spain |
Switzerland |
Czechia |
Germany |
Italy |
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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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |