| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
|
| 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 |
|
| 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 |
|
| 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).
- 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. |
|
| 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.
- Participants with historically or locally confirmed tumor MSI-H/dMMR status |
|
| 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
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Until death, up to 5 years after last Participant randomized
|
|
| 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/ QoLTUDD-physical function (TUDDPF), which is defined as time from randomization until definitive deterioration in the EORTC QLQ-C30 physical function scale score in randomized participants with PD-L1 CPS ≥ 1 and all randomized participants, respectively
6/ TUDD-quality of life (TUDD-QoL), which is defined as time until definitive deterioration in the EORTC QLQ-C30 global health status/QoL scale score in randomized participants with PD-L1 CPS ≥ 1 and all randomized participants, Respectively
7/ PFS, ORR, DoR by investigator per RECIST v1.1 in randomized participants with PD-L1 CPS = 1 and all randomized participants, respectively |
|
| 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 follow up visit 2, which is 135 days after last dose.
5, 6: up to follow up visit 2, which is 135 days after last dose.
7: Tumor assessments should continue until disease progression or
death or withdrawal of consent, whichever is earlier, up to 5 years after
last participant randomized |
|
| 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 |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Italy |
| Belgium |
| 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
|
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. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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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