| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | | Cutaneous melanoma is one of the most aggressive forms of skin 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 | 21.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10025650 | | E.1.2 | Term | Malignant melanoma | | 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 demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by PFS (progression-free survival). | |
| E.2.2 | Secondary objectives of the trial | - Demonstrate superiority of fianlimab (REGN3767) + cemiplimab compared to pembrolizumab, as measured by OS (overall survival)
- Demonstrate superiority in objective response rate (ORR) with fianlimab + cemiplimab compared to pembrolizumab
- Characterize ORR, PFS, and OS with fianlimab + cemiplimab compared to cemiplimab to inform the contribution of each component
- Assess immunogenicity of fianlimab and cemiplimab
- Assess impact of fianlimab + cemiplimab on physical functioning and role functioning and global health status/quality of life, as compared to pembrolizumab in adults
- Characterize safety and tolerability of treatment in patients 12 to <18 years of age
- Characterize ORR, PFS, and OS with treatment in patients 12 to <18 years of age
- Assess the safety and tolerability of fianlimab + cemiplimab compared to pembrolizumab and to cemiplimab
- Characterize pharmacokinetics (PK) of fianlimab and cemiplimab using sparse PK sampling in patients aged ≥12 years | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Age ≥12 years on the date of providing informed consent
2. Patients with histologically confirmed unresectable Stage III and Stage IV (metastatic) melanoma (AJCC, 8th revised edition) who have not received prior systemic therapy for advanced unresectable disease.
a. Patients who received adjuvant and/or neoadjuvant systemic therapies are eligible if they did not have evidence of progression or recurrence of disease and/or discontinued due to occurrence of unmanageable irAEs ≥ Grade 3 (with the exclusion of endocrinopathies which are fully controlled by hormone replacement ) while on such therapies. Also, patients must have had a treatment-free and disease-free interval of >6 months.
b. Patients with acral and mucosal melanomas are eligible. Accrual will be limited to 10% of the total population.
3. Measurable disease per RECIST v1.1
a. Previously irradiated lesions can only be counted as target lesions if they have been demonstrated to progress and no other target lesion is available
b. Cutaneous lesions should be evaluated as non-target lesions
4. Performance status:
a) For adult patients: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
b) For pediatric patients: Karnofsky performance status ≥70 (patients ≥16 years) or Lansky performance status ≥70 (patients <16 years)
5. Anticipated life expectancy of at least 3 months.
Please note other protocol-defined Inclusion criteria apply
| |
| E.4 | Principal exclusion criteria | Medical conditions:
1. Uveal melanoma
2. Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment.
3. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection.
4. Unknown BRAF V600 mutation status.
Prior/concomitant therapy:
5. Systemic immune suppression:
a. Use of immunosuppressive doses of corticosteroids (>10mg of prednisone per day or equivalent) within 14 days of the first dose of study medication. Physiologic replacement doses are allowed up to and including 10mg of prednisone/day or equivalent. Inhaled or topical steroids are permitted, provided if they are not for treatment of an autoimmune disorder.
b. Other clinically relevant forms of systemic immune suppression.
6. Treatment with other anti-cancer therapy including immuno- therapy, chemotherapy, radiotherapy, major surgery or biological therapy within 3 weeks prior to the first dose of trial treatment. Adjuvant hormonotherapy used for breast cancer or other hormone-sensitive cancers in long term remission is allowed.
Other comorbidities:
7. History or current evidence of significant (CTCAE Grade ≥2) local or systemic infection (e. g., cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication.
8. Active or untreated brain metastases or spinal cord compression. Patients with leptomeningeal disease are excluded. Patients with known brain metastases are eligible if they:
a. received radiotherapy or another appropriate standard therapy for the brain metastases,
b. have neurologically returned to baseline (except for residual signs and symptoms related to the CNS treatment) for at least 14 days prior to enrollment.
c. did not require immunosuppressive doses of corticosteroids therapy (>10mg of prednisone per day or equivalent) in the 14 days prior to enrollment.
d. are asymptomatic with a single untreated brain metastasis < 10 mm in size
Other protocol-defined Exclusion criteria apply
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| E.5 End points |
| E.5.1 | Primary end point(s) | | PFS (progression-free survival) | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | 1. Overall survival (OS)
2. Objective response rate (ORR)
3. Disease control rate (DCR)
4. Duration of response (DoR)
5. PFS
6. Incidence of Adverse Events (AEs)
7. Occurrence of interruption and discontinuation of study drug(s) due to AEs
8. Incidence of deaths
9. Incidence of laboratory abnormalities
10. Concentrations of cemiplimab in serum
11. Concentrations of fianlimab in serum
12. Incidence and titer of anti-drug antibodies (ADA) to fianlimab over time
13. Incidence and titer of ADA to cemiplimab over time
14. Incidence of neutralizing antibodies (NAb) to fianlimab over time
15. Incidence of NAb to cemiplimab over time
16. Patient-reported outcomes (PROs) as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)
17. PROs as measured by EQ-5D-5L
18. PROs as measured by Functional Assessment of Cancer Therapy (FACT)-melanoma (melanoma subscale only)
19. PROs as measured by Patient Global Impression of Severity (PGIS) 20. PROs as measured by Patient Global Impression of Change (PGIC) 21. Change in physical functioning per EORTC QLQ-C30
22. Change in role functioning per EORTC QLQ-C30
23. Change in global health status/quality of life (GHS/QoL) per EORTC QLQ-C30
24. Change in physical functioning per EORTC QLQ-C30
25. Change in role functioning per EORTC QLQ-C30
26. Change in GHS/QoL per EORTC QLQ-C30 | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1-4: Up to 96 months
2-5: Up to 27 months
6-7: Up to 90 days post last dose, approximately 6 years
8: Up to 6 years
9-11: Up to 90 days post last dose, approximately 6 years
12-15: Up to 30 days post last dose, approximately 6 years
16-18: Up to 90 days post last dose, approximately 6 years
19-20: Up to 21 days post last dose, approximately 6 years
21-23: Baseline to Week 25
24-26: Baseline to end of study, approximately 6 years | |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description | Immunogenicity
Incidence and titer of anti-drug antibodies (ADA) and incidence of neutralizing antibodies (NAb) to fianlimab and cemiplimab over time. | |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description | |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| 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 | | Brazil | | Canada | | Chile | | Mexico | | South Africa | | United States | | Austria | | France | | Poland | | Romania | | Spain | | Germany | | Italy | | Belgium | | Georgia | | Ireland | | Russian Federation | | Turkey | | Ukraine | | 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 | | The end of study is defined as the date the last patient completes the last study visit withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator). | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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 |
