Clinical Study of Fianlimab in Combination With Cemiplimab Versus Pembrolizumab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma

Eligibility 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
• 1. 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 imAEs ≥ 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. Accrual of these patients is limited to approximately 10% of the total population enrolled.
• 2. 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
• 1. Previously irradiated lesions can only be counted as target lesions if they have been demonstrated to progress and no other target lesion is available
• 2. Cutaneous lesions should be evaluated as non-target lesions
• 4. Performance status:
• 1. For adult patients: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• 2. 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
• 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 as described in the protocol
• 5. Systemic immune suppression:
• 1. 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, if they are not for treatment of an autoimmune disorder.
• 2. Other clinically relevant forms of systemic immune suppression
• 6. Treatment with other anti-cancer therapy including immuno- therapy, chemotherapy, major surgery or biological therapy within 21 days 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.
• 7. History or current evidence of significant (CTCAE Grade ≥2) local or systemic infection (e. g., cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 14 days 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:
• 1. Received radiotherapy or another appropriate standard therapy for the brain metastases,
• 2. Have neurologically returned to baseline (except for residual signs and symptoms related to the CNS treatment) for at least 14 days prior to enrollment
• 3. Did not require immunosuppressive doses of corticosteroids therapy (\>10mg of prednisone per day or equivalent) in the 14 days prior to enrollment
• 4. Are asymptomatic with a single untreated brain metastasis \<10 mm in size
• 9. Participants with a history of myocarditis.