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

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by progression-free survival (PFS) The secondary objectives of the study are: To demonstrate superiority of fianlimab (REGN3767) + cemiplimab compared to pembrolizumab, as measured by overall survival (OS) To demonstrate superiority in objective response rate (ORR) with fianlimab + cemiplimab compared to pembrolizumab To characterize ORR, PFS, and OS with fianlimab + cemiplimab compared to cemiplimab to inform the contribution of each component To assess immunogenicity of fianlimab and cemiplimab To assess impact of fianlimab + cemiplimab on physical functioning and role functioning and global health status/quality of life, as compared to pembrolizumab in adults To characterize safety and tolerability of treatment in patients 12 to <18 years of age To characterize ORR, PFS, and OS with treatment in patients 12 to <18 years of age To assess the safety and tolerability of fianlimab + cemiplimab compared to pembrolizumab and to cemiplimab To characterize pharmacokinetics (PK) of fianlimab and cemiplimab using sparse PK sampling in patients aged ≥12 years

Official Title
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A Phase 3 Trial of Fianlimab (REGN3767, Anti-LAG-3) + Cemiplimab Versus Pembrolizumab in Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Fianlimab
* Drug: Cemiplimab
* Drug: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥12 years on the date of providing informed consent 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 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. Patients with acral and mucosal melanomas are eligible. Accrual will be limited to 10% of the total population. Measurable disease per RECIST v1.1 Previously irradiated lesions can only be counted as target lesions if they have been demonstrated to progress and no other target lesion is available Cutaneous lesions should be evaluated as non-target lesions Performance status: For adult patients: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 For pediatric patients: Karnofsky performance status ≥70 (patients ≥16 years) or Lansky performance status ≥70 (patients ≤16 years) Anticipated life expectancy of at least 3 months Key Exclusion Criteria: Uveal melanoma 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. 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 Unknown BRAF V600 mutation status as described in the protocol Systemic immune suppression: 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. Other clinically relevant forms of systemic immune suppression 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. 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. Active or untreated brain metastases or spinal cord compression. Patients with leptomeningeal disease are excluded. Patients with known brain metastases are eligible if they: Received radiotherapy or another appropriate standard therapy for the brain metastases, Have neurologically returned to baseline (except for residual signs and symptoms related to the CNS treatment) for at least 14 days prior to enrollment Did not require immunosuppressive doses of corticosteroids therapy (>10mg of prednisone per day or equivalent) in the 14 days prior to enrollment Are asymptomatic with a single untreated brain metastasis <10 mm in size Note: Other protocol-defined Inclusion/ Exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: fianlimab+cemiplimab dose 1<br>Protocol Amendment 1: 40 participants randomized 2:1:1 (Futility Analysis) Protocol Amendment 3: 140 participants randomized 2:2:2:1 Protocol Amendment 3: 1050 participants randomized 2:2:2:1 ((PFS population) Protocol Amendment 3: 360 participants randomized 1:1:1 (OS Analysis) | Drug: Fianlimab<br>* Intravenous (IV) infusion<br>* Other names: REGN3767;Drug: Cemiplimab<br>* IV infusion<br>* Other names: Libtayo;|
| Experimental: A1: fianlimab+cemiplimab dose 2<br>Protocol Amendment 3: 140 participants randomized 2:2:2:1 Protocol Amendment 3: 1050 participants randomized 2:2:2:1 ((PFS population) Protocol Amendment 3: 360 participants randomized 1:1:1 (OS Analysis) | Drug: Fianlimab<br>* Intravenous (IV) infusion<br>* Other names: REGN3767;Drug: Cemiplimab<br>* IV infusion<br>* Other names: Libtayo;|
| Experimental: B: pembrolizumab+placebo<br>Protocol Amendment 1: 40 participants randomized 2:1:1 (Futility Analysis) Protocol Amendment 3: 140 participants randomized 2:2:2:1 Protocol Amendment 3: 1050 participants randomized 2:2:2:1 ((PFS population) Protocol Amendment 3: 360 participants randomized 1:1:1 (OS Analysis) | Drug: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda;Drug: Placebo<br>* IV infusion<br>|
| Experimental: C: cemiplimab+placebo<br>Protocol Amendment 1: 40 participants randomized 2:1:1 (Futility Analysis) Protocol Amendment 3: 140 participants randomized 2:2:2:1 Protocol Amendment 3: 1050 participants randomized 2:2:2:1 ((PFS population) | Drug: Cemiplimab<br>* IV infusion<br>* Other names: Libtayo;Drug: Placebo<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Blinded Independent Central Review (BICR) | Approximately 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | Up to 96 months | 
| Objective response rate (ORR) | per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on Blinded Independent Central Review (BICR) or based on investigator assessment according to RECIST 1.1 and immune RECIST (iRECIST) | Up to 27 months | 
| Disease control rate (DCR) | per RECIST 1.1 based on BICR or based on investigator assessment according to RECIST 1.1 and immune RECIST (iRECIST) | Up to 27 months | 
| Duration of response (DoR) | per RECIST 1.1 via BICR or based on investigator assessment according to RECIST 1.1 and immune RECIST (iRECIST) | Up to 27 months | 
| PFS | Based on investigator assessment according to RECIST 1.1 and immune RECIST (iRECIST) | Up to 27 months | 
| Incidence of Adverse Events (AEs) | Including treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and/ or immune-related adverse event (irAEs) | Up to 90 days post last dose, approximately 6 years | 
| Occurrence of interruption and discontinuation of study drug(s) due to AEs | Including TEAEs, AESIs, and/ or irAEs | Up to 90 days post last dose, approximately 6 years | 
| Incidence of deaths |  | Up to 6 years | 
| Incidence of laboratory abnormalities | Will be graded using the current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system (version 5.0) | Up to 90 days post last dose, approximately 6 years | 
| Concentrations of cemiplimab in serum |  | Up to 90 days post last dose, approximately 6 years | 
| Concentrations of fianlimab in serum |  | Up to 90 days post last dose, approximately 6 years | 
| Incidence of anti-drug antibodies (ADA) to fianlimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Titer of anti-drug antibodies (ADA) to fianlimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Incidence of ADA to cemiplimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Titer of ADA to cemiplimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Incidence of neutralizing antibodies (NAb) to fianlimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Incidence of NAb to cemiplimab over time |  | Up to 30 days post last dose, approximately 6 years | 
| Patient-reported outcomes (PROs) as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) | EORTC-QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Up to 90 days post last dose, approximately 6 years | 
| PROs as measured by EQ-5D-5L | The EQ-5D-5L consists of EQ-5D descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction. | Up to 90 days post last dose, approximately 6 years | 
| PROs as measured by Functional Assessment of Cancer Therapy (FACT)-melanoma (melanoma subscale only) | The FACT-M is a melanoma-specific quality of life questionnaire that is composed of items from the Functional Assessment of Cancer Therapy-General (FACT-G). The FACT-M is scored on a 5 point Likert-scale: Not at all, A little bit, Somewhat, Quite a bit, and Very much.. A Higher score represents higher Health Related Quality of Life (HRQoL). | Up to 90 days post last dose, approximately 6 years | 
| PROs as measured by Patient Global Impression of Severity (PGIS) | The PGIS is a single 1-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time by using a 4-point Likert scale that ranges from (1) = none (no symptoms) to (4) = severe. | Up to 21 days post last dose, approximately 6 years | 
| PROs as measured by Patient Global Impression of Change (PGIC) | The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) much better to (5) much worse, with (4) = no change | Up to 21 days post last dose, approximately 6 years | 
| Change in physical functioning per EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to Week 25 | 
| Change in role functioning per EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to Week 25 | 
| Change in global health status/quality of life (GHS/QoL) per EORTC QLQ-C30 | Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to Week 25 | 
| Change in physical functioning per EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to end of study, approximately 6 years | 
| Change in role functioning per EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to end of study, approximately 6 years | 
| Change in GHS/QoL per EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | Baseline to end of study, approximately 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unresectable, Metastatic, Stage III, Stage IV, Anti-Lymphocyte-activation gene 3 Pathway (LAG-3)