A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery

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 relapse free survival (RFS) The secondary objectives of the study are: To demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by overall survival (OS) To demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by melanoma specific survival (MSS) To evaluate whether post-operative adjuvant therapy improves distant metastasis-free survival (DMFS), in stage IIC or III patients receiving fianlimab + cemiplimab compared to pembrolizumab To assess impact of fianlimab + cemiplimab on quality of life as compared to pembrolizumab in adults To assess safety and tolerability of fianlimab + cemiplimab compared to pembrolizumab To characterize pharmacokinetics (PK) of fianlimab + cemiplimab using sparse PK sampling in patients 12 years of age and older To assess immunogenicity of fianlimab and against cemiplimab

Official Title
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A Phase 3 Trial of Fianlimab (Anti-LAG-3) and Cemiplimab Versus Pembrolizumab in the Adjuvant Setting in Patients With Completely Resected High-risk 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: All patients must be either stage IIC, III, or stage IV per American Joint Committee on Cancer (AJCC) 8th edition and have histologically confirmed melanoma that is completely surgically resected in order to be eligible as defined by the protocol Complete surgical resection must be performed within 12 weeks prior to randomization, and enrollment may occur only after satisfactory wound healing from the surgery All patients must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization, as described in the protocol Key Exclusion Criteria: Uveal melanoma Any evidence of residual disease after surgery by imaging, pathology, or cytology. Ongoing or recent (within 2 years) evidence of clinically significant autoimmune disease that required systemic treatment with immunosuppressive agents Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection, as described in the protocol Another malignancy that is currently progressing or that required active treatment in the past 5 years, as described in the protocol Adolescent patients (≥12 to <18 years old) with body weight <40 kg 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: Fianlimab HD + Cemiplimab<br>Patients will be administered one combination dose of fianlimab high dose (HD) and cemiplimab | Drug: Fianlimab<br>* Fianlimab will be administered by intravenous (IV) infusion every (Q) 3 weeks<br>* Other names: REGN3767;Drug: Cemiplimab<br>* Cemiplimab will be administered by IV infusion Q 3 weeks<br>* Other names: Libtayo;|
| Experimental: Fianlimab LD + Cemiplimab<br>Patients will be administered one combination dose of fianlimab low dose (LD) and cemiplimab | Drug: Fianlimab<br>* Fianlimab will be administered by intravenous (IV) infusion every (Q) 3 weeks<br>* Other names: REGN3767;Drug: Cemiplimab<br>* Cemiplimab will be administered by IV infusion Q 3 weeks<br>* Other names: Libtayo;|
| Active Comparator: Pembrolizumab<br>Patients will be administered one dose of pembrolizumab co-infused with saline/dextrose placebo | Drug: Pembrolizumab<br>* Pembrolizumab will be administered by IV infusion Q 3 weeks<br>* Other names: Keytruda;Drug: Placebo<br>* Matching placebo co-infused with pembrolizumab IV, will be administered by IV infusion Q 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival (RSF) | Time from randomization to the first documented recurrence of disease at any site (excluding new primary melanomas) or death from any cause, whichever occurs first. | Up to 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Time from randomization to the date of death. | Up to 5 Years | 
| Melanoma specific survival (MSS) | Defined as death due to melanoma | Up to 5 Years | 
| Distant metastasis-free survival (DMFS) | Time between the date of randomization and the date of the first distant metastasis. | Up to 5 Years | 
| Occurrence of treatment-emergent adverse events (TEAEs) | A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. | Up to 5 Years | 
| Occurrence of immune-mediated EAEs (im-EAEs) | imAEs are a unique set of toxicities thought to be caused by unrestrained cellular immune responses. | Up to 5 Years | 
| Occurrence of serious adverse events (SAEs) | An SAE is any untoward medical occurrence that at any dose: Results in death - includes all deaths, even those that appear to be completely unrelated to study drug (eg, a car accident in which a patient is a passenger). Is life-threatening Requires in-patient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect. Is an important medical event | Up to 5 Years | 
| Occurrence of adverse events of special interest (AESIs) | An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it | Up to 5 Years | 
| Occurrence of TEAEs resulting in death | A TEAE resulting in death is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. | Up to 5 Years | 
| Occurrence of dose-limiting toxicity (DLT) | A DLT is defined as a study-drug related TEAE, including imAEs, that could preclude enrolling additional adolescent patients at the selected dose. Dose-limiting toxicity will be evaluated in adolescents only. | Up to 5 Years | 
| Occurrence of interruption or discontinuation of study drug(s) due to TEAE | A TEAE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. | Up to 5 Years | 
| Occurrence of laboratory abnormalities | As assessed by the NCI-CTCAE grading system (≥ Grade 3 or higher) | Up to 5 Years | 
| Concentrations of fianlimab in serum over time | The concentrations of fianlimab over time will be summarized by descriptive statistics by study arm for the overall population and for adolescent patients. | Up to 5 Years | 
| Concentrations of cemiplimab in serum over time | The concentrations of cemiplimab over time will be summarized by descriptive statistics by study arm for the overall population and for adolescent patients. | Up to 5 Years | 
| Concentration of finalimab anti-drug antibodies (ADA) and neutralizing antibodies | Immunogenicity will be characterized per drug molecule by ADA and NAb status. | Up to 5 Years | 
| Concentration of cemiplimab anti-drug antibodies (ADA) and neutralizing antibodies | Immunogenicity will be characterized per drug molecule by ADA and NAb status. | Up to 5 Years | 
| Patient report outcomes (PRO) for adults as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30) | The EORTC QLQ-C30 (Version 3) uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4: 1 (Not at all), 2 (A little), 3 (Quite a bit) and 4 (Very much). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. The EORTC QLQ-C30 (Version 3) uses for the questions 29 and 30 a 7-points scale. The scale scores from 1 to 7: 1 (very poor) to 7 (excellent). Half points are not allowed. The range is 6. More points are considered to have a better outcome. | Up to 5 Year | 
| PRO for adults as measured by the European Quality of Life Dimension 5 (EQ-5D-5L) | The EQ-5D-5L a descriptive system that 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. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. | Up to 5 Years | 
| PRO for adults as measured by the Functional Assessment of Cancer Therapy (FACT) - melanoma | 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 5 Years | 
| PRO for adults as determined by the Patient Global Impressions Scale (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 5 Years | 
| PRO for adults as determined by the Patient Global Impressions of Change Scale (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 5 Years | 
| Time to global health status/quality of life deterioration per EORTC QLQ-C30 |  | Up to 5 years | 
| Time to physical functioning deterioration per EORTC QLQ-C30 |  | Up to 5 Years | 
| Time to role functioning deterioration per EORTC QLQ-C30 |  | Up to 5 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resected High Risk Melanoma, Skin Cancer, Stage IIC, Stage III, Stage IV, LAG-3 Lymphocyte activation gene 3, Adjuvant Setting, anti-PD-1 Monoclonal Antibody