A Study of SAR444245 Combined With Cemiplimab for the Treatment of Participants With Various Advanced Skin Cancers (Pegathor Skin 201)

Study Overview
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Brief Summary
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Primary Objective: -To determine the antitumor activity of SAR444245 in combination with cemiplimab. Secondary Objectives: To determine the recommended phase 2 dose and to assess the safety profile of SAR444245 when combined with cemiplimab To assess other indicators of antitumor activity To assess the concentrations of SAR444245 when given in combination with cemiplimab To assess the immunogenicity of SAR444245 To assess active concentrations of cemiplimab when given in combination with SAR444245

Detailed Description
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The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period [max 35 cycles or until PD], an end-of-treatment visit 30 days + 7 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or final cohort cut-off, whichever is earlier

Official Title
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A Phase 1/2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR- 707) Combined With Cemiplimab for the Treatment of Participants With Advanced Unresectable or Metastatic Skin Cancers

Conditions
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Malignant Melanoma, Squamous Cell Carcinoma of Skin

Intervention / Treatment
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* Drug: THOR-707
* Drug: Cemiplimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥18 years of age (or country's legal age of majority if >18 years), at the time of signing the informed consent. Participants with: Cohort A: Histologically confirmed unresectable locally advanced or metastatic melanoma that are not amenable to local therapy Cohort B: Histologically confirmed metastatic CSCC or locally advanced CSCC that are not candidates for curative surgery or radiation. Special considerations for the following categories: Participants with tumors arising on the cutaneous hair (non-glabrous) bearing lip with extension onto dry red lip (vermillion) may be eligible after communication with and approval from the Sponsor Participants with the primary site is nose are only eligible if the primary site was skin, not nasal mucosa with outward extension to skin (the Investigator confirmed) Participants with mixed histology in which the predominant histology is invasive CSCC may be eligible after communication with and approval from the Sponsor Participants in both cohorts must have at least one measurable lesion Provision of tumor tissue: For participants in the dose escalation: 16 µg/kg: at screening, biopsy is optional but highly recommended; and on-treatment not required 24 µg/kg: at screening, biopsy is mandatory and on-treatment, optional but highly recommended For the other participants : Mandatory baseline biopsy for the participants to enroll in cohort A with skin metastasis and in cohort B. Mandatory on-treatment biopsy for participants in Cohort A with skin metastasis and participants in Cohort B. Females are eligible to participate if they are not pregnant or breastfeeding, not a woman of childbearing potential (WOCBP) or are a WOCBP that agrees: to use approved contraception method and submit to regular pregnancy testing prior to treatment and for at least 180 days after discontinuing study treatment and to refrain from donating or cryopreserving eggs for 180 days after discontinuing study treatment. Males are eligible to participate if they agree to refrain from donating or cryopreserving sperm, and either abstain from heterosexual intercourse OR use approved contraception during study treatment and for at least 210 days after discontinuing study treatment. Capable of giving signed informed consent Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 Poor organ function Participants with baseline SpO2 ≤92% Active brain metastases or leptomeningeal disease. History of allogenic tissue/solid organ transplant. Last administration of prior antitumor therapy or any investigational treatment within 28 days or less than 5 times the half-life, whichever is shorter; major surgery or local intervention within 28 days. History of lung disease Comorbidity requiring corticosteroid therapy Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP Severe or unstable cardiac condition within 6 months prior to starting study treatment Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years Known second malignancy either progressing or requiring active treatment within the last 3 years For both cohorts: Prior immune checkpoint inhibitors except in the context of adjuvant or neoadjuvant; Participants who were on control arm of a study with an investigational anti-PD-1/PD-L1 are eligible. Received adjuvant or neoadjuvant therapy during the 6 months prior to development of metastatic disease. For Cohort A: any prior systemic treatment for advanced/metastatic disease For Cohort B: >2 prior lines of any systemic treatment for advanced/metastatic disease Inability to undergo any contrast-enhanced radiologic response assessment Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Melanoma<br>SAR444245 and cemiplimab administered every 3 weeks on Day 1 of each cycle (21 days per cycle) for up to 35 cycles. | Drug: THOR-707<br>* Solution for infusion: intravenous infusion<br>Drug: Cemiplimab<br>* Solution for infusion: intravenous infusion<br>* Other names: Libtayo® or generic;|
| Experimental: Cohort B: cutaneous squamous cell carcinoma (CSCC)<br>SAR444245 and cemiplimab administered every 3 weeks on Day 1 of each cycle (21 days per cycle) for up to 35 cycles. | Drug: THOR-707<br>* Solution for infusion: intravenous infusion<br>Drug: Cemiplimab<br>* Solution for infusion: intravenous infusion<br>* Other names: Libtayo® or generic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) in Cohort A (melanoma) | Cohort A (melanoma): Objective response rate (ORR) defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) determined by investigator per response evaluation criteria in solid tumors (RECIST) 1.1. | Baseline to the date of first documented progression or initiation of subsequent anticancer therapy or approximatively 9 months after the last participant receive first dose. | 
| Objective response rate (ORR) in Cohort B (CSCC) | Cohort B (CSCC): ORR defined as the proportion of participants who have a confirmed CR or PR determined by investigator per RECIST 1.1, or modified WHO criteria for medical photographs of external skin lesions, or composite criteria. | Baseline to the date of first documented progression or initiation of subsequent anticancer therapy or approximatively 9 months after the last participant receive first dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 dose determination | Incidence of Dose-limiting toxicities (DLTs) during DLT observation period | The observation period is 1 cycle (21 days) | 
| Assessment of SAR444245 safety profile when combined with cemiplimab-Treatment Emergent Adverse Events | Incidence of treatment-emergent adverse event (TEAEs) and laboratory abnormalities according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus gradings | From 1st IMP dose up to 30 days after the last dose of IMP | 
| Assessment of SAR444245 safety profile when combined with cemiplimab-Serious Adverse Events | Incidence of serious-adverse events (SAEs) and laboratory abnormalities according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus gradings | From 1st IMP dose up to 90 days after the last dose of IMP | 
| Complete Response rate | Complete Response rate (CRR) defined as the proportion of participants who have a confirmed CR determined by the Investigator per RECIST 1.1 for melanoma participants and when applicable for CSCC participants (CR in localized unresectable CSCC is exploratory) | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Time to Complete Response | Time to CR defined as the time from the first administration of IMP to the first tumor assessment at which the overall response was CR that is subsequently confirmed and determined by Investigator per RECIST 1.1 for melanoma participants and when applicable for CSCC participants | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Time to Response | Time to Response (TTR), defined as the time from first administration of IMP to the first tumor assessment at which the overall response was CR or PR that is subsequently confirmed and determined by Investigator per RECIST 1.1 or modified WHO Criteria or composite criteria whichever relevant | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Duration of Response (DoR) | Duration of Response (DoR), defined as the time from first tumor assessment at which the overall response was CR or PR that is subsequently confirmed until documented progressive disease (PD) determined by Investigator per RECIST 1.1 or modified WHO Criteria for medical photographs or composite criteria when relevant, or death from any cause, whichever occurs first | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate (CBR) including confirmed CR or PR at any time or stable disease (SD) of at least 6 months (determined by Investigator per RECIST 1.1 or modified WHO criteria for medical photographs or composite criteria whichever relevant). | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Progression Free Survival (PFS) | Progression Free Survival (PFS), defined as the time from the date of first IMP administration to the date of the first documented disease progression determined by Investigator per RECIST 1.1, or modified WHO Criteria for medical photographs when relevant or death due to any cause, whichever occurs first. | From the date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Concentration of SAR444245 |  | At Day1, Day2, Day3 of Cycle1 and Day 1 of Cycle 2-4-7-10 + every 5th cycle (each cycle is 21 days), maximum is up to approximately 24 months | 
| Incidence of anti-drug antibodies (ADAs) against SAR444245 |  | At Day1 and Day 15 of Cycle1, at Day 1 of Cycle 2-4-7-10 + every 5th cycle (each cycle is 21 days) and 30 days after last IMP administration, maximum is up to approximately 24 months. | 
| C trough of cemiplimab | Concentration observed just before treatment administration during repeated dosing (C trough) | Day 1 of Cycle 1-2-4-7-10 + every 5th cycle (each cycle is 21 days) and 30 days after the last IMP administration, maximum is up to approximately 24 months. | 
| C end_of_Infusion of cemiplimab | The concentration observed just after the end of infusion | Day 1 of Cycle 1-2-4-7-10 + every 5th cycle (each cycle is 21 days), maximum is up to approximately 24 months. |