A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With HNSCC (Master Protocol) (Pegathor Head and Neck 204)

Study Overview
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Brief Summary
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The is a phase 2 multi-cohort, non-randomized, open-label, multi-center study assessing the clinical benefit of SAR444245 combined with other anticancer therapies for the treatment of participants aged 18 years and older with HNSCC. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies. Substudy 1-Cohort A1 aims to establish proof-of-concept that SAR444245 combined with the anti-PD1 antibody pembrolizumab, will result in a significant increase in the observed number of objective responses in trial participants with HNSCC who are treatment-naïve for recurrent and/or metastatic (R/M) disease. Substudy 4-Cohort B1 aims to establish proof-of-concept that SAR444245 combined with the anti-PD1 antibody pembrolizumab, will result in a significant increase in the observed number of objective responses in trial participants with HNSCC who have received treatment with PD1/PD-L1 and platinum-based regimen. Substudy 5-Cohort B2 aims to establish proof-of-concept that SAR444245 combined with cetuximab will result in a significant increase in the observed number of objective responses in trial participants with HNSCC previously treated with platinum-based regimen & cetuximab-naive after failure of no more than 2 regimens for recurrent and/or metastatic (R/M) disease.

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 {cohort A1 and B1} = 735 days or until PD {cohort B2}]; max 35 cycles for SAR444245 and pembrolizumab] an end-of-treatment visit at least approximately 30 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier) and a follow-up visits 3 months after treatment discontinuation and every 3 months thereafter following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier

Official Title
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A Phase 2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR-707) Combined With Other Anticancer Therapies for the Treatment of Participants With Head and Neck Squamous Cell Carcinoma (HNSCC)

Conditions
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Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: Pembrolizumab (Keytruda®)
* Drug: SAR444245 (Thor-707)
* Drug: Cetuximab (Erbitux®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Participants must be ≥ 18 years of age inclusive, at the time of signing the informed consent Histologically or cytologically confirmed diagnosis of R/M HNSCC that is considered not amenable to further therapy with curative intent. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx (nasopharynx is excluded). Measurable disease. Baseline biopsy must be submitted for all cohort A1 Core Phase participants. Baseline biopsy must be submitted for all cohort B1, B2 Expansion Phase participants. Known HPV p16 status for oropharyngeal cancer. Participant agrees to follow protocol-specified contraception guidelines. Exclusion Criteria: -Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 Has received prior IL2-based anticancer treatment. -For participants in Cohort A1: Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1 pathway (participants who joined a study with an anti-PD-1/PD-L1 in the experimental arm but have written confirmation they have not received anti-PD-1/PD-L1 are allowed). For participants in Cohort B2: Prior treatment with cetuximab (prior cetuximab allowed if used for the treatment of locally advanced disease, with no progressive disease for at least 4 months from completion of prior cetuximab therapy). For participants in Cohort B2: Electrolytes (magnesium, calcium, potassium) outside the normal ranges. Participants under anti-hypertensive treatment who cannot temporarily (for at least 36 hours) withhold antihypertensive medications prior to each IMP dosing. Participants with baseline SpO2 ≤92% (without oxygen therapy). Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 2 weeks of IMP initiation. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder. Participants who require a brief course of steroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded.

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 A1 (sub study 01) treatment- naïve<br>Participants with HNSCC, who are treatment-naïve for R/M disease and have a PD-L1 Combined Positive Score (CPS) ≥1, will receive pembrolizumab followed by SAR444245. Both drugs administered by intravenous (IV) infusion on Day 1 of each 21-day treatment cycle for up to 35 cycles. | Drug: Pembrolizumab (Keytruda®)<br>* Pharmaceutical Form: Concentration for solution for infusion Route of Administration: Intravenous Infusion<br>Drug: SAR444245 (Thor-707)<br>* Pharmaceutical Form: Concentrate for solution for infusion Route of Administration: Intravenous Infusion<br>|
| Experimental: Cohort B1: (sub study 04) PD1/PD-L1 and platinum-based treatments<br>Participants with HNSCC who have received treatment with a PD1/PD-L1-based regimen & platinum-based regimen and have failed no more than 2 regimens for R/M disease, will receive pembrolizumab followed by SAR444244. Both drugs administered IV infusion on Day 1 of each 21-day treatment cycle for up to 35 cycles | Drug: Pembrolizumab (Keytruda®)<br>* Pharmaceutical Form: Concentration for solution for infusion Route of Administration: Intravenous Infusion<br>Drug: SAR444245 (Thor-707)<br>* Pharmaceutical Form: Concentrate for solution for infusion Route of Administration: Intravenous Infusion<br>|
| Experimental: Cohort B2: (sub study 05) cetuximab- naïve<br>Participants with R/M HNSCC, who are cetuximab-naïve, have received treatment with a platinum-based regimen, and have failed no more than 2 regimens for R/M disease, will receive treatment with cetuximab followed by SAR444245. Cetuximab IV will be given on days 1, 8, and 15 of each 21 day. SAR444245 will be administered by IV infusion on Day 1 of each 21-day treatment cycle. Dosing of both drugs is to continue until disease progression, unacceptable toxicity, or withdrawal of consent. | Drug: SAR444245 (Thor-707)<br>* Pharmaceutical Form: Concentrate for solution for infusion Route of Administration: Intravenous Infusion<br>Drug: Cetuximab (Erbitux®)<br>* Pharmaceutical Form: Solution for infusion Route of Administration: Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Objective response rate (ORR) defined as 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 approximately 9 months after the last participant receive first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety profile of SAR444245 when combined with other anti-cancer therapies (TEAEs) | Incidence of treatment-emergent adverse events (TEAEs) 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 grading | From first IMP dose up to 30 days after the last dose of IMP | 
| To assess the safety profile of SAR444245 when combined with other anti-cancer therapies (SAEs) | 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 grading | From first IMP dose up to 90 days after the last dose of IMP | 
| Time to response | Defined as the time from the first administration of investigational medicinal product (IMP) to the first tumor assessment at which the overall response was recorded as PR or CR that is subsequently confirmed and determined by investigator per RECIST 1.1. | 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) | Defined as the time from first tumor assessment at which the overall response was recorded as PR or CR that is subsequently confirmed until documented progressive disease (PD) determined by investigator per RECIST 1.1 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) | Including confirmed Complete Response (CR) or Partial Response (PR) at any time or stable disease (SD) of at least 6 months (determined by investigator per RECIST 1.1) | Baseline to the date of first documented progression or initiation of subsequent anticancer therapy or approximately 9 months after the last participant receive first dose | 
| Progression free survival (PFS) | Defined as the time from the date of first IMP administration to the date of first documented disease progression determine by Investigator as per RECIST 1.1, 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 | 
| To assess the concentrations of SAR444245 | Plasma concentrations of 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), maximum is up to approximately 24 months | 
| To assess the immunogenicity of SAR444245 | 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 |