A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Gastrointestinal Cancer (Master Protocol) (Pegathor Gastrointestinal 203)

Study Overview
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Brief Summary
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The study is 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 aged 18 years and older with advanced and metastatic gastrointestinal cancer. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies. Sub study 01 - Cohort A aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC). Sub study 02 - Cohort B1, B2 and B3 would focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior PD1/PD-L1-based regimens. Sub study 03 - Cohort C aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in participants with advanced unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens. Sub study 04 - Cohort D1 and D2 aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 antibody cetuximab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic colorectal cancer (mCRC).

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 A; B1,B2, B3, C and D1} = 735 days or until PD {cohort D2}], an end-of-treatment visit at least 30 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 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 Advanced and Metastatic Gastrointestinal Cancer

Conditions
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Oesophageal Squamous Cell Carcinoma, Gastric Cancer, Hepatocellular Carcinoma, Colorectal Cancer, Oseophageal Adenocarcinoma

Intervention / Treatment
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* Drug: THOR-707
* Drug: Pembrolizumab
* Drug: Cetuximab


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: Sub-study01: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic esophageal cancer of the squamous cell carcinoma subtype. Sub-study02: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ. Sub-study03: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic hepatocellular carcinoma (HCC), or clinically by AASLD criteria in cirrhotic patients. Sub-study04: Histologically or cytologically confirmed diagnosis of advanced unresectable or mCRC. Only patients with non-MSI-H disease are eligible. Participants (all sub-studies) must have at least one measurable lesion. Mandatory baseline biopsy for the first 20 participants to enroll in sub-study01, sub-study02 and sub-study04. On-treatment biopsy for at least 20 participants in sub-study04. On-treatment biopsies are otherwise optional per Investigator's discretion for the other cohorts. 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 120 days (for Cohort A, B1, B2, B3, C, and D1) or 60 days (for Cohort D2) [corresponding to the time needed to eliminate any study intervention(s)]. and to refrain from donating or cryopreserving eggs for 120 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 3 days [corresponding to time needed to eliminate SAR444245] after the last dose of SAR444245. Capable of giving signed informed consent. Exclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. Poor organ function. Active brain metastases or leptomeningeal disease. History of allogenic or 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 within 28 days prior to first IMP administration. 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). 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. Participants with baseline SpO2 ≤92% (without oxygen therapy). - Participant has received prior IL2-based anticancer treatment. Participants on sub-study02 cohort B1 and B2 or sub-study 04 - cohort D1 with prior treatment with an agent that blocks the PD-1/PD-L1 pathway. Receipt of a live-virus or live attenuated-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 (Sub-study 01): 2-3L ESCC Post PD-1/PD-L1<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort B1 (Sub-study 02): 1-3L GC/GEJ PD1/PD-L1 naïve non-MSI-H CPS ≥1<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort B2 (Sub-study 02): 1-3L GC/GEJ PD1/PD-L1 naïve non-MSI-H CPS < 1<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort B3 (Sub-study 02): 2-4L GC/GEJ Post PD1/PD-L1 non-MSI-H<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort C (Sub-study 03): 2-3L HCC Post PD-1/PD-L1<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort D1 (Sub-study 04): 3-6L CRC non-MSI-H any RAS<br>SAR444245 and pembrolizumab are 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: Pembrolizumab<br>* Solution for infusion: intravenous infusion<br>* Other names: Keytruda®;|
| Experimental: Cohort D2 (Sub-study 04): 3-6L CRC non-MSI-H RAS wild type<br>SAR444245 is administered every 3 weeks on Day 1 of each cycle (21 days per cycle) and cetuximab is administered on Day 1, Day 8 and Day 15 of each cycle until progressive disease. | Drug: THOR-707<br>* Solution for infusion: intravenous infusion<br>Drug: Cetuximab<br>* Solution for infusion: intravenous infusion<br>* Other names: Erbitux®;|

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 documentation of progression, assessed approximatively up to 9 months after the first dose of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of SAR444245 safety profile when combined with other anti-cancer therapies-Treatment-emergency adverse events (TEAEs) | Incidence 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 1st IMP dose up to 30 days after the last dose of IMP | 
| Assessment of SAR444245 safety profile when combined with other anti-cancer therapies-Serious Adverse Events (SAEs) | Incidence of 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 1st 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. | Baseline to the date of first documentation of progression, assessed approximatively up to 18 months after the last patient-in | 
| Duration of response | Defined as the time from first tumor assessment at which the overall response was recorded as CR or PR that is subsequently confirmed until documented progressive disease (PD) determined by Investigator per RECIST 1.1 or death from any cause, whichever occurs first. | Baseline to the date of first documentation of progression, assessed approximatively up to 18 months after the last patient-in | 
| Clinical benefit rate | 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 documentation of progression, assessed approximatively up to 18 months after the last patient-in | 
| Progression-free survival | 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 | Baseline to the date of first documentation of progression, assessed approximatively up to 18 months after the last patient-in | 
| Concentrations of SAR444245 |  | At Day 1 and Day 2 of Cycle1, at Day 3 and Day 4 of Cycle 1 (only for intensive PK participants), and at Day 1 of Cycle 2-3-4-6-8-10 + every 4th cycle (each cycle is 21 days), maximum up to approximately 24 months | 
| Incidence of anti-drug antibodies (ADAs) against SAR444245 |  | At Day 1 and Day 8 of Cycle1, at Day 1 of Cycle 2-3-4-6-8-10 + every 4th cycle (each cycle is 21 days) and 30 days after last IMP administration, maximum up to approximately 24 months | 
| Ctrough of infusion of cetuximab | Concentration observed just after treatment administration during repeated dosing | Day 1 of Cycle 1-2-3-4-6-8-10 + every 4th cycle (each cycle is 21 days), maximum up to approximately 24 months | 
| Cend of infusion of cetuximab |  | Day 1 of Cycle 1-2-3-4-6-8-10 + every 4th cycle (each cycle is 21 days), maximum up to approximately 24 months |