A First-in-human, Dose Escalation and Dose Expansion Study of SAR445877 in Adult Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1/2, open label, multiple cohort study to assess the safety and preliminary efficacy of SAR445877 as a monotherapy for participants aged at least 18 years with advanced unresectable or metastatic malignancies. The study will include 2 parts: A dose escalation Part 1: for finding the recommended dose(s) of SAR445877 in a monotherapy given every 2 weeks (Q2W) or weekly (QW). A multicohort dose expansion Part 2: for the assessment of safety and preliminary efficacy of SAR445877 in monotherapy (2 dose levels will be tested in at least 1 indication as applicable). Approximately 240 participants will be enrolled to the study intervention: For Part 1: approximately 75 participants, For Part 2: up to 30 participants will be enrolled in each cohort per dose level for a total of approximately 165.

Detailed Description
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The duration of the study for a participant will include: Screening Period: up to 28 days Treatment Period: enrolled and exposed participants will receive continuous treatment until progressive disease (PD), or an occurrence of an unacceptable AE, a withdrawal of consent, or until other permanent discontinuation criteria described in the protocol are met. The End of Treatment (EOT) visit will occur 30 days ±7 days from the last IMP administration or prior to the initiation of further therapy, whichever occurs first. The follow-up period will occur until disease progression, the start of new anticancer therapy, death, or withdrawal of participant's consent, whichever comes first.

Official Title
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A Phase 1/2, Open Label, First-in-human, Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics, and Anti-tumor Activity of SAR445877 Administered as Monotherapy in Adults With Advanced Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: SAR445877


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose escalation Part 1 Participants with advanced unresectable or metastatic solid tumors for which, in the judgement of the investigator, no standard alternative therapy is available or is not in the best interest of the participant Dose expansion Part 2 Cancer diagnosis: Participants in Cohort A: Histologically or cytologically confirmed diagnosis of metastatic non-small cell lung cancer (NSCLC) Participants in Cohort B: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic hepatocellular carcinoma (HCC), or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients (patients without cirrhosis must have had histological confirmation of diagnosis). Participants in Cohort C: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic gastric cancer (GC) or Siewert Type 2 & 3 gastro esophageal junction (GEJ) adenocarcinoma. For participants in Cohort C: Disease with CPS scoring of <1 as determined at local laboratory with an Agency approved test (for the other cohorts: Disease with any CPS scoring. No need for CPS determination at local laboratory). For participants in Cohort C: Participants must have MSI (metastatic microsatellite instability) or MMR (mismatch repair) status known or determined locally and must have non-MSI-H or proficient MMR (pMMR) disease to be eligible. For participants in Cohort C: Participants with unknown HER2/neu status must have their HER2/neu status determined locally. Participants with HER2/neu negative are eligible. Participants with HER2/neu positive tumors must have documentation of disease progression on treatment containing an approved HER2 targeted therapy to be eligible. Measurable Disease: At least 1 measurable lesion per RECIST 1.1 criteria Capable of giving signed informed consent. Exclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. Predicted life expectancy ≤3 months. For participants with HCC- Cohort B (Part 2): Child Pugh Class B or C liver score. Participants with Child Pugh Class B-7 score are allowed for Part 1. Diagnosed of any other malignancies, either progressing or requiring active treatments, within 2 years prior to enrollment. Known active brain metastases or leptomeningeal metastases. History of treatment-related immune-mediated (or immune-related) AEs from immune-modulatory agents (including but not limited to anti-PD1/PD-L1 agents and anti-cytotoxic T lymphocyte associated protein 4 monoclonal antibodies) that caused permanent discontinuation of the agent, or that were Grade 4 in severity or have not resolved to Grade ≤1. Has any condition requiring ongoing/continuous corticosteroid therapy (>10 mg prednisone/day or an anti-inflammatory equivalent) within 1 week prior to the first dose of the study medicine. Any clinically significant cardiac (including valvular) or vascular (thromboembolic disorders) disease, within 6 months prior to the first IMP administration. Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events. Has a known history or any evidence of interstitial lung disease or active, non-infectious pneumonitis within 3 years prior to the first dose of the study drug. Organ transplant requiring immunosuppressive treatment. Uncontrolled or active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, or has a diagnosis of immunodeficiency. NOTE: Other Inclusion/Exclusion criteria may apply. The above information is not intended to contain all considerations relevant to a 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR445877 Escalation Phase (Part 1)<br>SAR445877 monotherapy will be administered intravenously in patients with solid tumors over a 14-day cycle. | Drug: SAR445877<br>* Concentrate for solution for infusion<br>|
| Experimental: SAR445877 Expansion Phase: Cohort A (Part 2)<br>SAR445877 monotherapy will be administered intravenously (IV) in patients with non-small cell lung cancer (NSCLC). | Drug: SAR445877<br>* Concentrate for solution for infusion<br>|
| Experimental: SAR445877 Expansion Phase: Cohort B (Part 2)<br>SAR445877 monotherapy will be administered intravenously in patients with hepatocellular carcinoma (HCC). | Drug: SAR445877<br>* Concentrate for solution for infusion<br>|
| Experimental: SAR445877 Expansion Phase: Cohort C (Part 2)<br>Participants will receive SAR445877 monotherapy will be administered IV in patients with gastric cancer/gastro esophageal junction adenocarcinoma (GC/GEJ). | Drug: SAR445877<br>* Concentrate for solution for infusion<br>|
| Experimental: SAR445877 Expansion Phase: Cohort D (Part 2)<br>Participants will receive SAR445877 monotherapy will be administered IV in patients with immune infiltrated tumor type. | Drug: SAR445877<br>* Concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation: Presence of dose-limiting toxicities (DLTs) in Cycles 1 and 2 | DLTs will be defined using NCI CTCAE version 5.0 or ASTCT criteria for CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) | Cycles 1 & 2 - 14 day per cycle | 
| Dose escalation: Percentage of participants experiencing treatment-emergent adverse events (TEAEs) | Presence of TEAEs, SAEs, and lab abnormalities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading | The time from the first dose of study interventions up to 30 days after last dose of study interventions | 
| Dose expansion: Objective response rate (ORR) | Proportion of participants who have a confirmed complete response (CR) or a partial response (PR), as the best overall response (BOR) determined by the Investigator as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From baseline to the end of dose expansion (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation Objective response rate (ORR) | Proportion of participants who have a confirmed complete response (CR) or a partial response (PR), as the best overall response (BOR) determined by the Investigator as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From baseline to the end of dose escalation (up to 2 years) | 
| Dose escalation & expansion Duration of response (DoR) | DoR is defined as the time from first documented evidence of confirmed CR or PR until progressive disease (PD) determined by Investigator per RECIST 1.1 or death from any cause, whichever occurs first | From baseline to the end of study (up to 2 years) | 
| Dose escalation & expansion Assessment of SAR445877 Cmax | Maximum plasma concentration observed | Cycle 1 Day 1 to Day 8 or Day 14 (cycle duration of 14 days) | 
| Dose escalation & expansion Assessment of SAR445877 AUC0-T | Area under the concentration versus time curve calculated using the trapezoidal method during a dosing interval (T) | Cycle 1 Day 1 to Day 8 or Day 14 (cycle duration of 14 days) | 
| Dose escalation & expansion Incidence of anti-drug antibodies (ADAs) to SAR445877 | Incidence of patients with anti-drug antibodies (ADAs) to SAR445877 | From the first dose of Cycle 1 to 30 days after last dose of study interventions (cycle duration of 14 days) | 
| Time to response is defined as the time from the first administration of investigational medicinal product (IMP) to the first documented evidence of confirmed PR or CR determined by Investigator per RECIST 1.1 | Time to response is defined as the time from the first administration of investigational medicinal product (IMP) to the first documented evidence of confirmed PR or CR determined by Investigator per RECIST 1.1 | From baseline to end of dose expansion (up to 2 years) | 
| Clinical benefit rate including confirmed CR or PR at any time or stable disease (SD) of at least 6 months determined by Investigator per RECIST 1.1 | Clinical benefit rate including confirmed CR or PR at any time or stable disease (SD) of at least 6 months determined by Investigator per RECIST 1.1 | From baseline to end of dose expansion (up to 2 years) | 
| PFS is defined as the time from the date of first administration of IMP to the date of the first documented disease progression determined by Investigator as per RECIST 1.1 or death from any cause, whichever occurs first | PFS is defined as the time from the date of first administration of IMP to the date of the first documented disease progression determined by Investigator as per RECIST 1.1 or death from any cause, whichever occurs first | From baseline to end of dose expansion (up to 2 years) | 
| Number of participants with Adverse events (AE) | Presence of adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading | The time from the first dose of study interventions up to 30 days after last dose of study interventions. |