Study of SAR444881 Administered Alone and in Combination With Other Therapeutics in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The study will enroll advanced cancer patients with unresectable or metastatic disease who are refractory to or are not candidates for standard approved therapy. The study will be comprised of two parts - a dose escalation phase (Part 1) and a dose optimization/expansion phase (Part 2). Part 1 is comprised of three sub-parts: SAR444881 administered alone (Sub-Part 1A), SAR444881 administered in combination with pembrolizumab (Sub-Part 1B), and SAR444881 administered in combination with cetuximab (Sub-Part 1C). Part 2 is composed of two sub-parts: a dose optimization part where up to two doses of SAR444881 per indication are administered in combination with pembrolizumab, cetuximab, and/or carboplatin and pemetrexed (Sub-Part 2A); and a dose expansion part where SAR444881 is administered alone (Sub-Part 2B). In Sub-Part 2A, a two-stage design will be implemented to conduct dose optimization for each indication with combination therapy- Stage 1 (Preliminary Assessment) and Stage 2 (Randomization). Study is non-randomized except Stage 2 of Sub-Part 2A which will use randomization.

Detailed Description
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Estimated Study Duration: Dose Escalation (Part 1): Approximately 34 months Dose Optimization/Expansion (Part 2): Approximately 28 months

Official Title
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A Phase 1/2, Dose Escalation, Dose Expansion, and Dose Optimization Study of the Safety, Tolerability, and Anti-tumor Activity of SAR444881 Administered Alone and in Combination With Pembrolizumab, Cetuximab and/or Chemotherapy in Participants With Advanced Solid Tumors

Conditions
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Cancer, Neoplasm

Intervention / Treatment
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* Drug: SAR444881
* Drug: Pembrolizumab
* Drug: Cetuximab
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with unresectable or metastatic disease who are refractory to or are not candidates for standard approved therapy Histologic confirmation of malignancy Measurable disease per RECIST v1.1 Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 or 1 Participants must have adequate organ function as defined by laboratory tests Part 1: Following tumor types: Breast cancer, cervical cancer, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, hepatobiliary cancers (hepatocellular carcinoma (HCC), gallbladder cancer, cholangiocarcinoma), non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the skin, pancreatic adenocarcinoma, ovarian cancer or urothelial carcinoma Part 2: Following tumor types: Squamous cell carcinoma of the head and neck, Gastric or gastroesophageal junction adenocarcinoma, non-squamous non-small cell lung cancer, non-small cell lung cancer, colorectal carcinoma (CRC) any RAS, and/or Cholangiocarcinoma Exclusion Criteria: Active, known or suspected autoimmune disease Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications Brain or leptomeningeal metastases Known history of positive test for HIV Non-HCC patients: acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV); HCC patients: untreated active HBV or dual infection with HBV/HCV Participants after solid organ or allogeneic hematopoietic stem cell transplant History of life-threatening toxicity related to prior immune therapy History of life-threatening toxicity related to prior cetuximab or other anti-EGFR antibodies (for Sub-Part 1C) Unstable or deteriorating cardiovascular disease within the previous 6 months Any major surgery within 4 weeks of study drug administration Prior/Concomitant Therapy: Cytotoxic/Non-cytotoxic anti-cancer agents, unless at least 4 weeks have elapsed from last dose Use of other investigational drugs within 28 days Prior treatment with macrophage or natural killer (NK) cells activating therapies Administration of a live attenuated vaccine within 28 days The above information is not intended to contain all considerations relevant to the 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: SAR444881 Dose Escalation (Sub-Part 1A)<br>Standard 3 + 3 dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 will be administered intravenously (IV), every 2 weeks (Q2W). | Drug: SAR444881<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>* Other names: BND-22;|
| Experimental: SAR444881 in Combination with Pembrolizumab Dose Escalation (Sub-Part 1B)<br>Standard 3 + 3 dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 and pembrolizumab will be administered intravenously (IV), every 3 weeks (Q3W). | Drug: SAR444881<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>* Other names: BND-22;Drug: Pembrolizumab<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>|
| Experimental: SAR444881 in Combination with Cetuximab Dose Escalation (Sub-Part 1C)<br>Standard 3 + 3 dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 and cetuximab will be administered intravenously (IV), every 2 weeks (Q2W). | Drug: SAR444881<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>* Other names: BND-22;Drug: Cetuximab<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>|
| Experimental: SAR444881 Dose Optimization (Sub-Part 2A)<br>SAR444881 Dose Optimization in combination with pembrolizumab, cetuximab, and/or carboplatin and pemetrexed. The indication for the combination cohorts will be non-squamous non-small cell lung cancer (NSCLC), NSCLC, gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), colorectal carcinoma (CRC) any RAS. Enrollment will start after the recommended dose(s) of SAR444881 have been determined based on data from Sub-Parts 1A, 1B, and 1C. | Drug: SAR444881<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>* Other names: BND-22;Drug: Pembrolizumab<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>Drug: Carboplatin<br>* Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous<br>Drug: Pemetrexed<br>* Pharmaceutical form: Powder for concentrate for solution for infusion or concentrate for solution for infusion; Route of administration: Intravenous<br>|
| Experimental: SAR444881 Dose Expansion (Sub-Part 2B)<br>The indication for this monotherapy cohort will be either relapsed or refractory NSCLC, head and neck squamous cell carcinoma (HNSCC), cholangiocarcinoma, or GC/GEJ. Enrollment will be opened based on emerging data from the dose-escalation phase and combination optimization data. | Drug: SAR444881<br>* Pharmaceutical form: Solution for infusion; Route of administration: Intravenous<br>* Other names: BND-22;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Incidence of treatment-emergent adverse events (TEAEs) dose limiting toxicities (DLT) | Incidence of TEAEs meeting protocol defined DLT criteria | Cycle 1 (28 days) | 
| Part 1: Incidence of treatment-emergent adverse events and serious adverse events |  | Through study completion, an average of 5 months | 
| Part 2: Objective Response Rate (ORR) per RECIST v1.1 | Proportion of participants with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 | Through study completion, an average of 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective Response Rate (ORR) per RECIST v1.1 | Proportion of participants with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 | Through study completion, an average of 3 months | 
| Part 1: Maximum observed plasma concentration [Cmax] |  | Through study completion, an average of 2 months | 
| Part 1: Serum concentration at the end of the dosing interval (Ctrough) |  | Through study completion, an average of 2 months | 
| Part 1: time of maximum observed serum concentration (Tmax) |  | Through study completion, an average of 2 months | 
| Part 1: Terminal elimination half-life [T1/2] |  | Through study completion, an average of 2 months | 
| Part 1: Area under the plasma concentration-time curve [AUC] |  | Through study completion, an average of 2 months | 
| Part 1: Incidence of anti-drug antibodies (ADA) |  | Through study completion, an average of 5 months | 
| Part 2: Progression Free Survival | Time from the date of first dose of study drug to the date of first documented disease progression or death due to any cause, whichever occurs first | Through study completion, an average of 3 months | 
| Part 2: Duration of Response | Duration between first documentation of CR or PR to first documentation of disease progression or death due to any cause, whichever occurs first | Through study completion, an average of 6 months | 
| Part 2: Incidence of treatment-emergent adverse events and Serious Adverse Events |  | Through study completion, an average of 6 months | 
| Part 2: Cmax |  | Through study completion, an average of 3 months | 
| Part 2: Ctrough |  | Through study completion, an average of 3 months | 
| Part 2: Tmax |  | Through study completion, an average of 3 months | 
| Part 2: T1/2 |  | Through study completion, an average of 3 months | 
| Part 2: AUC |  | Through study completion, an average of 3 months | 
| Part 2: Incidence of ADA |  | Through study completion, an average of 6 months |