Safety and Efficacy Study of SAR442720 in Combination With Other Agents in Advanced Malignancies

Study Overview
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Brief Summary
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Primary Objectives: Part 1 To characterize the safety and tolerability of SAR442720 in combination with pembrolizumab in participants with advanced solid tumors. To define the MTD and RP2D for the combination of SAR442720 and pembrolizumab in participants with solid tumors. Part 2 To determine the anti-tumor activity of SAR442720 in combination with pembrolizumab. Part 3A To define the MTD and RP2D for the combination of SAR442720 and adagrasib in participants with KRAS G12C NSCLC To characterize the safety and tolerability of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC Part 3B To determine the anti-tumor activity of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC Part 4 To evaluate the impact of food on the PK of SAR442720 when dosed with pembrolizumab. To evaluate the impact of the formulations (formulation 1 and formulation 2) on the PK of SAR442720 when dosed with pembrolizumab. Secondary Objectives: Part 1 To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720. To estimate the anti-tumor effects of SAR442720 with pembrolizumab. Part 2 To assess the safety profile of SAR442720 combined with pembrolizumab. To assess other indicators of anti-tumor activity. To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720. Part 3A To characterize the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720. To estimate the anti-tumor effects of SAR442720 with adagrasib Part 3B To assess the safety profile of SAR442720 with adagrasib in participants with KRAS G12C NSCLC. To assess other indicators of anti-tumor activity. To assess the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720. Part 4 To assess the safety and tolerability of SAR442720 formulations with pembrolizumab To estimate the anti-tumor effects of SAR442720 with pembrolizumab.

Detailed Description
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This open label Phase 1 multicenter study is designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of SAR442720 in combination with pembrolizumab in participants with solid tumors in Part 1. In Part 2, in the expansion cohort (Cohort A) we will assess the antitumor activity and safety of SAR442720 combined with pembrolizumab in participants with metastatic 1L lung cancer. In Part 3, we will evaluate the safety, MTD, RP2D and antitumor activity of SAR442720 in combination with adagrasib in participants with lung cancer and KRAS G12C mutation. In Part 4, we will evaluate the impact of the formulations (formulation 1 and formulation 2) and of the food on the PK of SAR442720 when dosed in combination with pembrolizumab. The expected duration of study intervention for participants may vary, based on progression date; median expected duration of study per participant is estimated to be about 10 months in Part 1, Part 3 and Part 4 (up to 1 month for screening, a median of 6 months for treatment, and a median of 3 months for long term follow-up) and in Part 2 16 months (up to 1 month for screening, a median of 12 months for treatment and a median of 3 months for long term follow up.)

Official Title
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A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of SAR442720 in Combination With Other Agents in Participants With Advanced Malignancies

Conditions
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Metastatic Neoplasm

Intervention / Treatment
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* Drug: SAR442720
* Drug: Pembrolizumab
* Drug: Adagrasib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be ≥ 18 years of age. Histologically proven diagnosis of advanced solid tumors. Participants must have one or more of the following molecular aberrations (Part 1): KRAS mutations and amplifications, BRAF Class 3 mutations, or NF1 LOF mutations. Participants must have following molecular aberration (Part 3A and 3B): - KRAS G12C mutation. At least 1 measurable disease per RECIST 1.1 criteria. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Woman of childbearing potential must agree to follow contraceptive guidance. Capable of giving signed informed consent. Exclusion Criteria: Predicted life expectancy <3 months. Primary central nervous system (CNS) tumors. Symptomatic or impending cord compression. Stable CNS disease is allowed. History of cerebrovascular stroke or transient ischemic attack within previous 6 months. Prior solid organ or hematologic transplant. History or current retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vascular occlusion (RVO), neovascular macular degeneration. Any clinically significant cardiac disease. Active, known or suspected autoimmune disease. History of or current interstitial lung disease or pneumonitis. Receipt of a live-virus vaccination within 28 days, viral vaccine that do not contain live virus within 7 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Known infection with human immunodeficiency virus (HIV), known uncontrolled hepatitis B infection, active tuberculosis, or severe infection requiring parenteral antibiotic treatment. Inadequate hematologic, hepatic and renal function. Known second malignancy. Impairment of gastrointestinal function. Any unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol. History of severe allergic reaction to any of the study intervention components. 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR442720 + Pembrolizumab<br>Part 1: SAR442720 (also known as RMC-4630) will be administered orally twice a week (BIW) followed by pembrolizumab which is given intravenously (IV) once every 3 weeks (Q3W). The dose of SAR442720 will be escalated or de-escalated depending on the emerging safety data of the combination. | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Pembrolizumab<br>* Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion<br>|
| Experimental: SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score > 50%<br>Part 2: SAR442720 dose will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W) | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Pembrolizumab<br>* Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion<br>|
| Experimental: SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score 1-49%<br>Part 2: SAR442720 dose will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W) | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Pembrolizumab<br>* Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion<br>|
| Experimental: SAR444270 + adagrasib: Dose Escalation<br>Part 3A; SAR442720 and adagrasib will be administered orally on a continuous basis. | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Adagrasib<br>* Pharmaceutical form:Sterile Tablet Route of administration: Oral<br>|
| Experimental: SAR444270 + adagrasib: Dose Expansion<br>Part 3B: Once SAR442720 dose is confirmed in Part 3A SAR442720 and adagrasib will be administered orally on a continuous basis. | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Adagrasib<br>* Pharmaceutical form:Sterile Tablet Route of administration: Oral<br>|
| Experimental: SAR442720 + Pembrolizumab continuous<br>Part 4: SAR442720 will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W) | Drug: SAR442720<br>* Pharmaceutical form: Varies Route of administration: Varies<br>Drug: Pembrolizumab<br>* Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) SAR442720 and pembrolizumab | Part 1: Incidence, nature, and severity of treatment emergent AEs and serious adverse events (SAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 for the combination of SAR442720 and pembrolizumab. | 21 days | 
| Incidence of study-drug related Dose Limiting Toxicities (DLTs) | Part 1 and 3A: Incidence of study drug-related dose-limiting toxicities (DLTs) in Cycle 1. | up to 2 years | 
| Objective Response Rate (ORR) | Part 2 and 3B: Objective response rate defined as the proportion of participants who have a confirmed CR or partial response (PR) determined by investigator, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | up to 2 years | 
| Incidence of Adverse Events (AEs) SAR442720 and adagrasib | Part 3A: Incidence, nature, and severity of TEAEs and SAEs, graded according to NCI CTCAEv5.0 for the combination of SAR442720 and adagrasib. | up to 2 years | 
| Part 4: Plasma concentrations of SAR442720 in combination with pembrolizumab under impact of food |  | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Plasma concentrations of SAR442720 |  | up to 2 years | 
| Part 1 and 2: Serum concentration of pembrolizumab |  | up to 2 years | 
| Objective response rate (ORR) Part 1 and Part 4 | Part 1 and Part 4: Objective response rate of SAR442720 and pembrolizumab in all participants. ORR of combination therapy with SAR442720 and pembrolizumab will be based on Response Evaluation Criteria in Solid Tumors (RECIST) v1. | up to 2 years | 
| Duration of response (DoR) | Part 1 and Part 2 and 3B: Duration of response per RECIST v1.1 is defined as the interval from the first documentation of CR (complete response) or PR (partial response) to the earlier of the first documentation of definitive disease progression or death due to any cause, whichever occurs first. | up to 2 years | 
| Incidence of Adverse Events | Part 2 and 3B and Part 4: Incidence, nature, and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) graded according to the NCI CTCAE v5 for the combination of SAR442720 and pembrolizumab. | up to 2 years | 
| Time to Response (TTR) | Part 2 and 3B: Time to response (TTR) defined as the time from the first administration of investigational medicinal product (IMP) to the first documented evidence of PR or CR determined by the Investigator per RECIST v1.1 (for NSCLC). | up to 2 years | 
| Clinical Benefit Rate (CBR) | Part 2 and 3B: Clinical benefit rate (CBR) including confirmed CR or PR at any time or stable disease (SD) of at least 6 months (determined by the Investigator per RECIST v1.1. | up to 2 years | 
| Disease Control Rate (DCR) | Part 2 and 3B: Disease control rate (DCR) including confirmed CR or PR or stable disease (SD) as determined by the Investigator per RECIST v1.1. | up to 2 years | 
| Progression free survival (PFS) | Part 2 and 3B: 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 the Investigator as per RECIST v1.1 or death due to any cause, whichever occurs first. | up to 2 years | 
| Part 3A: Plasma concentrations of SAR442720 |  | up to 2 years | 
| Part 3A: Plasma concentrations of adagrasib |  | up to 2 years | 
| Objective Response Rate (ORR) of SAR442720 and adagrasib | Part 3A: ORR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1. | up to 2 years | 
| Duration of Response (DOR) of SAR442720 and adagrasib | Part 3: DOR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1. | up to 2 years | 
| Part 3B: Plasma concentrations of SAR442720 and adagrasib |  | up to 2 years |