Dose Escalation and Expansion Study of SAR443216 in Participants With Relapsed/Refractory HER2 Expressing Solid Tumors

Study Overview
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Brief Summary
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Primary Objectives: Part 1 (Dose Escalation) To determine the MTD/maximum administered dose (MAD) of SAR443216 administered as a single agent in participants with HER2 expressing solid tumors and determine the RD(s) for intravenous (IV) and subcutaneous (SC) administration in the dose escalation part. To determine the safety of SAR443216 after intravenous (IV) and subcutaneous (SC) administration. Part 2 (Dose expansion) • To assess preliminary clinical activity of single agent SAR443216 at the RD(s) in participants with HER2 expressing solid tumors, with various levels of HER2 expression. Secondary Objectives: Part 1 • To assess preliminary clinical activity of single agent SAR443216 after IV and SC administration at the RD(s) in participants with HER2 expressing solid tumors, with various levels of HER2 expression. Part 2 • To determine the safety of SAR443216. Part 1 and 2 To characterize the pharmacokinetic (PK) profile of SAR443216 when administered as a single agent after IV and SC (Part 1 only) administration. To evaluate the immunogenicity of SAR443216 after IV and SC administration. To assess preliminary clinical activity of single agent SAR443216 at the RD(s) in participants with HER2 expressing solid tumors, with various levels of HER2 expression.

Detailed Description
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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: 7.5 months (up to 1 month for screening, a median of 3.5 months for treatment, and a median of 3 months for long term follow-up) in escalation. 9.5 months (up to 1 month for screening, a median of 5.5 months for treatment, and a median of 3 months for long term follow-up) in expansion.

Official Title
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A Phase 1/1b Open-label, First-in-human, Single Agent, Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics, and Anti-tumor Activity of SAR443216 in Participants With Relapsed/Refractory HER2 Expressing Solid Tumors.

Conditions
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Neoplasm Malignant, Breast Cancer, Lung Neoplasm Malignant, Gastric Cancer, Neoplasm

Intervention / Treatment
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* Drug: SAR443216 IV
* Drug: SAR443216 SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be ≥ 18 years of age Histologically or cytologically confirmed diagnosis of metastatic solid tumors Eastern Cooperative Oncology Group (ECOG) performance status 0-1 All participants should have at least 1 measurable disease per RECIST v1.1. An irradiated lesion can be considered measurable only if progression has been demonstrated on the irradiated lesion. Body weight within [45 - 150 kg] (inclusive) All Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Capable of giving signed informed consent Exclusion Criteria: Any clinically significant cardiac disease History of or current interstitial lung disease or pneumonitis Uncontrolled or unresolved acute renal failure Prior solid organ or hematologic transplant. Known positivity with human immunodeficiency virus (HIV), known active hepatitis A, B, and C, or uncontrolled chronic or ongoing infectious requiring parenteral treatment. Receipt of a live-virus vaccination within 28 days of planned treatment start Participation in a concurrent clinical study in the treatment period. Inadequate hematologic, hepatic and renal function Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions. 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: SAR443216-Dose Escalation<br>Participants with metastatic solid tumors that express HER2 in tumor tissue and/or with HER2 aberration will receive SAR443216 as intravenous (IV) infusion or subcutaneous (SC) injection. | Drug: SAR443216 IV<br>* Pharmaceutical form: Powder for solution; Route of administration: IV infusion<br>Drug: SAR443216 SC<br>* Pharmaceutical form: Powder for solution; Route of administration: SC injection<br>|
| Experimental: SAR443216-Dose Expansion - metastatic breast cancers with HER2 high expression: Cohort A<br>Participants with metastatic breast cancers with HER2 high expression (with amplification) will receive SAR443216 as intravenous (IV) infusion. | Drug: SAR443216 IV<br>* Pharmaceutical form: Powder for solution; Route of administration: IV infusion<br>|
| Experimental: SAR443216-Dose Expansion- metastatic breast cancers with HER2 low expression: Cohort B<br>Participants with metastatic breast cancers with HER2 low expression or HER2 mutation (without amplification) will receive SAR443216 as intravenous (IV) infusion. | Drug: SAR443216 IV<br>* Pharmaceutical form: Powder for solution; Route of administration: IV infusion<br>|
| Experimental: SAR443216-Dose Expansion- metastatic gastric cancers with HER2 low expression: Cohort C<br>Participants with metastatic gastric cancers with HER2 low expression or HER2 mutation (without amplification) will receive SAR443216 as intravenous (IV) infusion. | Drug: SAR443216 IV<br>* Pharmaceutical form: Powder for solution; Route of administration: IV infusion<br>|
| Experimental: SAR443216-Dose Expansion - metastatic NSCLC with HER2 low or high expression: Cohort D<br>Participants with metastatic NSCLC with HER2 low or high expression and/or HER2 mutation will receive SAR443216 as intravenous (IV) infusion. | Drug: SAR443216 IV<br>* Pharmaceutical form: Powder for solution; Route of administration: IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Dose Escalation Determine the MTD/maximum administered dose (MAD) and RD(s) of SAR443216 | Incidence of study dose limiting toxicities (DLTs) | Cycle 1, cycle duration is 28 days for 2-week lead-in schedule and 35 days for 3-week lead-in schedule | 
| Part 1: Dose Escalation: Safety of SAR443216 | Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and lab abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. | Baseline until end of study, up to approximately 7.5 months | 
| Part 2: Dose Expansion Objective response rate (ORR) of SAR443216 in all participants | Objective response rate is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) per RECIST v1.1. | From date of enrollment until the end of treatment, up to approximately 5.5 months | 
| Part 2: Dose Expansion Duration of response (DoR) of SAR443216 in all participants. | Duration of response per RECIST v1.1 is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death due to any cause, whichever occurs first. | From date of enrollment until the end of treatment, up to approximately 5.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective response rate (ORR) of SAR443216 in all participants | Objective response rate is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) per RECIST v1.1. | From date of enrollment until the end of treatment, up to approximately 3.5 months | 
| Part 1: Duration of response (DoR) of SAR443216 in all participants | Duration of response per RECIST v1.1 is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death due to any cause, whichever occurs first | From date of enrollment until the end of treatment, up to approximately 3.5 months | 
| Part 1 and Part 2: Progression Free Survival (PFS) | Progression free survival (PFS) will be assessed by the Investigator per RECIST v1.1 and will be summarized using the Kaplan-Meier method | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part1 and 5.5 months for Part 2 | 
| Part 2: Safety of SAR443216 | Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and lab abnormalities according to NCI CTCAE Version 5.0 | Baseline until the end of the study, up to approximately 9.5 months | 
| Part 1 and Part 2: Pharmacokinetic Parameter: Cmax of SAR443216 | Maximum observed plasma concentration | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part 1 and 5.5 months for Part 2 | 
| Part 1 and Part 2: Pharmacokinetic Parameter: Ctrough of SAR443216 | Plasma concentration observed just before treatment administration during repeated dosing | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part 1 and 5.5 months for Part 2 | 
| Part 1 and Part 2: Pharmacokinetic Parameter: t 1/2 of SAR443216 | Terminal half-life associated with the terminal slope (λz) | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part 1 and 5.5 months for Part 2 | 
| Part 1 and Part 2: Pharmacokinetic Parameter: AUC0-τ of SAR443216 | Area under the plasma concentration versus time curve | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part 1 and 5.5 months for Part 2 | 
| Part 1 and Part 2: Evaluation of SAR443216 immunogenicity | Incidence of ADA induction and ADA persistence | From date of enrollment until the end of treatment, up to approximately 3.5 months for Part 1 and 5.5 months for Part 2 |