Evaluation of SAR408701 in Japanese Patients With Advanced Malignant Solid Tumors

Study Overview
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Brief Summary
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Primary Objective: To evaluate tolerability and safety of SAR408701 when administered as a single agent according to the investigational medicinal product (IMP) related dose limiting toxicities (DLTs) to determine the recommended dose (RD) of SAR408701 in Japanese patients with advanced malignant solid tumors. Secondary Objectives: To characterize the overall safety profile of SAR408701 monotherapy. To characterize the pharmacokinetic (PK) profile of SAR408701 and its metabolites. To evaluate the pharmacodynamic (PDy) effect of SAR408701 on levels of circulating carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for main dose escalation part. To assess preliminary efficacy according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria and other indicators of antitumor activity. To assess the potential immunogenicity of SAR408701.

Detailed Description
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The study duration per participant will include a period to assess eligibility (screening period) of up to approximately 4 weeks (28 days), a treatment period and an End-of-Treatment (EOT) visit around 30 days after the last administration of IMP, and at least one follow-up (FU) visit after the EOT visit.

Official Title
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A Phase I Study to Evaluate Safety and Pharmacokinetics of SAR408701 Administered Intravenously as Monotherapy in Japanese Patients With Advanced Malignant Solid Tumors

Conditions
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Neoplasm Malignant

Intervention / Treatment
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* Drug: SAR408701
* Drug: dexamethasone
* Drug: naphazoline
* Drug: diphenhydramine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Locally advanced or metastatic solid malignant tumor disease for which, in the judgement of the investigator, no standard alternative therapy is available. Inclusion is likely to be expressing CEACAM5. At least 6 x 5 μm slides from formalin-fixed paraffin-embedded (FFPE) archival tissue should be available for retrospective central evaluation of CEACAM5 expression. Patient understands and has signed the Written Informed Consent form and is willing and able to comply with the requirements of the trial. Exclusion criteria: Patient less than 20 years old. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2. Life expectancy <12 weeks. Known or symptomatic brain metastasis (other than totally resected or previously irradiated and non-progressive/relapsing) or lepto-meningeal carcinomatosis. Female patients of childbearing potential and male patients with female partners of childbearing potential who do not agree to use accepted and effective method of contraception during the study treatment period and for 6 months following discontinuation of IMP. Significant concomitant illnesses, including all severe medical conditions which, in the opinion of the Investigator or Sponsor, would impair the patient's participation in the study or interpretation of the results. Prior therapy targeting CEACAM5. Prior maytansinoid treatments (maytansinoid derivative 1 [DM1] or maytansinoid derivative 4 [DM4] antibody drug conjugates). Previous history and or unresolved corneal disorders. Medical conditions requiring concomitant administration of medications with narrow therapeutic window, metabolized by cytochrome P450 (CYP) and for which a dose reduction cannot be considered. Medical conditions requiring concomitant administration of strong CYP3A inhibitor, unless it can be discontinued at least 2 weeks before first administration of SAR408701. 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: 20 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR408701 Monotherapy<br>SAR408701 Dose escalation administered as a single agent intravenously, on Day 1 and once every two weeks, to patients with malignant solid tumors | Drug: SAR408701<br>* Pharmaceutical form: solution for infusion Route of administration: intravenous<br>* Other names: Tusamitamab ravtansine;Drug: dexamethasone<br>* Pharmaceutical form: solution for eye drop Route of administration: eye drop<br>* Other names: Santeson ophthalmic solution;Drug: naphazoline<br>* Pharmaceutical form: solution for eye drop Route of administration: eye drop<br>* Other names: Clearine;Drug: diphenhydramine<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Restamin Kowa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IMP-related dose limiting toxicities (DLT) | IMP-related DLTs are defined as adverse events (AE) related to the IMPs in absence of clear evidence to the contrary, after validation by the Study Committee, and if not related to a disease progression, graded using National Cancer Institute common Toxicity Criteria (NCI-CTC) scale v4.03 | 4 weeks, Dose escalation q3w part: 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent adverse events | Overall safety profile characterized in terms of the type, frequency, severity, seriousness, and relationship to study therapy of any AEs based on standard and systematic assessment including physical findings, laboratory tests or other investigations | Up to an average of 9 months | 
| Maximum observed concentration (Cmax) of SAR408701 | Cmax for SAR408701 will be assessed after single and repeat doses, as relevant | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| Cmax of DM4 and Me-DM4 | Cmax for DM4 and Me-DM4 will be assessed after single and repeat doses, as relevant | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| Time to reach maximum concentration (Tmax) of SAR408701 | Tmax for SAR408701 will be assessed after single and repeat doses, as relevant | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| Tmax of DM4 and Me-DM4 | Tmax for DM4 and Me-DM4 will be assessed after single and repeat doses, as relevant | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| Area under the concentration-time curve (AUC) of SAR408701 | AUC of SAR408701 from time zero extrapolated to infinity | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| AUC of DM4 and Me-DM4 | AUC of DM4 and Me-DM4 from time zero extrapolated to infinity | Main dose-escalation part: Cycle 1 and Cycle 4 (each cycle is 14 days); Dose-escalation bis part with loading dose: Cycle 1 (Cycle 1 is 14 days), Dose-escalation q3w part: Cycle 1 and Cycle2 day 1 (Cycle 1 is 21 days) | 
| Assessment of PDy effect | Assessment of plasma CEACAM5 levels in main dose-escalation part | Up to an average of 10 months | 
| Assessment of anti-tumor activity | Assessment of tumor response using standard imaging, as defined by RECIST 1.1 criteria | Up to an average of 10 months | 
| Detection of anti-SAR408701 antibody | Immunogenicity evaluation for anti-SAR408701 antibodies | Up to an average of 10 months |