Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Platinum-based Chemotherapy With or Without Pemetrexed in Patients With NSQ NSCLC (CARMEN-LC05)

Study Overview
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Brief Summary
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Primary Objective: Safety run-in part: to assess the tolerability and to determine the recommended doses of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed to be tested in the expansion part of the study in the NSQ NSCLC population Expansion part (including participants treated at the recommended dose for expansion [RDE] from the Safety Run-in part): to assess the antitumor activity of several dose levels (DLs; if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population Secondary Objectives: To assess the safety and tolerability of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, and platinum-based chemotherapy with pemetrexed in the NSQ NSCLC population To assess the antitumor activity of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population To assess the durability of the response to treatment with several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population To assess the antitumor activity of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy in the NSQ NSCLC population To assess the pharmacokinetics (PK) of tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin, each when given in combination as a doublet (tusamitamab ravtansine + pembrolizumab) or a triplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy) or a quadruplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy + pemetrexed) To assess the immunogenicity of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum based chemotherapy with or without pemetrexed

Detailed Description
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The expected duration of study intervention for participants may vary, based on disease progression date; median expected duration of study per participant is estimated at 10 months (up to 1 month for screening, a median of 6 months for treatment, a median of 1 month for EOT, and follow-up visit 90 days after the last IMP administration).

Official Title
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Open-label, Phase 2 Study of Tusamitamab Ravtansine (SAR408701) Combined With Pembrolizumab and Tusamitamab Ravtansine (SAR408701) Combined With Pembrolizumab and Platinum-based Chemotherapy With or Without Pemetrexed in Patients With CEACAM5 Positive Expression Advanced/Metastatic Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC)

Conditions
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Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC)

Intervention / Treatment
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* Drug: SAR408701 (Tusamitamab ravtansine)
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Histologically- or cytologically-confirmed diagnosis of advanced or metastatic NSQ NSCLC with no EGFR sensitizing mutation or BRAF mutation or ALK/ROS alterations. No prior systemic chemotherapy for the treatment of the participant's advanced or metastatic disease (treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as completed at least 6 months prior to diagnosis of advanced or metastatic disease). Expression of CEACAM5 as demonstrated prospectively by a centrally assessed Immunohistochemistry (IHC) assay of ≥2+ in intensity involving at least 1% of the tumor cell population in archival tumor sample (or if not available fresh biopsy sample). Measurable disease based on RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies Life expectancy of at least 3 months Exclusion criteria: Medical condition requiring concomitant administration of a medication with a strong CYP3A inhibitor. Uncontrolled brain metastases and history of leptomeningeal disease. Significant concomitant illness, including any severe medical condition that, in the opinion of the investigator or Sponsor, would impair the patient's participation in the study or interpretation of the results. History within the last 3 years of an invasive malignancy other than the one treated in this study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment. History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known HIV disease requiring antiretroviral treatment, or active hepatitis A, B, or C infection. History of active autoimmune disease that has required systemic treatment in the past 2 years. History of allogeneic tissue/solid organ transplantation. Active infection requiring IV systemic therapy within 2 weeks prior to randomization or active tuberculosis. Interstitial lung disease or history of pneumonitis that has required oral or IV steroids Non-resolution of any prior treatment-related toxicity to < Grade 2 according to NCI CTCAE V5.0, with the exception of alopecia, vitiligo, or active thyroiditis controlled with hormone replacement therapy. Unresolved corneal disorder or any previous corneal disorder considered by an ophthalmologist to predict higher risk of drug-induced keratopathy. The use of contact lenses is not permitted. Symptomatic herpes zoster within 3 months prior to screening. Significant allergies to humanized monoclonal antibodies. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis). Concurrent treatment with any other anticancer therapy. Have received prior chemotherapy treatment for advanced/metastatic NSCLC. The patient is a candidate for a curative treatment with either surgical resection and/or chemoradiation Washout period before the first administration of study intervention of less than 3 weeks or less than 5 times the half-life, whichever is shorter, for any investigational treatment). Any prior therapy targeting CEACAM5. Any prior treatment with any other anti-PD-1, or PD-L1 or programmed death ligand 2 (PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4. Any prior maytansinoid treatment (DM1 or DM4 ADC). Is receiving systemic steroid therapy ≤3 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication. Daily steroid replacement therapy or any corticosteroid premedication if applicable are allowed. Any radiation therapy to lung >30 Gy within 6 months of first study intervention administration. Has received or will receive a live vaccine within 30 days prior to the first study intervention administration. Any major surgery within the preceding 3 weeks of the first study intervention administration. Prior/concurrent clinical study experience Current participation in any other clinical study involving an investigational study treatment or any other type of medical research. Poor organ function 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tusamitamab ravtasine + Pembrolizumab<br>Pembrolizumab dose will be administered intravenously prior to intravenous administration of tusamitamab ravtansine dose every 3 weeks. | Drug: SAR408701 (Tusamitamab ravtansine)<br>* Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Tusamitamab ravtansine;Drug: Pembrolizumab<br>* Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Keytruda;|
| Experimental: Tusamitamab ravtansine + Pembrolizumab + carboplatin or cisplatin<br>Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Carboplatin will be infused over 15 to 60 minutes immediately after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. | Drug: SAR408701 (Tusamitamab ravtansine)<br>* Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Tusamitamab ravtansine;Drug: Pembrolizumab<br>* Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Keytruda;Drug: Cisplatin<br>* Pharmaceutical form: Lyophilized powder for reconstitution in solution Route of administration: Intravenous<br>Drug: Carboplatin<br>* Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous<br>|
| Experimental: Tusamitamab ravtansine + Pembrolizumab + carboplatin or cisplatin + pemetrexed<br>Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Pemetrexed will be infused over 10 minutes after tusamitamab ravtansine infusion on Day 1 and then Q3W. Carboplatin will be infused over 15 to 60 minutes immediately after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after pemetrexed infusion after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles. | Drug: SAR408701 (Tusamitamab ravtansine)<br>* Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Tusamitamab ravtansine;Drug: Pembrolizumab<br>* Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous<br>* Other names: Keytruda;Drug: Cisplatin<br>* Pharmaceutical form: Lyophilized powder for reconstitution in solution 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: Concentrate for solution for infusion Route of administration: Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug-related dose-limiting toxicity (DLTs) | Study drug-related dose-limiting toxicity (DLTs) at Cycle 1 (C1D1 to C1D21), including but not limited to corneal toxicity. Each cycle is 21 days. | Baseline up to 10 months after last participant treated | 
| Incidence of study drug-related dose-limiting toxicity (DLTs) at Cycle 1 (C1D1 to C1D21) | DLTs observed during the DLT observation period (Cycle 1) will be summarized on the DLT-evaluable population, by part, DL, and overall (if applicable) | Baseline up to 21 days | 
| Expansion part (including participants treated at the recommended dose for expansion [RDE] from the Safety Run-in part): Objective response rate (ORR) | ORR defined as proportion of participants who have a confirmed complete response (CR) or partial response (PR) as best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Baseline up to approximately 4.5 months after last participant first treated | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and laboratory abnormalities | TEAEs, SAEs and laboratory abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V5 - | Baseline up to 10 months after last participant treated | 
| Objective response rate (ORR) of tusamitamab ravtansine + pembrolizumab + platinum based chemotherapy, with or without pemetrexed | ORR is defined as proportion of participants who have a confirmed complete response (CR) or partial response (PR) as per response evaluation criteria in solid tumors (RECIST v1.1) | Baseline up to 10 months after last participant treated | 
| Incidence of anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine | Incidence of anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine | Baseline up to 10.5 months after first IMP administration of the last participant | 
| Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and laboratory abnormalities according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | An overall summary of TEAEs will be provided. The number and percentage of participants experiencing any of the following will be provided: TEAEs, Grade ≥3 TEAEs, Grade 5 TEAEs , Serious TEAEs, TEAEs leading to permanent treatment discontinuation, Treatment-related TEAEs, Treatment-related TEAEs Grade ≥3, Serious treatment-related TEAEs, Adverse events of special interest (AESI), deaths and clinical laboratory values according to CTCAE V5.0 | Baseline up to 30 days after last IMP administration | 
| Progression-free survival (PFS) | PFS is defined as the time from the first investigational medicinal product (IMP) administration to the date of the first documented disease progression or death due to any cause, whichever comes first (not for Part B). | Baseline up to 10.5 months after first IMP administration of the last participant | 
| Disease control rate (DCR) | DCR, defined as the percentage of participants who have achieved confirmed CR, confirmed PR, or stable disease (SD) as best overall response (BOR) per RECIST v1.1 Baseline up to 4.5 months after first IMP administration of the last participant | Baseline up to 4.5 months after first IMP administration of the last participant | 
| Duration of response (DOR) | DOR, defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined per RECIST v1.1 or death from any cause, whichever occurs first | Baseline up to 10.5 months after first IMP administration of the last participant | 
| ORR | ORR, defined as proportion of participants who have a confirmed CR or PR as per BOR per RECIST v1.1 | Baseline up to 4.5 months after first IMP administration of the last participant | 
| Pharmacokinetic concentrations | PK Ctrough at C2D1 for tusamitmab ravtansine (SAR408701, DM4, Me-DM4) and pembrolizumab PK End of infusion at C1D1 for cisplatin and carboplatin PK 30 min at C1D1 for pemetrexed | PK concentrations assessed at multiple timepoints up to C13 for tusamitamab ravtansine, up to cycle 8 for pembrolizumab, up to cycle 1 for cisplatin, carboplatin and pemetrexed |