Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Pretreated Patients With NSQ NSCLC (CARMEN-LC04)

Study Overview
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Brief Summary
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Primary Objectives: Doublet Cohort Part 1 (safety run-in): To assess the tolerability and to confirm the recommended dose of tusamitamab ravtansine in combination with ramucirumab in the NSQ NSCLC population. Part 2: To assess the antitumor activity of tusamitamab ravtansine in combination with ramucirumab in the NSQ NSCLC population. Triplet cohort To assess the tolerability and to confirm the recommended dose of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab in the NSQ NSCLC population. Secondary Objectives: Doublet Cohort To assess the safety and tolerability of tusamitamab ravtansine in combination with ramucirumab. To assess the durability of the response to treatment with tusamitamab ravtansine in combination with ramucirumab. To assess anti-tumor activity of tusamitamab ravtansine in combination with ramucirumab on progression free survival (PFS) and disease control rate (DCR). To assess the pharmacokinetic (PK) profiles of tusamitamab ravtansine (SAR408701) and ramucirumab when given in combination. To assess the immunogenicity of tusamitamab ravtansine (SAR408701) when given in combination with ramucirumab. Triplet cohort To assess the safety and tolerability of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab To assess the antitumor activity of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab in the NSQ NSCLC population. To assess the immunogenicity of tusamitamab ravtansine when given in combination with ramucirumab and pembrolizumab

Detailed Description
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The expected duration of the study intervention for participants may vary, based on progression date ; median expected duration of study per participant is estimated 11 months (up to 1 month for screening, a median of 6 months for treatment, and a median of 4 months for end-of-treatment assessments and safety follow-up visit)

Official Title
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Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

Conditions
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Non-small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Drug: SAR408701
* Drug: ramucirumab
* Drug: pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Metastatic disease progression fulfilling both of the following 2 criteria: Having progressive disease during or after platinum-based chemotherapy (at least 2 cycles). Maintenance therapy following platinum-based chemotherapy is not considered as a separate regimen. Adjuvant/neoadjuvant treatment for a patient who had a relapse with metastatic disease during or within 6 months of completing treatment will be considered as first-line treatment. AND Having progressive disease during or after 1 immune checkpoint inhibitor (anti-PD1/PD-L1); this could be given as monotherapy or in combination with platinum-based chemotherapy (whatever the order). Participants with carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 expression of ≥2+ in archival tumor sample (or if not available, fresh biopsy sample) involving at least 50 % of the tumor cell population as demonstrated prospectively by central laboratory via immune histochemistry (IHC). At least one measurable lesion by RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. A female participant who agrees to use effective contraceptive methods during and for at least 7 months after the last dose of study intervention. A male participant who agrees to use effective contraception methods during and for at least 4 months after the last dose of study intervention Signed informed consent Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: Patients with untreated brain metastases and history of leptomeningeal disease. Significant concomitant illnesses that 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. Non-resolution of any prior treatment related toxicity to < grade 2 according to NCI CTCAE V5.0, except for alopecia, vitiligo and active thyroiditis controlled with hormonal replacement therapy History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known HIV disease requiring antiretroviral treatment, or unresolved viral hepatitis Previous history of and/or unresolved corneal disorders. The use of contact lenses is not permitted. Radiographic evidence of major airway or blood vessel invasion or intratumor cavitation History of uncontrolled hereditary or acquired arterial thrombotic disorder or history of aneurism. Major surgery within 28 days prior to Day 1/first IMP infusion,. Postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months. History of gross hemoptysis within 2 months before the first administration of study intervention. Clinically relevant congestive heart failure (CHF; NYHA II-IV, or LVEF less than 50%) or symptomatic or poorly controlled cardiac arrhythmia. Any arterial thrombotic event within 6 months before the first administration of study intervention. Uncontrolled arterial hypertension (systolic ≥150 mmHg or diastolic ≥90 mmHg) despite standard medical management. Serious or nonhealing wound, skin ulcer, or bone fracture within 28 days before the first administration of study intervention. Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first administration of study intervention. Significant bleeding disorders, vasculitis, or Grade 3-4 gastrointestinal (GI) bleeding within 3 months before the first administration of study intervention. Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea. Medical condition requiring concomitant administration of a medication with a narrow therapeutic window and metabolized by CYP450 or a strong CYP3A inhibitor Concurrent treatment with any other anticancer therapy No more than 1-line previous chemotherapy in metastatic setting Prior treatment with ramucirumab or docetaxel Prior therapy targeting CEACAM5 or maytansinoid treatment (DM1 or DM4 antibody-drug conjugate) Contraindication to use of corticosteroid premedication Current therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible Previous enrollment in this study, current participation in any other clinical study involving an investigational study treatment, or any other type of medical research Poor bone marrow, liver or kidney functions Urine dipstick or routine analysis indicating proteinuria of 2+ or higher, unless a 24 hour urine collection demonstrates <1000 mg of protein. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.Most important exclusion criteria for potential participants Triplet cohort exclusions 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 first study intervention administration or active tuberculosis. Interstitial lung disease or history of pneumonitis that has required oral or IV steroids. Symptomatic herpes zoster within 3 months prior to screening. Significant allergies to humanized monoclonal antibodies. 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. Thyroid-stimulating hormone (TSH) out of normal limits. If TSH is not within normal limits at baseline, the subject may still be eligible if T3 and free T4 are within the normal limits 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab + SAR408701<br>Ramucirumab will be administered intravenously prior to intravenously adminstration of SAR408701 every two 2 weeks. | Drug: SAR408701<br>* Pharmaceutical form:concentrate for solution for injection Route of administration: intravenous infusion<br>Drug: ramucirumab<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion<br>|
| Experimental: Ramucirumab + pembrolizumab +SAR408701<br>Participants will be treated with tusamitamab ravtansine and ramucirumab and pembrolizumab to assess the tolerability of the combination | Drug: SAR408701<br>* Pharmaceutical form:concentrate for solution for injection Route of administration: intravenous infusion<br>Drug: ramucirumab<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion<br>Drug: pembrolizumab<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Doublet cohort Part 1: Incidence of study drug-related dose-limiting toxicity (DLT) at Cycle 1 and Cycle 2 | Drug-related dose-limiting toxicity (DLT) as observed during DLT-observation period tolerability in order to confirm the recommended dose of SAR408701 in combination with ramucirumab for the Part 2. | baseline up to Cycle 2 (approximatively 1 month) | 
| Doublet cohort Part 2: Objective response rate | Objective response rate defined as proportion of participants with confirmed complete response (CR) or partial response (PR) as best overall response determined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Baseline up to 6 months after the last patient treated | 
| Triplet cohort Incidence of study drug-related dose-limiting toxicity (DLT) at Cycle 1 (C1D1 to C1D21). Anticipated DLT includes, but is not limited to, corneal toxicity. |  | baseline up to Cycle 1 (approximatively 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Doublet cohort Incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) | Incidence of TEAEs and SAEs and laboratory abnormalities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V5.0. | Baseline up to 90 days after the last study treatment administration | 
| Doublet cohort Duration of response (DOR) | Duration of response (DOR) is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined per RECIST v.1.1 or death from any cause, whichever occurs first. | Baseline up to 6 months after the last patient treated | 
| Doublet cohort Progression-free survival (PFS) | Progression-free survival (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. | Baseline up to 6 months after the last patient treated | 
| Doublet cohort Disease control rate (DCR) | Disease control rate (DCR), defined as the percentage of participants who have achieved confirmed CR, confirmed PR or stable disease as per RECIST v1.1 | Baseline up to 6 months after the last patient treated | 
| Doublet cohort PK - Cmax of SAR408701 | Maximum concentration (Cmax) of SAR408701 observed after SAR408701 1st infusion. | Cycle 1 (each cycle = 2 weeks) | 
| Doublet cohort PK - AUC0-14d of SAR408701 | Area under the plasma SAR408701 concentration versus time curve calculated using the trapezoidal method from time 0 to 14 days (AUC0-14d) after SAR408701 1st infusion. | Cycle 1 (each cycle=2 weeks) | 
| Doublet cohort PK - Ctrough of SAR408701 | Concentration observed of SAR408701 just before SAR408701 treatment administration during repeated dosing. | Baseline up to cycle 13 (each cycle= 2 weeks) | 
| Doublet cohort Ctrough of ramucirumab | Concentration observed of ramucirumab just before ramucirumab treatment administration during repeated dosing. | Baseline to cycle 7 (each cycle= 2 weeks) | 
| Doublet cohort Incidence of anti-therapeutic antibodies (ATAs) against SAR408701 | Incidence of anti-therapeutic antibodies (ATAs) against SAR408701. | Baseline up to end of treatment (approximately 6 months) | 
| Triplet cohort Incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) | Incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) and laboratory abnormalities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | Baseline up to 90 days after the last study treatment administration | 
| Triplet cohort Objective response rate (ORR) | Objective response rate (ORR) defined as proportion of participants with confirmed complete response (CR) or partial response (PR) as best overall response (BOR) determined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Baseline up to 4.5 months after the last patient treated | 
| Triplet cohort Incidence of anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine (SAR408701) | Incidence of anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine (SAR408701) | Baseline up to end of treatment (approximately 4.5 months) |