Tusamitamab Ravtansine Monotherapy and in Combination in Patients With CEACAM5-positive Advanced Solid Tumors

Study Overview
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Brief Summary
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Primary Objective: For Cohort A, Cohort B, and Cohort C Part 2: To assess the antitumor activity of tusamitamab ravtansine in metastatic breast cancer (mBC) and tusamitamab ravtansine monotherapy and in combination with gemcitabine in metastatic pancreatic adenocarcinoma (mPAC) For Cohort C Part 1: Confirmation of the recommended tusamitamab ravtansine dose when administered in combination with gemcitabine Secondary Objectives: To assess the safety and tolerability of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine To assess other efficacy parameters of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine To assess the immunogenicity of tusamitamab ravtansine To assess the pharmacokinetics (PK) of tusamitamab ravtansine and gemcitabine when given in combination

Detailed Description
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The expected duration of study intervention for participants may vary, based on progression date and the cohort; median expected duration of study per participant is estimated at 8 months for Cohort A/C and 6 months for Cohort B (up to 1 month for screening, a median of 4 or 2 months for treatment in Cohort A/C and Cohort B respectively, 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, Multi-cohort, Phase 2 Trial, Evaluating the Efficacy and Safety of Tusamitamab Ravtansine (SAR408701) Monotherapy and in Combination in Patients With CEACAM5-positive Advanced Solid Tumors

Conditions
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Breast Cancer Metastatic, Pancreatic Carcinoma Metastatic

Intervention / Treatment
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* Drug: tusamitamab ravtansine
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 years of age Participants with at least one measurable lesion according to the RECIST v1.1 criteria that has not been irradiated (ie, newly arising lesions in previously irradiated areas are accepted). Participants with ECOG performance status 0 to 1. Evidence of metastatic disease. Expression of CEACAM 5 by centrally assessed IHC assay. Male and female participants willing to comply with contraceptive use consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Cohort A: mBC Histological or cytologic diagnosis of breast cancer. Have received at least 2 prior cytotoxic chemotherapy regimens for non-TNBC tumor type or at least 1 for TNBC tumor type but not more than 4 in the locally recurrent or metastatic setting. Cohorts B and C: mPAC - Have confirmed diagnosis of pancreatic ductal adenocarcinoma. Cohort B: mPAC: - Have documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine (or relapsed within 6 months of completion of gemcitabine adjuvant therapy) or a 5-fluorouracil based regimen (including capecitabine) but no more than 2 prior chemotherapy lines for locally advanced/metastatic disease. Cohort C: mPAC - Have documented radiographic progression or documented intolerance after 1st line fluoropyrimidine-containing chemotherapy (or relapsed within 6 months of completion of chemotherapy as adjuvant therapy) for locally advanced/metastatic disease. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical condition requiring concomitant administration of a medication with a narrow therapeutic window, that is metabolized by cytochrome P450 (CYP450), 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 the first administration of study intervention. Life expectancy less than 3 months. Untreated brain metastases or history of leptomeningeal disease. Significant concomitant illness 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 human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or active hepatitis A, B or C infection. 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 (HRT). Unresolved corneal disorder or any previous corneal disorder considered by an ophthalmologist to predict higher risk of drug-induced keratopathy. Use of contact lenses. Participants using contact lenses who are not willing to stop wearing them for the duration of the study intervention are excluded. Concurrent treatment with any other anti cancer therapy. 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 prior antitumor therapy (chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational treatment). Any prior therapy targeting CEACAM5. Prior maytansinoid DM4 treatment (ADC). Any major surgery within the preceding 2 weeks of the first study intervention administration. Previous enrollment in this study or current participation in any other clinical study involving an investigational study treatment or any other type of medical research. Poor renal function Poor hepatic function Poor bone marrow function Cohort C: mPAC - Any previous systemic therapy with taxane or gemcitabine (for Cohort C only). 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A metastatic breast cancer (mBC)<br>tusamitamab ravtansine every 2 weeks administered via intravenous infusion (IV) | Drug: tusamitamab ravtansine<br>* Pharmaceutical form:Concentrated solution for IV; Route of administration: IV infusion<br>* Other names: SAR408701;|
| Experimental: Cohort B metastatic pancreatic adenocarcinoma (mPAC)<br>tusamitamab ravtansine every 2 weeks administered via intravenous infusion (IV) | Drug: tusamitamab ravtansine<br>* Pharmaceutical form:Concentrated solution for IV; Route of administration: IV infusion<br>* Other names: SAR408701;|
| Experimental: Cohort C Metastatic pancreatic adenocarcinoma (mPAC)<br>tusamitamab ravtansine every 2 weeks combined with gemcitabine on Day 1, Day 8 and Day 15 every 4 weeks administered via intravenous infusion (IV) | Drug: tusamitamab ravtansine<br>* Pharmaceutical form:Concentrated solution for IV; Route of administration: IV infusion<br>* Other names: SAR408701;Drug: Gemcitabine<br>* Pharmaceutical form: Lyophilized powder for reconstitution or as a solution for infusion; Route of administration: IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR)- Cohort A, Cohort B, and Cohort C Part 2 | Objective Response Rate (ORR) of tusamitamab ravtansine in mBC and tusamitamab ravtansine monotherapy and in combination with gemcitabine in mPAC, defined as the 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 6 months after the last patient treated have 2 postbaseline tumor assessments | 
| Incidence of dose-limiting toxicites (DLTs)- Cohort C Part 1 | Incidence of dose-limiting toxicites (DLTs) in the 28 Day DLT observation period (Cycle 1) | 28 days (Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and laboratory abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | TEAEs, SAEs and laboratory abnormalities according to NCI CTCAE v5.0. | Baseline up to 90 days after the last study treatment administration | 
| Progression free survival (PFS) | PFS defined as the time from the date of first tusamitamab ravtansine 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 have 2 postbaseline tumor assessments | 
| Disease control rate (DCR) | DCR defined as the percentage of participants who have achieved CR, PR or stable disease as per RECIST v1.1. | Baseline up to 6 months after the last patient treated have 2 postbaseline tumor assessments | 
| Duration of Response (DOR) | DOR defined as the time from first documented evidence of CR or PR until progressive disease determined per RECIST v1.1 or death from any cause, whichever occurs first. | Baseline up to 6 months after the last patient treated have 2 postbaseline tumor assessments | 
| Incidence of participants with anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine | Incidence of participants with anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine. | Baseline until one month after last patient last treatment | 
| Maximum concentration observed after infusion (Cmax) of tusamitamab ravtansine | Pharmacokinetic parameter of tusamitamab ravtansine. | After 1st administration at Cycle 1 Day 1 (1 Cycle = 28 days) | 
| Area under the plasma concentration versus time curve from time 0 to 14 days (AUC0-14d) | Pharmacokinetic parameter of tusamitamab ravtansine. AUC0-14d calculated using the trapezoidal method. | After 1st administration at Cycle 1 Day 1 (1 Cycle = 28 days) | 
| Total body clearance (CL) | Pharmacokinetic parameter of gemcitabine. | After 1st administration at Cycle 1 Day 1 (1 Cycle = 28 days) | 
| Maximum concentration observed after infusion (Cmax) of gemcitabine metabolite | Pharmacokinetic parameter of gemcitabine metabolite. | After 1st administration at Cycle 1 Day 1 (1 Cycle = 28 days) |