Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab in Pretreated Participants With Gastric Cancer

Phase 2

Terminated

Conditions: Adenocarcinoma Gastric
Gastrooesophageal Cancer

Interventions: Drug: Ramucirumab (CYRAMZA®)
Drug: Tusamitamab ravtansine (SAR408701)

Registration Number: NCT05071053

Lead Sponsor: Sanofi

Brief Summary: Primary Objectives:

Part 1: to confirm the recommended tusamitamab ravtansine loading dose Q2W in combination with ramucirumab in advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma population

Part 2: to assess the antitumor activity of tusamitamab ravtansine loading dose Q2W in combination with ramucirumab in advanced gastric or GEJ adenocarcinoma

Secondary Objectives:

* To assess safety and tolerability

* To assess durability of response (DOR)

* To assess progression-free survival (PFS)

* To assess the disease control rate (DCR)

* To assess the pharmacokinetics (PK)

* To assess the immunogenicity

Detailed Description: 34 weeks (up to 4 weeks for screening, a median of 18 weeks for treatment, and a median of 12 weeks for end-of-treatment assessments and the safety follow-up visit).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Histologically or cytologically confirmed diagnosis of gastric or GEJ adenocarcinoma
Metastatic disease or locally advanced, unresectable disease
Participants who have measurable target lesion
Participants with high carcinoembryonic antigen-related cell adhesion molecule (CEACAM5) expression as per central assessment on tumor biospsy
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Female participant who agrees to use effective contraceptive methods during and for at least 7 months after the last dose of treatment administration
Male participant who agrees to use effective contraception methods during and for at least 4 months after the last dose of treatment administration
Signed informed consent

Exclusion Criteria

Untreated brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression
Significant concomitant illness
History within the last 3 years of an invasive malignancy other than that treated in this study
Known uncontrolled infection
Nonresolution of any prior treatment-related toxicity
Unresolved corneal disorder or any previous corneal disorder considered by an ophthalmologist to predict higher risk of drug-induced keratopathy
Use of contact lenses
Radiographic evidence of major airway or blood vessel invasion or intratumor cavitation
History of uncontrolled hereditary or acquired thrombotic disorder or history of aneurism
Major surgery within 28 days prior to Day 1/first IMP infusion; subcutaneous venous access device placement within 7 days prior to Day 1; or postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months
History of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 2 months before the first treatment administration
Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months before the first administration of treatment administration
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 treatment administration
Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first administration of treatment administration
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
Prior treatment targeting CEACAM5 or containing maytansinoid DM1 or DM4 or ramucirumab or taxane or targeting VEGF/VEGFR Poor organ function

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tusamitamab ravtansine+Ramucirumab	Ramucirumab (CYRAMZA®)	Participants received ramucirumab 8 milligram/kilogram (mg/kg) via intravenous (IV) infusion followed by tusamitamab ravtansine loading dose at 170 mg/meter square (m\^2) via IV infusion on Cycle 1 Day 1 (each cycle was 2 weeks); and then ramucirumab 8 mg/kg via IV infusion followed by tusamitamab ravtansine 100 mg/m\^2 via IV infusion at Cycle 2 and every 2 weeks (Q2W) in all subsequent cycles until disease progression, unacceptable adverse event (AE), death, initiation of a new anticancer therapy, or the participant's or investigator's decision to stop the treatment.
Tusamitamab ravtansine+Ramucirumab	Tusamitamab ravtansine (SAR408701)	Participants received ramucirumab 8 milligram/kilogram (mg/kg) via intravenous (IV) infusion followed by tusamitamab ravtansine loading dose at 170 mg/meter square (m\^2) via IV infusion on Cycle 1 Day 1 (each cycle was 2 weeks); and then ramucirumab 8 mg/kg via IV infusion followed by tusamitamab ravtansine 100 mg/m\^2 via IV infusion at Cycle 2 and every 2 weeks (Q2W) in all subsequent cycles until disease progression, unacceptable adverse event (AE), death, initiation of a new anticancer therapy, or the participant's or investigator's decision to stop the treatment.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Study-Drug Related Dose Limiting Toxicities (DLTs)	From Cycle 1 Day 1 to Cycle 2 Day 14; approximately 28 days	The following AEs occurred during the first 2 cycles of treatment, unless due to disease progression or to a cause obviously unrelated to study drug, were considered DLTs: * Grade 4 neutropenia for 7 or more consecutive days. * Grade 3 to 4 neutropenia complicated by fever (temperature \>=38.5 degree Celsius on more than 1 occasion) or microbiologically or radiographically documented infection. * Grade \>=3 thrombocytopenia associated with clinically significant bleeding requiring clinical intervention. * Grade 4 non-hematologic AE. * Grade \>=3 keratopathy. In addition, any other AE that the Investigators and sponsor deemed to be dose limiting, regardless of its grade, was also considered as DLT.
Objective Response Rate (ORR)	Tumor assessments performed at Baseline (Day 1), then every 6 weeks (±7 days) thereafter, approximately 88.1 weeks	The ORR was defined as percentage 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) version (v) 1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	From the first study drug administration (Day 1) up to 30 days after the last study drug administration, approximately 92.4 weeks	An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A SAE was defined as any untoward medical occurrence that, at any dose: resulted in death or was life-threatening or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent disability/incapacity or congenital anomaly/birth defect. TEAE was defined as AEs that developed, worsened, or became serious during the treatment-emergent period.
Duration of Response (DOR)	Tumor assessments performed at Baseline (Day 1), then every 6 weeks (±7 days) thereafter, approximately 88.1 weeks	The DOR was 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 occured first. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Progression-free Survival (PFS)	Tumor assessments performed at Baseline (Day 1), then every 6 weeks (±7 days) thereafter, approximately 88.1 weeks	The PFS was defined as the time from the first study drug administration to the date of the first documented disease progression or death due to any cause, whichever came first as per RECIST v1.1.
Disease Control Rate (DCR)	Tumor assessments performed at Baseline (Day 1), then every 6 weeks (±7 days) thereafter, approximately 88.1 weeks	The DCR was defined as the percentage of participants who achieved confirmed CR, confirmed PR or stable disease (SD) as per RECIST v1.1. The SD was defined as neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Individual Observed Predose Concentrations (Ctrough) of Tusamitamab Ravtansine	Pre-infusion on Cycle 2 Day 1	Blood samples were collected for the measurement of Ctrough of tusamitamab ravtansine.
Individual Observed Predose Concentrations (Ctrough) of Ramucirumab	Pre-infusion on Cycle 2 Day 1	Blood samples were collected for the measurement of Ctrough of concentrations of ramucirumab.
Number of Participants With Antitherapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine	Upto 92.1 weeks	Blood samples were collected to assess the presence of ATA against tusamitamab ravtansine in plasma from all participants. ATA incidence was defined as the number of participants found to have seroconverted (treatment-induced ATAs) or boosted their pre-existing ATA response (treatment-boosted ATAs) at any time after first study drug administration.

Trial Locations

Locations (21): Investigational Site Number : 3920004
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Matsuyama-shi, Ehime, Japan
Investigational Site Number : 3920002
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Kashiwa-shi, Chiba, Japan
Investigational Site Number : 7920003
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Ankara, Turkey
Investigational Site Number : 0560002
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Bruxelles, Belgium
Investigational Site Number : 0560003
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Edegem, Belgium
Investigational Site Number : 0560001
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Leuven, Belgium
Investigational Site Number : 3920003
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Sunto-gun, Shizuoka, Japan
Investigational Site Number : 4100001
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 6430003
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Pushkin, Saint- Petersburg, Saint- Petersburg, Russian Federation
Investigational Site Number : 6430001
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Arkhangelsk, Russian Federation
Investigational Site Number : 7240004
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Granada, Spain
Investigational Site Number : 4100004
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 4100003
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 4100002
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 7240003
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Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 7920002
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Istanbul, Turkey
Investigational Site Number : 7240002
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Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 7920001
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Istanbul, Turkey
Investigational Site Number : 7240001
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Madrid, Spain
Investigational Site Number : 7920004
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Malatya, Turkey
Investigational Site Number : 3920001
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Sapporo-shi, Hokkaido, Japan