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
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)
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Pharmaceutical form:concentrate for solution for injection Route of administration: intravenous infusion
Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion
Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion
Henry Ford Hospital Site Number : 8400005
Detroit, Michigan, United States
Roswell Park Cancer Institute Site Number : 8400003
Buffalo, New York, United States
McClinton Cancer Center Site Number : 8400002
Waco, Texas, United States
Investigational Site Number : 1000001
Plovdiv, Bulgaria
Investigational Site Number : 2030001
Ostrava - Vitkovice, Czechia
Investigational Site Number : 2030002
Prague, Czechia
Investigational Site Number : 6200001
Porto, Portugal
Investigational Site Number : 4100001
Seoul, Seoul-teukbyeolsi, South Korea
Investigational Site Number : 4100002
Seoul, Seoul-teukbyeolsi, South Korea
Investigational Site Number : 7240001
Barcelona / Sabadell, Catalunya [Cataluña], Spain
...and 3 more locations
Doublet Cohort - Part 1: Number of Participants With Study Drug-Related Dose-Limiting Toxicity (DLT)
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. • Grade \>=3 thrombocytopenia. • Elevated urine protein \>=3 gram(g)/24 hour. • Grade 4 non-hematologic AE. • Grade \>=3 keratopathy. • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed to be dose limiting, regardless of its grade, was also considered as DLT.
Time frame: From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days
Doublet Cohort - Part 2: Objective Response Rate (ORR)
The ORR is 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 is defined as disappearance of all target lesions. The PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
Triplet Cohort: Number of Participants With Study Drug-Related Dose-Limiting Toxicity
The following AEs occurred during the first cycle 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. • Grade \>=3 thrombocytopenia. • Elevated urine protein \>=3 g/24 hour. • Grade 4 non-hematologic AE. • Grade \>=3 keratopathy. • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed dose limiting, regardless of its grade, was also considered as DLT.
Time frame: From Cycle 1 Day 1 up to Cycle 1 Day 21
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is 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 is defined as any untoward medical occurrence that, at any dose: results in death or life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent disability/incapacity or congenital anomaly/birth defect. TEAE is defined as AEs that develop, worsen, or become serious during the treatment period.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology
Blood samples were collected to determine the hematology laboratory clinically significant abnormalities.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism
Blood samples were collected to determine the clinically significant abnormalities in metabolism.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes
Blood samples were collected to determine the clinically significant abnormalities in electrolytes.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Renal Function
Blood samples were collected to determine the renal function laboratory clinically significant abnormalities.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function
Blood samples were collected to determine the liver function laboratory clinically significant abnormalities.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG)
A single 12-lead ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis
Urine samples were collected to determine the clinically significant abnormalities in urine.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Doublet Cohort: Duration of Response (DOR)
The DOR is 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. The PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
Doublet Cohort: Progression-Free Survival (PFS)
The PFS is 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 comes first.
Time frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
Doublet Cohort: Disease Control Rate (DCR)
The DCR is defined as the percentage of participants who achieved confirmed CR, confirmed PR or stable disease (SD) as per RECIST v1.1. The SD is 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.
Time frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
Triplet Cohort: Objective Response Rate
The ORR is defined as percentage of participants with confirmed CR or PR as BOR determined per RECIST v1.1.
Time frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
Doublet Cohort: Maximum Observed Concentration (Cmax) of Tusamitamab Ravtansine
Blood samples were collected for the measurement of Cmax of tusamitamab ravtansine concentrations. Cmax of tusamitamab ravtansine was calculated using non-compartmental method.
Time frame: Day 1 of Cycles 1 and 4
Doublet Cohort: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 14 Days (AUC0-14d) of Tusamitamab Ravtansine
Blood samples were collected for the measurement of AUC0-14d of tusamitamab ravtansine concentrations. AUC0-14d was calculated using the trapezoidal method from time 0 to 14 days and non-compartmental method.
Time frame: Day 1 of Cycles 1 and 4
Doublet Cohort: Concentration Observed Before Treatment Administration During Repeated Dosing (Ctrough) of Ramucirumab
Blood samples were collected for the measurement of Ctrough of ramucirumab concentrations. Ctrough was calculated using non-compartmental method.
Time frame: Cycle 2 Day 1
Number of Participants With Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine
Blood samples were collected to assess the presence of ATA against tusamitamab ravtansine in plasma from all participants. Treatment-emergent ATA is defined as participant with at least 1 treatment-induced/boosted ATA during the treatment period.
Time frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
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