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
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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
57
Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous
Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous
Pharmaceutical form: Lyophilized powder for reconstitution in solution Route of administration: Intravenous
Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous
Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous
KU Medical Center_Investigational Site Number :8400002
Westwood, Kansas, United States
Centro Avancado de Oncologia CECAN - Liga Contra o Cancer Site Number : 0760004
Natal, Rio Grande do Norte, Brazil
Centro de Investigacion y Desarrollo Oncologico (CIDO) Hochstetter 599 of. 602-603-1001, Temuco_Investigational Site Number :1520005
Temuco, La Araucanía, Chile
ONCOCENTRO APYS Av. La Marina 1702, 2do piso, Viña del Mar_Investigational Site Number :1520003
Viña del Mar, Valparaiso, Chile
Orlandi Oncologia General Salvo 159, Providencia_Investigational Site Number :1520002
Santiago, Chile
All Cohorts: Number of Participants With Study Drug-Related Dose-Limiting Toxicities (DLTs)
DLTs were defined as: a) Hematological abnormalities: 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; b) Non-hematological abnormalities: grade 4 non-hematologic adverse event (AE), except AE symptoms related to the underlying disease as per the Investigator's judgment, grade ≥3 keratopathy. In addition, any other AE that the recruiting Investigators and sponsor deemed to be dose-limiting, regardless of its grade, was also considered as DLT.
Time frame: Cycle 1 Day 1 up to Cycle 1 Day 21 (cycle duration=3 weeks)
Doublet Cohort: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) per response evaluation criteria in solid tumors (RECIST) version (v) 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm). PR was 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, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 158.4 weeks
Quadruplet Cohort: Objective Response Rate
ORR was defined as the percentage of participants with a confirmed CR or PR as per RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was 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, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 139.9 weeks
All Cohorts: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious AE was defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity or was a congenital anomaly/birth defect. A TEAE was defined as an AE that developed, worsened or became serious during the treatment-emergent period.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment, approximately 162.4 weeks (doublet), 117 weeks (triplet), and 143.9 weeks (quadruplet)
Doublet and Quadruplet Cohorts: Progression-free Survival (PFS)
PFS was defined as the time from the first study treatment administration to the date of the first documented progressive disease (PD) or death due to any cause, whichever came first. 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 (including the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 1 or more new lesions was also considered progression.
Time frame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 158.4 weeks (doublet) and 139.9 weeks (quadruplet)
All Cohorts: Disease Control Rate (DCR)
DCR was defined as percentage of participants with a confirmed CR, confirmed PR or stable disease (SD) as BOR per RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 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. 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 (including the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 1 or more new lesions was also considered progression.
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ICEGCLINIC Avenida Serafín Zamora 190 Torre B, piso 4. La Florida_Investigational Site Number :1520006
Santiago, Chile
Fakultní nemocnice Olomouc Onkologická klinika I.P. Pavlova 6_Site Number :2030001
Olomouc, Czechia
Nemocnice AGEL Ostrava - Vitkovice Plicní oddělení Zalužanského 2214/35_Site Number :2030002
Ostrava - Vitkovice, Czechia
Institut Sainte-Catherine 250 Chemin de Baigne-Pieds_Investigational Site Number :2500005
Avignon, France
CHRU BREST 5 Avenue Foch_Investigational Site Number :2500003
Brest, France
...and 12 more locations
Time frame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 158.4 weeks (doublet), 113 weeks (triplet), and 139.9 weeks (quadruplet)
All Cohorts: Duration of Response (DOR)
DOR was defined as the time from first documented evidence of CR or PR until PD determined per RECIST v1.1 or death from any cause, whichever occurred first. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 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 (including the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 1 or more new lesions was also considered progression.
Time frame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 158.4 weeks (doublet), 113 weeks (triplet), and 139.9 weeks (quadruplet)
Triplet Cohort: Objective Response Rate
ORR was defined as the percentage of participants with a confirmed CR or PR as per RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was 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, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 113 weeks
All Cohorts: Trough Concentration (Ctrough) of Tusamitamab Ravtansine
Blood samples were collected for the measurement of tusamitamab ravtansine concentrations.
Time frame: Pre-dose on Day 1 of Cycle 2 (cycle duration=3 weeks)
All Cohorts: Ctrough of Pembrolizumab
Blood samples were collected for the measurement of pembrolizumab concentrations.
Time frame: Pre-dose on Day 1 of Cycle 2 (cycle duration=3 weeks)
Quadruplet Cohort: Plasma Concentration of Pemetrexed
Blood samples were collected for the measurement of pemetrexed concentrations.
Time frame: 30 minutes post-dose on Day 1 of Cycle 1 (cycle duration=3 weeks)
Triplet and Quadruplet Cohorts: Total Plasma Concentration Observed at the End of Infusion (Ceoi) of Cisplatin
Blood samples were collected for the measurement of cisplatin concentrations.
Time frame: At end of infusion on Day 1 of Cycle 1 (cycle duration=3 weeks)
Triplet and Quadruplet Cohorts: Total Plasma Concentration Observed at the End of Infusion of Carboplatin
Blood samples were collected for the measurement of carboplatin concentrations.
Time frame: At end of infusion on Day 1 of Cycle 1 (cycle duration=3 weeks)
All Cohorts: Number of Participants With Treatment-emergent Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine
Blood samples were collected to assess the presence of treatment-emergent ATA against tusamitamab ravtansine. ATA incidence was defined as the number of participants found to have treatment-emergent ATA response during the study.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment, approximately 162.4 weeks (doublet), 117 weeks (triplet), and 143.9 weeks (quadruplet)