Исследование BND-22, вводимого отдельно и в сочетании с другими терапевтическими средствами у участников с прогрессирующими солидными опухолями

Standard "3 + 3" dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 will be administered intravenously (IV), every 2 weeks (Q2W).

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

• БНД-22

Standard "3 + 3" dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 and pembrolizumab will be administered intravenously (IV), every 3 weeks (Q3W).

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

• БНД-22

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Standard "3 + 3" dose escalation design with enrollment of at least 3 participants per dose level cohort. SAR444881 and cetuximab will be administered intravenously (IV), every 2 weeks (Q2W).

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

• БНД-22

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

SAR444881 Dose Optimization in combination with pembrolizumab/carboplatin/pemetrexed, pembrolizumab, or cetuximab. The indication for the combination cohorts will be non-squamous non-small cell lung cancer (NSCLC), gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), colorectal carcinoma (CRC) any RAS. Enrollment will start after the recommended dose(s) of SAR444881 have been determined based on data from Sub-Parts 1A, 1B, and 1C.

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

• БНД-22

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Pharmaceutical form: Concentrate for solution for infusion; Route of administration: Intravenous

Pharmaceutical form: Powder for concentrate for solution for infusion or concentrate for solution for infusion; Route of administration: Intravenous

The indication for this monotherapy cohort is cholangiocarcinoma. Enrollment will be opened based on emerging data from the dose-escalation phase and combination optimization data.

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

• БНД-22

An AE was any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence, that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. A TEAE was any AE that developed, worsened, or became serious during the TE period. TE period was defined as the period from the first study treatment administration to the last study treatment administration + 30 days.

DLT=drug-related AEs using NCI CTCAE v5.0.Hematological:Grade (G)4 neutropenia >=7 days(D),G4 febrile neutropenia,G4 thrombocytopenia,G3 thrombocytopenia with bleeding,G4 anemia;>=G3/higher non-hematological excluding:increase in liver tests resolved in 7D,diarrhea/associated electrolyte abnormalities & nausea/vomiting controlled by optimal therapy & prophylaxis if lasting <72hours(hr),G3 hyperglycemia in diabetes mellitus/decreased glucose tolerance controlled,=>G3 hypophosphatemia,hypomagnesemia & hypocalcemia resolved by treatment in 72 hr,G3 endocrinopathy controlled,G3/G4 elevation of amylase or lipase not associated with pancreatitis,laboratory value out of normal range with no clinical correlate & resolved with medical management to =<G1 in 7D,G3 rash resolved to <=G1,cetuximab-related dermatologic toxicity,transient (<=24 hr) headache resolved to <=G1,G3 fatigue <7D,G3 tumor flare,G3 fever not associated with hemodynamic compromise,G3 infusion reaction returned to G1 in <6 hr.

ORR was defined as the percentage of participants in the population of interest with a best overall response (BOR) of either complete response (CR) or partial response (PR) 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.

ORR was defined as the percentage of participants in the population of interest with a BOR of either CR or PR 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. Percentages are rounded off to the tenth decimal place.

Blood samples were collected at specified timepoints to determine Cmax of SAR44488. Here, end of infusion (EOI) = 1 hour after infusion start for all doses except 0.1 mg/kg; 30 min after infusion start for 0.1 mg/kg dose.

Blood samples were collected at specified timepoints to determine Cmax of SAR44488. Here, EOI = 1 hour after infusion start.

Blood samples were collected at specified timepoints to determine Cmax of SAR44488. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints to determine Clast of SAR44488. Here, EOI = 1 hour after infusion start for all doses except 0.1 mg/kg; 30 min after infusion start for 0.1 mg/kg dose.

Blood samples were collected at specified timepoints to determine Clast of SAR44488. Here, EOI = 1 hour after infusion start.

Blood samples were collected at specified timepoints to determine Clast of SAR44488. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported.

Blood samples were collected at specified timepoints to determine Tmax of SAR44488. Here, EOI = 1 hour after infusion start for all doses except 0.1 mg/kg; 30 min after infusion start for 0.1 mg/kg dose.

Blood samples were collected at specified timepoints to determine Tmax of SAR44488. Here, EOI = 1 hour after infusion start.

Blood samples were collected at specified timepoints to determine Tmax of SAR44488. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported.

Blood samples were planned to be collected at specified timepoints to determine T1/2 of SAR44488. Because this immunoglobulin (Ig)G4 monoclonal antibody has a long elimination half-life, the PK sampling window between the 1st and 2nd doses was not long enough to characterize the terminal elimination phase. As a result, the terminal elimination rate constant - and therefore the terminal half-life - could not be estimated by noncompartmental analysis. In other words, the true half-life was equal to or exceeded the duration of the post-first-dose sampling period (dosing interval). This outcome measure is therefore not reported.

Blood samples were planned to be collected at specified timepoints to determine T1/2 of SAR44488. Because this IgG4 monoclonal antibody has a long elimination half-life, the PK sampling window between the 1st and 2nd doses was not long enough to characterize the terminal elimination phase. As a result, the terminal elimination rate constant - and therefore the terminal half-life - could not be estimated by noncompartmental analysis. In other words, the true half-life was equal to or exceeded the duration of the post-first-dose sampling period (dosing interval). This outcome measure is therefore not reported.

Blood samples were planned to be collected at specified timepoints to determine T1/2 of SAR44488. Because this IgG4 monoclonal antibody has a long elimination half-life, the PK sampling window between the 1st and 2nd doses was not long enough to characterize the terminal elimination phase. As a result, the terminal elimination rate constant - and therefore the terminal half-life - could not be estimated by noncompartmental analysis. In other words, the true half-life was equal to or exceeded the duration of the post-first-dose sampling period (dosing interval). This outcome measure is therefore not reported.

Blood samples were planned to be collected at specified timepoints to determine AUC of SAR44488. The long elimination half-life of this IgG4 monoclonal antibody meant that the sampling period between the 1st and 2nd doses was insufficient to capture the terminal elimination phase. Since AUC extrapolation to infinity relies on a reliably estimated terminal elimination rate constant, AUC could not be estimated by noncompartmental analysis. This outcome measure is therefore not reported.

Blood samples were planned to be collected at specified timepoints to determine AUC of SAR44488. The long elimination half-life of this IgG4 monoclonal antibody meant that the sampling period between the 1st and 2nd doses was insufficient to capture the terminal elimination phase. Since AUC extrapolation to infinity relies on a reliably estimated terminal elimination rate constant, AUC could not be estimated by noncompartmental analysis. This outcome measure is therefore not reported.

Blood samples were planned to be collected at specified timepoints to determine AUC of SAR44488. The long elimination half-life of this IgG4 monoclonal antibody meant that the sampling period between the 1st and 2nd doses was insufficient to capture the terminal elimination phase. Since AUC extrapolation to infinity relies on a reliably estimated terminal elimination rate constant, AUC could not be estimated by noncompartmental analysis. This outcome measure is therefore not reported.

Plasma samples were collected to assess the antibodies against SAR444881. Treatment-emergent ADA was defined as a participant with at least 1 treatment-induced/boosted ADA. Non-treatment emergent ADA was defined as participant without any treatment-induced/boosted ADA and without any inconclusive sample nor unclassified ADA during the TE period.

PFS was defined as the time from the first dosing date to the date of first objectively documented disease progression or death due to any cause, whichever occurred first.

PFS rate was defined as the percentage of participants in the population of interest with first objectively documented disease progression or death due to any cause, whichever occurred first.

DCR was defined as the percentage of participants in the population of interest whose BOR was either confirmed CR or PR, or stable disease (SD). 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 to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

DoR for a participant with a BOR of confirmed CR or PR was defined as the time between the date of first confirmed response and the date of the first objectively documented tumor progression per RECIST v1.1 or death, 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.

An AE was any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence, that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. A TEAE was any AE that developed, worsened, or became serious during the TE period. TE period was defined as the period from the first study treatment administration to the last study treatment administration + 30 days.