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

The following adverse events (AEs) that occurred during the first cycle of treatment, unless due to disease progression or to a cause obviously unrelated to study treatment, were considered DLTs: 1. Hematological abnormalities: grade 4 neutropenia for 7 or more consecutive days, grade 3 to 4 neutropenia complicated by fever or microbiologically or radiographically documented infection, grade greater than or equal to (≥) 3 thrombocytopenia associated with clinically significant bleeding requiring clinical intervention; 2. Non-hematological abnormalities: grade 4 non-hematologic AE, 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 (28 days)

Population: DLT-evaluable population (Cohort C Part 1) included participants who received 1 cycle with at least 80% of the intended dose for both tusamitamab ravtansine at each of the first 2 infusions and gemcitabine at each of the 3 first infusions unless they discontinued the study treatment before the end of Cycle 1 due to a DLT.

ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR was defined as disappearance of all target and non-target lesions, and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 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 of diameters.

Time frame: From date of first study treatment administration (Day 1) up to maximum exposure of treatment: 26.1 weeks (Cohort A), 51.6 weeks (Cohort B), 43.3 weeks (Cohort C)

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

Blood samples were collected for the measurement of AUC0-14d of tusamitamab ravtansine. AUC0-14d was calculated using non-compartmental method.

Time frame: Cycle 1: Day 1: Start of infusion, end of infusion, 3, 72, 168, and 336 hours post-start of infusion (cycle duration: 28 days)

Population: PK population included all treated participants with at least 1 post-baseline PK result with adequate documentation of dosing and sampling dates and times. Only those participants with data collected for this outcome measure are reported.

Blood samples were collected for the measurement of Cmax of dFdU. Cmax was calculated using non-compartmental method.

Time frame: Cycle 1: Days 1 and 8: Start of infusion, end of infusion, 0.25, 1, 1.5, and 2 hours post-start of infusion (cycle duration: 28 days)

Population: PK population included all treated participants with at least 1 post-baseline PK result with adequate documentation of dosing and sampling dates and times. Only those participants with data collected for this outcome measure are reported.

Blood samples were collected for the measurement of Cmax of tusamitamab ravtansine. Cmax was calculated using non-compartmental method.

Time frame: Cycle 1: Day 1: Start of infusion, end of infusion, 3, 72, 168, and 336 hours post-start of infusion (cycle duration: 28 days)

Population: Pharmacokinetic (PK) population included all treated participants with at least 1 post-baseline PK result with adequate documentation of dosing and sampling dates and times.

Blood samples were collected for the measurement of CL of gemcitabine. CL was calculated using non-compartmental method.

Time frame: Cycle 1: Days 1 and 8: Start of infusion, end of infusion, 0.25, 1, 1.5, and 2 hours post-start of infusion (cycle duration: 28 days)

Population: PK population included all treated participants with at least 1 post-baseline PK result with adequate documentation of dosing and sampling dates and times. Only those participants with data collected for this outcome measure are reported.

DCR was defined as the percentage of participants who achieved confirmed CR, confirmed PR or stable disease (SD) as per RECIST v1.1. CR was defined as disappearance of all target and non-target lesions, and normalization of tumor marker level. 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 of diameters. SD was defined as neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum of diameters while on study.

Time frame: From date of first study treatment administration (Day 1) up to maximum exposure of treatment: 26.1 weeks (Cohort A), 51.6 weeks (Cohort B), 43.3 weeks (Cohort C)

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

DOR was defined as the time from first documented evidence of confirmed CR or confirmed PR until progressive disease determined per RECIST v1.1 or death from any cause, whichever occurred first. CR was defined as disappearance of all target and non-target lesions, and normalization of tumor marker level. 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 of diameters. Disease progression was defined as unequivocal progression of existing non-target lesions; at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From date of first study treatment administration (Day 1) up to maximum exposure of treatment: 26.1 weeks (Cohort A), 51.6 weeks (Cohort B), 43.3 weeks (Cohort C)

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered. Only participants with response are analyzed. None of the participants in Cohort A had confirmed CR or PR; hence DOR could not be derived.

Blood samples were collected to determine the abnormalities in hematology/coagulation and clinical chemistry. Abnormality criteria was assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Hematological and coagulation parameters assessed were white blood cells, platelets, neutrophils, lymphocytes, and international normalized ratio. Clinical chemistry parameters assessed were albumin, sodium, potassium, calcium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Only those categories in which at least 1 participant had \>2 grade worsening in laboratory abnormalities are reported.

Time frame: From date of first study treatment administration (Day 1) up to 30 days after the last dose of study treatment, approximately 86.6 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered. Only those participants with data collected for the specified category are reported.

An AE was defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious adverse event was defined as any AE that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via an authorized medicinal product. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment-emergent period (defined as the period from the first study treatment administration to the last study treatment administration + 30 days).

Time frame: From date of first study treatment administration (Day 1) up to 30 days after the last dose of study treatment, approximately 86.6 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

Blood samples were collected for assessing the presence of ATA against tusamitamab ravtansine in plasma. The number of participants with treatment-emergent ATA i.e., either seroconverted (treatment-induced ATAs) or boosted their pre-existing ATA response (treatment-boosted ATAs) during the study are reported.

Time frame: From date of first study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration [maximum exposure of treatment: 26.1 weeks (Cohort A), 51.6 weeks (Cohort B), 43.3 weeks (Cohort C)]

Population: ATA population included all treated participants with at least 1 post-baseline ATA result.

PFS was defined as the time from the date of first tusamitamab ravtansine administration to the date of the first documented disease progression according to RECIST v1.1 or death due to any cause, whichever came first. Disease progression was defined as unequivocal progression of existing non-target lesions; at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From date of first study treatment administration (Day 1) up to maximum exposure of treatment: 26.1 weeks (Cohort A), 51.6 weeks (Cohort B), 43.3 weeks (Cohort C)

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.