A Study of Ladiratuzumab Vedotin in Advanced Solid Tumors

An adverse event (AE) was any untoward medical occurrence in a participant/ clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. AEs included both SAEs ad all non-SAEs. TEAEs were defined as newly occurring (not present at baseline)/worsening after first dose of study treatment. TESAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity \& may cause congenital anomaly/birth defect. Treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 4.03 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening).

An AE was any untoward medical occurrence in a participant, or a clinical investigational participant administered a medicinal product, and which does not necessarily have a causal relationship with this treatment. AEs included both SAEs ad all non-SAEs. TEAEs were defined as newly occurring (not present at baseline) or worsening after first dose of study treatment. TESAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent or significant disability or incapacity and may cause congenital anomaly or birth defect. Treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v4.03 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening).

DCR was defined as percentage of participants who achieved confirmed and unconfirmed CR or PR per RECIST v1.1 or met stable disease (SD) criteria at least once after start of study treatment at minimum interval of 5 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR was defined as >= 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference smallest sum diameters while on study. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression.

DCR was defined as percentage of participants who achieved confirmed and unconfirmed CR or PR per RECIST v1.1 or met SD criteria at least once after start of study treatment at a minimum interval of 5 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR was defined as >= 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 centimeter (cm). Appearance of one or more new lesions was also considered progression.

DOR:time from 1st documentation of OR(confirmed CR/PR per RECIST Version 1.1) to 1st documentation of PD/death due to any cause,whichever occurred first.CR:disappearance of all target lesions.Any pathological lymph nodes must have reduction in short axis to <10 mm.PR:>=30 % decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Participants do not have PD and are still on study at time of analysis/are removed from study prior to documentation of PD were censored at last disease assessment documenting absence of PD. Participants who started new anticancer treatment prior to documentation of PD were censored at last disease assessment prior to start of new treatment.PD:at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study.In addition to relative increase of 20%, sum must demonstrate absolute increase of 0.5 cm.Appearance of one/more new lesions was considered progression. Kaplan-Meier method was used.

DOR:time from 1st documentation of OR(confirmed CR/PR per RECIST Version 1.1) to 1st documentation of PD/death due to any cause,whichever occurred first.CR:disappearance of all target lesions.Any pathological lymph nodes must have reduction in short axis to <10 mm.PR:>=30 % decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Participants do not have PD and are still on study at time of analysis/are removed from study prior to documentation of PD were censored at last disease assessment documenting absence of PD. Participants who started new anticancer treatment prior to documentation of PD were censored at last disease assessment prior to start of new treatment.PD:at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study.In addition to relative increase of 20%, sum must demonstrate absolute increase of 0.5 cm.Appearance of one/more new lesions was considered progression. Kaplan-Meier method was used.

PSA-DOR was defined as the time from the first documentation of PSA response (subsequently confirmed at least 3 weeks apart) to the first documentation of PSA progression or death due to any cause, whichever occurred first. Confirmed PSA response rate was defined as the percentage of participants with a reduction from baseline PSA level of at least 50%, measured twice >= 3 weeks apart. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD was censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. The confidence interval (CI) was calculated using the complementary log-log transformation method.

PFS: time from start of study treatment to the first documentation of PD by RECIST v1.1 or clinical PD. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD were censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. PD: At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression. Median was estimated using the Kaplan-Meier method and the CI was calculated using the complementary log-log transformation method.

PFS: time from start of study treatment to the first documentation of PD by RECIST v1.1 or clinical PD. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD were censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. PD: At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression. Median was estimated using the Kaplan-Meier method and the CI was calculated using the complementary log-log transformation method.

PSA-PFS: time from start of study treatment to first documentation of PSA progression or death due to any cause, whichever occurred first. Participants who do not have PD and are still on study at time of analysis or who are removed from study prior to documentation of PD was censored at date of last disease assessment documenting absence of PD. Participants who started new anticancer treatment prior to documentation of PD were censored at date of last disease assessment prior to the start of new treatment. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression. Median was estimated using Kaplan-Meier method and CI was calculated using the complementary log-log transformation method.

OS was defined as the time from the start of study treatment to date of death due to any cause. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD was censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. Median was estimated using the Kaplan-Meier method.

OS was defined as the time from the start of study treatment to date of death due to any cause. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD was censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. Median was estimated using the Kaplan-Meier method.

Area under the observed concentration-time curve from the time of dosing to Day 21 of LV was calculated by noncompartmental analysis.

Cmax according to ADC pharmacokinetic parameters was reported.

Area under the observed concentration-time curve from the time of dosing to Day 21 of TAB was calculated by noncompartmental analysis.

Cmax according to TAB pharmacokinetic parameters was reported.

Area under the observed concentration-time curve from the time of dosing to Day 21 of MMAE was calculated by noncompartmental analysis.

Cmax according to MMAE pharmacokinetic parameters was reported.

Area under the observed concentration-time curve from the time of dosing to Day 7 of ADC was calculated by noncompartmental analysis.

Cmax according to ADC pharmacokinetic parameters was reported.

Area under the observed concentration-time curve from the time of dosing to Day 7of TAB was calculated by noncompartmental analysis.

Cmax according to TAB pharmacokinetic parameters was reported.

Area under the observed concentration-time curve from the time of dosing to Day 7 of MMAE was calculated by noncompartmental analysis.

Cmax according to MMAE pharmacokinetic parameters was reported.

A positive baseline ATA result was considered positive post-baseline if the post-baseline ATA titer result was at least four times higher than the baseline result.

A positive baseline ATA result was considered positive post-baseline if the post-baseline ATA titer result was at least four times higher than the baseline result.