The purpose of this study was to determine the antitumor activity of enfortumab vedotin (EV) confirmed by the objective response rate (ORR). This study also evaluated the effect of antibody-drug conjugate (ADC), total antibody (TAb) and monomethyl auristatin E (MMAE) in Chinese participants with locally advanced or metastatic urothelial cancer. In addition, the study also evaluated the duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and immunogenicity determined by the incidence of antitherapeutic antibodies (ATA). Safety and tolerability of EV in participants with locally advanced or metastatic urothelial cancer was also evaluated.
This study comprised of a single group of participants who received one dose of enfortumab vedotin (EV) on Days 1, 8 and 15 of every 4-week (28 days) cycle. Participants continued on study treatment until discontinuation. After treatment discontinuation, participant had an end of treatment (EOT) visit for a 30-day Safety Follow-up. Participants to discontinue to treatment for reasons other than disease progression were followed for response assessments. A Pharmacokinetic (PK) cohort was available at some study centers. Participants enrolled at the PK cohort site(s) had intense PK samples collected after single and repeated doses.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Intravenous Infusion
Site CN86001
Beijing, China
Site CN86009
Changsha, China
Site CN86002
Guangzhou, China
Site CN86006
Hangzhou, China
Site CN86007
Nanjing, China
Site CN86004
Shanghai, China
Site CN86003
Wuhan, China
Objective Response Rate (ORR) as Per Response Evaluation Criteria in Solid Tumors V1.1 (RECIST V1.1)
ORR was defined as the percentage of participants with best overall response (BOR) as complete response (CR) or partial response (PR) based on the RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Pharmacokinetics (PK) of Antibody-Drug Conjugate (ADC), Total Antibody (TAb), in Serum: Maximum Concentration (Cmax) at Cycle 1 Day 1
Cmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1: pre-dose, end of infusion (EOI), 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of Monomethyl Auristatin E (MMAE) in Serum: Maximum Concentration (Cmax) at Cycle 1 Day 1
Cmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1: pre-dose, end of infusion (EOI), 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb in Serum: Maximum Concentration (Cmax) at Cycle 1 Day 15
Cmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of MMAE in Serum: Maximum Concentration (Cmax) at Cycle 1 Day 15
Cmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC , TAb in Serum: Trough Concentration (Ctrough) at Cycle 1 Day 1
As per planned analysis, if more than 50% of PK concentrations were below the limit of quantification (i.e 0) at a given time point, standard deviation was not reported.
Time frame: Cycle 1 Day 1: pre-dose
PK of MMAE in Serum: Trough Concentration (Ctrough) at Cycle 1 Day 1
As per planned analysis, if more than 50% of PK concentrations were below the limit of quantification (i.e 0) at a given time point, standard deviation was not reported.
Time frame: Cycle 1 Day 1: pre-dose
PK of ADC, TAb in Serum: Trough Concentration (Ctrough) at Cycle 1 Day 15
Ctrough was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose
PK of MMAE in Serum: Trough Concentration (Ctrough) at Cycle 1 Day 15
Ctrough was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose
PK of ADC, TAb, MMAE in Serum: Time to Maximum Concentration (Tmax) at Cycle 1 Day 1
Tmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Time to Maximum Concentration (Tmax) at Cycle 1 Day 15
Tmax was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Area Under Concentration-time Curve From 0 to Day 28 (AUC0-28d) at Cycle 1 Day 1
AUC0-28d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Area Under Concentration-time Curve From 0 to Day 28 (AUC0-28d) at Cycle 1 Day 15
AUC0-28d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb in Serum: Area Under Concentration-time Curve From 0 to Day 7 (AUC0-7d) at Cycle 1 Day 1
AUC0-7d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1 : pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of MMAE in Serum: Area Under Concentration-time Curve From 0 to Day 7 (AUC0-7d) at Cycle 1 Day 1
AUC0-7d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 1 : pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb in Serum: Area Under Concentration-time Curve From 0 to Day 7 (AUC0-7d) at Cycle 1 Day 15
AUC0-7d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of MMAE in Serum: Area Under Concentration-time Curve From 0 to Day 7 (AUC0-7d) at Cycle 1 Day 15
AUC0-7d was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Plasma: Accumulation Ratio of Cmax (RacCmax)
Accumulation ratio is the ratio of Cmax after the dosing interval (Cycle 1 Day 15) divided by Cmax after the first dosing interval (Cycle 1 Day 1).
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Accumulation Ratio of AUC0-7d ( RacAUC0-7d)
RacAUC0-7d was calculated using AUC0-7d and derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Terminal Elimination Half-life (t1/2)
t1/2 was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Systemic Clearance (CL)
CL was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
PK of ADC, TAb, MMAE in Serum: Volume of Distribution at Steady State (Vss)
Vss was derived from the PK blood samples collected.
Time frame: Cycle 1 Day 15: pre-dose, EOI, 2 hour, 4 hour post-dose (each cycle = 28 days)
Duration of Response (DOR) as Per RECIST V1.1 Per IRC
DOR: time from the date of the first CR/PR (whichever is first recorded) that was subsequently confirmed as assessed by IRC to the date of documented progressive disease. or death due to any cause whichever occurred first. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. Progressive Disease:\>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression.
Time frame: From date of the first CR/PR up to progressive disease or death (maximum duration: 9.33 months)
Duration of Response (DOR) as Per RECIST V1.1 Per Investigator's Assessment
DOR: time from the date of the first CR/PR (whichever is first recorded) that was subsequently confirmed as assessed by Investigator's Assesment to the date of documented progressive disease or death due to any cause whichever occurred first. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. Progressive disease:\>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression.
Time frame: From date of the first CR/PR up to progressive disease or death (maximum duration: 9.33 months)
Objective Response Rate (ORR) as Per Investigator Assessment
ORR was defined as the percentage of participants with BOR as CR or PR based on the RECIST v1.1 as per investigator's assesment. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
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Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Disease Control Rate (DCR) as Per RECIST V1.1 Per IRC
DCR: percentage of participants with a CR, PR or SD based on RECIST v1.1 as assessed by IRC. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. Progressive disease:\>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression.
Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Disease Control Rate (DCR) as Per RECIST V1.1 Per Investigator's Assesment
DCR: percentage of participants with a CR, PR or SD based on RECIST v1.1 as assessed by investigator's assessment. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. Progressive disease:\>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression.
Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Progression Free-Survival Per RECIST V1.1 Per IRC
PFS: time from first dose of the study drug until date of documented radiological disease progression per IRC based on RECIST V1.1, or until death due to any cause, whichever occurred first. Progressive disease: \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression. A participant who neither progressed nor died was censored at date of last radiological assessment (RA)/ date of randomization if no post-baseline RA was available. Participants who received any further anticancer therapy (ACT) for disease before radiological progression was censored at date of last RA before ACT started and participants who had PD/death after \>=2 missed RAs were censored at last RA prior to 2 or more missed RAs. Kaplan-Meier estimates was used.
Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Progression Free-Survival Per RECIST V1.1 Per Investigator's Assessment
PFS: time from first dose of the study drug until date of documented radiological disease progression per investigator based on RECIST V1.1, or until death due to any cause, whichever occurred first. Progressive disease: \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression. A participant who neither progressed nor died was censored at date of last RA/ date of randomization if no post-baseline RA was available. Participants who received any further ACT for disease before radiological progression was censored at date of last RA before ACT started and participants who had progressive disease/death after \>=2 missed RAs were censored at last RA prior to 2 or more missed RAs. Kaplan-Meier estimates was used.
Time frame: From first dose up to progressive disease or death (maximum duration: 9.33 months)
Overall Survival (OS)
OS was defined as the time from first dose of the study drug until the documented date of death from any cause. OS was analyzed using Kaplan-Meier estimates. Participants who were still alive at the time of data cutoff date were to be censored at the last known alive date or at the data cutoff date, whichever was earlier.
Time frame: From first dose up to death (maximum duration: 9.33 months)
Number of Participants With Antitherapeutic Antibodies (ATA)
Number of participants with ATA were reported.
Time frame: From first dose until 9.33 months
Number of Participants With Treatment Emergent Adverse Events
An AE is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE is defined as an adverse event observed after starting administration of the study drug and within 30 days after taking the last dose of study drug.
Time frame: Baseline up to 9.33 months
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead. Number of participants with ECOG PS was reported."
Time frame: End of Treatment (Baseline up to 9.33 months)