A Study of Enfortumab Vedotin in Japanese Subjects With Locally Advanced or Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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The objective of this study is to assess the safety, tolerability and pharmacokinetics of enfortumab vedotin (ASG-22CE) when administered intravenously to Japanese subjects with locally advanced or metastatic urothelial carcinoma. This study will also assess the immunogenicity as defined by the incidence of anti-drug antibody (ADA) and anti-tumor activity of enfortumab vedotin (ASG-22CE) when administered intravenously to Japanese subjects with locally advanced or metastatic urothelial carcinoma.

Detailed Description
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All subjects will receive a single 30 minute intravenous (IV) infusion of enfortumab vedotin (ASG-22CE) once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 28 days.

Official Title
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An Open-label, Randomized, Phase 1 Safety and Pharmacokinetic Study of Enfortumab Vedotin (ASG-22CE) in Japanese Patients With Locally Advanced or Metastatic Urothelial Carcinoma

Conditions
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Metastatic Urothelial Cancer

Intervention / Treatment
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* Drug: Enfortumab vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have histologically confirmed, locally advanced (TNM classification T3b and any N; or T and N2-3) or metastatic Transitional Cell Carcinoma of the Urothelium (TCCU) (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with Urothelial Carcinoma with squamous differentiation or mixed cell types are eligible. Subject must be able to submit a tumor tissue samples for Nectin-4 expression analysis at central laboratory. Subject must have failed at least one prior chemotherapy regimen for advanced disease. Urothelial and bladder cancer subjects are not required to have failed prior chemotherapy regimen if considered unfit for cisplatin-based chemotherapy. Subject must have measurable disease according to Response Evaluation Criteria in Solid Tumor (RECIST) (version 1.1). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: Preexisting sensory neuropathy Grade ≥ 2. Preexisting motor neuropathy Grade ≥ 2. Uncontrolled central nervous system metastasis that requires active treatment. Any anticancer therapy within 14 days prior to the first dose of study drug. Subjects with pre-existing immunotherapy-related adverse events requiring high doses of systemic steroids are not eligible.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Enfortumab vedotin 1.0 mg/kg<br>All subjects assigned will receive a single 30 minute intravenous infusion of enfortumab vedotin (ASG-22CE) once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 28 days. | Drug: Enfortumab vedotin<br>* All subjects assigned will receive a single 30 minute intravenous infusion of enfortumab vedotin (ASG-22CE) once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 28 days.<br>* Other names: Padcev;|
| Experimental: Arm B: Enfortumab vedotin 1.25 mg/kg<br>All subjects assigned will receive a single 30 minute intravenous infusion of enfortumab vedotin (ASG-22CE) once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 28 days. | Drug: Enfortumab vedotin<br>* All subjects assigned will receive a single 30 minute intravenous infusion of enfortumab vedotin (ASG-22CE) once weekly for 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 28 days.<br>* Other names: Padcev;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessed by incidence of adverse events | Adverse events will be coded using MedDRA. Adverse events collection begins after signing informed consent and collected until 28 days after the last dose of study drug. | Up to 12 months | 
| Safety assessed by laboratory tests: Hematology | Descriptive statistics will be used to summarize results. | Up to 12 months | 
| Safety assessed by laboratory tests: Biochemistry | Descriptive statistics will be used to summarize results. | Up to 12 months | 
| Safety assessed by laboratory tests: Urinalysis | Descriptive statistics will be used to summarize results. | Up to 12 months | 
| Safety assessed by laboratory tests: Coagulation studies | Descriptive statistics will be used to summarize results. | Up to 12 months | 
| Number of participants with vital sign abnormalities and/or adverse events | Number of participants with potentially clinically significant vital sign values. | Up to 12 months | 
| Safety assessed by electrocardiogram (ECG) | Before measurement of ECGs, the participant should be resting in a supine position for at least 5 minutes. The investigator will assess the ECG charts as normal, abnormal (not clinically significant) or abnormal (clinically significant). Abnormal (not clinically significant) and abnormal (clinically significant) findings will be recorded. | Up to 12 months | 
| Pharmacokinetics (PK) parameter for total antibody (TAb): Concentration at the end of infusion (CEOI) | CEOI will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| Pharmacokinetics (PK) parameter for antibody drug conjugate (ADC): CEOI | CEOI will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| Pharmacokinetics (PK) parameter for Monomethyl Auristatin E (MMAE): CEOI | CEOI will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for TAb: Maximum observed concentration (Cmax) | Cmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for ADC: Cmax | Cmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for MMAE: Cmax | Cmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for TAb: Trough concentration (Ctrough) | Ctrough will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for ADC: Ctrough | Ctrough will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for MMAE: Ctrough | Ctrough will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for TAb: Time to maximum concentration (Tmax) | Tmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for ADC: Tmax | Tmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for MMAE: Tmax | Tmax will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for TAb: Partial area under the serum concentration-time curve after first dose and as appropriate (AUC0-7) | AUC0-7 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for ADC: AUC0-7 | AUC0-7 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for MMAE: AUC0-7 | AUC0-7 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for TAb: Terminal or apparent terminal half-life (t1/2) | T1/2 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for ADC: t1/2 | T1/2 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 
| PK parameter for MMAE: t1/2 | T1/2 will be derived from the PK blood samples collected. | Days 1-4, 8, 15-18, 22 of Cycle 1, Day 1 of Cycle 2 and 3, and subsequent cycles up to an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Anti-Drug Antibody (ADA) | Blood samples for anti-drug antibody (ADA) analysis will be collected. | Up to 12 months | 
| Overall Response Rate | Defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) | Up to 12 months | 
| Disease Control Rate | Defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial Carcinoma, Enfortumab vedotin, ASG-22CE, Padcev, ASG-22ME, Metastatic Urothelial Cancer