A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

This is a study that will test how an experimental drug (enfortumab vedotin) affects patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra that has spread to nearby tissues or to other areas of the body.

This clinical trial will enroll patients who were previously treated with a kind of anticancer drug called an immune checkpoint inhibitor (CPI). Some CPIs have been approved for the treatment of urothelial cancer.

This study will test if the cancer shrinks with treatment. This study will also look at the side effects of the drug. A side effect is a response to a drug that is not part of the treatment effect.

Patients who sign up for this trial must also fall into one of these categories:

* Patients have already received treatment with platinum-containing chemotherapy
* Patients have never received platinum-containing treatment and are not eligible for treatment with cisplatin.

Japan Pharmaceuticals and Medical Devices Agency (PMDA) has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan.

This study will examine the safety and anticancer activity of enfortumab vedotin given intravenously to patients with locally advanced or metastatic urothelial cancer who previously received a CPI and either previously received platinum-containing chemotherapy (Cohort 1) or are platinum-naïve and cisplatin-ineligible (Cohort 2). Patients who received platinum in the adjuvant/neoadjuvant setting and did not progress within 12 months of completion will be considered platinum-naïve. Approximately 100 patients are expected to be enrolled in each cohort. The primary goal of the study is to determine the confirmed ORR of enfortumab vedotin.

Eligibility Criteria:
Inclusion Criteria:

* Histologically documented urothelial carcinoma (squamous differentiation or mixed cell types allowed).
* Metastatic disease or locally advanced disease that is not resectable.
* Must have received prior treatment with a CPI in the locally advanced or metastatic urothelial cancer setting. A CPI is defined as a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 3 months of therapy completion are eligible.
* Must either have prior treatment with platinum-containing chemotherapy (Cohort 1) or be platinum-naïve and ineligible for treatment with cisplatin at time of enrollment (Cohort 2).
* Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy.
* Tumor tissue samples must be available for submission to the sponsor prior to study treatment.
* Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1).
* An Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1 for Cohort 1 or ≤2 for Cohort 2.
* Anticipated life expectancy of ≥3 months as assessed by the investigator.

Exclusion Criteria:

* Ongoing sensory or motor neuropathy Grade ≥2.
* Active central nervous system (CNS) metastases.
* Immunotherapy related myocarditis, colitis, uveitis, or pneumonitis.
* Prior enrollment in an enfortumab vedotin study or prior treatment with other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
* Uncontrolled tumor-related pain or impending spinal cord compression.