Summary

This is a global, multicenter, randomized, open-label study. The main objective of the study is to measure the clinical activity and safety of zelenectide pevedotin formally BT8009, in combination with pembrolizumab versus chemotherapy, and as monotherapy in participants with locally advanced or metastatic urothelial cancer (UC). The study includes a dose selection for zelenectide pevedotin and is comprised of 2 cohorts. Cohort 1 will include participants who have not received any prior systemic therapy for locally advanced or metastatic UC and are eligible to receive platinum-based chemotherapy, whereas Cohort 2 will include participants who have received ≥ 1 prior systemic therapy for locally advanced or metastatic UC.

Age: 18 Years and older

Gender: All

Start Date: 01/24/2024

Primary Completion Date (Estimated): 03/01/2028

Study Completion Date (Estimated): 03/01/2028

Accepts Healthy Volunteers: No

Trial Purpose and Description

Eligibility Criteria

Age: 18 Years and older

Gender: All

Accepts Healthy Volunteers: No

Key inclusion criteria:

* Life expectancy ≥ 12 weeks.

* Measurable disease as defined by RECIST v1.1.

* Histologically or cytologically confirmed locally advanced (unresectable) or metastatic UC of the renal pelvis, ureter, bladder, or urethra.

* Archival or fresh tumor tissue comprising primary or metastatic UC should be available for submission to central laboratory.

* Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose).

* Cohort 1: Previously Untreated: Eligible to receive platinum-based chemotherapy (either cisplatin- or carboplatin-based chemotherapy based on Investigator decision.

* Cohort 1: Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions:

1. Prior local intravesical chemotherapy, local surgery when full resection is not achieved, local immunotherapy, and radiotherapy are permitted if completed at least 4 weeks prior to the initiation of study treatment and all acute toxicities have resolved.

2. Prior neoadjuvant/adjuvant chemotherapy or monomethyl auristatin E (MMAE)-based therapy with recurrence \>12 months from completion of therapy.

3. Prior neoadjuvant/adjuvant immune checkpoint inhibitor therapy with recurrence \>12 months from completion of therapy.

* Cohort 2: Previously Treated: Participants must have received ≥ 1 prior systemic treatment for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy.

* Cohort 2: Progression or recurrence of UC during or following receipt of most recent therapy.

Key exclusion criteria:

* Active keratitis or corneal ulcerations.

* Requirement, while receiving study medications, for treatment with strong inhibitors or strong inducers of human cytochrome P450 3A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors.

* Any condition requiring current treatment with high dose corticosteroids (\> 10 mg daily prednisone or equivalent).

* Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.

* Has not adequately recovered from recent major surgery (excluding placement of vascular access).

* Receipt of live or attenuated vaccine within 30 days of first dose.

* Cohort 1: Previously Untreated: Prior treatment with a checkpoint inhibitor (CPI) for any other malignancy within the last 12 months.

* Cohort 2: Previously Treated: Received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy.

* Cohort 2: Prior treatment with enfortumab vedotin or any other MMAE-based therapy