NCT06225596 - Study BT8009-230 in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2) | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Cohort 1: Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1(RECIST v1.1) by blinded central independent review (BICR) of optimal dose zelenectide pevedotin with pembrolizumab versus chemotherapy

The time from randomization to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 2: PFS per RECIST v1.1 assessed by BICR of zelenectide pevedotin monotherapy in each treatment regimen

The time from randomization to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 2: Objective response rate (ORR) per RECIST v1.1 assessed by BICR of zelenectide pevedotin monotherapy in each treatment regimen

Time frame: Up to approximately 4 years

Secondary Outcomes

Cohort 1: PFS per RECIST v1.1 assessed by BICR of zelenectide pevedotin combined treatment arms versus chemotherapy

The time from randomization to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 1: ORR per RECIST v1.1 assessed by BICR of optimal dose zelenectide pevedotin in combination with pembrolizumab versus chemotherapy.

Time frame: Up to approximately 4 years

Cohort 1: ORR per RECIST v1.1 assessed by BICR of zelenectide pevedotin combined treatment arms versus chemotherapy

Time frame: Up to approximately 4 years

Cohort 1: Overall survival (OS) rate of optimal dose zelenectide pevedotin in combination with pembrolizumab versus chemotherapy

The time from randomization to date of death from any cause.

Time frame: Up to approximately 4 years

Cohort 1: Duration of response (DoR) per RECIST v1.1 assessed by BICR of optimal dose of zelenectide pevedotin in combination with pembrolizumab

The time from time of first documentation of objective response that is subsequently confirmed to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 1: Disease control rate (DCR) per RECIST v1.1 assessed by BICR of optimal dose of zelenectide pevedotin in combination with pembrolizumab

The time from randomization to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 1: PFS per RECIST v1.1 assessed by BICR of unselected zelenectide pevedotin dose in combination with pembrolizumab

The time from randomization to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 1: OS rate of zelenectide pevedotin combined treatment arms in combination with pembrolizumab versus chemotherapy

The time from randomization to date of death from any cause

Time frame: Up to approximately 4 years

Cohort 2: DoR per RECIST v1.1 assessed by BICR in each treatment regimen

The time from time of first documentation of objective response that is subsequently confirmed to date of first documentation of disease progression or death.

Time frame: Up to approximately 4 years

Cohort 2: DCR per RECIST v1.1 assessed by BICR in each treatment regimen

The time from cycle 1 Day 1 to date of first documentation of disease progression or death

Time frame: Up to approximately 4 years

Cohort 2: OS rate in each treatment regimen

The time from randomization to date of death from any cause

Time frame: Up to approximately 4 years

Cohorts 1 and 2: Safety and tolerability of each treatment regimen

Safety will be reported as incidence, severity, seriousness, relationship to study and types of adverse events

Time frame: Until 30 days post last dose, up to approximately 4 years

Cohorts 1 and 2: Exposure-efficacy relationships for zelenectide pevedotin area under the plasma concentration-time curve (AUC)

Quantitative modeling of the association between measured zelenectide pevedotin pharmacokinetic (PK) parameter (AUC) and ORR.