Study of GB-4362 With Enfortumab Vedotin and Pembrolizumab for Advanced Urothelial Cancer

This is a Phase 1, open-label, multicenter, dose-finding study designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-4362 administered in combination with standard-of-care enfortumab vedotin and pembrolizumab in participants with locally advanced or metastatic urothelial cancer.

Enfortumab vedotin is an antibody-drug conjugate containing the cytotoxic payload monomethyl auristatin E (MMAE). Systemic exposure to unconjugated (free) MMAE has been associated with dose-limiting toxicities, including peripheral neuropathy. GB-4362 is a monoclonal antibody designed to selectively bind and neutralize free MMAE in circulation, with the goal of reducing off-target toxicity while preserving the anti-tumor activity of enfortumab vedotin.

The study consists of two parts: dose escalation and dose expansion. Multiple dose levels of GB-4362 will be evaluated using a cohort-based escalation design to assess safety, identify dose-limiting toxicities, and characterize PK and PD, including the extent of free MMAE reduction. Dose escalation decisions will be reviewed by a Safety Monitoring Committee.

Following dose escalation, a dose expansion phase will enroll additional participants at the selected GB-4362 dose level to further evaluate safety, PK and PD. Exploratory assessments will include evaluation of peripheral neuropathy, dose modifications of enfortumab vedotin, and descriptive analyses of anti-tumor activity.

Inclusion criteria

• Planned to receive standard-of-care treatment with enfortumab vedotin (EV) (starting dose 1.25 mg/kg) in combination with pembrolizumab for locally advanced or metastatic urothelial cancer.
• Age ≥18 years.
• ECOG Performance Status score of 0 or 1 (ECOG 2 excluded in Dose Escalation but allowed in Dose Expansion).
• Weight ≥50 kg at screening.
• Life expectancy ≥3 months, as determined by the investigator.
• Participants must provide written informed consent before any study-related activities are carried out and must be able to understand the nature and purpose of the study, including potential risks and adverse effects.
• Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion criteria

• Previously received enfortumab vedotin (EV) or other MMAE-based antibody-drug conjugates (ADCs).
• Received anti-cancer treatment with chemotherapy, biologics, or investigational agents within 4 weeks before the first dose of EV/pembrolizumab.
• Uncontrolled diabetes.
• Active CNS metastases. Participants with treated CNS metastases are permitted if all of the following criteria are met:
• CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis.
• The participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment).
• The participant does not have leptomeningeal disease.
• Ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to Grade ≤1 or returned to baseline.
• History of a severe (Grade ≥3) allergic or infusion-related reaction to any monoclonal antibody.
• Another underlying medical condition that, in the opinion of the investigator, would impair the ability of the participant to receive or tolerate the planned treatment and follow-up.
• Known psychiatric or substance abuse disorders that would interfere with cooperating with study requirements