Overview
The purpose of this study is to evaluate the safety and tolerability of an investigational drug called GB-4362 when it is given together with enfortumab vedotin and pembrolizumab in adults with advanced or metastatic urothelial cancer. GB-4362 is a monoclonal antibody designed to bind and neutralize free monomethyl auristatin E (MMAE), a chemotherapy payload released from enfortumab vedotin that is associated with side effects such as peripheral neuropathy.
Description
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.
Eligibility
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
