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

Official title

A Phase 1, Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of GB-4362 Administered With Enfortumab Vedotin and Pembrolizumab in Participants With Advanced Urothelial Cancer

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.

Detailed 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.

Interventions

• Drug GB-4362
  GB-4362 is an investigational monoclonal antibody
• Drug enfortumab vedotin (EV)
  Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4 that delivers the cytotoxic payload monomethyl auristatin E (MMAE).
• Drug Pembrolizumab
  Pembrolizumab is a programmed death-1 (PD-1) immune checkpoint inhibitor administered as standard-of-care therapy for advanced urothelial cancer.

Primary outcome measures

• Incidence of AEs and SAEs [Time frame: From first dose of GB-4362 through 18 weeks after the last dose of GB-4362 (or prior to initiation of subsequent anti-cancer therapy, whichever occurs first).]

Secondary outcome measures (3)

• Pharmacokinetics of GB-4362 [Time frame: From first dose of GB-4362 through 18 weeks after the last dose of GB-4362 (or prior to initiation of subsequent anti-cancer therapy, whichever occurs first).]
• Reduction of Free MMAE Levels [Time frame: From first dose of GB-4362 through 18 weeks after the last dose of GB-4362 (or prior to initiation of subsequent anti-cancer therapy, whichever occurs first).]
• Immunogenicity of GB-4362 [Time frame: From first dose of GB-4362 through 18 weeks after the last dose of GB-4362 (or prior to initiation of subsequent anti-cancer therapy, whichever occurs first).]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• City of Hope — Duarte
• COH Lennar — Irvine
• Orlando Health — Orlando
• COH Atlanta — Tucker
• COH Chicago — Zion
• Rutgers — New Brunswick
• Start New York, LLC — Lake Success
• MSK — New York
• … and 2 more centers

Identifiers

NCT: NCT07484022 · GB-4362-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗