Advanced Urothelial Cancer, Metastatic Urothelial Carcinoma
Conditions
Keywords
GB-4362, Enfortumab Vedotin, Pembrolizumab, Peripheral Neuropathy, Antibody-Drug Conjugate, MMAE, Phase 1 Oncology, Dose Escalation, Dose Expansion
Brief summary
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
DRUGGB-4362
GB-4362 is an investigational monoclonal antibody
Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4 that delivers the cytotoxic payload monomethyl auristatin E (MMAE).
DRUGPembrolizumab
Pembrolizumab is a programmed death-1 (PD-1) immune checkpoint inhibitor administered as standard-of-care therapy for advanced urothelial cancer.
Sponsors
Generate Biomedicines
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label, sequential dose-escalation and dose-expansion study in which participants are enrolled in cohorts to receive increasing dose levels of GB-4362 administered in combination with standard-of-care enfortumab vedotin and pembrolizumab. Dose escalation decisions are based on cumulative safety and pharmacodynamic data from previously enrolled participants.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of AEs and SAEs | 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
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of GB-4362 | 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). | Maximum plasma concentration (Cmax) of GB-4362 following administration with enfortumab vedotin and pembrolizumab. |
| Reduction of Free MMAE Levels | 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 | 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). | Incidence of treatment emergent anti-drug antibody against GB-4362 |
Countries
United States
Contacts
CONTACTStudy Contact
Outcome results
None listed