NCT07492628

Dual-Target Nectin-4/HER2 CAR-NK Cells in Advanced Urothelial Carcinoma

A Phase 1, Open-Label, Multicenter, Non-Randomized, Dose-Escalation and Dose-Expansion Study of Allogeneic Dual-Target Nectin-4/HER2 CAR-NK Cells Following Fludarabine/Cyclophosphamide Lymphodepletion in Adults With Relapsed/Refractory, Locally Advanced or Metastatic Urothelial Carcinoma

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 42 (estimated)
• Sponsor: Beijing Biotech · Industry
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

This hypothetical first-in-human study is designed to evaluate the safety, feasibility, and preliminary anti-tumor activity of an allogeneic dual-target Nectin-4/HER2 CAR-NK cell product in adults with relapsed/refractory locally advanced or metastatic urothelial carcinoma. Based on public urothelial-cancer evidence, Nectin-4 was selected as the lead antigen because it has the strongest disease-specific clinical validation; HER2/ERBB2 was chosen as the secondary co-target to broaden tumor coverage and reduce antigen-escape risk. EpCAM is not selected as a therapeutic co-target in this example because of broader normal epithelial expression and weaker tumor specificity in urothelial carcinoma.

Detailed description

Advanced urothelial carcinoma remains a high-unmet-need disease after platinum-based chemotherapy, PD-1/PD-L1 inhibition, and-where available-Nectin-4- or HER2-directed therapies. Public trial activity in urothelial cancer strongly supports Nectin-4 as the best validated anchor antigen, while HER2 identifies a clinically relevant and actionable subset. Because both antigens can be heterogeneous, this example protocol uses mandatory pre-treatment central biomarker testing and favors fresh biopsy after the most recent systemic therapy, especially after prior enfortumab vedotin or HER2-directed treatment. The investigational product in this example is an allogeneic cord-blood-derived CAR-NK cell therapy engineered to co-recognize Nectin-4 and HER2/ERBB2 and to include an inducible caspase-9 safety switch. The product is administered intravenously after lymphodepletion with fludarabine and cyclophosphamide. Part A uses a 3+3 dose-escalation design with sentinel dosing at each new level to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Part B expands the RP2D to better characterize safety and generate preliminary efficacy data. To better address the original target shortlist, the protocol also incorporates exploratory translational analyses of EpCAM expression, circulating tumor DNA, tumor antigen co-expression, NK-cell persistence, and mechanisms of resistance. This allows future protocol versions to revisit EpCAM only if patient-specific biomarker data show a favorable therapeutic window. Tumor assessments are performed by RECIST v1.1 for measurable metastatic disease. Patients are monitored closely for dose-limiting toxicities (DLTs), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), graft-versus-host disease (GvHD), infusion reactions, and organ-specific on-target/off-tumor toxicities. Because HER2 is used as a secondary antigen, this example explicitly incorporates enhanced cardiopulmonary monitoring and conservative dose-escalation rules.

Conditions

• Bladder Cancer
• Urothelial Carcinoma
• Metastatic Urothelial Carcinoma
• Locally Advanced Urothelial Carcinoma
• Upper Tract Urothelial Carcinoma

Interventions

Type	Name	Description
BIOLOGICAL	EB-DT-NK-UC101	Allogeneic cord-blood-derived dual-target Nectin-4/HER2 CAR-NK cells with inducible caspase-9 safety switch.
DRUG	Cyclophosphamide	Lymphodepleting chemotherapy given before the first CAR-NK infusion.
DRUG	Fludarabine	Lymphodepleting chemotherapy given before the first CAR-NK infusion

Timeline

• Start date: 2026-03-02
• Primary completion: 2027-06-14
• Completion: 2028-05-17
• First posted: 2026-03-25
• Last updated: 2026-03-25

Locations

1 site across 1 country: China