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

NCT07492628 | Recruiting Phase 1 DMC

• 1 other identifier: EB-DT-NK-UC-105
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

CAR-NK; allogeneic NK cells; Nectin-4; HER2; ERBB2; urothelial carcinoma; bladder cancer; dual-target; lymphodepletion; solid tumor immunotherapy; EpCAM; RP2D

Outcome Measures

Primary Outcomes (2)

• Incidence of dose-limiting toxicities (DLTs)

  28 Days

• Incidence and severity of treatment-emergent adverse

  Incidence and severity of treatment-emergent adverse events graded by CTCAE v5.0,including CRS, ICANS, infusion reactions, GvHD, and organ-specific toxicities

  12 months

Secondary Outcomes (5)

• Objective response rate (ORR) by RECIST v1.1

  12 months

• Disease control rate

  12 months

• Duration of response

  24 months

• Progression-free survival

  24 months

• Overall survival

  24 months

Study Arms (2)

Dose Escalation

EXPERIMENTAL

Participants receive lymphodepletion with cyclophosphamide and fludarabine followed by EB-DT-NK-UC101 IV infusions on Day 1 and Day 8 of a 21-day cycle. Planned dose levels: 1 × 10\^7, 3 × 10\^7, and 1 × 10\^8 CAR-NK cells/kg

Biological: EB-DT-NK-UC101; Drug: Cyclophosphamide; Drug: Fludarabine

Dose Expansion

EXPERIMENTAL

Participants receive the RP2D identified in Arm A using the same lymphodepletion backbone and infusion schedule. Expansion enriches for Nectin-4-positive disease and captures HER2 co-expression prospectively.

Biological: EB-DT-NK-UC101; Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

EB-DT-NK-UC101 BIOLOGICAL

Allogeneic cord-blood-derived dual-target Nectin-4/HER2 CAR-NK cells with inducible caspase-9 safety switch.

Dose Escalation; Dose Expansion

Cyclophosphamide DRUG

Lymphodepleting chemotherapy given before the first CAR-NK infusion.

Dose Escalation; Dose Expansion

Fludarabine DRUG

Lymphodepleting chemotherapy given before the first CAR-NK infusion

Also known as: lymphodepletion

Dose Escalation; Dose Expansion

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years at consent.
• Histologically confirmed urothelial carcinoma of the bladder, ureter, renal pelvis, or urethra that is unresectable locally advanced or metastatic.
• Disease progression after, intolerance to, or ineligibility for standard therapy, including platinum-based chemotherapy and PD-1/PD-L1 blockade when appropriate for the patient and region. Prior enfortumab vedotin and prior HER2-directed therapy are allowed, but a fresh biopsy is strongly preferred after the latest systemic regimen.
• At least one measurable lesion per RECIST v1.1.
• Tumor tissue available for central review demonstrating Nectin-4 positivity (for example, IHC ≥1+ in ≥10% tumor cells) and HER2 status assessed by IHC/ISH. At least one of the selected therapeutic targets must be present; dose expansion preferentially enrolls Nectin-4-positive disease.
• ECOG performance status 0-1.
• Adequate bone marrow, hepatic, renal, and coagulation function.
• Life expectancy of at least 12 weeks.
• Negative pregnancy test for women of childbearing potential and agreement to use highly effective contraception during study treatment and follow-up as defined in the protocol.
• Ability to understand and sign informed consent.

You may not qualify if:

• Active or untreated central nervous system metastases or leptomeningeal disease. Previously treated CNS disease is allowed if clinically stable and off escalating corticosteroids.
• Prior allogeneic hematopoietic stem cell transplant, prior solid-organ transplant, or active graft-versus-host disease.
• Clinically significant autoimmune disease requiring systemic immunosuppression within the defined washout window.
• Uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, sepsis, or active tuberculosis.
• Clinically significant cardiac disease, active myocarditis, unstable angina, recent myocardial infarction, uncontrolled arrhythmia, or clinically meaningful decline in left ventricular ejection fraction that would increase risk from HER2-directed cell therapy.
• Clinically significant pulmonary disease (for example, uncontrolled interstitial lung disease or oxygen-dependent respiratory compromise).
• Use of systemic corticosteroids or other immunosuppressive medications above protocol-allowed limits within the washout window.
• History of severe hypersensitivity to fludarabine, cyclophosphamide, or cell-product excipients.
• Pregnancy or breastfeeding.
• Another active malignancy requiring systemic therapy or likely to interfere with protocol assessments, except for protocol-allowed low-risk cancers.

Sponsors & Collaborators

• Beijing Biotech: lead

Study Sites (1)

Peking University Shenzhen Hospital

Shenzhen, Guangdong, 518036, China

RECRUITING

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Central Study Contacts

Seni S Lu, Phd

CONTACT

+86 13076790030; Seni-Lu@beijing-biotech.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A: 3+3 dose-escalation with sentinel dosing of allogeneic dual-target Nectin-4/HER2 CAR-NK cells after fludarabine/cyclophosphamide lymphodepletion to determine MTD/RP2D. Part B: dose-expansion at RP2D to further define safety, feasibility, and preliminary anti-tumor activity in biomarker-positive urothelial carcinoma

Study Record Dates

• First Submitted: March 20, 2026
• First Posted: March 25, 2026
• Study Start: March 2, 2026
• Primary Completion (Estimated): June 14, 2027
• Study Completion (Estimated): May 17, 2028
• Last Updated: March 25, 2026

Record last verified: 2026-03

Locations

CN (1)