Dual-target Nectin-4 and HER2 CAR-NK therapy for 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
This treatment will try dual-target CAR-NK cells that recognize Nectin‑4 and HER2 in adults with relapsed or metastatic urothelial carcinoma after standard therapies.
Quick facts
| Phase | Phase 1 |
|---|---|
| Study type | Interventional |
| Enrollment | 42 (estimated) |
| Ages | 18 Years to 75 Years |
| Sex | All |
| Sponsor | Beijing Biotech Industry-sponsored |
| Drugs / interventions | enfortumab, chemotherapy, cyclophosphamide, fludarabine |
| Locations | 1 site (Shenzhen, Guangdong) |
| Trial ID | NCT07492628 on ClinicalTrials.gov |
What this trial studies
This first-in-human Phase 1 protocol uses allogeneic cord-blood-derived CAR-NK cells engineered to co-recognize Nectin‑4 and HER2 and to include an inducible caspase‑9 safety switch. Patients receive lymphodepletion with fludarabine and cyclophosphamide followed by intravenous infusion of the CAR‑NK product; Part A follows a 3+3 dose-escalation with sentinel dosing and Part B expands at the recommended dose. Mandatory central biomarker testing (preferably on a fresh biopsy) determines Nectin‑4/HER2 status and preferentially enrolls Nectin‑4-positive disease for dose expansion. The protocol includes exploratory translational studies such as EpCAM expression, circulating tumor DNA, tumor antigen co-expression, NK-cell persistence, and resistance mechanisms.
Who should consider this trial
Good fit: Adults 18–75 with unresectable locally advanced or metastatic urothelial carcinoma who have progressed after or are ineligible for standard therapy, have measurable disease, adequate organ function, ECOG 0–1, and tumor testing showing Nectin‑4 and/or HER2 expression are the intended candidates.
Not a fit: Patients without detectable Nectin‑4 or HER2 expression, with ECOG performance status ≥2, or with significant organ dysfunction are unlikely to benefit from this protocol.
Why it matters
Potential benefit: If successful, this approach could shrink tumors and offer a new treatment option for patients whose urothelial carcinoma has progressed after standard therapies.
How similar studies have performed: Nectin‑4 and HER2-directed therapies have shown clinical activity in urothelial cancer, but a dual-target allogeneic CAR‑NK product is first-in-human and largely untested.
Eligibility criteria
Show full inclusion / exclusion criteria
Inclusion Criteria: * 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. Exclusion Criteria: * 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.
Where this trial is running
Shenzhen, Guangdong
- Peking University Shenzhen Hospital — Shenzhen, Guangdong, China (Recruiting)
Study contacts
- Study coordinator: Seni S Lu, Phd
- Email: Seni-Lu@beijing-biotech.com
- Phone: +86 13076790030
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.