Metastatic Cutaneous Melanoma, Metastatic Uveal Melanoma, Unresectable Melanoma
Conditions
Keywords
CAR-NK, allogeneic NK cells, CSPG4, GD2, advanced melanoma, uveal melanoma, cell therapy, biomarker-guided, solid tumor
Brief summary
This is a first-in-human, open-label, multicenter phase 1/2 study evaluating the safety, feasibility, recommended phase 2 dose (RP2D), and preliminary antitumor activity of allogeneic dual-target CSPG4/GD2 CAR-NK cells (EBDTKN-401) after lymphodepleting chemotherapy in adults with unresectable or metastatic cutaneous melanoma or metastatic uveal melanoma whose disease has progressed after standard therapy
Detailed description
The target-selection review favored CSPG4/GD2 because it gives the strongest melanoma-centered rationale across both cutaneous and uveal disease. EBDTKN-401 is an allogeneic donor-derived NK-cell product engineered with an OR-gate/tandem CAR recognizing CSPG4 or GD2 and an inducible caspase-9 safety switch. Part A uses 3+3 dose escalation to identify the RP2D. Part B evaluates the RP2D in expansion cohorts for cutaneous melanoma and uveal melanoma. Key secondary objectives are objective response, disease control, durability, progression-free survival, overall survival, CAR-NK persistence, and baseline biomarker-response relationships.
Interventions
BIOLOGICALEB-DTKN-401 allogeneic dual-target CSPG4/GD2 CAR-NK cells
Genetically engineered natural killer (NK) cells expressing dual chimeric antigen receptors targeting CSPG4 and GD2 are expanded ex vivo and infused (IV) into patients. These cells recognize tumor antigens and induce targeted cytotoxicity, aiming to improve tumor killing and reduce antigen escape in CSPG4/GD2-positive cancers.
DRUGFludarabine
Fludara
DRUGCyclophosphamide
Cyclophosphamide
Sponsors
Beijing Biotech
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label conduct is appropriate because cell-product identity, dose level, and near-real-time toxicity management must remain visible to investigators and treating teams in a first-in-human adoptive cell-therapy study.
Intervention model description
Part A uses a 3+3 dose-escalation design across three planned dose levels (1×10\^7, 3×10\^7, and 1×10\^8 CAR-NK cells/kg). After RP2D selection, Part B opens parallel subtype-specific expansion cohorts for cutaneous melanoma and uveal melanoma at the RP2D. Participants are not randomized.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-75 years at consent. * Histologically confirmed unresectable/metastatic cutaneous melanoma or metastatic uveal melanoma. * Disease progression after standard therapy, intolerance to standard therapy, or no remaining standard option expected to provide meaningful benefit. For cutaneous melanoma: prior anti-PD-1/L1 (with or without antiCTLA-4) unless contraindicated; if BRAF V600-mutant, prior BRAF/MEK inhibitor therapy or documented unsuitability. For uveal melanoma: prior tebentafusp if HLA-A\*02:01-positive and eligible, or documented unsuitability/unavailability plus at least one prior systemic therapy. * Tumor demonstrates CSPG4 and/or GD2 expression in archival or fresh tissue by central testing (suggested positivity threshold: at least 25% viable tumor cells by IHC or equivalent validated assay). * At least 1 measurable lesion by RECIST v1.1. * ECOG performance status 0-1. * Adequate bone marrow, renal, hepatic, cardiac, and pulmonary function per protocol. * Life expectancy of at least 12 weeks. * Treated, stable brain metastases are allowed if neurologically stable for at least 4 weeks and not requiring escalating corticosteroids. * Willingness to use effective contraception and comply with protocol-required visits, blood sampling, and requested biopsies.
Exclusion criteria
* Active symptomatic CNS metastases, leptomeningeal disease, or uncontrolled seizure disorder. * Prior allogeneic stem cell transplant or solid organ transplant; prior gene-modified cellular therapy within 12 weeks; or anti-cancer therapy too close to lymphodepletion per protocol washout rules. * Requirement for systemic immunosuppression greater than 10 mg prednisone equivalent/day or uncontrolled autoimmune/inflammatory disease requiring systemic treatment. * Active uncontrolled infection, including uncontrolled HIV, HBV, or HCV, or fever/sepsis at the time lymphodepletion would begin. * Clinically significant cardiovascular disease, uncontrolled arrhythmia, recent myocardial infarction, or uncontrolled thromboembolic disease. * Grade 2 or higher unresolved toxicities from prior therapy, except stable endocrinopathy, alopecia, or vitiligo. * Pregnancy or breastfeeding. * Any condition that, in the investigator's judgment, would make lymphodepletion or CAR-NK infusion unsafe.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of dose-limiting toxicities (DLTs) using CTCAE v5.0 | 28 Days |
| Recommended Phase 2 Dose (RP2D) | 42 Days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent adverse events ( TEDE ) | 12 Month | Treatment-emergent adverse events including CRS, ICANS, prolonged cytopenias, neuropathic pain, ocular toxicity, and GVHD |
| Objective response rate (ORR) by RECIST v1.1 | 12 Month | — |
| Disease control rate (DCR) by RECIST v1.1 | 12 Month | — |
| Duration of response | 24 Month | — |
| Progression-free survival (PFS) | 24 Month | — |
| Overall survival | 24 Months | — |
Countries
China
Contacts
CONTACTSeni S Lu, Phd
Outcome results
None listed