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This study is an open-label, multi-center, adaptive Phase 1/2 trial evaluating the safety, feasibility, and preliminary antitumor activity of allogeneic dual-target CAR-NK cell products in adults with relapsed or refractory small cell lung cancer (SCLC). Three candidate dual-target constructs (DLL3/CD56, DLL3/GD2, and CD56/GD2) will be assessed during dose escalation; a pre-specified interim assessment will select the most suitable construct to proceed into an expansion cohort at the recommended Phase 2 dose (RP2D).
Rationale: SCLC is characterized by rapid progression, early relapse after platinum-based therapy, and antigen heterogeneity. DLL3, CD56 (NCAM1), and GD2 are frequently evaluated SCLC-associated surface targets. Dual-target CAR designs may reduce antigen-escape risk compared with single-target approaches. Investigational products: Three off-the-shelf allogeneic CAR-NK cell products are evaluated. Each product is manufactured from healthy-donor NK cells and engineered to express a dual-target CAR plus a safety switch (e.g., inducible caspase-9) and a persistence support element (e.g., IL-15 support). The exact construct features can be adapted to the sponsor's platform. Study schema: (1) Screening and biomarker assessment, including tumor antigen profiling for DLL3, CD56, and GD2 by immunohistochemistry (IHC) or validated equivalent assay. (2) Phase 1 dose escalation in up to three parallel arms (one arm per dual-target construct) using a modified 3+3 design to determine MTD and/or RP2D. (3) Interim construct selection based on a composite of safety (DLT rate), manufacturability/feasibility, in vivo expansion/persistence, and preliminary efficacy. (4) Phase 2 expansion cohort treated with the selected construct at RP2D to further characterize safety and estimate antitumor activity. Conditioning and dosing: Participants receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide) followed by CAR-NK infusion(s). Because NK-cell persistence can be limited, repeat dosing within a cycle is permitted (e.g., Day 0, Day 7, Day 14), and a second cycle may be allowed in responders without prohibitive toxicity. Safety monitoring: Participants are monitored for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infusion reactions, cytopenias, infections, and other adverse events. An independent safety monitoring committee reviews cumulative safety at each dose level and prior to construct selection. Follow-up: Clinical follow-up continues for 24 months for efficacy and late toxicity. Long-term follow-up for gene-modified cell products (up to 15 years) may be conducted per local regulatory requirements to monitor delayed adverse events.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| DLL3/CD56 Dual-Target CAR-NK (EB-DART-NK01) | Experimental | Allogeneic dual-target CAR-NK cells targeting DLL3 and CD56 (NCAM1) following lymphodepleting chemotherapy. |
|
| DLL3/GD2 Dual-Target CAR-NK (EB-DART-NK02) | Experimental | Allogeneic dual-target CAR-NK cells targeting DLL3 and GD2 following lymphodepleting chemotherapy. |
|
| CD56/GD2 Dual-Target CAR-NK (EB-DART-NK03) | Experimental | Allogeneic dual-target CAR-NK cells targeting CD56 (NCAM1) and GD2 following lymphodepleting chemotherapy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EB-DART-NK01 (DLL3/CD56 CAR-NK cells) | Biological | EB-DART-NK01 (DLL3/CD56 CAR-NK cells) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 28 Days | |
| Maximum tolerated dose (MTD) | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Objective response rate (ORR) | 12 months | |
| Progression-free survival (PFS) | 24 months | |
| Overall survival (OS) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Seni S Lu, Phd | Contact | +86 13076790030 | Seni-Lu@beijing-biotech.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Peking University Shenzhen Hospital | Recruiting | Shenzhen | Guangdong | 518036 | China |
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During Phase 1, participants are treated in one of three arms corresponding to a dual-target CAR-NK construct. Assignment is non-randomized and guided by tumor antigen profiling (and/or slot availability). After interim analysis, one construct is selected for Phase 2 expansion at RP2D.
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No masking is used. Radiographic response assessments may undergo blinded independent central review to support objectivity.
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| Lymphodepleting chemotherapy | Drug | (fludarabine + cyclophosphamide) |
|
| 24 months |
| ID | Term |
|---|---|
| D055752 | Small Cell Lung Carcinoma |
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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