Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)

Summary

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).

Eligibility

Inclusion Criteria:

* Age 18 to 75 years at the time of consent.
* Histologically or cytologically confirmed small cell lung cancer (SCLC) that is metastatic, extensive-stage, or unresectable, and relapsed or refractory after at least 1 prior systemic regimen (must include a platinum-based regimen unless contraindicated).
* At least one measurable lesion per RECIST v1.1.
* ECOG performance status 0 to 1.
* Adequate organ function (hematologic, renal, hepatic, and cardiac) as defined in the protocol (examples: ANC \>= 1.0 x10\^9/L, platelets \>= 75 x10\^9/L, creatinine clearance \>= 50 mL/min, AST/ALT \<= 3 x ULN, total bilirubin \<= 1.5 x ULN).
* Life expectancy \>= 12 weeks.
* Tumor tissue available (archival or fresh) for antigen profiling (DLL3, CD56/NCAM1, GD2).
* Negative pregnancy test for persons of childbearing potential; agreement to use effective contraception for the protocol-defined duration.

Exclusion Criteria:

* Active or uncontrolled CNS metastases or leptomeningeal disease (treated/stable CNS metastases may be allowed per protocol).
* Prior treatment with CAR-T, CAR-NK, or other gene-modified cellular therapy within 6 months (or any prior therapy directed against the investigational target antigens if it would confound safety/efficacy assessment).
* Allogeneic hematopoietic stem cell transplant within 6 months or active graft-versus-host disease.
* Active uncontrolled infection, including uncontrolled HIV, active hepatitis B or C with viremia, or active tuberculosis.
* Clinically significant cardiovascular disease (e.g., recent myocardial infarction within 6 months, uncontrolled arrhythmia, LVEF \< 45%).
* Active autoimmune disease requiring systemic immunosuppression; chronic systemic corticosteroid use \> 10 mg/day prednisone equivalent (unless for physiologic replacement).
* Concurrent malignancy requiring active treatment (exceptions may apply for certain non-melanoma skin cancers or in situ cancers).
* Pregnant or breastfeeding.
* Any condition that, in the investigator's opinion, would make participation unsafe or interfere with compliance.

Conditions5

Interventions2

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