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

Official title

A Phase 1/2 Adaptive Dose-Escalation and Expansion Study of Dual-Targeting Chimeric Antigen Receptor Natural Killer (CAR-NK) Cells Directed Against DLL3, CD56 (NCAM1), and/or GD2 in Adults With Relapsed/Refractory Small Cell Lung Cancer

Overview

This example 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).

Detailed description

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

Interventions

• Biological EB-DART-NK01
  Allogeneic dual-target CAR-NK cells engineered to enhance tumor recognition and cytotoxicity against heterogeneous solid tumors.
• Drug Lymphodepleting chemotherapy
  An alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity.

Primary outcome measures

• Incidence of dose-limiting toxicities [Time frame: 28 Days]
• maximum tolerated dose (MTD) [Time frame: 12 months]

Secondary outcome measures (2)

• Objective response rate [Time frame: 12 months]
• Disease control rate [Time frame: 12 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Shenzhen Hospital — Shenzhen

Identifiers

NCT: NCT07744256 · EB-CARNK-SCLC-014

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗