Adaptive Phase 1/2 Study of Dual-Target CAR-NK Cells in Relapsed/Refractory Small Cell Lung Cancer (SCLC)
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
Studieoversikt
Status
Intervensjon / Behandling
Detaljert beskrivelse
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
Studietype
Registrering (Antatt)
Fase
- Fase 2
- Fase 1
Kontakter og plasseringer
Studiekontakt
- Navn: shan S Lu, Phd
- Telefonnummer: +86 13076790030
- E-post: Seni-Lu@beijing-biotech.com
Studiesteder
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Guangdong
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Shenzhen, Guangdong, Kina, 518036
- Rekruttering
- Peking University Shenzhen Hospital
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Ta kontakt med:
- Zhen J Peng, Phd
- Telefonnummer: +86 13076790039
- E-post: Zhen-Peng@beijing-biotech.com
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
- Voksen
- Eldre voksen
Tar imot friske frivillige
Beskrivelse
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.
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Ikke-randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
|---|---|
|
Eksperimentell: DLL3/CD56 Dual-Target CAR-NK
Allogeneic dual-target CAR-NK cells targeting DLL3 and CD56 (NCAM1) following lymphodepleting chemotherapy.
|
Allogeneic dual-target CAR-NK cells engineered to enhance tumor recognition and cytotoxicity against heterogeneous solid tumors.
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.
|
|
Eksperimentell: DLL3/GD2 Dual-Target CAR-NK
Allogeneic dual-target CAR-NK cells targeting DLL3 and GD2 following lymphodepleting chemotherapy.
|
Allogeneic dual-target CAR-NK cells engineered to enhance tumor recognition and cytotoxicity against heterogeneous solid tumors.
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.
|
|
Eksperimentell: CD56/GD2 Dual-Target CAR-NK
Allogeneic dual-target CAR-NK cells targeting CD56 (NCAM1) and GD2 following lymphodepleting chemotherapy.
|
Allogeneic dual-target CAR-NK cells engineered to enhance tumor recognition and cytotoxicity against heterogeneous solid tumors.
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.
|
Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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Incidence of dose-limiting toxicities
Tidsramme: 28 Days
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28 Days
|
|
|
maximum tolerated dose (MTD)
Tidsramme: 12 months
|
maximum tolerated dose (MTD) of the drug
|
12 months
|
Sekundære resultatmål
Resultatmål |
Tidsramme |
|---|---|
|
Objektiv svarprosent
Tidsramme: 12 måneder
|
12 måneder
|
|
Sykdomskontrollrate
Tidsramme: 12 måneder
|
12 måneder
|
Samarbeidspartnere og etterforskere
Sponsor
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Antatt)
Studiet fullført (Antatt)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Faktiske)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
Sist bekreftet
Mer informasjon
Begreper knyttet til denne studien
Nøkkelord
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- EB-CARNK-SCLC-014
Legemiddel- og utstyrsinformasjon, studiedokumenter
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