This example planning study proposes a phase 1/2 evaluation of an allogeneic, cord-blood-derived dual-target CAR-NK product directed against CLDN18.2 and HER2 (ERBB2) in adults with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma after prior standard systemic therapy. CLDN18.2 is selected as the anchor antigen because it has the more disease-specific gastric/GEJ cell-therapy development footprint, while HER2 is retained as the complementary second antigen to address co-expressing or heterogeneous disease. Phase 1 uses a 3+3 dose-escalation design after fludarabine/cyclophosphamide lymphodepletion followed by three intravenous CAR-NK infusions on Days 0, 3, and 7. Phase 2 expansion evaluates the recommended phase 2 dose and preliminary antitumor activity
This draft is intentionally modeled on current CLDN18.2- and HER2-directed cell-therapy studies on ClinicalTrials.gov and related primary publications. The key strategic choice is that HER2 and ERBB2 are treated as the same target; therefore the meaningful dual-target construct in gastric/GEJ cancer is CLDN18.2 plus HER2. The study is designed as a biomarker-driven, non-randomized phase 1/2 program. In phase 1, patients will receive fludarabine/cyclophosphamide lymphodepletion on Days -5 to -3, followed by three infusions of EB-DT-CAR-NK on Days 0, 3, and 7. A 3+3 dose-escalation structure with three planned dose levels will be used to determine dose-limiting toxicities, maximum tolerated dose, and/or recommended phase 2 dose. In phase 2, patients will receive the recommended dose on the same schedule in an expansion cohort focused on CLDN18.2-positive gastric/GEJ adenocarcinoma, with prespecified subgroup analyses by HER2 status. The study will assess safety, objective response rate, disease control, durability, survival outcomes, and CAR-NK expansion/persistence. Correlative studies will explore the relationship between baseline CLDN18.2/HER2 expression and clinical outcome.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Allogeneic, cord-blood-derived CAR-NK cells engineered to target CLDN18.2 and HER2 (ERBB2). Planned phase 1 dose levels: 2 x 10\^6, 4 x 10\^6, and 8 x 10\^6 cells/kg/infusion. Administered intravenously on Days 0, 3, and 7.
Lymphodepleting chemotherapy administered intravenously at 30 mg/m\^2/day on Days -5 to -3.
Lymphodepleting chemotherapy administered intravenously at 500 mg/m\^2/day on Days -5 to -3.
Peking University Shenzhen Hospital
Shenzhen, Guangdong, China
RECRUITINGIncidence of dose-limiting toxicities (DLTs)
DLTs graded by CTCAE v5.0, with CRS and ICANS graded using ASTCT criteria.
Time frame: 28 days
Determination of MTD
Dose-escalation decision based on DLT frequency and overall tolerability across planned cohorts.
Time frame: 6 months
Objective response rate (ORR)
Confirmed complete response plus partial response according to RECIST v1.1 in evaluable subjects in the expansion cohort.
Time frame: 12 months
Progression-free survival (PFS)
Time from first infusion to disease progression or death from any cause.
Time frame: 12 months
Overall survival (OS)
Time from first infusion to death from any cause.
Time frame: 24 months
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