Dual-Target CLDN18.2/HER2 CAR-NK Cells for Advanced Esophageal Adenocarcinoma
A Phase 1/2, Open-Label, Biomarker-Selected Study of Allogeneic Dual-Target CLDN18.2/HER2 Chimeric Antigen Receptor Natural Killer Cells (EBNK-1822H2) in Adults With Relapsed, Refractory, or Metastatic Esophageal Adenocarcinoma
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background and target-selection logic. Esophageal adenocarcinoma shares biomarker biology with GEJ adenocarcinoma. In the current public development landscape, CLDN18.2 and HER2 are the two most clinically actionable candidates for a first esophageal adenocarcinoma dual-target CAR-NK concept.
This example therefore advances a CLDN18.2/HER2 tandem-target product and treats EGFR as a pre-specified exploratory biomarker, not as the primary CAR target in version 1.
Investigational product. EBNK-1822H2 is a hypothetical off-the-shelf NK-cell product derived from cord blood and engineered with a tandem CAR recognizing CLDN18.2 and HER2, together with a persistence-support module (for example, membrane-bound IL-15) and an inducible caspase-9 safety switch. This is an example investigational product description for protocol-drafting purposes only.
Study structure. Phase 1 uses an open-label dose-escalation design after fludarabine/cyclophosphamide lymphodepletion to identify the maximum tolerated dose (MTD) and recommended phase 2 dose/schedule (RP2D/RP2S). Phase 2 expands at the selected regimen in three biomarker-defined strata: (1) CLDN18.2-positive/HER2-negative, (2) HER2-positive/CLDN18.2-low or negative, and (3) dual-positive disease. Participants receive one intravenous infusion on Day 0; a protocol-defined repeat infusion on Day 21 may be allowed in the expansion portion if there is no DLT or uncontrolled grade 3+ immune toxicity.
Correlative program. Screening includes central or local assessment of CLDN18.2 and HER2, with EGFR captured prospectively at baseline and, when feasible, at progression. Correlative studies include ctDNA response, cytokine profiling, CAR-NK persistence, tumor microenvironment markers, and antigen-pattern analyses to inform future multi-target program evolution.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: shan S Lu, Phd
- Phone Number: +86 13076790030
- Email: Seni-Lu@beijing-biotech.com
Study Locations
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Guangdong
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Shenzhen, Guangdong, China, 518036
- Recruiting
- Peking University Shenzhen Hospital
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Contact:
- Zhen J Peng, Phd
- Phone Number: +86 13076790039
- Email: Zhen-Peng@beijing-biotech.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Histologically confirmed esophageal adenocarcinoma or Siewert I/II gastroesophageal junction adenocarcinoma judged biologically consistent with esophageal adenocarcinoma, unresectable/recurrent/metastatic, and not amenable to curative therapy.
- Disease progressed after at least 1 prior systemic regimen for advanced disease, or the participant is intolerant of / ineligible for standard therapy. Biomarker-directed therapy must have been received or deemed inappropriate/unavailable where standard in the local setting.
- At least 1 measurable lesion by RECIST v1.1.
Evidence of at least one selected target: CLDN18.2-positive by validated IHC (example threshold: membranous staining in
≥75% of tumor cells with moderate/strong intensity or protocol-specified central threshold), and/or HER2-positive by IHC 3+ or IHC 2+/ISH-amplified disease.
- ECOG performance status 0-1.
- Adequate marrow, renal, hepatic, pulmonary, and cardiac function per protocol laboratory thresholds.
- Life expectancy ≥12 weeks.
- Resolution of clinically significant prior-therapy toxicities to grade ≤1 (except alopecia or stable endocrinopathies).
- Willingness to provide archival tumor tissue and to undergo fresh biopsy when safely feasible.
- Negative pregnancy test for participants of childbearing potential and agreement to protocol-defined contraception.
Exclusion Criteria:
- Esophageal squamous cell carcinoma or non-adenocarcinoma histology.
- Known active CNS metastases or leptomeningeal disease; previously treated stable CNS disease may be allowed only if asymptomatic and off escalating steroids per protocol.
- Prior gene-modified cellular therapy within 12 weeks, or another investigational therapy likely to confound interpretation of safety or efficacy.
- Active uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV viremia, sepsis, or clinically significant opportunistic infection.
- Ongoing systemic immunosuppressive therapy above physiologic steroid replacement.
- Active autoimmune disease requiring systemic treatment within 2 years.
- Clinically significant interstitial lung disease/pneumonitis, uncontrolled cardiovascular disease, or left ventricular ejection fraction <50%.
- Active gastrointestinal perforation, uncontrolled bleeding, or clinically significant mucosal ulceration that would increase study-treatment risk.
- Prior solid organ transplant or active graft-versus-host disease.
- Pregnant or breastfeeding.
- Another active malignancy requiring systemic therapy, except protocol-permitted low-risk cancers.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: EBNK-1822H2 after lymphodepletion
Participants receive fludarabine and cyclophosphamide lymphodepletion followed by intravenous infusion of allogeneic dual-target CLDN18.2/HER2
CAR-NK cells on Day 0. A protocol-defined repeat infusion on Day 21 may be permitted in dose expansion if safety criteria are met.
|
Illustrative allogeneic cord blood-derived NK-cell product engineered to recognize CLDN18.2 and HER2.
Other Names:
Lymphodepletion backbone
Other Names:
Lymphodepletion backbone
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Incidence of dose-limiting toxicities (DLTs)
Time Frame: 28 days
|
28 days
|
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Incidence and severity of treatment-emergent adverse events
Time Frame: 12 months
|
12 months
|
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Recommended phase 2 dose
Time Frame: 6 months
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Objective response rate (ORR) by RECIST v1.1
Time Frame: 12 months
|
12 months
|
|
Disease control rate (DCR) by RECIST v1.1
Time Frame: 12 months
|
12 months
|
|
Duration of response
Time Frame: 12 Months
|
12 Months
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Disease Attributes
- Pathological Conditions, Signs and Symptoms
- Recurrence
- Adenocarcinoma Of Esophagus
- Organic Chemicals
- Hydrocarbons
- Phosphoramide Mustards
- Nitrogen Mustard Compounds
- Mustard Compounds
- Hydrocarbons, Halogenated
- Phosphoramides
- Organophosphorus Compounds
- Cyclophosphamide
- fludarabine
- fludarabine phosphate
Other Study ID Numbers
- EBNK-EAC-1822H2-116
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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