Biliary Tract Cancer, Cholangiocarcinoma, Extrahepatic Cholangiocarcinoma, Gallbladder Carcinoma, Intrahepatic Cholangiocarcinoma
Conditions
Keywords
CAR-NK, dual-target cell therapy, HER2, ERBB2, CEA, CEACAM5, cholangiocarcinoma, biliary tract cancer, allogeneic, off-the-shelf, adoptive cell therapy
Brief summary
This example phase 1/2, open-label, biomarker-selected study evaluates EB-HC01, an allogeneic dual-target CARNK product composed of a 1:1 mixture of HER2-CAR-NK and CEACAM5-CAR-NK cells, in adults with unresectable or metastatic cholangiocarcinoma or other biliary tract cancers after standard therapy. Part A determines safety, dose-limiting toxicities (DLTs), and the recommended phase 2 dose (RP2D) after reduced-intensity lymphodepletion. Part B evaluates preliminary anti-tumor activity, CAR-NK persistence, and biomarker-response associations.
Detailed description
Biliary tract cancers remain highly lethal after progression on gemcitabine/platinum-based therapy, and only a biomarker-defined minority have actionable cell-surface targets. HER2 has the strongest clinical validation among the antigens under consideration, including active HER2-targeted drug development and prior HER2 CAR-T experience in advanced BTC. CEACAM5 is retained as a complementary second target because it may reduce antigen escape and improve coverage of heterogeneous disease; however, it is treated conservatively because prior CEA-directed cell therapy has shown gastrointestinal and pulmonary toxicity in other solid tumors. EpCAM is not used for enrollment in this example because physiologic expression in the biliary tree may narrow the safety window for a first systemic study. EB-HC01 is designed as an off-the-shelf cord bloodderived NK-cell product manufactured as a fixed 1:1 mixture of HER2-CAR-NK and CEACAM5-CAR-NK cells. After fludarabine/cyclophosphamide lymphodepletion, participants receive intravenous EB-HC01 on Days 0 and 7 of a 28-day cycle. In Part A, a standard 3+3 doseescalation design evaluates 3 flat-dose levels to identify the RP2D. In Part B, an expansion cohort at RP2D better defines safety and preliminary activity in biomarkerconfirmed dual-positive BTC. Key correlative studies include central HER2 and CEACAM5 testing, ctDNA analysis, serum CA19-9 and CEA,and serial blood assessments of CAR-NK persistence and cytokine kinetics. EpCAM testing is retained as an exploratory biomarker to inform future protocol amendments but is not used to determine eligibility.
Interventions
BIOLOGICALEB-HC01 dual-target CARNK cells
EB-HC01 dual-target CARNK cells
DRUGFludarabine
Fludarabine
DRUGCyclophosphamide
Cyclophosphamide
Sponsors
Beijing Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two-part, open-label, single-group study. Part A uses a 3+3 dose-escalation design across 3 flat-dose levels (1 x10\^8, 3 x 10\^8, and 1 x 10\^9 total CAR-NK cells per infusion, delivered as a 1:1 mixture of HER2-CAR-NK and CEACAM5-CAR-NK cells). All participants receive lymphodepletion on Days -5 to -3 and EB-HC01 on Days 0 and 7 of each 28-day cycle. Part B is an expansion cohort at RP2D to better define safety and preliminary efficacy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed unresectable, recurrent, or metastatic intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder carcinoma. * Disease progression after at least 1 prior gemcitabine/platinum-containing regimen in the advanced setting; prior durvalumab and prior HER2-targeted therapy are allowed. * Central biomarker confirmation of HER2 positivity (IHC 3+ or IHC 2+/ISH+ or ERBB2 amplification) and CEACAM5/CEA positivity (membranous expression in \>=20% of viable tumor cells by IHC). * At least 1 measurable lesion according to RECIST 1.1. * ECOG performance status 0-1. * Adequate marrow, renal, hepatic, and cardiac function as defined by the protocol. * Resolved biliary obstruction or stable internal/external drainage for \>=7 days before lymphodepletion, with no active cholangitis. * Life expectancy \>=12 weeks. * Willingness to provide archival or fresh tumor tissue and serial blood samples for central biomarker testing and correlative studies. * Agreement to use protocol-specified contraception
Exclusion criteria
* Prior HER2-directed or CEA-directed gene-modified cell therapy. * Untreated or unstable CNS metastases or leptomeningeal disease. * Active uncontrolled infection, including uncontrolled cholangitis, sepsis, or clinically significant uncontrolled hepatitis or HIV infection. * Ongoing systemic immunosuppression greater than 10 mg/day prednisone equivalent within 7 days before lymphodepletion. * Clinically significant interstitial lung disease, uncontrolled heart failure, unstable arrhythmia, or recent myocardial infarction. * Child-Pugh B or C liver disease, hepatic encephalopathy, or clinically significant refractory ascites. * Prior allogeneic solid organ transplant or allogeneic stemcell transplant. * Active autoimmune disease requiring systemic therapy within the previous 2 years. * Pregnancy or breastfeeding. * Any condition that, in the investigator's judgment, would make lymphodepletion or EB-HC01 infusion unsafe or would interfere with protocol compliance.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose-Limiting Toxicities | 28 Days |
| Treatment-Emergent Adverse Events | 12 months |
Secondary
| Measure | Time frame |
|---|---|
| Objective Response Rate | 12 months |
| Disease Control Rate | 12 months |
| Duration of Response | 24 months |
| Progression-Free Survival | 24 months |
| Overall Survival | 24 months |
Countries
China
Contacts
CONTACTSeni S Lu, Phd
Outcome results
None listed