Pancreatic Ductal Adenocarcinoma (PDAC), Unresectable Locally Advanced or Metastatic Disease
Conditions
Keywords
Pancreatic cancer, PDAC, CAR-NK, Natural killer cells, Mesothelin, MSLN, MUC1, Claudin 18.2, CLDN18.2, Adoptive cell therapy, Immunotherapy, Biomarker-guided
Brief summary
This example study evaluates the safety, tolerability, and preliminary anti-tumor activity of investigational, dual-targeting chimeric antigen receptor natural killer (CAR-NK) cell products for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Participants are assigned to one of two biomarker-defined cohorts based on tumor antigen expression: (A) Mesothelin (MSLN) and/or MUC1, or (B) Claudin 18.2 (CLDN18.2) and/or MUC1. The study uses a dose-escalation followed by dose-expansion design to define a recommended Phase 2 dose (RP2D) and to estimate response rates in each cohort.
Detailed description
* Rationale: PDAC is characterized by aggressive biology, antigen heterogeneity, and an immunosuppressive tumor microenvironment. Dual-targeting CAR designs aim to reduce antigen-escape by enabling recognition of either target antigen on tumor cells. * Investigational products: Two off-the-shelf (allogeneic) CAR-NK products are evaluated. EB-DNK101 targets MSLN and MUC1. EB-DNK102 targets CLDN18.2 and MUC1. Both products are engineered to enhance persistence (e.g., membrane-bound or secreted IL-15; example) and incorporate an inducible safety switch (e.g., iCasp9; example). * Target assessment and cohort assignment: Tumor tissue (archival or fresh biopsy) is tested centrally by immunohistochemistry (IHC) for MSLN, MUC1, and CLDN18.2. Participants are assigned to Arm A (MSLN/MUC1) or Arm B (CLDN18.2/MUC1) based on predefined positivity thresholds. If more than one cohort is eligible, assignment prioritizes the strongest antigen expression and product availability. * Conditioning and administration: Participants receive lymphodepleting chemotherapy (fludarabine + cyclophosphamide; example regimen) followed by intravenous infusion of the assigned CAR-NK product. Repeat infusions (up to 3 total) may be permitted in the absence of prohibitive toxicity and with at least stable disease. • Safety monitoring: Participants are monitored closely for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infusion reactions, and other adverse events. Dose-limiting toxicities (DLTs) are assessed during the first 28 days after first infusion. * Efficacy and biomarker assessments: Tumor response is assessed by imaging (RECIST v1.1) at regular intervals (e.g., every 8 weeks). Exploratory endpoints include CAR-NK expansion/persistence, cytokine profiling, and association of antigen density with response. * Target down-selection plan , After completion of Part 1 and an initial subset of Part 2 expansion participants, an internal scientific review compares antigen prevalence, manufacturability, safety, and preliminary activity across cohorts to prioritize the lead dual-target construct for subsequent confirmatory development.
Interventions
Allogeneic CAR-NK cells engineered with a dual-recognition CAR targeting MSLN and MUC1. Administered as an IV infusion on Day 0 (dose level dependent).
Allogeneic CAR-NK cells engineered with a dual-recognition CAR targeting CLDN18.2 and MUC1. Administered as an IV infusion on Day 0 (dose level dependent)
Example regimen: fludarabine (Days -5 to -3) and cyclophosphamide (Days -5 to -4) prior to CAR-NK infusion.
Sponsors
Beijing Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label design due to the nature of cellular infusion and required safety monitoring.
Intervention model description
Biomarker-guided, multi-cohort study with a dose-escalation (Part 1) followed by dose-expansion (Part 2) within each cohort/arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 75 years at the time of consent. * Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC). * Unresectable locally advanced or metastatic disease with progression after at least 1 prior standard systemic therapy regimen, or intolerance/ineligibility for standard therapy. * At least 1 measurable lesion per RECIST v1.1. * Tumor antigen expression by central IHC (archival or fresh biopsy): • Arm A eligibility: MSLN positive and/or MUC1 positive. • Arm B eligibility: CLDN18.2 positive and/or MUC1 positive. (Example threshold: IHC 2+ or 3+ staining in \>=50% of tumor cells, or H-score above protocol-defined cutoff.) * ECOG performance status 0-1. * Adequate organ function (example): ANC \>= 1.0 x 10\^9/L; platelets \>= 75 x 10\^9/L; hemoglobin \>= 8 g/dL; AST/ALT \<= 3x ULN (\<= 5x ULN with liver metastases); total bilirubin \<= 1.5x ULN; creatinine clearance \>= 50 mL/min. * Life expectancy \>= 12 weeks. * Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined follow-up period. * Ability to understand and willingness to sign written informed consent.
Exclusion criteria
* Active or untreated CNS metastases or carcinomatous meningitis. * Clinically significant uncontrolled infection (including uncontrolled bacterial, fungal, or viral infection). * Known active hepatitis B or hepatitis C with detectable viral load; known uncontrolled HIV infection * Prior allogeneic hematopoietic stem cell transplant or solid organ transplant. * Prior gene-modified cellular therapy (e.g., CAR-T/CAR-NK) within 6 months or prior therapy targeting the same antigen(s)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 28 Days |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | 12 months |
| Maximum tolerated dose (MTD) | 12 months |
Secondary
| Measure | Time frame |
|---|---|
| Objective response rate (ORR) per RECIST v1.1 | 12 months |
| Disease control rate (DCR) | 12 months |
| Duration of response (DOR) | 24 months |
| Progression-free survival (PFS) | 24 months |
| Overall survival (OS) | 24 months |
Countries
China
Contacts
CONTACTSeni S Lu, Phd
Outcome results
None listed