Dual-Targeting CAR-NK Cells Targeting Mesothelin (MSLN) and MUC1 in Advanced Pancreatic Ductal Adenocarcinoma

Official title

A Phase 1/2, Open-label, Biomarker-guided, Dose-escalation and Expansion Study of Dual-targeting CAR-NK Cells Directed Against Mesothelin (MSLN) and MUC1, With an Exploratory CLDN18.2/MUC1 Dual-target Cohort, in Patients With Unresectable or Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)

Overview

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

• Biological EB-DNK101 dual-targeting CAR-NK cells (MSLN + MUC1)
  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).
• Biological EB-DNK102 dual-targeting CAR-NK cells (CLDN18.2 + MUC1)
  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)
• Drug Lymphodepleting chemotherapy (Flu/Cy)
  Example regimen: fludarabine (Days -5 to -3) and cyclophosphamide (Days -5 to -4) prior to CAR-NK infusion.

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: 28 Days]
• Incidence and severity of treatment-emergent adverse events (TEAEs) [Time frame: 12 months]
• Maximum tolerated dose (MTD) [Time frame: 12 months]

Secondary outcome measures (5)

• Objective response rate (ORR) per RECIST v1.1 [Time frame: 12 months]
• Disease control rate (DCR) [Time frame: 12 months]
• Duration of response (DOR) [Time frame: 24 months]
• Progression-free survival (PFS) [Time frame: 24 months]
• Overall survival (OS) [Time frame: 24 months]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Shenzhen Hospital — Shenzhen

Identifiers

NCT: NCT07480928 · ESSEN-PDAC-DNK-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗