Dual-Target CAR-NK Cells for Advanced Breast Cancer (HER2+ and TNBC)

Official title

Phase 1/2, Biomarker-guided, Open-label Study of Allogeneic Dual-target CAR-NK Cells Directed Against HER2/ERBB2, MUC1, and/or ROR1 in Patients With Advanced or Metastatic Breast Cancer (Including HER2-positive and Triple-negative Disease).

Overview

This study tests the safety and preliminary anti-tumor activity of an investigational dual-target chimeric antigen receptor natural killer (CAR-NK) cell therapy in adults with advanced breast cancer. After a tumor antigen assessment (HER2/ERBB2, MUC1, ROR1, and in some TNBC cases mesothelin), each participant will receive the most suitable dual-target CAR-NK product for their tumor profile, following short-course lymphodepleting chemotherapy.

Detailed description

Natural killer (NK) cells can recognize and kill abnormal cells as part of the innate immune system. CAR engineering can enhance NK-cell recognition of tumor-associated antigens and may improve anti-tumor activity in solid tumors. This is a two-part, first-in-program study. Part A uses dose escalation to identify a safe and feasible dose of a dual-target CAR-NK cell product. Part B evaluates preliminary efficacy in biomarker-defined expansion cohorts for HER2-positive breast cancer and triple-negative breast cancer (TNBC).

Target selection is biomarker-guided. A fresh or archival tumor sample is tested by immunohistochemistry (IHC) for HER2/ERBB2, MUC1, and ROR1 expression. Participants are assigned to one of three dual-target CAR-NK constructs based on a predefined algorithm prioritizing highest and most homogeneous target expression. In TNBC, mesothelin testing may be performed to support an exploratory sub-cohort.

All participants receive lymphodepleting chemotherapy (fludarabine + cyclophosphamide) before CAR-NK infusion. The CAR-NK product is an allogeneic, cryopreserved NK-cell therapy engineered to express a dual-specific CAR and an inducible safety switch; the product is administered intravenously.

Interventions

• Biological Dual-target CAR-NK cells (EB-DT-CAR-NK)
  Route: IV infusion. Schedule: single infusion on Day 0; optional second infusion on Day 7 in the absence of dose-limiting toxicity (DLT) and with adequate clinical status.
• Drug Lymphodepleting chemotherapy
  fludarabine (Days -5 to -3) and cyclophosphamide (Days -5 to -4), prior to CAR-NK infusion.
• Other Supportive care
  Premedication per institutional standard (e.g., acetaminophen and antihistamine). Tumor lysis and infection prophylaxis per institutional guidelines.

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: 28 Days]
• Safety profile [Time frame: 12 months]
• Recommended Phase 2 Dose [Time frame: 56 days]

Secondary outcome measures (5)

• Objective response rate (ORR) by RECIST v1.1 (and iRECIST, if immunotherapy response patterns are suspected). [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

• Histologically confirmed breast carcinoma that is locally advanced, unresectable, or metastatic.
• Disease subtype: HER2-positive breast cancer or triple-negative breast cancer (TNBC).
• Progression after, intolerance to, or ineligibility for standard therapies appropriate for the disease subtype and line of therapy.
• At least one measurable lesion per RECIST v1.1.
• Tumor antigen assessment available (fresh or archival): expression of at least one candidate target antigen (HER2/ERBB2, MUC1, or ROR1). For TNBC, mesothelin assessment may be performed for exploratory analyses.
• ECOG performance status 0-1.
• Adequate organ function (example thresholds): ANC ≥ 1.0 x 10\^9/L; platelets ≥ 75 x 10\^9/L; hemoglobin

• 8 g/dL; AST/ALT ≤ 3x ULN (≤ 5x with liver metastases); total bilirubin ≤ 1.5x ULN; creatinine clearance
• 50 mL/min.
• Left ventricular ejection fraction (LVEF) ≥ 45% and no uncontrolled cardiac arrhythmia.
• Negative pregnancy test for participants of childbearing potential; agreement to use effective contraception during study treatment and for 6 months after last CAR-NK infusion.
• Ability to understand and willingness to sign informed consent.

Exclusion criteria

• Active, untreated central nervous system (CNS) metastases or leptomeningeal disease. Patients with treated CNS metastases may be eligible if clinically stable for ≥ 4 weeks and off high-dose steroids.
• Prior gene-modified cellular therapy (e.g., CAR-T or CAR-NK) within 6 months or unresolved grade ≥ 2 toxicity from prior cellular therapy.
• Clinically significant active autoimmune disease requiring systemic immunosuppression (physiologic steroid replacement permitted).
• Uncontrolled infection, including uncontrolled HBV, HCV, or HIV infection (controlled infections may be eligible per investigator).
• History of severe hypersensitivity to fludarabine or cyclophosphamide.
• Pregnant or breastfeeding.
• Concurrent participation in another interventional study that could confound safety or efficacy assessments.
• Any condition that, in the investigator's judgment, would make the participant unsuitable for the study (e.g., uncontrolled comorbidity, inability to comply with protocol procedures).

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

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Shenzhen Hospital — Shenzhen

Identifiers

NCT: NCT07486089 · EB-CARNK-BC01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗