Breast Cancer (Locally Advanced or Metastatic), HER2-positive Breast Cancer, Triple-Negative Breast Cancer (TNBC)
Conditions
Keywords
CAR-NK; dual targeting, doptive cellular immunotherapy, HER2 / ERBB2, MUC1, ROR1, mesothelin, solid tumor, biomarker-guided cohort assignment, Lymphodepletion, fludarabine, cyclophosphamide
Brief summary
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
BIOLOGICALDual-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.
fludarabine (Days -5 to -3) and cyclophosphamide (Days -5 to -4), prior to CAR-NK infusion.
OTHERSupportive care
Premedication per institutional standard (e.g., acetaminophen and antihistamine). Tumor lysis and infection prophylaxis per institutional guidelines.
Sponsors
Beijing Biotech
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label design; no blinding of participants, investigators, or outcome assessors.
Intervention model description
Part A: 3+3 dose-escalation across 3 planned dose levels. Part B: biomarker-guided, non-randomized expansion cohorts based on tumor antigen expression with cohort-specific Simon two-stage stopping rules for futility.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 28 Days | Incidence of dose-limiting toxicities (DLTs) (including cytokine release syndrome and neurotoxicity) graded by CTCAE v5.0 and ASTCT consensus criteria for CRS/ICANS |
| Safety profile | 12 months | Safety profile by type, frequency, severity, and relatedness of treatment-emergent adverse events (AEs) and serious AEs. |
| Recommended Phase 2 Dose | 56 days | Recommended Phase 2 Dose (RP2D) based on DLTs, overall safety, and biologic activity (CAR-NK expansion/persistence). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) by RECIST v1.1 (and iRECIST, if immunotherapy response patterns are suspected). | 12 months | — |
| Disease control rate (DCR) | 12 months | Disease control rate (DCR) (CR+PR+SD) |
| 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