Phase 1 dose escalation and expansion study of TROP2 CAR-engineered IL-15-transduced cord blood-derived NK cells in combination with cetuximab in patients with colorectal cancer (CRC) with minimal residual disease (MRD).

TPS275 Background: CRC is the second most common cause of cancer-related mortality in the U.S. Despite successful curative treatments, patients often relapse, likely because of undetected micro-metastatic foci. Tumor-informed ctDNA testing has helped in identifying patients before they develop radiographic evidence of disease, introducing the concept of MRD in solid tumors. Currently, there are no standard-of-care treatment options available for CRC patients with MRD. Therefore, we designed a phase I trial of anti-TROP2 CAR-NK-cell therapy in combination with cetuximab to explore the role of cellular therapy for CRC. Methods: This is a first-in-human, single-center, open-label, Phase 1 dose escalation and dose expansion study evaluating the safety and preliminary efficacy of TROP2-CAR-NK cells in combination with cetuximab in CRC patients with MRD. The study consists of dose escalation and dose expansion parts. A Bayesian Optimal Interval Phase I/II (BOIN12) design is used to determine the MTD/RP2D (maximum tolerated dose/recommended phase 2 dose) of TROP2-CAR-NK cells. Patients receive a preparative lymphodepleting chemotherapy regimen consisting of cyclophosphamide and fludarabine on Day -5 to Day -3, and cetuximab on D-1 before TROP2-CAR-NK cell infusion on Day 0. All therapies and infusions are administered on an outpatient basis. The primary endpoints are safety and ctDNA clearance at 3 months. Secondary endpoints are progression-free survival (PFS), percentage of allogenic donor TROP2-CAR-NK in peripheral blood versus time profile, and presence of blood and tissue biomarkers. Exploratory endpoints are lymphocyte populations in the tumor microenvironment before and after TROP-2CAR-NK cell infusion, as assessed by single-cell transcriptional and immune profiling, change in ctDNA levels from TROP2-CA-NK infusion to progression or initiation of new cancer therapy, clinical benefit, and quality of life (QoL) assessment. Post-study treatment assessments will be performed in the GI Medical Oncology Clinic. Clinical trial information: NCT06358430 .