A phase I trial evaluating an optimized B7-H3xCD3 T cell engager for treatment of solid cancer.

Abstract

TPS2667 Background: T cell-based immunotherapy has revolutionized oncological treatment of various malignancies. However, many patients still do not respond to immunotherapy, and long-term remissions remain rare, particularly in solid tumors. B7-H3 (CD276) is overexpressed in multiple cancer entities on both tumor cells and tumor microenvironment, the latter facilitating access of effector cells into the tumor site as prerequisite for success of therapeutically targeting solid cancers. To address the high medical need of patients with colorectal cancer (CRC), breast cancer (BC), penile cancer as well as bone and soft tissue sarcoma, we developed and validated a CD276xCD3 T cell engager (TCE) termed CC-3. CC-3 mediated pronounced antitumor activity in vitro and displayed the expected long half-life and potent antitumor activity in murine models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors (Zekri et al, Mol Ther, 2023). Methods: This is an ongoing open label, multi-center phase I clinical trial evaluating CC-3 in patients with metastatic CRC, BC, penile cancer as well as bone and soft tissue sarcoma. Key eligibility criteria include diagnosis of progressive metastatic disease and exhaustion of standard of care. The trial comprises a dose escalation part to determine the maximum tolerated dose followed by a dose expansion part to define the recommended phase II dose and collect first signs of efficacy. During the dose escalation, initially an accelerated titration design with single patient cohorts is employed. Here, each patient receives a fixed dose level (starting with 50µg for the first patient). Dose levels are increased by up to 100%, based on the decision of a safety review committee (SRC). Upon occurrence of adverse events (AEs) grade ≥2, dose limiting toxicity (DLT), or reaching a dose level of ≥800µg, treatment switches to a standard 3+3 dose escalation design. After maximum tolerated dose (MTD) is determined, defined as no more than one of six patients experiencing DLT, an additional 14 patients receive CC-3 at the MTD level in the dose expansion phase. Primary endpoints are incidence and severity of AEs, as well as the best objective response to treatment according to RECIST 1.1. Secondary endpoints include overall safety, efficacy, survival, quality of life, and pharmacokinetic investigations. At present, the accelerated titration phase employing cohorts 1 - 4 has been completed without DLT; likewise, in the so far completed cohorts 5-8 of the standard titration phase, no DLT was observed. Enrollment to cohort 9 began in May 2025. Clinical trial information: NCT05999396. Clinical trial information: 2022-503084-15-00.