Phase I dose escalation trial to evaluate safety and preliminary efficacy of ACR246, an innovative 5T4- antibody drug conjugate (ADC), in patients (pts) with advanced solid tumors

BackgroundThe oncofetal antigen 5T4 is overexpressed in many solid tumors with limited expression in normal adult tissues. Overexpression of 5T4 is associated with poor prognosis. 5T4 on tumor cell surface is rapidly internalized when bound to antibody and is thus an ideal target for the development of ADC drugs. Previously, several 5T4-ADCs were developed and advanced to phase 1 clinical trials, including PF-06263507, ASN004 and SYD1875. These ADCs incorporated either MMAF or duocarmycin as their payloads and thus encountered safety concerns. ACR246 is a next generation 5T4-ADC consisting of a fully human mAb that is site-specifically conjugated to a novel DNA topoisomerase I inhibitor, via a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8. ACR246 was carefully designed to improve the safety and efficacy in treating 5T4 positive solid tumors. In preclinical studies, ACR246 demonstrated robust in vivo anti-tumor activity, superior efficacy compared to a Dxd-5T4 ADC (as a reference), and excellent tolerability, supporting further development for clinical use.Trial designThis is a first-in-human, phase 1, multicenter, dose escalation study of ACR246 to be injected intravenously to adult pts with advanced solid tumors. A Bayesian optimal interval design is adopted to assess 5 dose levels of ACR246, 0.6, 1.2, 2.4, 3.6 and 4.5 mg/kg, administered Q3W on a 21-day cycle. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D); the second objectives include PK, immunogenicity and preliminary clinical efficacy. The study will enroll a total of ∼ 37 pts of ≥ 18 years of age with advanced solid tumors that have histologically or cytologically been diagnosed recurrent or metastatic unresectable advanced disease and have failed or are intolerant of systemic standard therapy or standard therapy is not available. The toxicity will be assessed by Common Terminology Criteria for Adverse Events v5.0 and the tumor response will be determined per RECIST v1.1. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 21 days.Clinical trial identificationNCT06238401.Legal entity responsible for the studyHangzhou Adcoris Biopharma Co., Ltd.FundingThis study was undertaken by ClinChoice sponsored by Hangzhou Adcoris Biopharma Co., Ltd.DisclosureY. Lu, X. Wang, Y. Huang, F. Wang, Y. Huang: Financial Interests, Personal, Full or part-time Employment: Hangzhou Adcoris Biopharma Co., Ltd. All other authors have declared no conflicts of interest.