Phase 1/2 study of CLIO-8221, a HER2-targeted, dual-payload exatecan and ATR inhibitor antibody-drug conjugate (ADC) in patients with advanced HER2-expressing solid tumors.

Abstract

TPS3162 Background: CLIO-8221 is a novel anti-HER2 ADC designed to overcome topoisomerase 1 inhibitor (Topo1i) resistance by incorporating both Topo1i (exatecan) and ataxia telangiectasia and rad3-related protein inhibitor (ATRi; berzosertib) payloads. Enabled by proprietary dual-payload ADC linker technology, CLIO-8221 uses an Fc-engineered trastuzumab, site-specifically conjugated with a stable protease-cleavable linker designed for optimal efficacy and tolerability. Trastuzumab deruxtecan (T-DXd) has redefined the treatment paradigm for HER2-expressing breast cancer and is emerging as a frontline treatment option. However, most patients develop resistance and disease progression. Topo1i-induced replication stress triggers activation of the DNA damage response pathway, which is an important driver of Topo1i resistance. Studies show that ATRi synergizes with Topo1i to enhance DNA damage and increase antitumor activity. In preclinical studies, CLIO-8221 binds with high affinity and specificity to HER2-expressing tumor cells and is rapidly internalized to release the Topo1i and ATRi payloads to drive direct tumor cell killing with a strong bystander effect. CLIO-8221 shows superior in vivo efficacy across tumor models with a range of T-DXd sensitivity, inducing tumor regression after a single dose in T-DXd resistant and refractory xenograft models. Additionally, CLIO-8221 is designed to minimize off-target uptake through Fc engineering for abrogated FcγR binding, and a proprietary hydrophilic linker for reduced macropinocytosis. CLIO-8221 is well tolerated in nonclinical toxicity studies in non-human primates. Methods: CLIO-8221-001 is a Phase 1/2, first in human dose-escalation and -expansion study. Eligible patients are adults with metastatic or unresectable HER2-expressing solid tumors, including those who previously received T-DXd. Patients must have measurable disease per RECISTv1.1 and have previously received therapies known to confer clinical benefit unless ineligible, refused by the patient, or not available in the region. CLIO-8221 will initially be given by intravenous infusion on Day 1 of a 21-day cycle; treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to assess the safety and tolerability of CLIO-8221 and to identify the maximum tolerated dose, if reached, and recommended Phase 2 dose. Phase 1 of the study utilizes a BOIN dose-escalation design with an expansion phase, while Phase 2 comprises tumor-specific expansion cohorts treated at the doses recommended from Phase 1. Antitumor activity, PK, immunogenicity, and biomarkers including HER2 status and ctDNA dynamics will also be evaluated. Enrollment is planned at sites in Australia, US, and China (NCT07300943). Clinical trial information: NCT07300943 .