First-in-human study of the B7-H4 antibody-drug conjugate (ADC) AZD8205 in patients with advanced/metastatic solid tumors.

TPS3153 Background: ADCs are a class of anti-cancer agents that leverage the selectivity of monoclonal antibodies to preferentially target and deliver chemotherapeutic agents to cancer cells. AZD8205 is an ADC, administered by IV infusion, that consists of a human anti-B7-H4 antibody conjugated via a cleavable linker to a topoisomerase I inhibitor (TOP1i) warhead. B7-H4 is a transmembrane protein that binds to an unknown receptor on activated T cells, inhibiting their function. It is highly expressed by a wide variety of tumors including cholangiocarcinoma (CCA) and breast, ovarian and endometrial cancers, and is associated with poor prognosis. AZD8205 specifically binds to B7-H4 expressing tumor cells and is internalized. The TOP1i warhead is released, interfering with TOP1 during DNA replication leading to transcription-mediated DNA damage and cell death. TOP1i ADCs have shown clinical activity in several tumor types including breast cancer. In preclinical studies, AZD8205 has shown promising antitumor activity in various patient-derived xenograft models and an acceptable toxicity profile. This first-in-human study (NCT05123482) is evaluating AZD8205 for the treatment of selected advanced/metastatic tumors. Methods: This phase I/IIa, open-label, dose-escalation and dose-expansion study is currently investigating AZD8205 monotherapy in patients ≥18 years old (≥20 years for Japan) with CCA, breast, ovarian or endometrial cancers. Eligibility criteria include relapsed/metastatic disease following standard of care treatment, measurable disease per RECIST v1.1, and ECOG PS 0–1. Key exclusion criteria include spinal cord compression or leptomeningeal carcinomatosis, symptomatic brain metastases, and history of interstitial lung disease/pneumonitis. Expression of B7-H4 will be evaluated using a validated central laboratory immunohistochemistry assay on tumor samples collected before, during, and when feasible, after AZD8205 treatment. In the escalation phase, patients will receive AZD8205 followed by 21 days of observation for dose-limiting toxicities. Patients will be enrolled in escalating dose cohorts using the modified toxicity probability interval-2 model with at least 3 evaluable patients per dose level. Patients will continue on study treatment until disease progression, initiation of alternate anticancer therapy, unacceptable toxicity, or withdrawal of consent. Primary objectives are to determine the safety and tolerability of AZD8205 and identify the maximum tolerated dose and/or recommended phase 2 dose. Secondary objectives include assessing initial activity (objective response and progression-free survival by RECIST v1.1, and overall survival), pharmacodynamics, pharmacokinetics, and immunogenicity. The trial is currently recruiting and will enroll patients globally. Clinical trial information: NCT05123482.