1474 Optimal dose estimation using an integrated approach from phase I data of givastomig, a novel Claudin18.2×4–1BB bispecific antibody

<h3>Background</h3> Givastomig/ABL111 (Giva) is a first-in-class, bispecific antibody that targets Claudin (CLDN) 18.2 and is engineered to conditionally induce 4-1BB signaling for T-cell activation specifically at tumor sites, thereby avoiding systemic toxicities. A phase 1 study was designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of Giva. The objective of this analysis was to identify the optimal dose range for givastomig in patients with advanced gastroesophageal adenocarcinoma (GEC). <h3>Methods</h3> Modeling was conducted utilizing an integrated approach, including target exposure estimation, PK/PD characterization, population analysis, and modeling and simulation methodologies. The data in the analysis were collected from nonclinical studies, clinical phase 1 dose escalation and expansion study [Giva, 0.1 to 15 mg/kg intravenously (IV) Q2W]. <h3>Results</h3> As of February 1, 2024, confirmed partial response (PR) was observed in 5 patients (1 PR each at 5 and 8 mg/kg, and 3 PRs at 12 mg/kg). Dose-dependent induction and saturation of soluble 4-1BB indicated that immune activation increased with dose, reaching a plateau at doses ranging between 8–12 mg/kg IV Q2W. A target threshold of 12 µg/mL was estimated based on clinical PK/PD relationship. In addition, a comparable target threshold was established through CLDN18.2-dependent IL-2 release study and mouse model analyses, demonstrating plateaued tumor killing or tumor growth inhibition, assuming a 5% tumor penetration rate. Population PK modeling and simulation indicated the target threshold can be achieved at dose levels of 8–12 mg/kg IV Q2W to produce trough concentrations at steady state being above the target threshold in the majority (&gt;90%) of the simulated patient population. <h3>Conclusions</h3> This evaluation of the optimal givastomig dose was performed using clinical data from patients with solid tumors treated with givastomig, including patients with CLDN18.2-positive advanced GEC. Based on the totality of evidence, 8–12 mg/kg IV Q2W was identified as the current optimal dose range for heavily pre-treated GEC patients. A study investigating givastomig in combination with standard of care treatment in first-line metastatic GEC is ongoing. <h3>Trial Registration</h3> NCT04900818. <h3>Ethics Approval</h3> This study was conducted in accordance with the protocol and with the following: - Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines - Applicable ICH Good Clinical Practice (GCP) Guidelines. - Applicable laws and regulations. The Protocol, Protocol Amendments, ICF, Investigator Brochure, and other relevant documents (e.g., advertisements) were submitted to an IRB by the Investigator and reviewed and approved by the IRB before the study was initiated.