Abstract CT245: NEON-1: A first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies
Authors: Yang Jing , Means Gary , Tercero Almudena , Manjarrez Kristi , Hillson Jan , Peng Stanford L. 
Published: September 2020

Abstract
Background: Checkpoint inhibitors (CPI) targeting the PD-(L)1 and CTLA-4 pathways have demonstrated significant clinical benefit in many cancers, but the majority of patients unfortunately still fail to demonstrate objective responses and/or develop resistance, at least in part due to insufficient activation and/or excessive exhaustion of tumor-specific T cells. Strong preclinical rationale has emerged for combining CPIs with T cell costimulatory agonists, but such approaches have not yet translated into significantly improved clinical benefit. The majority of these approaches, though, have not targeted CD28, a well-known, critical T cell costimulatory pathway. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. As monotherapy, ALPN-202 has demonstrated superiority to CPI-only therapies in preclinical tumor models, while demonstrating a favorable safety profile in rat and monkey toxicology studies. It is in development for the treatment of multiple advanced malignancies. Methods: This is a cohort-based, open-label dose escalation and expansion study in adults with advanced solid tumors or lymphoma (NCT04186637). The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics (PK), anti-drug antibodies (ADA), and pharmacodynamics (PD) of ALPN-202. Subjects who are refractory or resistant to standard therapy (including approved CPIs), or without available standard or curative therapy are eligible. ALPN-202 will be administered by IV infusion. Dose escalation will initially use single-subject cohorts as an accelerated titration strategy to minimize the number of patients that will receive dose levels with low likelihood to elicit clinically meaningful PD activity. At dose levels predicted to elicit clinically meaningful PD activity, a standard 3+3 strategy will be used in two arms studying different dose schedules–Q1W and Q3W. Thereafter, an expansion cohort(s) will enroll subjects at a selected dose(s) and selected indication(s). Outcomes include safety assessments such as adverse events and dose-limiting toxicities. Tumor responses will be categorized by RECIST v1.1 for solid tumors, and by Lugano Classification for lymphoma. Biomarkers will include tumor measurements of PD-L1, CD28, CD80 and CD86 to explore the possible relationship between baseline expression and outcomes. Other PD will include target saturation, inflammatory cytokines and immunophenotyping of circulating leukocytes.
Citation Format: Jing Yang, Gary Means, Almudena Tercero, Kristi Manjarrez, Jan Hillson, Stanford L. Peng. NEON-1: A first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT245.