Abstract CT244: A phase 1a/1b study of STK-012, an α/β IL-2 receptor selective partial agonist as monotherapy and in combination with pembrolizumab in advanced solid tumors (NCT05098132)
Authors: Spigel David , Spira Alexander , Zamarin Dmitriy , McDermott David F. , Luke Jason , Heymach John V. , Previs Rebecca , Sullivan Ryan , Gandhi Leena , Azrilevich Alex , Rizvi Naiyer , Oft Martin , Busby Natalie , Izar Benjamin 
Published: June 2022

Abstract
Background: High dose intravenous (IV) interleukin-2 (IL-2) induces complete responses in certain cancers, but its use is limited due to toxicities including severe hypotension and capillary leak syndrome (CLS), and the requirement for inpatient administration. Recent approaches to develop IL-2 therapies with an expanded therapeutic index have targeted the dimeric form (β/γ) of the IL-2 receptor, which is predominantly expressed on naïve T cells and NK cells, rather than the high affinity trimeric form (α/β/γ), predominantly expressed on antigen activated T cells and Tregs. Preclinical data support the hypothesis that this “non-α” approach favors activating cells that serve as principal mediators of toxicity (NK cells) over antitumor activity (antigen activated T cells). STK-012 is a pegylated, α/β-IL-2R selective partial agonist engineered to preferentially stimulate antigen-activated CD25+ T cells and avoid systemic NK and naïve T cell activation. In syngeneic tumor models, subcutaneously (SQ) injected STK-012 mouse surrogate demonstrated reduced toxicities and improved efficacy relative to mouse wild-type IL-2 or a non-α IL-2. In cynomolgus monkeys, acute lung inflammation was induced by aldesleukin and non-α-IL-2, but not by STK-012. STK-012 is in development as monotherapy and in combination with pembrolizumab for the treatment of advanced solid tumors.
Methods: This is a first-in-human, open-label, dose escalation and expansion study in adults with advanced solid tumors (NCT05098132). The objectives of this study are to evaluate the safety, pharmacokinetics, immunogenicity, preliminary efficacy, and pharmacodynamics of STK-012 as monotherapy and in combination with pembrolizumab. Dose escalation will follow a standard 3+3 design for STK-012 monotherapy and in combination with pembrolizumab. STK-012 will be dosed SQ weekly, and pembrolizumab will be dosed IV every 3 weeks. Eligible participants for dose escalation include individuals with non-small cell lung cancer, head and neck squamous cell cancer, malignant melanoma, renal cell carcinoma, ovarian cancer, cervical cancer and microsatellite instability-high or mismatch repair deficient cancers who are relapsed/refractory to, intolerant to, or refuse standard of care treatment. Expansion cohorts will enroll participants at selected dose(s) and indications on the basis of dose escalation findings. The primary endpoint of safety includes outcomes such as adverse events and dose-limiting toxicities. Efficacy, a secondary endpoint, will include assessments of tumor response according to RECIST v1.1. Exploratory biomarker assessments will include peripheral and tumor measures of immune cell populations and relevant gene/protein expression. Enrollment in STK-012 monotherapy dose escalation has been initiated.
Citation Format: David Spigel, Alexander Spira, Dmitriy Zamarin, David F. McDermott, Jason Luke, John V. Heymach, Rebecca Previs, Ryan Sullivan, Leena Gandhi, Alex Azrilevich, Naiyer Rizvi, Martin Oft, Natalie Busby, Benjamin Izar. A phase 1a/1b study of STK-012, an α/β IL-2 receptor selective partial agonist as monotherapy and in combination with pembrolizumab in advanced solid tumors (NCT05098132) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT244.