Abstract CT250: An open-label, phase 1a/b study of AB248, a CD8+ selective IL-2 mutein fusion protein, alone or in combination with pembrolizumab in patients with advanced solid tumors

Abstract

Abstract Background: High-dose interleukin-2 (HD IL-2) induces durable clinical responses in a subset of patients with melanoma and RCC, but severe toxicity limits its therapeutic utility. Early clinical data from several not-α IL-2Rβγ agonists suggest better tolerability but lower objective response rates compared to historical HD IL-2 data.1-2 In patients, these not-α IL-2s demonstrate a profound NK cell bias, while retaining activity on Tregs, and exhibiting limited CD8+ T cell expansion.3-5AB248 is a CD8+ selective IL-2 that demonstrates more than 500-fold selectivity for CD8+ T cells over other immune cell types. AB248 has demonstrated a highly differentiated preclinical profile, with compelling anti-tumor activity and less toxicity when given alone and in combination with anti-PD1 in multiple murine tumor models. These data suggest that AB248 may have an improved therapeutic index compared to broad-acting IL-2Rβγ agonists by increasing CD8+ T cell expansion and activation, avoiding NK cell-driven toxicity and avoiding Treg-mediated immunosuppression. Here we introduce the first-in-human study which aims to investigate AB248 when administered alone and in combination with pembrolizumab in subjects with advanced solid tumors who failed prior standard of care therapies. Methods: This open-label phase 1a/b study consisting of a dose escalation and expansion phase aims to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AB248 alone or in combination with pembrolizumab in subjects with locally advanced/metastatic tumors, including melanoma, renal cell carcinoma, NSCLC and SCCHN, who failed prior therapies, including prior anti-PD(L)1, as well as in first-line SCCHN during the expansion phase. Key eligibility criteria include age ≥18 years, ECOG ≤1, measurable disease per RECIST v1.1, adequate end-organ function, and no autoimmune disease. The dose escalation phase will follow the Bayesian Optimal Interval (BOIN) design and enroll subjects at multiple dose levels and schedules for the AB248 monotherapy and pembrolizumab combination portion. Upon identifying suitable dose and schedule based on the totality of cumulative data including safety, PK, PD and preliminary efficacy, additional subjects will be enrolled in indication specific cohorts in the expansion phase according to the Simon 2-stage design. The primary objectives for this study are to assess the safety and tolerability of AB248 alone or in combination with pembrolizumab. Secondary objectives include assessing the PK, PD changes, immunogenicity, and antitumor activity. Exploratory objectives include evaluating the potential response-predictive and/or associated changes in immune cells, blood, and tissue biomarkers. Tumor assessments will be performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter. Adverse events will be assessed by CTCAE v5.0. The study is currently open for enrollment in the dose escalation phase at multiple sites in the US. Citation Format: Elizabeth I. Buchbinder, David R. Spigel, Costantine Albany, Michael Chisamore, Kelly D. Moynihan, Xiaohan Liu, Christopher DelNagro, Matt Axt, Andrea Pirzkall. An open-label, phase 1a/b study of AB248, a CD8+ selective IL-2 mutein fusion protein, alone or in combination with pembrolizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT250.