Abstract B038: Clinical and biological activity of ST101, a peptide antagonist of C/EBPβ, in recurrent Glioblastoma (rGBM) patients. Results from the rGBM cohort of a multi-cohort Phase 2 Study

Abstract Background: CCAAT/enhancer-binding protein β (C/EBPβ) is a master regulator of mesenchymal transformation in GBM (Carro, 2010) and has been proposed as a master regulator of the immunosuppressive M2 program in macrophages. ST101 is a first-in-class peptide antagonist of C/EBPβ, that promotes selective tumor cell death in multiple cancers without impacting normal cell viability (Darvishi, 2022). Additionally, we have shown in vitro that ST101 induces a shift in PBMC-derived M2 macrophages and human iPS-derived microglia, resident macrophage of the CNS, from an M2-like immunosuppressive phenotype toward an immune-active M1-like identity. Methods: In an ongoing Phase 1-2 study (NCT04478279), we enrolled a cohort of patients (pts) with rGBM. The primary objective was to evaluate the safety/tolerability of ST101 and assess efficacy parameters. Patients with progressive disease (PD) after standard first-line treatment (surgery, radiation, and temozolomide) were enrolled and treated with monotherapy ST101 500 mg, IV, QW. Disease assessment by MRI was performed every 9 weeks, and response assessed by mRANO. Results: As of 05 July 2023, 33 pts were enrolled, and 30 were evaluable for efficacy. Clinical activity was observed in 9 pts, with 30% disease control rate (DCR) composed of 1 patient with a PR (for 54 weeks) and 8 patients with stable disease (SD) (median of 5 months (~3 – 8 months)). Two pts with SD remain on treatment, 16 pts are still alive, and evaluation of survival is still ongoing. Current median OS (95% CI) is 9.8 months (7.3-NE), with a 6-month OS of 74%. Analysis of tumor tissue from a pt with pseudo-PD and who was clinically stable for >22 weeks and underwent tumor resection 21 days after discontinuation of ST101, showed significant geographical necrosis within the tumor. The tumor also stained positive for ST101 by immunohistochemistry (IHC), demonstrating blood-brain-barrier penetration as well as long-standing retention. Tissue samples assessment from a sub-study in rGBM patients are currently under evaluation. The assessment will include gene expression and IHC analysis and aim to determine whether ST101 restricts glioblastoma growth by direct suppression of glioblastoma cells, reprogramming of macrophages and microglia toward an immune-promoting and cancer-suppressive phenotype, or both. ST101 was shown to be safe and well tolerated, with infusion-related reactions (IRR) being the most commonly reported AE. IRRs are managed by pre-medication (antihistamines and leukotriene antagonist) and infusion rate adjustment, and show tolerance over time, with 79% of patients having IRRs on the first infusion with 21% on the eighth infusion. Conclusion: ST101 as a single agent demonstrated clinical activity and tissue treatment effect. Assessment of tissue samples from a sub-study in rGBM pts is ongoing and aiming to determine the MOA of ST101 directly on tumors and within the tumor microenvironment. Encouraging response and survival data warrants further assessment of ST101 in combination therapy for the treatment of pts with GBM. Citation Format: Fabio Iwamoto, Robin Buerki, Nicholas Butowski, Katherine B. Peters, Anja Williams, Gerald Falchook, Jim Rotolo, Rob Michel, Stephen Kaesshaefer, Claudio Scuoppo, Abi Vainstein-Haras. Clinical and biological activity of ST101, a peptide antagonist of C/EBPβ, in recurrent Glioblastoma (rGBM) patients. Results from the rGBM cohort of a multi-cohort Phase 2 Study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B038.