Abstract OT2-01-01: Phase 1 study of ST101, a first-in-class peptide antagonist of CCAAT/enhancer-binding protein β (C/EBPβ), in patients with advanced solid tumors, with a phase 2 expansion in patients with hormone receptor positive breast cancer (HR+ BC)
Authors: Bexon Alice S , Arkenau Hendrik-Tobias , Evans Jeff , Falchook Gerald S , Symeonides Stefan N , McKean Meredith A , Fontana Elisa , Bupath Manojkumar , McLaren Alistair , Chandana Sreenivasa , Ding Tze-en , Lim Emerson A , Rotolo Jim , Capiaux Gina , Michel Rob , Kaesshaefer Stephen , Lakhani Nehal J 
Published: March 2022

Abstract
Background: CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells. C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis. In breast cancer, C/EBPβ drives the expression of factors that promote tumor survival, proliferation and inhibit differentiation. ST101 is a cell-penetrating all D amino acid peptide antagonist of C/EBPβ. ST101 exposure inhibits C/EBPβ target gene expression, leading to selective tumor cell death in multiple human cancer cell lines, including hormone receptor positive breast cancer (HR+ BC) and triple negative breast cancer (TNBC), without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to proteolytic degradation. Potent ST101 anti-tumor activity, demonstrated by dose-dependent inhibition of tumor growth in subcutaneous HR+ and orthotopic TNBC xenograft models in vivo, supported advancing ST101 into clinical development.Trial design: This phase 1-2 study uses a standard 3+3 design with dose doubling for the first 4 dose levels then 50% escalations thereafter. The recommended phase 2 dose will be used in 4 expansion cohorts in specific tumor types, including HR+ BC. Patients receive intravenous ST101 once weekly.Eligibility criteria: The dose-escalation phase is enrolling patients ≥18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. In expansion, patients with HR+ BC must have progressed after 1-3 prior hormone-based therapies. Previous treatment with CDK 4/6 inhibitor, mTOR inhibitor, or chemotherapy is allowed as monotherapy or in combination. Specific aims: The primary objective of phase 1 is to evaluate safety and tolerability of ST101. Secondary objectives include the recommendation of a dose and regimen of ST101 for further evaluation, analysis of pharmacokinetics, assessment of several pharmacodynamic measures, and to assess preliminary efficacy. Statistical design: The recommended phase 2 dose will be used in a 15-30 patient HR+ BC expansion cohort, with a Simon 2-stage design, which requires one response to expand the cohort to 30 patients. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.Accrual: We began recruitment in August 2020. Enrollment is ongoing, and by July 2021, 18 patients were recruited in five dose-escalation cohorts up to 6 mg/kg; a 6th cohort (9 mg/kg) is ongoing. Dose escalation should be complete by Sept 2021, and the phase 2 portion in the HR+ BC cohort will be underway (n=15-30). Please contact rob.michel@bexonclinical.com if you have a specific interest in this trial.
Citation Format: Alice S Bexon, Hendrik-Tobias Arkenau, Jeff Evans, Gerald S Falchook, Stefan N Symeonides, Meredith A McKean, Elisa Fontana, Manojkumar Bupath, Alistair McLaren, Sreenivasa Chandana, Tze-en Ding, Emerson A Lim, Jim Rotolo, Gina Capiaux, Rob Michel, Stephen Kaesshaefer, Nehal J Lakhani. Phase 1 study of ST101, a first-in-class peptide antagonist of CCAAT/enhancer-binding protein β (C/EBPβ), in patients with advanced solid tumors, with a phase 2 expansion in patients with hormone receptor positive breast cancer (HR+ BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-01-01.