Abstract P06-03: ST101, a peptide targeting oncogenic transcription factor C/EBPβ: initial safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data from an ongoing phase 1 dose escalation study in patients with advanced, metastatic solid tumors
Authors: Lakhani Nehal J. , Arkenau Hendrik-Tobias , Symeonides Stefan N. , Evans Jeffry , 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 , Bexon Alice S. , Falchook Gerald S. 
Published: December 2021

Abstract
Introduction: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) is normally active in embryofetal development, but inactive and suppressed in mature cells. Upregulation or activation of C/EBPβ in cancer promotes tumor survival and proliferation while inhibiting its differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in glioblastoma (GBM), breast cancer (BC), prostate cancer (PC), melanoma, and other models. ST101 penetrates the blood-brain barrier, as demonstrated in a mouse model and biodistribution studies. We have also demonstrated the tumor-specificity of ST101 in numerous in vitro cell lines. Methods: We conducted the phase 1 portion of a phase 1-2 study in patients with refractory solid tumors. The primary objective was to evaluate safety and tolerability of ST101. Secondary and exploratory objectives included PK, preliminary efficacy, and PD from serial biopsies. The study used a 3+3 design, dosing ST101 IV at 0.5, 1, 2, 4, 6, and 8 (now modified to 9) mg/kg weekly (QW). Phase 2 will include four cohorts of patients with specific cancers: HR+ breast cancer, cutaneous melanoma, GBM, and castrate-resistant PC at the recommended phase 2 dose (RP2D). Results: As of July 2021, 18 pts were enrolled, and the last cohort (9 mg/kg) is underway. Patients received a median of 6 weeks’ treatment (range 2 – 45). There were no dose-limiting toxicities, dose modifications, or SAEs related to ST101. The only adverse events (AEs) of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 100% pts on the 1st dose of ST101 at 4mg/kg. Montelukast was added to the antihistamine premedication regimen in the 6 mg/kg cohort, which attenuated IRRs. 66% of patients in the 6 mg/kg experienced an IRR on the first dose. The intensity and frequency of IRRs decreased with repeat dosing across all cohorts. No other AEs were consistently reported. PK was dose-proportionate, with continued exposure. There was no evidence of accumulation, and no anti-drug antibodies were detected. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and a trend of decreased Ki67 staining (proliferation marker) after ST101 exposure. One confirmed partial response in a patient with metastatic cutaneous melanoma refractory to standard therapy is still on study, and 3 pts with varied histologies have had stable disease lasting 18-45 weeks (1 ongoing). Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses. PK and PD support a dose relationship for efficacy, and we will select a QW RP2D for the phase 2 expansion cohorts by September 2021.
Citation Format: Nehal J. Lakhani, Hendrik-Tobias Arkenau, Stefan N. Symeonides, Jeffry Evans, 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, Alice S. Bexon, Gerald S. Falchook. ST101, a peptide targeting oncogenic transcription factor C/EBPβ: initial safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) data from an ongoing phase 1 dose escalation study in patients with advanced, metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-03.