Abstract LB114: Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors
Authors: Falchook Gerald , McKean Meredith , Lakhani Nehal , Arkenau Tobias , Symeonides Stefan , Evans Jeff , Lim Emerson , Rotolo Jim , Michel Rob , Bexon Alice 
Published: July 2021

Abstract
Background: Increased activation of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a therapeutic peptide designed to antagonize C/EBPβ; it penetrates the blood-brain barrier and has anti-tumor activity in multiple human cancer cell lines and animal models. Methods: This was a first-in-human, open-label, phase 1-2 dose-finding study. The primary objective was to evaluate safety and tolerability in patients with cancer. Secondary and exploratory objectives included ST101 pharmacokinetics (PK) and pharmacodynamics (PD). Phase 1 enrolled patients with advanced/metastatic solid tumors refractory or intolerant to all therapeutic options. Patients received ST101 intravenously 0.5, 1, 2, 4, 8 mg/kg QW and 16 mg/kg Q2W in a standard 3+3 design. The recommended phase 2 dose will be further investigated in expansion cohorts of patients with breast cancer, melanoma, glioblastoma, and castration-resistant prostate cancer. Results: As of 01.05.21 9 patients have enrolled into phase 1. Patients received 1-5 prior lines of therapy and had an ECOG status of 0 or 1. PK was predictable and consistent with pre-clinical data. Mean Cmax and AUC(0-t) increased proportionally with increasing dose. Maximum concentrations were observed at the end of 90-minute infusion and mean T1/2 was calculated as 18h and 31h, respectively in Cohort 1 and Cohort 2. Concentrations of ST101 were similar on Days 8 and 15 when compared to Day 1 in each cycle. Immunohistochemistry of tumor samples taken shortly after the 4th infusion from 2/2 patients in Cohort 1 and 1/1 patient in cohort 2 stained positive for ST101.
No ST101-related serious adverse events were observed. There were no dose limiting toxicities, dose modifications or withdrawals due to toxicity. Symptoms of infusion related reactions (max grade 2) were reported in five patients and were managed with antihistamine and/or anti-inflammatory prophylaxis and by decreasing the infusion rate. Five patients withdrew due to progression of their cancer. Conclusions: ST101 was safe and well tolerated at the doses and schedule tested, and PK appeared predictable. ST101 was designed to have a prolonged plasma T1/2 and these results confirm preclinical observations, demonstrating a longer than expected T1/2 for a drug of this class. Tumor uptake of ST101 was demonstrated at the lowest dose level.
ST101 dose(mg/Kg)CyclenMean Cmax (ng/mL)Mean Tmax (h)Mean AUC(0-t)(h*ng/mL)Mean Tlast (h)Mean AUC(0-inf)(h*ng/mL)Mean T1/2(h)Mean extrapolation(%)0.51316001.59000271500018230.52214001.539006NDNDND0.53211339001.5390007245000311512148001.5180008NDNDND131
Citation Format: Gerald Falchook, Meredith McKean, Nehal Lakhani, Tobias Arkenau, Stefan Symeonides, Jeff Evans, Emerson Lim, Jim Rotolo, Rob Michel, Alice Bexon. Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB114.