Background: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in prostate cancer (PC), glioblastoma (GBM), breast cancer (BC), melanoma, and other pre-clinical models. Methods: This phase 1 study enrolled patients (pts) with refractory solid tumors with varying histologies. The primary objective was to evaluate safety/tolerability of ST101 and to determine the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), preliminary efficacy (RECIST 1.1), and pharmacodynamic (PD) evaluation. The study used a 3+3 dose-escalation design, with once-weekly IV infusion dosing of ST101 at 0.5, 1, 2, 4, 6, 9 mg/kg or a flat dose of 500 mg. Results: Enrollment in phase 1 was completed in November 2021 with a total of 25 pts with multi-metastatic disease that were refractory to standard therapy. As of February 15, 2022, five pts remain on study with a median treatment duration of 27 weeks’ (16-77). There were no DLTs, dose modifications, or serious adverse events (SAEs) related to ST101. The only 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 93% of pts on the first dose at ≥4mg/kg and led to prolongation of infusion time. Intensity and frequency of IRRs decrease with repeat dosing. No other AEs were consistently reported. There was no evidence of accumulation upon continued exposure of ST101 and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and decreased tumor proliferation in several pts represented by decreased Ki67 expression. Population PK analysis supported flat dosing in phase 2. Five pts continue on treatment with one confirmed partial response in a patient with cutaneous melanoma lasting >42 weeks and four pts with ongoing stable disease. Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses and in pts with melanoma. PK and PD support a dose relationship for efficacy and selection of 500 mg as the RP2D. Pts are now enrolling in phase 2 cohorts to assess response in cutaneous melanoma, GBM, castrate-resistant PC, and HR⁺ BC. Clinical trial information: NCT04478279.

+indicates ongoing treatment.