Modular phase I/II clinical trial evaluating the selective MET-kinase inhibitor OMO-1 in patients with advanced malignancies: Safety and proof of mechanism.

Abstract

3062 Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.