A multicenter, open-label, dose-escalation, first-in-man study of MetAP2 inhibitor M8891 in patients with advanced solid tumours
Carducci MA, Wang D, Habermehl C, Bödding M, Rohdich F, Stinchi S, Karpenko O, Gimmi C, and LoRusso P. A multicenter, open-label, dose-escalation, first-in-man study of MetAP2 inhibitor M8891 in patients with advanced solid tumours. Annals of Oncology 2020; 31:S486.
Annals of Oncology
Background: Methionine aminopeptidase 2 (MetAP2) removes N-terminal Met residues from nascent proteins. MetAP2 inhibition affects protein functionality, which directly affects tumour and endothelial cells, leading to cell cycle arrest and anti-angiogenesis. M8891, a first-in-class, orally available, selective, reversible MetAP2 inhibitor, has anti-angiogenic and anti-tumour effects in preclinical models. We report preliminary results from a phase 1, open-label, dose-escalation study of M8891 alone in patients with advanced solid tumours (NCT03138538). Methods: Patients with biopsy-accessible, histologically confirmed advanced solid tumours received M8891 once daily (QD) in 21-day cycles until disease progression or unacceptable toxicity. Dose escalation aims to determine the maximum tolerated dose, recommended Phase 2 dose, safety, tolerability and pharmacokinetic (PK)/pharmacodynamic profile. Methionyl-elongation factor 1α (a MetAP2 substrate) is a biomarker of target engagement in tumours. Results: Of 24 patients enrolled across six dose levels (7, 12, 20, 35, 60, 80 mg QD), common adverse events were nausea, abdominal pain, constipation, vomiting and Grade 1–2 lipase increases. Transaminase increases were mainly due to underlying disease. Although platelet count reduced and thrombocytopenia was observed (n=10; ≤Grade 4), no bleeding events were reported. Two dose-limiting toxicities occurred at 60 and 80 mg QD (both Grade 4 thrombocytopenia). Exposure increased dose-proportionally up to 35 mg QD, but less than dose-proportionally above 35 mg QD. At steady state (Day 1–15), the M8891 accumulation ratio (AUC) was 1.8–2.9, in line with a half-life of ∼30 hours and QD dosing. Target engagement, observed at 7 mg QD, increased dose-dependently, along with exposure. No objective tumour responses were observed in these preliminary data. Conclusions: M8891 has a manageable safety profile, and a favourable PK profile with high exposure and low inter-patient variability. Dose/exposure-dependent target engagement was observed in tumours. Dose selection will be based on safety and exposure; cohort expansion at 35 mg is ongoing. Indication-based cohort in preparation. Clinical trial identification: NCT03138538.