Abstract 566P
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.
Editorial acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by David Lester, of Bioscript Science (Macclesfield, UK).
Legal entity responsible for the study
Merck KGaA, Damstadt Germany and EMD Serono, a business of Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Disclosure
M.A. Carducci: Advisory/Consultancy: Roche; Research grant/Funding (institution): EMD Serono ; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): BMS; Research grant/Funding (institution): AstraZeneca. C. Habermehl: Full/Part-time employment: Merck KGaA. M. Bödding: Full/Part-time employment: Merck KGaA. F. Rohdich: Full/Part-time employment: Merck KGaA. S. Stinchi: Full/Part-time employment: Merck KGaA. O. Karpenko: Advisory/Consultancy, Travel/Accommodation/Expenses: Merck KGaA. C. Gimmi: Leadership role, Travel/Accommodation/Expenses, Full/Part-time employment: Merck KGaA. P. LoRusso: Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): ADC Therapeutics SA; Advisory/Consultancy: Agenus; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Astellas Pharmaceuticals US, Inc ; Advisory/Consultancy, Research grant/Funding (institution): Astex Pharmaceuticals, Inc; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bayer Healthcare Pharmaceuticals, Inc; Advisory/Consultancy: Black Diamond; Research grant/Funding (institution): Boehringer Ingelheim Pharmaceuticals, Inc; Research grant/Funding (institution): Bristol-Myers Squibb Research & Development; Research grant/Funding (institution): Corvus Pharmaceuticals, Inc; Advisory/Consultancy: Cybrexa; Advisory/Consultancy, Research grant/Funding (institution): CytomX Therapeutics; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eisai Pharmaceuticals; Research grant/Funding (institution): Eli Lilly & Company ; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy, Research grant/Funding (institution): Five Prime Therapeutics, Inc; Research grant/Funding (institution): Rapt Therapeutics; Research grant/Funding (institution): F-Star Delta Limited; Advisory/Consultancy, Research grant/Funding (institution): Genentech, Inc; Advisory/Consultancy, Research grant/Funding (institution): Genmab, Inc; Advisory/Consultancy: Glaxo-Smith Kline; Advisory/Consultancy: Halozyme; Advisory/Consultancy: I-MAB; Advisory/Consultancy: ImmunoMet; Research grant/Funding (institution): Incyte Corporation; Advisory/Consultancy: IQVIA, MacroGenics, Pfizer, QED Therapeutics, Salarius, Shattuck, Silverback, Takeda, TRIGR, Tyme; Research grant/Funding (institution): Linnaeus Therapeutics, Inc; MedImmune, Inc; Merck Sharp & Dohme; Moderna Therapeutics, Inc; NextCure, Inc; Novartis Pharmaceuticals; Radius Pharmaceuticals; Sotio; Stemline Therpeutics, Inc . All other authors have declared no conflicts of interest.