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Ref Type Abstract
PMID
Authors T.A. Yap A.W. Tolcher R. Plummer J. Mukker M. Enderlin C. Hicking G. Locatelli Z. Szucs I. Gounaris J.S. de Bono
Title A phase I study of ATR inhibitor M1774 in patients with solid tumours (DDRiver Solid Tumours 301): Part A1 results
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 33 SUPPLEMENT 7 September 01, 2022
URL https://www.annalsofoncology.org/article/S0923-7534(22)02437-1/fulltext
Abstract Text Background Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor, exerts antitumour activity in preclinical models. Methods Part A1 of this open-label, single-arm study (NCT04170153) evaluated the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of M1774 in patients with advanced solid tumours. A safety monitoring committee determined dose escalation, guided by a Bayesian 2-parameter logistic regression model. Biomarkers were assessed, and target engagement evaluated via γ-H2AX modulation in peripheral blood mononuclear cells (PBMCs). Results 55 patients received M1774 in 21d cycles over 14 cohorts (Table). 11 patients experienced DLTs (Table). The Bayesian model suggested the MTD was 180 mg (QD continuously). Across doses, M1774 was rapidly absorbed and eliminated (median tmax ∼0.5–3.5h; mean t½ ∼1.2–5.6h) with ≤2.4-fold accumulation. Up to 180 mg, exposure was approx. dose proportional but was slightly more than proportional at higher doses. At 180 mg QD, mean exposure over 24h at steady state was ∼30-fold higher than the in vitro pCHK1 drug concentration required for 90% inhibition. From 130 mg QD, γ-H2AX levels in PBMCs reduced by >80% 3h after the first dose, showing target engagement. In 13/35 patients of cohorts 1–11, loss of function mutations were detected by next-generation sequencing in baseline ctDNA samples, among them BRCA1/2 (6), ATM (3), ARID1A (4), ATRX (2). One patient with platinum and PARP inhibitor resistant BRCAwt ovarian cancer and ATRX mutation achieved RECIST v1.1 partial response.

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