Reference Detail

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATRX inact mut	ovarian cancer	predicted - sensitive	M1774	Case Reports/Case Series	Actionable	In a Phase I trial (DDRiver Solid Tumours 301), a patient with ovarian cancer harboring an inactivating mutation in ATRX experienced a partial response on treatment with M1774 (Ann Oncol (2022) 33 (suppl_7): S747-S748; NCT04170153).	detail...