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First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.

T. Yap,D. Tan,Angelika Terbuch,Reece Caldwell,Christina Guo,B. Goh,V. Heong,N. Haris,S. Bashir,Y. Drew,D. Hong,F. Meric-Bernstam,G. Wilkinson,J. Hreiki,A. Wengner,F. Bladt,A. Schlicker,Matthias Ludwig,Yinghui Zhou,Li Liu,Sonal Bordia,Ruth Plummer,E. Lagkadinou,J. D. de Bono

Published 2020 in Cancer Discovery

ABSTRACT

Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses greater than or equal to 40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.

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