American Association for Cancer Research
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Supplementary Data from First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors

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posted on 2023-04-03, 22:45 authored by Timothy A. Yap, David S.P. Tan, Angelika Terbuch, Reece Caldwell, Christina Guo, Boon Cher Goh, Valerie Heong, Noor R. Md. Haris, Saira Bashir, Yvette Drew, David S. Hong, Funda Meric-Bernstam, Gary Wilkinson, Joseph Hreiki, Antje M. Wengner, Friedhelm Bladt, Andreas Schlicker, Matthias Ludwig, Yinghui Zhou, Li Liu, Sonal Bordia, Ruth Plummer, Eleni Lagkadinou, Johann S. de Bono

Supplementary Data

Funding

Cancer Prevention and Research Institute of Texas

Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy

Center for Clinical and Translational Sciences

National Center for Advancing Translational Sciences

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MD Anderson Cancer Center

Singapore Ministry of Health's National Medical Research Council

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ARTICLE 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 to 80 mg twice daily in 21 patients with advanced solid tumors. The MTD was 40 mg twice daily 3 days on/4 days off. Most common adverse events were manageable and reversible hematologic 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 ≥40 mg twice daily. 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. Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.See related commentary by Italiano, p. 14.This article is highlighted in the In This Issue feature, p. 1

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