First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors
| Autor: | Ruth Plummer, Reece Caldwell, Saira Bashir, Yinghui Zhou, Funda Meric-Bernstam, Matthias Ludwig, Christina Guo, Yvette Drew, Andreas Schlicker, Noor R. Md. Haris, Eleni Lagkadinou, Antje Margret Wengner, Boon Cher Goh, Timothy A. Yap, Valerie Heong, Friedhelm Bladt, Johann S. de Bono, David S.P. Tan, Gary Wilkinson, Joseph Hreiki, Angelika Terbuch, David S. Hong, Li Liu, Sonal Bordia |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
DNA damage Ataxia Telangiectasia Mutated Proteins 03 medical and health sciences Ataxia Telangiectasia 0302 clinical medicine Neoplasms Medicine Humans In patient Adverse effect Protein Kinase Inhibitors business.industry First in human medicine.disease 030104 developmental biology Oncology Mechanism of action 030220 oncology & carcinogenesis Pharmacodynamics Ataxia-telangiectasia Cancer research medicine.symptom business Ataxia telangiectasia and Rad3 related DNA Damage |
| Zdroj: | Cancer discovery. 11(1) |
| ISSN: | 2159-8290 |
| Popis: | 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. Significance: 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 |
| Databáze: | OpenAIRE |
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