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Updated: Dec 7, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with
Timothy A Yap1, David S P Tan2, Angelika Terbuch3,4
1The University of Texas MD Anderson Cancer Center, Houston, Texas.
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. 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.
Insights
The oral ATR inhibitor BAY 1895344 shows promise for treating advanced solid tumors with DNA damage response defects, particularly those with ATM loss. This drug is well-tolerated and demonstrates antitumor activity in patients with specific genetic mutations.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Targeting the ATR enzyme is a key anticancer strategy for tumors with DNA damage response (DDR) defects.
- Tumors with ATM signaling inactivation are potential candidates for ATR inhibition.
- Replication stress is a hallmark of cancers that may respond to ATR inhibitors.
Purpose of the Study:
- To evaluate the safety and tolerability of the oral ATR inhibitor BAY 1895344 in a phase I dose-escalation trial.
- To identify the maximum tolerated dose (MTD) of BAY 1895344.
- To assess the preliminary antitumor activity and pharmacodynamics of BAY 1895344 in patients with advanced solid tumors.
Main Methods:
- Phase I, first-in-human, dose-escalation study of oral BAY 1895344.
- Intermittent dosing schedule (5 to 80 mg twice daily) in 21 patients with advanced solid tumors.
- Assessment of adverse events, MTD, objective responses, and pharmacodynamic markers.
Main Results:
- The MTD was determined to be 40 mg twice daily on a 3 days on/4 days off schedule.
- Most adverse events were manageable hematologic toxicities.
- Partial responses were observed in 4 patients and stable disease in 8 patients, with a median duration of response of 315.5 days.
Conclusions:
- BAY 1895344 is well-tolerated and exhibits antitumor activity in patients with advanced solid tumors, especially those with ATM loss or deleterious ATM mutations.
- Pharmacodynamic data support the drug's mechanism of action, involving increased DNA damage.
- Further investigation in patients with DDR deficiencies is warranted.
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