First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors

Timothy A. Yap; David S.P. Tan; Angelika Terbuch; Reece Caldwell; Christina Guo; Boon Cher Goh; Valerie Heong; Noor R. Noor; 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

doi:10.1158/2159-8290.CD-20-0868

First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors

Timothy A. Yap, David S.P. Tan, Angelika Terbuch, Reece Caldwell, Christina Guo, Boon Cher Goh, Valerie Heong, Noor R. Noor, 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 LiuSonal Bordia, Ruth Plummer, Eleni Lagkadinou, Johann S. de Bono

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

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) signal-ing. 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 del-eterious 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.

Original language	English
Pages (from-to)	80-91
Number of pages	12
Journal	Cancer Discovery
Volume	11
Issue number	1
DOIs	https://doi.org/10.1158/2159-8290.CD-20-0868
State	Published - Jan 2021
Externally published	Yes

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Yap, T. A., Tan, D. S. P., Terbuch, A., Caldwell, R., Guo, C., Goh, B. C., Heong, V., Noor, N. R., Bashir, S., Drew, Y., Hong, D. S., Meric-Bernstam, F., Wilkinson, G., Hreiki, J., Wengner, A. M., Bladt, F., Schlicker, A., Ludwig, M., Zhou, Y., ... de Bono, J. S. (2021). First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors. Cancer Discovery, 11(1), 80-91. https://doi.org/10.1158/2159-8290.CD-20-0868

@article{7c7742b295c7414dae3f9ed13476e171,

title = "First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors",

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) signal-ing. 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 del-eterious 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.",

author = "Yap, {Timothy A.} and Tan, {David S.P.} and Angelika Terbuch and Reece Caldwell and Christina Guo and Goh, {Boon Cher} and Valerie Heong and Noor, {Noor R.} and Saira Bashir and Yvette Drew and Hong, {David S.} and Funda Meric-Bernstam and Gary Wilkinson and Joseph Hreiki and Wengner, {Antje M.} and Friedhelm Bladt and Andreas Schlicker and Matthias Ludwig and Yinghui Zhou and Li Liu and Sonal Bordia and Ruth Plummer and Eleni Lagkadinou and {de Bono}, {Johann S.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2021",

month = jan,

doi = "10.1158/2159-8290.CD-20-0868",

language = "English",

volume = "11",

pages = "80--91",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "1",

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Yap, TA, Tan, DSP, Terbuch, A, Caldwell, R, Guo, C, Goh, BC, Heong, V, Noor, NR, Bashir, S, Drew, Y, Hong, DS, Meric-Bernstam, F, Wilkinson, G, Hreiki, J, Wengner, AM, Bladt, F, Schlicker, A, Ludwig, M, Zhou, Y, Liu, L, Bordia, S, Plummer, R, Lagkadinou, E & de Bono, JS 2021, 'First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors', Cancer Discovery, vol. 11, no. 1, pp. 80-91. https://doi.org/10.1158/2159-8290.CD-20-0868

TY - JOUR

T1 - First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors

AU - Yap, Timothy A.

AU - Tan, David S.P.

AU - Terbuch, Angelika

AU - Caldwell, Reece

AU - Guo, Christina

AU - Goh, Boon Cher

AU - Heong, Valerie

AU - Noor, Noor R.

AU - Bashir, Saira

AU - Drew, Yvette

AU - Hong, David S.

AU - Meric-Bernstam, Funda

AU - Wilkinson, Gary

AU - Hreiki, Joseph

AU - Wengner, Antje M.

AU - Bladt, Friedhelm

AU - Schlicker, Andreas

AU - Ludwig, Matthias

AU - Zhou, Yinghui

AU - Liu, Li

AU - Bordia, Sonal

AU - Plummer, Ruth

AU - Lagkadinou, Eleni

AU - de Bono, Johann S.

PY - 2021/1

Y1 - 2021/1

N2 - 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) signal-ing. 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 del-eterious 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.

AB - 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) signal-ing. 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 del-eterious 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.

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U2 - 10.1158/2159-8290.CD-20-0868

DO - 10.1158/2159-8290.CD-20-0868

M3 - Article

C2 - 32988960

AN - SCOPUS:85099549853

SN - 2159-8274

VL - 11

SP - 80

EP - 91

JO - Cancer Discovery

JF - Cancer Discovery

IS - 1

ER -

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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