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 (US) |
|---|---|
| Pages (from-to) | 80-91 |
| Number of pages | 12 |
| Journal | Cancer discovery |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
ASJC Scopus subject areas
- Oncology
MD Anderson CCSG core facilities
- Precision Oncology Decision Support
- Clinical Trials Office
Fingerprint
Dive into the research topics of 'First-in-human trial of the oral ataxia telangiectasia and rad3-related (Atr) inhibitor bay 1895344 in patients with advanced solid tumors'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: Cancer discovery, Vol. 11, No. 1, 01.2021, p. 80-91.
Research output: Contribution to journal › Article › peer-review
}
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.
N1 - Funding Information: Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; travel, accommodations, and expenses: AACR, ASCO, Bayer, Gen-mab, LOXO, miRNA, and SITC; consulting or advisory role: Acuta, Adaptimmune, Alpha Insights, Amgen, Axiom, Baxter, Bayer, COG, Ecor1, Genentech, GLG, groupH, Guidepoint, Infinity, Janssen, Med-scape, Merrimack, Numab, Pfizer, prIME Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and other ownership interests: Molecular Match (advisor), OncoResponse (founder), Pres-agia Inc (founder and advisor)]. F. Meric-Bernstam reports grants and personal fees from Debiopharm (consulting; sponsored research), eFFECTOR Therapeutics (consulting; sponsored research), Genen-tech (consulting; sponsored research), and Puma Biotechnology (advisory committee; sponsored research); personal fees from Aduro BioTech (consulting), Alkermes (consulting), F. Hoffman-La Roche Ltd. (consulting), IBM Watson (consulting), Immunomedics (advisory committee), Inflection Biosciences (advisory committee), Jackson Laboratory (consulting), Kolon Life Science (consulting), Mersana Therapeutics (advisory committee), OrgiMed (consulting), PACT Pharma (consulting), Parexel International (consulting), Pfizer (consulting), Samsung Bioepis (consulting), Seattle Genetics (consulting; advisory board), Silverback Therapeutics (advisory committee), Spectrum Pharmaceuticals, (advisory committee), Tyra Biosciences (consulting), Xencor (consulting), Zentalis (advisory committee), and Zymeworks (consulting); grants from Aileron Therapeutics (sponsored research), AstraZeneca (sponsored research), Bayer HealthCare Pharmaceuticals (sponsored research), Calithera Biosciences (sponsored research), Curis, Inc. (sponsored research), CytomX Therapeutics (sponsored research), Daiichi Sankyo (sponsored research), Guardant Health (sponsored research), Millennium Pharmaceuticals (sponsored research), Novartis (sponsored research), and Taiho Pharmaceuticals (sponsored research); other from Beth Israel Deaconess Medical Center (travel related), Chugai Biopharma-ceuticals (honoraria - speaking engagement), Mayo Clinic (honoraria - speaking engagement), and Rutgers Cancer Institute of New Jersey (honoraria - speaking engagement) outside the submitted work. G. Wilkinson reports other from Bayer AG (employee and shareholder) outside the submitted work. A.M. Wengner reports personal fees from Bayer AG (employed at Bayer AG) during the conduct of the study; in addition, A.M. Wengner has several patents pending and ownership interest in Bayer, including patents. F. Bladt reports personal fees from Bayer AG (Bayer AG employee) during the conduct of the study and outside the submitted work. A. Schlicker reports personal fees from Bayer AG and other from Bayer AG (shareholder) during the conduct of the study; in addition, A. Schlicker has a patent for use (for 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (BAY 1895344) for treating hyperproliferative diseases which are characterized by biomarkers) pending. M. Ludwig reports employment with Bayer Pharma AG, Berlin, Germany. Y. Zhou reports other from Bayer (employee) during the conduct of the study and outside the submitted work. L. Liu reports other from Bayer (employee) during the conduct of the study; other from Bayer (stock holder) outside the submitted work; in addition, L. Liu has a patent for US/08.12.17/ USP210762596356 pending and issued. S. Bordia reports other from Bayer (part of Bayer Clinical Trial Team) during the conduct of the study. R. Plummer reports other from Bayer (clinical trial costs to institution) during the conduct of the study; and personal fees from Bayer (honorarium for SAB) outside the submitted work. J.S. de Bono reports grants and other from Bayer (trial funding and grant for preclinical studies to the ICR) during the conduct of the study; and personal fees from Astellas (advisory board), AstraZeneca (advisory board), Bayer (advisory board), Daiichi Sankyo (advisory board), Jans-sen (advisory board), Merck Serono (advisory board), MSD (advisory board), and Sanofi Aventis (advisory board), outside the submitted work; in addition, J.S. de Bono has a patent for PARP inhibition for patients with DNA Repair defects licensed and with royalties paid from The Institute of Cancer Research (no personal income). No potential conflicts of interest were disclosed by the other authors. Funding Information: This study was supported by research funding from Bayer AG. This work at The University of Texas MD Anderson Cancer Center was supported in part by the Cancer Prevention and Research Institute of Texas (RP1100584, to F. Meric-Bernstam), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964, to T.A. Yap, F. Meric-Bernstam), the Center for Clinical and Translational Sciences grant (UL1 TR000371, to F. Meric-Bernstam), and the MD Anderson Cancer Center support grant (P30 CA016672, to T.A. Yap, D.S. Hong, F. Meric-Bernstam). Participating UK sites received support from the Experimental Cancer Medicine Centre, jointly funded by Cancer Research UK, the National Institute for Health Research in England, and the Departments of Health for Scotland, Wales, and Northern Ireland (to A. Terbuch, R. Caldwell, C. Guo, N.R. Md. Haris, S. Bashir, Y. Drew, R. Plummer, J.S. de Bono). This work was supported by funding from the Singapore Ministry of Health’s National Medical Research Council under its Centre Grant scheme to National University Cancer Institute Funding Information: T.A. Yap reports grants from Artios (research support to institution), Constellation (research support to institution), Cyteir (research support to institution), Eli Lilly (research support to institution), Forbius (research support to institution), Genentech (research support to institution), GlaxoSmithKline (research support to institution), ImmuneSensor (research support to institution), Ipsen (research support to institution), Jounce (research support to institution), Karyopharm Therapeutics (research support to institution), Kyowa (research support to institution), Novartis (research support to institution), Regeneron (research support to institution), Ribon Therapeutics (research support to institution), Sanofi (research support to institution), Scholar Rock (research support to institution), Tesaro (research support to institution), and Vertex Pharmaceuticals (research support to institution); grants and personal fees from AstraZeneca (research support to institution; consultant), Bayer (research support to institution; consultant), Clovis (research support to institution; consultant), EMD Serono (research support to institution; consultant); F-star (research support to institution; consultant), Merck (research support to institution; consultant), Pfizer (research support to institution; consultant), Repare (research support to institution; consultant), and Seattle Genetics (research support to institution; consultant), and personal fees from Aduro (consultant), Almac (consultant), Atrin (consultant), Axiom (consultant), Bristol Myers Squibb (consultant), Calithera Biosciences (consultant), Cybrexa (consultant), Guidepoint (consultant), Ignyta (consultant), I-Mab (consultant), Janssen (consultant), Roche (consultant), Rubius (consultant), Schrödinger (consultant), Varian (consultant), and Zai Lab (consultant) outside the submitted work. D.S.P. Tan reports grants and other from Singapore Ministry of Health’s National Medical Research Council [NMRC; NMRC Clinician Scientist Award (NMRC/CSA-INV/0016/2017) with grant and salary support]; grants from Singapore Ministry of Health’s National Medical Research Council (Centre Grant scheme to National University Cancer Institute, Singapore) during the conduct of the study and grants from Karyopharm Therapeutics; grants and personal fees from Astra-Zeneca and Bayer; personal fees and nonfinancial support from Eisai, MSD, and Roche; personal fees from Merck Serono outside the submitted work; and charitable research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund. B.C. Goh reports grants from Bayer Oncology (Bayer Oncology covered the costs of conducting the study) during the conduct of the study; in addition, B.C. Goh has a patent for Detection Of Biomarkers for Non-Small Cell Lung Cancer pending to Sengenics Ltd (PCT patent application no. PCT/SG2019/050611) and a patent for Modulation of Signal Transducer and Activator Of Transcription 3 (STAT3) Expression pending to Apterna (patent filed); and stock ownership (Blueprint Medicines and Gilead Sciences). V. Heong reports grants from National University Cancer Institute Singapore (Yong Loo Lin fellowship grant for salary support to the institution) during the conduct of the study; and honoraria and fees for consulting from AstraZeneca and Pfizer. Y. Drew reports consultancy, honoraria, and advisory boards for AstraZeneca, Clovis, Genmab, Merck, and Tesaro; institution received research funding from AstraZeneca, Clovis, Oncology, Merck, and Tesaro Inc. D.S. Hong reports grants from Bayer (institutional funding for clinical trial) and personal fees from Bayer (advisory board) during the conduct of the study; and disclosures [last 36 months: research/grant funding: AbbVie, Adaptim-mune, Aldi-Norte, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Fate Therapeutics, Genentech, Gen-mab, Ignyta, Infinity, Kite, Kyowa, LOXO, MedImmune, Merck, Funding Information: This study was supported by research funding from Bayer AG. This work at The University of Texas MD Anderson Cancer Center was supported in part by the Cancer Prevention and Research Institute of Texas (RP1100584, to F. Meric-Bernstam), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964, to T.A. Yap, F. Meric-Bernstam), the Center for Clinical and Translational Sciences grant (UL1 TR000371, to F. Meric-Bernstam), and the MD Anderson Cancer Center support grant (P30 CA016672, to T.A. Yap, D.S. Hong, F. Meric-Bernstam). Participating UK sites received support from the Experimental Cancer Medicine Centre, jointly funded by Cancer Research UK, the National Institute for Health Research in England, and the Departments of Health for Scotland, Wales, and Northern Ireland (to A. Terbuch, R. Caldwell, C. Guo, N.R. Md. Haris, S. Bashir, Y. Drew, R. Plummer, J.S. de Bono). This work was supported by funding from the Singapore Ministry of Health?s National Medical Research Council under its Centre Grant scheme to National University Cancer Institute and Clinician Scientist Award (NMRC/CSA-INV/0016/2017, to D.S.P. Tan). The authors wish to thank the patients and their families, coinves-tigators, and referring physicians who participated in this study. DDR genomic variant functional annotation was undertaken prospectively by the Precision Oncology Decision Support Group at the Khalifa Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. Laura Valenzo, PhD, of Complete HealthVizion, McCann Health Medical Communications, provided medical writing support for this manuscript, based on detailed discussion and feedback from all the authors; this assistance was funded by Bayer AG. Publisher Copyright: © 2020 American Association for Cancer Research.
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.
UR - http://www.scopus.com/inward/record.url?scp=85099549853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099549853&partnerID=8YFLogxK
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 -