{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:39:15Z","timestamp":1791581955145,"version":"4.3.4"},"reference-count":44,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2025,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Ataxia telangiectasia and Rad3\u2010related (ATR) inhibition with berzosertib potentiates the efficacy of irinotecan in preclinical models. The authors hypothesize that this combination is well tolerated, modulates the DNA damage response to irinotecan, and is associated with clinical activity in advanced solid tumors.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this phase 1 study (NCT02595931), berzosertib 60\u2013270 mg\/m\n 2<\/jats:sup>\n was administered with irinotecan 180 mg\/m\n 2<\/jats:sup>\n every 2 weeks in a 4\u2010week cycle. The primary end point was determination of the maximum tolerated dose and recommended phase 2 dose (RP2D). Antitumor activity, pharmacokinetics, and pharmacodynamics were secondary end points.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Sixty\u2010three patients were enrolled, the majority with colorectal cancer (49%) or pancreatic cancer (21%). Median number of prior lines of therapy was four (range, 2\u20137). Two dose\u2010limiting toxicities, both febrile neutropenia, occurred among 45 patients treated with berzosertib 270 mg\/m\n 2<\/jats:sup>\n and irinotecan 180 mg\/m\n 2<\/jats:sup>\n . The most common treatment\u2010related grade \u22653 toxicities were lymphopenia (30%), neutropenia (29%), and anemia (25%). Two partial responses occurred in patients with pancreatic cancer and ataxia telangiectasia mutated (ATM) alterations: 32% decrease in an ATM E11828\/ATM K1109* tumor lasting 15.8 months and 57% decrease in an ATM R3008H\/germline ATM R1882* tumor lasting 13.6 months. Induction of DNA damage markers \u03b3H2AX and pNBS1 was observed in one tumor biopsy obtained post berzosertib and irinotecan combination treatment compared with post irinotecan alone.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Berzosertib 270 mg\/m\n 2<\/jats:sup>\n and irinotecan 180 mg\/m\n 2<\/jats:sup>\n was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cncr.70157","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:51:30Z","timestamp":1761763890000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phase 1 clinical trial of the ataxia telangiectasia and Rad3\u2010related inhibitor berzosertib with irinotecan in patients with advanced solid tumors (ETCTN 9938)"],"prefix":"10.1002","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-523X","authenticated-orcid":false,"given":"Liza C.","family":"Villaruz","sequence":"first","affiliation":[{"name":"Cancer Therapeutics Program UPMC Hillman Cancer Center Pittsburgh Pennsylvania USA"},{"name":"Division of Hematology\/Oncology Department of Medicine School of Medicine University of Pittsburgh Pittsburgh 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