{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:51:10Z","timestamp":1789757470482,"version":"4.0.1"},"reference-count":39,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"9","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n            <jats:title>PURPOSE<\/jats:title>\n            <jats:p>We conducted a phase I trial of the combination of cisplatin with the ataxia-telangiectasia\u2013related protein kinase inhibitor berzosertib and the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib, with the objective of creating a DNA damage response (DDR)\u2013impaired, BRCA null\u2013like phenotype to potentiate the antitumor activity of cisplatin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>PATIENTS AND METHODS<\/jats:title>\n            <jats:p>In this open label, 3 + 3 trial design, cisplatin and berzosertib were administered intravenously on day 1 (D1) and D8, and D2 and D9, respectively, together with twice-daily oral veliparib on D1-D3 and D8-D10 in 21-day cycles. Previous platinum and PARPi therapy were permitted. A pharmacodynamic study compared tumor nuclear DDR biomarker response on C1D1 and C1D9 at the combination maximum tolerated dose (MTD).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS<\/jats:title>\n            <jats:p>\n              Fifty-three patients enrolled with 46 evaluable for response (41 with measurable disease). The MTD and recommended phase II dose (RP2D) were determined to be cisplatin 40 mg\/m\n              <jats:sup>2<\/jats:sup>\n              once daily on D1\/D8, berzosertib 210 mg\/m\n              <jats:sup>2<\/jats:sup>\n              once daily on D2\/D9, and veliparib 200 mg twice a day on D1-D3 and D8-D10. Three patients achieved confirmed partial responses (PRs; 3\/41, 7.3%); two patients experienced unconfirmed PRs. Median time on study was four cycles (range, 1-25), and 35 patients (66.0%) required at least one dose reduction. The most common grade 3\/4 adverse events were myelosuppressive (anemia [37.7%], thrombocytopenia [32.1%], leukopenia [24.5%], neutropenia [22.6%], lymphopenia [20.8%]); no new safety signals were observed. Adding berzosertib to veliparib\/cisplatin increased the frequency of RAD51-positive tumor cells in\n              <jats:italic toggle=\"yes\">BRCA<\/jats:italic>\n              -wildtype biopsy specimens.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSION<\/jats:title>\n            <jats:p>\n              This combination shows antitumor activity, including in patients with and without homologous recombination\u2013compromised tumors and those previously treated with platinum. Adding berzosertib further increases the DDR response elicited by combination cisplatin\/veliparib treatment in\n              <jats:italic toggle=\"yes\">BRCA<\/jats:italic>\n              -wildtype patients, indicating increased replication stress at the RP2D\/MTD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1200\/po-25-00055","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T20:00:26Z","timestamp":1752696026000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia\u2013Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors"],"prefix":"10.1200","clinical-trial-number":[{"clinical-trial-number":"nct02723864","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2918-6326","authenticated-orcid":true,"given":"Geraldine","family":"O'Sullivan Coyne","sequence":"first","affiliation":[{"name":"Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-8899","authenticated-orcid":true,"given":"Khanh T.","family":"Do","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute\/Brigham and Women's Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-1627","authenticated-orcid":true,"given":"Shivaani","family":"Kummar","sequence":"additional","affiliation":[{"name":"Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, 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