{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:31:15Z","timestamp":1790937075626,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T00:00:00Z","timestamp":1690934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007052","name":"Memorial Sloan Kettering Cancer Center","doi-asserted-by":"publisher","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"id":[{"id":"10.13039\/100007052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000982","name":"Conquer Cancer Foundation","doi-asserted-by":"publisher","award":["NCI P30CA008748"],"award-info":[{"award-number":["NCI P30CA008748"]}],"id":[{"id":"10.13039\/100000982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n\u2005=\u20053; 35 mg: n\u2005=\u20053; 25 mg: n\u2005=\u20051). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (\u226510%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at \u226515 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>ClinicalTrials.gov Identifier<\/jats:title>\n                  <jats:p>NCT03770494.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/oncolo\/oyad215","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T15:07:35Z","timestamp":1690988855000},"page":"e131-e140","source":"Crossref","is-referenced-by-count":23,"title":["A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors"],"prefix":"10.1093","volume":"29","author":[{"given":"Elena","family":"Garralda","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Institute of Oncology (VHIO) , Barcelona , 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