2026-04-13T05:58:46Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/109222024-06-06T08:39:35Zcom_2072_378070com_2072_378040col_2072_378092

2024-06-06T08:39:35Z urn:hdl:11351/10922 A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors Schram, Alison Schwartz, Gary K Yuen, Eunice McNeely, Samuel C GARRALDA, Elena Bedard, Philippe Càncer - Tractament Proteïnes quinases - Inhibidors - Ús terapèutic CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors Other subheadings::Other subheadings::/therapeutic use DISEASES::Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas Otros calificadores::Otros calificadores::/uso terapéutico ENFERMEDADES::neoplasias Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia Cyclin-dependent kinase inhibitor; Solid tumors Inhibidor de quinasas dependent de la ciclina; Tumors sòlids Inhibidor de quinasas dependiente de la ciclina; Tumores sólidos Background 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. Materials and Methods 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. Results 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 = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) 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 ≥15 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. Conclusion 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. ClinicalTrials.gov Identifier NCT03770494. This work was supported by Eli Lilly and Company. Employees of Eli Lilly and Company participated in the study design, collection, analysis, and interpretation of the data, writing of this report, and decision to submit this article for publication. 2024-06-06T08:39:35Z 2024-06-06T08:39:35Z 2024-01-29T08:07:20Z 2024-01-29T08:07:20Z 2024-01 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/11351/10922 The Oncologist;29(1) https://doi.org/10.1093/oncolo/oyad215 Attribution-NonCommercial 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess Oxford University Press Scientia