2026-04-13T07:19:31Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/58702025-10-24T10:44:35Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Harding, James J. author Tan, Daniel S. W. author Bedard, Philippe L. author Rodon Ahnert, Jordi author Doi, Toshihiko author Bauer, Todd author 2021-04-16T14:24:14Z 2021-04-16T14:24:14Z 2018 2019-04-15 CLR457; Inhibidor Pan-PI3K; Fase I CLR457; Inhibidor Pan-PI3K; Fase I CLR457; Pan-PI3K inhibitor; Phase I Background CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms. Novartis Pharmaceuticals Corporation. http://hdl.handle.net/11351/5870 Tumors Inhibidors enzimàtics CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors DISEASES::Neoplasms COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas ENFERMEDADES::neoplasias Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor