2026-04-17T03:30:42Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/112872024-06-06T08:39:58Zcom_2072_378070com_2072_378040col_2072_378092

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors Janku, Filip Choong, Grace Opyrchal, Mateusz Dowlati, Afshin Hierro Carbó, Cinta Rodon, Jordi Proteïnes quinases - Inhibidors - Ús terapèutic Càncer - Tractament Posologia DISEASES::Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose 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 ENFERMEDADES::neoplasias Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada 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 PI3K/mTOR inhibitor; Intermittent dosing schedule; Solid tumor Inhibidor de PI3K/mTOR; Programa de dosificació intermitent; Tumor sòlid Inhibidor de PI3K/mTOR; Programa de dosificación intermitente; Tumor sólido Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations. The study was sponsored by PIQUR Therapeutics. 2024-06-06T08:39:58Z 2024-06-06T08:39:58Z 2024-06-06T08:39:58Z 2024-04-05T07:34:20Z 2024-04-05T07:34:20Z 2024-03-13 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/11351/11287 Cancers;16(6) https://doi.org/10.3390/cancers16061137 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess MDPI Scientia