Sistema de Salut de Catalunya
Institut Català de la Salut
[Janku F] The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [Choong GM] Mayo Clinic Rochester, Department of Oncology, Rochester, MN, USA. [Opyrchal M] Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [Dowlati A] University Hospitals of Cleveland, Cleveland, OH, USA. [Hierro C] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Rodon J] The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2024-04-05T07:34:20Z
2024-04-05T07:34:20Z
2024-03-13
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.
Article
Published version
English
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
MDPI
Cancers;16(6)
https://doi.org/10.3390/cancers16061137
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3440]
