{Reference Type}: Journal Article
{Title}: A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.
{Author}: Doi T;Takahashi S;Aoki D;Yonemori K;Hara H;Hasegawa K;Takehara K;Harano K;Yunokawa M;Nomura H;Shimoi T;Horie K;Ogasawara A;Okame S;
{Journal}: Cancer Chemother Pharmacol
{Volume}: 93
{Issue}: 6
{Year}: 2024 Jun 27
{Factor}: 3.288
{DOI}: 10.1007/s00280-023-04631-7
{Abstract}: <B>OBJECTIVE: </B>TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated.<BR><B>METHODS: </B>This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity.<BR><B>RESULTS: </B>Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response.<BR><B>CONCLUSIONS: </B>Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.<BR><B>BACKGROUND: </B>jRCT2080222728 (January 29, 2015).