PMID- 38411735
OWN - NLM
STAT- Publisher
LR  - 20240227
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
DP  - 2024 Feb 27
TI  - A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in 
      patients with advanced solid tumors.
LID - 10.1007/s00280-023-04631-7 [doi]
AB  - PURPOSE: 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. METHODS: 
      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. RESULTS: 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. CONCLUSION: 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. TRIAL 
      REGISTRATION: jRCT2080222728 (January 29, 2015).
CI  - (c) 2024. The Author(s).
FAU - Doi, Toshihiko
AU  - Doi T
AUID- ORCID: 0000-0003-2042-6829
AD  - National Cancer Center Hospital East, Kashiwa, Japan. tdoi@east.ncc.go.jp.
FAU - Takahashi, Shunji
AU  - Takahashi S
AD  - Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 
      Japan.
FAU - Aoki, Daisuke
AU  - Aoki D
AD  - Keio University School of Medicine, Tokyo, Japan.
AD  - Akasaka Sannou Medical Center, Tokyo, Japan.
AD  - International University of Health and Welfare Graduate School, Tokyo, Japan.
FAU - Yonemori, Kan
AU  - Yonemori K
AD  - National Cancer Center Hospital, Tokyo, Japan.
FAU - Hara, Hiroki
AU  - Hara H
AD  - Saitama Cancer Center, Kita-Adachi, Japan.
FAU - Hasegawa, Kosei
AU  - Hasegawa K
AD  - Saitama Medical University International Medical Center, Hidaka, Japan.
FAU - Takehara, Kazuhiro
AU  - Takehara K
AD  - NHO Shikoku Cancer Center, Matsuyama, Japan.
FAU - Harano, Kenichi
AU  - Harano K
AD  - National Cancer Center Hospital East, Kashiwa, Japan.
FAU - Yunokawa, Mayu
AU  - Yunokawa M
AD  - Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 
      Japan.
FAU - Nomura, Hiroyuki
AU  - Nomura H
AD  - Keio University School of Medicine, Tokyo, Japan.
AD  - Fujita Health University, Toyoake, Japan.
FAU - Shimoi, Tatsunori
AU  - Shimoi T
AD  - National Cancer Center Hospital, Tokyo, Japan.
FAU - Horie, Koji
AU  - Horie K
AD  - Saitama Cancer Center, Kita-Adachi, Japan.
FAU - Ogasawara, Aiko
AU  - Ogasawara A
AD  - Saitama Medical University International Medical Center, Hidaka, Japan.
FAU - Okame, Shinichi
AU  - Okame S
AD  - NHO Shikoku Cancer Center, Matsuyama, Japan.
LA  - eng
PT  - Journal Article
DEP - 20240227
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
SB  - IM
OTO - NOTNLM
OT  - AKT inhibitor
OT  - Advanced solid tumor
OT  - First-in-human
OT  - Pharmacodynamics
OT  - Pharmacokinetics
EDAT- 2024/02/27 12:43
MHDA- 2024/02/27 12:43
CRDT- 2024/02/27 11:08
PHST- 2023/08/08 00:00 [received]
PHST- 2023/12/08 00:00 [accepted]
PHST- 2024/02/27 12:43 [medline]
PHST- 2024/02/27 12:43 [pubmed]
PHST- 2024/02/27 11:08 [entrez]
AID - 10.1007/s00280-023-04631-7 [pii]
AID - 10.1007/s00280-023-04631-7 [doi]
PST - aheadofprint
SO  - Cancer Chemother Pharmacol. 2024 Feb 27. doi: 10.1007/s00280-023-04631-7.