PMID- 33560503
OWN - NLM
STAT- MEDLINE
DCOM- 20220202
LR  - 20220202
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 39
IP  - 4
DP  - 2021 Aug
TI  - A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor 
      TAS4464 in patients with advanced solid tumors.
PG  - 1036-1046
LID - 10.1007/s10637-020-01055-5 [doi]
AB  - Background This open-label, phase 1 study investigated TAS4464, a potent 
      NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid 
      tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was 
      dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated 
      using an accelerated titration design. Methods The starting 10-mg/m(2) dose was 
      followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver 
      function test (LFT) results, a 14-day, 20-mg/m(2) dose lead-in period was 
      implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and 
      gastrointestinal effects were the most common treatment-related adverse events 
      (AEs). DLTs with 56-mg/m(2) weekly dosing occurred in 1/5 patients; five patients 
      had grade >/= 2 abnormal LFT changes at 40- and 56-mg/m(2) weekly doses. Further 
      dose escalation ceased because of the possibility of severe abnormal LFT changes 
      occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 
      56-mg/m(2) dose; MTD could not be determined because discontinuation criteria for 
      additional enrollment at that particular dose level were met. As no further 
      enrollment at lower doses occurred, dose escalation assessment was discontinued. 
      Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs 
      were all related to abnormal LFT changes, suggesting that TAS4464 administration 
      could affect liver function. This effect was dose-dependent but considered 
      reversible. Complete or partial responses to TAS4464 were not observed; one 
      patient achieved prolonged stable disease. Conclusions MTD could not be 
      determined due to TAS4464 effects on liver function. Further evaluation of the 
      mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is 
      required. Trial registration number JapicCTI-173,488 (registered with Japan 
      Pharmaceutical Information Center). Registration date 13 January 2017.
CI  - (c) 2021. The Author(s).
FAU - Yamamoto, Noboru
AU  - Yamamoto N
AUID- ORCID: 0000-0002-0787-2851
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. nbryamam@ncc.go.jp.
FAU - Shimizu, Toshio
AU  - Shimizu T
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Yonemori, Kan
AU  - Yonemori K
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Kitano, Shigehisa
AU  - Kitano S
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
AD  - Division of Cancer Immunotherapy Development, Cancer Institute Hospital of the 
      Japanese Foundation for Cancer Research, Tokyo, Japan.
FAU - Kondo, Shunsuke
AU  - Kondo S
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Iwasa, Satoru
AU  - Iwasa S
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Koyama, Takafumi
AU  - Koyama T
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Sudo, Kazuki
AU  - Sudo K
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Sato, Jun
AU  - Sato J
AD  - Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
FAU - Tamura, Kenji
AU  - Tamura K
AD  - Department of Breast and Medical Oncology, National Cancer Center Hospital, 
      Tokyo, Japan.
AD  - Innovative Cancer Center, Shimane University Hospital, Shimane, Japan.
FAU - Tomomatsu, Junichi
AU  - Tomomatsu J
AD  - Department of Medical Oncology, Cancer Institute Hospital of the Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Ono, Makiko
AU  - Ono M
AD  - Department of Medical Oncology, Cancer Institute Hospital of the Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Fukuda, Naoki
AU  - Fukuda N
AD  - Department of Medical Oncology, Cancer Institute Hospital of the Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Takahashi, Shunji
AU  - Takahashi S
AD  - Department of Medical Oncology, Cancer Institute Hospital of the Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210209
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (TAS4464)
RN  - EC 6.2.1.45 (Ubiquitin-Activating Enzymes)
RN  - EC 6.3.2.- (NAE protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/adverse effects
MH  - Chemical and Drug Induced Liver Injury/etiology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Liver Function Tests
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/pathology
MH  - Pyrimidines/*administration & dosage/adverse effects
MH  - Pyrroles/*administration & dosage/adverse effects
MH  - Treatment Outcome
MH  - Ubiquitin-Activating Enzymes/*antagonists & inhibitors
MH  - Young Adult
PMC - PMC8279981
OTO - NOTNLM
OT  - NEDD8 activating enzyme E1 inhibitor
OT  - Pharmacokinetics
OT  - Phase 1
OT  - Safety
OT  - Solid tumors
OT  - TAS4464
COIS- Noboru Yamamoto reports grants from Chugai, Taiho, Eisai, Eli Lilly, Quintiles, 
      Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer 
      Ingelheim, Kyowa Hakko Kirin, Bayer, Ono, Takeda, GlaxoSmithKline, Sumitomo 
      Dainippon Pharma, Chiome Bioscience Inc., Janssen, MSD, and Merck; and personal 
      fees from Ono, Chugai, AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb, 
      Eisai, Otsuka, Takeda, Boehringer Ingelheim, Cimic, and Sysmex, outside the 
      submitted work. Toshio Shimizu reports grants from Novartis, Eli Lilly, 
      Daiichi-Sankyo, Bristol-Myers Squibb, Eisai, AbbVie, AstraZeneca, Takeda 
      Oncology, Incyte, Pfizer, Chordia Therapeutics, 3D-Medicine, Symbio 
      Pharmaceuticals, PharmaMar, Five Prime, and Astellas; and personal fees from 
      Taiho, Boehringer Ingelheim, Chugai, Ono, Takeda, and AbbVie, outside the 
      submitted work. Kan Yonemori reports personal fees from Ono, Pfizer, Takeda, 
      Eisai, Novartis, AstraZeneca, and Chugai, outside the submitted work. Shigehisa 
      Kitano reports personal fees from Nippon Kayaku, Meiji Seika Pharma, Taiho, 
      Novartis, Daiichi-Sankyo, MSD, Kyowa Hakko Kirin, Celgene, Sumitomo Dainippon 
      Pharma, Bristol-Myers Squibb, AYUMI Pharmaceutical Corporation, Rakuten Medical, 
      PMDA (Pharmaceuticals and Medical Devices Agency), and GSK; grants and personal 
      fees from Boehringer Ingelheim, Eisai, Ono, and REGENERON; and grants from 
      Astellas, Gilead Sciences, AMED (Japan Agency for Medical Research and 
      Development), and JSPS (Japan Society for the Promotion of Science), outside the 
      submitted work. Shunsuke Kondo has received research funding from ASLAN 
      Pharmaceuticals, Eisai, AstraZeneca, Bayer, Eli Lilly, MSD, and Pfizer. Satoru 
      Iwasa reports personal fees from Taiho, Merck-Serono, Eli Lilly, and Chugai; 
      grants and personal fees from Ono; and grants from Daiichi-Sankyo, Bristol-Myers 
      Squibb, Bayer, and Astellas, outside the submitted work. Takafumi Koyama reports 
      honoraria from Cysmex and Chugai, outside the submitted work. Jun Sato reports 
      personal fees from Chugai, during the conduct of the study. Junichi Tomomatsu 
      reports personal fees from Eisai, during the conduct of the study. Naoki Fukuda 
      reports personal fees from Eisai, outside the submitted work. Shunji Takahashi 
      reports grants and personal fees from Taiho, during the conduct of the study; and 
      grants and personal fees from MSD, AstraZeneca, Chugai, Ono, Bristol-Myers 
      Squibb, and Eisai, and grants from Novartis, outside the submitted work. Kazuki 
      Sudo, Kenji Tamura, and Makiko Ono have nothing to disclose.
EDAT- 2021/02/10 06:00
MHDA- 2022/02/03 06:00
PMCR- 2021/02/09
CRDT- 2021/02/09 12:11
PHST- 2020/11/17 00:00 [received]
PHST- 2020/12/16 00:00 [accepted]
PHST- 2021/02/10 06:00 [pubmed]
PHST- 2022/02/03 06:00 [medline]
PHST- 2021/02/09 12:11 [entrez]
PHST- 2021/02/09 00:00 [pmc-release]
AID - 10.1007/s10637-020-01055-5 [pii]
AID - 1055 [pii]
AID - 10.1007/s10637-020-01055-5 [doi]
PST - ppublish
SO  - Invest New Drugs. 2021 Aug;39(4):1036-1046. doi: 10.1007/s10637-020-01055-5. Epub 
      2021 Feb 9.