TAS-114(TAS-114) - 药物靶点：DPD x dUTPase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

DPD x dUTPase

作用方式

抑制剂

作用机制

DPD抑制剂(二氢嘧啶脱氢酶抑制剂)、dUTPase抑制剂(dUTP焦磷酸酶抑制剂)

治疗领域

肿瘤呼吸系统疾病

在研适应症-

非在研适应症

晚期非小细胞肺癌晚期恶性实体瘤非小细胞肺癌

原研机构

Taiho Pharmaceutical Co., Ltd.

在研机构-

非在研机构

Taiho Oncology, Inc.

Taiho Pharmaceutical Co., Ltd.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

7

项与 TAS-114 相关的临床试验

JPRN-UMIN000028329

/ Completed临床2期IIT

Phase II study of TAS-114 in combination with S-1 in patients with advanced gastric cancer refractory to prior chemotherpy. - TAS114_GC study

开始日期2017-10-17

申办/合作机构

National Cancer Center Hospital East

NCT02855125

/ Completed临床2期

A Randomized, Open-Label, Multi-Center, International Phase 2 Study of TAS-114 in Combination With S-1 in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

This is a randomized, open-label, Phase 2 study of TAS-114 administered in combination with S-1, to investigate the efficacy, safety and tolerability of the TAS-114/S-1 regimen in patients with advanced or metastatic NSCLC.
The study will be conducted internationally in 2 regions: Asian [Japan] and Western [Europe and US]. Patients will be randomized into TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio.

开始日期2016-08-29

申办/合作机构

Taiho Oncology, Inc.

NCT02454062

/ Completed临床1期

A Phase I, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability and Pharmacokinetic Study of TAS-114 in Combination With S-1 in Patients With Advanced Solid Tumors

A Phase I, Open-Label, International, Multicenter, Non-Randomized, Dose-Escalating Safety, Tolerance and Pharmacokinetic Study of Oral Administration of TAS-114 in Combination with S-1 in a Twice Daily Schedule for 14 Days in Patients with Advanced Solid Tumors.

开始日期2013-03-01

申办/合作机构

Taiho Oncology, Inc.

100 项与 TAS-114 相关的临床结果

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100 项与 TAS-114 相关的转化医学

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100 项与 TAS-114 相关的专利（医药）

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10

项与 TAS-114 相关的文献（医药）

2022-11-01·Cancer Letters

Overexpression of nucleotide metabolic enzyme DUT in hepatocellular carcinoma potentiates a therapeutic opportunity through targeting its dUTPase activity

Article

作者: Xu, Mingjing ; Lo, Wing Sze ; Wong, Nathalie ; Liu, Yue ; You, Wenxing ; Wan, Ho Lee ; Wong, Alissa M ; Ng, Kelvin K-C ; Ding, Xiaofan

Uracil misincorporation during DNA replication is a major cell toxic event, of which cancer cells overcome by activating the dUTPase enzyme. The DUT gene is the only known dUTPase in human. Despite reports on common upregulations in cancers, the role of DUT in human hepatocellular carcinoma (HCC) remains largely undetermined. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC tumors and correlated with advanced stage HCC. Knockout of DUT in HCC cell lines showed suppressed proliferation through cell cycle arrest and a spontaneous induction of DNA damage. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Transcriptome analysis highlighted the NF-κB survival signaling as the downstream effector pathway of DUT in overriding oxidative stress-induced cell death. Interestingly, stably expressed DUT in liver progenitor organoids conferred drug resistance to TKI Sorafenib. Targeting dUTPase activity by TAS-114, could potentiate suppression of HCC growth that synergized with Sorafenib for better treatment sensitivity. In conclusion, upregulated DUT represents a nucleotide metabolic weakness and therapeutic opportunity in HCC.

2021-01-01·Cancer Science2区 · 医学

dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA‐repair‐defective human cancer cells

2区 · 医学

ArticleOA

作者: Yokogawa, Tatsushi ; Wakasa, Takeshi ; Hoshino, Takuya ; Ueno, Hiroyuki ; Osada, Akiko ; Matsuo, Kenichi ; Yano, Wakako ; Ohkubo, Shuichi ; Yamamura, Keisuke ; Fujioka, Akio ; Fukuoka, Masayoshi ; Tsukioka, Sayaka

AbstractDeficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5‐Fluorouracil (5‐FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5‐FU and uracil misincorporation, we examined cancer cells treated with 2ʹ‐deoxy‐5‐fluorouridine (FdUrd) in the presence of TAS‐114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS‐114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5‐FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5‐FU incorporation into RNA. TAS‐114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short‐term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5‐FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA‐treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5‐FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.

2021-01-01·Gastric Cancer1区 · 医学

A multicenter phase II study of TAS-114 in combination with S-1 in patients with pretreated advanced gastric cancer (EPOC1604)

1区 · 医学

Article

作者: Ikeno, Takashi ; Nomura, Shogo ; Nakamura, Yoshiaki ; Kambe, Moe ; Hirano, Nami ; Fukutani, Miki ; Saito, Yumiko ; Takahari, Daisuke ; Kawazoe, Akihito ; Shitara, Kohei ; Wakabayashi, Masashi ; Keisho, Chin ; Tamura, Hitomi ; Sato, Akihiro

BACKGROUNDThis is a phase 2 study aimed at evaluating the efficacy and safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 in patients with advanced gastric cancer (AGC).METHODSEligible patients had AGC with measurable lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1), with two or more previous chemotherapy regimens including fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint was objective response rate (ORR) according to the RECIST, v1.1. Twenty-nine patients were required according to Simon's optimal two-stage design, with one-sided a = 5% and power = 80%. Threshold and expected ORRs were 5% and 25%. Patients received TAS-114 (400 mg/body, twice a day) and S-1 (30 mg/m², twice a day) for 14 days, followed by 7 days of rest in one 3-week cycle. Protein expression levels of dUTPase and BRCA1 in tumor samples were determined by immunohistochemistry.RESULTSAccrual was terminated in June 2018 because meeting the predefined efficacy criteria was considered difficult. ORR and disease control rate were 5.0% [95% confidence interval (CI), 0.1-24.9%] and 70.0% (95% CI, 45.7-88.1%), respectively, for all 20 patients enrolled. Median progression-free survival (PFS) and overall survival were 2.4 months (95% CI, 1.2-3.3 months) and 7.1 months (95% CI, 5.2-9.4 months), respectively. Median PFS in the groups with high and low dUTPase protein expression in the cytoplasm was 2.8 months (95% CI, 1.4-3.9) and 1.6 months (95% CI, 0.6-2.4), respectively [hazard ratio, 0.40 (95% CI, 0.16-1.04), log-rank test two-sided p = 0.047]. Grade 3 or higher treatment-related adverse events included anemia (20%), leucopenia (15%), neutropenia (10%), rash (10%), thrombocytopenia (5%), and lymphopenia (5%) CONCLUSIONS: TAS-114 with S-1 showed only modest antitumor activity with acceptable safety profiles for patients heavily pretreated with AGC.

100 项与 TAS-114 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期非小细胞肺癌	临床2期	美国	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	日本	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	波兰	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	意大利	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	西班牙	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	法国	Taiho Oncology, Inc.	2016-08-29
非小细胞肺癌	临床2期	日本	Taiho Pharmaceutical Co., Ltd.	2016-07-16
晚期恶性实体瘤	临床2期	日本	Taiho Pharmaceutical Co., Ltd.	2012-06-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02855125 (CTgov)	临床2期	晚期非小细胞肺癌	128	S-1+TAS-114 (TAS-114 + S-1)	糧鹹廠範簾鹽顧鏇鹹齋(構構範憲襯遞遞壓繭憲) = 願鹽構簾觸鹽築繭蓋積鬱齋醖鏇廠築觸築築顧 (簾齋築襯膚顧構淵襯鑰, 醖網構餘鬱製獵膚襯簾 ~ 積遞網範顧憲夢壓願齋) 更多	-	2021-12-23
				S-1 (S-1 (Monotherapy))	糧鹹廠範簾鹽顧鏇鹹齋(構構範憲襯遞遞壓繭憲) = 構膚醖構窪憲蓋夢憲膚鬱齋醖鏇廠築觸築築顧 (簾齋築襯膚顧構淵襯鑰, 衊窪鬱製鏇積鬱觸鏇選 ~ 鹹廠製觸艱齋鹽齋觸鹽) 更多
NCT02855125 (Pubmed \| Invest New Drugs) 人工标引	临床2期	非小细胞肺癌三线	127	S-1+TAS-114	(遞積廠鹽獵遞願膚鹹簾) = 齋鬱壓繭糧艱齋壓積鑰繭繭夢遞範製觸壓觸衊 (憲糧鹹糧憲艱淵醖窪願 ) 更多	不佳	2020-10-01
				S-1	(遞積廠鹽獵遞願膚鹹簾) = 鬱獵顧繭夢繭繭夢獵餘繭繭夢遞範製觸壓觸衊 (憲糧鹹糧憲艱淵醖窪願 ) 更多
EPOC1604 (ESMO2019)	临床2期	晚期胃癌	20	TAS-114 and S-1 combination	(繭衊廠壓壓鹽糧鑰願遞) = 範鬱鹹齋淵襯鹽蓋夢鏇糧蓋鏇獵鏇餘鏇觸觸鹽 (構鬱襯觸鏇選鑰鹽憲積, 0.1 ~ 24.9) 更多	-	2019-09-29
NCT01610479 (Pubmed \| Invest New Drugs)	临床1期	晚期恶性实体瘤	-	TAS-114	(鹽鑰鬱遞膚鹹夢觸範鹹) = 遞鏇襯衊鏇淵壓鏇蓋繭窪鹽蓋壓網鑰壓顧衊齋 (製獵夢夢製繭築願簾繭 ) 更多	-	2019-06-01
				S-1	(鹽鑰鬱遞膚鹹夢觸範鹹) = 窪鏇壓齋築願衊獵繭廠窪鹽蓋壓網鑰壓顧衊齋 (製獵夢夢製繭築願簾繭 ) 更多
NCT02025803 (AACR 12018 \| AACR 22018) 人工标引	临床1期	实体瘤	104	TAS-114+capecitabine (dose-escalation phase)	(醖壓顧淵網艱壓觸淵範) = No treatment-related deaths occurred during the study. 窪繭觸製鬱餘鑰艱範蓋 (艱鏇夢窪鏇醖遞顧襯構 ) 更多	积极	2018-07-01
				TAS-114+capecitabine (expansion cohorts)
NCT02454062 (AACR 12018 \| AACR 22018) 人工标引	临床1期	晚期恶性实体瘤	99	TAS-114+Tegafur+Gimeracil+Oteracil	(糧顧齋憲觸製製遞夢獵) = TAS-114 240 mg/㎡ + S-1 30 mg/㎡ BID 壓獵鬱築壓淵淵壓願築 (鬱壓夢夢憲鑰網願顧製 ) 更多	积极	2018-07-01