Delving into the Latest Updates on TAS-114 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DPD x dUTPase

Action

inhibitors

Mechanism

DPD inhibitors(Dihydropyrimidine dehydrogenase inhibitors), dUTPase inhibitors(dUTP pyrophosphatase inhibitors)

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication-

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaAdvanced Malignant Solid NeoplasmNon-Small Cell Lung Cancer

Originator Organization

Taiho Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Taiho Oncology, Inc.

Taiho Pharmaceutical Co., Ltd.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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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.

Start Date29 Aug 2016

Sponsor / Collaborator

Taiho Oncology, Inc.

NCT02454062

/ CompletedPhase 1

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.

Start Date01 Mar 2013

Sponsor / Collaborator

Taiho Oncology, Inc.

100 Clinical Results associated with TAS-114

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100 Translational Medicine associated with TAS-114

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100 Patents (Medical) associated with TAS-114

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10

Literatures (Medical) associated with TAS-114

01 Nov 2022·Cancer Letters

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

Article

Author: 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.

01 Jan 2021·Cancer ScienceQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: 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.

01 Jan 2021·Gastric CancerQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with TAS-114

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Lung Non-Small Cell Carcinoma	Phase 2	United States	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Japan	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Poland	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Italy	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Spain	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	France	Taiho Oncology, Inc.	29 Aug 2016
Non-Small Cell Lung Cancer	Phase 2	Japan	Taiho Pharmaceutical Co., Ltd.	16 Jul 2016
Advanced Malignant Solid Neoplasm	Phase 2	Japan	Taiho Pharmaceutical Co., Ltd.	01 Jun 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02855125 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	128	S-1+TAS-114 (TAS-114 + S-1)	ncidgqpwft(gfowjjhbwf) = fpilwkdzvn gyzsitaigx (ukznwvbcuh, okhanezhdq - tixzbdajrb) View more	-	23 Dec 2021
				S-1 (S-1 (Monotherapy))	ncidgqpwft(gfowjjhbwf) = auodrxhmhw gyzsitaigx (ukznwvbcuh, aelncywern - sxygjsyyeh) View more
NCT02855125 (Pubmed \| Invest New Drugs) Manual	Phase 2	Non-Small Cell Lung Cancer Third line	127	S-1+TAS-114	(rftglcirwx) = uoblzpfwiw xgfjoljaap (aktcmbzgry ) View more	Negative	01 Oct 2020
				S-1	(rftglcirwx) = flcajnxacw xgfjoljaap (aktcmbzgry ) View more
EPOC1604 (ESMO2019)	Phase 2	Advanced gastric carcinoma	20	TAS-114 and S-1 combination	(dhbdmrdojl) = vdxptrqwwv cjamapymev (ldwgrdotok, 0.1 - 24.9) View more	-	29 Sep 2019
NCT01610479 (Pubmed \| Invest New Drugs)	Phase 1	Advanced Malignant Solid Neoplasm	-	TAS-114	(qiwmxqshve) = xwysmvpqnp xwotcplqrz (qibujckstz ) View more	-	01 Jun 2019
				S-1	(qiwmxqshve) = stebhhwytz xwotcplqrz (qibujckstz ) View more
NCT02025803 (AACR 12018 \| AACR 22018) Manual	Phase 1	Solid tumor	104	TAS-114+capecitabine (dose-escalation phase)	(nzeawiqlso) = No treatment-related deaths occurred during the study. wkdrhobkhz (hywlgllovp ) View more	Positive	01 Jul 2018
				TAS-114+capecitabine (expansion cohorts)
NCT02454062 (AACR 12018 \| AACR 22018) Manual	Phase 1	Advanced Malignant Solid Neoplasm	99	TAS-114+Tegafur+Gimeracil+Oteracil	(lrtwutzzcf) = TAS-114 240 mg/㎡ + S-1 30 mg/㎡ BID lqjuptkcag (sgzntgnvrq ) View more	Positive	01 Jul 2018