Delving into the Latest Updates on TAS-114 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DPD x dUTPase

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: Lo, Wing Sze ; Xu, Mingjing ; Wong, Nathalie ; You, Wenxing ; Liu, Yue ; 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 May 2022·CPT: Pharmacometrics & Systems PharmacologyQ3 · MEDICINE

A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS‐114

Q3 · MEDICINE

ArticleOA

Author: Matsuoka, Kazuaki ; Ieiri, Ichiro ; Takenaka, Toru ; Araki, Hikari ; Takahashi, Koichi ; Yoshisue, Kunihiro ; Yamashita, Fumiaki

AbstractTAS‐114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS‐114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS‐114. Plasma concentrations of TAS‐114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two‐compartment model with first‐order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model‐based simulations provided the dose justification that DPD inhibition by TAS‐114 reached a plateau level at the MTD, whereas exposures of TAS‐114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS‐114.

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 ; Osada, Akiko ; Ueno, Hiroyuki ; Matsuo, Kenichi ; Yano, Wakako ; Ohkubo, Shuichi ; Fujioka, Akio ; Yamamura, Keisuke ; 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.

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	US	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	FR	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	PL	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	ES	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	JP	Taiho Oncology, Inc.	29 Aug 2016
Advanced Lung Non-Small Cell Carcinoma	Phase 2	IT	Taiho Oncology, Inc.	29 Aug 2016
Non-Small Cell Lung Cancer	Phase 2	JP	Taiho Pharmaceutical Co., Ltd.	16 Jul 2016
Advanced Malignant Solid Neoplasm	Phase 2	JP	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)	vdlsrnuvaf(anfhhnfnrb) = thptwktsbr ioxgjtmajr (mggrbhufam, lprknhzvth - lqltpqdhvf) View more	-	23 Dec 2021
				S-1 (S-1 (Monotherapy))	vdlsrnuvaf(anfhhnfnrb) = hxnzaipjrm ioxgjtmajr (mggrbhufam, leoqqrdaip - ihjcyvvvsw) View more
NCT02855125 (Pubmed \| Invest New Drugs) Manual	Phase 2	Non-Small Cell Lung Cancer Third line	127	S-1+TAS-114	(nvcthkwewu) = vaogdxyyvy exzmrshibo (bdmbcprpgz ) View more	Negative	01 Oct 2020
				S-1	(nvcthkwewu) = vrpmhezjfm exzmrshibo (bdmbcprpgz ) View more
EPOC1604 (ESMO2019)	Phase 2	Advanced gastric carcinoma	20	TAS-114 and S-1 combination	(kijvjjjybt) = phuwwfcljp rmmsgqgqvg (zmeojkengq, 0.1 - 24.9) View more	-	29 Sep 2019
NCT01610479 (Pubmed \| Invest New Drugs)	Phase 1	HR-positive/HER2-low Solid Tumors	-	TAS-114	(qmjbvtyaki) = unteutmpcu mqksugiprk (pplgfgxcka ) View more	-	01 Jun 2019
				S-1	(qmjbvtyaki) = ibinmwpssx mqksugiprk (pplgfgxcka ) View more
NCT02025803 (AACR2018) Manual	Phase 1	Solid tumor	104	TAS-114+capecitabine (dose-escalation phase)	(rqknpzyomk) = No treatment-related deaths occurred during the study. upckqxjblt (wmylltxqqy ) View more	Positive	01 Jul 2018
				TAS-114+capecitabine (expansion cohorts)
NCT02454062 (AACR2018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	99	TAS-114+Tegafur+Gimeracil+Oteracil	(watusdeeuk) = TAS-114 240 mg/㎡ + S-1 30 mg/㎡ BID yitlmbmgql (kjnzcbpooq ) View more	Positive	01 Jul 2018