65 TAS-114 Enhances S-1 Activity in Vivo When Used in Combination

Yokogawa, Tatsushi; Wakasa, Takeshi; Yano, Wakako; Yoshisue, Kunihiro; Fujioka, Akio; Eshima, Kiyoshi; Fukuoka, Muneyoshi; Matsuo, Kayoko; Noguchi, K; Utsugi, Teruhiro

doi:10.1016/s0959-8049(12)71863-4

Cited by 4 publications

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“…1 . In preclinical studies, when TAS-114 was combined with 5-FU agents such as S-1 or capecitabine, it enhanced antitumor activity compared with 5-FU alone in various human cancer xenograft models [ 15 , 16 ]. Previously, the first-in-human phase 1 trial of TAS-114 was conducted in healthy male volunteers to assess its pharmacokinetics (PK) and safety [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors

et al. 2018

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Summary Background This first-in-human phase 1 study assessed the safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 to determine its maximum tolerated dose (MTD) and recommended dose (RD). Methods In this dose-escalation study with a 3 + 3 design, TAS-114 and S-1 were concurrently administered orally under fasting conditions at 5–240 mg/m 2 and 30–36 mg/m 2 , respectively, in patients with advanced solid tumors. Safety, efficacy, and pharmacokinetics (PK) were evaluated. Results Seventy-six patients were enrolled. The MTD and RD were TAS-114 200 mg/m 2 plus S-1 36 mg/m 2 and TAS-114 240 mg/m 2 plus S-1 30 mg/m 2 , respectively. Common treatment-related adverse events were anemia, lymphocytopenia, leukopenia, neutropenia, decreased appetite, rash, nausea, and pigmentation disorder. Partial response (PR) was observed in 10 patients (non-small cell lung cancer [NSCLC], n = 5; pancreatic neuroendocrine tumor, n = 2; gastric cancer, n = 2; gallbladder cancer, n = 1). Of these, four patients achieved PR despite prior treatment history with S-1. Patients administered TAS-114 exhibited linear PK and CYP3A4 induction, with no effect on the PK of S-1. Conclusion TAS-114 plus S-1 showed tolerable, safe, and potentially effective results. To confirm safety and efficacy, two phase 2 studies are ongoing in NSCLC and gastric cancer patients. Clinical trial registration ClinicalTrials.gov ( NCT01610479 ) . Electronic supplementary material The online version of this article (10.1007/s10637-018-0697-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors

et al. 2018

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“…Incorporation of both FdUTP and dUTP induces DNA dysfunction, resulting in tumor death. Significant enhancement in antitumor activity was observed, especially when TAS-114 was combined with a 5-FU oral prodrug such as S-1 (18) (Fig. 3) or capecitabine (19) (Fig.…”

Section: The Challenge Of Developing Pyrimidine Derivativesmentioning

confidence: 99%

“…From an efficacy standpoint, a significant enhancement above that of capecitabine monotherapy has been observed in preclinical models, due to DNA dysfunction induced by DNA incorporation of FdUTP in addition to the inhibition of TS. In S-1 combination (18), the DPD-inhibitory effect of TAS-114 is negligible because it is masked by the strong DPD inhibitor gimeracil, which is one of the subcomponents of S-1. Phase I clinical trials of TAS-114 in combination with S-1 (TAS-114S) or capecitabine (TAS-114C) are in progress.…”

Section: The Challenge Of Developing Pyrimidine Derivativesmentioning

confidence: 99%

New Challenges and Inspired Answers for Anticancer Drug Discovery and Development

Utsugi

2013

Japanese Journal of Clinical Oncology

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Many pharmaceutical companies worldwide specialize in oncology drug development and marketing. Among them, we have continued to take up the challenge of understanding the metabolism of pyrimidines as essential components of deoxyribonucleic acid for many years, and have provided unique products such as UFT® and TS-1 for cancer patients. Using our cumulative experience and knowledge, we are currently developing novel agents such as TAS-114, a dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and TAS-102, a unique pyrimidine derivative inducing deoxyribonucleic acid dysfunction in cancer cells. Regarding molecular-targeted drugs, we have made huge efforts to establish ideal drug discovery platforms for the last several years. For kinase inhibitors, we established three core platforms such as a kinase-directed chemical library, a kinase assay panel and a target selection informatics system. The core platforms were further combined with peripheral technologies to measure essential parameters such as physicochemical properties, pharmacokinetics, efficacy and toxicities. Unique drug candidates have been identified at an early stage by assessing all important parameters. Several promising programs are proceeding simultaneously in the clinical or preclinical development stage such as TAS-115, a dual inhibitor of c-Met and vascular endothelial growth factor receptor, TAS-2104, a selective Aurora A inhibitor, TAS-117, an allosteric Akt inhibitor, TAS-2985, an irreversible fibroblast growth factor receptor inhibitor and TAS-2913, a T790M mutant selective epidermal growth factor receptor inhibitor. Other than kinase inhibitors, another drug discovery engine was established based on the fragment-based drug discovery technology. TAS-116, a new class of Hsp-90α/β inhibitor, is one of the products. Taiho's final goal is to provide innovative anticancer drugs together with companion diagnostics that are truly beneficial for patients.

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“…Although TAS-114 itself does not show antitumor activity, it can increase the amount of FdUTP in the tumor for selective incorporation into DNA. This enhances antitumor activity of 5-FU or fluoropyrimidines, such as S-1 or capecitabine, compared with 5-FU alone in various human cancer xenograft models [12,13]. Furthermore, a phase 1 study of TAS-114 in combination with S-1 in Japanese patients showed its tolerability and preliminary antitumor signals for patients with non-small cell lung cancer (NSCLC) and AGC [14].…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2020

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Background This 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). Methods Eligible 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/m 2 , 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. Results Accrual 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 dUT-Pase 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.

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65 TAS-114 Enhances S-1 Activity in Vivo When Used in Combination

Cited by 4 publications

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First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors

First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors

New Challenges and Inspired Answers for Anticancer Drug Discovery and Development

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

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