TAS-114 / Otsuka - LARVOL DELTA

Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer (AACR 2023) - "In conclusion, our study showed that upregulated DUT conferred growth advantage to HCC cells by reducing uracil misincorporation and favoring nucleotide synthesis. Targeting DUT with its first-in-class inhibitor TAS-114 in combination with Sorafenib represents an effective treatment regime for HCC."

Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Overexpression of nucleotide metabolic enzyme DUT in hepatocellular carcinoma potentiates a therapeutic opportunity through targeting its dUTPase activity. (PubMed, Cancer Lett) - "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."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS-114. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "TAS-114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. 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."

Clinical • Journal • PK/PD data • DUT

Phase I study of TAS-114 in combination with capecitabine in patients with advanced solid tumors (AACR 2018) - P1; "TAS-114 combined with capecitabine at 30% of its standard dose achieved an equivalently efficacious 5-FU exposure as the standard capecitabine dose alone, with acceptable safety and preliminary efficacy in pts with advanced solid tumors. 1. Aoyama T et al."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Hormone Receptor Breast Cancer

A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors (AACR 2018) - P1; "TAS-114 combined with S-1 demonstrated an acceptable safety profile and preliminary efficacy in heavily pretreated pts with advanced solid tumors."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer

dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells. (PubMed, Cancer Sci) - "To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. These results suggest 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."

Journal • Oncology • TYMS

A multicenter phase II study of TAS-114 in combination with S-1 in patients with pretreated advanced gastric cancer (EPOC1604). (PubMed, Gastric Cancer) - "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. 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%) TAS-114 with S-1 showed only modest antitumor activity with acceptable safety profiles for patients heavily pretreated with AGC."

Clinical • Combination therapy • Journal • P2 data • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • BRCA1

Phase 1 Study of first-in-class dUTPase inhibitor, TAS-114 in combination with capecitabine in patients with advanced solid tumors (EORTC-NCI-AACR 2016) - Ambassador: Heinz-Josef Lenz; Presentation time: Thursday, December 1, 2016; Abstract #P040; P1, N=56; "TAS-114 in combination with Capecitabine was well tolerated in pts with heavily treated advanced solid tumors, resulting in the promising antitumor efficacy. The activity of the combination regimen is being further evaluated in an ongoing MTD expansion stage for BC and CRC pts population."

P1 data • GI (CRC, Pancreatic cancer) KOL Tracker

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer. (PubMed, Invest New Drugs) - P2 | "Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016."

Clinical • Combination therapy • Journal • P2 data

First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors. (PubMed, Invest New Drugs) - P1; "To confirm safety and efficacy, two phase 2 studies are ongoing in NSCLC and gastric cancer patients. Clinical trial registration ClinicalTrials.gov ( NCT01610479 ) ."

Clinical • Combination therapy • Journal • P1 data

A Trial of TAS-114 in Combination With S-1 (clinicaltrials.gov) - P1; N=120; Completed; Sponsor: Taiho Oncology, Inc.; Recruiting ➔ Completed

Clinical • Combination therapy • Trial completion

A multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604) (ESMO 2019) - " The main eligibility criteria is pts with AGC after two or more previous chemotherapy regimens containing fluoropyrimidines, platinum agents, and taxanes or irinotecan. TAS-114 with S-1 showed modest antitumor activity with acceptable safety profiles for heavily pretreated pts with AGC. Legal entity responsible for the study: The authors. Funding: Taiho."

BRCA Biomarker • Clinical • Combination therapy • P2 data

TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-based Chemotherapy. (PubMed, Mol Cancer Ther) - "Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment."

Clinical • Journal