A multicenter phase II study of TAS-114 in combination with S-1 in patients with pretreated advanced gastric cancer (EPOC1604).
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Drug Combinations
Female
Humans
Male
Middle Aged
Oxonic Acid
/ administration & dosage
Progression-Free Survival
Proportional Hazards Models
Pyrimidines
/ administration & dosage
Pyrophosphatases
/ metabolism
Response Evaluation Criteria in Solid Tumors
Stomach Neoplasms
/ drug therapy
Sulfonamides
/ administration & dosage
Tegafur
/ administration & dosage
Ubiquitin-Protein Ligases
/ metabolism
Advanced gastric cancer
S-1
TAS-114
Journal
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
ISSN: 1436-3305
Titre abrégé: Gastric Cancer
Pays: Japan
ID NLM: 100886238
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
09
05
2020
accepted:
13
07
2020
pubmed:
24
7
2020
medline:
11
11
2021
entrez:
24
7
2020
Statut:
ppublish
Résumé
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). 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 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 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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 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.
Identifiants
pubmed: 32700159
doi: 10.1007/s10120-020-01107-y
pii: 10.1007/s10120-020-01107-y
doi:
Substances chimiques
Drug Combinations
0
Pyrimidines
0
Sulfonamides
0
TAS-114
0
S 1 (combination)
150863-82-4
Tegafur
1548R74NSZ
Oxonic Acid
5VT6420TIG
BRAP protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Pyrophosphatases
EC 3.6.1.-
dUTP pyrophosphatase
EC 3.6.1.23
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
190-196Références
International Agency for Research on Cancer. Globocan 2018: stomach. https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf . Accessed 4 Oct 2018.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.
doi: 10.1056/NEJMoa073149
Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21.
doi: 10.1016/S1470-2045(08)70035-4
Bang YJ, Van Cutsem E, Feyereislova A, Takagane A, Akiya T, Takagi M, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010;376:687–97.
doi: 10.1016/S0140-6736(10)61121-X
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–355.
doi: 10.1016/S1470-2045(14)70420-6
Kang JH, Lee SI, Lim Do H, Park KW, Oh SY, Kwon HC. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–8.
doi: 10.1200/JCO.2011.39.4585
Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4:e180013.
doi: 10.1001/jamaoncol.2018.0013
Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71.
doi: 10.1016/S0140-6736(17)31827-5
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:1437–48.
doi: 10.1016/S1470-2045(18)30739-3
Canman CE, Radany EH, Parsels LA, Davis MA, Lawrence TS, Maybaum J. Induction of resistance to fluorodeoxyuridine cytotoxicity and DNA damage in human tumor cells by expression of Escherichia coli deoxyuridine triphosphatase. Cancer Res. 1994;54:2296–8.
pubmed: 8162567
Ladner RD, Lynch FJ, Groshen S, Xiong YP, Sherrod A, Caradonna SJ, et al. dUTP nucleotidohydrolase isoform expression in normal and neoplastic tissues: association with survival and response to 5-fluorouracil in colorectal cancer. Cancer Res. 2000;60:3493–503.
pubmed: 10910061
Yano W, Yokogawa T, Wakasa T, Yamamura K, Fujioka A, Yoshisue K, et al. TAS-114, a first-in-class dual dUTPase/DPD inhibitor, demonstrates potential to improve therapeutic efficacy of fluoropyrimidine-based chemotherapy. Mol Cancer Ther. 2018;17:1683–93.
doi: 10.1158/1535-7163.MCT-17-0911
Yokogawa T, Wakasa T, Yano W, Yoshisue K, Fujioka A, Eshima K, et al. TAS-114 enhances S-1 activity in vivo when used in combination. Eur J Cancer. 2012;48:22.
doi: 10.1016/S0959-8049(12)71863-4
Doi T, Yoh K, Shitara K, Takahashi H, Ueno M, Kobayashi S, et al. First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors. Invest New Drugs. 2019;37:507–18.
doi: 10.1007/s10637-018-0697-3
Fasolo A, Aoyama T, Stathis A, et al. A large phase I study of TAS-114 in combination with S-1 in patients with advanced solid tumors. Proceedings: AACR Annual Meeting 2018; 14–18 April 2018; Chicago, IL. Abstract #CT014.
Kunz CU, Wason JM, Kieser M. Two-stage phase II oncology designs using short-term endpoints for early stopping. Stat Methods Med Res. 2017;26:1671–83.
doi: 10.1177/0962280215585819
Yamamoto N, Hayashi H, Planchard D, Morán T, Gregorc V, Dowell J, et al. 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. Invest New Drugs. 2020. https://doi.org/10.1007/s10637-020-00930-5 (Epub ahead of print).
doi: 10.1007/s10637-020-00930-5
pubmed: 32940872
pmcid: 7497678
Ito T, Honma Y, Hirano H, Shoji H, Okita N, Iwasa S, et al. S-1 monotherapy after failure of platinum plus 5-fluorouracil chemotherapy in recurrent or metastatic esophageal carcinoma. Anticancer Res. 2019;39:3931–6.
doi: 10.21873/anticanres.13545
Yasui H, Yoshino T, Boku N, Onozawa Y, Hironaka S, Fukutomi A, et al. Retrospective analysis of S-1 monotherapy in patients with metastatic colorectal cancer after failure to fluoropyrimidine and irinotecan or to fluoropyrimidine, irinotecan and oxaliplatin. Jpn J Clin Oncol. 2009;39:315–20.
doi: 10.1093/jjco/hyp014
Ono A, Boku N, Onozawa Y, Hironaka S, Fukutomi A, Yasui H, et al. Activity of S-1 in advanced or recurrent gastric cancer patients after failure of prior chemotherapy, including irinotecan + cisplatin or fluorouracil (except S-1). Jpn J Clin Oncol. 2009;39:332–5.
doi: 10.1093/jjco/hyp018
Yan Y, Han X, Qing Y, Condie AG, Gorityala S, Yang S, et al. Inhibition of uracil DNA glycosylase sensitizes cancer cells to 5-fluorodeoxyuridine through replication fork collapse-induced DNA damage. Oncotarget. 2016;7:59299–313.
doi: 10.18632/oncotarget.11151
Tsukioka S, Yano W, Yokogawa T, Wakasa T, Fujioka A, Yamamura K, et al. Expression of DNA damage repair enzymes determine the efficacy of a novel dUTPase inhibitor, TAS-114. Presented at the AACR-NCI-EORTC International Conference: molecular targets and cancer therapeutics, Boston, MA, USA, 19–23 October 2013.