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

• Published in: Investigational new drugs 2019-06, Vol.37 (3), p.507-518
• Main Authors: Doi, Toshihiko, Yoh, Kiyotaka, Shitara, Kohei, Takahashi, Hideaki, Ueno, Makoto, Kobayashi, Satoshi, Morimoto, Manabu, Okusaka, Takuji, Ueno, Hideki, Morizane, Chigusa, Okano, Naohiro, Nagashima, Fumio, Furuse, Junji
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anemia; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - therapeutic use; Appetite loss; Cancer; Drug Combinations; Drug Therapy, Combination; dUTP pyrophosphatase; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Female; Follow-Up Studies; Gallbladder; Gallbladder cancer; Gastric cancer; Humans; Inhibitors; Leukopenia; Lung cancer; Lymphopenia; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Nausea; Neoplasms - drug therapy; Neoplasms - pathology; Neuroendocrine tumors; Neutropenia; Non-small cell lung carcinoma; Oncology; Oxonic Acid - pharmacokinetics; Oxonic Acid - therapeutic use; Pancreas; Pancreatic cancer; Patients; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Pigmentation; Prognosis; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Pyrophosphatases - antagonists & inhibitors; Safety; Solid tumors; Studies; Sulfonamides - pharmacokinetics; Sulfonamides - therapeutic use; Tegafur - pharmacokinetics; Tegafur - therapeutic use; Tissue Distribution; Triphosphatase; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-018-0697-3

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 ) .