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.