Abstract
SummaryBackground 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/m2 and 30–36 mg/m2, 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/m2 plus S-1 36 mg/m2 and TAS-114 240 mg/m2 plus S-1 30 mg/m2, 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) .
Highlights
Given the complexity and variability of the molecular processes that lead to cancer development [1, 2], current cancer therapy is multifaceted
This study was conducted in accordance with Declaration of Helsinki and Good Clinical Practice guidelines, and it was approved by the institutional review boards of the participating centers
A total of 76 patients were enrolled at four sites in Japan between May 2012 and April 2016, of whom all patients (Part 1, n = 48; Part 2, n = 28) were eligible and received at least 1 dose of TAS-114 and S-1; 64 and 12 patients were assigned to the S-1 30 mg/m2 and S-1 36 mg/m2 cohorts, respectively
Summary
Given the complexity and variability of the molecular processes that lead to cancer development [1, 2], current cancer therapy is multifaceted. It includes molecular targeted therapy [1], immune therapy [2, 3], and other specific agents targeting cellular regulatory factors, oncogenic signalling pathways, tumor-associated angiogenesis, and host immune responses [1–3]. Despite these advances, cytotoxic agents still play an important role in systemic chemotherapy for several tumor types [4–6]. Fluoropyrimidines are the cornerstone therapy for different types of cancer, and various efforts to improve their efficacy have been attempted in the past three decades. There is a need for the development of a new, highly
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