Phase I trial of GBS‐01 for advanced pancreatic cancer refractory to gemcitabine

Abstract

GBS‐01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS‐01 based on the frequency of the dose‐limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS‐01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non‐hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS‐01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ‐glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression‐free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS‐01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN‐CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000005787.

Experimental study of the anti-tumour activity and pharmacokinetics of arctigenin and its valine ester derivative

“…There was no overt toxicity in the 60 mg/kg group except the stimulus response at the administration location, but repeated subcutaneous injection of large doses of ARG can induce injury to the liver and biliary duct and strengthen the reaction to the stimulus caused by PEG in dogs. Masafumi Ikeda 44 has studied the pharmacokinetics of ARG in patients with advanced pancreatic cancer refractory to gemcitabine. The results showed that ARG in patients exists as arctigenin glucuronide (AGG), and second peaks of ARG and AGG were observed, indicating enterohepatic circulation.…”

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer

“…Seven patients were received more than one couse (28days) of GBS-01 administration but disease progression was observed within the following 28 days (PD) and clinical response was not evaluated in three patients patients because administration was ceased before one course completion [ 15 ]. Association between lactate AUC or Cmax and progression free survival time and overall survival of patients was analyzed by Kaplan-Meiyer methods among of lactate high and low groups that were divided in to two by median of Cmax or AUC, but no significant difference was observed in two groups either in terms of progression free survival time or overall survival time ( S3 Fig ).…”

“…lappa (GBS-01). The results showed high bioavailability of AG after oral administration, a good safety profile, and promising clinical antitumor activity responses [ 15 ].…”

Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

“…The antitumor activity of this lignan has been studied widely. An oral drug, GBS-01, which contains high levels of arctigenin was found to have a beneficial effect on pancreatic cancer in a phase I clinical study ( Ikeda et al, 2016 ). Arctigenin selectively induced apoptosis by upregulating apoptosis-related genes, including Bax, Fas , and caspase in A549 cells ( Susanti et al, 2013 ).…”