A phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.

Abstract

2559 Background: Arctigenin, which is abundant in the seeds of Arctium lappa Linné, was found by a novel strategy to attenuate cancer cells’ tolerance to glucose deprivation (antiausterity) and showed antitumor activity in mouse xenograft models. GBS-01 is an orally administered drug and contains rich arctigenin extracted from Arctium lappa Linné, which is one of the traditional herbal medicine. This study investigated the maximum-tolerated dose of GBS-01 based on the frequency of dose-limiting toxicities (DLT) in patients with refractory advanced pancreatic cancer, which is considered as one of the hypoxic cancer. Methods: Histologically or cytologically proven advanced pancreatic adenocarcinoma patients refractory to gemcitabine were enrolled. GBS-01 was administered orally at escalating doses from 3g to 12g qd. DLT was defined as grade 4 hematological toxicities and grade 3 or 4 non-hematological toxicities during first 28 days of the treatment. Response evaluation based on RECIST criteria and progression-free survival were set as secondary endpoint for efficacy evaluation. Results: Fifteen patients (GBS-01 3g: 3 patients, 7.5g: 3 patients, 12g: 9 patients) were enrolled in this trial. All patients were refractory to S-1 as well as gemcitabine. All patients at the three dose levels did not demonstrate any sign of DLT. The main adverse events of this agent were increased γGTP, hyperglycemia, and increased total bilirubin, but all toxicities were extremely mild. Of all 15 enrolled patients, 1 patient showed a partial response and 4 patients had a stable disease. The median progression-free and overall survival time for all patients were 1.05 months and 5.68 months, respectively. Conclusions: The recommended dose of GBS-01 was 12 g qd (4 g as a extract of Arctium lappa Linné), and favorable clinical responses were obtained. A multicenter phase II trial is being planned to evaluate the efficacy and safety of this agent. Clinical trial information: 000005787.

Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L

“…The pharmacokinetic profile of AR in humans after oral administration was investigated in a phase I clinical trial of the herbal product GBS-01. After oral administration of GBS-01 at a dose of 12 g AR per person, the peak concentration of AR in the plasma of the pancreatic cancer patients was 66.56±26.81 ng/mL, and the AUC was 487.97±368.86 ng*h/mL [75] . Given the low molecular weight of AR and its high permeability demonstrated in the absorption models, the poor oral bioavailability of AR should be mainly due to its extensive first-pass metabolism rather than limita-www.nature.com/aps Gao Q et al tions of membrane permeability.…”

“…The hydrolysis of AR was mediated by human paraoxonase 1 in plasma [73] , and glucuronidation of AR was mediated by UGT1A9, UGT2B7 and UGT2B17 in the liver and intestine [74] . A phase I clinical trial of the herbal product GBS-01 on pancreatic cancer patients demonstrated that after oral administration of GBS-01 at a dose of 12 g AR per person, the area under the plasma concentration versus time curve (AUC) of arctigenin-glucuronide was almost 1000 times higher than that of AR [75] . Notably, the extent of metabolism of AR might be different between species.…”

Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation

“…Thus, selectively targeting metabolically stressed (glucose-deprived) tumor cells, including PEL, may represent a promising strategy with which to inhibit tumor cell proliferation without affecting normal cells. In this regard, arctigenin has been shown to preferentially induce tumor growth suppression and apoptosis in glucose-deprived tumor cells (34)(35)(36). In this study, we examined a novel biological function of arctigenin and the molecular mechanisms through which it preferentially induces the apoptosis of glucosestarved PEL cells.…”

“…In addition to affecting cell signaling, arctigenin influences ER stress and inhibits or activates the UPR, resulting in apoptosis or protection against ER stress (28)(29)(30). Arctigenin has been shown to exhibit anticancer activity in numerous types of cancer, including hepatocellular carcinoma (23), colon cancer (25), gastric cancer (31), pancreatic cancer (32), gallbladder cancer (27), breast cancer (24,26), ovarian cancer (33) and pancreatic cancer (34,35). One of the interesting anticancer properties of arctigenin is that it can preferentially induce the apoptosis of cancer cells under conditions of glucose starvation (34,36).…”

“…One of the interesting anticancer properties of arctigenin is that it can preferentially induce the apoptosis of cancer cells under conditions of glucose starvation (34,36). Furthermore, arctigenin (GBS-01) has presented a high safety profile and good therapeutic effects in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer due to its anticancer and anti-austerity activity (35). However, the effects of arctigenin on aggressive PEL phenotypes remain unclear.…”