Satoshi Yomoda

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

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.

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

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Abstract CT213: Arctigenin, an antiausterity agent shows high safety and promising clinical response in phase I clinical trial in patient with gemcitabine-refractory pancreatic cancer

Cancer microenvironment is characterized by severe hypoxia and nutrient deprivation, especially glucose. Cancer depends largely on glycolysis for energy production (Warburg effect), therefore tumor hypoxia is mainly caused by poor blood supply despite vigorous angiogenesis. Severe tumor hypoxia and glucose deprivation promote tumor progression and affects tumor behavior especially resistance to anticancer drugs. We have focused on the invention of agents that cancel cancer cells9 ability to tolerate poor oxygen and glucose supply (antiausterity) and found many agents including kigamicin, pyrvinium pamoate, and arctigenin. Because antitumor activity and safety profile were excellent in preclinical test, arctigenin was chosen for the first compound for clinical trial. Arctigenin is rich in fruit of Arctinum lappa which is filed in Japanese Pharmacopoeia, we have invented an extraction method to enrich arctigenin (GBS-01, Kracie Pharma, Ltd.) and used in clinical trial. GBS-01 contained arctigenin about 10% in weight. Pancreatic cancer is characterized for its hypovascularity and severe hypoxia in cancer tissue has been reported and, in addition, only limited benefit of chemotherapy has been achieved so far. Patients, material and design of trial: Pancreatic cancer patients refractory to gemcitabine were selected for the phase I clinical trial of GBS-01. Primary endpoint of the trial was determination of recommended dose by assessing DLT in dose escalation study from 1 g/day to 4 g/day, corresponding to 100 mg to 400 mg arctigenin/day. GBS-01 administration was continued until either unacceptable adverse effcts or evident progression of the cancer appeared. Pharmacokinetic study was also carried out as a secondary endpoint. Results:Fifteen patients were enrolled and three patients were not evaluated because of early stopping due to progression of the disease. Results: Among 12 patients evaluated, no DLT was observed. No serious adverse effects on bone marrow, liver and kidney function was observed. Pharmacokinetic study revealed that arctigenin is efficiently absorbed and rapidly conjugated with glucuronic acid. Serum concentration of arctgenin glucuronide was about 100 to several hundreds higher than that of arctigenin, indicating glucuronidation in the first pass. Urinary secretion of arctigenin and its glucuronide was more than half of administered dose in more than half of patients, indicating high bioavailability. Regarding clinical tumor response, partial response was observed in one patient at 2.5 g/day (level 2) for 2 months followed by 2four months stable disease (SD) and SD was observed in other four patients. Median progression free survival was 1.05 months and median overall survival was 5.68 months.Conclusion: Arctigenin showed high bioavailability, high safety profile, and promising clinical responses. Citation Format: Hiroyasu Esumi, Satoshi Owada, Rumi Fujioka, Katsuya Tsuchihara, Atsushi Ohtsu, Aihiro Sato, Masafumi Ikeda, Nobuo Mochizuki, Satoshi Kishino, Takanori Kawashima, Satoshi Yomoda. Arctigenin, an antiausterity agent shows high safety and promising clinical response in phase I clinical trial in patient with gemcitabine-refractory pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT213. doi:10.1158/1538-7445.AM2014-CT213