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.
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Masafumi
M
Ikeda
Clinical Trial Section, National Cancer Center Hospital East, Kashiwa, Japan.
Akihiro
A
Sato
Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Tokyo, Japan.
Nobuo
N
Mochizuki
Clinical Trial Section, National Cancer Center Hospital East, Kashiwa, Japan.
Kayo
K
Toyosaki
Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Chika
C
Miyoshi
Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Rumi
R
Fujioka
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Shuichi
S
Mitsunaga
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Izumi
I
Ohno
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Yusuke
Y
Hashimoto
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Hideaki
H
Takahashi
Clinical Trial Section, National Cancer Center Hospital East, Kashiwa, Japan.
Hiromi
H
Hasegawa
Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Kashiwa, Japan.
Shogo
S
Nomura
Kampo Research Laboratory, Kracie Pharma, Ltd., Toyama, Japan.
Ryuji
R
Takahashi
Kampo Research Laboratory, Kracie Pharma, Ltd., Toyama, Japan.
Satoshi
S
Yomoda
Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Katsuya
K
Tsuchihara
Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Tokyo, Japan.
Satoshi
S
Kishino
Division of Translational Research, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.|Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan.
Hiroyasu
H
Esumi
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000093542:Gemcitabine
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D000093542:Gemcitabine
Arctigenin; chemotherapy; gemcitabine; natural anticancer compound; pancreatic cancer; phase I trial
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