Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.
OBJECTIVE
We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment.


METHODS
Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed.


RESULTS
Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively.


CONCLUSIONS
The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Japan, masikeda@east.ncc.go.jp.
Masafumi
M
Ikeda
Shuichiro
S
Shiina
Kohei
K
Nakachi
Shuichi
S
Mitsunaga
Satoshi
S
Shimizu
Yasushi
Y
Kojima
Hideki
H
Ueno
Chigusa
C
Morizane
Shunsuke
S
Kondo
Yasunari
Y
Sakamoto
Yoshinari
Y
Asaoka
Ryosuke
R
Tateishi
Kazuhiko
K
Koike
Hitoshi
H
Arioka
Takuji
T
Okusaka
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000078183:Oxindoles; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011758:Pyrroles; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C412603:orantinib