Phase I, pharmacokinetic, and biological studies of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, administered after meals with solid tumors.
OBJECTIVE
TSU-68 is a low molecular weight inhibitor of the tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factors receptor 1. In this study, we assessed the recommended dose with TSU-68 administration of twice-daily (b.i.d.) or thrice-daily (t.i.d.) after meals for 4 weeks in Japanese patients with solid tumors based on the safety and tolerability and investigated the relationship between angiogenesis biomarker and clinical outcomes.


METHODS
The study design was a dose-escalation method with alternating enrollment of b.i.d. administration and t.i.d. administration after meal by traditional three-patient cohort.


RESULTS
We enrolled 24 patients at doses of 200, 400, and 500 mg/m(2) b.i.d. or 200 and 400 mg/m(2) t.i.d. No dose-limiting toxicity (DLT) occurred in the 200 mg/m(2) b.i.d. or t.i.d., and 3 patients experienced DLTs at 400 mg/m(2) b.i.d. or 400 mg/m(2) t.i.d. As main toxicity, blood albumin decreased, malaise, diarrhea, alkaline phosphatase increased, anorexia, abdominal pain, nausea, and vomiting were observed as almost all grade 1-2. There were no apparent differences in pharmacokinetic parameters between days 2 and 28 after the repeated b.i.d. and t.i.d. doses. Although tumor shrinkage was not observed, the disease control rate was 41.7%. As an angiogenesis-related factor of stratified analysis, plasma vascular endothelial growth factor and plasminogen activator inhibitor-1 were detected as a significant increase with progressive disease patients.


CONCLUSIONS
A recommended dosage of TSU-68 for this administration schedules was estimated to be 400 mg/m(2) or less b.i.d.
Murakami
Haruyasu
H
Division of Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Ueda
Yutaka
Y
Shimoyama
Tatsu
T
Yamamoto
Noboru
N
Yamada
Yasuhide
Y
Arioka
Hitoshi
H
Tamura
Tomohide
T
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000078183:Oxindoles; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D019518:Postprandial Period; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D000078183:Oxindoles; D017395:Plasminogen Activator Inhibitor 1; D011422:Propionates; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C412603:orantinib; D011505:Protein-Tyrosine Kinases