Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors.
OBJECTIVE
A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies.


METHODS
Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4 week administration at each dose level.


RESULTS
Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200 mg/m(2) bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800 mg/m(2) bid. Three patients discontinued continuous oral administration for 4 weeks at 400 and 800 mg/m(2) bid. At 1,200 mg/m(2) bid, 2 patients discontinued the treatment over 4 weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1-2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, C(max) and AUC(0-t) after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels.


CONCLUSIONS
The tolerable dose in this administration schedule for continuing treatment is thought to be 800 mg/m(2) or less bid.
Ueda
Yutaka
Y
Division of Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Shimoyama
Tatsu
T
Murakami
Haruyasu
H
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 / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000097:blood; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000078183:Oxindoles; D019518:Postprandial Period; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; C412603:orantinib; D011505:Protein-Tyrosine Kinases