• Sang Joon Shin, Minkyu Jung, Hei-Cheul Jeung, Hye Ryun Kim, Sun Young Rha, Jae Kyung Roh, Hyun Cheol Chung, and Joong Bae Ahn.
• Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, 250 Seongsanno, Seodaemun-gu, 120-752 Seoul, South Korea.
• Invest New Drugs. 2012 Aug 1; 30 (4): 1501-10.

AbstractTSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m(2) b.i.d. on Days 1-14 and oxaliplatin 130 mg/m(2) i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. C(max) and AUC(0-t) of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased C(max) and AUC(0-t) less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.

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