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Investigational New Drugs
Published in: Investigational New Drugs 4/2012

01-08-2012 | PHASE I STUDIES

A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy

Authors: Sang Joon Shin, Minkyu Jung, Hei-Cheul Jeung, Hye Ryun Kim, Sun Young Rha, Jae Kyung Roh, Hyun Cheol Chung, Joong Bae Ahn

Published in: Investigational New Drugs | Issue 4/2012

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Summary

TSU-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/m2 b.i.d. on Days 1–14 and oxaliplatin 130 mg/m2 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. Cmax and AUC0-t of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased Cmax and AUC0-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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Metadata
Title
A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy
Authors
Sang Joon Shin
Minkyu Jung
Hei-Cheul Jeung
Hye Ryun Kim
Sun Young Rha
Jae Kyung Roh
Hyun Cheol Chung
Joong Bae Ahn
Publication date
01-08-2012
Publisher
Springer US
Published in
Investigational New Drugs / Issue 4/2012
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-011-9683-8

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