Abstract
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/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.
MeSH terms
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Colorectal Neoplasms / blood
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / pathology
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Dose-Response Relationship, Drug
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Drug Combinations
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Female
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Fibroblast Growth Factors / antagonists & inhibitors
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Fibroblast Growth Factors / metabolism
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Humans
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Indoles / administration & dosage
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Indoles / adverse effects
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Indoles / pharmacokinetics*
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Indoles / therapeutic use*
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Male
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Middle Aged
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Neoplasm Metastasis
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Organoplatinum Compounds / administration & dosage
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Organoplatinum Compounds / adverse effects
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Organoplatinum Compounds / therapeutic use*
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Oxaliplatin
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Oxindoles
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Oxonic Acid / administration & dosage
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Oxonic Acid / adverse effects
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Oxonic Acid / therapeutic use*
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Platelet-Derived Growth Factor / antagonists & inhibitors
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Platelet-Derived Growth Factor / metabolism
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Propionates / administration & dosage
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Propionates / adverse effects
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Propionates / pharmacokinetics*
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Propionates / therapeutic use*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Kinase Inhibitors / therapeutic use
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Pyrroles
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Tegafur / administration & dosage
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Tegafur / adverse effects
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Tegafur / therapeutic use*
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Treatment Outcome
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Antineoplastic Agents
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Drug Combinations
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Indoles
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Organoplatinum Compounds
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Oxindoles
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Platelet-Derived Growth Factor
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Propionates
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Protein Kinase Inhibitors
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Pyrroles
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Oxaliplatin
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S 1 (combination)
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Tegafur
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Oxonic Acid
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Fibroblast Growth Factors
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orantinib
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Vascular Endothelial Growth Factor Receptor-2