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

Sang Joon Shin, Minkyu Jung, Hei Cheul Jeung, Hye Ryun Kim, SunYoung Rha, Jae Kyung Roh, Hyuncheol Chung, Joong Bae Ahn

Research output: Contribution to journalArticle

17 Citations (Scopus)

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/ 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.

Original languageEnglish
Pages (from-to)1501-1510
Number of pages10
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
Publication statusPublished - 2012 Aug 1

Fingerprint

oxaliplatin
Vascular Endothelial Growth Factor Receptor-2
Protein-Tyrosine Kinases
Colorectal Neoplasms
Pharmacokinetics
Drug Therapy
Maximum Tolerated Dose
5-((1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-propanoic acid
S 1 (combination)
Hiccup
Platelet-Derived Growth Factor Receptors
Fibroblast Growth Factor Receptors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

@article{705c2f3cf03540e894fd89b1900b3251,
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",
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/ 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.",
author = "Shin, {Sang Joon} and Minkyu Jung and Jeung, {Hei Cheul} and Kim, {Hye Ryun} and SunYoung Rha and Roh, {Jae Kyung} and Hyuncheol Chung and Ahn, {Joong Bae}",
year = "2012",
month = "8",
day = "1",
doi = "10.1007/s10637-011-9683-8",
language = "English",
volume = "30",
pages = "1501--1510",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "4",

}

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. / Shin, Sang Joon; Jung, Minkyu; Jeung, Hei Cheul; Kim, Hye Ryun; Rha, SunYoung; Roh, Jae Kyung; Chung, Hyuncheol; Ahn, Joong Bae.

In: Investigational New Drugs, Vol. 30, No. 4, 01.08.2012, p. 1501-1510.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Shin, Sang Joon

AU - Jung, Minkyu

AU - Jeung, Hei Cheul

AU - Kim, Hye Ryun

AU - Rha, SunYoung

AU - Roh, Jae Kyung

AU - Chung, Hyuncheol

AU - Ahn, Joong Bae

PY - 2012/8/1

Y1 - 2012/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84866735754&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866735754&partnerID=8YFLogxK

U2 - 10.1007/s10637-011-9683-8

DO - 10.1007/s10637-011-9683-8

M3 - Article

C2 - 21567184

AN - SCOPUS:84866735754

VL - 30

SP - 1501

EP - 1510

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 4

ER -