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A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer

 Jeeyun Lee  ;  Sang Joon Shin  ;  Ik Joo Chung  ;  Tae Won Kim  ;  Hoo-Geun Chun  ;  Dong Bok Shin  ;  Yeul Hong Kim  ;  Hong Suk Song  ;  Sae-Won Han  ;  Jong Gwang Kim  ;  Sun Young Kim  ;  Young Jin Choi  ;  Hyun Cheol Chung 
 INVESTIGATIONAL NEW DRUGS, Vol.32(3) : 561-568, 2014 
Journal Title
Issue Date
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; C-Reactive Protein/metabolism ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/drug therapy* ; Disease-Free Survival ; Drug Combinations ; Female ; Humans ; Indoles/administration & dosage ; Indoles/adverse effects ; Interleukin-6/blood ; Interleukin-8/blood ; L-Lactate Dehydrogenase/blood ; Male ; Middle Aged ; Organoplatinum Compounds/administration & dosage ; Organoplatinum Compounds/adverse effects ; Oxonic Acid/administration & dosage ; Oxonic Acid/adverse effects ; Platelet-Derived Growth Factor/metabolism ; Propionates/administration & dosage ; Propionates/adverse effects ; Proto-Oncogene Proteins c-sis/blood ; Tegafur/administration & dosage ; Tegafur/adverse effects ; Vascular Cell Adhesion Molecule-1/blood ; Vascular Endothelial Growth Factor A/blood
Colorectal cancer ; Chemotherapy ; TSU-68
Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX. Methods This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS). Results A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 (p = 0.012). Conclusion TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
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