title: 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.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine,Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, jyunlee@skku.edu.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Ik Joo
authors.initials: IJ
authors.lastname: Chung
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Hoo-Geun
authors.initials: HG
authors.lastname: Chun
authors.forename: Dong Bok
authors.initials: DB
authors.lastname: Shin
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
authors.forename: Hong Suk
authors.initials: HS
authors.lastname: Song
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Jong Gwang
authors.initials: JG
authors.lastname: Kim
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077214:Becaplermin; D002097:C-Reactive Protein / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D000078183:Oxindoles; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects; D020574:Proto-Oncogene Proteins c-sis / Q000097:blood; D011758:Pyrroles; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: C508606:CXCL8 protein, human; D004338:Drug Combinations; C508600:IL6 protein, human; D007211:Indoles; D015850:Interleukin-6; D016209:Interleukin-8; D009944:Organoplatinum Compounds; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor; D011422:Propionates; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; C467484:VEGFA protein, human; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D000077214:Becaplermin; D010094:Oxonic Acid; D002097:C-Reactive Protein; C412603:orantinib; D007770:L-Lactate Dehydrogenase