title: Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma.
abstract: BACKGROUND
  The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC.
  
  
  METHODS
  In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD.
  
  
  RESULTS
  Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%).
  
  
  CONCLUSIONS
  Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka. Electronic address: naito@uro.med.kyushu-u.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Naito
authors.affiliation: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki.
authors.forename: H
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Urology, National Hospital Organization Shikoku Cancer Center, Matsuyama.
authors.forename: K
authors.initials: K
authors.lastname: Hashine
authors.affiliation: Department of Urology, Yamagata University Faculty of Medicine, Yamagata.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo.
authors.forename: N
authors.initials: N
authors.lastname: Shinohara
authors.affiliation: Department of Urology, Kobe University School of Medicine, Kobe.
authors.forename: M
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto.
authors.forename: M
authors.initials: M
authors.lastname: Eto
authors.affiliation: Department of Urology, Hamamatsu University School of Medicine, Hamamatsu.
authors.forename: S
authors.initials: S
authors.lastname: Ozono
authors.affiliation: Department of Strategic Investigation on Comprehensive Cancer Network, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Akaza
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010094:Oxonic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D010671:Phenylurea Compounds; C079198:S 1 (combination); D005641:Tegafur; D009536:Niacinamide; D010094:Oxonic Acid; D000077157:Sorafenib
keywords: S-1; metastatic renal cell carcinoma; sorafenib