title: A phase I study of the combination of panitumumab and bevacizumab in KRAS wild-type colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, irinotecan and bevacizumab.
abstract: OBJECTIVE
  The clinical benefit of combination treatment with panitumumab and bevacizumab (PB) based on bevacizumab beyond progression (BBP) after the failure of second-line chemotherapy remains unclear. We assessed the tolerability and efficacy of PB as BBP in Japanese patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  This phase I study comprised two parts: (1) PB part to estimate the recommended PB dose, (2) CPB part to investigate the safety of PB with irinotecan (CPB). Three panitumumab doses (4, 5, and 6 mg/kg at Levels -1, 0 and 1, respectively) were set for the PB part, starting with Level 0. Bevacizumab was administered at a fixed dose of 5 mg/kg, regardless of panitumumab dose levels. All drugs were administered on day 1 and repeated every 2 weeks.
  
  
  RESULTS
  No dose-limiting toxicities were observed at Levels 0 (n = 3) and 1 (n = 3) for the PB part, determining the recommended dose as Level 1. During the whole treatment course at Level 1, grade 3 acneiform rash was observed in two patients with a partial response. For six patients (irinotecan biweekly, 150 mg/m(2) n = 3, 120 mg/m(2) n = 3) enrolled in the CPB part, grade 3 toxicities were leukopenia/neutropenia (n = 1), mucositis (n = 1), diarrhea (n = 1), rash acneiform (n = 1) and thromboembolic event (n = 1), and two of six patients achieved partial responses.
  
  
  CONCLUSIONS
  Recommended doses for the PB regimen in mCRC were panitumumab 6 mg/kg and bevacizumab 5 mg/kg. PB and CPB showed manageable toxicities in KRAS wild-type patients previously managed with standard treatment, including bevacizumab.
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwasa
authors.affiliation: Multidisciplinary Treatment Cancer Center, Kurume University Hospital, Kurume, Fukuoka, 830-0011, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Fukahori
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shoji
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Honma
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Natsuko Tsuda
authors.initials: NT
authors.lastname: Okita
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Division of Clinical Oncology, Kochi Health Sciences Center, 2125-1 Ike, Kochi, 781-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Honda
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. yasuhide-yamada@amed.go.jp.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D044466:Asian People; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D000068258:Bevacizumab; D000077544:Panitumumab; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D002166:Camptothecin
keywords: Bevacizumab; Bevacizumab beyond progression; Colorectal cancer; KRAS; Panitumumab