title: Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer.
abstract: It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC.
  
  
  
  Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2on day 1; 5-FU continuous I.V. 2400 mg/m2on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. Electronic address: tyoshino@east.ncc.go.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Surgical Specialties, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.affiliation: Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery, Kitasato University, Sagamihara, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naitoh
authors.affiliation: Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Research.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Medical Affairs, Takeda Pharmaceutical Company, Ltd, Tokyo, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Department of Medical Affairs, Takeda Pharmaceutical Company, Ltd, Tokyo, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Soeda
authors.affiliation: Department of Medical Affairs, Takeda Pharmaceutical Company, Ltd, Tokyo, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Hihara
authors.affiliation: Department of Biostatistics, Yokohama City University, Yokohama, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Department of Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000556:secondary; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077544:Panitumumab; D012107:Research Design; D015996:Survival Rate; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077544:Panitumumab; D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil
keywords: Anti-EGFR; Anti-angiogenesis; Clinical trial; Overall survival; VEGF