title: A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study).
abstract: BACKGROUND
  We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.
  
  
  METHODS
  The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.
  
  
  RESULTS
  Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p=0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p=0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of <3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p=0.289) but showed a delayed response.
  
  
  CONCLUSIONS
  Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of <3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.
  
  
  BACKGROUND
  Trial registration: UMIN000001791.
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Japan. hazama@yamaguchi-u.ac.jp.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
authors.forename: Ko
authors.initials: K
authors.lastname: Tahara
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Shimizu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ozasa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Etoh
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sugiura
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okuno
authors.forename: Takumi
authors.initials: T
authors.lastname: Furuya
authors.forename: Taku
authors.initials: T
authors.lastname: Nishimura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sakata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yoshimatsu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takenouchi
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Tsunedomi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inoue
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kanekiyo
authors.forename: Yoshitaro
authors.initials: Y
authors.lastname: Shindo
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shinozaki
authors.forename: Akira
authors.initials: A
authors.lastname: Kamiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Fujita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010455:Peptides / Q000008:administration & dosage; D016019:Survival Analysis
chemical_list: D006680:HLA Antigens; D009944:Organoplatinum Compounds; D010455:Peptides; D000077150:Oxaliplatin