title: Phase I and pharmacokinetic study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese patients with solid tumors.
abstract: OBJECTIVE
  rhuMAb 2C4 (pertuzumab, RO4368451), a human epidermal growth factor receptor-2 (HER2) targeted antibody that binds to an epitope distinct from trastuzumab, blocks ligand-associated heterodimerization of HER2 with other HER receptor family members. This study evaluated the toxicity, pharmacokinetics and anti-tumor activities of pertuzumab in Japanese patients with solid tumors.
  
  
  METHODS
  Patients with solid tumors refractory to standard therapy were administered pertuzumab 5, 10, 15, 20 and 25 mg/kg intravenously once every 3 weeks. Grade 3 toxicities were considered as dose limiting. The maximum tolerated dose (MTD) was a dose at which two out of six patients had Grade 3 toxicities.
  
  
  RESULTS
  Eighteen patients, aged 38-66 (median 57) years, with solid tumors were enrolled and a total of 32 cycles of pertuzumab were administered. Toxicities were generally acceptable. Grade 3 elevation of gamma-glutamyl transpeptidase was observed in one patient at 25 mg/kg and was considered to be dose limiting. MTD was not reached up to a dose level of 25 mg/kg. The serum concentration of pertuzumab declined slowly (terminal half-life is approximately 3 weeks). The AUC proportionally increased over the dose range tested. There was limited evidence of activity (stable disease 2; progressive disease 13; and not evaluable 3); however, tumor shrinkage and tumor marker decrease were observed in an ovarian cancer and a non-small-cell lung cancer patient, respectively.
  
  
  CONCLUSIONS
  Pertuzumab is well tolerated up to 25 mg/kg. Although objective tumor response was not observed, it is worth evaluating as a flat dose and in combination with other cytotoxics and molecular-targeted agents.
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan. nbryamam@ncc.go.jp
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000601:surgery; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003967:Diarrhea / Q000139:chemically induced; D004067:Digestive System Neoplasms / Q000188:drug therapy / Q000601:surgery; D003875:Drug Eruptions / Q000209:etiology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000175:diagnosis / Q000209:etiology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000601:surgery; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000601:surgery; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000601:surgery; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy / Q000601:surgery; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000601:surgery; D018714:Radiotherapy, Adjuvant; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020097:Natriuretic Peptide, Brain; D018719:Erb-b2 Receptor Tyrosine Kinases; C485206:pertuzumab