title: Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.
abstract: OBJECTIVE
  Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.
  
  
  METHODS
  Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks.
  
  
  RESULTS
  Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients.
  
  
  CONCLUSIONS
  These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.
authors.affiliation: Cedars-Sinai Prostate Cancer Center and Medical Center, Los Angeles, CA 90048, USA. david.agus@cshs.org
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Charles
authors.initials: C
authors.lastname: Taylor
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Natale
authors.forename: Beth
authors.initials: B
authors.lastname: Karlan
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.forename: David E
authors.initials: DE
authors.lastname: Allison
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Gracie
authors.initials: G
authors.lastname: Lieberman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kelsey
authors.forename: Gwen
authors.initials: G
authors.lastname: Fyfe
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C485206:pertuzumab