title: Phase I pharmacokinetic and pharmacodynamic dose-escalation study of RG7160 (GA201), the first glycoengineered monoclonal antibody against the epidermal growth factor receptor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G(1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity.
  
  
  METHODS
  Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design.
  
  
  RESULTS
  No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patients), infusion-related reactions (77%), and hypomagnesemia (56%). Grades 3 and 4 AEs were rash (grade 3, 25%), infusion-related reaction (grade 3, 7%; grade 4, 1%), paronychia (grade 3, 3%), and hypomagnesemia (grade 3, 1%; grade 4, 1%). RG7160 exposure increased greater than proportionally over the 50- to 400-mg dose range (with greater than proportional decline in clearance) and approximately dose proportionally above 400 mg (where clearance plateaued). A marked reduction in circulating natural killer cells and increased infiltration of immune effector cells into skin rash were seen. Clinical efficacy included one complete response and two partial responses in patients with colorectal cancer (including one with KRAS mutation) and disease stabilization in 27 patients.
  
  
  CONCLUSIONS
  RG7160 had an acceptable safety profile with manageable AEs and demonstrated promising efficacy in this heavily pretreated patient cohort. On the basis of modeling of available PK parameters, the RG7160 dose selected for part two of this study is 1,400 mg on days 1 and 8 followed by 1,400 mg every 2 weeks.
authors: Instituto de Biomedicina de Sevilla and Hospital Universitario Virgen del Rocio, Seville, Spain.
authors: Luis G
authors: LG
authors: Paz-Ares
authors: Carlos
authors: C
authors: Gomez-Roca
authors: Jean-Pierre
authors: JP
authors: Delord
authors: Andres
authors: A
authors: Cervantes
authors: Ben
authors: B
authors: Markman
authors: Jesus
authors: J
authors: Corral
authors: Jean-Charles
authors: JC
authors: Soria
authors: Yann
authors: Y
authors: Bergé
authors: Desamparados
authors: D
authors: Roda
authors: Fiona
authors: F
authors: Russell-Yarde
authors: Simon
authors: S
authors: Hollingsworth
authors: José
authors: J
authors: Baselga
authors: Pablo
authors: P
authors: Umana
authors: Luigi
authors: L
authors: Manenti
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006023:Glycoproteins; D066246:ErbB Receptors; C569293:imgatuzumab