title: A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors.
abstract: OBJECTIVE
  Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose.
  
  
  METHODS
  Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses.
  
  
  RESULTS
  Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C(min) was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. (18)F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively.
  
  
  CONCLUSIONS
  Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Francesco
authors.initials: F
authors.lastname: Atzori
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Jordi
authors.initials: J
authors.lastname: Andreu
authors.forename: Edith
authors.initials: E
authors.lastname: Rodríguez-Braun
authors.forename: Amparo
authors.initials: A
authors.lastname: Domingo
authors.forename: Jorge
authors.initials: J
authors.lastname: Guijarro
authors.forename: Cristina
authors.initials: C
authors.lastname: Gamez
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.forename: Holly
authors.initials: H
authors.lastname: Brown
authors.forename: Jason
authors.initials: J
authors.lastname: Clark
authors.forename: James S
authors.initials: JS
authors.lastname: Hardwick
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.forename: William D
authors.initials: WD
authors.lastname: Hanley
authors.forename: Karl
authors.initials: K
authors.lastname: Hsu
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.forename: Susana
authors.initials: S
authors.lastname: Roselló
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Langdon
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D017526:Receptor, IGF Type 1 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C569480:dalotuzumab; D017526:Receptor, IGF Type 1