title: Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors.
abstract: OBJECTIVE
  This phase I study was undertaken to define the maximum tolerated dose, safety, and pharmacokinetic profile of CP-751,871.
  
  
  METHODS
  Using a rapid dose escalation design, patients with advanced nonhematologic malignancies were treated with CP-751,871 in four dose escalation cohorts. CP-751,871 was administered i.v. on day 1 of each 21-day cycle. Pharmacokinetic evaluation was done in all treatment cohorts during cycles 1 and 4.
  
  
  RESULTS
  Twenty-four patients received 110 cycles at four dose levels. The maximum tolerated dose exceeded the maximal feasible dose of 20 mg/kg and, thus, was not identified. Treatment-related toxicities were generally mild. The most common adverse events were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, elevated gamma-glutamyltransferase, diarrhea, hyperuracemia, and fatigue. At 20 mg/kg, 10 of 15 patients experienced stability of disease. Two of these patients experienced long-term stability. There were no objective responses. Pharmacokinetic analysis revealed a dose-dependent increase in CP-751,871 exposure and approximately 2-fold accumulation on repeated dosing in 21-day cycles. Plasma concentrations of CP-751,871 attained were several log-fold greater than the biologically active concentration. Treatment with CP-751,871 increased serum insulin and human growth hormone levels, with modest increases in serum glucose levels.
  
  
  CONCLUSIONS
  CP-751,871 has a favorable safety profile and was well tolerated when given in continuous cycles. At the maximal feasible dose of 20 mg/kg, there was a moderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. haluska.paul@mayo.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Heather M
authors.initials: HM
authors.lastname: Shaw
authors.forename: Gretchen N
authors.initials: GN
authors.lastname: Batzel
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Roberts
authors.forename: Amarnath
authors.initials: A
authors.lastname: Sharma
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007328:Insulin / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D007328:Insulin; D013006:Growth Hormone; D017526:Receptor, IGF Type 1; C525021:figitumumab