title: Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma.
abstract: OBJECTIVE
  A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti-insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.
  
  
  METHODS
  After informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.
  
  
  RESULTS
  No CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.
  
  
  CONCLUSIONS
  These data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.
authors.affiliation: Mayo Clinic, Divisions of Hematology and Cardiovascular Diseases, Rochester, MN, USA.
authors.forename: Martha Q
authors.initials: MQ
authors.lastname: Lacy
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Paccagnella
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Melvin
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Amarnath
authors.initials: A
authors.lastname: Sharma
authors.forename: M
authors.initials: M
authors.lastname: Enriquez Sarano
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D003907:Dexamethasone; C525021:figitumumab; D020123:Sirolimus