title: Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin.
abstract: BACKGROUND
  This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
  
  
  METHODS
  Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05-20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated.
  
  
  RESULTS
  Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts.
  
  
  CONCLUSIONS
  F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
authors.affiliation: The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Karp
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Peter D
authors.initials: PD
authors.lastname: Eisenberg
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Laurence
authors.initials: L
authors.lastname: Demers
authors.forename: Kim
authors.initials: K
authors.lastname: Leitzel
authors.forename: Mary L
authors.initials: ML
authors.lastname: Hixon
authors.forename: Leon W
authors.initials: LW
authors.lastname: Terstappen
authors.forename: Linda
authors.initials: L
authors.lastname: Garland
authors.forename: Luis G
authors.initials: LG
authors.lastname: Paz-Ares
authors.forename: Felipe
authors.initials: F
authors.lastname: Cardenal
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D016190:Carboplatin; D017526:Receptor, IGF Type 1; D017239:Paclitaxel; C525021:figitumumab