title: Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors.
  
  
  METHODS
  Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab.
  
  
  RESULTS
  Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses.
  
  
  CONCLUSIONS
  Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.
authors.affiliation: Premiere Oncology, Santa Monica, California, USA. lrosen@mednet.ucla.edu
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Gregory
authors.initials: G
authors.lastname: Friberg
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Ian
authors.initials: I
authors.lastname: McCaffery
authors.forename: Shaunita A
authors.initials: SA
authors.lastname: Michael
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Marilyn
authors.initials: M
authors.lastname: Mulay
authors.forename: Poornima
authors.initials: P
authors.lastname: Shubhakar
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D000077544:Panitumumab; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D003841:Deoxycytidine; D009536:Niacinamide; D000077544:Panitumumab; D000077157:Sorafenib; C545764:ganitumab; D000069347:Erlotinib Hydrochloride; D017526:Receptor, IGF Type 1; D000093542:Gemcitabine