title: Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors.
abstract: OBJECTIVE
  Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT).
  
  
  METHODS
  Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated.
  
  
  RESULTS
  Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed.
  
  
  CONCLUSIONS
  Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
authors.affiliation: University of California, Los Angeles Medical Center, Los Angeles, CA, USA. tapw@mskcc.org
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: George
authors.initials: G
authors.lastname: Demetri
authors.forename: Phillip
authors.initials: P
authors.lastname: Barnette
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: Petr
authors.initials: P
authors.lastname: Kavan
authors.forename: Richard
authors.initials: R
authors.lastname: Tozer
authors.forename: Pasquale W
authors.initials: PW
authors.lastname: Benedetto
authors.forename: Gregory
authors.initials: G
authors.lastname: Friberg
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.forename: Ian
authors.initials: I
authors.lastname: McCaffery
authors.forename: Ian
authors.initials: I
authors.lastname: Leitch
authors.forename: Sunita
authors.initials: S
authors.lastname: Badola
authors.forename: Sung
authors.initials: S
authors.lastname: Chang
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D058405:Desmoplastic Small Round Cell Tumor / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D012512:Sarcoma, Ewing / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000556:secondary; D017423:Sequence Analysis, RNA; D013997:Time Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D007334:Insulin-Like Growth Factor I; C545764:ganitumab; D017526:Receptor, IGF Type 1