title: A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors.
  
  
  METHODS
  In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks.
  
  
  RESULTS
  Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed.
  
  
  CONCLUSIONS
  Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.
authors.affiliation: Authors' Affiliations: Institut de Cancérologie Gustave Roussy, Villejuif; Centre Francois Baclesse, CHU Côte de Nacre, Caen; Centre Léon Bérard Lyon, Lyon, France; Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona; 12 de Octubre University Hospital, Madrid, Spain; Fox Chase Cancer Center, Philadelphia; Janssen Research & Development, Spring House, Pennsylvania; formerly University of Texas, MD Anderson Cancer Center, Houston, Texas; currently UC San Diego Moores Cancer Center, San Diego, California; Erasme University Hospital; Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels; AZ Sint-Augustinus, Antwerp; Janssen Research & Development, Beerse, Belgium; Southampton University Hospitals NHS Trust, Southampton; Western General Hospital, Edinburgh; University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom; and Janssen Research & Development, Leiden, the Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
authors.forename: Rastilav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: van Laethem
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lopez-Martin
authors.forename: Sally
authors.initials: S
authors.lastname: Clive
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.forename: Neil
authors.initials: N
authors.lastname: Steven
authors.forename: Manjula
authors.initials: M
authors.lastname: Reddy
authors.forename: Brett
authors.initials: B
authors.lastname: Hall
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bandekar
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Brenda
authors.initials: B
authors.lastname: Tromp
authors.forename: Jessica
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009154:Mutation; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C504234:siltuximab