title: Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease.
  
  
  METHODS
  We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036.
  
  
  RESULTS
  We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis).
  
  
  CONCLUSIONS
  Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease.
  
  
  BACKGROUND
  Janssen Research & Development.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: vanrheefrits@uams.edu.
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.affiliation: Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Wong
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.affiliation: CHU de Montpellier, Hôpital St Eloi, Montpellier, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Rossi
authors.affiliation: Peking University Third Hospital, Beijing, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Ke
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fosså
authors.affiliation: North Shore Hospital, Takapuna Auckland, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Simpson
authors.affiliation: Hospital Mãe de Deus, Porto Alegre, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Capra
authors.affiliation: West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Ruey Kuen
authors.initials: RK
authors.lastname: Hsieh
authors.affiliation: Singapore General Hospital, Singapore.
authors.forename: Yeow Tee
authors.initials: YT
authors.lastname: Goh
authors.affiliation: Beijing Cancer Hospital, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Seoul St Mary's Hospital, Seoul, South Korea.
authors.forename: Seok-Goo
authors.initials: SG
authors.lastname: Cho
authors.affiliation: Peking University First Hospital, Beijing, China.
authors.forename: Hanyun
authors.initials: H
authors.lastname: Ren
authors.affiliation: The Christie NHS Foundation Trust and University of Manchester, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: Cavet
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bandekar
authors.affiliation: Janssen Research & Development, Washington, GA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Rothman
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Reddy
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.affiliation: Janssen Research & Development, Leiden, Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vermeulen
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Casper
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D005871:Castleman Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C504234:siltuximab