title: A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease.
abstract: OBJECTIVE
  To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.
  
  
  METHODS
  In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.
  
  
  RESULTS
  Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR.
  
  
  CONCLUSIONS
  No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.
authors: MD Anderson Cancer Center, University of Texas, Houston, Texas, USA. rkurzrock@ucsd.edu
authors: Razelle
authors: R
authors: Kurzrock
authors: Peter M
authors: PM
authors: Voorhees
authors: Corey
authors: C
authors: Casper
authors: Richard R
authors: RR
authors: Furman
authors: Luis
authors: L
authors: Fayad
authors: Sagar
authors: S
authors: Lonial
authors: Hossein
authors: H
authors: Borghaei
authors: Sundar
authors: S
authors: Jagannath
authors: Lubomir
authors: L
authors: Sokol
authors: Saad Z
authors: SZ
authors: Usmani
authors: Helgi
authors: H
authors: van de Velde
authors: Xiang
authors: X
authors: Qin
authors: Thomas A
authors: TA
authors: Puchalski
authors: Brett
authors: B
authors: Hall
authors: Manjula
authors: M
authors: Reddy
authors: Ming
authors: M
authors: Qi
authors: Frits
authors: F
authors: van Rhee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005871:Castleman Disease / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006454:Hemoglobins; C504234:siltuximab