Frits van Rhee1, Raymond S Wong2, Nikhil Munshi3, Jean-Francois Rossi4, Xiao-Yan Ke5, Alexander Fosså6, David Simpson7, Marcelo Capra8, Ting Liu9, Ruey Kuen Hsieh10, Yeow Tee Goh11, Jun Zhu12, Seok-Goo Cho13, Hanyun Ren14, James Cavet15, Rajesh Bandekar16, Margaret Rothman17, Thomas A Puchalski16, Manjula Reddy16, Helgi van de Velde18, Jessica Vermeulen19, Corey Casper20. 1. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: vanrheefrits@uams.edu. 2. Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. 3. Dana-Farber Cancer Institute, Boston, MA, USA. 4. CHU de Montpellier, Hôpital St Eloi, Montpellier, France. 5. Peking University Third Hospital, Beijing, China. 6. Oslo University Hospital, Oslo, Norway. 7. North Shore Hospital, Takapuna Auckland, New Zealand. 8. Hospital Mãe de Deus, Porto Alegre, Brazil. 9. West China Hospital, Sichuan University, Chengdu, China. 10. Mackay Memorial Hospital, Taipei, Taiwan. 11. Singapore General Hospital, Singapore. 12. Beijing Cancer Hospital, Beijing, China. 13. Seoul St Mary's Hospital, Seoul, South Korea. 14. Peking University First Hospital, Beijing, China. 15. The Christie NHS Foundation Trust and University of Manchester, Manchester, UK. 16. Janssen Research & Development, Spring House, PA, USA. 17. Janssen Research & Development, Washington, GA, USA. 18. Janssen Research & Development, Beerse, Belgium. 19. Janssen Research & Development, Leiden, Netherlands. 20. Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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 interleukin6-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. FINDINGS: We screened 140 patients, 79 of whom were randomly assigned tosiltuximab (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). INTERPRETATION: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. FUNDING: Janssen Research & Development.
RCT Entities:
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. FINDINGS: 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). INTERPRETATION: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. FUNDING: Janssen Research & Development.
Authors: David C Fajgenbaum; Thomas S Uldrick; Adam Bagg; Dale Frank; David Wu; Gordan Srkalovic; David Simpson; Amy Y Liu; David Menke; Shanmuganathan Chandrakasan; Mary Jo Lechowicz; Raymond S M Wong; Sheila Pierson; Michele Paessler; Jean-François Rossi; Makoto Ide; Jason Ruth; Michael Croglio; Alexander Suarez; Vera Krymskaya; Amy Chadburn; Gisele Colleoni; Sunita Nasta; Raj Jayanthan; Christopher S Nabel; Corey Casper; Angela Dispenzieri; Alexander Fosså; Dermot Kelleher; Razelle Kurzrock; Peter Voorhees; Ahmet Dogan; Kazuyuki Yoshizaki; Frits van Rhee; Eric Oksenhendler; Elaine S Jaffe; Kojo S J Elenitoba-Johnson; Megan S Lim Journal: Blood Date: 2017-01-13 Impact factor: 22.113
Authors: Bennett G Childs; Martina Gluscevic; Darren J Baker; Remi-Martin Laberge; Dan Marquess; Jamie Dananberg; Jan M van Deursen Journal: Nat Rev Drug Discov Date: 2017-07-21 Impact factor: 84.694