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Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial

Summary 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... Full description

Journal Title: The lancet oncology 2014, Vol.15 (9), p.966-974
Main Author: van Rhee, Frits, Prof
Other Authors: Wong, Raymond S, Prof , Munshi, Nikhil, Prof , Rossi, Jean-Francois, Prof , Ke, Xiao-Yan, Prof , Fosså, Alexander, MD , Simpson, David, MD , Capra, Marcelo, MD , Liu, Ting, MD , Hsieh, Ruey Kuen, MD , Goh, Yeow Tee, MD , Zhu, Jun, MD , Cho, Seok-Goo, MD , Ren, Hanyun, MD , Cavet, James, MD , Bandekar, Rajesh, PhD , Rothman, Margaret, PhD , Puchalski, Thomas A, PharmD , Reddy, Manjula, MSc , van de Velde, Helgi, MD , Vermeulen, Jessica, MD , Casper, Corey, Prof
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 1470-2045
Link: https://www.ncbi.nlm.nih.gov/pubmed/25042199
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title: Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
format: Article
creator:
  • van Rhee, Frits, Prof
  • Wong, Raymond S, Prof
  • Munshi, Nikhil, Prof
  • Rossi, Jean-Francois, Prof
  • Ke, Xiao-Yan, Prof
  • Fosså, Alexander, MD
  • Simpson, David, MD
  • Capra, Marcelo, MD
  • Liu, Ting, MD
  • Hsieh, Ruey Kuen, MD
  • Goh, Yeow Tee, MD
  • Zhu, Jun, MD
  • Cho, Seok-Goo, MD
  • Ren, Hanyun, MD
  • Cavet, James, MD
  • Bandekar, Rajesh, PhD
  • Rothman, Margaret, PhD
  • Puchalski, Thomas A, PharmD
  • Reddy, Manjula, MSc
  • van de Velde, Helgi, MD
  • Vermeulen, Jessica, MD
  • Casper, Corey, Prof
subjects:
  • Adult
  • Aged
  • Antibodies, Monoclonal - administration & dosage
  • Antibodies, Monoclonal - adverse effects
  • Castleman Disease - diagnosis
  • Castleman Disease - drug therapy
  • Castleman Disease - mortality
  • Clinical trials
  • Confidence Intervals
  • Cytokines
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug-Related Side Effects and Adverse Reactions - etiology
  • Drug-Related Side Effects and Adverse Reactions - physiopathology
  • Female
  • Follow-Up Studies
  • Hematology, Oncology and Palliative Medicine
  • Human immunodeficiency virus
  • Humans
  • Infusions, Intravenous
  • International Cooperation
  • Male
  • Medical treatment
  • Middle Aged
  • Monoclonal antibodies
  • Pain
  • Reference Values
  • Risk Assessment
  • Severity of Illness Index
  • Survival Rate
  • Treatment Outcome
ispartof: The lancet oncology, 2014, Vol.15 (9), p.966-974
description: Summary 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1470-2045
fulltext: fulltext
issn:
  • 1470-2045
  • 1474-5488
url: Link


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titleSiltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
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creatorvan Rhee, Frits, Prof ; Wong, Raymond S, Prof ; Munshi, Nikhil, Prof ; Rossi, Jean-Francois, Prof ; Ke, Xiao-Yan, Prof ; Fosså, Alexander, MD ; Simpson, David, MD ; Capra, Marcelo, MD ; Liu, Ting, MD ; Hsieh, Ruey Kuen, MD ; Goh, Yeow Tee, MD ; Zhu, Jun, MD ; Cho, Seok-Goo, MD ; Ren, Hanyun, MD ; Cavet, James, MD ; Bandekar, Rajesh, PhD ; Rothman, Margaret, PhD ; Puchalski, Thomas A, PharmD ; Reddy, Manjula, MSc ; van de Velde, Helgi, MD ; Vermeulen, Jessica, MD ; Casper, Corey, Prof
creatorcontribvan Rhee, Frits, Prof ; Wong, Raymond S, Prof ; Munshi, Nikhil, Prof ; Rossi, Jean-Francois, Prof ; Ke, Xiao-Yan, Prof ; Fosså, Alexander, MD ; Simpson, David, MD ; Capra, Marcelo, MD ; Liu, Ting, MD ; Hsieh, Ruey Kuen, MD ; Goh, Yeow Tee, MD ; Zhu, Jun, MD ; Cho, Seok-Goo, MD ; Ren, Hanyun, MD ; Cavet, James, MD ; Bandekar, Rajesh, PhD ; Rothman, Margaret, PhD ; Puchalski, Thomas A, PharmD ; Reddy, Manjula, MSc ; van de Velde, Helgi, MD ; Vermeulen, Jessica, MD ; Casper, Corey, Prof
descriptionSummary 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.
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languageeng
publisherEngland: Elsevier Ltd
subjectAdult ; Aged ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Castleman Disease - diagnosis ; Castleman Disease - drug therapy ; Castleman Disease - mortality ; Clinical trials ; Confidence Intervals ; Cytokines ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Drug-Related Side Effects and Adverse Reactions - etiology ; Drug-Related Side Effects and Adverse Reactions - physiopathology ; Female ; Follow-Up Studies ; Hematology, Oncology and Palliative Medicine ; Human immunodeficiency virus ; Humans ; Infusions, Intravenous ; International Cooperation ; Male ; Medical treatment ; Middle Aged ; Monoclonal antibodies ; Pain ; Reference Values ; Risk Assessment ; Severity of Illness Index ; Survival Rate ; Treatment Outcome
ispartofThe lancet oncology, 2014, Vol.15 (9), p.966-974
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2Munshi, Nikhil, Prof
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15Bandekar, Rajesh, PhD
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17Puchalski, Thomas A, PharmD
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20Vermeulen, Jessica, MD
21Casper, Corey, Prof
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descriptionSummary 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.
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2Antibodies, Monoclonal - administration & dosage
3Antibodies, Monoclonal - adverse effects
4Castleman Disease - diagnosis
5Castleman Disease - drug therapy
6Castleman Disease - mortality
7Clinical trials
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9Cytokines
10Dose-Response Relationship, Drug
11Double-Blind Method
12Drug Administration Schedule
13Drug-Related Side Effects and Adverse Reactions - etiology
14Drug-Related Side Effects and Adverse Reactions - physiopathology
15Female
16Follow-Up Studies
17Hematology, Oncology and Palliative Medicine
18Human immunodeficiency virus
19Humans
20Infusions, Intravenous
21International Cooperation
22Male
23Medical treatment
24Middle Aged
25Monoclonal antibodies
26Pain
27Reference Values
28Risk Assessment
29Severity of Illness Index
30Survival Rate
31Treatment Outcome
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titleSiltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
authorvan Rhee, Frits, Prof ; Wong, Raymond S, Prof ; Munshi, Nikhil, Prof ; Rossi, Jean-Francois, Prof ; Ke, Xiao-Yan, Prof ; Fosså, Alexander, MD ; Simpson, David, MD ; Capra, Marcelo, MD ; Liu, Ting, MD ; Hsieh, Ruey Kuen, MD ; Goh, Yeow Tee, MD ; Zhu, Jun, MD ; Cho, Seok-Goo, MD ; Ren, Hanyun, MD ; Cavet, James, MD ; Bandekar, Rajesh, PhD ; Rothman, Margaret, PhD ; Puchalski, Thomas A, PharmD ; Reddy, Manjula, MSc ; van de Velde, Helgi, MD ; Vermeulen, Jessica, MD ; Casper, Corey, Prof
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4Castleman Disease - diagnosis
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6Castleman Disease - mortality
7Clinical trials
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9Cytokines
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28Risk Assessment
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31Treatment Outcome
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abstractSummary 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.
copEngland
pubElsevier Ltd
pmid25042199
doi10.1016/S1470-2045(14)70319-5