Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials.

Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to siltuximab treatment. 18 patients discontinued before study completion, either to receive siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Janssen R&D and EUSA Pharma.

van Rhee F ，Casper C ，Voorhees PM ，Fayad LE ，Gibson D ，Kanhai K ，Kurzrock R ... -  《Lancet Haematology》

A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease.

van Rhee F ，Casper C ，Voorhees PM ，Fayad LE ，van de Velde H ，Vermeulen J ，Qin X ，Qi M ，Tromp B ，Kurzrock R ... -  《Oncotarget》

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

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. 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. 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). 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. Janssen Research & Development.

van Rhee F ，Wong RS ，Munshi N ，Rossi JF ，Ke XY ，Fosså A ，Simpson D ，Capra M ，Liu T ，Hsieh RK ，Goh YT ，Zhu J ，Cho SG ，Ren H ，Cavet J ，Bandekar R ，Rothman M ，Puchalski TA ，Reddy M ，van de Velde H ，Vermeulen J ，Casper C ... -  《-》

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.

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. 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. 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. 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.

Kurzrock R ，Voorhees PM ，Casper C ，Furman RR ，Fayad L ，Lonial S ，Borghaei H ，Jagannath S ，Sokol L ，Usmani SZ ，van de Velde H ，Qin X ，Puchalski TA ，Hall B ，Reddy M ，Qi M ，van Rhee F ... -  《-》

Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program.

Because of the rarity of the disease, randomized clinical trials for multicentric Castleman disease (MCD) remain a challenge and, as a consequence, there is no established standard of care. Siltuximab is a chimeric immunoglobulin G1κ monoclonal antibody against human IL-6 which was recently approved by FDA. Eligible patients in Italy were granted early access through a Named Patient Program (NPP). The aim of this observational multicenter retrospective study was to analyze outcomes and toxicity data of relapsed or refractory MCD patients treated with siltuximab in a real life context. All the 9 patients who received siltuximab in Italy under the NPP were enrolled. Median duration of treatment was 285 days (range, 104-1113 days). The global overall response rate was 33.3%. At the time of this analysis, none of the 3 responder patients had subsequently disease relapse: response duration was 20, 23, and 37 months, respectively. Grade 1 to 2 fatigue and pruritus were observed in 2 (22.2%) patients, and weight gain was reported in only 1 patient (grade 1); local edema was reported in 2 patients with a grade 2 presentation. The most common side effect was upper respiratory tract infection reported in 3 (33.3%) patients but in these cases was grades 1 to 2. No patient developed an infusion-related reaction. Our NPP data support siltuximab as single agent in the real-life experience of the treatment of relapse/refractory MCD patients in effectiveness, safety profile, and sustained disease control.

Tonialini L ，Bonfichi M ，Ferrero S ，Malipiero G ，Nozza A ，Argnani L ，Zinzani PL ... -  《-》