A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of The Efficacy and Safety Of Siltuximab, An Anti-Interleukin-6 Monoclonal Antibody, In Patients With Multicentric Castleman’s Disease

Multicentric Castleman’s disease (MCD) is a rare, lymphoproliferative disorder with high morbidity. MCD signs and symptoms are driven by dysregulated interleukin (IL)-6 production. Preliminary data suggest efficacy of siltuximab, a chimeric mAb against human IL-6, in MCD patients (van Rhee et al. J Clin Oncol 2010;28:3701-8).

We evaluated the efficacy and safety of siltuximab in patients with symptomatic, measurable, HIV- and HHV-8-negative MCD in a phase 2, randomized, double-blind, controlled, multicenter study. Patients could be newly diagnosed/pre-treated and on stable, low-dose corticosteroids. Patients were randomly assigned 2:1 to siltuximab 11 mg/kg or placebo given by 1-h IV infusion q3w. All patients also received best supportive care to manage MCD symptoms. Patients received study agent until protocol-defined treatment failure, after which patients randomized to placebo could cross over to unblinded siltuximab. Primary analysis occurred after the last treated patient completed assessments at 48 wks. Primary endpoint was durable tumor and symptomatic response defined as PR or CR (Cheson criteria) by independent review and improvement/stabilization in MCD-related symptoms for ≥18 wks. Secondary endpoints included additional predefined efficacy measures and safety.

79 patients were randomized and treated with siltuximab (n=53) or placebo (n=26) from Feb 2010 to Feb 2013. Treatment arms were well balanced. Median age was 48 yrs, 48% were Asian, 39% were white, 66% were male, 30% were on corticosteroids, and 58% had prior systemic therapy. Patients had mixed (44%), hyaline vascular (33%), or plasmacytic (23%) histologic subtypes by pre-randomization central pathology review. Baseline MCD symptoms included fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia and pruritus (37% each). Median treatment duration was 375 vs. 152 d with siltuximab vs. placebo, with 64% vs. 27% completing 48 wks of treatment.

A higher percentage of durable tumor and symptomatic response was observed with siltuximab compared with placebo (34% (1 CR, 17 PR) vs. 0%; p=0.0012). Investigator-reported response provided consistent conclusions. Median duration of tumor and symptomatic response in siltuximab-treated patients of 340 d indicates prolonged disease control. Tumor response rate by central radiology review was 38% vs. 4% (p=0.0022). Median time to treatment failure was not reached vs. 134 d (p=0.0084). Median time to next treatment was not reached vs. 280 d (p=0.0013). Durable symptomatic response rate was 57% vs. 19% (p=0.0018), including complete symptom resolution in 25% vs. 0% (p=0.0037). Hb improvement by ≥15 g/L at wk 13 was seen in 61% vs. 0% anemic patients (p=0.0002). Sustained decreases in CRP (a marker of IL-6 bioactivity), ESR, and fibrinogen, and increase in albumin were seen with siltuximab. 13 of 26 patients on placebo crossed over to siltuximab.

The safety profile as defined by frequencies of treatment-emergent AEs was similar between siltuximab and placebo despite the >2x longer treatment duration with siltuximab: gr ≥3 AEs 47% vs. 54%, SAEs 23% vs. 19%, AEs leading to discontinuation 23% vs. 38% (mostly due to PD), AEs leading to treatment interruption 28% vs. 19%. Infusion reactions with siltuximab were infrequent (8%) and low grade, except for 1 anaphylactic reaction that led to treatment discontinuation. Gr ≥3 AEs frequently reported with siltuximab were fatigue (9%); night sweats (8%); and hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight increased (4% each). Gr ≥3 AEs reasonably related to siltuximab reported in >1 patient were neutropenia and thrombocytopenia (4% each). 3 (6%) patients had SAEs reasonably related to siltuximab. 2 (4%) patients in siltuximab died due to PD after treatment discontinuation. 4 (15%) noncrossover patients in placebo died (1 AE, 3 PD).

This is the first randomized study in MCD. The efficacy of siltuximab in MCD patients was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, Hb levels, and sustained reduction in inflammatory markers. In conjunction with the tolerable safety profile in this population, this study provides compelling evidence that siltuximab should be considered a new treatment of choice for MCD patients.