Article

Siltuximab, a Novel Anti-Interleukin-6 Monoclonal Antibody, for Castleman's Disease

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 17.88). 08/2010; 28(23):3701-8. DOI: 10.1200/JCO.2009.27.2377
Source: PubMed

ABSTRACT Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.
We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria.
Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).
These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.

0 Followers
 · 
241 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory cells and mediators are an essential component of the tumor microenvironment. Inflammatory circuits can differ considerably in different tumors in terms of cellular and cytokine networks and molecular drivers. However, macrophages are a common and fundamental component of cancer promoting inflammation. Drivers of macrophage functional orientation include tumor cells, cancer-associated fibroblasts, T cells and B cells. Dissection of the diversity of cancer-related inflammation is instrumental to the design of therapeutic approaches that target cancer-related inflammation.
    Seminars in Cancer Biology 12/2011; 22(1):33-40. DOI:10.1016/j.semcancer.2011.12.005 · 9.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments. We analyzed results of a randomized, double-blind trial comparing siltuximab 11 mg/kg every 3 weeks with placebo to treat MCD. Subjects (N = 79) completed the recently developed MCD-Symptom Scale (MCD-SS), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, and the Short Form (SF)-36 at predetermined time points throughout the treatment period. Scores were compared at baseline and over time between the treatment arms and PRO instruments. At baseline, the mean number of symptoms reported was 9.2 (standard deviation 3.76) out of 16 total, as measured by the MCD-SS. Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD-SS and FACIT-Fatigue scale. Statistically significant improvements in five SF-36 domains were observed in siltuximab-treated patients, namely role physical, role emotional, vitality, bodily pain, and mental health. Patients with MCD commonly report impairments in functioning, wellbeing, and fatigue at baseline. Siltuximab-treated patients reported significant improvements in these outcomes after treatment.
    The patient 03/2015; 8(2). DOI:10.1007/s40271-015-0120-5 · 1.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: HIV-associated multicentric Castleman disease (HIV MCD) is a rare lymphoproliferative disorder, the incidence of which appears to be increasing in the highly active antiretroviral therapy era. Current knowledge of the disease is limited and this review will discuss what is known about the pathophysiology, diagnosis, management, and prognosis of HIV MCD. HIV MCD has been shown to be associated with infection with human herpesvirus-8. Vascular endothelial growth factor and the cytokine interleukin-6 (IL-6) are also thought to play a role in the pathogenesis of MCD. Currently, rituximab is often used alone or in combination with chemotherapy for treatment of MCD. Novel monoclonal antibodies targeting IL-6 and the IL-6 receptor are also being studied for the management of this disease. Because HIV MCD is an uncommon diagnosis, comprehensive clinical studies have not been done, and understanding of the disease is incomplete. Further studies are needed to make definitive conclusions regarding optimal treatment of HIV MCD.
    Current opinion in oncology 09/2011; 23(5):475-81. DOI:10.1097/CCO.0b013e328349c233 · 3.76 Impact Factor