A Phase I, Open-Label Study of Siltuximab, an Anti-IL-6 Monoclonal Antibody, in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease.
ABSTRACT PURPOSE: To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric mAb in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). EXPERIMENTAL DESIGN: In an open-label, dose-finding, seven-cohort, phase I study, patients with NHL, MM, or symptomatic CD received siltuximab 3, 6, 9, or 12 mg/kg qw, q2w, or q3w. 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 CD. RESULTS: 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. There was no DLT, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possibly drug-related AEs 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. CRP suppression was most pronounced at 12-mg/kg q3w. Mean terminal-phase half-life ranged 17.73-20.64 days. 32/37 (86%) CD patients improved in ≥1 CBR component; 12/36 evaluable CD patients had radiologic response (CR, n=1; PR, n=11), including 8/19 treated with 12 mg/kg; 2/14 (14%) evaluable NHL patients had PR; 2/13 (15%) MM patients had CR. CONCLUSIONS: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12-mg/kg-q3w was recommended based on the high response rates in CD and the sustained CRP suppression. Randomized studies are ongoing in CD and MM.
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ABSTRACT: Multicentric Castleman's disease is a rare lymphoproliferative disorder whose hallmark is atypical lymph node hyperplasia. Symptoms can include fever, splenomegaly, and abnormal blood cell counts. High levels of interleukin 6 (IL-6) are observed frequently in this disorder and are believed to drive the disease. Recently, therapies that target interleukin-6 or its receptor have been shown to be effective in Castleman's disease. We report the case of a 76-year-old Caucasian man with aggressive biopsy-proven Castleman's disease who experienced pulmonary and lymph node involvement, as well as fever and weight loss. He was treated with siltuximab, a chimeric anti-interleukin-6 antibody. After 5 months, fluorodeoxyglucose positron emission tomography computed tomography scans showed marked improvement in his lungs, but worsening mediastinal disease, consistent with a mixed response. Biopsy of the mediastinal disease revealed lymphoplasmacytic infiltrate with non-caseating, ill-defined granulomas and scarring consistent with sarcoidosis. Prednisone 50mg by mouth daily was started, which was tapered to 2.0-5.0mg daily. Siltuximab was continued. A subsequent fluorodeoxyglucose positron emission tomography computed tomography scan showed near-complete resolution of lung and mediastinal disease, now ongoing for 3.5+ years without serious adverse events. Lymphomas have previously been reported to coexist with sarcoidosis, albeit rarely, but there has been only a single previous case of this type with Castleman's disease. Of importance, early recognition of the presence of sarcoidosis in our patient prevented discontinuation of siltuximab therapy due to "progression." Our experience may also have broader implications in that it suggests that etiology of "mixed responses" should be confirmed by performing biopsies on the progressive tumor.
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ABSTRACT: Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n = 17), multiple myeloma (n = 13), or CD (n = 17). Siltuximab was administered as 2.8, 5.5, or 11 mg/kg q2wks, 11 mg/kg q3wks, or 5.5 mg/kg weekly. Simulations of studied or hypothetical siltuximab dosage regimens (15 mg/kg q4wks) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1 mg/L. A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously. PD parameter estimates were physiologically plausible. For all disease types, simulations showed that 11 mg/kg q3wks or 15 mg/kg q4wks would reduce serum CRP to below 1 mg/L after the second dose and throughout the treatment period. PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.Cancer Chemotherapy and Pharmacology 03/2015; DOI:10.1007/s00280-015-2720-0 · 2.57 Impact Factor
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ABSTRACT: The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti-interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.Pharmacological reviews 04/2015; 67(2):280-309. DOI:10.1124/pr.114.009639 · 18.55 Impact Factor