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

• Published in: Clinical cancer research Vol. 19; no. 13; pp. 3659 - 3670
• Main Authors: KURZROCK, Razelle, VOORHEES, Peter M, DE VELDE, Helgi Van, XIANG QIN, PUCHALSKI, Thomas A, HALL, Brett, REDDY, Manjula, MING QI, RHEE, Frits Van, CASPER, Corey, FURMAN, Richard R, FAYAD, Luis, LONIAL, Sagar, BORGHAEI, Hossein, JAGANNATH, Sundar, SOKOL, Lubomir, USMANI, Saad Z
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2013
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Castleman Disease - drug therapy; Castleman Disease - pathology; Female; Hematologic and hematopoietic diseases; Hemoglobins - metabolism; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - pathology; Male; Medical sciences; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Neoplasm Staging; Other diseases. Hematologic involvement in other diseases; Pharmacology. Drug treatments; Treatment Outcome; Antineoplastic agent; Human; Siltuximab; Immunopathology; Benign lymphadenopathy; Cytokine; Patient; Malignant hemopathy; B-Lymphocyte; Monoclonal antibody; Non Hodgkin lymphoma; Myeloma; Interleukin 6; Immunoglobulinopathy; Lymphoproliferative syndrome; Castleman disease; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-3349

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.