Long-Term Safety in a Phase 1 Study of Siltuximab (CNTO 328), an Anti-Interleukin-6 Monoclonal Antibody, in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease,

Interleukin (IL)-6 serves as a growth factor for B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Castleman's disease (CD). Siltuximab (CNTO 328) is a chimeric monoclonal antibody that neutralizes the biological activity of human IL-6. We have previously reported interim safety and efficacy of siltuximab, which is highly notable in CD (van Rhee et al, Blood 2008;112:1008; Kurzrock et al, Blood 2008;112:1009). We now report the long-term safety of siltuximab in the 29 patients who were treated for more than 1 yr.

An open-label, dose-finding, phase 1 trial of siltuximab in patients with B-cell NHL, MM, or CD was conducted. Five dose-escalation cohorts with increasing total dose exposure [3 mg/kg q 2 weeks (n=6), 6 mg/kg q 2 weeks (n=7), 12 mg/kg q 3 weeks (n=10), 6 mg/kg q 1 week (n=6), 12 mg/kg q 2 weeks (n=6)] were studied initially. Two additional cohorts were subsequently added: 12 mg/kg q 3 weeks as a 1-hour infusion (n=12) and a CD extension cohort with exploratory biomarkers (9 mg/kg q 3 weeks, n=12; 12 mg/kg q 3 weeks, n=8). Between Jun 2005 and Sep 2009, 67 patients (37 CD, 13 MM, 17 NHL) with median age 54 (range 18–82) yrs were enrolled.

Twenty-nine patients (24 CD, 3 MM, 2 NHL) were treated for at least 1 yr, including 19 and 15 patients treated for >2 and >3 yrs, respectively, with maximum duration of therapy up to 5 yrs. The grade ≥3 AEs most commonly reported between yrs 1 and 2 (irrespective of attribution to siltuximab) were infections (n=7, 24%), including device-related infection and bacteraemia (n=1), staph bacteraemia (n=1), wound abscess and pneumonia (n=1), limb and vulval abscesses (n=1), rectal abscess (n=1), bronchitis (n=1), and herpes zoster (n=1). Other common grade ≥3 AEs were blood and lymphatic system disorders (14%, most were neutropenia [10%]), and gastrointestinal disorders (10%, most were nausea [7%]). Incidence of AEs in these system-organ classes did not increase with longer duration of treatment. AEs of all grades reported in >10% of patients between yrs 1 and 2 were: nausea (31%); diarrhea, upper respiratory tract infection (each 28%); leukopenia, hepatic function abnormal, hypertriglyceridemia (each 21%); anemia, neutropenia, thrombocytopenia, sinusitis, hypercholesterolemia (each 14%). However, the majority of these AEs were low grade and tended to decrease with time. SAEs did not increase over time (n=5 between yrs 1–2, n=2 between yrs 2–3, n=4 at >3 yrs), and no specific SAE was reported in more than 1 patient. No patient discontinued therapy due to an AE during the long-term follow-up period, and there were no treatment-related deaths. Although some patients experienced clinically significant laboratory-related AEs, the laboratory results showed that mean levels of creatinine and triglycerides remained stable over time. In the 15 patients treated for ≥3 yrs, the following laboratory parameters showed modest trends of increase in mean value at 36 mos: hemoglobin increased to 13.9 g/dL from 12.4 g/dL at baseline, cholesterol increased to 201.07 mg/dL from 160.73 mg/dL at baseline, and bilirubin increased to 0.76 mg/dL from 0.49 mg/dL at baseline. On the other hand, at 36 mos in these 15 patients, the mean neutrophil count decreased to 3.70 x10³/μL from 6.65 x10³/μL at baseline, and the mean platelet count decreased to 216.0 x10³/μL from 381.8 x10³/μL at baseline. No severe infusion-related reactions were reported. At the time of database lock, 20 patients (1 MM, 19 CD) were still receiving study treatment. All 24 CD patients treated for ≥1 yr had sustained clinical responses, and half (n=12) also had an objective radiologic response, including 1 CR and 11 PR based on central radiology review. Ten of the 12 responders were treated with the highest dose of siltuximab (12 mg/kg), including 1 patient who responded after switching to 12 mg/kg. In addition, 3 unconfirmed PR were seen in the CD patients. Five patients with MM or NHL treated for ≥1 yr also had clinical benefit, including 2 CR and 1 prolonged SD in 3 MM patients and durable PR (>4 mos) in 2 NHL patients.

Siltuximab appears to have a favorable safety profile suitable for chronic dosing and shows clinical activity as a single agent, especially in treating Castleman's disease. Phase 2 and 3 studies are ongoing to further evaluate the safety and efficacy of siltuximab in patients with multicentric Castleman's disease and in combination with other agents in patients with multiple myeloma.

Kurzrock:Centocor Ortho Biotech Research & Development: Research Funding. Voorhees:Pfizer: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Centocor Ortho Biotech: Consultancy, Research Funding; Celgene: Research Funding; MedImmune: Consultancy, Research Funding. Casper:Johnson & Johnson: Research Funding. Fayad:Centocor Ortho Biotech Research & Development: Research Funding. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Borghaei:Genetech: Honoraria; Amgen: Honoraria; Eli Lilly: Honoraria. Jagannath:Educational Concepts Group: Teaching/Lectures; Envision Communication: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; Imedex, LLC: Teaching/Lectures; Japanese Society of Hematology: Teaching/Lectures; Medical Learning Institute: Teaching/Lectures; Becker Pharmaceutical: Questionnaire regarding drug usage; Clinical Care Options, LLC: Teaching/Lectures; American Society of Clinical Oncology (ASCO): Editorial Board – Cancer.net; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Investigator's Meeting; Janssen Pharmaceuticals: Teaching/Lectures; Johnson & Johnson Pharmaceutical: Member, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; MMRF: Teaching/Lectures; PER Group: Teaching/Lectures; Prime Oncology: Teaching/Lectures; South Carolina Oncology Society: Teaching/Lectures; CIG Media Group: Editor for Clinical Lymphoma Myeloma Leukemia Journal; Research to Practice: Teaching/Lectures. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Qin:Ortho Biotech Oncology Research & Development: Employment. Qi:Ortho Biotech Oncology Research & Development: Employment. Cornfeld:Janssen Pharmaceuticals: Employment, Equity Ownership. van Rhee:Johnson & Johnson Pharmaceuticals: Consultancy, Research Funding.