A Phase I Study of 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 is a multifunctional cytokine that serves as a growth factor for B-cell non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and Castleman’s Disease (CD). CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. Interim results are presented here from an ongoing open-label, dose-finding, phase I trial to assess the safety, pharmacokinetics, pharmacodynamics and clinical activity of CNTO 328 in patients with B-cell NHL (including Waldenstrom’s macroglobulinemia [WM]), MM, and CD. Evaluation of six dose cohorts with the following infusion schedules: 3 mg/kg q 2 weeks, 6 mg/kg q 2 weeks, 12 mg/kg q 3 weeks, 6 mg/kg q 1 week, 12 mg/kg q 2 weeks, 12 mg/kg q 3 weeks has been completed. A seventh cohort evaluating CNTO 328 9-mg/kg administered with a tri-weekly infusion schedule in CD patients is also ongoing. Fifty-two patients (NHL n=17, MM n=13, CD n=22) have been enrolled. The median age is 56 years (range 21-82). Patients received an average of 15 doses (up to 87 doses) of CNTO 328 with a median exposure of 131 days (up to 1051 days). Preliminary pharmacokinetic data from cohorts 1 through 5 show that serum concentrations declined in a bi-exponential manner with a terminal half-life of ~15 days. Dose-proportional increases in Cmax and AUC (0-14 days) were observed. No apparent differences in pharmacokinetics were observed when comparing patients with NHL, MM or CD. The median baseline C-reactive protein (CRP) level, a surrogate for IL-6 activity (n=47) was 9.21 mg/L (range 1-260 mg/L). Of patients with post-baseline CRP values, 83% of patients demonstrated complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment (median baseline level of 13.6 mg/L (range 1-260 mg/L).  CNTO 328 was well tolerated with no dose-limiting toxicity observed in any of the study cohorts. Forty-nine (94%) of 52 patients had one or more adverse events. Of these 49 patients, 23 (47%) had adverse events with a maximum toxicity grade of grade 2 or less . The following adverse events were observed in more than 15% of patients: upper respiratory or urinary tract infection, thrombocytopenia, neutropenia, leukopenia, anemia, elevated ALT, hypertriglyceridemia, nausea, diarrhea, fatigue, headache. Adverse events of  Grade 3 or higher, observed in more than 5% of patients overall, were limited to neutropenia (21%, none febrile), thrombocytopenia (8%), anemia (6%), cellulitis (8%), and pleural effusion (6%); most were not attributable to CNTO 328. Clinical activity has been seen in all diseases types, particularly CD and WM.  Among patients with NHL, 1 patient with MALT lymphoma, 1 with follicular lymphoma and 1 with mantle cell lymphoma demonstrated stable disease for more than 6 months. Among patients with WM, 2 demonstrated  partial response (1 not yet confirmed) and the remaining 3 showed stable disease. Among patients with MM, 3 had at least partial response (the low baseline serum M-protein levels of 2 patients became undetectable during treatment) and 2 patients had long-lasting stable disease (1 patient for 224 days, 1 patient for more than 533 days). A high response rate was observed in patients with CD; whose results are presented in a separate abstract. In summary, these interim results show that CNTO 328 appears to have a favorable safety profile and demonstrate clinical activity as a single agent in the treatment of MM, NHL, WM and CD.