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
Mené sur 66 patients atteints d'un lymphome non hodgkinien à cellules B ou d'un myélome multiple ou d'une maladie de Castleman, cet essai de phase I évalue la toxicité et l'activité antitumorale du siltuximab, un anticorps monoclonal chimérique anti IL-6
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.