A phase 1/2, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors
Mené sur 84 patients atteints d'une tumeur solide de stade avancé et/ou réfractaire, cet essai de phase I/II évalue la toxicité, l'efficacité et des paramètres pharmacocinétiques du siltuximab, un anticorps monoclonal chimérique anti-interleukine 6
Purpose: This phase 1/2 study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin-6 mAb derived from a new CHO cell line in patients with advanced/refractory solid tumors. Experimental Design: In the phase 1 dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received 2.8 or 5.5 mg/kg q2w or 11 or 15 mg/kg q3w IV. In the phase 1 expansion (n=24) and phase 2 cohorts (n=40), patients with KRAS mutant tumors; ovarian; pancreatic; or anti-EGFR refractory/resistant NSCLC, colorectal, or H&N cancer received 15 mg/kg q3w. The phase 2 primary efficacy endpoint was CR, PR, or SD >6 weeks. Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, 11 other) received a median of 3 (range 1−45) cycles. One DLT occurred at 5.5 mg/kg. Common grade ≥3 AEs were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 AEs. Neutropenia (4%) was the only possibly-related AE grade ≥3 reported in >1 patient. SAEs were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appeared similar to the previous cell line. No objective responses occurred; 5/84 patients had SD >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33/47 patients. At 11 and 15 mg/kg, complete sustained CRP suppression was observed. Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS mutant cancers. The recommended phase 2 doses were 11 and 15 mg/kg q3w.