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Angevin E , Tabernero J , Elez E , Cohen SJ , Bahleda R , van Laethem JL , Ottensmeier C , Lopez-Martin JA , Clive S , Joly F , Ray-Coquard I , Dirix L , Machiels JP , Steven N , Reddy M , Hall B , Puchalski TA , Bandekar R , van de Velde H , Tromp B , Vermeulen J , Kurzrock R
A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors
Clin Cancer Res. 2014 Apr 15;20(8) :2192-204
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Abstract
PURPOSE: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. EXPERIMENTAL DESIGN: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. RESULTS: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade >/=3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade >/=3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade >/=3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased >/=1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein 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 II doses were 11 and 15 mg/kg every 3 weeks.
Notes
Angevin, Eric Tabernero, Josep Elez, Elena Cohen, Steven J Bahleda, Rastilav van Laethem, Jean-Luc Ottensmeier, Christian Lopez-Martin, Jose A Clive, Sally Joly, Florence Ray-Coquard, Isabelle Dirix, Luc Machiels, Jean-Pascal Steven, Neil Reddy, Manjula Hall, Brett Puchalski, Thomas A Bandekar, Rajesh van de Velde, Helgi Tromp, Brenda Vermeulen, Jessica Kurzrock, Razelle eng Clinical Trial, Phase I Clinical Trial, Phase II Research Support, Non-U.S. Gov't Clin Cancer Res. 2014 Apr 15;20(8):2192-204. doi: 10.1158/1078-0432.CCR-13-2200. Epub 2014 Feb 21.