A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors

Eric Angevin, Josep Tabernero, Elena Elez, Steven J Cohen, Rastilav Bahleda, Jean-Luc van Laethem, Christian Ottensmeier, Jose A Lopez-Martin, Sally Clive, Florence Joly, Isabelle Ray-Coquard, Luc Dirix, Jean-Pascal Machiels, Neil Steven, Manjula Reddy, Brett Hall, Thomas A Puchalski, Rajesh Bandekar, Helgi van de Velde, Brenda TrompJessica Vermeulen, Razelle Kurzrock

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93 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2192-204
Number of pages13
JournalClinical Cancer Research
Issue number8
Publication statusPublished - 15 Apr 2014


  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal
  • Area Under Curve
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Fatigue
  • Female
  • Humans
  • Interleukin-6
  • Liver
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Mutation
  • Nausea
  • Neoplasms
  • Neutropenia
  • Proto-Oncogene Proteins
  • Treatment Outcome
  • ras Proteins


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