A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer

Gary Hudes, Scott T. Tagawa, Young E. Whang, Ming Qi, Xiang Qin, Thomas A. Puchalski, Manjula Reddy, Mark Cornfeld, Mario Eisenberger

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. Patients and Methods In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m2 q3w plus siltuximab 6 mg/kg q2w (n = 12), 9 mg/kg q3w (n = 12), or 12 mg/kg q3w (n = 15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. Results DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. Conclusion These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Original languageEnglish (US)
Pages (from-to)669-676
Number of pages8
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 1 2013

Keywords

  • C-reactive protein
  • Docetaxel
  • Interleukin-6
  • Prostate cancer
  • Siltuximab

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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