Clinical Research Papers:
A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease
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Frits van Rhee1, Corey Casper2, Peter M. Voorhees3, Luis E. Fayad4, Helgi van de Velde5, Jessica Vermeulen6, Xiang Qin7, Ming Qi7, Brenda Tromp6, Razelle Kurzrock4
1Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2Fred Hutchinson Cancer Research Center, Seattle, WA, USA
3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
4MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
5Janssen Research & Development LLC, Beerse, Belgium
6Janssen Research & Development LLC, Leiden, Netherlands
7Janssen Research & Development LLC, Spring House, PA, USA
Frits van Rhee, e-mail: [email protected]
Keywords: multi-centric Castleman's disease, interleukin-6, siltuximab, clinical trial
Received: February 26, 2015 Accepted: July 23, 2015 Published: August 03, 2015
Background: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD.
Methods: This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented.
Results: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-≥3 adverse events (AEs) reported in >1 patient included hypertension (n = 3) and nausea, cellulitis, and fatigue (n = 2 each). Grade-≥3 AEs at least possibly attributed to siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia (n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule.
Conclusions: All MCD patients in this extension study have received siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive siltuximab.
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