Oncotarget

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

Frits van Rhee _, Corey Casper, Peter M. Voorhees, Luis E. Fayad, Helgi van de Velde, Jessica Vermeulen, Xiang Qin, Ming Qi, Brenda Tromp and Razelle Kurzrock

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Oncotarget. 2015; 6:30408-30419. https://doi.org/10.18632/oncotarget.4655

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Abstract

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

Correspondence to:

Frits van Rhee, e-mail: vanrheefrits@uams.edu

Keywords: multi-centric Castleman's disease, interleukin-6, siltuximab, clinical trial

Received: February 26, 2015     Accepted: July 23, 2015     Published: August 03, 2015

ABSTRACT

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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