PMID- 26327301 OWN - NLM STAT- MEDLINE DCOM- 20160802 LR - 20200502 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 6 IP - 30 DP - 2015 Oct 6 TI - 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. PG - 30408-19 LID - 10.18632/oncotarget.4655 [doi] AB - 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. FAU - van Rhee, Frits AU - van Rhee F AD - Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. FAU - Casper, Corey AU - Casper C AD - Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Voorhees, Peter M AU - Voorhees PM AD - Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. FAU - Fayad, Luis E AU - Fayad LE AD - MD Anderson Cancer Center, The University of Texas, Houston, TX, USA. FAU - van de Velde, Helgi AU - van de Velde H AD - Janssen Research & Development LLC, Beerse, Belgium. FAU - Vermeulen, Jessica AU - Vermeulen J AD - Janssen Research & Development LLC, Leiden, Netherlands. FAU - Qin, Xiang AU - Qin X AD - Janssen Research & Development LLC, Spring House, PA, USA. FAU - Qi, Ming AU - Qi M AD - Janssen Research & Development LLC, Spring House, PA, USA. FAU - Tromp, Brenda AU - Tromp B AD - Janssen Research & Development LLC, Leiden, Netherlands. FAU - Kurzrock, Razelle AU - Kurzrock R AD - MD Anderson Cancer Center, The University of Texas, Houston, TX, USA. LA - eng GR - UL1 TR000371/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - T4H8FMA7IM (siltuximab) RN - Multi-centric Castleman's Disease SB - IM MH - Adolescent MH - Adult MH - Aged MH - Antibodies, Monoclonal/administration & dosage/adverse effects/*therapeutic use MH - Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use MH - Castleman Disease/*drug therapy/pathology MH - Disease-Free Survival MH - Drug Administration Schedule MH - Female MH - Humans MH - Infusions, Intravenous MH - Male MH - Middle Aged MH - Time Factors MH - Treatment Outcome MH - United States MH - Young Adult PMC - PMC4745809 OTO - NOTNLM OT - clinical trial OT - interleukin-6 OT - multi-centric Castleman's disease OT - siltuximab COIS- CONFLICTS OF INTEREST HvdV, JV, XQ, MQ, and BT are current or former employees of Janssen Research & Development and have owned stock in Johnson & Johnson. FvR has had an advisory role for and received research funding from Janssen Research & Development. CC has received research funding from Janssen Research & Development and the US National Institutes of Health, done consultancy with Janssen Research & Development, has had an advisory role for St Jude Children's Hospital and Research Center and Hutchinson Cancer Research Institute-Uganda, and has received royalties from UpToDate. PMV has received commercial research support from Janssen and is a consultant/advisory board member for MedImmune. RK has received a commercial research grant from Janssen Research & Development. LEF has no potential conflicts of interest to disclose. EDAT- 2015/09/04 06:00 MHDA- 2016/08/03 06:00 PMCR- 2015/10/06 CRDT- 2015/09/02 06:00 PHST- 2015/02/26 00:00 [received] PHST- 2015/07/23 00:00 [accepted] PHST- 2015/09/02 06:00 [entrez] PHST- 2015/09/04 06:00 [pubmed] PHST- 2016/08/03 06:00 [medline] PHST- 2015/10/06 00:00 [pmc-release] AID - 4655 [pii] AID - 10.18632/oncotarget.4655 [doi] PST - ppublish SO - Oncotarget. 2015 Oct 6;6(30):30408-19. doi: 10.18632/oncotarget.4655.