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.
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.
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Frits
F
van Rhee
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Corey
C
Casper
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Peter M
PM
Voorhees
MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
Luis E
LE
Fayad
Janssen Research & Development LLC, Beerse, Belgium.
Helgi
H
van de Velde
Janssen Research & Development LLC, Leiden, Netherlands.
Jessica
J
Vermeulen
Janssen Research & Development LLC, Spring House, PA, USA.
Xiang
X
Qin
Janssen Research & Development LLC, Spring House, PA, USA.
Ming
M
Qi
Janssen Research & Development LLC, Leiden, Netherlands.
Brenda
B
Tromp
MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
Razelle
R
Kurzrock
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005871:Castleman Disease / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C504234:siltuximab
clinical trial; interleukin-6; multi-centric Castleman's disease; siltuximab