Siltuximab induced durable tumor and symptom response in patients with multicentric Castleman disease, according to results of a randomized, placebo-controlled, double blind, phase 2 study presented at the ASH Annual Meeting and Exhibition.
Prior research suggested siltuximab (CNTO 328, Janssen), an anti-interleukin (IL)–6 monoclonal antibody, demonstrated activity in multicentric Castleman disease, a rare lymphoproliferative disorder.
“We now understand that IL-6 has a central role in driving the signs and symptoms of multicentric Castleman Disease,” Raymond S. Wong, MD, of Prince of Wales Hospital at the Chinese University of Hong Kong, said during a press conference. “Siltuximab is a monoclonal antibody, which specifically targets the human IL-6 and blocks this function.”
The current study by Wong and colleagues included 79 patients. Histologic subtypes included mixed (44%), hyaline vascular (33%) or plasmacytic (23%).
Median age was 48 years; 48% were Asian and 39% were non-Hispanic white; and 66% were men. Thirty percent of patients were on corticosteroids and 58% had received prior systemic therapy.
Researchers assigned 53 patients to 11 mg/kg siltuximab administered via IV infusion every 3 weeks. The other 26 patients received placebo.
Durable tumor and symptomatic response — defined as partial and complete response and improvement or stabilization in disease-related symptoms for at least 18 weeks — served as primary endpoints.
Median treatment duration was 375 days for siltuximab and 152 days for placebo. A higher percentage of patients assigned to siltuximab completed 48 weeks of treatment (64% vs. 27%).
One patient assigned to siltuximab achieved complete response and 17 achieved partial response. The durable tumor and symptomatic response rate was significantly higher in patients assigned to siltuximab than placebo (34% vs. 0%; P=.0012).
Wong and colleagues reported prolonged disease control with siltuximab, as median tumor and symptomatic response duration was 340 days.
A central radiology review indicated the tumor response rate was 38% with siltuximab vs. 4% with placebo (P=.0022).
The durable symptomatic response rate was 57% with siltuximab vs. 19% with placebo (P=.0018). Twenty-five percent of patients assigned to siltuximab exhibited complete symptom resolution vs. 0% of those assigned to placebo (P=.0037).
Among patients who were anemic at baseline, 61% of those assigned to siltuximab and 0% assigned to placebo demonstrated hemoglobin improvement of ≥15 g/L by week 13 of treatment (P=.0002).
Researchers observed sustained decreases in C-reactive protein, electron spin resonance and fibrinogen, as well as increases in albumin, in the siltuximab arm.
Wong and colleagues reported similar rates of grade ≥3 adverse events in both arms (47% for siltuximab vs. 54% for placebo). Adverse events that caused treatment discontinuation, primarily due to progressive disease, were more common with placebo (38% vs. 23%). However, adverse events that led to treatment interruption were more common with siltuximab (28% vs. 19%).
The most common grade ≥3 adverse events associated with siltuximab were fatigue (9%) and night sweats (8%). Four percent of patients experienced hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension or weight gain.
Two patients assigned to siltuximab died after progressive disease led to treatment discontinuation. Four patients assigned to placebo died.
“In this study, the efficacy of siltuximab in multicentric Castleman disease patients, was clearly demonstrated by evidence of durable tumor and symptom response,” Wong said. “These results are very exciting and highlight the potential for siltuximab to be a new and valuable treatment option for multicentric Castleman disease patients who unfortunately, until now, had no approved treatment options.”
For more information:
Wong RS. Abstract #505. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.
Disclosure: The researchers report board membership, speakers’ bureau, employment, advisory board or consultant roles with, research funding and honoraria from, and equity ownership in Alexion, Amgen, Baxter, Bayer, Biogen Idec, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, Pfizer and Roche.