Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma

Abstract

Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro. We evaluated the safety, pharmacokinetics, immunogenicity, and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. This open-label, phase 1, dose-escalating study used two doses of siltuximab: 5.5 and 11.0 mg/kg (administered on day 1 of each 21-day cycle). In total, nine patients were treated. The most common grade 3/4 adverse events, lymphopenia (89 %) and thrombocytopenia (44 %), occurred in patients receiving both doses of siltuximab; however, no dose-limiting toxicities (DLTs) were observed. Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg, the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner. Mean half-life, total systemic clearance, and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg. Across both doses, six of the nine patients had complete or partial response (22 and 44 %, respectively). In conclusion, as no DLT was observed, the recommended dose for this combination is 11.0 mg/kg once every 3 weeks. The study is registered at http://www.clinicaltrials.gov as NCT01309412.

From obesity to cancer: a review on proposed mechanisms

“…Taken together, on the basis of these findings, IL‐6 can be considered as a therapeutic target in cancer. At present, some antibodies against IL‐6 or IL‐6R are under evaluation in phase I/II clinical trials including siltuximab (CNTO 328), a monoclonal antibody against IL‐6, has shown promising results for non‐small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, and multiple myeloma …”

Emerging Therapeutic Strategies for Overcoming Proteasome Inhibitor Resistance

“…Despite promising preclinical results and the strong molecular rationale for targeting IL-6 and the IL-6 receptor in combination with Btz, clinical trials conducted to date have not demonstrated overwhelming benefit for combining the two agents. A recent phase I study of single agent siltuximab, an IL-6-targeted monoclonal antibody (MAb), in Japan showed good tolerability and activity in refractory MM patients (Suzuki et al, 2015), although a phase II, double-blind, placebo-controlled trial of siltuximab in combination with Btz showed no significant improvement in progressionfree survival (PFS) or OS compared to siltuximab plus placebo (Orlowski et al, 2015). Similar results were observed when siltuximab was added to a multidrug regimen that included Btz.…”

Siltuximab (CNTO 328): a promising option for human malignancies

“… 17 Based on the above results, siltuximab addition was considered for melphalan-based or bortezomib-based therapies. 27 However, in another study, the addition of siltuximab to the bortezomib–melphalan–prednisone regimen does not seem to improve complete response, progression-free survival, and overall survival, it only improves very good partial responses in patients who are transplant ineligible with newly diagnosed MM. 4 …”

“…Across both doses, 66% patients had complete or partial response, and 11.0 mg/kg once every 3 weeks is recommended. 27 In the Phase II randomized controlled clinical trial, the safety and efficacy of siltuximab plus bortezomib with placebo in patients with relapsed/refractory MM were assessed. Siltuximab was given by 6 mg/kg intravenous every 2 weeks, and after the study, it was found that the addition of siltuximab to bortezomib did not improve progression-free survival or overall survival despite a numerical increase in response rate in patients with relapsed or refractory MM.…”