Abstract
This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed. Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.
Highlights
Siltuximab is a chimeric monoclonal antibody with high binding affinity for human interleukin (IL)-6 [1,2,3]
Serious adverse events were reported in 42%; most were related to underlying disease
The pharmacokinetic profile of Chinese hamster ovary (CHO)-derived siltuximab appears similar to the previous cell line
Summary
Siltuximab is a chimeric (murine–human) monoclonal antibody with high binding affinity for human interleukin (IL)-6 [1,2,3]. High IL-6 levels are prognostic and correlate with tumor metastasis, disease stage, and short survival in renal, prostate, breast, pancreatic, and ovarian cancers [4,5,6,7,8,9]. Ovarian cancer cell lines produce IL-6 protein in the range of 10 to 104 pg/105 cells, which can be further increased by treatment with gonadotrophins or lysophosphatidic acid [10, 11]. IL-6 may act as an autocrine growth factor for ovarian cancer tumor cells [10]. Kirsten rat sarcoma-2 (KRAS) mutations are prevalent among many malignancies that respond poorly to available treatment options. More than 90% of patients with pancreatic cancer exhibit KRAS mutations [12]. In non–small cell lung cancer (NSCLC) and colorectal cancer, KRAS
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