A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors

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-e...

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Bibliographic Details
Published in:Clinical cancer research 2014-04, Vol.20 (8), p.2192-2204
Main Authors: ANGEVIN, Eric, TABERNERO, Josep, RAY-COQUARD, Isabelle, DIRIX, Luc, MACHIELS, Jean-Pascal, STEVEN, Neil, REDDY, Manjula, HALL, Brett, PUCHALSKI, Thomas A, BANDEKAR, Rajesh, VAN DE VELDE, Helgi, TROMP, Brenda, ELEZ, Elena, VERMEULEN, Jessica, KURZROCK, Razelle, COHEN, Steven J, BAHLEDA, Rastilav, VAN LAETHEM, Jean-Luc, OTTENSMEIER, Christian, LOPEZ-MARTIN, Jose A, CLIVE, Sally, JOLY, Florence
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Antibodies, Monoclonal - adverse effects
Antibodies, Monoclonal - pharmacokinetics
Antibodies, Monoclonal - therapeutic use
Antineoplastic agents
Area Under Curve
Biological and medical sciences
CHO Cells
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Fatigue - chemically induced
Female
Humans
Interleukin-6 - immunology
Liver - drug effects
Liver - physiopathology
Male
Medical sciences
Metabolic Clearance Rate
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutation
Nausea - chemically induced
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
Neutropenia - chemically induced
Pharmacology. Drug treatments
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
Treatment Outcome
Tumors
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Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-13-2200