Faculty Collaboration Database

A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 2014 Apr 15;20(8):2192-204

Date

02/25/2014

Pubmed ID

24563479

DOI

10.1158/1078-0432.CCR-13-2200

Scopus ID

2-s2.0-84898967209 (requires institutional sign-in at Scopus site)   144 Citations

Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Author List

Angevin E, Tabernero J, Elez E, Cohen SJ, Bahleda R, van Laethem JL, Ottensmeier C, Lopez-Martin JA, Clive S, Joly F, Ray-Coquard I, Dirix L, Machiels JP, Steven N, Reddy M, Hall B, Puchalski TA, Bandekar R, van de Velde H, Tromp B, Vermeulen J, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
Antibodies, Monoclonal
Area Under Curve
CHO Cells
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Fatigue
Female
Humans
Interleukin-6
Liver
Male
Metabolic Clearance Rate
Middle Aged
Mutation
Nausea
Neoplasms
Neutropenia
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
Treatment Outcome
ras Proteins