A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors
| Autor: | Jean-Luc Van Laethem, Brenda B. Tromp, Jessica Vermeulen, Josep Tabernero, Brett Hall, Neil N. Steven, Sally S. Clive, Rajesh Bandekar, Eric Angevin, Thomas A. Puchalski, Isabelle Ray-Coquard, Christian C. Ottensmeier, Jose A. Lopez-Martin, Elena Elez, Luc Dirix, Jean-Pascal Machiels, Razelle Kurzrock, Rastilav Bahleda, Helgi van de Velde, Florence Joly, Steven Cohen, Manjula Reddy |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Neutropenia Metabolic Clearance Rate medicine.drug_class CHO Cells Pharmacology Monoclonal antibody medicine.disease_cause Gastroenterology Siltuximab Proto-Oncogene Proteins p21(ras) chemistry.chemical_compound Cricetulus Refractory Pharmacokinetics Cricetinae Neoplasms Proto-Oncogene Proteins Internal medicine medicine Animals Humans Fatigue Aged Dose-Response Relationship Drug biology Interleukin-6 business.industry Antibodies Monoclonal Nausea Middle Aged medicine.disease Dose–response relationship Treatment Outcome Liver Oncology chemistry Area Under Curve Mutation ras Proteins biology.protein Female KRAS Antibody business |
| Zdroj: | Clinical Cancer Research. 20:2192-2204 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. Clin Cancer Res; 20(8); 2192–204. ©2014 AACR. |
| Databáze: | OpenAIRE |
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