A phase I II trial of sorafenib and infliximab in advanced renal cell carcinoma

• Published in: British journal of cancer Vol. 103; no. 8; pp. 1149 - 1153
• Main Authors: Larkin, J M G, Ferguson, T R, Pickering, L M, Edmonds, K, James, M G, Thomas, K, Banerji, U, Berns, B, de Boer, C, Gore, M E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2010; Nature Publishing Group
• Subjects: 631/154/436/108; 692/699/67/589/1588/1351; 692/700/565/1436/1437; Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzenesulfonates - administration & dosage; Benzenesulfonates - adverse effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Clinical Study; Disease Progression; Drug Resistance; Epidemiology; Female; Humans; Infliximab; Kidney Neoplasms - drug therapy; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Kidneys; Male; Medical sciences; Middle Aged; Molecular Medicine; Nephrology. Urinary tract diseases; Niacinamide - analogs & derivatives; Oncology; Phenylurea Compounds; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Pyridines - administration & dosage; Pyridines - adverse effects; Survival Analysis; Treatment Outcome; Tumors; Tumors of the urinary system; sorafenib; renal cell carcinoma; infliximab; Kidney disease; Antineoplastic agent; Urinary system disease; Carcinoma; Tyrosine kinase inhibitor; Cytokine; Enzyme inhibitor; Monoclonal antibody; Malignant tumor; Anti-Tumor Necrosis Factor-alpha; Cancerology; Infliximab; Sorafenib; Anticytokine; Kidney cancer; Phase II trial; Phase I trial; Grawitz tumor; Advanced stage; Multikinase inhibitor; Antiangiogenic agent; Tumor necrosis factor α; Cancer; renal cell carcinoma: sorafenib
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605889

BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor- α (TNF- α ) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF- α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg −1 ) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg −1 were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand–foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS 6 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.