title: A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma.
abstract: 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 (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Renal Oncology, The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW36JJ, UK. james.larkin@rmh.nhs.uk
authors.forename: J M G
authors.initials: JM
authors.lastname: Larkin
authors.forename: T R
authors.initials: TR
authors.lastname: Ferguson
authors.forename: L M
authors.initials: LM
authors.lastname: Pickering
authors.forename: K
authors.initials: K
authors.lastname: Edmonds
authors.forename: M G
authors.initials: MG
authors.lastname: James
authors.forename: K
authors.initials: K
authors.lastname: Thomas
authors.forename: U
authors.initials: U
authors.lastname: Banerji
authors.forename: B
authors.initials: B
authors.lastname: Berns
authors.forename: C
authors.initials: C
authors.lastname: de Boer
authors.forename: M E
authors.initials: ME
authors.lastname: Gore
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D000069285:Infliximab; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D000069285:Infliximab