title: Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma.
abstract: OBJECTIVE
  To determine the safety, maximum tolerated dose, pharmacokinetics, and efficacy, and to evaluate biomarkers, of the multikinase inhibitor sorafenib plus IFN alpha-2a in advanced renal cell carcinoma (RCC) or melanoma.
  
  
  METHODS
  Patients received 28-day cycles of continuous, oral sorafenib twice daily and s.c. IFN thrice weekly: sorafenib 200 mg twice daily plus IFN 6 million IU (MIU) thrice weekly (cohort 1); and sorafenib 400 mg twice daily plus IFN 6 MIU thrice weekly (cohort 2); or plus IFN 9 MIU thrice weekly (cohort 3). Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and dynamic contrast-enhanced ultrasonography.
  
  
  RESULTS
  Thirteen patients received at least one dose of sorafenib plus IFN (12 RCC; one melanoma). The maximum tolerated dose was not reached [only one dose-limiting toxicity (grade 3 asthenia)]. Most frequently reported drug-related adverse events were grade 2 or less in severity, including fatigue, diarrhea, nausea, alopecia, and hand-foot skin reaction. One (7.7%) RCC patient achieved partial response and eight (61.5%) had stable disease (including the melanoma patient). Good responders assessed by dynamic contrast-enhanced ultrasonography had increased progression-free survival and overall survival, relative to poor responders. IFN had no effect on the pharmacokinetics of sorafenib. There were no significant changes in absolute values of lymphocytes, levels of proangiogenic cytokines, or inhibition of phosphorylated extracellular signal-regulated kinase in T cells or natural killer cells, with combination therapy.
  
  
  CONCLUSIONS
  This sorafenib combination was well tolerated, with preliminary antitumor activity in advanced RCC and melanoma patients. There were no drug-drug interactions and the recommended dose for future studies is sorafenib 400 mg twice daily plus IFN 9 MIU.
authors.affiliation: Department of Medicine, Institut Gustave Roussy, Villejuif, France. escudier@igr.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lassau
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Linda
authors.initials: L
authors.lastname: Chami
authors.forename: Michele
authors.initials: M
authors.lastname: Lamuraglia
authors.forename: Eric
authors.initials: E
authors.lastname: Zafarana
authors.forename: Veronique
authors.initials: V
authors.lastname: Landreau
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Eric
authors.initials: E
authors.lastname: Brendel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011725:Pyridines; D011994:Recombinant Proteins; D009536:Niacinamide; D000077157:Sorafenib