title: A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.
abstract: BACKGROUND
  Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies.
  
  
  METHODS
  A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months.
  
  
  RESULTS
  A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics.
  
  
  CONCLUSIONS
  This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: G M
authors.initials: GM
authors.lastname: Beasley
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: A P
authors.initials: AP
authors.lastname: Coleman
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: A
authors.initials: A
authors.lastname: Raymond
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: G
authors.initials: G
authors.lastname: Sanders
authors.affiliation: Department of Pathology, Duke University, Durham, NC.
authors.forename: M A
authors.initials: MA
authors.lastname: Selim
authors.affiliation: Cancer Center Biostatistics, Duke University, Durham, NC.
authors.forename: B L
authors.initials: BL
authors.lastname: Peterson
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: M S
authors.initials: MS
authors.lastname: Brady
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.|Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: M A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Surgery, Duke University, Durham, NC.|VA Medical Center, Durham, NC.
authors.forename: C
authors.initials: C
authors.lastname: Augustine
authors.affiliation: Department of Surgery, Duke University, Durham, NC.|VA Medical Center, Durham, NC.
authors.forename: D S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005121:Extremities / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D040081:Protein Array Analysis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077157:Sorafenib; D014018:Tissue Distribution
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D008558:Melphalan