title: A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma.
abstract: CONCLUSIONS
  This study is a rare example of effective doses of both targeted agents being both administered and tolerated.This combination should not be used in melanoma.
  
  
  BACKGROUND
  Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib-mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib.
  
  
  METHODS
  Patients with metastatic melanoma were enrolled in dose-escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose-limiting toxicity (DLT). Efficacy, as measured by 6-month progression-free survival and response rate per RECIST, was documented.
  
  
  RESULTS
  Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m(2) weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months.
  
  
  CONCLUSIONS
  The combination of sorafenib and bortezomib is safe but not active in patients with melanoma.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; rsullivan7@partners.org.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA;
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
authors.forename: Julie
authors.initials: J
authors.lastname: Aldridge
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA;
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA;
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
authors.forename: Christine
authors.initials: C
authors.lastname: Conley
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000069286:Bortezomib; D000077157:Sorafenib