title: A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets.
abstract: OBJECTIVE
  Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-kappaB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-kappaB activity in blood (if possible tumor), and characterizing antitumor activity.
  
  
  METHODS
  Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m(2)) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m(2)) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-kappaB biomarker activity.
  
  
  RESULTS
  Bortezomib (1.3 mg/m(2)) and temozolomide (75 mg/m(2)) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease >or=4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-kappaB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome.
  
  
  CONCLUSIONS
  We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-kappaB activation.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37027, USA.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Su
authors.forename: Katayoun I
authors.initials: KI
authors.lastname: Amiri
authors.forename: Linda W
authors.initials: LW
authors.lastname: Horton
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Yu
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Koehler
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D018925:Chemokines / Q000097:blood; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000097:blood; D046988:Proteasome Endopeptidase Complex / Q000097:blood; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D018925:Chemokines; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003606:Dacarbazine; D046988:Proteasome Endopeptidase Complex; D000077204:Temozolomide