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A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets.

Su Y, Amiri KI, Horton LW, Yu Y, Ayers GD, Koehler E, Kelley MC, Puzanov I, Richmond A, Sosman JA
Clin Cancer Res. 2010 16 (1): 348-57

PMID: 20028756 · PMCID: PMC3205975 · DOI:10.1158/1078-0432.CCR-09-2087

PURPOSE - 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.

EXPERIMENTAL DESIGN - 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.

MeSH Terms (20)

Adult Aged Antineoplastic Combined Chemotherapy Protocols Boronic Acids Bortezomib Chemokines Dacarbazine Drug Administration Schedule Female Humans Male Melanoma Middle Aged NF-kappa B Proteasome Endopeptidase Complex Proteasome Inhibitors Pyrazines Skin Neoplasms Temozolomide Treatment Outcome

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