A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets
| Autor: | Jeffrey A. Sosman, Gregory D. Ayers, Mark C. Kelley, Katayoun I. Amiri, Yingjun Su, Yingchun Yu, Igor Puzanov, Ann Richmond, Elizabeth Koehler, Linda W. Horton |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Proteasome Endopeptidase Complex Cancer Research Skin Neoplasms Dacarbazine Population Pharmacology Peripheral blood mononuclear cell Article Drug Administration Schedule Bortezomib Antineoplastic Combined Chemotherapy Protocols Temozolomide medicine Humans education Melanoma Aged education.field_of_study Performance status business.industry NF-kappa B Middle Aged medicine.disease Boronic Acids Treatment Outcome Oncology Pyrazines Proteasome inhibitor Female Chemokines business Proteasome Inhibitors medicine.drug |
| Zdroj: | Clinical Cancer Research. 16:348-357 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-2087 |
| Popis: | Purpose: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-κB 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-κB activity in blood (if possible tumor), and characterizing antitumor activity. Experimental Design: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m2) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m2) 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-κB biomarker activity. Results: Bortezomib (1.3 mg/m2) and temozolomide (75 mg/m2) 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 ≥4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-κB 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-κB activation. Clin Cancer Res; 16(1); 348–57 |
| Databáze: | OpenAIRE |
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