A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets

Abstract

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.

Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

“…To explore the potential relevance of these findings in human melanoma, we evaluated CCL11 expression in macrophages (CD163 + ) of biopsy specimens from 6 patients with melanoma before and after treatment with the proteasome inhibitor, bortezomib (VELCADE), and temozolomide in a phase I/II clinical trial (24). VELCADE, an FDA-approved agent in some cancers, inhibits degradation of phosphorylated-IκB, thus reducing NF-κB activity by retaining RelA/p65 in the cytoplasm, but also affects a number of additional pathways (25–28).…”

Transcription alterations of members of the ubiquitin–proteasome network in prostate carcinoma

“…[14][15] Additionally, trials for other haematological and solid tumours, including PCA have been initiated. [16][17][18][19] NEDD4L acts as an E3 ubiquitin ligase, and thereby regulates diverse cellular processes such as excretion, plasma membrane channel regulation, protein catabolism and TGF-b signalling. NEDD4L negatively regulates TGF-b signalling by ubiquitination of TGF-b receptor type I (TGFb-R1) and Smad2.…”

Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma

“…We were aware while we were designing and conducting our study that others, motivated by the same preclinical findings, were pursuing the combination of bortezomib and temozolomide in melanoma [15]. We thought that simultaneous pursuit of both projects was reasonable given the promising preclinical results and contemporary paucity of promising therapeutic concepts.…”