Phase I Trial of Bortezomib and Dacarbazine in Melanoma and Soft Tissue Sarcoma

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2013 Jan 15

PMID 23315028

Citations 11

Authors

Andrew Poklepovic

Leena E Youssefian

Leena Youseffian

Mary Winning

Christine A Birdsell

Nancy A Crosby

Viswanathan Ramakrishnan

Marc S Ernstoff

John D Roberts

Affiliations

Soon will be listed here.

Abstract

Purpose: Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination.

Experimental Design: Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0.

Results: Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response.

Conclusions: Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

Citing Articles

Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro.

Takacs A, Lajko E, Lang O, Istenes I, Kohidai L Sci Rep. 2020; 10(1):14287.

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Synergistic Effects of Bortezomib-OV Therapy and Anti-Invasive Strategies in Glioblastoma: A Mathematical Model.

Kim Y, Lee J, Lee D, Othmer H Cancers (Basel). 2019; 11(2).

PMID: 30781871 PMC: 6406513. DOI: 10.3390/cancers11020215.

Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations.

Friedman A, Xia Y, Trippa L, Le L, Igras V, Frederick D Clin Cancer Res. 2017; 23(16):4680-4692.

PMID: 28446504 PMC: 5559310. DOI: 10.1158/1078-0432.CCR-16-3029.

The Proteasome Inhibitor Bortezomib Affects Chondrosarcoma Cells via the Mitochondria-Caspase Dependent Pathway and Enhances Death Receptor Expression and Autophagy.

Lohberger B, Steinecker-Frohnwieser B, Stuendl N, Kaltenegger H, Leithner A, Rinner B PLoS One. 2016; 11(12):e0168193.

PMID: 27978543 PMC: 5158315. DOI: 10.1371/journal.pone.0168193.

The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma.

Suarez-Kelly L, Kemper G, Duggan M, Stiff A, Noel T, Markowitz J Oncotarget. 2016; 7(49):81172-81186.

PMID: 27783987 PMC: 5348384. DOI: 10.18632/oncotarget.12791.

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