BACKGROUND: The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. PATIENTS AND METHODS: The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). RESULTS: Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m(2) and PTX 100mg/m(2). The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3-4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant (p<0.05) and consistent changes (>70% of patients) in transcriptome were observed. CONCLUSIONS: The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.
BACKGROUND: The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. PATIENTS AND METHODS: The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). RESULTS: Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m(2) and PTX 100mg/m(2). The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3-4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant (p<0.05) and consistent changes (>70% of patients) in transcriptome were observed. CONCLUSIONS: The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.
Authors: Janice M Mehnert; Antoinette R Tan; Rebecca Moss; Elizabeth Poplin; Mark N Stein; Mika Sovak; Kelly Levinson; Hongxia Lin; Michael Kane; Murugesan Gounder; Yong Lin; Weichung Joe Shih; Eileen White; Eric H Rubin; Vassiliki Karantza Journal: Mol Cancer Ther Date: 2011-06-16 Impact factor: 6.261
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Authors: William J Irvin; Robert Z Orlowski; Wing-Keung Chiu; Lisa A Carey; Frances A Collichio; Philip S Bernard; Inge J Stijleman; Charles Perou; Anastasia Ivanova; E Claire Dees Journal: Clin Breast Cancer Date: 2010-12-01 Impact factor: 3.225
Authors: Bhuvaneswari Ramaswamy; Tanios Bekaii-Saab; Larry J Schaaf; Gregory B Lesinski; David M Lucas; Donn C Young; Amy S Ruppert; John C Byrd; Kristy Culler; Diedre Wilkins; John J Wright; Michael R Grever; Charles L Shapiro Journal: Cancer Chemother Pharmacol Date: 2009-09-23 Impact factor: 3.333
Authors: Mei Lan Tan; Jer Ping Ooi; Nawfal Ismail; Ahmed Ismail Hassan Moad; Tengku Sifzizul Tengku Muhammad Journal: Pharm Res Date: 2009-04-30 Impact factor: 4.200
Authors: R C Turkington; C Purcell; C R James; J Millar; E Napier; D Law; R Gallagher; M Morris; R H Wilson; M M Eatock Journal: Invest New Drugs Date: 2013-05-11 Impact factor: 3.850