A phase I study of the Heat Shock Protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced, solid tumours.

S.C. Pacey, Richard Wilson, M. Walton, Martin Eatock, A. Hardcastle, H. Zetterlund, H- Arkenau, R. Beecham, W. Aherne, J.S. De Bono, F. Raynaud, P. Workman, I. Judson

Research output: Contribution to journalArticlepeer-review

140 Citations (Scopus)

Abstract

PURPOSE: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which = 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P
Original languageEnglish
Pages (from-to)1561-1570
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number6
DOIs
Publication statusPublished - 15 Mar 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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