Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Metastatic Melanoma

• DOI: 10.1158/1078-0432.ccr-08-1002
• Publication Date: 2008-12-15T08:23:53Z
• Authors: David B. Solit; Iman Osman; David Polsky; Katherine S. Pana...; Adil Daud; James S. Goydos; Jerrold Teitcher; Jedd D. Wolchok; F. Joseph Germino; Susan E. Krown; Daniel Coit; Neal Rosen; Paul B. Chapman
• Keywords: Hsp90 inhibitor; V600E

Abstract Purpose: Activation of the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase/AKT seems to be critical for melanoma proliferation. Components these pathways are client proteins heat-shock 90 (hsp90), suggesting that inhibition hsp90 could have significant antimelanoma effects. We conducted a phase II trial using inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in patients. The primary end points were clinical responses whether treatment inhibited MAPK activity. Experimental Design: Melanoma patients with measurable disease stratified on basis or not their tumor harbored V600E BRAF mutation. 17-AAG was administered i.v. once weekly ×6 weeks at 450 mg/m2. Tumor biopsies obtained pretreatment 18 50 hours after first dose 17-AAG, snap-frozen. Results: Fifteen evaluable treated; nine had mutations six wild-type. No objective observed. Western blot analysis showed an increase hsp70 decrease cyclin D1 expression posttreatment but no effect RAF kinases phospho–extracellular signal-regulated expression. Plasma analyzed by mutant-specific PCR 86% sensitivity 67% specificity predicting DNA sequencing results. Conclusions: At this schedule effects short-lived, seen. Future trials should focus more potent formulation can chronically prolonged suppression pathway.