Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma

Abstract

Purpose: Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity.

Experimental design: Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly x 6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen.

Results: Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1 expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho-extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results.

Conclusions: At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.

Fig. 1

Western blot analyses of pretreatment and posttreatment tumors. A, densitometric measurements were expressed as fold-change (posttreatment reading/pretreatment reading). Each circle represents a single patient. Results from patients 1and 7 were excluded from the analyses because of lack of tumor material in the pretreatment (patient 7) or posttreatment (patient 1) biopsy. Horizontal lines indicate median values. *, indicate P = 0.02 compared with actin values using a nonpaired t test. B, Western blot results from four representative patients. Two of the patients shown harbored mutated BRAF genes in their tumors; two patients had wild-type BRAF, as indicated.