A phase I trial of 17-allylamino-geldanamycin (17AAG) in patients with advanced cancer

3030 Background: Therapy directed at the molecular chaperone HSP90 causes degradation of multiple client proteins critical in cancer cell proliferation and survival. 17AAG, a HSP90 directed agent, has demonstrated in vitro and in vivo antitumor effects in a variety of cancers. Methods: We performed a phase I trial to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of 17AAG infused on days 1, 4, 8 and 11 of a 21 day cycle, to characterize the pharmacokinetics of 17AAG and its effect on chaperone and client proteins in peripheral blood mononuclear cells (PBMCs). An accelerated titration design was utilized. Surrogate markers were measured in PBMCs at baseline, day 1 and 4. Pharmacokinetic analysis was performed on day 1 only. Results: Twelve patients received 35 courses (median, 2) at 6 dose levels. Both patients treated at 308 mg/m2 experienced one or more of the non-hematologic DLTs: hyperglycemia, dehydration, diarrhea (with maximal supportive treatment), ALT, AST, and a...