Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer

Matthew P. Goetz, David Toft, Joel Reid, Matthew Ames, Bridget Stensgard, Stephanie Safgren, Araba A. Adjei, Jeff Sloan, Pamela Atherton, Vlad Vasile, Sandra Salazaar, Alex Adjei, Gary Croghan, Charles Erlichman

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301 Scopus citations

Abstract

Purpose: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion: The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

Original languageEnglish (US)
Pages (from-to)1078-1087
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number6
DOIs
StatePublished - Feb 20 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Goetz, M. P., Toft, D., Reid, J., Ames, M., Stensgard, B., Safgren, S., Adjei, A. A., Sloan, J., Atherton, P., Vasile, V., Salazaar, S., Adjei, A., Croghan, G., & Erlichman, C. (2005). Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Journal of Clinical Oncology, 23(6), 1078-1087. https://doi.org/10.1200/JCO.2005.09.119