Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1078-1087
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.09.119
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
From the Divisions of Medical Oncology, Biochemistry and Molecular Biology, Developmental Oncology Research, Biostatistics, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN
Address reprint requests to Charles Erlichman, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: erlichman.charles{at}mayo.edu
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.
Supported in part by grant Nos. CA15083, CA90390, and CA69912 (National Cancer Institute), and M01-RR00585 (NCRR).
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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July 1, 2005;
106(1):
318 - 327.
[Abstract]
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R. K. Ramanathan, D. L. Trump, J. L. Eiseman, C. P. Belani, S. S. Agarwala, E. G. Zuhowski, J. Lan, D. M. Potter, S. P. Ivy, S. Ramalingam, et al.
Phase I Pharmacokinetic-Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin (17AAG, NSC 330507), a Novel Inhibitor of Heat Shock Protein 90, in Patients with Refractory Advanced Cancers
Clin. Cancer Res.,
May 1, 2005;
11(9):
3385 - 3391.
[Abstract]
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K. Flatten, N. T. Dai, B. T. Vroman, D. Loegering, C. Erlichman, L. M. Karnitz, and S. H. Kaufmann
The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons
J. Biol. Chem.,
April 8, 2005;
280(14):
14349 - 14355.
[Abstract]
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P. WORKMAN
Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics
Cold Spring Harb Symp Quant Biol,
January 1, 2005;
70(0):
499 - 515.
[Abstract]
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