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Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4152-4161
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.00.612
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Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies

Udai Banerji, Anne O'Donnell, Michelle Scurr, Simon Pacey, Sarah Stapleton, Yasmin Asad, Laura Simmons, Alison Maloney, Florence Raynaud, Maeli Campbell, Michael Walton, Sunil Lakhani, Stanley Kaye, Paul Workman, Ian Judson

From the Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research; Section of Medicine, The Institute of Cancer Research; The Royal Marsden Hospital, Sutton; Cancer Research UK, Drug Development Office; and Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom

Address reprint requests to Ian Judson, MD, FRCP, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, UK; e-mail: Ian.Judson{at}icr.ac.uk; or Paul Workman, PhD, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, UK; e-mail: Paul.Workman{at}icr.ac.uk

PURPOSE: To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials.

PATIENTS AND METHODS: This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated.

RESULTS: The highest dose level reached was 450 mg/m2/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m2/week and two at 450 mg/m2/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m2/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r2 = .71) over the dose range 10 to 450 mg/m2/week, with peak plasma concentrations of 8,998 µg/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m2/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment.

CONCLUSION: It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m2/week. We recommend this dose for phase II clinical trials.

Supported by Cancer Research UK.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 1, 2003; 93rd Annual Meeting of the American Association of Cancer Research, San Francisco, CA, April 6-10, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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K. J. Pienta and D. Bradley
Mechanisms underlying the development of androgen-independent prostate cancer.
Clin. Cancer Res., March 15, 2006; 12(6): 1665 - 1671.
[Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
S. Sanderson, M. Valenti, S. Gowan, L. Patterson, Z. Ahmad, P. Workman, and S. A. Eccles
Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis.
Mol. Cancer Ther., March 1, 2006; 5(3): 522 - 532.
[Abstract] [Full Text] [PDF]

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 BloodHome page
C. S. Mitsiades, N. S. Mitsiades, C. J. McMullan, V. Poulaki, A. L. Kung, F. E. Davies, G. Morgan, M. Akiyama, R. Shringarpure, N. C. Munshi, et al.
Antimyeloma activity of heat shock protein-90 inhibition
Blood, February 1, 2006; 107(3): 1092 - 1100.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
O. M. Grbovic, A. D. Basso, A. Sawai, Q. Ye, P. Friedlander, D. Solit, and N. Rosen
V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors
PNAS, January 3, 2006; 103(1): 57 - 62.
[Abstract] [Full Text] [PDF]

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 Integr Cancer TherHome page
M. F. McCarty and K. I. Block
Multifocal Angiostatic Therapy: An Update
Integr Cancer Ther, December 1, 2005; 4(4): 301 - 314.
[Abstract] [PDF]

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 Cancer Res.Home page
S. da Rocha Dias, F. Friedlos, Y. Light, C. Springer, P. Workman, and R. Marais
Activated B-RAF Is an Hsp90 Client Protein That Is Targeted by the Anticancer Drug 17-Allylamino-17-Demethoxygeldanamycin
Cancer Res., December 1, 2005; 65(23): 10686 - 10691.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. O. Ibrahim, T. Hahn, C. Franke, D. P. Stiehl, R. Wirthner, R. H. Wenger, and D. M. Katschinski
Induction of the Hypoxia-Inducible Factor System by Low Levels of Heat Shock Protein 90 Inhibitors
Cancer Res., December 1, 2005; 65(23): 11094 - 11100.
[Abstract] [Full Text] [PDF]

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 JCOHome page
H. I. Scher and C. L. Sawyers
Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis
J. Clin. Oncol., November 10, 2005; 23(32): 8253 - 8261.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
U. Banerji, M. Walton, F. Raynaud, R. Grimshaw, L. Kelland, M. Valenti, I. Judson, and P. Workman
Pharmacokinetic-Pharmacodynamic Relationships for the Heat Shock Protein 90 Molecular Chaperone Inhibitor 17-Allylamino, 17-Demethoxygeldanamycin in Human Ovarian Cancer Xenograft Models
Clin. Cancer Res., October 1, 2005; 11(19): 7023 - 7032.
[Abstract] [Full Text] [PDF]

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 Cold Spring Harb Symp Quant BiolHome page
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] [PDF]


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