Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies

Banerji, Udai, O'Donnell, Anne, Scurr, Michelle, Pacey, Simon, Stapleton, Sarah, Asad, Yasmin, Simmons, Laura, Maloney, Alison, Raynaud, Florence, Campbell, Maeli, Walton, Micheal, Lakhani, Sunil, Kaye, Stanley, Workman, Paul and Judson, Ian (2005) Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. Journal of Clinical Oncology, 23 18: 4152-4161. doi:10.1200/JCO.2005.00.612


Author Banerji, Udai
O'Donnell, Anne
Scurr, Michelle
Pacey, Simon
Stapleton, Sarah
Asad, Yasmin
Simmons, Laura
Maloney, Alison
Raynaud, Florence
Campbell, Maeli
Walton, Micheal
Lakhani, Sunil
Kaye, Stanley
Workman, Paul
Judson, Ian
Title Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
Journal name Journal of Clinical Oncology   Check publisher's open access policy
ISSN 0732-183X
1527-7755
Publication date 2005-06
Sub-type Article (original research)
DOI 10.1200/JCO.2005.00.612
Volume 23
Issue 18
Start page 4152
End page 4161
Total pages 10
Place of publication Alexandria, VA, United States
Publisher American Society of Clinical Oncology
Language eng
Subject 321015 Oncology and Carcinogenesis
Formatted abstract
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/m(2)/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m(2)/week and two at 450 mg/m(2)/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m(2)/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 (r(2) = .71) over the dose range 10 to 450 mg/m(2)/week, with peak plasma concentrations of 8,998 mu g/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/m(2)/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/m(2)/week. We recommend this dose for phase II clinical trials.
Keyword Oncology
Molecular chaperone
Signal-transduction
Androgen receptor
Cancer cells
Hsp90
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes 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.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 17 Oct 2007, 13:40:31 EST