Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: Clinical results from phase I trial.

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Abstracts

2008 ASCO Annual Meeting

Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: Clinical results from phase I trial.

Sub-category:

Gastrointestinal Stromal Tumors

Category:

Sarcoma

Meeting:

2008 ASCO Annual Meeting

Session Type and Session Title:

Clinical Science Symposium, Emerging Targets for Sarcoma Therapy

Abstract No:

10503

Citation:

J Clin Oncol 26: 2008 (May 20 suppl; abstr 10503)

Author(s):

A. J. Wagner, J. A. Morgan, R. Chugh, L. S. Rosen, S. George, M. S. Gordon, C. M. Devine, A. D. Van den Abbeele, D. Grayzel, G. D. Demetri

Abstract:

Background: Laboratory studies have demonstrated that inhibition of the Hsp90 chaperone protein results in selective destruction of the mutated KIT kinase in human GIST cell lines across multiple genotypes which confer TKI resistance. Other histopathologic subtypes of soft tissue sarcoma (STS) are also sensitive in vitro. To test this clinically, we conducted a phase I trial of IPI-504, a water-soluble Hsp90 inhibitor, for patients (pts) with metastatic, TKI-resistant GIST or metastatic STS. Methods: Pts with metastatic, TKI-resistant GIST or advanced/metastatic STS received IPI-504 in 21 day cycles (IV in 250 cc of normal saline over 30 min) either twice weekly for 2 weeks followed by 1 week off treatment (Schedule A) or twice weekly continuously for 3 weeks (Schedule B). Serial monitoring with ¹⁸FDG-PET imaging at baseline, day 11, and day 21, as well as PK profiling of IPI-504 and its major active metabolites (17-AAG and 17-AG) were performed. Results: 54 pts (38 GIST; 16 STS) have been entered at 5 dose levels (90 mg/m² IPI-504 [n=6], 150 [6], 225 [9], 300 [3], 400 [23] 500 [7]). The GIST pts had progressed despite prior imatinib and sunitinib in 100% and 95% respectively, as well as other agents in 38%. 45/54 pts received Schedule A. The maximum tolerated dose (MTD) was 400 mg/m² on Schedule A based on 2 DLTs (G3 headache, G3 myalgia) observed at the 500 mg/m² dose level. In the 18 GIST pts assessed by PET, 22% had a PET partial response and an additional 66% had stable disease according to the EORTC PET response criteria. Although no RECIST- defined responses were observed, 29/37 (78%) evaluable pts had a best response of SD. Conclusions: IPI-504 has been well-tolerated overall and shows promising early evidence of activity in the treatment of pts with TKI-resistant GIST. The MTD for twice-weekly IPI-504 for 2 weeks with 1 week off treatment is 400 mg/m²; expansion of this cohort is ongoing. Targeting Hsp90 represents a novel therapeutic strategy for patients with metastatic GIST.

Abstract Disclosures

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy and are designated with a caret symbol (^) here and in the print version.

Associated Presentation(s):

1. Results from Phase 1 Trial of IPI-504, a Novel HSP90 Inhibitor, in Tyrosine Kinase Inhibitor - Resistant GIST and other Sarcomas

Meeting: 2008 ASCO Annual Meeting
Presenter: Andrew J Wagner, MD, PhD
Session: Emerging Targets for Sarcoma Therapy (Clinical Science Symposium)

Other Abstracts in this Sub-Category:

		1. Activity of sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): A phase II trial of the University of Chicago Phase II Consortium. Meeting: 2008 ASCO Annual Meeting Abstract No: 10502 First Author: L. Wiebe Category: Sarcoma - Gastrointestinal Stromal Tumors
		2. Insulin-like growth factor 1 receptor (IGF-1R): A potential therapeutic target for gastrointestinal stromal tumors (GIST). Meeting: 2008 ASCO Annual Meeting Abstract No: 10507 First Author: A. K. Godwin Category: Sarcoma - Gastrointestinal Stromal Tumors
		3. Time dependence of critical deletions as prognostic factor for relapse-free survival (RFS) in localised GIST. A Spanish Group for Sarcoma Research (GEIS) study. Meeting: 2008 ASCO Annual Meeting Abstract No: 10508 First Author: J. Martin Category: Sarcoma - Gastrointestinal Stromal Tumors
		More...

Abstracts by A. J. Wagner :

		1. A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. Meeting: 2010 ASCO Annual Meeting Abstract No: 2541 First Author: D. D. Von Hoff Category: Developmental Therapeutics - Clinical Pharmacology and Immunotherapy - Phase I Studies
		2. A first-in-human, phase I study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advanced solid tumors or non-Hodgkin's lymphoma. Meeting: 2010 ASCO Annual Meeting Abstract No: 3079 First Author: S. Dolly Category: Developmental Therapeutics - Experimental Therapeutics - Other Novel Agents
		3. A phase I pharmacodynamic and pharmacokinetic study of a Ras inhibitor, PRLX 93936, in patients with advanced solid tumors. Meeting: 2010 ASCO Annual Meeting Abstract No: e13042 First Author: R. K. Ramanathan Category: Developmental Therapeutics - Clinical Pharmacology and Immunotherapy - Phase I Studies
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Presentations by A. J. Wagner :

		1. Discussion Meeting: 2010 ASCO Annual Meeting Discussant: Andrew J. Wagner, MD, PhD Session: Sarcoma (Oral Abstract Session)
		2. A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. Meeting: 2009 ASCO Annual Meeting Presenter: Andrew J Wagner, MD, PhD Session: Beyond mTORC1 - New PI3 Kinase Pathway Inhibitors (Clinical Science Symposium)
		3. Results from Phase 1 Trial of IPI-504, a Novel HSP90 Inhibitor, in Tyrosine Kinase Inhibitor - Resistant GIST and other Sarcomas Meeting: 2008 ASCO Annual Meeting Presenter: Andrew J Wagner, MD, PhD Session: Emerging Targets for Sarcoma Therapy (Clinical Science Symposium)
		More...

Educational Book Manuscripts by A. J. Wagner :

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