An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST.

Demetri, G. D.; Heinrich, M. C.; Chmielowski, Bartosz; Morgan, Jon; George, Shaji; Bradley, Rosie; Blackman, Ronald K.; Teofilovici, Florentina; Fletcher, J.; Tap, William D.; Mehren, Margaret von

doi:10.1200/jco.2011.29.15_suppl.10011

Cited by 35 publications

(22 citation statements)

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“…For example, in mutant EGFR (L858R/T790M) NCI-H1975 NSCLC xenografts, depletion of mutant EGFR has been documented to last a duration of 72 hours or shorter in response to a single dose of AT13387 or ganetespib (13,14). In a clinical evaluation of once-weekly ganetespib in GIST (29), tumor biopsies demonstrated only transient depletion of KIT and inhibition of downstream signaling pathways, suggesting that the once-weekly regimen was suboptimal for producing prolonged client protein depletion. Similarly, in one of the first phase I studies of the geldanamycin 17-AAG, depletion of c-RAF and CDK4 in tumor biopsies could be demonstrated at 24 hours, but not at 5 days after treatment (22).…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

Shapiro

Kwak

Dezube

et al. 2015

Clinical Cancer Research

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Purpose: AT13387 is a potent second-generation, fragmentderived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.Experimental Design: Standard 3þ3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.Results: Sixty-two patients were treated with doses ranging from 10 to 120 mg/m 2 twice weekly and 150 to 310 mg/m 2 once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m 2 , which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m 2 as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.Conclusion: AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.

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Section: Discussionmentioning

confidence: 99%

First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

Shapiro

Kwak

Dezube

et al. 2015

Clinical Cancer Research

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“…However, paired tumor biopsies in 4 patients did not show prolonged inhibition of activated KIT or its downstream pathways. Accrual has been limited to patients with PDGFRA mutations to allow alternative schedules and combinations [99]. …”

Section: Clinical Studies With Hsp90 Inhibitors In Cancersmentioning

confidence: 99%

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Jhaveri

Taldone

Modi

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

400

426

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Hsp90 is an ATP dependent molecular chaperone protein which integrates multiple oncogenic pathways. As such, Hsp90 inhibition is a promising anti-cancer strategy. Several inhibitors that act on Hsp90 by binding to its N-terminal ATP pocket have entered clinical evaluation. Robust pre-clinical data suggested anti-tumor activity in multiple cancer types. Clinically, encouraging results have been demonstrated in melanoma, acute myeloid leukemia, castrate refractory prostate cancer, non-small cell lung carcinoma and multiple myeloma. In breast cancer, proof-of-concept was demonstrated by first generation Hsp90 inhibitors in combination with trastuzumab mainly in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer. There are a multitude of second generation Hsp90 inhibitors currently under investigation. To date, however, there is no FDA approved Hsp90 inhibitor nor standardized assay to ascertain Hsp90 inhibition. This review summarizes the current status of both first and second generation Hsp90 inhibitors based on their chemical classification and stage of clinical development. It also discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors. Ultimately, these efforts will aid in maximizing the full potential of this class of agents.

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“…Single agent ganetespib has also been evaluated in Phase II trials in patients with NSCLC [53], MBC [54] and GIST [55]. The drug was well tolerated, with the most frequent toxicities being grade 1/2 diarrhea, nausea and fatigue.…”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

“…Patients with GIST who had failed prior therapy with imatinib and sunitinib were treated with single agent ganetespib weekly for 3 weeks in a 28-day cycle [55]. Correlatives included positron emission tomography (PET) imaging, and HSP90 client proteins were evaluated using pre- and post-treatment biopsies.…”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Jhaveri

Ochiana

Dunphy

et al. 2014

Expert Opinion on Investigational Drugs

155

173

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Introduction Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

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An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST.

Cited by 35 publications

References 0 publications

First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

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