Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies

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Abstract

Purpose

Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer.

Experimental design

17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs).

Results

A total of 31 patients received 92 courses of treatment. The MTD was 21 mg/m2/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2–22) months. Both Cmax and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable.

Conclusion

Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.

Introduction

Heat shock proteins (Hsps) are intracellular molecular chaperones that maintain correct protein folding and prevent non-specific aggregation of misfolded or unfolded proteins. Hsp90 has emerged as an important chaperone in cancer cells, where it helps maintain the stability, and consequently function, of proteins necessary for a wide range of signalling pathways, including tumour proliferation, metastasis, angiogenesis and resistance to apoptosis.1, 2 Hsp90 is therefore a target of considerable interest for oncologic drug development. Hsp90 activity is dependent on an ATP binding site in the N-terminus of Hsp90. Molecules that bind to this site are able to disrupt the interaction of Hsp90 with various client proteins, such as HER-2, RAF, mutant p53, cyclin-dependent kinase 4, Src, AKT and nuclear factor-kB,3, 4, 5, 6, 7, 8, 9 many of which are involved in maintaining the malignant phenotype,3, 5, 10 resulting in increased ubiquitin-mediated proteasomal degradation of these proteins.

The benzoquinone ansamycin geldanamycin was the first inhibitor of Hsp90 to be identified, but it caused significant hepatotoxicity and was not developed further. A 17-carbon derivative of geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), was investigated in clinical trials; however, the drug was also associated with hepatotoxicity and is poorly soluble, necessitating the use of dimethyl sulfoxide and egg phospholipids for solubilisation.11 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), also a benzoquinone ansamycin, is a water-soluble analogue of 17-AAG. 17-DMAG was more potent and had a lower IC70 than 17-AAG in in vitro clonogenic assays evaluating 64 different patient-derived tumour explants.12 17-DMAG also demonstrated anti-tumour effects in a wide range of xenograft models, including MDA-MB-231 (breast), NCI-H522 (adenocarcinoma), melanomas MEXF 989 and MEXF 276, and an orthotopic liver metastasis model using the AsPC-1 human pancreatic tumour.13, 14

We designed a phase I dose-escalation study to evaluate the toxicity and determine the MTD of 17-DMAG administered on a twice-weekly schedule in 28-d cycles. To assess drug effect on its target we used peripheral blood mononuclear cells (PBMCs) and measured levels of Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90.15, 16

Section snippets

Eligibility criteria

Patients (age ⩾18 years) were eligible for this study if they had pathologically confirmed metastatic or unresectable malignancy for which there were no acceptable standard therapies; an Eastern Cooperative Oncology Group performance status ⩽2 (Karnofsky ⩾50%); and adequate organ and marrow function defined as leucocytes ⩾3.0 × 109/L, absolute neutrophil count ⩾1.5 × 109/L, platelets ⩾100 × 109/L, total bilirubin ⩽ 1.5 × the upper limit of normal (ULN), aspartate aminotransferase and/or alanine

Patients

Patient characteristics are detailed in Table 1. Thirty-one patients enrolled between December 2004 and July 2007 are included in the analysis. One male patient went off study before receiving 17-DMAG and is therefore not included in the analysis. Twenty-three patients had at least three prior chemotherapy regimens (range, zero to seven regimens).

Toxicity

Patients received 92 courses of treatment at nine different dose levels (Table 2). The median number of courses was two (range, 1–23 courses). No

Discussion

The development of small molecule benzoquinone ansamycin inhibitors of Hsp90 has been hindered by toxicities and poor solubility. 17-DMAG was developed as a water-soluble analogue of 17-AAG that was more potent than 17-AAG in preclinical testing. 17-DMAG has undergone clinical evaluation with varying schedules of daily and weekly administration.16, 20, 21, 22 Intermittent dosing was shown to improve the safety profile of this drug. Additionally, xenograft models showed that drug effect on Hsp90

Conflict of interest statement

None declared.

Acknowledgements

We would like to thank Gina Uhlenbrauck, SAIC-Frederick, Inc., for editorial assistance in the preparation of this manuscript.

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    This paper was written with support from the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This work was supported by the Intramural Research Programme of the NIH, National Cancer Institute, Center for Cancer Research.

    d

    Both authors contributed equally to the manuscript.

    e

    Present address: Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.

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