Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers

Abstract

Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase IIdose of17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly  3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 Heat shock protein (HSP) 90 constitutes 1% to 2% of all cytosolic proteins, and its primary function is to chaperone multiple client proteins involved in cell signaling, proliferation, and survival (1, 2). HSP90 plays an important role in mediating conformational folding and activation of oncoproteins, such as mutant p53, HER-2/neu, Raf-1, and Bcr-Abl (1 -4). Geldanamycin and its analogues bind to HSP90 and prevent its chaperone function (5). The first geldamycin analogue to enter clinical trials is 17-(allylamino)-17-demethoxygeldanamycin (17AAG; refs. 6 -10). Previous phase I studies of 17AAG in adults have evaluated weekly, daily Â3 schedule, or daily Â5 schedule (Table 1; refs. 6 -10).The recommended phase 2 dose of 17AAG is 295 to 308 mg/m 2 when administered weekly Â3, every 4 weeks (7,8), and 450 mg/m 2 when administered weekly on a continuous schedule (6). In contrast, administration of 17AAG daily Â5 or daily Â3 is associated with doselimiting toxicity (DLT) at substantially lower doses, and the DLT, which was primarily reversible hepatitis (9, 10), reflected preclinical animal toxicology studies (11).17AAG is metabolized primarily by CYP3A, with the major metabolite, 17-(amino)-17-demethoxygeldanamycin, being equipotent to 17AAG in its ability to affect . The pharmacokinetics of 17AAG in humans is now well characterized. 17AAG and 17-(amino)-17-demethoxygeldanamycin are excreted primary through the liver and biliary system, and urinary excretion accounts for <10% of a dose. (6 -10, 15, 16).Biomarkers that may be affected by 17AAG therapy have been evaluated in clinical trials (6 -10). HSP90 has not shown a consistent increase or decrease in response to 17AAG therapy. However, several animal and human studies have shown HSP70 increases resulting from 17AAG-HSP90 interaction. (6 -13).

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

“…The earlier geldanamycin analogues (i.e., 17-AAG or 17-DMAG), despite potent in vitro and in vivo preclinical activity, have not shown clear clinical benefit (5,31). It is believed that the disappointing clinical activity is due to their poor pharmaceutical properties, selectivity, and toxicity profiles in patients (22,23,31). Given this precedent, we set out to identify novel Hsp90 inhibitors with a superior potency, pharmacologic, and tolerability profile.…”

“…One approach will be to optimize the route, dose, and schedule of Hsp90 inhibitors. On one hand, the dose-limiting toxicities (DLT) of 17-AAG have been shown to be schedule dependent (22). On the other hand, the dosing schedule might have to be tailored to the duration and extent of the desired suppression of a particular client protein (23).…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…In the case of geldanamycin, extensive medicinal chemistry efforts have been made to replace the 17-methoxy substituent and generate analogs with improved pharmaceutical properties. One of these derivatives, 17-allyamino-17-demethoxygeldanamycin (17-AAG, compound 34, Figure 5; Jia et al, 2003), a first-in-class Hsp90 drug, has provided proof-of-concept for Hsp90 inhibition in patients at tolerated doses-(phase I studies are reviewed in Ramanathan et al, 2007). More recently, KOS953 (tanespimycin), which contains a proprietary form of 17-AAG in a novel, optimized formulation-polyethoxylated castor oil-achieved clinical proof-of-concept with trastuzumab.…”

Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

“…[2][3][4] The benzoquinone ansamycin geldanamycin derivatives are smallmolecule inhibitors of Hsp90, being developed in a variety of malignancies. 5,6 Alvespimycin (17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) KOS-1022) is a water-soluble analog of tanespimycin (17-allylamino-17-demethoxygeldanamycin (17-AAG)). When compared with tanespimycin, alvespimycin has higher potency against Hsp90, longer plasma half-life and oral bioavailability.…”