Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer

Abstract

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m 2 daily for 5 days with cycles repeated every 21days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily  3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m 2 on the daily  5 schedule; 112 mg/m 2 on the daily  3 schedule; and 220 mg/m 2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily  5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stress-survival response, protein refolding, and the conformational maturation of a subset of signaling proteins (1 -3). Several natural products that bind selectively to Hsp90 and inhibit its function have been used to determine its biological role (4 -7). These natural products, which include geldanamycin and radicicol, induce the selective degradation of proteins whose activity and/or expression are regulated by . Sensitive Hsp90 clients include protein kinases [human epidermal growth factor receptor 2 (HER2), Raf-1, and Akt], steroid hormone receptors (androgen receptor and estrogen receptor), and mutant oncoproteins (mutant p53,.Geldanamycin, the lead compound of the class, proved too toxic for clinical use (16). However, 17-allylamino-17-demethoxygeldanamycin (17-AAG) has activity in human xenograft and genetic murine tumor models as a single agent (12, 17 -20). Hsp90 inhibition also has additive and synergistic effects in combination with cytotoxics, biologics, radiation, and antiangiogenics (17, 20 -24). The objectives of the current trial were to determine the safety, pharmacokinetics, and pharmacodynamics of 17-AAG and to define a dose and schedule of administration that could be used in ...

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.…”

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

“…Numerous HSP90 inhibitors have been developed, including the ansamycins, that specifically inhibit the intrinsic ATPase activity of HSP90 (15). Effective ansamycin derivatives have been isolated, including 17-(allylamino)-17-demethoxygeldanamycin (17AAG) that has recently completed several phase I clinical trials (16)(17)(18)(19)(20)(21)(22)(23) and is now undergoing evaluation in phase II. Initial results are encouraging, although problems were noted with formulation and hepatotoxicity.…”

Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma

“…HSP90 is ubiquitously expressed in both normal and malignant tissues, but its altered 'high-affinity' conformation in tumor cells confers 100-fold selectivity for HSP90 inhibitors (11). Consequently, several HSP90 inhibitors derived from the ansamycin antibiotic geldanamycin (GA) are in clinical trials for the treatment of cancer (5,12,13). Ansamycin compounds bind tightly to the ATP-binding pocket of HSP90 to prevent its stable interaction with substrates and to target them for proteasomal degradation (14,15).…”

“…Ansamycin compounds bind tightly to the ATP-binding pocket of HSP90 to prevent its stable interaction with substrates and to target them for proteasomal degradation (14,15). HSP90 inhibitors have shown promising but limited signs of clinical activity (5,12,13). It therefore remains important to understand how 17-DMAG acts as an effective anti-tumor agent and if its efficacy is likely to be challenged by features of tumor cells that confer resistance to conventional therapies.…”