Purpose-To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer.Patients and Methods-Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition.Results-Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. Conclusions-Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

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 ...

Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

An RT-PCR-based assay for PSA mRNA can detect circulating cells in the peripheral blood of patients with prostatic cancer. The frequency of positivity increases with tumor stage. A unique observation was the detection of cells in patients with no measurable PSA on hormonal therapy. This suggests that continued seeding of distant sites may still be occurring in these patients, despite seemingly successful therapy. The relationship between continued seeding, disease progression, and survival will require further study.