Abstract
Abstract Background: HE3235 (17α-ethynyl-5α-androstane-3α, 17β-diol) is an androstenediol analog, which shows activity in preclinical CRPC and breast cancer models. HE3235 decreased AR expression in LNCaP cells in vitro, in the CRPC LuCaP 35V xenograft, and suppressed ER-a expression in MNU-induced breast tumors in rats. HE3235 also decreased intra-tumoral androgen synthesis (both T and DHT) in the LuCaP 35V tumors. In toxicology studies, it decreased steroidogenesis (DHEA and T in male dogs and sex steroids in female rats). HE3235 did not inhibit CYP17 in H295R adrenal tumor cells, but inhibited the conversion of d-cholesterol to d-pregnenolone. We are therefore conducting a Phase I/II clinical study in CRPC patients to determine safety, tolerance, pharmacokinetics, maximum tolerated dose and activity of this compound. Methods: Men with CRPC and an ECOG PS of <2 who progressed either radiographically or biochemically through at least one taxane-containing chemotherapy regimen are eligible. HE3235 is given orally, twice daily in cohorts of 3–6 pts. Cohorts were defined by doses of 10 mg, 20 mg, 30 mg, 50 mg or higher until MTD is observed. Cohorts may be expanded based on dose limiting toxicity, activity or pharmacokinetics demonstrating adequate blood concentrations of drug to deliver a therapeutic effect. Subjects were treated on 28-day cycles until toxicity or disease progression. Scans were obtained every 2 cycles. The Prostate Cancer Consortium Clinical Trials consortium sites were supported by a grant form the Department of Defense. Results: 22 subjects have been treated to date at doses of 10 mg/day (n=7), 20 mg/day (n=9) and 30 mg/day (n=6). Dose escalation continues to determine the MTD. Pharmacokinetics was dose proportional with a drug half-life of 11–14 hours. HE3235 was well tolerated. Nine of 22 subjects experienced a drop in PSA during treatment with 6 of 22 equal to or greater than 20%. No patient had a 50% decline in PSA. Eight of 17 (47%) subjects who were evaluable for response had stable disease. Median time to progression was 56 days (IQR 55, 224) for 10 mg/day, 112 days (IQR 56, 168) for 20 mg/days, 112 days (IQR 56, >122) for 30 mg/day and 112 days (IQR 56, 168) for all 22 subjects. Conclusion: HE3235 is a novel, small orally delivered compound with preclinical activity for CRPC. It is well tolerated through a dose of 30 mg, and has a T1/2 linear to dose in cohorts tested to date. The trial continues to accrue, and a cohort of patients with chemotherapy-naïve CRPC will be enrolled into the ongoing Phase I/II Study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A221.
Published Version
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