A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal® dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC)

Abstract

Purpose: 2ME2 (Panzem®) is a non-estrogenic derivative of estradiol with antiproliferative and antiangiogenic activity. Preclinical data support antitumor activity in prostate cancer. This trial evaluated the efficacy of 2ME2 NCD in patients with taxane-refractory, metastatic CRPC.

Experimental design: Patients with metastatic CRPC who had progressed on only one prior taxane-based regimen were eligible. All patients received 2ME2 NCD at 1,500 mg orally four times daily, repeated in 28 day cycles. The primary endpoint was progression-free survival at month 6, with a secondary endpoint of PSA response. An exploratory endpoint was metabolic response on FDG-PET imaging.

Results: A total of 50 pts was planned. The study was terminated after 21 pts when a futility analysis showed the primary endpoint was unlikely to be reached. The median number of cycles on study was 2 (range <1 to 12). Adverse events (AE) of grade ≥3 related to the study drug occurred in 7 unique patients (33%): elevations in liver function tests, fatigue or weakness, gastrointestinal hemorrhage, and hyponatremia. Paired FDG-PET scans were obtained for 11 pts. No metabolic responses were observed.

Conclusions: 2ME2 NCD did not appear to have clinically significant activity in this study. 2ME2 NCD was well-tolerated and showed some evidence of biologic activity. Given the aggressive biology in this taxane-refractory population, the potential benefit from a cytostatic agent like 2ME2 might better be realized in the pre-chemotherapy (or rising PSA only) stage of CRPC.

Trial registration: ClinicalTrials.gov NCT00394810.

Figures

Figure 1

Kaplan-Meier plot of progression-free survival in the intention-to-treat population (solid line). Dashed lines indicate the upper and lower 95% confidence interval bands. One subject terminated at day 329 alive and without recorded progression of disease.

Figure 2

Waterfall plot showing maximal prostate-specific antigen (PSA) change post-therapy (at any time point) compared with baseline (n = 18). Three patients discontinued the study before a post-therapy PSA was drawn. Values are truncated at +100%.

Figure 3

Pharmacokinetics. Plasma Concentrations of 2ME2 and 2ME2 in Prostate Cancer Patients after Oral Administration of 1500 mg Panzem® NCD Four Times Daily.