A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naive prostate cancer

作者：Lin Jianqing; Zahurak Marianna; Beer Tomasz M; Ryan Charles J; Wilding George; Mathew Paul; Morris Michael; Callahan Jennifer A; Gordon Gilad; Reich Steven D; Carducci Michael A^*; Antonarakis Emmanuel S

来源：Urologic Oncology-Seminars and Original Investigations, 2013, 31(5): 581-588.

DOI：10.1016/j.urolonc.2011.04.009

• ATN-224
• Prostate cancer
• Phase II

Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-superoxide dismutase 1 (SOD 1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naive prostate cancer. %26lt;br%26gt;Methods: Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) %26lt; 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels %26gt; 150 ng/dl) were eligible. ATN-224 was administered at 2 dose-levels, 300 mg (n = 23) or 30 mg (n = 24) daily, by way of randomization. PSA progression was defined as a %26gt;= 50% increase (and %26gt;5 ng/ml) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the 2 treatment groups. %26lt;br%26gt;Results: At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% Cl 17%-77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21-40(+)) and 26 weeks (95% CI 24-39(+)) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (P = 0.006) and a significant mean PSADT increase (P = 0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. %26lt;br%26gt;Conclusions: Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.

• 出版日期2013-7