Abstract
5135 Background: ATN-224 (choline tetrathiomolybdate) is an orally active, small molecule that has antiangiogenic and antitumor effects in prostate cancer (PCa) models. ATN-224 targets Cu2+/Zn2+superoxide dismutase 1 (SOD1) and suppress the generation of H2O2 leading to activation of a number of phosphatases, a group of negative growth regulatory enzymes. We hypothesized that ATN-224 may induce antitumor effect as an antiangiogenic (at 30 mg dose level) and possesses direct antitumor activity at higher dose (300 mg/day). Methods: PCa pts with PSA doubling time (PSADT) of < 12 months, no radiographic evidence of metastasis, no hormonal therapy within 6 months were enrolled. All pts had testosterone > 150 ng/dL at baseline. ATN-224 was administered at 2 dose levels. PSA progression was defined as at least a 50% increase in PSA and >5 ng/mL increase from baseline or post-treatment nadir and confirmed. Endpoints included the proportion of pts who did not have PSA progression for 24 weeks, change in PSA slope/PSADT, and assessment of safety and tolerability. The study was not powered to detect difference between the two groups. Results: 52 pts were enrolled at 6 centers. Fourteen of 27 (52%) in the low dose and 6/25 (24%) in the high dose cohort were PSA progression free for 24 weeks. One patient in high dose cohort showed PSA >50% decrease of 40 days duration. Pre- and on-treatment PSA kinetics are shown below. Median duration on study was 134 days in both groups. ATN-224 was well tolerated with a few reversible Grade 3/4 neutropenia and Grade 3 skin rash (both 4%). Conclusions: ATN-224 may have biologic activity in men with androgen-dependent PCa at low doses, as demonstrated by > 50% of pts being PSA progression free at 6 month and a significant decrease in mean PSA slope. The implication of this study is not clear without a comparative design and ceruloplasmin correlation which is still pending. [Table: see text] [Table: see text]
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