title: 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-naïve prostate cancer.
abstract: OBJECTIVE
  ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+)-superoxide dismutase 1 (SOD1) 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-naïve prostate cancer.
  
  
  METHODS
  Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) < 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels > 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 ≥ 50% increase (and >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.
  
  
  RESULTS
  At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% CI 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.
  
  
  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.
authors.affiliation: Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Lin
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Michael
authors.initials: M
authors.lastname: Morris
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Callahan
authors.forename: Gilad
authors.initials: G
authors.lastname: Gordon
authors.forename: Steven D
authors.initials: SD
authors.lastname: Reich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005221:Fatigue / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D008982:Molybdenum / Q000009:adverse effects / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D017430:Prostate-Specific Antigen