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.
RCT Entities:
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 cancerpatients 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: G J Brewer; R D Dick; D K Grover; V LeClaire; M Tseng; M Wicha; K Pienta; B G Redman; T Jahan; V K Sondak; M Strawderman; G LeCarpentier; S D Merajver Journal: Clin Cancer Res Date: 2000-01 Impact factor: 12.531
Authors: A M Janssen; C B Bosman; W van Duijn; M M Oostendorp-van de Ruit; F J Kubben; G Griffioen; C B Lamers; J H van Krieken; C J van de Velde; H W Verspaget Journal: Clin Cancer Res Date: 2000-08 Impact factor: 12.531
Authors: Emmanuel S Antonarakis; Marianna L Zahurak; Jianqing Lin; Daniel Keizman; Michael A Carducci; Mario A Eisenberger Journal: Cancer Date: 2012-03-15 Impact factor: 6.860
Authors: Jose C Juarez; Mari Manuia; Mark E Burnett; Oscar Betancourt; Benoit Boivin; David E Shaw; Nicholas K Tonks; Andrew P Mazar; Fernando Doñate Journal: Proc Natl Acad Sci U S A Date: 2008-05-14 Impact factor: 11.205
Authors: Jianqing Lin; Tingting Zhan; Danielle Duffy; Jean Hoffman-Censits; Deborah Kilpatrick; Edouard J Trabulsi; Costas D Lallas; Inna Chervoneva; Kimberly Limentani; Brooke Kennedy; Sarah Kessler; Leonard Gomella; Emmanuel S Antonarakis; Michael A Carducci; Thomas Force; Wm Kevin Kelly Journal: Am J Cancer Ther Pharmacol Date: 2014-09-07
Authors: Christopher H Stuart; Ravi Singh; Thomas L Smith; Ralph D'Agostino; David Caudell; K C Balaji; William H Gmeiner Journal: Nanomedicine (Lond) Date: 2016-04-14 Impact factor: 5.307
Authors: Emmanuel S Antonarakis; Marianna L Zahurak; Jianqing Lin; Daniel Keizman; Michael A Carducci; Mario A Eisenberger Journal: Cancer Date: 2012-03-15 Impact factor: 6.860
Authors: Rachid Safi; Erik R Nelson; Satish K Chitneni; Katherine J Franz; Daniel J George; Michael R Zalutsky; Donald P McDonnell Journal: Cancer Res Date: 2014-10-15 Impact factor: 12.701
Authors: Ji Young Yoo; Jason Pradarelli; Amy Haseley; Jeffrey Wojton; Azeem Kaka; Anna Bratasz; Christopher A Alvarez-Breckenridge; Jun-Ge Yu; Kimerly Powell; Andrew P Mazar; Theodoros N Teknos; E Antonio Chiocca; Joseph C Glorioso; Matthew Old; Balveen Kaur Journal: Clin Cancer Res Date: 2012-07-02 Impact factor: 12.531