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

Jianqing Lin, Marianna Zahurak, Tomasz (Tom) Beer, Charles J. Ryan, George Wilding, Paul Mathew, Michael Morris, Jennifer A. Callahan, Gilad Gordon, Steven D. Reich, Michael A. Carducci, Emmanuel S. Antonarakis

    Research output: Contribution to journalArticle

    26 Citations (Scopus)

    Abstract

    Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-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.

    Original languageEnglish (US)
    Pages (from-to)581-588
    Number of pages8
    JournalUrologic Oncology: Seminars and Original Investigations
    Volume31
    Issue number5
    DOIs
    StatePublished - Jul 2013

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    Superoxide Dismutase
    Zinc
    Copper
    Prostatic Neoplasms
    Hormones
    Prostate-Specific Antigen
    Ceruloplasmin
    Angiogenesis Inhibitors
    Random Allocation
    Choline
    Disease-Free Survival
    tetrathiomolybdate
    Therapeutics
    Biomarkers
    Safety
    Serum
    Population

    Keywords

    • ATN-224
    • Phase II
    • Prostate cancer

    ASJC Scopus subject areas

    • Oncology
    • Urology

    Cite this

    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. / Lin, Jianqing; Zahurak, Marianna; Beer, Tomasz (Tom); Ryan, Charles J.; Wilding, George; Mathew, Paul; Morris, Michael; Callahan, Jennifer A.; Gordon, Gilad; Reich, Steven D.; Carducci, Michael A.; Antonarakis, Emmanuel S.

    In: Urologic Oncology: Seminars and Original Investigations, Vol. 31, No. 5, 07.2013, p. 581-588.

    Research output: Contribution to journalArticle

    Lin, Jianqing ; Zahurak, Marianna ; Beer, Tomasz (Tom) ; Ryan, Charles J. ; Wilding, George ; Mathew, Paul ; Morris, Michael ; Callahan, Jennifer A. ; Gordon, Gilad ; Reich, Steven D. ; Carducci, Michael A. ; Antonarakis, Emmanuel S. / 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. In: Urologic Oncology: Seminars and Original Investigations. 2013 ; Vol. 31, No. 5. pp. 581-588.
    @article{044330cedf2f479cb25a121f4752a15f,
    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-na{\"i}ve prostate cancer",
    abstract = "Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-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-na{\"i}ve 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.",
    keywords = "ATN-224, Phase II, Prostate cancer",
    author = "Jianqing Lin and Marianna Zahurak and Beer, {Tomasz (Tom)} and Ryan, {Charles J.} and George Wilding and Paul Mathew and Michael Morris and Callahan, {Jennifer A.} and Gilad Gordon and Reich, {Steven D.} and Carducci, {Michael A.} and Antonarakis, {Emmanuel S.}",
    year = "2013",
    month = "7",
    doi = "10.1016/j.urolonc.2011.04.009",
    language = "English (US)",
    volume = "31",
    pages = "581--588",
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    TY - JOUR

    T1 - 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

    AU - Lin, Jianqing

    AU - Zahurak, Marianna

    AU - Beer, Tomasz (Tom)

    AU - Ryan, Charles J.

    AU - Wilding, George

    AU - Mathew, Paul

    AU - Morris, Michael

    AU - Callahan, Jennifer A.

    AU - Gordon, Gilad

    AU - Reich, Steven D.

    AU - Carducci, Michael A.

    AU - Antonarakis, Emmanuel S.

    PY - 2013/7

    Y1 - 2013/7

    N2 - Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-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.

    AB - Objective: ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-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.

    KW - ATN-224

    KW - Phase II

    KW - Prostate cancer

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