Original article
Clinical–prostate
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

https://doi.org/10.1016/j.urolonc.2011.04.009Get rights and content

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.

Introduction

ATN-224 (choline tetrathiomolybdate) is an orally-available inorganic small molecule that inhibits the copper/zinc-dependent enzyme, superoxide dismutase 1 (Cu/Zn-SOD1), in endothelial and tumor cells [1], [2], [3]. It is a second-generation choline salt of a copper-binding compound tetrathiomolybdate, which has been shown to have efficacy as an antiangiogenic and antitumor agent in several murine models of cancer [4], [5], [6], [7], and has been tested as an antineoplastic agent in several clinical trials [8], [9].

SOD1 is an abundant cytosolic enzyme that dismutates superoxide (O2) into molecular oxygen and hydrogen peroxide (H2O2), a promiscuous second messenger essential to mitogen signaling. In the presence of ATN-224, the generation of H2O2 is suppressed through the inhibition of SOD1. Mitogen-induced kinase cascades are down-regulated leading to the inhibition of cell proliferation and/or apoptosis [3]. In addition, ATN-224 directly blocks the phosphorylation of the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors, and inhibits the translocation of the p65 subunit of nuclear factor κB (NF-κB) to the nucleus. These actions may potentially explain ATN224's antiangiogenic and apoptotic effects in tumor cells [4].

In addition to inhibiting SOD1, ATN-224 may also mediate antitumor effects by lowering systemic copper levels, which has been demonstrated to down-regulate the expression of numerous factors associated with tumor angiogenesis and progression, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, NF-κB, interleukin (IL)-6, and IL-8 [5], [10].

The antiangiogenic and antitumor activities of ATN-224 exhibit substantially different dose-responses with maximal antiangiogenic activity observed at doses that are approximately 10-fold lower than those required to inhibit tumor progression in tumor xenograft models. This is consistent with in vitro studies where ATN-224 inhibits the proliferation of endothelial cells in culture at concentrations that are 5- to 10-fold lower than those required to inhibit proliferation of the most highly ATN224-sensitive tumor cell lines [3].

We hypothesized that ATN-224 would have the potential to delay the progression of prostate cancer by mechanisms that include both antiangiogenic and antitumor effects. A prostate cancer population with presumed lower tumor burden was chosen to test this hypothesis, using PSA parameters to define the primary endpoint. Two distinct dose-levels were examined in this study. The high-dose group received 300 mg/day for 2 weeks followed by a titrated dose targeting ceruloplasmin (Cp) levels within the range of 5–15 ng/mL; the low-dose group received one-tenth of this dose (30 mg/d).

Section snippets

Eligibility

Patients with histologically confirmed adenocarcinoma of prostate with evidence of biochemical relapse after local therapy were eligible. Patients had no detectable disease as assessed by physical examination and radiographic measures (bone scan and CT of the abdomen/pelvis) within 4 weeks of study entry, and had a PSA doubling time (PSADT) of <12 months. PSADT was calculated using the natural log of 2 (0.693) divided by the slope of the relationship of log PSA against time (in months). The

Patient characteristics

Study participants were recruited at 6 centers from the PCCTC, namely Johns Hopkins Kimmel Cancer Center (Baltimore, MD), Oregon Health and Science University Knight Cancer Institute (Portland, OR), University of California San Francisco (San Francisco, CA), University of Wisconsin (Madison, WI), Memorial Sloan-Kettering Cancer Center (New York, NY), and M. D. Anderson Cancer Center (Houston, TX) between 12/2006 and 10/2008. Fifty-two patients were accrued but 1 patient did not receive any

Discussion

Biochemically-relapsed, non-metastatic, hormone-naïve prostate cancer represents a unique disease state [16], [17]. As many as 70,000 men per year in the United States fall into this category where a rising PSA is the only manifestation of illness [17], [18]. In men with PSA progression after local therapy, management options include surveillance, initiation of androgen deprivation therapy (ADT), dietary intervention, or clinical trial participation. A subset of patients may benefit from

Acknowledgments

The authors are grateful to the PCCTC Coordinating Center, Ting Wang, and all the research nurses and study coordinators.

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    This study was supported by funding from DOD W81XWH-09-1-0149, NCI 5P30CA006973.

    1

    Current address: Thomas Jefferson University, Philadelphia, PA.

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