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Title
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Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer : multi-centre phase I/II study
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Author
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Abstract
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| Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 beta-hydroxysteroid dehydrogenase type 5 (17 beta HSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models. Material and methods: This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. Results: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t(1/2)) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. Conclusions: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity. |
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Language
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English
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Source (journal)
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Investigational new drugs. - Boston, Mass.
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Publication
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Boston, Mass.
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2014
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ISSN
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0167-6997
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DOI
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10.1007/S10637-014-0101-X
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Volume/pages
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32
:5
(2014)
, p. 995-1004
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ISI
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000342411500021
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Pubmed ID
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24771350
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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