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

Invest New Drugs. 2014 Oct;32(5):995-1004. doi: 10.1007/s10637-014-0101-x. Epub 2014 Apr 27.

Abstract

Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; 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 (t1/2) 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.

Trial registration: ClinicalTrials.gov NCT01352208.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • Aged
  • Aldo-Keto Reductase Family 1 Member C3
  • Androgen Antagonists / adverse effects
  • Androgen Antagonists / pharmacokinetics
  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Count
  • Dihydrotestosterone / blood
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Kallikreins / blood
  • Male
  • Middle Aged
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Testosterone / blood
  • Treatment Outcome

Substances

  • 1-(1-((5-methoxy-1H-indol-2-yl)carbonyl)piperidin-4-yl)-2-methylpropan-2-ol
  • Androgen Antagonists
  • Antineoplastic Agents
  • Indoles
  • Piperidines
  • Dihydrotestosterone
  • Testosterone
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • KLK3 protein, human
  • Kallikreins
  • Prostate-Specific Antigen

Associated data

  • ClinicalTrials.gov/NCT01352208