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Investigational New Drugs

, Volume 32, Issue 5, pp 995–1004 | Cite as

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

  • Yohann Loriot
  • Karim Fizazi
  • Robert J. Jones
  • Jan Van den Brande
  • Rhoda L. Molife
  • Aurelius Omlin
  • Nicholas D. James
  • Edwina Baskin-Bey
  • Marten Heeringa
  • Benoit Baron
  • Gertjan M. Holtkamp
  • Taoufik Ouatas
  • Johann S. De Bono
PHASE II STUDIES

Summary

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.

Keywords

17beta-hydroxysteroid dehydrogenase type 5 AKR1C3 Androgen deprivation therapy Androgen synthesis Castration-resistant prostate cancer Testosterone 

Notes

Acknowledgments

The authors are grateful Ismar Healthcare NV for medical writing assistance funded by Astellas Pharma Europe BV. The study was funded by Astellas Pharma Europe BV.

Ethical approval

Independent ethics committee (IEC) approval was obtained at each study site. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, Good Clinical Practice, International Conference on Harmonisation guidelines and applicable laws and regulations of the involved institutions and countries. All patients included in the study signed an IEC-approved written informed consent before the conduct of any study procedures and after a full explanation of the study to the patient by a study investigator.

Conflicts of interest statement

Y Loriot received a research grant from Astellas and is principal investigator of the PREVAIL study at Institute Gustave Roussy.

K Fizazi participated to advisory boards for Astellas-Medivation, Janssen-Cougar, Orion, Sanofi-Aventis, Bayer and Amgen.

RJ Jones has received speaker’s honoraria and has acted as a consultant to Astellas. He also received research funding from Astellas.

J Van den Brande has no conflicts of interest.

LR Molife has no conflicts of interest.

A Omlin has no conflicts of interest.

ND James has no conflicts of interest.

JS De Bono served as a paid advisor to Astellas.

E Baskin-Bey, M Heeringa, B Baron, T Ouatas and GM Holtkamp are employees of Astellas Pharma Europe BV.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yohann Loriot
    • 1
    • 7
  • Karim Fizazi
    • 1
  • Robert J. Jones
    • 2
  • Jan Van den Brande
    • 3
  • Rhoda L. Molife
    • 4
  • Aurelius Omlin
    • 4
  • Nicholas D. James
    • 5
  • Edwina Baskin-Bey
    • 6
  • Marten Heeringa
    • 6
  • Benoit Baron
    • 6
  • Gertjan M. Holtkamp
    • 6
  • Taoufik Ouatas
    • 6
  • Johann S. De Bono
    • 4
  1. 1.Institute Gustave Roussy, Department of Cancer MedicineUniversity of Paris SudVillejuifFrance
  2. 2.Beatson West of Scotland Cancer CentreUniversity of GlasgowGlasgowUK
  3. 3.University Hospital AntwerpEdegemBelgium
  4. 4.Drug Development Unit, The Royal Marsden NHS Foundation Trust/Institute of Cancer Research (ICR)SuttonUK
  5. 5.School of Cancer SciencesUniversity of BirminghamBirminghamUK
  6. 6.Astellas Pharma Europe BVLeidenNetherlands
  7. 7.Department of Cancer Medicine and Department of Early Phase Clinical Trials (DITEP)Gustave Roussy, Cancer Campus, Grand Paris, University of ParisVillejuifFrance

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