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Investigational New Drugs

, Volume 33, Issue 3, pp 679–690 | Cite as

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

  • A. Omlin
  • R. J. Jones
  • R. van der Noll
  • T. Satoh
  • M. Niwakawa
  • S. A. Smith
  • J. Graham
  • M. Ong
  • R. D. Finkelman
  • J. H. M. Schellens
  • A. Zivi
  • M. Crespo
  • R. Riisnaes
  • D. Nava-Rodrigues
  • M. D. Malone
  • C. Dive
  • R. Sloane
  • D. Moore
  • J. J. Alumkal
  • A. Dymond
  • P. A. Dickinson
  • M. Ranson
  • G. Clack
  • J. de Bono
  • T. Elliott
PHASE I STUDIES

Summary

Background AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). Methods In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. Results In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. Conclusion AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

Keywords

(5) Castration-resistant prostate cancer Phase I First-in-human AZD3514 Selective androgen receptor down-regulator 

Notes

Acknowledgments

Aurelius Omlin’s work is supported by a grant by the Swiss Cancer League (BIL KLS-02592-02-2010). Professor Johann de Bono is supported by The Prostate Cancer Foundation (Santa Monica); Prostate Cancer UK; Cancer Research UK and an Experimental Cancer Medical Centre Grant for Cancer Research UK and the UK Department of Health and a Biomedical Research Grant to the Royal Marsden NHS Foundation Trust. Robert Jones is supported by Cancer Research UK and an Experimental Cancer Medicine Centre Grant from Cancer Research UK and the Chief Scientist’s Office (Scotland). Malcolm Ranson was supported by Cancer Research UK and an Experimental Cancer Medical Centre Grant for Cancer Research UK and the UK Department of Health.

The authors thank the study participants, without whom this study would never have been accomplished, and Dr. Ken-ichi Tabata (Kitasato University School of Medicine) for participation in this study.

Conflict of interest

vdNR, JHMS, RR, N-R D, JJA, AZ, MC, MO, JG, CD, RS, DM, MN: no conflict of interest.

TE: Advisory role for Astellas, AstraZeneca, Janssen, Sanofi.

AO: Advisory role for Pfizer, Janssen, Bayer, Sanofi, Astellas, AstraZeneca.

RJJ: Consultancy for Janssen, Astellas, Sanofi, Dendreon; speaker honoraria for Astellas, Janssen, Sanofi, Ferring. Research funding from AstraZeneca, Janssen, Astellas, Medivation, Sanofi.

MR: Advisory role for AstraZeneca.

SAS, GC, PD, AD, MM, RDF: (1) AstraZeneca stock ownership; (2) AstraZeneca employee at the time of this study.

JDB: has received consulting fees and travel support from AstraZeneca, and grant support from AstraZeneca

TS: Speaking fees from Daiichi Sanko, AstraZeneca, Astellas, Janssen

None of the above mentioned conflicts of interest have affected the publication of this work.

Funding

This trial was sponsored by AstraZeneca.

Supplementary material

10637_2015_235_MOESM1_ESM.doc (3.3 mb)
ESM 1 (DOC 3356 kb)

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi: 10.3322/caac.20073 CrossRefPubMedGoogle Scholar
  2. 2.
    Attard G, Cooper CS, de Bono JS (2009) Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell 16(6):458–462. doi: 10.1016/j.ccr.2009.11.006 CrossRefPubMedGoogle Scholar
  3. 3.
    de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005. doi: 10.1056/NEJMoa1014618 CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368(2):138–148. doi: 10.1056/NEJMoa1209096 CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197. doi: 10.1056/NEJMoa1207506 CrossRefPubMedGoogle Scholar
  6. 6.
    Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. doi: 10.1056/NEJMoa1405095 PubMedCentralGoogle Scholar
  7. 7.
    Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN (2013) Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol: Off J Eur Soc Med Oncol ESMO. doi: 10.1093/annonc/mdt138 Google Scholar
  8. 8.
    Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, Albiges L, Attard G, Fizazi K, De Bono JS, Massard C (2013) Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol: Off J Eur Soc Med Oncol ESMO. doi: 10.1093/annonc/mdt136 Google Scholar
  9. 9.
    Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, Jentzmik F, Stoeckle M, Schrader M, Herrmann E, Cronauer MV (2013) Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. doi: 10.1016/j.eururo.2013.06.042 Google Scholar
  10. 10.
    Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R, Zivi A, Attard G, Chowdhury S, de Bono JS (2013) Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer. doi: 10.1016/j.ejca.2013.08.020 PubMedGoogle Scholar
  11. 11.
    Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, Chen Y, Greene GL, Shen Y, Sawyers CL (2013) Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2:e00499. doi: 10.7554/eLife.00499 CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM (2013) Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73(2):483–489. doi: 10.1158/0008-5472.CAN-12-3630 CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB (2011) Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res: Off J Am Assoc Cancer Res 17(18):5913–5925. doi: 10.1158/1078-0432.CCR-11-0728 CrossRefGoogle Scholar
  14. 14.
    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J (2014) AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371(11):1028–1038. doi: 10.1056/NEJMoa1315815 CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Loddick SA, Ross SJ, Thomason AG, Robinson DM, Walker GE, Dunkley TP, Brave SR, Broadbent N, Stratton NC, Trueman D, Mouchet E, Shaheen FS, Jacobs VN, Cumberbatch M, Wilson J, Jones RD, Bradbury RH, Rabow A, Gaughan L, Womack C, Barry ST, Robson CN, Critchlow SE, Wedge SR, Brooks AN (2013) AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. Mol Cancer Ther 12(9):1715–1727. doi: 10.1158/1535-7163.MCT-12-1174 CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, Hatter G, Hayter BR, Hill KJ, Howe NJ, Jones RD, Jude D, Lamont SG, Loddick SA, McFarland HL, Parveen Z, Rabow AA, Sharma-Singh G, Stratton NC, Thomason AG, Trueman D, Walker GE, Wells SL, Wilson J, Wood JM (2013) Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett 23(7):1945–1948. doi: 10.1016/j.bmcl.2013.02.056 CrossRefPubMedGoogle Scholar
  17. 17.
    Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol: Off J Am Soc Clin Oncol 26(7):1148–1159. doi: 10.1200/JCO.2007.12.4487 CrossRefGoogle Scholar
  18. 18.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi: 10.1016/j.ejca.2008.10.026 CrossRefPubMedGoogle Scholar
  19. 19.
    Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC (2008) Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol: Off J Am Soc Clin Oncol 26(2):190–195. doi: 10.1200/JCO.2007.12.7712 CrossRefGoogle Scholar
  20. 20.
    Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res: Off J Am Assoc Cancer Res 10(20):6897–6904. doi: 10.1158/1078-0432.CCR-04-0378 CrossRefGoogle Scholar
  21. 21.
    Yu Z, Cai C, Gao S, Simon NI, Shen HC, Balk SP (2014) Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor. Clin Cancer Res: Off J Am Assoc Cancer Res 20(15):4075–4085. doi: 10.1158/1078-0432.CCR-14-0292 CrossRefGoogle Scholar
  22. 22.
    Taplin ME, Chi K, Chu F, Cochran J, Edenfield W, Eisenberger M, Emmenegger U, Heath E, Hussain A, Koletsky A, Lipsitz D, Nordquist L, Pili R, Rettig M, Sartor O, Shore N, Dhillon R, Roberts J, Montgomery B (2014) Galeterone in 4 patient populations of men with CRPC: Results from ARMOR2. ESMO conference 2014, Madrid Abstract 757OGoogle Scholar
  23. 23.
    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Chen Y, Roeser JC, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Judith Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J (2014) Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 32:5s, 2014 (suppl; abstr 5001)Google Scholar
  24. 24.
    Cao B, Qi Y, Zhang G, Xu D, Zhan Y, Alvarez X, Guo Z, Fu X, Plymate SR, Sartor O, Zhang H, Dong Y (2014) Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5(6):1646–1656PubMedGoogle Scholar
  25. 25.
    Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, Yang YC, Tavakoli I, Haile S, Watt K, McEwan IJ, Plymate S, Andersen RJ, Sadar MD (2013) An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest 123(7):2948–2960. doi: 10.1172/JCI66398 CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Dalal K, Roshan-Moniri M, Sharma A, Li H, Ban F, Hessein M, Hsing M, Singh K, LeBlanc E, Dehm S, Guns ES, Cherkasov A, Rennie PS (2014) Selectively targeting the DNA binding domain of the androgen receptor as a prospective therapy for prostate cancer. J Biol Chem. doi: 10.1074/jbc.M114.553818 PubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • A. Omlin
    • 1
  • R. J. Jones
    • 2
  • R. van der Noll
    • 3
  • T. Satoh
    • 4
  • M. Niwakawa
    • 5
  • S. A. Smith
    • 6
  • J. Graham
    • 2
  • M. Ong
    • 1
  • R. D. Finkelman
    • 7
  • J. H. M. Schellens
    • 3
    • 8
  • A. Zivi
    • 1
  • M. Crespo
    • 1
  • R. Riisnaes
    • 1
  • D. Nava-Rodrigues
    • 1
  • M. D. Malone
    • 6
  • C. Dive
    • 11
  • R. Sloane
    • 11
  • D. Moore
    • 11
  • J. J. Alumkal
    • 9
  • A. Dymond
    • 6
  • P. A. Dickinson
    • 6
  • M. Ranson
    • 10
  • G. Clack
    • 6
  • J. de Bono
    • 1
  • T. Elliott
    • 10
  1. 1.Prostate Targeted Therapy Group and Drug Development UnitThe Royal Marsden NHS Foundation Trust and The Institute of Cancer ResearchSuttonUK
  2. 2.The Beatson West of Scotland Cancer CentreGlasgowUK
  3. 3.The Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Department of UrologyKitasato University School of MedicineSagamiharaJapan
  5. 5.Division of UrologyShizuoka Cancer Center HospitalShizuokaJapan
  6. 6.AstraZenecaMacclesfieldUK
  7. 7.AstraZenecaWilmingtonUSA
  8. 8.Utrecht Institute for Pharmaceutical Sciences (UIPS)UtrechtThe Netherlands
  9. 9.Knight Cancer Institute at Oregon Health & Science UniversityOregonUSA
  10. 10.The Christie NHS Foundation TrustManchesterUK
  11. 11.Cancer Research UK Manchester InstituteManchesterUK

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