1. Academic Validation
  2. 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

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

  • Invest New Drugs. 2015 Jun;33(3):679-90. doi: 10.1007/s10637-015-0235-5.
A Omlin 1 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
Affiliations

Affiliation

  • 1 Prostate Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK.
Abstract

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.

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