A first-in-human study of the oral selective androgen receptor down-regulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC).

Genitourinary (Nonprostate) Cancer
Session Type and Session Title: 
Clinical Science Symposium, The Future of Androgen Pathway Targeting in Prostate Cancer
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 4511)
Aurelius Gabriel Omlin, Robert J. Jones, Ruud van der Noll, Janet Graham, Michael Ong, Richard D. Finkelman, Jan HM Schellens, Andrea Zivi, Mateus Crespo, Glen Clack, Joshi J. Alumkal, Angela Dymond, Andrew Dickinson, Malcolm Ranson, Michael D Malone, Johann Sebastian De Bono, Tony Elliott; The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands; AstraZeneca Pharmaceuticals LP, Wilmington, DE; AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; Oregon Health & Science University Knight Cancer Institute, Portland, OR; AstraZeneca United Kingdom, Macclesfield, United Kingdom; AstraZeneca, Macclesfield, United Kingdom; Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom

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Abstract Disclosures


Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been 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 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) & G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395.

AZD3514 Dose (mg) N PSA decline ≥50% PSA decline ≥30% CTC conversion (N/Eval. pts; %) CTC decline ≥30%
(N/Eval. pts; %)
100 QD 5 0% 0% 0/1 (0%) 0/1 (0%)
250 QD 6a 0% 0% 1/5 (20%) 2/5 (40%)
500 QD 12 17% (2) 25% (3) 1/5 (20%) 3/5 (60%)
1000 QD 12 25% (3) 42% (5) 2/6 (33%) 5/6 (83%)
1000 BD 9a 25% (2) 38% (3) 1/3 (33%) 3/3 (100%)
2000 BD 5b NA NA 1/2 (50%) 2/2 (100%)

a1 pt. b All pts non evaluable.