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A first-in-human study of the oral selective androgen receptor down-regulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC).
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
Abstracts by A. G. Omlin:
A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma.Meeting: 2011 ASCO Annual Meeting | Abstract No: 3021
- Meeting: 2011 ASCO Annual Meeting | Abstract No: e19547