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
; 33(3): 679-90, 2015 Jun.
Article
em En
| MEDLINE
| ID: mdl-25920479
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridazinas
/
Receptores Androgênicos
/
Regulação para Baixo
/
Neoplasias de Próstata Resistentes à Castração
Tipo de estudo:
Clinical_trials
/
Diagnostic_studies
Limite:
Aged
/
Aged80
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Invest New Drugs
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido