PMID- 25920479
OWN - NLM
STAT- MEDLINE
DCOM- 20160216
LR  - 20240210
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 33
IP  - 3
DP  - 2015 Jun
TI  - 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.
PG  - 679-90
LID - 10.1007/s10637-015-0235-5 [doi]
AB  - 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.
FAU - Omlin, A
AU  - Omlin A
AD  - 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.
FAU - Jones, R J
AU  - Jones RJ
FAU - van der Noll, R
AU  - van der Noll R
FAU - Satoh, T
AU  - Satoh T
FAU - Niwakawa, M
AU  - Niwakawa M
FAU - Smith, S A
AU  - Smith SA
FAU - Graham, J
AU  - Graham J
FAU - Ong, M
AU  - Ong M
FAU - Finkelman, R D
AU  - Finkelman RD
FAU - Schellens, J H M
AU  - Schellens JH
FAU - Zivi, A
AU  - Zivi A
FAU - Crespo, M
AU  - Crespo M
FAU - Riisnaes, R
AU  - Riisnaes R
FAU - Nava-Rodrigues, D
AU  - Nava-Rodrigues D
FAU - Malone, M D
AU  - Malone MD
FAU - Dive, C
AU  - Dive C
FAU - Sloane, R
AU  - Sloane R
FAU - Moore, D
AU  - Moore D
FAU - Alumkal, J J
AU  - Alumkal JJ
FAU - Dymond, A
AU  - Dymond A
FAU - Dickinson, P A
AU  - Dickinson PA
FAU - Ranson, M
AU  - Ranson M
FAU - Clack, G
AU  - Clack G
FAU - de Bono, J
AU  - de Bono J
FAU - Elliott, T
AU  - Elliott T
LA  - eng
GR  - 19278/CRUK_/Cancer Research UK/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150430
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (AR protein, human)
RN  - 0 (AZD3514)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyridazines)
RN  - 0 (Receptors, Androgen)
RN  - EC 3.4.21.77 (Prostate-Specific Antigen)
SB  - IM
MH  - Administration, Oral
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - *Down-Regulation
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplastic Cells, Circulating/pathology
MH  - Prostate-Specific Antigen/metabolism
MH  - Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/*drug therapy
MH  - Pyridazines/administration & dosage/adverse effects/pharmacokinetics/*therapeutic 
      use
MH  - Radiography
MH  - Receptors, Androgen/*metabolism
EDAT- 2015/04/30 06:00
MHDA- 2016/02/18 06:00
CRDT- 2015/04/30 06:00
PHST- 2015/03/20 00:00 [received]
PHST- 2015/03/24 00:00 [accepted]
PHST- 2015/04/30 06:00 [entrez]
PHST- 2015/04/30 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
AID - 10.1007/s10637-015-0235-5 [doi]
PST - ppublish
SO  - Invest New Drugs. 2015 Jun;33(3):679-90. doi: 10.1007/s10637-015-0235-5. Epub 
      2015 Apr 30.