PMID- 21285985
OWN - NLM
STAT- MEDLINE
DCOM- 20110419
LR  - 20211020
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 104
IP  - 5
DP  - 2011 Mar 1
TI  - Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral 
      histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.
PG  - 756-62
LID - 10.1038/bjc.2011.13 [doi]
AB  - BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) 
      inhibitor selective for class I, II and IV histone deacetylases. Preclinical 
      evaluation of SB939 revealed a profile suggesting improved efficacy compared to 
      other HDAC inhibitors. This phase I study was carried out to determine the 
      safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as 
      pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily x 5 
      schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts 
      of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on 
      days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose 
      levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral 
      blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points 
      for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 
      patients received a total of 96 cycles of treatment. The maximal administered 
      dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The 
      most frequent non-hematologic adverse events (AEs) of at least possible 
      attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. 
      Pharmacokinetic analysis showed dose-proportional increases in AUC across the 
      doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear 
      relationship between AcH3 changes and dose level or anti-tumour response. 
      CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The 
      RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The 
      toxicities of SB939 are consistent with other HDAC inhibitors.
FAU - Razak, A R A
AU  - Razak AR
AD  - Drug Development Program, Department of Medical Oncology and Haematology, 
      Princess Margaret Hospital, Suite 5-718 (5th Floor), 610 University Avenue, 
      Toronto, Ontario, M5G 2M9 Canada.
FAU - Hotte, S J
AU  - Hotte SJ
FAU - Siu, L L
AU  - Siu LL
FAU - Chen, E X
AU  - Chen EX
FAU - Hirte, H W
AU  - Hirte HW
FAU - Powers, J
AU  - Powers J
FAU - Walsh, W
AU  - Walsh W
FAU - Stayner, L-A
AU  - Stayner LA
FAU - Laughlin, A
AU  - Laughlin A
FAU - Novotny-Diermayr, V
AU  - Novotny-Diermayr V
FAU - Zhu, J
AU  - Zhu J
FAU - Eisenhauer, E A
AU  - Eisenhauer EA
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20110201
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (SB939 compound)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Benzimidazoles/pharmacokinetics/*therapeutic use
MH  - Drug Administration Schedule
MH  - Fatigue/chemically induced
MH  - Female
MH  - Histone Deacetylase Inhibitors/*administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Nausea/chemically induced
MH  - Neoplasms/*drug therapy/metabolism
MH  - Vomiting/chemically induced
PMC - PMC3048208
EDAT- 2011/02/03 06:00
MHDA- 2011/04/20 06:00
PMCR- 2012/03/01
CRDT- 2011/02/03 06:00
PHST- 2011/02/03 06:00 [entrez]
PHST- 2011/02/03 06:00 [pubmed]
PHST- 2011/04/20 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - bjc201113 [pii]
AID - 10.1038/bjc.2011.13 [doi]
PST - ppublish
SO  - Br J Cancer. 2011 Mar 1;104(5):756-62. doi: 10.1038/bjc.2011.13. Epub 2011 Feb 1.