PMID- 24131779
OWN - NLM
STAT- MEDLINE
DCOM- 20140926
LR  - 20211203
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 11
DP  - 2013 Oct 16
TI  - A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel 
      cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced 
      malignancies.
PG  - 259
LID - 10.1186/1479-5876-11-259 [doi]
AB  - BACKGROUND: Dinaciclib, a small-molecule, cyclin-dependent kinase inhibitor, 
      inhibits cell cycle progression and proliferation in various tumor cell lines in 
      vitro. We conducted an open-label, dose-escalation study to determine the safety, 
      tolerability, and bioactivity of dinaciclib in adults with advanced malignancies. 
      METHODS: Dinaciclib was administered starting at a dose of 0.33 mg/m2, as a 
      2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 
      28-day cycle), to determine the maximum administered dose (MAD), dose-limiting 
      toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. 
      Pharmacodynamics of dinaciclib were assessed using an ex vivo phytohemagglutinin 
      lymphocyte stimulation assay and immunohistochemistry staining for retinoblastoma 
      protein phosphorylation in skin biopsies. Evidence of antitumor activity was 
      assessed by sequential computed tomography imaging after every 2 treatment 
      cycles. RESULTS: Forty-eight subjects with solid tumors were treated. The MAD was 
      found to be 14 mg/m2 and the RP2D was determined to be 12 mg/m2; DLTs at the MAD 
      included orthostatic hypotension and elevated uric acid. Forty-seven (98%) 
      subjects reported adverse events (AEs) across all dose levels; the most common 
      AEs were nausea, anemia, decreased appetite, and fatigue. Dinaciclib administered 
      at the RP2D significantly inhibited lymphocyte proliferation, demonstrating a 
      pharmacodynamic effect. Ten subjects treated at a variety of doses achieved 
      prolonged stable disease for at least 4 treatment cycles. CONCLUSIONS: Dinaciclib 
      administered every week for 3 weeks (on days 1, 8, and 15 of a 28-day cycle) was 
      generally safe and well tolerated. Initial bioactivity and observed disease 
      stabilization support further evaluation of dinaciclib as a treatment option for 
      patients with advanced solid malignancies. TRIAL REGISTRATION: ClinicalTrials.gov 
      # NCT00871663.
FAU - Nemunaitis, John J
AU  - Nemunaitis JJ
AD  - Mary Crowley Cancer Research Centers, 1700 Pacific Avenue, Suite 1100, Dallas, TX 
      75201, USA. jnemunaitis@marycrowley.org.
FAU - Small, Karen A
AU  - Small KA
FAU - Kirschmeier, Paul
AU  - Kirschmeier P
FAU - Zhang, Da
AU  - Zhang D
FAU - Zhu, Yali
AU  - Zhu Y
FAU - Jou, Ying-Ming
AU  - Jou YM
FAU - Statkevich, Paul
AU  - Statkevich P
FAU - Yao, Siu-Long
AU  - Yao SL
FAU - Bannerji, Rajat
AU  - Bannerji R
LA  - eng
SI  - ClinicalTrials.gov/NCT00871663
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131016
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Cyclic N-Oxides)
RN  - 0 (Indolizines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridinium Compounds)
RN  - 4V8ECV0NBQ (dinaciclib)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Bridged Bicyclo Compounds, Heterocyclic/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Cyclic N-Oxides
MH  - Cyclin-Dependent Kinases/*antagonists & inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Indolizines
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Protein Kinase Inhibitors/adverse effects/pharmacokinetics/*therapeutic use
MH  - Pyridinium Compounds/adverse effects/pharmacokinetics/*therapeutic use
PMC - PMC3853718
EDAT- 2013/10/18 06:00
MHDA- 2014/09/27 06:00
PMCR- 2013/10/16
CRDT- 2013/10/18 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/09/24 00:00 [accepted]
PHST- 2013/10/18 06:00 [entrez]
PHST- 2013/10/18 06:00 [pubmed]
PHST- 2014/09/27 06:00 [medline]
PHST- 2013/10/16 00:00 [pmc-release]
AID - 1479-5876-11-259 [pii]
AID - 10.1186/1479-5876-11-259 [doi]
PST - epublish
SO  - J Transl Med. 2013 Oct 16;11:259. doi: 10.1186/1479-5876-11-259.