PMID- 22392572
OWN - NLM
STAT- MEDLINE
DCOM- 20120803
LR  - 20240322
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 69
IP  - 6
DP  - 2012 Jun
TI  - Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and 
      VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.
PG  - 1507-18
LID - 10.1007/s00280-012-1854-6 [doi]
AB  - PURPOSE: Vascular endothelial growth factor receptor (VEGFR) and epidermal growth 
      factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and 
      proliferation, making tyrosine kinase (TK) receptors logical targets for 
      treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and 
      VEGFR, in recurrent glioblastoma patients. METHODS: In this dose-escalation, 
      phase I study, patients with recurrent glioblastoma received AEE788 once daily in 
      28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing 
      anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing 
      anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by 
      surgical eligibility. Primary objectives were to determine dose-limiting toxicity 
      (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) 
      safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor 
      activity. RESULTS: Sixty-four glioblastoma patients were enrolled. Two Group A 
      patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, 
      therefore, the highest dose evaluated and dose limiting. One Group B patient 
      receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for 
      dose-expansion phase for Group A was 400 mg; additional patients received 250 mg 
      to assess the hepatotoxicity. Most frequently reported adverse events (AEs) 
      included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function 
      test elevations, were responsible for treatment discontinuation in 17% of 
      patients. AEE788 concentrations were reduced by EIACD. The best overall response 
      was stable disease (17%). CONCLUSIONS: Continuous, once-daily AEE788 was 
      associated with unacceptable toxicity and minimal activity for the treatment of 
      recurrent glioblastoma. The study was, therefore, discontinued prematurely.
FAU - Reardon, David A
AU  - Reardon DA
AD  - Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, 
      SW-460F, Boston, MA 02215, USA. David_Reardon@DFCI.harvard.edu
FAU - Conrad, Charles A
AU  - Conrad CA
FAU - Cloughesy, Timothy
AU  - Cloughesy T
FAU - Prados, Michael D
AU  - Prados MD
FAU - Friedman, Henry S
AU  - Friedman HS
FAU - Aldape, Kenneth D
AU  - Aldape KD
FAU - Mischel, Paul
AU  - Mischel P
FAU - Xia, Jane
AU  - Xia J
FAU - DiLea, Clifford
AU  - DiLea C
FAU - Huang, Jerry
AU  - Huang J
FAU - Mietlowski, William
AU  - Mietlowski W
FAU - Dugan, Margaret
AU  - Dugan M
FAU - Chen, Wei
AU  - Chen W
FAU - Yung, W K Alfred
AU  - Yung WK
LA  - eng
GR  - UL1 TR000124/TR/NCATS NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20120307
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - F9JLR95I3I (AEE 788)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Biomarkers, Tumor/analysis
MH  - Brain Neoplasms/*drug therapy
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Female
MH  - Glioblastoma/*drug therapy
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Purines/adverse effects/pharmacokinetics/*therapeutic use
MH  - Receptors, Vascular Endothelial Growth Factor/*antagonists & inhibitors
PMC - PMC4351868
MID - NIHMS666060
EDAT- 2012/03/07 06:00
MHDA- 2012/08/04 06:00
PMCR- 2015/03/06
CRDT- 2012/03/07 06:00
PHST- 2011/08/10 00:00 [received]
PHST- 2012/02/15 00:00 [accepted]
PHST- 2012/03/07 06:00 [entrez]
PHST- 2012/03/07 06:00 [pubmed]
PHST- 2012/08/04 06:00 [medline]
PHST- 2015/03/06 00:00 [pmc-release]
AID - 10.1007/s00280-012-1854-6 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2012 Jun;69(6):1507-18. doi: 
      10.1007/s00280-012-1854-6. Epub 2012 Mar 7.