Abstract | PURPOSE: 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.
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Authors | David A Reardon, Charles A Conrad, Timothy Cloughesy, Michael D Prados, Henry S Friedman, Kenneth D Aldape, Paul Mischel, Jane Xia, Clifford DiLea, Jerry Huang, William Mietlowski, Margaret Dugan, Wei Chen, W K Alfred Yung |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 69
Issue 6
Pg. 1507-18
(Jun 2012)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 22392572
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Biomarkers, Tumor
- Protein Kinase Inhibitors
- Purines
- ErbB Receptors
- Receptors, Vascular Endothelial Growth Factor
- AEE 788
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Topics |
- Adult
- Aged
- Biomarkers, Tumor
(analysis)
- Brain Neoplasms
(drug therapy)
- ErbB Receptors
(antagonists & inhibitors)
- Female
- Glioblastoma
(drug therapy)
- Humans
- Male
- Middle Aged
- Neoplasm Recurrence, Local
(drug therapy)
- Protein Kinase Inhibitors
(therapeutic use)
- Purines
(adverse effects, pharmacokinetics, therapeutic use)
- Receptors, Vascular Endothelial Growth Factor
(antagonists & inhibitors)
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