Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma.

Abstract

PURPOSE:

Treating glioblastoma through the simultaneous inhibition of multiple transduction pathways may prove more effective than single-pathway inhibition. We evaluated the safety, biologic activity, and pharmacokinetic profile of oral AEE788, a selective inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), plus oral RAD001, a mammalian target of rapamycin inhibitor, in glioblastoma patients.

METHODS:

This phase IB/II, open-label, multicenter, 2-arm, dose-escalation study enrolled adult glioblastoma patients at first or second recurrence/relapse. Primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of AEE788 combined with RAD001. Secondary objectives included determining the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of the combination.

RESULTS:

Sixteen patients were enrolled (AEE788 200 mg/day + RAD001 5 mg/day, 2 patients; AEE788 150 mg/day + RAD001 5 mg every other day [qod], 14); all patients discontinued the study most commonly because of disease progression. Four patients experienced DLT (AEE788 200 mg/day + RAD001 5 mg/day, 1 patient; AEE788 150 mg/day + RAD001 5 mg qod, 3). Both patients receiving AEE788 (200 mg/day) plus RAD001 (5 mg/day) experienced clinically significant thrombocytopenia requiring a dose reduction/interruption. AEE788 appeared to inhibit the metabolism of RAD001. The study was terminated prematurely before an MTD was determined because of safety findings in other studies evaluating AEE788 monotherapy.

CONCLUSIONS:

The coadministration of AEE788 and RAD001 in glioblastoma patients caused a clinically significant thrombocytopenia and a higher-than-expected RAD001 area under the curve concentration when dosed at 200 and 5 mg/day, respectively. After a dose reduction to AEE788 (150 mg/day) and RAD001 (5 mg qod), the combination appeared to be better tolerated.

• Authors: David A Reardon, Timothy Cloughesy, Jeremy Rich, W K Alfred Yung, Lotus Yung, Clifford DiLea, Jerry Huang, Margaret Dugan, William Mietlowski, Andrea Maes, Charles Conrad
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 1 Pg. 281-7 (Jan 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 21984222 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Purines
• Everolimus
• AEE 788
• Sirolimus

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Dose-Response Relationship, Drug
• Drug Interactions
• Everolimus
• Female
• Glioblastoma (drug therapy, pathology)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Purines (administration & dosage)
• Sirolimus (administration & dosage, analogs & derivatives)
• Thrombocytopenia (chemically induced)
• Treatment Outcome