title: Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma.
abstract: OBJECTIVE
  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: Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, SW-460F, Boston, MA 02215, USA. David_Reardon@DFCI.harvard.edu
authors: David A
authors: DA
authors: Reardon
authors: Timothy
authors: T
authors: Cloughesy
authors: Jeremy
authors: J
authors: Rich
authors: W K
authors: WK
authors: Alfred Yung
authors: Lotus
authors: L
authors: Yung
authors: Clifford
authors: C
authors: DiLea
authors: Jerry
authors: J
authors: Huang
authors: Margaret
authors: M
authors: Dugan
authors: William
authors: W
authors: Mietlowski
authors: Andrea
authors: A
authors: Maes
authors: Charles
authors: C
authors: Conrad
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000068338:Everolimus; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011687:Purines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013921:Thrombocytopenia / Q000139:chemically induced*; D016896:Treatment Outcome
chemical_list: D011687:Purines; D000068338:Everolimus; C489254:AEE 788; D020123:Sirolimus