title: A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation.
abstract: OBJECTIVE
  We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome.
  
  
  METHODS
  Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry.
  
  
  RESULTS
  Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h(-1) m(-2) in comparison to 12.1 L h(-1) m(-2) in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results.
  
  
  CONCLUSIONS
  Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients.
authors.affiliation: BC Cancer Agency, Vancouver, Canada. bthiessen@bccancer.bc.ca
authors.forename: Brian
authors.initials: B
authors.lastname: Thiessen
authors.forename: Clinton
authors.initials: C
authors.lastname: Stewart
authors.forename: Ming
authors.initials: M
authors.lastname: Tsao
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
authors.forename: Warren
authors.initials: W
authors.lastname: Mason
authors.forename: Jacob
authors.initials: J
authors.lastname: Easaw
authors.forename: Karl
authors.initials: K
authors.lastname: Belanger
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.forename: Lynn
authors.initials: L
authors.lastname: McIntosh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D020641:Polymorphism, Single Nucleotide; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D066246:ErbB Receptors; D000077341:Lapatinib; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human