A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation.
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.
Thiessen
Brian
B
BC Cancer Agency, Vancouver, Canada. bthiessen@bccancer.bc.ca
Stewart
Clinton
C
Tsao
Ming
M
Kamel-Reid
Suzanne
S
Schaiquevich
Paula
P
Mason
Warren
W
Easaw
Jacob
J
Belanger
Karl
K
Forsyth
Peter
P
McIntosh
Lynn
L
Eisenhauer
Elizabeth
E
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
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