A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas.
The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. jraizer@nmff.org
Jeffrey J
JJ
Raizer
Lauren E
LE
Abrey
Andrew B
AB
Lassman
Susan M
SM
Chang
Kathleen R
KR
Lamborn
John G
JG
Kuhn
W K Alfred
WK
Yung
Mark R
MR
Gilbert
Kenneth D
KD
Aldape
Patrick Y
PY
Wen
Howard A
HA
Fine
Minesh
M
Mehta
Lisa M
LM
Deangelis
Frank
F
Lieberman
Timothy F
TF
Cloughesy
H Ian
HI
Robins
Janet
J
Dancey
Michael D
MD
Prados
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008577:Meningeal Neoplasms / Q000188:drug therapy*; D008579:Meningioma / Q000188:drug therapy*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride