Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma.
BACKGROUND
This study determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.


METHODS
All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.


RESULTS
A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.


CONCLUSIONS
Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet-derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity.
Reardon
David A
DA
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA. reard003@mc.duke.edu
Egorin
Merrill J
MJ
Desjardins
Annick
A
Vredenburgh
James J
JJ
Beumer
Jan H
JH
Lagattuta
Theodore F
TF
Gururangan
Sridharan
S
Herndon
James E
JE
Salvado
August J
AJ
Friedman
Henry S
HS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068877:Imatinib Mesylate; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence; D016896:Treatment Outcome
D001549:Benzamides; D010793:Phthalazines; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; C404768:vatalanib; D000068877:Imatinib Mesylate; D006918:Hydroxyurea