Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma.
OBJECTIVE
Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ).


METHODS
A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs.


RESULTS
Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT.


CONCLUSIONS
Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.
Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, MA 02115, USA.
Jan
J
Drappatz
Andrew D
AD
Norden
Eric T
ET
Wong
Lisa M
LM
Doherty
Debra C
DC
Lafrankie
Abigail
A
Ciampa
Santosh
S
Kesari
Christine
C
Sceppa
Mary
M
Gerard
Phuong
P
Phan
David
D
Schiff
Tracy T
TT
Batchelor
Keith L
KL
Ligon
Geoffrey
G
Young
Alona
A
Muzikansky
Stephanie E
SE
Weiss
Patrick Y
PY
Wen
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004238:Diverticulitis / Q000139:chemically induced; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000139:chemically induced; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D010880:Piperidines; D011799:Quinazolines; D003606:Dacarbazine; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077204:Temozolomide; C452423:vandetanib