Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.
OBJECTIVE
Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma.


METHODS
Patients (age > or = 18 to < or = 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months.


RESULTS
Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified.


CONCLUSIONS
Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.
Stupp
Roger
R
Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, Lausanne, Switzerland. roger.stupp@chuv.ch
Hegi
Monika E
ME
Neyns
Bart
B
Goldbrunner
Roland
R
Schlegel
Uwe
U
Clement
Paul M J
PM
Grabenbauer
Gerhard G
GG
Ochsenbein
Adrian F
AF
Simon
Matthias
M
Dietrich
Pierre-Yves
PY
Pietsch
Torsten
T
Hicking
Christine
C
Tonn
Joerg-Christian
JC
Diserens
Annie-Claire
AC
Pica
Alessia
A
Hermisson
Mirjam
M
Krueger
Stefan
S
Picard
Martin
M
Weller
Michael
M
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D001707:Biopsy, Needle; D001932:Brain Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D016001:Confidence Intervals; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D019635:Neurosurgical Procedures / Q000379:methods; D011336:Probability; D018714:Radiotherapy, Adjuvant; D020266:Radiotherapy, Conformal; D018570:Risk Assessment; D012910:Snake Venoms / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D012910:Snake Venoms; C422910:Cilengitide; D003606:Dacarbazine; D000077204:Temozolomide