title: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.
abstract: 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.
authors.affiliation: Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, Lausanne, Switzerland. roger.stupp@chuv.ch
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Roland
authors.initials: R
authors.lastname: Goldbrunner
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.forename: Paul M J
authors.initials: PM
authors.lastname: Clement
authors.forename: Gerhard G
authors.initials: GG
authors.lastname: Grabenbauer
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Christine
authors.initials: C
authors.lastname: Hicking
authors.forename: Joerg-Christian
authors.initials: JC
authors.lastname: Tonn
authors.forename: Annie-Claire
authors.initials: AC
authors.lastname: Diserens
authors.forename: Alessia
authors.initials: A
authors.lastname: Pica
authors.forename: Mirjam
authors.initials: M
authors.lastname: Hermisson
authors.forename: Stefan
authors.initials: S
authors.lastname: Krueger
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: 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
chemical_list: D018906:Antineoplastic Agents, Alkylating; D012910:Snake Venoms; C422910:Cilengitide; D003606:Dacarbazine; D000077204:Temozolomide