title: EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma.
abstract: BACKGROUND
  Glioblastoma is a highly vascularised tumour with a high expression of both vascular endothelial growth factor (VEGF) and VEGFR. PTK787/ZK222584 (PTK/ZK, vatalanib), a multiple VEGF receptor inhibitor, blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation.
  
  
  METHODS
  The study was designed as an open-label, phase I/II study. A classic 3+3 design was selected. PTK/ZK was added to standard concomitant and adjuvant treatment, beginning in the morning of day 1 of radiotherapy (RT), and given continuously until disease progression or toxicity. PTK/ZK doses started from 500 mg with subsequent escalations to 1000 and 1250 mg/d. Adjuvant or maintenance PTK after the end of radiochemotherapy was given at a previously established dose of 750 mg twice daily continuously with TMZ at the standard adjuvant dose.
  
  
  RESULTS
  Twenty patients were enrolled. Dose-limiting toxicities at a once daily dose of 1250 mg were grade 3 diarrhoea (n=1), grade 3 ALT increase (n=2), and myelosuppression with grade 4 thrombocytopenia and neutropenia (n=1). The recommended dose of PTK/ZK in combination with radiotherapy and temozolomide (TMZ) is 1000 mg once a day. This treatment is safe and well tolerated.
  
  
  CONCLUSIONS
  In our phase I study once daily administration of up to 1000 mg of PTK/ZK in conjunction with concomitant temozolomide and radiotherapy was feasible and safe. Prolonged administration of this oral agent is manageable. The planned randomised phase II trial was discontinued right at its onset due to industry decision not to further develop this agent.
authors: Bellaria and Maggiore Hospitals, Bologna, Department of Medical Oncology, Italy. alba.brandes@yahoo.it
authors: Alba A
authors: AA
authors: Brandes
authors: Roger
authors: R
authors: Stupp
authors: Peter
authors: P
authors: Hau
authors: Denis
authors: D
authors: Lacombe
authors: Thierry
authors: T
authors: Gorlia
authors: Alicia
authors: A
authors: Tosoni
authors: Renè O
authors: RO
authors: Mirimanoff
authors: Johan M
authors: JM
authors: Kros
authors: Martin J
authors: MJ
authors: van den Bent
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D018714:Radiotherapy, Adjuvant; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D003606:Dacarbazine; D000077204:Temozolomide