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

Brandes, Alba A.; Stupp, Roger; Hau, Peter; Lacombe, Denis; Gorlia, Thierry; Tosoni, Alicia; Mirimanoff, Renè O.; Kros, Johan M.; van den Bent, Martin J.

doi:10.1016/j.ejca.2009.10.029

« Previous Next »European Journal of Cancer
Volume 46, Issue 2 , Pages 348-354, January 2010

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

Alba A. Brandes
- Bellaria and Maggiore Hospitals, Bologna, Department of Medical Oncology, Italy
- Corresponding author: Address: Medical Oncology, Bellaria and Maggiore Hospitals, Azienda ASL Bologna, Via Altura 3, Bologna, Italy. Tel.: +39 0516225101; fax: +39 0516225057.
Roger Stupp
- Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
Peter Hau
- Department of Neurology, University of Regensburg, Germany
Denis Lacombe
- EORTC – European Organization for Research and Treatment of Cancer Data Center, Bruxelles, Belgium
Thierry Gorlia
- EORTC – European Organization for Research and Treatment of Cancer Data Center, Bruxelles, Belgium
Alicia Tosoni
- Bellaria and Maggiore Hospitals, Bologna, Department of Medical Oncology, Italy
Renè O. Mirimanoff
- Department of Radiation Oncology, Lausanne, Switzerland
Johan M. Kros
- Department of Pathology, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
Martin J. van den Bent
- Department of Neuro-Oncology, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

Received 3 September 2009; received in revised form 22 October 2009; accepted 29 October 2009. published online 30 November 2009.

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.

Patients and 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 500mg with subsequent escalations to 1000 and 1250mg/d. Adjuvant or maintenance PTK after the end of radiochemotherapy was given at a previously established dose of 750mg twice daily continuously with TMZ at the standard adjuvant dose.

Results

Twenty patients were enrolled. Dose-limiting toxicities at a once daily dose of 1250mg 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 1000mg once a day. This treatment is safe and well tolerated.

Conclusion

In our phase I study once daily administration of up to 1000mg 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.

Keywords: Glioblastoma, Radiotherapy, Temozolomide, PTK/ZK, Phase I