EORTC Study 26041–22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with or without PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma—Results of a phase I trial

Abstract

2026 Background: VEGF is an essential mediator of angiogenesis. PTK/ZK is an orally available tyrosine kinase inhibitor of all known VEGF receptors. The EORTC has initiated a randomized phase I/II study in which PTK/ZK is being investigated in combination with standard RT and concomitant TMZ. The results of the safety and dose-finding run-in of the triple combination are reported here. Methods: Escalating doses of PTK/ZK QD continuously (using classical 3+3 design) and concomitant RT (60 Gy) and TMZ (75 mg/m2/day) during 6–7 weeks were to be administered. During the adjuvant/maintenance part, PTK/ZK was prescribed at a fixed standard dose of 750mg bid until progression. Dose limiting toxicities (DLT) were defined as >G3 toxicity occurring during RT + 2 weeks. Results: 18 GBM pts (M/F: 11/7, median age: 53 years, PS 0/1) have been enrolled and complete data for 15 pts are currently available. DL1 (500 mg): 4 pts; no DLT; DL2 (1000 mg): 6 pts: 1 DLT: G3, liver enzyme (ALAT) elevation and hyponatremia DL3 (1250 mg); 8 pts: 3 DLTs: G3 hepatic toxicity (2 pts) and G3 platelets and G4 neutrophil (1 pt). In a 4th patient a G3 diarrhea and hepatic DLT leading to PTK/ZK interruption was doubtful therefore it was decided to extend DL3. Frequently observed possibly related non-dose limiting drug adverse events of all grades included: abdominal pain/cramping (2 pts), ALAT/ASAT elevation (10 pts), creatinine elevation (2 pts), allergic reaction (2 pts), constipation (4 pts), diarrhea (5 pts), fatigue (11 pts), hypertension (6 pts), nausea (8 pts), vomiting (3 pts), and weight loss (4 pts). All toxicities were reversible. Conclusions: MTD has been reached at 1250 mg and the recommended dose of PTK/ZK in combination with RT and TMZ is 1000 mg/day. A randomized 3-arm phase II will start accrual in January 2007. Patients will receive standard TMZ/RT alone or with PTK/ZK starting at the beginning of radiotherapy or at the beginning of adjuvant therapy 4 weeks after the end of radiotherapy. [Table: see text]