Treatment > Antiangiogenesis · Lomustine · Temozolomide Clinical Trials

Meeting Abstract

A phase I trial of PTK787/ZK 222584 (PTK/ZK), an oral VEGF tyrosine kinase inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme (GBM)

D. Reardon, H. S. Friedman, W. K. A. Yung, M. Brada, C. Conrad, J. Provenzale, E. F. Jackson, H. Serajuddin, D. Laurent, D. Reitsma

Duke University Medical Center, Durham, NC; The University of Texas MD Anderson Cancer Center, Houston, TX; Royal Marsden NHS Trust, Surrey, UK; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Schering AG, Berlin, Germany

Vascular endothelial growth factor (VEGF)-mediated signaling is integral to GBM neovascularization and therefore an attractive therapeutic target.
PTK/ZK is an oral, once-daily inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinases.
The primary objective of this trial was to determine the safety profile and maximum tolerated dose (MTD) of PTK/ZK via continuous daily dosing in combination with either temozolomide (TMZ) or lomustine (CCNU) in patients with GBM.
Secondary objectives evaluated pharmacokinetic interactions and antitumor activity.
Using a 3+3 phase I dose-escalation design, the starting dose of PTK/ZK was 500 mg/day and escalated to 1,000 mg, 1,250 mg, and 1,500 mg/day in cohorts of 3 to 6 patients.
Concurrently, patients also received either TMZ (200 mg/m²/day for 5 days every 28 days) or CCNU (130 mg/m² every 6 weeks).
To date, 21 evaluable patients have been treated with PTK/ZK and TMZ at the 500 (n = 6), 1,000- (n = 6), 1,250- (n = 3), and 1,500-mg (n = 6) dose levels.
Only 1 dose-limiting toxicity (DLT) occurred (grade 3 dizziness) in a patient treated at the 1,500-mg dose level.
Best response includes 1 partial response (PR) at 1,250 mg/day, and stable disease (SD) in 3 of 6 patients treated at the 500- or 1,000-mg dose levels and 5 of 6 treated at the 1,500-mg dose level in combination with TMZ.
Eleven evaluable patients have been treated with PTK/ZK plus CCNU at the 500- (n = 5) and 1,000-mg (n = 6) dose levels.
Among these patients, DLTs included grade 3 fever/neutropenia in 1 patient each at the 500- and 1,000-mg levels, and grade 4 transaminase elevation in 1 patient treated at the 1,000-mg level, which may be related to CCNU.
The PTK/ZK dose level was reduced to 750 mg/day plus CCNU, and accrual is ongoing.
One patient achieved a PR at the 1,000-mg/day level in the CCNU arm and 3 patients at the 500-mg/day level and 4 at 1,000 mg/day had SD.
Continuous once daily dosing of oral PTK/ZK was well tolerated and demonstrated encouraging antitumor activity when combined with either TMZ or CCNU. Accrual is ongoing in both arms, and the respective MTDs have yet to be determined.

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