|
|
A phase I/II trial of
single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor,
in patients with recurrent glioblastoma multiforme (GBM)
C. Conrad, H. Friedman, D. Reardon, J. Provenzale, E. Jackson, H. Serajuddin,
D. Laurent, B. Chen, W. K. A. Yung
University of Texas M. D. Anderson Cancer Center, Houston, TX;
Duke University Medical Center, Durham, NC; Novartis Pharmaceuticals
Corporation, East Hanover, NJ; Schering AG, Berlin, Germany
Background. VEGF-mediated signaling pathways
may be critical to GBM neovascularization, and inhibition of VEGF pathways may
be an important therapeutic target in GBM.
PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known
vascular endothelial growth factor receptors (VEGFRs), and therefore blocks
signaling by VEGF-A, -B, -C, and -D.
Methods.
PTK/ZK was administered once daily as oral monotherapy starting at 150 mg/day
and escalating to 500, 1,000, 1,500, or 2,000 mg/day, with dose expansion at the
1,200- and 1,500-mg/day dose levels.
The primary objective was to determine the safety and tolerability of continuous
oral PTK/ZK in patients with recurrent GBM.
A secondary endpoint was response to treatment (defined as decreases in tumor
blood supply by dynamic contrast-enhanced [DCE] and dynamic
susceptibility-change [DSC] MRI) and tumor response.
Results. To
date, 55 patients have been treated at these dose levels: 150 mg/day (n = 3);
500 mg/day (n = 6); 1,000 mg/day (n = 6); 1,200 mg/day (n = 20); 1,500 mg/day (n
= 14); and 2,000 mg/day (n = 6).
Median age was 54 years (range, 21 - 73 years), and median prior number of
therapies was 4 (range, 1 - 12 therapies).
Dose-limiting toxicities included liver enzyme elevation and deep-vein
thrombosis (in 1/6 patients at 1,000 mg/day), insomnia or cerebral edema (in
2/14 patients at 1,500 mg/day), and fatigue or nausea/vomiting (in 2/6 patients
at 2,000 mg/day).
Among 47 evaluable patients, best responses were 2 (4%) partial responses, 31
(56%) stable disease, and 14 (25%) disease progression.
Median duration of stable disease was 12.1 weeks (95% CI = 9.9, 15.1
weeks).
DCE- and DSC-MRI scanning showed decreases in vascular permeability and cerebral
blood volume, respectively, at days 2 and 30 of treatment; the decreases in both
parameters at day 30 appeared dose dependent.
Further assessment by blinded reviewers is ongoing.
Conclusions.
PTK/ZK monotherapy at 1,200 and 1,500 mg/day was well tolerated in patients with
recurrent GBM, demonstrated changes in vascular permeability and blood volume,
and stabilized disease in the majority of patients.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-002298,00.asp
|
