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A
phase I trial of single-agent PTK 787/ZK 222584 (PTK/ZK), an oral VEGFR tyrosine
kinase inhibitor, in patients with recurrent glioblastoma multiforme
W.
K. A. Yung, H. Friedman, C. Conrad, D. Reardon, J. Provenzale, E. Jackson, N.
Leeds, H. Serajuddin, D. Laurent, D. Reitsma
University
of Texas MD Anderson Cancer Center, Houston, TX; Duke University Medical Center,
Durham, NC; Novartis Pharmaceuticals, East Hanover; Schering AG, Berlin, Germany
PTK/ZK
is an oral, once-daily angiogenesis inhibitor that selectively targets VEGFR-1,
VEGFR-2, and VEGFR-3 tyrosine kinases.
Glioblastoma multiforme (GBM), characterized by vascular proliferation and
over-expression of VEGF, is an appropriate target tumor type to test
antiangiogenesis agents such as PTK/ZK.
This phase I trial in recurrent GBM used a 3+3 design wherein PTK/ZK was given
orally once daily starting at 150 mg/day and escalating to 500, 1,000, 1,500,
and 2,000 mg/day.
Extended cohorts were added at the 1,200- and 1,500-mg/day dose levels.
The primary endpoint was to determine the safety profile for PTK/ZK given in a
continuous daily schedule.
The secondary endpoint was to assess response to treatment, defined as decreases
in tumor vascular permeability (determined by dynamic contrast-enhanced {DCE}
and dynamic susceptibility change {DSC} MRI scanning).
To date, 43 patients have been enrolled at 150 mg/day (n = 3); 500 mg/day (n =
6); 1,000 mg/day (n = 6); 1,200 mg/day (n = 8); 1,500 mg/day (n = 14); and 2,000
mg/day (n = 6).
Dose-limiting toxicities observed include deep vein thrombosis and liver enzyme
elevation (1/6 patients at 1,000 mg/day), insomnia, cerebral edema (in 2/14
patients at 1,500 mg/day), and fatigue, nausea/vomiting (2/6 patients at 2,000
mg/day).
Other common grade 3/4 adverse events included ataxia and confusion.
Of 31 evaluable patients receiving > 4 weeks of treatment, 1 patient had a
partial response at 500 mg/day PTK/ZK, 20 patients (65%) achieved stable disease
as best response (7 patients remained stable for over 120 days), and 10 patients
(32%) experienced disease progression.
Dynamic MRI scanning showed decreases in vascular permeability (DCE) and
cerebral blood volume (DSC) at Day 2 and Day 30 post-treatment; decreases in
both parameters at Day 30 appeared dose-dependent.
In summary, PTK/ZK at 1,200 and 1,500 mg/day appears well tolerated in patients
with recurrent GBM.
More interestingly, the majority of patients achieved stable disease, and
correlative changes in vascular permeability and volume can be demonstrated by 2
different dynamic MRI scanning techniques.
© Copyright 2003
American Society of Clinical Oncology All rights
reserved worldwide
Source:
http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00103243-00_29-00A,00.asp?cat=CNS+Tumors&parent=
Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4
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