Thema: News: PTK 787/ZK 222584 - oral angiogenesis inhibitor
News: PTK 787/ZK 222584 - oral angiogenesis inhibitor
Karen[a]
08.06.2004 21:53:48
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).
Abstract No: 1512
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Charles Conrad, MD
Session: Central Nervous System Tumors
Abstract No: 1512
Author(s): 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.
Event: 2004 ASCO Annual Meeting
Presenter: Charles Conrad, MD
Session: Central Nervous System Tumors
Karen[a]
