Treatment > Antiangiogenesis

Meeting Abstract

A phase I trial of PTK787/ZK 222584 (PTK/ZK), a novel oral VEGFR TK inhibitor in recurrent glioblastoma

W.K. A Yung, Henry Friedman, E Jackson, J Provenzale, N Leeds, C Conrad, A Walker, A Henry, J Huang, D Laurent, M Dugan

UT MD Anderson Cancer Ctr, Houston, TX; Duke University Medical Ctr, Durham, NC; Novartis, E. Hanover, NJ; Schering AG, Berlin, Germany

PTK 787 is a novel oral small molecule antiangiogenesis agent.
It acts as a tyrosine kinase competitive inhibitor of the ATP binding site of the VEGF receptors.
It is also active against the PDGFR and c-Kit tyrosine kinase receptors.
Glioblastoma multiforme, characterized by vascular proliferation and over-expression of VEGF, is one of the most appropriate tumor types to test the biological effect of an anti VEGFR agent like PTK/ZK.
A phase I trial is in progress, in which patients with recurrent glioblastoma are treated with PTK/ZK on a continuous once daily dosing schedule starting at a dose of 500 mg per day escalating to 1000 mg, 1500 mg and 2000 mg per day.
3 patients were enrolled into each cohort according to a conventional phase I (3+3) design.
The primary end-point is to determine the safety and tolerability of PTK/ZK, while response to therapy is a secondary end-point.
Biological activity was determined with dynamic MRI scanning to assess the vascular permeability and tumor blood flow pre and during treatment.
To date 20 patients (pts) have been enrolled into the study (3 pts at 500 mg, 6 at 1000 mg, and 11 at 1500mg).
Grade 3 toxicities seen so far include DVT, pedal edema and elevated liver enzyme.
Of the 15 pts evaluable for response, 10 have failed after 1 cycle, 3 are stable in 2nd cycle of treatment, 1 was stable but failed after 3 cycles, 1 achieved PR and progressed after cycle #6.
More interestingly, dynamic MRI scanning shows decrease of vascular permeability immediately after first dose of treatment.
In the patient who achieved PR, the vascular permeability index decreased and remained lower than the baseline at follow up.
In summary, PTK/ZK at 1500 mg per day appears to be well tolerated in patients with recurrent glioblastoma.
Most excitingly, early response has been seen, and dynamic MRI scanning is capable of demonstrating physiological or biological effect of blocking VEGFR/VEGF activity.