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A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs) resistant to imatinib mesylate.

9531 Background: PTK787/ZK222584 (PTK/ZK) is a novel, oral selective inhibitor of certain receptor tyrosine kinases that may be important in the molecular pathogenesis of GIST (KIT, PDGFRs, VEGFR-1 and VEGFR-2). The efficacy and safety of PTK/ZK are not known in the treatment of imatinib resistant GIST.


METHODS
Pts who had histologically diagnosed, metastatic GIST that had progressed after at least 4 weeks of treatment with imatinib were eligible. Prior therapy with KDR inhibitor therapy was not allowed. PTK/ZK was administered orally 1,250 mg once daily until treatment failure. No concomitant systemic cancer treatments were allowed. Treatment response was monitored at 4 to 8 wk intervals and evaluated using the RECIST criteria. Adverse events (AE) were scored using the NCI/NIH Common Toxicity Criteria v. 2.0. A total of 15 pts were planned to be accrued as a 2-stage procedure. The highest prior imatinib dose: 400 mg, n=1; 600 mg, n=2; 800 mg, n=11; 1,000 mg, n=1. Prior response to imatinib: PR, n=8; SD, n=5; PD, n=1; unknown, n=1.


RESULTS
All 15 pts (M 12, F 3) enrolled were eligible. Two (13%) pts achieved PR, 8 (53%) had SD for 3 months or longer, and 5 progressed. The clinical benefit rate (PR+SD) was 67% (95% CI, 38% to 86%). The duration of the 2 PRs was 95 + and 225+ days and 8 SDs from 93+ to 346+ days. All PRs and SDs are ongoing to date. The median time to treatment failure (TTTF) has not been reached. PTK/ZK was well tolerated. The most frequently recorded AEs were dizziness (n=6), nausea/vomiting (n=6), abdominal pain/abdominal pain upper (n=4) and asthenia (n=4). All recorded AEs were either of grade 1 or 2 except for 2 events (grade 4 hypercalcemia, n=1; grade 4 pain, n=1).


CONCLUSIONS
PTK787/ZK222584 showed signs of activity in this series of GIST patients who progressed during imatinib treatment. The dose of 1,250 mg o.d. is generally well tolerated. [Table: see text].