The researchers conducted a phase I study to identify the dose-limiting toxic effects of imatinib in patients with advanced soft tissue sarcomas, including gastrointestinal stromal tumors (GISTs).
They reported their findings in the latest issue of the Lancet.
GISTs are rare tumors of the gastrointestinal tract characterized by cell-surface expression of the tyrosine kinase KIT (CD117).
No effective systemic treatment is available.
Imatinib (STI571) inhibits a similar tyrosine kinase, BCR-ABL, leading to responses in chronic myeloid leukemia. It has also been shown to inhibit KIT.
A total of 40 patients (of whom 36 had GISTs) received imatinib. The doses given were 400 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice daily.
Toxic effects and hematological, biochemical, and radiological measurements were assessed during 8 weeks of follow-up.
|89% of symptomatic patients showed improvement with imatinib.
18Fluorodeoxy-glucose positron-emission tomography (PET) was used for response assessment in one center.
Five patients on 500 mg of imatinib twice daily were found to have dose-limiting toxic effects. These were severe nausea, vomiting, edema, or rash.
Inhibition of tumor growth was seen in all but 4 patients with GISTs. It resulted in 19 confirmed partial responses and 6 as yet unconfirmed partial responses of more than 20% regressions.
The researchers found that 24 of 27 clinically symptomatic patients showed improvement, and 29 of 36 were still on treatment after more than 9 months.
PET scan responses predicted subsequent computed tomography responses.
Professor Allan T. van Oosterom, of the Catholic University of Leuven, Belgium, said on behalf of fellow authors, "Imatinib at a dose of 400 mg twice daily is well tolerated during the first 8 weeks. Side-effects diminish with continuing treatment, and it has significant activity in patients with advanced GISTs."
"Our results provide evidence of a role for KIT in GISTs, and show the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers," he concluded.