PKC412+Gleevec: stability for some

Dr. Peter Reichardt was the first author of abstract no. 3016, a phase I/II trial of PKC412 in combination with Gleevec (imatinib mesylate) in patients with Gleevec-resistant GIST.

Secondary kinase mutations represent the most common mechanism of resistance in GIST patients progressing on Gleevec therapy. In-vitro (test-tube) data suggests that PKC412 has activity against many of these secondary mutations. In-vitro data also suggests that PKC412 and Gleevec show synergistic activity when used in combination.

Nineteen patients were given 200 mg. per day of PKC combined with Gleevec at doses ranging from 600 mg. to 1000 mg. Using this combination, Gleevec exposure (blood concentrations) decreased ~70 percent after one month on the combination, either due to enzyme induction (liver enzymes metabolize Gleevec), or protein binding interactions. At the same time, PKC levels increased ~twofold by day 28 over those that were expected from previous studies of PKC alone in AML. The study was therefore amended to allow for dose escalation of Gleevec and temporary dose reduction of PKC. This resulted in reduced toxicity and increased levels of Gleevec in the blood equal to 600 mg. of Gleevec alone.

Two of five patients evaluable for response had stable disease at four months. The authors concluded that the preliminary evidence indicates the combination of PKC412 and Gleevec for Gleevec-resistant GIST works, and the study is ongoing.