A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

Gastrointestinal Stromal Tumor

Completed

1

Age of Trial (yrs)

Gleevec-resistant

KIT/PDGFRA inhibitor

Block KIT + Block related tumor signal paths

Specifically GIST and only GIST

Novartis

Oral

This phase I/II trial is completed.
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.