Exisulind/Camptosar: Phase I

MIAMI BEACH—The combination of exisulind (Aptosyn) and irinotecan (Camptosar) had no dose-limiting toxicity in a phase I trial presented at Molecular Targets and Cancer Therapeutics (abstract 295), a conference sponsored by the American Association for Cancer Research, National Cancer Institute, and European Organization for Research and Treatment of Cancer.

Exisulind, under development by Cell Pathways, Inc., is the first of the selective apoptotic antineoplastic drugs (or SAANDS). Exisulind inhibits cyclic GMP phosphodiesterase, which selectively induces apoptosis in colon tumor cells through the activation of protein kinase G (PKG).

The 14 patients had a variety of solid tumors, including colorectal, gastric, non-small-cell lung cancer, pancreas, and breast. All patients had received at least two prior regimens of chemotherapy. Patients received exisulind orally twice daily throughout the trial at doses ranging from 100 mg to 250 mg twice daily, and irinotecan on days 1 and 8, repeated every 21 days.

The drug combination was generally well tolerated at doses up to and including 250 mg of exisulind twice daily and 125 mg/m² of irinotecan, said principal investigator John L. Marshall MD, of the Lombardi Cancer Center of Georgetown University Medical Center.

He reported an 80% reduction in tumor in one patient with heavily pretreated gastric cancer and stable disease in another gastric cancer patient.

"We are extending our investigation to accrue additional patients who will receive escalating doses of irinotecan while maintaining Aptosyn at 250 mg twice daily," Dr. Marshall said. He was particularly encouraged that study participants experienced less severe diarrhea, a known dose-limiting toxicity of irinotecan, than anticipated.

Once the final dose is chosen, he said, 10 additional colorectal cancer patients will be accrued, and paired tumor biopsies will be performed to analyze the tumor for molecular changes in PKG and apoptosis pathways.