Potential Advantages of Oral Irinotecan Defined in Phase I Studies

ROCHESTER, Minnesota—According to Richard M. Goldberg, MD, the potential advantages of oral irinotecan include prolonged blood levels, less toxicity, greater convenience, and reduced cost. Interestingly, more complete responses and sustained remissions were associated with oral irinotecan vs IV administration in mice with CX-1 colon cancer xenografts. Dr. Goldberg is chair of gastrointestinal oncology research at the Mayo Clinic in Rochester, Minnesota.

Pharmacology studies in mice showed that oral irinotecan was rapidly absorbed, with SN-38 detected within 5 minutes of dosing. "Absolute oral bioavailability was 21%, and the molar ratio of the SN-38 metabolite to irinotecan was three times higher after oral than after intravenous doses. This may be a consequence of the activity of gut carboxylesterases," Dr. Goldberg said.

Alternative Formulations

Irinotecan has also been studied as a prolonged infusion given daily for 5 days for 2 consecutive weeks. Dose-limiting toxicities were diarrhea and neutropenia, and the maximum tolerated dose (MTD) on this schedule was 22 mg/m²/d.

"Dr. Mace Rothenberg also tried intravenous irinotecan given orally," Dr. Goldberg said. "The taste was a problem, and he finally settled on IV solution mixed with CranGrape juice given on days 1 to 5 every 3 weeks." Twenty-eight patients were treated with this regimen, and the MTD was 50 mg/m²/d. Dose-limiting toxicities were diarrhea and neutropenia. Irinotecan peaked in 1 to 2 hours, and SN-38 peaked in 2 to 4 hours.

Powder Filled Capsules

More easily used oral formulations were subsequently developed including powder-filled capsules and a semi-solid matrix. "These have less variable bioavailability than the IV form taken orally, and the capsule has a better shelf life," Dr. Goldberg said.

Powder-filled capsules were tested in a phase I trial in 19 patients. Data submitted for presentation at the 2001 annual meeting of the American Society of Clinical Oncology (ASCO), describe a series of patients treated with the capsules daily for 14 days every 3 weeks. Dose-limiting toxicities were nausea, vomiting, and diarrhea. There was no neutropenia. Dr. Goldberg said that half-life calculations were precluded by the fact that plasma irinotecan and metabolites were measurable for only 6 to 10 hours. "We think that the phase II dose is likely to be 30 mg/m²/d," he said.

Twenty-three patients have been treated in a phase I trial of irinotecan powder-filled capsules given daily for 5 days every 3 weeks. Dr. Goldberg said that the MTD was 50 mg/m² and that dose-limiting toxicities at 60 mg/m² were nausea, vomiting, diarrhea, and febrile neutropenia. There were no objective tumor responses.

Data from a European phase I study that used a daily ´ 5 schedule are also expected to be presented at ASCO. Results included partial responses in 2 of 47 patients, both in melanomas.

Dr. Goldberg said that data from a recent US phase I trial of capsules given for 14 days, repeating every 3 weeks, showed no responses in 24 treated patients. The MTD was 30 mg/m², and dose-limiting toxicity was grade 3 nausea.

"This points up certain differences in mice vs men," Dr. Goldberg said. "In mice the lactone form predominates, there is a high tumor/blood ratio with oral irinotecan, and irinotecan exists as the carboxylate or open salt. Salts cause toxicity, while lactones have antitumor activity. In man, high concentrations of carboxylesterases in the GI tract promote presystemic conversion to SN-38. Low pH in the GI tract favors the lactone form."

During the discussion period, Langdon Miller, MD, of Pharmacia Oncology in Peapack, New Jersey, said the company has moved from the powder-filled capsules used in most of these studies to the semi-solid matrix formulation to limit the risk that workers will be exposed to aerosolized irinotecan powder, which is potentially mutagenic.