Irinotecan Every 2 Weeks With Capecitabine Is Well Tolerated

MANHASSET, New York—Early results from a phase I trial at North Shore University Hospital, Manhasset, New York, found irinotecan (CPT-11, Camptosar) with capecitabine (Xeloda) to be well tolerated by patients with inoperable or metastatic solid tumors who had failed standard therapy or had no therapy options, according to an abstract published at the American Society of Clinical Oncology annual meeting (abstract 2127).

"This is one of several trials that are looking at Xeloda combinations," said Daniel R. Budman, MD, professor of medicine, New York University School of Medicine. "The advantages of Xeloda are that it offers continuous exposure and concentrates in the tumor."

Researchers designed the trial to incorporate recent preclinical evidence indicating that irinotecan upregulates thymidine phosphorylase, a critical enzyme in capecitabine activation and tumor targeting. Dosages and scheduling were based on xenograft models showing synergism when irinotecan is given first with a 24-hour delay before starting capecitabine.

"This is the closest trial to the xenograft mouse data, which comes from Drs. S. Cao and Y. Rustum of Roswell Park Cancer Institute. They showed curative potential if you give irinotecan on day 1 then wait 24 hours before using capecitabine," Dr. Budman said.

Patients with inoperable or metastatic solid tumors who had failed standard therapy or did not have a therapy option were enrolled. Eligibility criteria include performance scores of 0 to 2, age 18 or older, normal organ function, and no prior treatment with fluorouracil or irinotecan.

Enrollment

The trial has enrolled 16 patients to date, 8 male and 8 female. They range in age from 40 to 76 years. Thirteen had received prior chemotherapy, and four radiation therapy.

All patients received an intravenous infusion of irinotecan 100 mg/m² on day 1 and every 2 weeks. Patients in four cohorts took different dosages of capecitabine on days 2 through 8, every 2 weeks.

Three patients received capecitabine 500 mg/m² bid for a total of eight cycles (range, 1 to 6). Four patients were given capecitabine 750 mg/m² bid for a total of 17 cycles (range, 1 to 12). Six patients received capecitabine 1,000 mg/m² bid for a total of 15 cycles (range, 1 to 4).

At the time of the ASCO conference, researchers had given three patients capecitabine 1,250 mg/m² bid for a total of four cycles. This portion of the trial is ongoing. Patients did not receive prophylactic antidiarrheal agents. The trial continues to accrue patients to the 1,250 mg/m² bid dose regimen.

Investigators evaluated patients weekly in the absence of toxicities. No grade 3 or higher toxicities were observed in patients receiving capecitabine 500 mg/m² bid. At 750 mg/m² bid, researchers reported grade 3 or higher fatigue and nausea and vomiting in one patient who was noncompliant. A patient in the 1,000 mg/m² bid cohort experienced grade 3 or higher diarrhea, vomiting, and vertigo. And at 1,250 mg/m² bid, there was one report of grade 3 or higher abdominal pain.

The maximum treatment dose has not been reached in the phase I trial. Activity was seen at all dose levels. Researchers expect the maximum tolerated dose to be at or above irinotecan 100 mg/m² every 2 weeks with capecitabine 1,250 mg/m² bid on days 2 through 8. They have noted leukopenia at day 8, and feel gastrointestinal toxicity is manageable. "It is a well tolerated regimen, but this is only a phase I trial, so although we have seen some activity, we cannot say at this time that it is any better than anything else. It’s going to have to go to phase II, and, if really good, phase III. And we’re working on that," he said.