European Data Support Benefit of Capecitabine/Irinotecan Regimen in Advanced Colorectal Cancer Patients

ORLANDO—Combination therapy with irinotecan (CPT-11, Camptosar) and capecitabine (Xeloda) has the potential to become a mainstay of treatment for colorectal cancer, according to David J. Kerr, MD, Rhodes Professor of Therapeutics and Clinical Pharmacology and director of the National Translational Cancer Research Network, Oxford University.

Both drugs are active as single agents, show minimal overlap in toxicities, and have been highly active in xenograft models.

Speaking at an industry-sponsored symposium held in conjunction with the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), Dr. Kerr discussed European phase I/II clinical trials of the combination and future phase III investigations.

Dr. Kerr is the lead investigator in an irinotecan/capecitabine study conducted in the United Kingdom and The Netherlands.

"The patients in the UK/Netherlands study may have received fluorouracil (5-FU)/leucovorin in an adjuvant setting, but they were chemotherapy naïve in terms of treatment for their advanced disease," Dr. Kerr said. "We saw responses at every dose level. Looking at the totality, there was a 52% overall response rate. So the combination maintained a very decent response rate, and we saw it all the way across."

Dose-limiting toxicities were diarrhea and neutropenia. The investigators chose a dosage level of 250 mg/m² bid of irinotecan and 1,000 mg/m² bid of capecitabine on days 1 to 14 for their upcoming phase III trial. At this dosage level, hand-foot syndrome was not a problem.

Confirmatory Studies

A multicenter French trial by J.P. Delord et al (abstract 397) confirmed the results of the UK/Netherlands study in a group of patients with a wide range of gastrointestinal tumors. Many of the 23 patients had been treated with first- and second-line chemotherapy, Dr. Kerr said, and represented a more conventionally refractory phase I trial grouping.

The French investigators defined the same recommended dose schedule of 250 mg/m² of irinotecan and 1,000 mg/m² bid of capecitabine, Dr. Kerr said.

Dose-limiting toxicities, as expected, were diarrhea and neutropenia.

"It is always very comforting in phase I when you see a convergence of efforts from different trial groups in defining the same regimen," he noted. "In terms of preliminary treatment results, again this was a very different patient population from ours, with multiple previous cycles for advanced disease. But even here, you had some responses and stable disease."

Italian Study

An Italian phase II trial of irinotecan and capecitabine compared irinotecan (300 mg/m² on day 1) and capecitabine (1,250 mg/m² bid on days 2 to 15) with a split dose of irinotecan (150 mg/m² on days 1 and 8) and capecitabine (1,250 mg/m² bid on days 2 to 15).

The investigators had to lower these doses because of unacceptable levels of grade 3-4 toxicities. The lower
doses were 240 mg/m² of irinotecan and 1,000 mg/m² bid of capecitabine, similar again to those defined in the UK/Netherlands trial.

Gastrointestinal toxicity was the most common side effect but was reduced with the lowered dosages. Dr. Kerr noted, however, that there was one treatment-related death due to dehydration from diarrhea and that the fractionated irinotecan dose appeared to be more toxic.

Total response rates were well maintained at around 50% for both arms of the trial—51% for arm 1 (full-dose irinotecan) and 45% for arm 2 (fractionated-dose irinotecan). These results again were similar to those of the UK/Netherlands trial.

"You get the feeling that there is quite a large emerging database pointing us toward what we feel is the right regimen," Dr. Kerr said. "Grade 3-4 toxicity rates are running about 10% to 15%, and response rates are running about 50%."

Upcoming Trials

Upcoming trials include a phase III trial (EORTC 40015) that will randomize close to 700 patients to the irinotecan/capecitabine regimen of the UK/Netherlands trial or the European gold-standard of biweekly infused 5-FU/leucovorin plus irinotecan at 180 mg/m² on day 1 every 14 days. Patients will be further randomized to additional celecoxib (Celebrex) (400 mg twice a day) or placebo.

QUASAR Group

In addition, the QUASAR (Quick and Simple and Reliable) group plans to enroll about 3,500 stage II/III colorectal cancer patients in a phase III adjuvant trial evaluating three treatment regimens:

• Bolus 5-FU (370 mg/m²) and leucovorin (20 mg/m²) weekly for 30 weeks or the same regimen delivered on days 1 to 5 every 28 days for 24 weeks.

• Capecitabine (1,000 mg/m² bid on days 1 to 14) plus irinotecan (250 mg/m² on day 1 every 21 days) for 12 weeks.

• Capecitabine (1,000 mg/m² bid on days 1 to 14) plus irinotecan (250 mg/m² on day 1 every 21 days) for 24 weeks.

"Capecitabine has the potential to replace IV 5-FU in combination therapy for colorectal cancer," Dr. Kerr concluded. "It is an effective and convenient—and scientifically logical—partner for irinotecan. The planned phase III trials should give us a much clearer definition of the role of this combination both in the management of advanced colorectal cancer and in the adjuvant setting."