Phase III Trial of Irinotecan and Gemcitabine Underway in Pancreatic Cancer

September 1, 2001

TAMPA, Florida-Phase II studies have shown that the combination of irinotecan (Camptosar) and gemcitabine (Gemzar) are well tolerated and active in advanced or metastatic pancreatic cancer, and this combination is now being tested in randomized phase II and phase III trials, said Caio Max S. Rocha Lima, MD. Dr. Rocha Lima is assistant professor of medicine at the University of South Florida’s H. Lee Moffitt Cancer Center in Tampa, Florida.

TAMPA, Florida—Phase II studies have shown that the combination of irinotecan (Camptosar) and gemcitabine (Gemzar) are well tolerated and active in advanced or metastatic pancreatic cancer, and this combination is now being tested in randomized phase II and phase III trials, said Caio Max S. Rocha Lima, MD. Dr. Rocha Lima is assistant professor of medicine at the University of South Florida’s H. Lee Moffitt Cancer Center in Tampa, Florida.

Dr. Rocha Lima said that two phase II trials have shown that irinotecan has single-agent activity in pancreatic cancer. A trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) included 34 patients who had advanced pancreatic cancer and no prior chemotherapy. They were treated on the European schedule of irinotecan at 350 mg/m² given over 30 minutes every 3 weeks. Dr. Rocha Lima said that in 32 evaluable patients there were 3 partial responses (PR, 9%) and 13 patients with stable disease (SD, 39%), for a response rate of around 10%. Median survival was 5.2 months. "This is in the same range as single-agent gemcitabine for pancreatic cancer," Dr. Rocha Lima said.

Japanese researchers did a similar phase II trial in 61 patients with advanced pancreatic cancer. Two regimens tested irinotecan 100 mg/m² weekly for 4 weeks on, 2 weeks off, or irinotecan 150 mg/m² every 2 weeks. Dr. Rocha Lima said that in 35 patients evaluable for response there were 4 PRs (11.4%).

"Preclinical data suggest synergistic interactions for the combination of irinotecan and gemcitabine," Dr. Rocha Lima said. "In the phase I trial we had three previously untreated pancreatic cancer patients, and there were partial responses in two of these patients. A third patient with metastatic adenocarcinoma of unknown primary with distribution of disease below the diaphragm and potentially another pancreatic cancer patient also had a durable PR."

Dr. Rocha Lima’s group then pursued a phase II trial that has been completed and submitted for publication. This trial included 45 patients with previously untreated advanced and/or metastatic pancreatic cancer. The treatment schema included gemcitabine 1,000 mg/m² over 30 minutes and irinotecan 100 mg/m² over 90 minutes, both on days 1 and 8. The cycle repeated every 21 days, as a 2 weeks on, 1 week off schedule. "Three fourths of the population had metastatic disease. Only three patients had prior radiation therapy and 5-FU," Dr. Rocha Lima said.

The combination produced 9 (20%) radiologically confirmed partial responses (CI, 7%-29%). Twenty-five (66%) of the patients with elevated CA19-9 levels at entry had a drop of at least 25%, and 31% had CA 19-9 decrease by more than 50%. Time to progression was 2.8 months, and 1-year survival was 27%.

Response rates were not affected by patient age, gender, extent of disease, or number of involved organ sites. Only 6.7% of patients had grade 3 diarrhea, and there was no grade 4 diarrhea. "The reason was probably the day 1 and day 8, every 21-day cycle," Dr. Rocha Lima said. "There was little nausea and vomiting (2.2% grade 3-4), and myelosuppression was acceptable."

Dr. Rocha Lima said that experience in this and related phase II trials led to development of a Cancer and Leukemia Group B (CALGB) randomized phase II trial of irinotecan and gemcitabine in advanced and metastatic pancreatic cancer (CALGB-89904) and to a phase III trial comparing irinotecan/gemcitabine to single-agent gemcitabine.

"The primary endpoint of the phase III trial is survival with follow-up up to 2 years, and we’re going to collect post-protocol cancer therapy information. We will wait until 310 deaths happen to analyze the overall results. The target accrual is 175 patients per arm, which will enable us to detect a 40% or greater improvement in survival," Dr. Rocha Lima said. "Current accrual is 224 patients, and we hope to close this study before the end of the year."