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Trials With Irinotecan and Gemcitabine for Pancreatic Cancer Proceed to Phase III

Trials With Irinotecan and Gemcitabine for Pancreatic Cancer Proceed to Phase III

CHARLESTON, South Carolina—Irinotecan/gemcitabine combinations have looked sufficiently promising for pancreatic cancer in phase II trials that researchers are proceeding with randomized phase II and phase III studies, Caio Max S. Rocha Lima, MD, told those attending the Vanderbilt University Symposium. Dr. Rocha Lima is assistant professor of medicine in the Hematology Oncology Division at the Medical University of South Carolina in Charleston.

In the pivotal phase III trial where gemcitabine (Gemzar) was compared to fluorouracil (5-FU) in advanced and metastatic pancreatic cancer, the median survival (5.45 months for gemcitabine vs 4.1 months for 5-FU) and 1-year survival (18.5% for gemcitabine vs 2.0% for 5-FU) favored gemcitabine, despite the response rate of 5.4%.

A study by the European Organization for the Research and Treatment of Cancer (EORTC) of irinotecan (Camptosar) in 34 previously untreated patients with advanced pancreatic cancer reported median survival of 5.2 months, partial response (PR) in 3/32 evaluable patients (9%), and stable disease in 13/32 (39%). A study comparing two irinotecan regimens in 61 patients reported 11.4% PR, 10.3% response in the primary tumor, and 10.5% response in liver metastases.

"These studies showed that irinotecan had activity and a median survival in advanced/metastatic pancreatic cancer in the same range as single-agent gemcitabine," Dr. Rocha Lima said.

Refractory Malignancies

Preclinical work performed at the Medical University of South Carolina demonstrated dose dependent synergistic interactions between gemcitabine and irinotecan. This led to a phase I trial of irinotecan and gemcitabine in patients with refractory malignancies. "In this protocol both drugs are given on days 1 and 8 every 3 weeks. There is a potential 100% of the single-agent dose intensity of irinotecan when given weekly for 4 weeks every 6 weeks, and 80% of the single-dose intensity of gemcitabine when given weekly for 3 weeks every 4 weeks. This schedule avoids day 15 treatment," Dr. Rocha Lima said. The maximum tolerated dose was 100 mg/m2 of irinotecan and 1,000 mg/m2 of gemcitabine.

Among the first 18 evaluable patients in this phase I study, 3 experienced partial responses (2 of 3 previously treated for pancreatic cancer and 1 with metastatic adenocarcinoma of unknown primary) and 7 patients had stable disease.

Untreated Advanced Disease

These encouraging results led to design of a phase II trial of irinotecan and gemcitabine in patients with previously untreated advanced and metastatic pancreas cancer. Gemcitabine was given at 1,000 mg/m2 IV over 30 minutes on days 1 and 8. Irinotecan was given at 100 mg/m2 IV over 90 minutes on the same days. The cycle repeated every 3 weeks.

Dr. Rocha Lima reported preliminary results from this trial, which included 45 patients enrolled from 10 clinical centers. Median age was 60 years, and three patients had prior radiation therapy. All patients had at least 18 months follow-up.

Grade 4 toxicities included neutropenia (2.2%), thrombocytopenia(2.2%), and grade 3/4 vomiting (2.2%). Grade 3 toxicities included neutropenia (15.6%), diarrhea (6.7%), and thrombocytopenia (6.7%). "There were instances of grade 4 diarrhea," Dr. Rocha Lima said.

"A total of 202 cycles were administered, 89.8% at full doses of irinotecan, and 87.0% at full doses of gemcitabine. Full doses of both were given in 86.3% of cycles," Dr. Rocha Lima said.

The overall response rate was 18% (8 patients, 95% CI 7%-29%). Time to progression was 2.8 months (range 0.3-10.8), and 1-year survival was 27% . Dr. Rocha Lima said that 66% of patients (25) had decreases in CA19-9 levels, including 50% or greater decreases in 31% of patients (14).

Similar results, Dr. Rocha Lima noted, were seen in the Greek Cooperative Group for Pancreatic Cancer phase II study of 28 previously untreated patients with advanced or metastatic pancreatic cancer. The investigators reported PRs in 3 (15%) patients, stable disease in 8 (40%) patients, and a median time to progression of 30 weeks. This trial used a slightly different 3-week treatment schedule: gemcitabine 900 mg/m2 over 30 minutes IV on days 1 and 8, irinotecan 300 mg/m2 over 1 hour IV only on day 8.

"These phase II trials show that the combination is well tolerated and active in advanced or metastatic pancreatic cancer, and the results have led to randomized phase II and phase III trials," Dr. Rocha Lima said.

More Gemcitabine Combinations

Cancer and Leukemia Group B (CALGB) trial 89904 (Mathew Kulke, MD, and Margaret Tempero, MD, principal investigators) is an ongoing randomized phase II study, where four regimens are being studied:

  • gemcitabine 1,000 mg/m2, days 1, 8, 15 plus cisplatin 50 mg/m2 days 1, 15

  • a gemcitabine-fixed dose of 1,500 mg days 1, 8, 15, given as 10 mg/mL/min infusions over 150 min

  • gemcitabine 1,000 mg/m2 and docetaxel 400 mg/m2, both on days 1 and 8

  • gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2, both on days 1 and 8

Dr. Rocha Lima said that a phase III trial is also underway, comparing gemcitabine plus irinotecan to gemcitabine alone in 350 patients with locally advanced or metastatic pancreatic adenocarcinoma. Patients are randomized either to irinotecan 100 mg/m2 and gemcitabine 1,000 mg/m2 on days 1 and 8, repeating every 21 days, or to gemcitabine 1,000 mg/m2 weekly for 7 weeks, then on days 1, 8, and 15 every 28 days. Thus far, 104 patients have been enrolled.

"The primary endpoint is overall survival, and patients will be followed for up to 2 years. Secondary endpoints include time to progression, the overall response rate, time to confirmed response, duration of confirmed response, quality of life, and clinical benefit," Dr. Rocha Lima said.

Other Ongoing Trials

An ongoing phase II trial is looking at irinotecan/gemcitabine induction followed by concomitant gemcitabine/radiation for locally advanced pancreas cancer. A phase I trial involving solid tumors is studying two sequences of treatment: gemcitabine/irinotecan/cisplatin vs cisplatin/gemcitabine/irinotecan.

The phase I study has yielded several preliminary results.

  • One of four previously treated patients with pancreatic cancer had a pathologic complete remission on combination therapy.

  • One of two previously treated non-small-cell lung cancer patients had a partial response lasting for 8 cycles while the other had stable disease for six cycles.

  • One out of two previously treated colorectal cancer patients had a partial response lasting for 8 cycles while the other had stable disease for 4 cycles.

  • The single liver cancer patient has had stable disease for 8 cycles.

No apparent differences in toxicity have been observed between the two arms. Accrual to this trial continues.

 
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