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Gemcitabine and ISIS-2503 for Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma: A North Central Cancer Treatment Group Phase II Trial

From the Mayo Clinic and Mayo Foundation, Rochester, MN; Rapid City Regional Oncology Group, Rapid City; Sioux Community Cancer Consortium, Sioux Falls, SD; Meritcare Hospital CCOP, Fargo, ND; Wichita Community Clinical Oncology Program, Wichita, KS; Carle Cancer Center CCOP, Urbana, IL; Geisinger Clinic & Medical Center CCOP, Danville, PA; and Scottsdale CCOP, Scottsdale, AZ

Address reprint requests to Steven R. Alberts, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: alberts.steven{at}mayo.edu

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study.

METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m² intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks.

RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism.

CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.

This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-35101, CA-35195, CA-35448, CA-35415, CA-60276, CA-63848, CA-52352, CA-37417, CA-35103, and CA-63849 from the National Cancer Institute Department of Health and Human Services.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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