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Phase I Study of Oxaliplatin, Full-Dose Gemcitabine, and Concurrent Radiation Therapy in Pancreatic Cancer

Sameer P. Desai, Edgar Ben-Josef, Daniel P. Normolle, Isaac R. Francis, Joel K. Greenson, Diane M. Simeone, Alfred E. Chang, Lisa M. Colletti, Theodore S. Lawrence, Mark M. Zalupski

From the Division of Hematology/Oncology, Department of Radiation Oncology, Department of Radiology, Department of Pathology, and Department of Surgery, University of Michigan, Ann Arbor, MI

Address reprint requests to Mark M. Zalupski, MD, University of Michigan, 3-219 Cancer and Geriatrics Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0934; e-mail: Zalupski{at}umich.edu

Purpose: To determine a biweekly dose of oxaliplatin for combination with full-dose gemcitabine and concurrent radiation therapy (RT) in pancreatic cancer.

Patients and Methods: Patients with previously untreated pancreatic cancer received gemcitabine days 1, 8, and 15, and oxaliplatin days 1 and 15, repeated at 28-day intervals. RT (27 Gy in 1.8-Gy fractions) was administered during cycle 1. Dose escalation was guided using the time-to-event continuous reassessment method. Dose levels 1 to 4 included gemcitabine 1 g/m² intravenously (IV) during 30 minutes and oxaliplatin 40, 55, 70, or 85 mg/m² IV during 90 minutes, respectively; for dose levels 5 and 6, oxaliplatin dose remained 85 mg/m² but infusion time for gemcitabine 1 g/m² was increased to 65 or 100 minutes, respectively. The trial objective was to determine the dose level associated with dose-limiting toxicity (DLT) through cycle 2 in 20% of patients.

Results: Forty-four patients were enrolled (median age, 64 years; 27 men, 17 women) with resectable (n = 12), unresectable (n = 29), and metastatic (n = 3) pancreatic cancer. Ten DLTs occurred in nine patients, including grade 4 platelets (n = 4), decline in performance status (n = 2), GI bleeding (n = 2), and GI toxicity (n = 2). The estimated probability of DLT for dose level 3 was .21 (90% posterior probability interval [PI], .12 to .33); for dose level 4, the estimated probability was .24 (90% PI, .14 to .36).

Conclusion: The addition of oxaliplatin 85 mg/m² days 1 and 15 to full-dose gemcitabine and radiation therapy was well tolerated. On the basis of these results, a multi-institutional neoadjuvant phase II study in resectable pancreatic cancer is planned.

Supported in part by Sanofi-aventis.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and at the American Society of Clinical Oncology GI Symposium, January 26-28, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article

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