A Phase 2 Trial of Glufosfamide in Combination With Gemcitabine in Chemotherapy-Naive Pancreatic Adenocarcinoma

Objectives: A dose-escalation study of glufosfamide plus gemcitabine showed that the combination could be administered safely at full doses. The purpose of this phase II study was to evaluate the safety and efficacy of this combination in chemotherapy-naive pancreatic adenocarcinoma. Methods: Eligible patients had metastatic and/or locally advanced pancreatic adenocarcinoma, Karnofsky performance status >= 70, creatinine clearance (CrCL) >= 60 mL/min, and acceptable organ function. Patients received glufosfamide 4500 mg/m(2) intravenous on day 1 and gemcitabine 1000 mg/m2 intravenous on Days 1, 8, and 15 of every 28-day cycle. The primary end point was response rate. Results: Twenty-nine patients were enrolled; 14 male, median age 58 years. Twenty-three (79%) patients had distant metastases. Median cycles on treatment was 4 (range: 1-18+). Of 28, 5 (18%; 95% CI: 6%-37%) patients had a confirmed partial response (median duration: 8.4 months) and 1 had an unconfirmed partial response. Eleven patients (39%) had stable disease. Median progression-free survival was 3.7 months, median overall survival was 6 months, and 1-year survival was 32%. Grade 3/4 neutropenia occurred in 23 (79%) patients and grade 3/4 thrombocytopenia in 10 (34%) patients. The CrCL fell below 60 mL/min in 10 of 27 (37%) patients. Renal failure occurred in 4 patients. Decrease in CrCL was correlated with glufosfamide and isophosphoramide mustard pharmacokinetic area under the curve. Conclusions: The combination of glufosfamide plus gemcitabine is active in pancreatic cancer; however, hematologic and renal toxicity were pronounced. Alternative dosing of glufosfamide plus gemcitabine should be explored.