Trial Information

Phase I Study to Determine the Safety, Maximum Tolerated Dose, and Efficacy of Biweekly Oxaliplatin (Eloxatin) in Combination With Gemcitabine, Irinotecan, and 5-FU/Leucovorin (G-Flie) in Patients With Metastatic Solid Tumors or Adenocarcinoma of the Exocrine Pancreas

Pancreatic cancer is a major health problem in the United States and other developed
nations. Approximately thirty thousand cases of adenocarcinoma of the exocrine pancreas are
diagnosed in the United States each year. The majority of these tumors are unresectable at
the time of diagnosis. Unresectable and metastatic pancreatic cancer is often resistant to
treatment with response rates of less than 10% and median survival times of less than six
months associated with single agent chemotherapy. As of July 2003, gemcitabine remains the
standard of care palliative chemotherapy for patients with locally advanced or metastatic
pancreatic cancer. This drug has modest clinical activity. In a phase III randomized
controlled trial, 126 patients with advanced symptomatic pancreatic cancer were randomized
to receive either gemcitabine 1000 mg/m2 weekly x 7 followed by a week of rest and then
weekly x 3 every 4 weeks thereafter or fluorouracil 600 mg/m2 once weekly. The primary
endpoint was a score of clinical benefit response (CBR) derived from a composite of pain,
performance status, and weight. CBR was experienced by 24% of the gemcitabine treated
patients compared with 5% of 5-FU treated patients. The median survival durations were 5.65
and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively. The one
year survival was 18% for patients treated with gemcitabine compared to 2% for patients
treated with 5-FU. The effectiveness of gemcitabine may be improved by altering the standard
infusion schedule to a fixed dose rate. Gemcitabine requires intracellular phosphorylation
to form active di- and triphosphates, which is dose rate dependent. A phase II trial
randomized patients to either receive gemcitabine 2200 mg/m2 over a standard 30 minute
infusion or gemcitabine 1500 mg/m2 at a fixed rate of 10 mg/m2/min weekly x 3 every 4 weeks.
The fixed rate infusion of 10 mg/m2/min was associated with a higher response rate of 16.6%
v 2.7%, longer median survival 6.1 v 4.7 months, and a higher percentage of patients
surviving one year or more, 23% v 0%. The fixed rate infusion schedule was also associated
with significantly higher median gemcitabine triphosphate levels in peripheral circulating
mononuclear cells after each infusion.