In a phase I-II study, 28 patients with advanced pancreatic adenocarcinoma were treated with cisplatin, high-dose cytarabine (ARA-C), and caffeine. This clinical trial was based on a nude mouse-human tumor xenograft model, which demonstrated synergism of these agents by inhibiting the growth of human pancreatic tumors. Toxic effects noted in the clinical study included myelosuppression, moderate nausea and vomiting, and mild renal insufficiency. No toxic effects were directly attributable to caffeine. Eighteen of the 28 patients had measurable or assessable disease; seven (39%) had partial responses (95% confidence intervals, 18%-63%). The median response duration was 6.2 months. Median survival for responders was 9.5 months with two patients surviving for more than 18 months. Median survival for all patients was 6.1 months. The combination of cisplatin, ARA-C, and caffeine is an active and tolerable regimen in the treatment of advanced pancreatic cancer. A phase III trial in which this regimen is being compared with standard therapy is in progress.