A multi-center phase II study of arsenic trioxide (AT) in patients (Pts) with advanced pancreatic cancer (PC) refractory to gemcitabine

Abstract

4114 Background: There is no effective chemotherapy for PC pts who progress after treatment with Gemcitabine. Novel agents with unique mechanisms of action are clearly needed for this chemo-refractory disease. Arsenicals have been used in Chinese folk remedies for 2000 years. In vitro, AT has a potent anti-proliferative effect against PC. AT is thought to induce apoptosis in PC cell lines by activating the caspase cascade via the mitochondrial pathway and by decreasing Bcl-2 expression. Thus, we postulated that AT might have activity in PC pts. Methods: Eligibility required advanced PC that had progressed on a gemcitabine-containing regimen, measurable disease, ECOG PS 0–1, normal organ function, QTc < 500ms, no evidence of NYHA functional class III or IV heart failure. AT 0.3 mg/kg was administered intravenously over 1 hour daily for 5 consecutive days every 28 days. CT scans were obtained every 2 cycles. Results: 13 pts enrolled 12/02–11/03 at 5 centers. 21 cycles were administered (median 2; range 1–2). There were no grade 3/4 hematologic toxicities; grade 1/2 anemia occurred in 50% pts and grade 1/2 leukopenia in 25%. Two pts developed Grade 4 small bowel obstruction attributed to their cancer. Grade 3 toxicities included fatigue 17%, thrombosis 17%, nausea/vomiting 8%, diarrhea 8%, constipation 8%, hypocalcemia 8%, and elevated liver transaminases 8%. Only 1 pt developed prolongation of the QTc interval (Grade 1). There were no objective responses. Median progression-free survival was 7 weeks (95% CI, 5.4–8.1). Median survival was 16.6 weeks (95% CI, 6.9–29.7). Conclusions: Despite in vitro activity in PC cell lines, AT has no clinical activity in PC pts who develop progressive disease after gemcitabine. Multi-center phase II trials are feasible in this patient population, though they are challenging due to the rapid clinical deterioration that occurs following front-line chemotherapy in PC. Trials of novel agents are urgently needed. Supported by NCI grant N01-CM-17102. No significant financial relationships to disclose.