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Background Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. Methods Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). Findings In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. Interpretation VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer., Highlights • Vitamin E δ-tocotrienol is the bioactive form of one of the natural vitamin E with activity against cancer cells • Vitamin E δ-tocotrienol is safe in patients up to 3200 mg • Vitamin E δ-tocotrienol selectively kills pancreatic tumor cells when compared with normal cells at 400, 600, and 800 mg/day • The biomarker effect of vitamin E δ-tocotrienol suggest significant anticancer activity in patients, justifying further study Vitamin E has been an intriguing vitamin to humans for its potential to promote human health. However, large-scale research with vitamin E to prevent cancer has had mixed results. Because recent laboratory studies have shown that the form of vitamin E used in previous interventions to reduce cancer risk have not been the active tocotrienol form of vitamin E, there is a question as to whether the lack of vitamin activity is due to the use of inactive forms of vitamin E in clinical trials. Based on our laboratory data, which showed that the vitamin E δ-tocotrienol (VEDT) form of vitamin E was active against pancreatic cancer, we tested the ability of VEDT to kill pancreatic tumor cells in patients using a window-of-opportunity design, with measurement of apoptosis as an intermediate endpoint. We found that VEDT was well tolerated at up to 3200 mg when taken for 2 weeks before surgery. We also found that, at doses of 400 to 800 mg, VEDT selectively killed pancreatic tumor cells.