A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia

Abstract

BackgroundVitamin 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.MethodsPatients 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).FindingsIn 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.InterpretationVEDT 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.

Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites

“…Previous studies assessing the pharmacokinetics have utilized a mixture of different isoforms of tocotrienols rather than a single pure form of tocotrienol [3, 4, 13]. We had recently reported the results of a phase I trial in 25 patients with resectable pancreatic cancer who received VEDT at escalating doses (200 mg to 3200 mg) for 14 days prior to surgical resection [23]. Similar to this study, no dose-limiting toxicities were observed.…”

“…Furthermore, VEDT has been demonstrated to augment the activity of gemcitabine in pancreatic cancer [11]. In the recently conducted neoadjuvant trial in patients with pancreatic cancer, we demonstrated that administration of VEDT induced apoptosis in neoplastic cells as measured by increase in caspase-3 levels [23]. …”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…Vitamin E δ-tocotrienol, a natural vitamin E from plants, exhibits chemopreventive effects in preclinical KRAS transgenic mouse models via induction of apoptosis [102]. In a phase I safety trial, Vitamin E δ-tocotrienol is well tolerated and induces apoptosis in patients [102]. All in all, lycopene and vitamins are potent chemopreventive drugs without side effects.…”

“…Vitamin E has 2 structurally similar compounds, α-, β-, γ-and δ-tocopherols and α-, β-, γ-and δ-tocotrienols [101,102]. Tocotrienols with their anti-oxidative, proapoptotic and other anti-cancer effects like inhibition of epithelial mesenchymal transition, VEGF, the induction of anti-tumour immunity and the anti-cancer stem cell effects are superior to tocopherols in their chemopreventive impact shown in cells [101,103].…”

“…Tocotrienols with their anti-oxidative, proapoptotic and other anti-cancer effects like inhibition of epithelial mesenchymal transition, VEGF, the induction of anti-tumour immunity and the anti-cancer stem cell effects are superior to tocopherols in their chemopreventive impact shown in cells [101,103]. Vitamin E δ-tocotrienol, a natural vitamin E from plants, exhibits chemopreventive effects in preclinical KRAS transgenic mouse models via induction of apoptosis [102]. In a phase I safety trial, Vitamin E δ-tocotrienol is well tolerated and induces apoptosis in patients [102].…”