title: A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.
abstract: 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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Gastrointestinal Oncology, Tampa, FL, USA.
authors: Gregory M
authors: GM
authors: Springett
authors: Department of Gastrointestinal Oncology, Tampa, FL, USA.
authors: Kazim
authors: K
authors: Husain
authors: Translational Research Core, Tampa, FL, USA.
authors: Anthony
authors: A
authors: Neuger
authors: Department of Cytopathology, Tampa, FL, USA.
authors: Barbara
authors: B
authors: Centeno
authors: Biostatistics Core, Tampa, FL, USA.
authors: Dung-Tsa
authors: DT
authors: Chen
authors: Department of Gastrointestinal Oncology, Tampa, FL, USA.
authors: Tai Z
authors: TZ
authors: Hutchinson
authors: Translational Research Core, Tampa, FL, USA.
authors: Richard M
authors: RM
authors: Lush
authors: Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors: Saïd
authors: S
authors: Sebti
authors: Department of Gastrointestinal Oncology, Tampa, FL, USA.
authors: Mokenge P
authors: MP
authors: Malafa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D011300:Preoperative Care; D016896:Treatment Outcome; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014810:Vitamin E; C082097:tocotrienol, delta
keywords: Chemoprevention; Pancreatic cancer; Presurgical trial; Tocotrienols; Vitamin E