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

EBioMedicine. 2015 Nov 14;2(12):1987-95. doi: 10.1016/j.ebiom.2015.11.025. eCollection 2015 Dec.

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).

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.

Keywords: Chemoprevention; Pancreatic cancer; Presurgical trial; Tocotrienols; Vitamin E.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Biomarkers
  • Carcinoma, Pancreatic Ductal / diagnosis
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / diagnosis
  • Pancreatic Neoplasms / drug therapy*
  • Preoperative Care*
  • Treatment Outcome
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology
  • Vitamin E / therapeutic use

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Vitamin E
  • tocotrienol, delta

Associated data

  • ClinicalTrials.gov/NCT00985777