Abstract 1299: A phase I dose-escalation study of the safety, PK, and PD of vitamin E Δ-tocotrienol administered to subjects with resectable pancreatic exocrine neoplasia (2011)

Abstract Background: Δ-Tocotrienol, a natural Vitamin-E analog, which significantly inhibits the growth and survival of pancreatic neoplastic cells by inhibiting signal transduction pathways which are altered in pancreatic neoplasia such as those driven by mutant K-ras. It is hypothesized that this micronutrient may have a role in the prevention and treatment of subjects with pancreatic exocrine neoplasia for which no effective chemoprevention treatment strategy currently exists. We have initiated a phase 1 dose escalation trial of Δ-tocotrienol in order to determine the recommended phase 2 dose and to characterize the safety, tolerability and biologically effective dose. Methods: Eligible patients must have a resectable tumor or cyst arising from the exocrine pancreas for which they are about to undergo resection. This pre-surgical trial design was chosen to allow for acquisition of sufficient tissue for detailed analysis of Δ-tocotrienol's biological effect on signaling within the patient's tumor. Between October 2009 and August 2010, 12 subjects were accrued to the first 4 of 6 planned dose escalation levels. Three patients each were treated at a total of 200, 400, 600 and 800 mg/day divided into 2 doses. Each dose is taken with meals. Treatment was daily for 13-15 days. Blood samples were collected for pharmacokinetic (PK) analysis pre-dose on day 1 and then at 30 min., 1,2,4,6,8 and 12 hours after dosing. Additional samples were obtained pre-dose on day 8 and on the day of surgery. Toxicity assessments were on days 1, 8, the day of surgery and 3-6 weeks after surgery. Study endpoints are to determine 1) safety and tolerability, 2) plasma PK, 3) to evaluate pharmacodynamic markers of Δ-tocotrienol activity such as apoptisis, Ki-67 and p27 expression and 4) the distribution of Δ-tocotrienol in normal and neoplastic pancreatic tissue. Results: Thus far no drug related toxicities have been observed. No elevation in the post-operative complication rate has been observed. To date, the first 12 patients enrolled were evaluated for PK parameters. Interpatient variability within and amongst cohorts was observed. This may be due to varying light breakfast intake amongst subjects leading to differing absorption. The data has been modeled by non-compartmental analysis and the dose independent PK parameters are as follows: Terminal half-life – 3.4 (+/-1.7)hrs; Tmax – 4.9 (+/-2.0) hrs; Volume of Distribution – 229.9 (+/-169.6) L; Clearance – 39.1 (+/-22.5) L/hr. Conclusion: Δ-tocotrienol is well tolerated at doses up to 800 mg daily. Further dose escalation to 3200 mg/day is planned. PD biomarker analysis will be presented. This study demonstrates the feasibility of employing a pre-surgical trial design for determination of biologically effective doses to modulate signaling pathways in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2011-1299