Phase 1 pharmacogenetic and pharmacodynamic study of sorafenib with concurrent radiation therapy and gemcitabine in locally advanced unresectable pancreatic cancer

E. Gabriela Chiorean, Bryan P. Schneider, Fatih M. Akisik, Susan M. Perkins, Stephen Anderson, Cynthia S. Johnson, John Dewitt, Paul Helft, Romnee Clark, Erica L. Johnston, A. John Spittler, Jill Deluca, Guixue Bu, Safi Shahda, Patrick J. Loehrer, Kumar Sandrasegaran, Higinia R. Cardenes

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19 Scopus citations

Abstract

Purpose To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer. Methods and Materials Patients received gemcitabine 1000 mg/m2 intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m2 intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms). Results Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline Ktrans in responding patients. Conclusions Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.

Original languageEnglish (US)
Pages (from-to)284-291
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume89
Issue number2
DOIs
StatePublished - Jun 1 2014

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ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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