Abstract CT405: A phase 1 study of neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel, followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in locally advanced pancreatic cancer
Authors: Park Haeseong , Poklepovic Andrew 
Published: May 2015

Abstract
Background:
A third of pancreatic tumors initially deemed borderline or unresectable at diagnosis are ultimately able to undergo resection after neoadjuvant therapy. Survival rates improve significantly when curative resection with negative margins is achieved.
Gemcitabine-based chemoradiation following combination chemotherapy is a common neoadjuvant regimen. Combination of gemcitabine and nab-paclitaxel is shown to be beneficial in metastatic disease, and is undergoing evaluation for use in neoadjuvant setting.
Sorafenib is shown to reduce activation of c-kit, ERK, and VEGFR2 while gemcitabine inhibits Akt phosphorylation, leading to the synergistic inhibition of cell proliferation and the induction of apoptosis. Vorinostat has also been shown to sensitize pancreatic cancer cell lines to gemcitabine by enhancing the pro-apoptotic actions of gemcitabine, as evidenced by increased levels of the cleaved form of PARP and caspase 3 activities.
Sorafenib and vorinostat kill carcinoma cells synergistically by activating CD95. Vorinostat appears to enhance tyrosine-phosphorylation of CD95 in a Src-dependent fashion, which also increases PDGFRβ inhibition by sorafenib. The combination also potently radiosensitizes pancreatic cancer cells in vivo by inducing cytosolic calcium, increasing reactive oxygen species and promoting CD95 activation. Full-dose radiation therapy with both agents has not been investigated in the clinical setting to date, and this represents a novel treatment modality appropriate for phase 1 study in a disease with limited treatment options.
Methods:
This is a phase 1 study using a traditional 3+3 dose-escalation design for the treatment combination dose escalation to determine appropriate phase 2 doses of sorafenib, vorinostat, and gemcitabine with radiation. Patients are treated with two cycles of combination chemotherapy with gemcitabine and nab-paclitaxel initially, followed by chemoradiation with the investigational agents with 50.4Gy of radiation. Patients will have locally advanced, non-metastatic pancreatic cancer with borderline resectable, unresectable, or node-positive disease, with ECOG performance status of 0 or 1, and preserved hepatic and endocrine pancreatic function with adequate bone marrow reserve by laboratory values. Patients who had prior radiation therapy, known intolerance to the agents, or other significant comorbidities such as poor cardiac function and prolonged QT interval are excluded. In correlative portion of the study, peripheral blood will be analyzed for circulating tumor cells, CD95 surface density and the degree of HDAC inhibition. Pretreatment biopsies obtained for diagnosis will be evaluated for CD95 expression, stromal density along with MCL1, SPARC, and PDGFR expression in tumor and desmoplastic stroma.
Citation Format: Haeseong Park, Andrew Poklepovic. A phase 1 study of neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel, followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in locally advanced pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT405. doi:10.1158/1538-7445.AM2014-CT405