Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer (NEOPACHI-001)

• "Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
  In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.
  
  

• Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0. [ Time Frame: End of study follow-up (up to 2 years). ] [ Designated as safety issue: Yes ]
  Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).
  
  

• Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
  
• Effect of treatment on selected biomarkers in tumor resection specimens. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
  The objective is to identify within pre-therapeutic samples and surgical specimens several specific biomarkers involved (1) in the Hedgehog signalling pathway (GLI1, Sonic Hedgehog, Patched, Smoothened immunohistochemical patterns protein expression) and predicting response to anti-Hh therapy, (2) in the metabolization of gemcitabine (human equilibrative nucleoside transporter 1, deoxycytidine kinase) and predicting response to gemcitabine therapy, and (3) in the relative contribution of both anti-Hh therapy and gemcitabine therapy.
  
  

Pancreatic cancer is characterized by a high stromal density and is a hypoperfused tumor, precluding cytotoxics delivery to the epithelial tumoral compartment. There is thus a rationale for combining chemotherapy and antistromal drugs like Hedgehog inhibitors. Targeting the resectable primary tumor offers an appropriate setting to (1) evaluate and monitor early treatment effects on the tumor, (2) correlate dynamic imaging changes (perfusion and diffusion coefficient) to pre- and post-therapeutic tissue changes, (3) identify specific predictive biomarkers for the drugs used (i.e. gemcitabine transporters and Hedgehog pathway genes and proteins) and (4) assess if this early "dynamic and biomolecular response" can predict treatment benefit and patient outcome.