Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer (NEOPACHI-001)
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers and is considered as a sanctuary, resistant to most of the drugs used. Identification of new molecular targets involved in its pathogenesis is urgently needed and required both proper and innovative efficacy assessment.
This proof-of-concept trial is studying the "dynamic" tumor response after the administration of a short course (4 weeks) neoadjuvant combination of gemcitabine and a Hedgehog inhibitor (Vismodegib) before surgery in patients with operable pancreatic cancer.
Pancreatic Adenocarcinoma Resectable
Procedure: Neoadjuvant chemotherapy
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Evaluation of Tumoral Perfusion Modification by Dynamic Imaging After Neoadjuvant Chemotherapy Combining Gemcitabine and a Hedgehog Inhibitor (Vismodegib) in Patients With Resectable Pancreatic Adenocarcinoma|
- "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.
|Study Start Date:||December 2012|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4
Other Name: GEMZARDrug: Vismodegib
150 mg capsule, oral, once daily
Other Name: GDC-0449Procedure: Neoadjuvant chemotherapy
Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery
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.
|Contact: Jean-Luc Van Laethem, MD, PhDfirstname.lastname@example.org|
|Antwerp University Hospital (UZA)||Not yet recruiting|
|Edegem, Antwerpen, Belgium, 2650|
|Contact: Marc Peeters, MD,PhD email@example.com|
|Principal Investigator: Marc Peeters, MD, PhD|
|Erasme University Hospital (ULB)||Not yet recruiting|
|Brussels, Belgium, 1070|
|Contact: Jean-Luc Van Laethem, MD, PhD firstname.lastname@example.org|
|Principal Investigator: Jean-Luc Van Laethem, MD, PhD|
|Sub-Investigator: Raphaël Maréchal, MD, PhD|
|Sub-Investigator: Anne Demols, MD, PhD|
|Principal Investigator:||Jean-Luc Van Laethem, MD, PhD||Erasme University Hospital|