Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

摘要: Abstract Background/Objectives Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting these may be clinically beneficial. This Phase I study combined HH EGFR inhibition metastatic PDAC patients. Methods Combined effects using Vismodegib Erlotinib with or without gemcitabine solid tumors were assessed by CT. Another cohort patients was evaluated FDG-PET tumor biopsies-derived biomarkers. Results Treatment well tolerated maximum dose experiencing no grade 4 toxicities though 25% experienced 3 adverse effects. Recommended phase II each 150 mg daily. No responses observed although 16 achieved stable disease for 2–7 cycles. Paired biopsy analysis before after first cycle therapy showed reduced GLI1 mRNA, phospho-GLI1 associated target genes all cases. However, only half cases levels desmoplasia changes fibroblast markers. Most had decreased phospho-EGFR levels. Conclusions combination well-tolerated overall not significantly impacted treatment. Biomarker suggests direct targets affecting stromal compartment. These findings conflict pre-clinical mouse models, thus warrant further investigation into how upstream is circumvented PDAC.