Phase 2 SMART-PANC tests SMAD4-guided neoadjuvant chemo (DNA synthesis/tubulin inhibitors) in PDAC

Northwestern University is running this single-center, non-randomized Phase 2 pilot in resectable and borderline-resectable pancreatic ductal adenocarcinoma (PDAC) to see whether pre-treatment SMAD4 status can be used to tailor standard neoadjuvant chemotherapy choices and improve the chance of reaching surgery and achieving an R0/R1 resection. Patients must have prior tumor next-generation sequencing documenting SMAD4-mutant or SMAD4–wild-type status, then receive gemcitabine + nab-paclitaxel (gemcitabine: DNA synthesis/ribonucleotide reductase-pathway cytotoxic; nab-paclitaxel: microtubule/tubulin cytotoxic) in one cohort, and physician’s-choice gemcitabine + nab-paclitaxel or FOLFIRINOX (5-FU thymidylate synthase-pathway cytotoxic + irinotecan topoisomerase I inhibitor + oxaliplatin DNA-crosslinking platinum + leucovorin modulation) in the other, with radiation allowed per usual practice and surgery planned after chemotherapy. The scientific angle is using SMAD4—genomically altered in roughly 20% of PDAC in modern sequencing cohorts, although broader measures of SMAD4 loss/inactivation yield higher estimates—as a practical, clinic-ready stratifier for “which standard chemo first,” rather than adding a new investigational agent. Today’s care for resectable/borderline PDAC is neoadjuvant multi-agent chemotherapy (often modified FOLFIRINOX or gemcitabine/nab-paclitaxel) ± chemoradiation followed by resection when feasible, and this study tests whether a biomarker-guided selection of those same regimens can improve completion of curative-intent surgery.