n-(3-4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2-3-dihydroxypropyl)cyclopropane-1-sulfonamide and Pancreatic-Neoplasms

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.. Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.. Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m. Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.

Topics: Antimetabolites, Antineoplastic; Deoxycytidine; Diphenylamine; Disease-Free Survival; Female; Gemcitabine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Sulfonamides; Treatment Outcome

Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.

Topics: Animals; Carcinoma, Pancreatic Ductal; Diffusion Magnetic Resonance Imaging; Diphenylamine; Disease Models, Animal; Humans; Image Processing, Computer-Assisted; MAP Kinase Kinase Kinases; Mice; Neoadjuvant Therapy; Pancreatic Neoplasms; Protein Kinase Inhibitors; Response Evaluation Criteria in Solid Tumors; Sulfonamides

Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.. Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo.. RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro.. Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.

Topics: Animals; Antineoplastic Agents; Bromodeoxyuridine; Cell Cycle; Cell Line, Tumor; Diphenylamine; Enzyme Inhibitors; Humans; Male; MAP Kinase Kinase Kinases; Mice; Neoplasm Transplantation; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Sulfonamides