Within a third review, AZD6244 was compared to capecitabine in patients with metastatic colorectal cancer who had failed prior irino tecan and/or oxaliplatin regimens. Similarly, no differ ence was observed among the 2 treatments inside the number of individuals with sickness progression. Last but not least, the results of a phase II study of AZD6244 in individuals with superior or metastatic hepatocellular auto cinoma had been recently reported. The study was stopped prematurely due to the lack of radiographic response. Other phase II trials are presently ongoing inside a wide variety of tumor styles. GDC 0973 GDC 0973 is a potent, selective, orally energetic inhibitor of MEK1/2 with an IC50 of one nM in vitro. In cellular scientific studies, the compound inhibits ERK1/2 phosphorylation at subnanomolar concentra tions, and exerts antiproliferative effects in numerous tumor cell lines harboring KRAS or BRAF mutations.
In vivo pharmacodynamic studies have shown that in the know just one oral dose of GDC 0973 inhibits phospho ERK1/2 in tumors for as much as 48 hrs, translating into potent inhi Triciribine clinical trial bition of tumor growth in human xenograft models. Notably, GDC 0973 appears to possess reduced activity inside the brain, which could reduce the possible of central nervous process unwanted effects. A phase I dose escalating research of GDC 0973 was initiated in subjects with sound tumors. Preliminary outcomes from 13 individuals indicates that GDC 0973 is properly tolerated with no drug connected serious adverse events being reported. 1 patient with non little cell lung cancer had stabilization of dis ease for seven months and continues on therapy. One more phase I trial of GDC 0973 in mixture with all the phosphatidylinositol three kinase inhibitor GDC 0941 is planned. RDEA119 RDEA119 is another orally obtainable, allosteric inhibitor of MEK1/2.
In vitro, RDEA119 selectively inhibits MEK1 and MEK2 within a non ATP aggressive guy ner. Cellular assays showed that RDEA119 potently inhi bits ERK1/2 phosphorylation and cell proliferation in a panel of human cancer cell lines. In vivo, RDEA119 exhibits potent antitumor activ ity in xenograft models of human melanoma, colon and epidermal carcinoma. Interestingly, pharmacodynamic research have uncovered that the compound has minimal central nervous process penetration. RDEA119 is now staying evaluated as single agent inside a phase I research in sophisticated cancer patients, and inside a phase I/II study in combination using the multikinase and Raf inhibitor sorafenib. GSK1120212 GSK1120212 is definitely an orally accessible, selective inhibitor of MEK1/2 with reported antitumor activity in mouse xenograft designs. A phase I research of GSK1120212 was undertaken in 2008 in patients with solid tumors and lymphoma. Preliminary evaluation of six patients taken care of at 4 dose ranges indicates that GSK1120212 is effectively tolerated without any dose limiting toxicity reported so far.