TKI258 Dovitinib r one had a triple negative breast cancer

negative, HER2 negative that was PIK3CA wild type, without PTEN loss and KRAS mutant, and the other had a ER PR positive, HER2 negative tumor with a confirmed PIK3CA mutation. Additionally, 20 of patients remained on study for at least 8 months. XL147, also known as SAR245408, is another pan p110 inhibitor. It has shown preclinical activity in a variety TKI258 Dovitinib of xenograft models of human cancer, including those of breast, lung and prostate cancer. Initial data from the first 60 patients treated with this agent as monotherapy in a phase I study was presented at the same ASCO meeting. Rash was the DLT, setting the MTD at 600mg on either an intermittent or continuous daily dosing schedules, with fatigue, nausea, vomiting and diarrhea also attributable to the drug.
Of the patients GSK1070916 evaluable for response, there was a partial response in a non PI3K PTEN mutated non small cell lung cancer patient, and 19 of patients continued on treatment for a minimum of 16 weeks. The semisynthetic wortmannin derivative PX 866, also a pan isoform inhibitor of class I PI3Ks, differs from other agents targeting PI3K in that it covalently binds to the ATPbinding site of p110 and is thus irreversible. In vivo studies demonstrate that PIK3CA mutant or PTEN null xenografts were sensitive to treatment with PX 866. Final results from 60 patients treated on the phase I study of PX 866 have been presented. The MTD was defined as 8mg and 12mg on the continuous and intermittent schedules, respectively, with DLTs of diarrhea and elevated liver enzymes.
Nausea, vomiting and fatigue were also amongst the more common adverse events seen. No responses were seen amongst the 53 evaluable patients, but 25 of these heavily pretreated patients achieved stable disease for a median of 57 days. PI103 was one of the earlier new generation PI3K inhibitors that showed proof of concept whereby targeting members of the PI3K family with high selectivity was able to achieve target modulation with resultant in vivo antitumor activity. Its rapid metabolism precluded clinical development, but proved a valuable tool that ultimately led to development of GDC 0941 another pan isoform class I PI3K inhibitor. This derivative of thienopyrimidine has demonstrated tumor growth inhibition in xenograft models including those harboring mutations in PI3K or PTEN.
In a phase I study of GDC 0941 administered as monotherapy, the most frequently reported drug related adverse events were mild or moderate nausea, fatigue, diarrhea, and dysgeusia. The three DLTs reported were headache, pleural effusion and decreased lung diffusion capacity. One partial response has been observed in a breast cancer patient, and encouraging activity has also been seen in patients with ovarian cancer. Finally, there has been interest in developing isoformspecific inhibitors as it may permit more complete target inhibition with a more tolerable adverse effect profile. The most advanced is a p110 specific in