Our results support the clinical testing of combina tions of PI3K inhibition wi

Similar geometric mean ratios were obtained for AUC0 to 48 hours after QW dosing with trastuzumab. The pharmacoki netic results were consistent with data from a prior monotherapy study of MK 2206, suggesting that trastu zumab did not appreciably alter the pharmacokinetics of MK 2206. In addition, the trough levels of all patients receiving 45 mg or 60 mg QOD doses of MK 2206 with trastuzumab ARQ 197 msds was at or above the clinical monotherapy efficacy trough target of 56. 8 nM. Similarly, 10 out of 11 patients receiving 135 mg or 200 mg QW doses of MK 2206 also achieved the 48 hour target of at least 56. 8 nM. Circulating nucleic acid All patients enrolled in the study had a baseline blood sample collection for analysis of circulating nucleic acid for mutations in PIK3CA.<br><br> Only three of the 37 AZD0530 価格 patients enrolled were found to have PIK3CA gene mutations, two patients with breast cancer who went on to receive treatment had an H1047L mutation in exon 9 and an E545K mutation, and the third patient had a less predominant M1043I mutation but withdrew prior to documentation of progression of disease. Discussion Trastuzumab is effective therapy for HER2 breast can cers and gastric cancers. However, relative resistance to trastuzumab is common via multiple mechanisms. Through unbiased RNA interference screening analyses, activation of the PI3K pathway has been implicated as a major mediator of trastuzumab resistance. Based on these data and preclinical findings that HER2 signaling is highly dependent on PI3K AKT signaling, we hy pothesized that tumors could have compensatory activa tion of this pathway, thereby avoiding the impact of HER2 inhibitors.<br><br> To begin clinical exploration of com bined HER2 and AKT signaling blockade, we evaluated treatment AMN-107 bcr-Abl 阻害剤 with trastuzumab and the allosteric AKT in hibitor MK 2206 in this phase 1 study. Previously, monotherapy with MK 2206 given either QOD or QW was tolerable, leading us to examine both dosing sched ules combined with trastuzumab. The majority of patients enrolled in the study had exposure to trastu zumab and had progressed on treatment. Our study demonstrated that the combination of trastuzumab and MK 2206 was as tolerable as the same dosing schedule using MK 2206 monotherapy, with no evidence of en hanced toxicities with combined therapy.<br><br> A true MTD for MK 2206 in combination with trastuzumab was not established, but the 60 mg QOD and 135 mg QW doses are reasonable doses for future evaluation in phase 2 tri als. The pharmacokinetic profile of MK 2206 in this study was similar to that observed when MK 2206 was administered as monotherapy. In addition, the DLT of the combination therapy was skin rash, which was the same as the DLT of MK 2206 given as monotherapy. Other observed AEs were also consistent with those of MK 2206 single agent therapy. The combination of MK 2206 and trastuzumab also demonstrated preliminary evidence of therapeutic efficacy in patients with HER2 breast cancer or gastroesophageal cancer, with a clinical benefit response rate of approxi mately 24% and a median time to progression of 72 days. One patient with metastatic breast cancer, whose disease progressed on the right chest wall around the previous mastectomy scar while on maintenance therapy with tras tuzumab, achieved CR following combination therapy with MK 2206.