survival compared with placebo in an unselected patient population. Mechanisms of resistance to EGFR inhibitors include activation of the phosphoinositide 3 kinase /AKT pathway and increased secretion Everolimus of angiogenic factors including vascular endothelial growth factor. Because enzastaurin suppresses VEGF mediated angiogenesis through PKCß inhibition and inhibits the PI3 K/AKT pathway, it was hypothesized that the combination of erlotinib and enzastaurin would offer a mechanistic advantage. In preclinical models combining enzastaurin with gefitinib, an EGFR inhibitor similar in mechanism to erlotinib, synergism was found in a variety of both gefitinib sensitive and gefitinib resistant cancer cell lines. In previous studies, when administered in combination with other agents, enzastaurin did not lead to an increased toxicity profile.
Based on these promising data and the expected effects on common signaling pathways, a phase I/II study was initiated to evaluate P450 Inhibitors the combination of enzastaurin and erlotinib, phase I results are presented here. As both drugs are metabolized through the liver cytochrome p450 CYP3A4, a dose escalation trial was designed to ensure that there were no significant drug drug interactions. The primary objective of the phase I portion of the trial was to determine the recommended phase II dose of the combination of erlotinib and enzastaurin in previously treated patients with advanced NSCLC and other advanced solid malignancies, secondary objectives included evaluation of the pharmacokinetic interaction between enzastaurin and erlotinib and the safety of the combination.
Methods Eligibility criteria Eligible patients included those with an incurable solid malignancy, no more than three prior systemic Marbofloxacin 115550-35-1 treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, an estimated life expectancy of at least 2 months, nonmeasurable or measurable disease defined by Response Evaluation Criteria in Solid Tumors, adequate hematologic function including white blood cell count C3.0 9 109/L, absolute neutrophil count C1.5 9 109/L, platelet count C75.0 9 109/L, and hemoglobin C10.0 g/dL, adequate hepatic function including bilirubin B1.5 times the upper limit of normal and alkaline phosphatase, aspartate transaminase, and alanine transaminase B2.
5 times Candesartan 139481-59-7 the ULN, or\5 times the ULN with liver metastases, and adequate renal function with serum creatinine B1.5 times the ULN. Patients who were unable to swallow tablets, unable to stop taking enzyme inducing anti epileptic drugs, or were previously treated with an EGFR inhibitor or enzastaurin were excluded from the study. Patients with symptomatic interstitial lung disease, a serious heart condition, second primary cancer, or who were pregnant or breast feeding were also excluded. Patients with central language nervous system metastases were allowed only if they had completed local therapy and were off corticosteroids for at least 4 weeks. Prior chemotherapy or radiotherapy had to be completed at least 2 weeks before study enrollment and surgical intervention at least 4 weeks before enrollment. The study protocol and informed consent were approved by the Stanford Institutional Review Board. All patients signed an informed consent document.