Background: Downregulation of a number of signaling pathways, including the mammalian target of rapamycin (mTOR) pathway, has been demonstrated to be efficacious in a large range of solid tumors such as breast, colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we find that rapamycins lead to suppression of a negative feedback loop from S6 Kinase 1 (S6K1) to Protein Kinase B (PKB), leading to hyperactivation of PKB. In pre-clinical studies using a mouse model of carcinogen-induced HCC, we have demonstrated that combining BEZ235 (a potent and highly selective reversible ATP site competitive inhibitor of PI3K and mTOR) with everolimus (an allosteric inhibitor of mTOR) synergizes to inhibit tumor growth. BEZ235, an orally administered agent, has demonstrated preliminary antitumor activity in a first-in-human phase I study. The current study will evaluate this combination in patients with a variety of solid malignancies that includes glioblastoma multiforme (GBM). Methods: This study is divided into a phase 1b portion designed to determine safety of increasing doses of the combination, with extensive pharmacokinetics, pharmacodynamics and pharmacogenomics analysis; and a phase 2 portion that includes both solid tumors and GBM based on predominance of the mTOR and PI3K deregulation in these tumors, to determine preliminary anti-tumor activity and the recommended dose for phase 2 studies. We will also integrate biomarker assessment for gene expression products of the mTOR downstream pathway such as eukaryotic initiation factor 4E binding protein (4EBP1) and S6 kinase (S6K). The phase 1b portion has started accruing.