MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

Background: * The PI3K-AKT (protein kinase B) and RAF/MEK (methyl ethyl ketone)/ERK (extracellular-signal regulated kinase) pathways are two of the most frequently activated signaling pathways in cancer, including colorectal cancer (CRC). KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) mutations are detected in approximately 40% of patients with CRC and predict for resistance to EGFR (epidermal growth factor receptor) inhibitors. AKT is upregulated in approximately 60% of CRC. * Preclinical studies demonstrate that activating mutations in the PI3K-AKT pathway and increased phosphorylated Akt through a MEK-EGFR-PI3K feedback loop are implicated in resistance to the antitumor effect of MEK inhibition. * MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS (Rat Sarcoma) pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression. The combination is being studied in a Phase I trial and appears tolerable. Primary Objectives: * Determine reduction of pERK and pAKT in tumor biopsies on C1D1 (cycle 1 day 1) post-administration of the combination of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced colorectal cancer, stratified for KRAS mutation status. * Evaluate for recovery of pAKT levels in tumor biopsy samples obtained on C1D4 (cycle 1, day 4) after administration of the combination of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced colorectal cancer, stratified for KRAS mutation status. * Determine reduction of Ki-67 in tumor biopsies post-administration of the combination of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced colorectal cancer, stratified for KRAS mutation status. Secondary Objectives: * Evaluate reduction of pERK and pAKT in peripheral blood mononuclear cells (PBMCs) after administration of the combination of AZD6244 hydrogen sulfate and MK-2206 and correlate these reductions with those seen in tumor biopsy samples. * Evaluate antitumor activity of the combination of MK-2206 with AZD6244 hydrogen sulfate. Eligibility: -Patients with histologically documented colorectal cancer that has progressed or recurred after oxaliplatin- and irinotecan-based chemotherapy for metastatic disease. KRAS mutation analysis results must be available prior to enrollment. Patients must have disease amenable to biopsy, and be willing to undergo pre-and post-treatment tumor biopsies. Study Design: * MK-2206 135 mg PO (by mouth) once weekly and AZD6244 hydrogen sulfate 100 mg PO (by mouth) once daily will be administered in 28-day cycles, beginning on C1D1 (cycle 1, day 1). * Patients will be stratified for KRAS mutation status. * Blood samples and paired mandatory tumor biopsies will be obtained for pharmacodynamic studies. * CT (computed tomography) scans will be performed every 2 cycles for restaging.