Safety, PK of AKT and MEK Combination

Inclusion Criteria:

• Part 1 - Dose Escalation

Subjects eligible for enrollment in the study must meet all of the following criteria:

• Male or female 18 years or older, at the time of signing the informed consent.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Histologically or cytologically-confirmed diagnosis of solid tumor malignancy that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects who refuse standard therapy.
• Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Able to swallow and retain oral medication.
• A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] > 40 MlU/ml and estradiol < 40 pg/ml [<140 pmol/L] is confirmatory). Females on hormone replacement therapy [HRT] and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 7.3.2 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraception methods listed in Section 7.3.2 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until four weeks after the last dose of study medication.

Note: Oral contraceptives are not reliable due to potential drug-drug interaction.

• Male subjects must agree to use one of the contraception methods listed in protocol. This criterion must be followed from the time of the first dose of study medication until three months after the last dose of study medication. However, the Sponsor advises that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm).
• Adequate organ system function as defined in protocol. Definitions of Adequate Organ Function

Absolute neutrophil count (ANC) ≥ 1.5 X 109/L Hemoglobin ≥ 9.5 g/dL Platelets ≥ 75 X 109/L PT/INR and PTT ≤ 1.1 X ULN

Total bilirubin ≤ 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) AST and ALT ≤ 2.5 X ULN

Creatinine ≤ ULN OR Calculated creatinine clearance ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min

Calcium phosphate product (CPP) ≤4.0 mmol2/L2 (50mg2/dL)

Fasting Serum Glucose < 126mg/dL Cardiac Ejection fraction ≥ LLN by ECHO or MUGA

Inclusion Criteria for Part 2 - Expansion Cohort:

• Histologically- or cytologically-confirmed diagnosis of metastatic pancreatic cancer, metastatic endometrial cancer or metastatic colorectal cancer.
• Subjects with metastatic pancreatic cancer and an ECOG Performance Status of 2 may enroll.

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:

• Chemotherapy, radiotherapy, or immunotherapy within 28 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of GSK2141795. Cancer therapy given continuously or on a weekly basis with limited potential for delayed toxicity is permitted with approval of a GSK Medical Monitor if dosing of that therapy is terminated at least five half-lives prior to the first dose of the investigational study drug and any drug-related toxicity has recovered to Grade 1 or less.
• Use of an investigational anti-cancer drug within 28 days or five half-lives, whichever is shorter, prior to the first dose of the investigational study drugs. A minimum of 10 days between termination of the investigational drug and administration of GSK1120212 and GSK2141795 is required. In addition, any drugrelated toxicity should have recovered to Grade 1 or less.
• Current use of a prohibited medication (see Section 6.2) or requires any of these medications during treatment with the investigational drugs.
• Anticoagulants at therapeutic doses (e.g., warfarin, low molecular weight heparin, direct thrombin inhibitors) are permitted only after consultation with the GSK Medical Monitor. Low dose (prophylactic) anticoagulants are permitted provided that the subject's PT and PTT meet entry criteria and do not increase from baseline while taking study drug.
• Unresolved toxicity greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4) Grade 1 from previous anti-cancer therapy unless agreed to by a GSK Medical Monitor and the Investigator, and where a GSK Medical Monitor and the investigator consider that the ongoing toxicity will not introduce additional risk factors and will not interfere with the study procedures.
• Presence of active GI disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs or may predispose a subject to GI ulceration.
• Previously diagnosed with diabetes mellitus (type 1 or 2).
• History of known HIV infection.
• Primary malignancy of the central nervous system.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Subjects who were previously treated for these conditions, and are stable for 3 months and who have been without anti-epileptic medications or steroids for at least 2 months are eligible.
• QTc interval ≥ 480 msecs.
• History of acute coronary syndromes (including unstable angina and myocardial infarction), atrial fibrillation, coronary angioplasty, or stenting within the past 24 weeks.
• Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients. To date there are no known FDA approved drugs chemically related to the investigational study drugs.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease).
• Pregnant or lactating females.
• History of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
• Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein thrombosis or central serous retinopathy.
• Intraocular pressure > 21mm Hg measured by tonography.
• Glaucoma diagnosed within one month prior to the first dose of the investigational study drug(s).
• Other clinically significant ECG abnormalities including 2nd degree (type II) or 3rd degree atrioventricular (AV) block.
• History of hepatitis B or C. NOTE: Subjects with evidence of cleared hepatitis B infection are permitted.