Inclusion Criteria:

• Phase I
• Written informed consent provided.
• 18 years old or older.
• Subjects must have relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Subjects with poor-risk myelodysplasia (MDS) and chronic melomonocytic leukemia (CMML) are also eligible. Relapsed/refractory leukemias include acute non-lymphocytic leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) in blast crisis. Subjects with agnogenic myeloid metaplasia (AMM) are also eligible. Subjects with a haematological malignancy associated with human immunodeficiency virus (HIV) infection or solid organ transplant are NOT eligible.
• Subjects who have previously received an autologous stem cell transplant are allowed if a minimum of three months has elapsed from the time of transplant (T0) and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK1120212.
• Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met: transplant was greater than 100 days prior to study enrolment, subject has not taken immunosuppressive medications (per protocol) for at least 1 month, no signs or symptoms of graft versus host disease other than Grade 1 skin involvement, no active infection, subject meets the remainder of the eligibility criteria outlined in this protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2.
• Life expectancy of at least four weeks.
• Able to swallow and retain oral medication.
• Male subjects must agree to use one of the contraception methods listed in the protocol.
• Female subjects must be of non-childbearing potential as listed in the protocol or using a contraception method listed in the protocol.
• Calcium Phosphate Product less than or equal to 4.0 mmol (squared)/L (squared) or 50mg (squared)/dL (squared).
• Subjects must have adequate organ function as specified in the protocol.
• Phase II
• Confirmed diagnosis of one of the following: Relapsed or refractory acute myeloid leukemia (AML), Secondary AML including AML arising from antecedent hematologic diseases (e.g., myelodysplastic syndrome, myeloproliferative disorders, or therapyrelated AML), CMML, or MDS.

Cohorts 1: RAS Positive AML/MDS Cohort 2: Wild Type AML/MDS/CMML Cohort 3: RAS Positive CMML

Exclusion Criteria:

• Phase I
• Currently receiving cancer therapy as specified in the protocol.
• Received corticosteroids or imatinib within 24h of GSK1120212 administration.
• Received gemtuzumab ozogamicin (myelotarg) within two weeks of GSK1120212 adminstration.
• Received an investigational anti-cancer drug within four weeks or five half-lives, whichever is shorter of GSK1120212 administration, as specified in the protocol.
• Received major surgery, radiotherapy, or immunotherapy within four weeks of GSK1120212 administration.
• Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks.
• Received a MEK inhibitor.
• Current use of a prohibited medication per protocol.
• Current use of warfarin. Low molecular weight heparin and prophylactic low-dose warfarin are permitted per protocol.
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
• History of RVO.
• Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein thrombosis.
• Intraocular pressure greater than 21mm Hg as measured by tonography.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Condition that in the investigator's opinion would jeopardize compliance with the protocol.
• Symptomatic or untreated central nervous system involvement by the hematologic malignancy, including primary CNS lymphoma. Subjects who were previously treated for CNS involvement, and are asymptomatic without anti-epileptic medications for at least two months are eligible.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease).
• Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except alopecia (if applicable) unless agreed to by a GSK Medical Monitor and the investigator.
• QTc interval greater than 480 msecs.
• History of acute coronary syndromes (including unstable angina), 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.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients (See Section 3.10). (To date there are no known FDA approved drugs chemically related to GSK1120212).
• Pregnant or lactating female.
• Unwillingness or inability to follow the procedures outlined in the protocol.