A Phase I, Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of the BRAF Inhibitor GSK2118436 in Subjects With Solid Tumors

Inclusion Criteria:

- Written informed consent provided.

- 18 years old or older. Subjects enrolled in the midazolam cohort need to be younger
than 65 years old.

- Histologically or cytologically confirmed diagnosis of a solid tumor that is not
responsive to standard therapies or for which there is no approved or curative
therapy. Subjects must have BRAF mutant positive tumors.

- Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology
Group (ECOG) scale.

- Able to swallow and retain oral medication.

- Male subjects must agree to use one of the contraception methods listed in the
protocol. The criterion must be followed from the time of the first dose of study
medication until 16 weeks after the last dose of study medication.

- A female subject is eligible to participate if she is of non-childbearing potential
or postmenopausal as defined in the protocol. A female of child-bearing potential may
participate if she agrees to use one of the contraception methods listed in the
protocol.

- Adequate organ system function as defined in the protocol.

- Part 2/Cohorts A, B and C: Must have radiologically and/or clinically documented
disease with at least one measurable lesion as defined by RECIST criteria.

- Part 2/Cohort C only: Must have BRAF positive melanoma with the V600E mutation.

Exclusion Criteria:

- Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno-therapy,
biologic therapy, hormonal therapy, surgery and/or tumor embolization).

- Use of an investigational anti-cancer drug within 28 days preceding the first dose of
GSK2118436.

- Current use of a prohibited medication as defined in the protocol or requires any of
these medications during treatment with GSK2118436.

- Current use of therapeutic warfarin.

- Any major surgery, radiotherapy, or immunotherapy within 4 weeks prior to first dose.
Limited radiotherapy within 2 weeks prior to first dose.

- Chemotherapy regimens with delayed toxicity within four weeks prior to first dose (6
weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given
continuously or on a weekly basis with limited potential for delayed toxicity within
2 weeks prior to first dose.

- Unresolved toxicity greater than National Cancer Institute Common Terminology
Criteria for Adverse Events, version 3.0 Grade 1 from previous anti-cancer therapy
except alopecia unless agreed to by a GSK Medical Monitor and the investigator.

- Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism, or excretion of drugs.

- A history of known HIV infection.

- Primary malignancy of the central nervous system.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. Subjects previously treated for these conditions that are asymptomatic
and off corticosteroids for at least two weeks are permitted. Brain metastases must
be stable for at least 3 months with verification by imaging (brain MRI completed at
screening). Subjects are not permitted to receive enzyme inducing anti-epileptic
drugs (EIAEDs). In Part 2 of the study, subjects with asymptomatic, untreated brain
metastases that have not been stable for 3 months may be enrolled with approval of
the GSK medical monitor. These subjects can be on a stable dose of corticosteroids.

- History of alcohol or drug abuse within 6 months prior to the screen visit.

- 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.

- QTc interval greater than or equal to 480 msecs.

- History of acute coronary syndromes (including unstable angina), coronary
angioplasty, or stenting within 24 weeks prior to the first dose.

- Class II, III, or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system.

- Abnormal cardiac valve morphology (subjects with minimally abnormalities can be
entered on study with approval from the GSK medical monitor).

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug, or excipients as described in the protocol (to
date there are no known FDA approved drugs chemically related to GSK2118436).

- Pregnant or lactating female.

- Unwillingness or inability to follow the procedures outlined in the protocol.

- Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.

- Patients positive for HPV. Entry on study allowed only at the discretion of subject
and investigator after informed consent regarding discussion of the risk of
papillomavirus infection. If enrolled, these subjects must use condoms for sexual
activity, regardless of the use of other contraceptive measures and childbearing
status.

- Prior treatment with a BRAF or MEK inhibitor unless approved by the GSK medical
monitor.