An Open-Label, Three-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E or V600K Positive Colorectal Cancer

Inclusion Criteria

INCLUSION CRITERIA

- Written informed consent provided.

- At least 18 years of age or older.

- Able to swallow and retain oral medication.

- No clinically significant gastrointestinal (GI) abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach and/or
bowels.

- Confirmed diagnosis of advanced or metastatic BRAF V600E or V600K mutation positive
colorectal cancer (CRC).

- Archival tissue is required; if archival tissue is not available or found to not
contain tumor tissue, a fresh biopsy is required.

- Measurable disease per RECIST version 1.1.

- Performance Status Score of 0 or 1 according to the Eastern Cooperative Oncology
Group scale.

- Men must have either:

had a prior vasectomy, or agree to use one of the contraception methods listed in the
protocol from the time of the first dose of study drug(s) and until 6 months after the
last dose of panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib,
based on the life cycle of sperm.

- Female subjects are eligible if:

Non-childbearing potential defined as:

pre-menopausal females with a documented tubal ligation or hysterectomy; or
post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with
a follicle-stimulating hormone (FSH) level >40MIU/mL and estradiol level <40pg/mL.

Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will
be required to use one of the contraception methods in the protocol 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
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 contraceptive methods listed in the
protocol for an appropriate period of time as determined by the product label and
applicable IBs) prior to the start of dosing to sufficiently minimize risk of pregnancy at
that point.

- Female subjects must agree to use contraception from the time of the first dose of
study drug(s) until 60 days after the last dose of any study drug. Note: oral
contraceptives are not reliable due to potential drug-drug interactions.

- Women of childbearing potential must have had a negative serum pregnancy test within
7 days prior to the first dose of study drug(s).

- Adequate organ system functions, including:

absolute neutrophil count greater than or equal to 1.2X10^9/L, hemoglobin greater than or
equal to 9 g/dL or 5.6 mmol/L, platelets greater than or equal to75 × 10^9/L, Prothrombin
Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less
than or equal to 1.5Xupper limit of normal (ULN) serum magnesium greater than or equal to
the lower limit of normal (LLN) albumin greater than or equal to 2.5 g/dL or 25 g/L, total
bilirubin less than or equal to 1.5XULN, and AST and ALT less than or equal to 2.5XULN
creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than
or equal to 50mL/min left ventricular ejection fraction (LVEF) greater than or equal to
the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA).

EXCLUSION CRITERIA

- History of prior malignancy, other than colorectal cancer.

- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures.

- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator's assessment).

- History of sensitivity to heparin or heparin-induced thrombocytopenia.

- Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or
biologic therapy), as described in the protocol.

- Prior exposure to BRAF or MEK inhibitors.

- Prior exposure to EGFR inhibitors, including anti-EGFR antibodies or EGFR (for
patients enrolling in Part 2 ONLY)

- Known presence of KRAS-mutation based on previous KRAS-testing.

- Received an investigational or approved anti-cancer drug within 4 weeks, or within 5
half-lives (whichever is shorter) of the first dose of study drug(s). At least 14
days must have passed between the last dose of prior investigational agent and the
first dose of study drug(s).

- Current use of a prohibited medication or requirement to dose with any of these
medications during treatment with study drug(s).

- Known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can
be enrolled with approval of the GSK Medical Monitor.

- Current use of therapeutic warfarin. Therapeutic dosing of warfarin is defined as
resulting in an INR greater than 1.3. Low molecular weight heparin (LMWH) is
permitted provided that the subject's PT and PTT meet entry criteria. Subjects
requiring therapeutic levels of LMWH must receive approval from GSK Medical Monitor
and must be monitored appropriately as clinically indicated.

- Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first
dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose
of study drug(s).

- Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of
study drug(s). Chemotherapy regimens given continuously or on a weekly basis with
limited potential for delayed toxicity within 2 weeks prior to first dose of study
drug(s).

- Unresolved toxicity greater than National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE; version 4) Grade 1 from previous anti-cancer
therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory
values that are allowed per inclusion criteria.

- History of retinal vein occlusion (RVO) or central serous retinopathy (CSR),
predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus,
or a history of hyperviscosity or hypercoagulability syndromes).

- Visible retinal pathology as assessed by ophthalmic examination that is considered a
risk for RVO or CSR, such as:

Evidence of new optic disc cupping. Evidence of new visual field defects. Intraocular
pressure greater than 21mm Hg as measured by tonography.

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

- Subjects with brain metastases are excluded, unless:

All known lesions must be previously treated with surgery or stereotactic radiosurgery,
and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion
size) for greater than or equal to 90 days prior to first dose of study drug(s). This
must be documented with two consecutive MRI or CT scans using contrast, and Asymptomatic
with no corticosteroids requirement for greater than or equal to 30 days prior to first
dose of study drug(s), and No enzyme-inducing anticonvulsants for greater than or equal to
14 days prior to first dose of study drug(s).

In addition, for subjects that had brain metastases but currently have no evidence of
disease (NED), NED for greater than or equal to 12 weeks is required and must be confirmed
by two consecutive MRI or CT scans (using contrast) separated by greater than or equal to
6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet
the above criteria requires approval of a GSK Medical Monitor.

- Psychological, familial, sociological or geographical conditions that do not permit
compliance with the protocol.

- History or evidence of cardiovascular risk including any of the following:

LVEF less than LLN A QT interval corrected for heart rate using the Bazett's formula
(QTcB) greater than or equal to 480 msec; History or evidence of current clinically
significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial
fibrillation for greater than 30 days prior to randomization are eligible.

History of acute coronary syndromes (including myocardial infarction and unstable angina),
coronary angioplasty, or stenting within 6 months prior to randomization.

History or evidence of current greater than or equal to Class II congestive heart failure
as defined by New York Heart Association (NYHA).

Treatment refractory hypertension defined as a blood pressure of systolic greater than 140
mmHg and/or diastolic greater than 90 mm Hg which cannot be controlled by
anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent
pacemakers; Known cardiac metastases;

- Unstable pulmonary embolism, deep vein thrombosis, or other significant
arterial/venous thromboembolic event less than or equal to 30 days before
randomization. If on anticoagulation, subject must be on stable therapeutic dose
prior to randomization.

- Subjects with a history of pneumonitis or interstitial lung disease (ILD).

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug(s) or their excipients.

- Pregnant or lactating female.

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

- Uncontrolled diabetes or other medical condition that may interfere with assessment
of toxicity.