Inclusion Criteria:

Inclusion Criteria

Subject must meet all of the inclusion criteria to participate in this study:

Age ≥18 years Signed written informed consent Histologically confirmed V600E BRAF mutant
melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2

Normal organ function as defined by the following:

- Absolute neutrophil count >1.2 × 109/L

- Hemoglobin >9 g/dL, platelets >75 × 109/L

- PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may
enroll with INR established within the therapeutic range prior to D1 of treatment)

- Albumin >2.5 g/dL

- Total bilirubin <1.5 x ULN

- AST and ALT < 2.5× ULN

- CrCl ≥50mL/min per Cockcroft-Gault Willing to undergo biopsy for research purposes
only Females of child-bearing potential: willing to use two forms of effective
contraception, and to continue use for 4 weeks post last dose of study medication.
Effective contraception is defined as any medically recommended method (or
combination of methods) as per standard of care, including abstinence. Females of
non-childbearing potential are those who are postmenopausal greater than 1 year or
who have had a bilateral tubal ligation or hysterectomy. Men with a female partner of
childbearing potential must have either had a prior vasectomy or agree to use
effective contraception as described from 14 days prior to D1 of treatment,
throughout the treatment period, and for 16 weeks after the last dose of study
treatment.

In women of child-bearing potential, negative serum pregnancy test within 48 hours prior
to day 1 of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow
and retain oral medication Left ventricular ejection fraction by ECHO ≥ institutional
lower limit of normal

Exclusion Criteria:

Any subject meeting any of the following exclusion criteria at baseline will be ineligible
for study participation:

Patients with a history of a prior malignancy are excluded unless they have been disease
free for 3 or more years or unless they have a completely resected non-melanoma skin
cancer, and/or subjects with indolent second malignancies.

Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib
(GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not
limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the
number of other prior therapies, and patients may be previously untreated.

Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

Active GI or intracranial hemorrhage

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

- QTc ≥ 480 msec;

- History or evidence of current clinically significant uncontrolled arrhythmias;

o Exception: Subjects with controlled atrial fibrillation for >30 days prior to D1
of study treatment are eligible.

- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within 6 months prior to study entry;

- Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg
and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy;

- Patients with intra-cardiac defibrillators or permanent pacemakers;

- Known cardiac metastases;

- Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects
with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
study). Subjects with moderate valvular thickening should not be entered on study.

History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

Brain metastases are excluded unless:

- All known lesions were previously treated with surgery or stereotactic surgery
(whole-brain radiation is not allowed unless given after definitive treatment with
surgery or stereotactic surgery), AND

- Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in
lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be
confirmed with two consecutive magnetic resonance image (MRI) or computed tomography
(CT) scans with contrast, AND

- Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 of study
treatment, AND

- No enzyme inducing anticonvulsants for ≥ 4 weeks prior to D1 of study treatment

NOTE: if study subject has history of brain metastasis, but currently has no evidence of
disease in brain (NED), confirmation by two consecutive scans separated by ≥6 weeks prior
to D1 of treatment is required.

Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis
Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and
HCV infection which will be allowed) Currently active GI disease, or prior surgery that
may affect ability to absorb oral medications

History or current evidence/risk 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 history of hyperviscosity or hypercoagulability syndromes)

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

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 21 mm Hg Currently receiving cancer therapy
(chemotherapy, radiotherapy, immunotherapy, or biologic therapy) NOTE:
palliative radiation therapy is permitted for non-target lesions that are either
new or present at baseline provided total dose does not exceed 30 Gy Use of
other prohibited medications within 5 half-lives or 14 days prior to the first
dose of study drugs or requires any of these medications while receiving
medication on this study Pregnant or lactating female