A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, Trametinib, to Investigate the Safety and Anti-Cancer Activity in Subjects With Melanoma With BRAF Non-V600 Mutations

• Signed written informed consent

• Histologically or cytologically confirmed diagnosis of melanoma

• BRAF mutation in loci other than V600 (BRAF nonV600 MUT) or BRAF fusion detected by genetic testing of the primary tumor or regional/distant metastasis

• Subjects must provide either a fresh or archived tumor sample for correlative study analyses

• For subjects with melanoma, archived or freshly biopsied tumor tissue (preferred) must be obtained prior to enrollment. Tissue shipment tracking information should be provided before administration of study treatment is initiated. However, if shipping will be delayed and tissue shipment tracking information is unavailable, study drug may be administered prior to tissue receipt pending discussion with principal investigator.

• Measurable disease (i.e., present with at least one measurable lesion per Response Evaluation Criteria In Solid Tumors \[RECIST\], version 1.1)

• All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be =\< grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomization. Subjects with endocrinopathies (e.g. hypopituitarism, hypothyroidism, hypoadrenalism) caused by immune therapies currently on adequate hormone replacement WILL be permitted.

• Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception

• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Absolute neutrophil count (ANC) \> or = 1.0 × 10\^9/L

• Hemoglobin \> or = 9 g/dL

• Platelet count \> or = 75 x 10\^9/L

• Prothrombin time (PT)/international normalized ratio (INR)\* = or \< 1.3 x upper limit of normal (ULN)

⁃ Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization; PT and partial thromboplastin time (PTT) \> 1.5 x ULN are permitted in these subjects

• PTT =or \< 1.3 x ULN

• Albumin \>or = 2.5 g/dL

• Total bilirubin = or \< 1.5 x ULN

• Alanine aminotransferase (ALT) = or \< 2.5 x ULN

• Creatinine = or \< 1.5 ULN or calculated creatinine clearance\* \> or = 50 mL/min

⁃ Calculate creatinine clearance using standard Cockcroft-Gault formula; creatinine clearance must be \> or = 50 mL/min to be eligible

• Left ventricular ejection fraction (LVEF) \> or = lower limit of normal (LLN) by echocardiogram (ECHO)