Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations

Inclusion Criteria

• 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 = 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 1.5 x ULN are permitted in these subjects
• PTT =or or = 2.5 g/dL
• Total bilirubin = or 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)

Exclusion Criteria

• No prior therapy with inhibitors affecting the mitogen-activated protein kinase (MAPK) pathways at any level (BRAF, mitogen-activated protein [MAP]/extracellular signal-related kinase [ERK] kinase [MEK], neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS], ERK inhibitors) for unresectable stage IIIC or stage IV (metastatic) melanoma; no limit to other therapies (immunotherapy or chemotherapy); prior systemic treatment in the adjuvant setting is allowed; (note: ipilimumab treatment must end at least 8 weeks prior to study day 1)
• BRAFV600 mutation positive
• NRAS codon 12, 13, or 61 mutation
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to study day 1, or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to study day 1
• Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to study day 1
• Current use of a prohibited medication as described
• History of another malignancy
• Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected, non-melanoma skin cancer, or subjects with indolent second malignancies are eligible. T1a melanoma and melanoma in situ are permitted. Consult Medical Monitor if unsure whether second malignancies meet requirements specified above.
• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted)
• History of leptomeningeal disease or spinal cord compression secondary to metastasis
• Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase in lesion size) for at least 6 weeks with two consecutive magnetic resonance imaging (MRI) scans using contrast prior to study day 1; enzyme inducing anticonvulsants are not allowed while patients are on study treatment
• A history or evidence of cardiovascular risk including any of the following:
• A QT interval corr