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

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 corrected for heart rate using the Bazett's formula (QTc) \> or = 480 msec
• •* A history or evidence of current clinically significant uncontrolled arrhythmias
• •* Exception: subjects with atrial fibrillation controlled for \> 30 days prior to study day 1
• •* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study day 1
• •* A history or evidence of current \>= class I congestive heart failure as defined by the New York Heart Association (NYHA) guidelines
• •* 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
• •A history or current evidence of retinal vein occlusion (RVO) including:
• •* History of RVO or
• •* Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO such as:
• •* Evidence of new optic disc cupping
• •* Evidence of new visual field defects
• •* Intraocular pressure \> 21 mmHg as measured by tonography
• •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
• •History of interstitial lung disease or pneumonitis
• •Females who are pregnant or nursing