Trametinib With or Without Whole Brain Radiation Therapy in Treating Patients With Brain Metastases

Exclusion Criteria

• •Prior radiation therapy to the whole brain (prior stereotactic radiosurgery or fractionated stereotactic radiation therapy to focal areas is allowed)
• •Evidence of leptomeningeal metastases
• •Urgent need of treatment to prevent acute neurologic deterioration
• •Radiosensitive primary tumor such as small cell lung cancer, germ cell tumors, lymphoma, leukemia, or multiple myeloma
• •History of another malignancy that makes determination of the source of the brain metastases uncertain
• •History of interstitial lung disease or pneumonitis
• •Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 14 days prior to enrollment and/or daily or weekly chemotherapy with the potential for delayed toxicity within 14 days prior to enrollment
• •Use of other anti-cancer therapies within five half-lives from the previous dose of the prior anti-cancer therapy preceding enrollment and during the study
• •Symptomatic or untreated spinal cord compression
• •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO)
• •Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
• •* Other anti-cancer therapy while on study treatment; (note: megestrol \[Megace\] if used as an appetite stimulant is allowed)
• •* Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to enrollment; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
• •* Concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra \[ma huang\], gingko biloba, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng)
• •Drugs that potently inhibit or induce CYP3A4 should be administered with caution; below are a few examples of the agents:
• •* Drugs that may increase exposure of trametinib (CYP3A4 inhibitors):
• •* Antivirals: amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir
• •* Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin
• •* Antifungals: fluconazole, itraconazole, ketoconazole, voriconazole
• •* Antidepressants: nefazodone
• •* Calcium channel blockers: mibefradil, diltiazem, verapamil
• •* Miscellaneous: aprepitant
• •* Drugs that may decrease exposure of trametinib (CYP3A4 inducers)
• •* Antivirals: efavirenz, nevirapine
• •* Antibiotic: rifampin
• •* Anticonvulsants: carbamazepine, phenobarbital, phenytoin
• •* Caution should be exercised when dosing trametinib concurrently with medications with narrow therapeutic windows that are substrates of CYP2C8; below are a few examples of the agents
• •* Drug metabolism potentially affected by trametinib resulting in increased exposure of these substrates
• •* 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA)-reductase inhibitors: cerivastatin
• •* Thiazolidinediones: rosiglitazone, pioglitazone
• •* Miscellaneous: chloroquine, zopiclone, repaglinide
• •* As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• •History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):
• •* History of RVO or RPED, or predisposing factors to RVO or RPED (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 RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure \> 21 mm Hg
• •History or evidence of cardiovascular risk including any of the following:
• •* LVEF \< lower limit of normal (LLN)
• •* A QT interval corrected for heart rate using the Bazett's formula QTcB \>= 480 msec
• •* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for \> 30 days prior to registration are eligible)
• •* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to registration
• •* History or evidence of current \>= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
• •* Treatment-refractory hypertension defined as a blood pressure of systolic \> 140 mmHg and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy
• •* Patients with intra-cardiac defibrillators
• •* Known cardiac metastases