Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets

Inclusion Criteria:

1. Histologically-confirmed BRAFV600E melanoma
2. Up to 4 untreated brain metastases (at least 1 \> 0.5 cm) with no metastasis larger than 3 cm as assessed by a gadolinium-enhanced MRI of the brain. Detection of additional lesions at time of Gamma Knife radiosurgery MRI scan will not be considered exclusionary if the detection of these lesions are thought to be due solely to difference in imaging techniques (i. e. higher sensitivity, double gadolinium contrast MRI utilized at the time of Gamma Knife radiosurgery compared with conventional MRI imaging).
3. ECOG PS 0-2
4. 14 days elapsed from last treatment with surgery.
5. At least 28 days or five half-lives (whichever is longer) have elapsed from last dose of any approved or investigational therapy for metastatic melanoma.
6. Appropriate birth control for men and women with childbearing potential
7. Corticosteroid dose stable for at least 14 days
8. Adequate end-organ function:

   * ANC ≥ 1.5x109/L
   * Hemoglobin ≥ 9 g/dL
   * Platelets ≥100 x109/L
   * Total bilirubin ≤ 1.5x ULN
   * AST and ALT ≤ 2.5x ULN
   * Creatinine ≤ 1.5 mg/dL
   * PT/PTT ≤ 1.5x ULN
   * LVEF ≥ 50%
9. Age ≥ 18 years
10. Recipients of prior radiation therapy to the brain including stereotactic radiosurgery or whole brain irradiation may be included if there are 1-4 untreated or progressing brain lesions. At his discretion, the Study Chair may review any enrollment decision regarding which subjects will be enrolled prior to the initiation of treatment on trial.

Exclusion Criteria:

1. Neurological symptoms from melanoma brain metastases
2. Patients may not have received prior therapy with dabrafenib, vemurafenib, or other potent, highly effective BRAF inhibitors. Prior therapy with sorafenib is permitted.
3. Any indication for urgent or emergent neurosurgery. Patient may enroll after neurosurgery at least 14 days after neurosurgery as long as they meet all other study qualifications.
4. Pregnant or lactating women. The effects of dabrafenib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use a highly effective method of contraception including: hormonal contraceptives (oral contraceptives, Nuvaring, Depo Provera) an intrauterine device, true abstinence or two barrier methods of birth control including condoms with cervical cap or diaphragm. Baseline pregnancy testing is required for all women of child-bearing potential. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol who are sexually active with women of child bearing potential must also agree to use adequate contraception prior to and during the study as outlined above, and for, and four months after completion of study drug administration.
5. History of known cardiac arrhythmias or acute coronary syndromes within the past 24 weeks.
6. History of a second malignancy with evidence of active disease within the past 3 years except non-melanoma skin cancer, indolent prostate cancer, and stable CLL without lymphadenopathy
7. Complete resection of a single brain metastasis or of all known brain metastases. Patients who have undergone subtotal resection are eligible providing residual disease is \< 2.0 cm in maximum diameter.
8. Patients with metastases within 2 mm of the optic nerve or optic chiasm so that some portion of the optic nerve or chiasm would receive \> 9 Gy from radiosurgery.
9. Patients with metastases in the brainstem.
10. Contraindication to MRI (such as cardiac pacemaker).
11. The following medications or non-drug therapies are prohibited:

    * Other anti-cancer therapy while on treatment in this study.
    * Use of other investigational drugs within 28 days preceding the first dose of dabrafenib.
    * Antiretroviral drugs. Subjects with known HIV are ineligible for study participation.
    * Herbal remedies (i.e., St. John's wort).
    * Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, p-glycoprotein (Pgp) or Bcrp transporter because they may alter dabrafenib concentrations. The list may be modified based on emerging data. These include but are not limited to those listed in Appendix 2; consider therapeutic substitutions for these medications.
12. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Grade 2 or higher from previous anti-cancer therapy, except alopecia.
13. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the Study Chair for permission to enroll the subject. Study Chair has final decision regarding which subjects will be enrolled.
14. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of HBV clearance may be enrolled with permission of the GSK medical monitor.
15. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
16. Corrected QT (QTc) interval ≥480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; abnormal cardiac valve morphology documented by echocardiogram (subjects with minimal abnormalities including mild regurgitation/stenosis can be entered on study with approval from the GSK medical monitor); or history of known cardiac arrhythmias.
17. 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.
18. History of RVO or CSR, or predisposing factors to RVO or CSR(e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as diabetes mellitus, hypertension, or history of hyperviscosity or hypercoagulability syndromes)
19. 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 as measured by tonography
20. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.