Concurrent Dabrafenib + Trametinib With Sterotactic Radiation in BRAF Mutation-Positive Malignant Melanoma and Brain Metastases

Inclusion Criteria:

* Histologically confirmed melanoma metastatic to brain and determined to be BRAF V600 mutated.
* Age ≥ 18 years.
* Karnofsky Performance Status of 70-100 (Appendix I).
* Patients must have a life expectancy of at least 12 weeks.
* Presence of measurable disease (i.e. present with at least one measurable CNS lesion per RECIST 1.1).
* Presence of 1-10 brain metastases as confirmed on a thin slice axial T1 post-gadolinium MRI sequence. The maximum diameter of a single brain lesion should be ≤ 4 cm and presence of a measurable lesion ≥ 1cm based on baseline MRI of brain.
* All CNS metastases amenable to single fraction SRS and or fractionated SRS. Hemorrhagic lesions are allowed if the treating radiation oncologist deems the lesion amenable to focal SRS.
* 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.
* Laboratory requirements (within 14 days prior to registration):

  * ANC ≥ 1.2 x 10\^9/L
  * Hemoglobin ≥ 90 g/L
  * Platelet count ≥ 100 x 10\^9/L
  * PT/INR \& PTT ≤ 1.3 x ULN
  * Total bilirubin ≤ 1.5 x ULN
  * AST and ALT ≤ 2.5 x ULN
  * Serum creatinine or ≤ 1.5 x ULN or Creatinine Clearance ≥ 50 ml/min (calculated by Cockcroft and Gault)
  * LVEF ≥ LLN (within 28 days prior to registration)
  * No prior treatment with a BRAF inhibitor or MEK inhibitor.
  * No known ocular or primary mucosal melanoma.
  * No prior systemic anti-cancer treatment within the last 2 weeks preceding the frist dose of dabrafenib and trametinib. Patients must have recoved from clinical manifestations of toxicity related to prior systemic therapy and have adequate washout as follows: Longest of one of the following:

    * two weeks
    * 5 half-lives for investigational agents
    * Standard cycle length of standard therapies
  * Prior systemic treatment in the adjuvant setting is allowed.
  * No current use of a prohibited medication as described in section 7.2.
  * No history of malignancy with confirmed activating RAS mutation at any time.
  * No history of malignancy other than disease under study within 3 years of study enrollment.
  * No leptomeningeal metastases or metastases causing spinal cord compression that are symptomatic or untreated or not stable for ≥ 3 months. Subjects on stable dose of corticosteroids \> 2 weeks or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of CCTG.
  * No serious or unstable pre-existing medical conditions, psychiatric disorders or other conditions that could interfere with the subject's safety, obtaining informed consent or compliance with study procedures.
  * No history of Hepatitis B Virus or Hepatitis C Virus infection
  * No history or evidence of cardiovascular risk No history or current eveidence/risk of retinal vein occlusion or central serous retinopathy
  * No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide.
  * No pregnant or lactating women.
  * No hisotry of interstitial lung disease or active pneumonitis.
  * Presence of any one brain metastases \>4cm in maximal diameter, and/or presence of brain metastase of less than 1cm.
  * No prior whole brain radiation
  * No brainstem metastses
  * No contrindications to MRI and/or Gadolinimum contrast or sterotactic brain radiation therapy.