Patient case: 64-year-old male with melanoma; genetic feature: BRAF (V600E)

Clinical trial: Concurrent Dabrafenib and Trametinib With Sterotactic Radiation in Patients With BRAF Mutation-Positive Malignant Melanoma and Brain Metastases

Summary: Dabrafenib and trametinib are drugs that are usually given for the treatment of melanoma. Combinations of dabrafenib and trametinib have also been studied and when used together have shown to increase tumour shrinkage in animals compared to either drug alone. Dabrafenib and trametinib have also shown potential to penetrate the blood-brain-barrier when given together and have an effect on brain metastases. Giving these drugs at the same time and then giving brain stereotactic radiosurgery (SRS) may also be preferred in patients with brain metastases

Detailed description: The purpose of this study is to find out the effects of giving dabrafenib in combination with trametinib continuously with stereotactic radiotherapy (SRS) has on melanoma and brain metastases.
  Stereotactic Radiosurgery (SRS) is a non-surgical radiation therapy used to treat tumours of the brain. It can deliver precisely targeted radiation. Currently SRS alone is the usual treatment for patients with up to 4 brain lesions. This study will include 2 groups 1) patients with 1-4 brain lesions treated with SRS concurrently with dabrafenib and trametinib and 2) patients with 5-10 brain lesions treated with SRS concurrently with dabrafenib and trametinib.

Eligibility: Inclusion Criteria:
  -  Histologically confirmed melanoma metastatic to brain and determined to be BRAF V600 mutation-positive.
  -  Age ≥ 18 years.
  -  ECOG performance status of 0 or 1 (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 lesion should be ≤ 4 cm.
  -  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 109/L
  -  Hemoglobin ≥ 90 g/L
  -  Platelet count ≥ 100 x 109/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)
  Exclusion Criteria:
  -  No prior treatment with a BRAF inhibitor or a MEK inhibitor.
  -  No known ocular or primary mucosal melanoma.
  -  No prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within the last 2 weeks preceding the first dose of combination. Patients must have recovered from any treatment related toxicity with no risk of delayed toxicity. Prior systemic treatment in the adjuvant setting is allowed.
  -  No current use of a prohibited medication
  -  No history of malignancy with confirmed activating RAS mutation at any time.
  -  No history of malignancy other than disease under study within 3 years.
  -  No leptomeningeal metastases or metastases causing spinal cord compression that are symptomatic or untreated or not stable for ≥ 3 months (must be documented by imaging). Subjects on a stable dose of corticosteroids > 2 weeks or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the CCTG.
  -  No 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.
  -  No history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted).
  -  No history or evidence of cardiovascular risk (see 4.2.10 for details).
  -  No history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) (see 4.2.11 for complete details).
  -  No known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  -  No pregnant or lactating women.
  -  No history of interstitial lung disease or active pneumonitis.
  -  Presence of any one metastases > 4 cm in maximal diameter.
  -  No prior whole brain radiation.
  -  No brainstem metastases.
  -  No contraindications to MRI and/or Gadolinium contrast or stereotactic brain radiation therapy.

Relevance to patient case: possibly relevant