While targeted therapies can successfully block oncogenic signaling in BRAF mutant melanoma,
      activation of an immune response with agents such as talimogene laherparepvec can induce
      durable responses in a subset of patients. Combining BRAF inhibitors and immunotherapy may
      specifically target the BRAF driver mutation in the tumor cells and potentially sensitize the
      immune system to target tumors.

      The study will enroll up to 20 patients with advanced melanoma and activating mutations in
      the BRAF gene for the local administration of talimogene laherparepvec in conjunction with
      oral therapy with dabrafenib and trametinib, to describe the safety and tolerability of this
      combination.

      Talimogene laherparepvec will be administered by intralesional injection into injectable
      cutaneous, subcutaneous, or nodal lesions with or without image ultrasound guidance.
      Talimogene laherparepvec will not be administered into any visceral organ or mucosal membrane
      lesions. The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 plaque forming
      units (PFU)/mL. Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL.
      The second dose of talimogene laherparepvec (the first dose of the 108 PFU formulation), will
      be administered at least 21 days following the initial dose. Subsequent doses will be given
      approximately every 2 weeks.

      Dabrafenib at a dose of 150mg will be self-administered orally twice per day. Trametinib at a
      dose 2mg will be self-administered orally once per day.

      Subjects will be evaluated by physical exam at the beginning of Cycle 1 (Week 1), Cycle 2
      (Week 4), Cycle 3 (Week 6), Cycle 4 (Week 8), and every two cycles thereafter. Subjects will
      be evaluated for dose-limiting toxicities (defined in protocol) at Cycle 2 (Week 4), Cycle 3
      (Week 6), and Cycle 4 (Week 8). Efficacy evaluation will be performed by tumor measurements
      using clinical assessment, CT or PET/CT every 4 cycles with the first non-baseline
      measurement prior to Cycle 4. Tumor response will be evaluated using RECIST 1.1. Adverse
      events will be recorded and graded using the Common Terminology Criteria for Adverse Events
      Version 4.0 (CTCAE v4.0). Other safety assessments will include clinical laboratory values
      and physical exam findings. Reporting of adverse events, serious adverse events, and
      documentation of concomitant medications will occur as needed and at every cycle. Biopsy of a
      melanoma lesion (preferably uninjected) should occur at least one day prior to Cycle 4 (Week
      8). Blood for biomarker analysis will be obtained immediately prior to the on-treatment
      biopsy, or if the on-treatment biopsy cannot be performed, immediately prior to Cycle 4 (Week
      8).