Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases
Condition: Melanoma
MeSH terms: Melanoma; Brain Neoplasms
Intervention: Vemurafenib
Intervention description: Single arm trial
Intervention MeSH terms: Vemurafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: B-raf V600E; V600K mutation; metastatic melanoma

Summary:

      The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain
      metastases harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations that are
      not amenable to stereotactic radiosurgery based on size, number of lesions or location, to
      measure cerebrospinal fluid (CSF) levels of vemurafenib as an indicator of central nervous
      system penetrance and to measure levels of vemurafenib in normal brain tissue and brain
      metastases in those in whom surgical management is feasible.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations.

          -  Untreated brain metastases

          -  At least one cerebral metastasis that is not amenable to stereotactic radiosurgery
             (SRS) or surgical resection based on size or location OR four or more lesions

          -  Patients may be symptomatic at the time of enrollment, but after any necessary local
             therapy and/or corticosteroids, the patient should be asymptomatic when vemurafenib is
             initiated.

          -  Age >18

          -  Adequate organ function

          -  ECOG performance status < 3

          -  No prior therapies with selective inhibitors of mutated BRAF; other prior therapies
             must have been administered at least 4 weeks before administration of vemurafenib

          -  Life expectancy of at least 3 months

          -  Understanding and willingness to consent

          -  The use of corticosteroids to control cerebral edema or treat symptoms will be allowed

          -  A history of whole brain radiotherapy for brain metastases is allowed, but any stable
             lesion that was present at the time of WBRT will NOT be considered evaluable. A
             minimum of 1 week break will be required between prior WBRT and initiation of
             vemurafenib therapy.

        Exclusion Criteria:

          -  Presence of leptomeningeal disease based on positive CSF cytology.

          -  History or presence of clinically significant ventricular or atrial dysrhythmias ≥
             Grade 2 (NCI CTCAE, v4.0), Corrected QT (QTc) interval >450 ms at baseline or history
             of congenital long QT syndrome

          -  Uncontrolled medical illness, such as uncontrolled infection, congestive heart failure
             and MI within 2 months.

          -  Second active, untreated malignancy, which is likely to result in the patient's demise
             prior to death from uncontrolled melanoma CNS metastases. This will be determined on a
             case by case basis by the PIs.

          -  Unwillingness to undergo monitoring for a secondary malignancy including clinical
             dermatologic examinations and head and neck examinations and serial CT scans.