The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Vemurafenib
Intervention description: Vemurafenib will be administered at the FDA approved dose of 960 mg approximately 12 hours apart with or without a meal. Vemurafenib is provided at 240-mg film-coated tablets packed in bottles for oral administration. Vemurafenib should be swallowed whole with a glass of water and the medication should not be chewed or crushed. Management of symptomatic adverse events may require dose reductions, treatment interruptions, or treatment discontinuation. Dose reductions below 480 mg twice daily are not recommended.
Intervention MeSH terms: Vemurafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: melanoma; unresectable; mutation; BRAF protein

Summary:

      Approximately 40-60 % of cutaneous melanomas select for a mutation in a protein called BRAF
      which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK)
      pathway. When BRAF is mutated the MAPK pathway remains active allowing for melanoma to grow.
      Vemurafenib is an oral treatment which blocks the activity of BRAF which leads to decreasing
      the activity of the MAPK pathway. When patients with melanoma expressing specific mutation in
      BRAF are treated with vemurafenib approximately 50% will develop a response to treatment with
      shrinkage of tumor. When compared to a standard chemotherapy called dacarbazine used to treat
      melanoma, treatment with vemurafenib leads to a statistically significant overall survival or
      living longer benefit. Because of this survival benefit vemurafenib was Food and Drug
      Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF
      mutation called V600E BRAF. There is increasing evidence that the immune system can also be
      important in affecting melanoma growth and survival and there are immune treatments FDA
      approved for the treatment of metastatic melanoma. There is some limited evidence that
      blocking BRAF with vemurafenib may affect the activity of components of the immune system. It
      is important to better characterize and understand the effects of vemurafenib treatment on
      various components of the immune system. The purpose of this study is to systematically
      evaluate the effects of vemurafenib treatment (at FDA approved dosing regimen) on parts of
      the immune systems called the innate and adaptive immune systems. The hypothesis is that
      vemurafenib treatment will affect the immune system.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed stage IV or unresectable stage III melanoma with documented
             BRAF V600 mutation

          -  Age > 18 years

          -  ECOG Performance Status 0,1, or 2

          -  Measurable disease by RECIST v1.1

          -  Adequate organ function: Hemoglobin > 9 g/dl, ANC> 1.5 x 109/L, platelets > 100 x
             109/L, AST and ALT < 2.5 x upper limit of normal, bilirubin < 1.5 x upper limit
             normal, Cr < 1.5 x upper limit normal

          -  Adequate recovery from prior systemic or local melanoma therapy. No systemic
             anticancer therapy in the 4 weeks and no ipilimumab in the 6 weeks from planned
             vemurafenib administration. No radiation therapy in 2 weeks prior to date plan to
             initiate vemurafenib treatment and no surgery in 3 weeks prior to date of planned
             vemurafenib administration.

          -  Agreement for females of childbearing potential use 2 acceptable methods
             contraception. Men with female partners of childbearing potential must agree to use of
             latex condom and advise female partner to use additional method contraception during
             the study and 6 months after discontinuation of vemurafenib

          -  Negative serum or urine pregnancy test within 7 days prior to and including the
             morning of day -7 (first potential day of research blood draw and tumor biopsy)

          -  Agreement not to donate blood or blood products or to donate sperm during the study
             and for at least 6 months after discontinuation of vemurafenib.

        Exclusion Criteria:

          -  Prior vemurafenib treatment

          -  Use of oral or intravenous corticosteroids or other immunosuppressive medications such
             as cyclosporine or azathioprine. Subjects must not have received any systemic
             immunosuppressive drug such as corticosteroids for at least 2 weeks prior to study
             entry. Maintenance inhaled corticosteroids for controlled asthma or COPD or
             maintenance systemic steroids to correct autoimmune endocrinopathy due to prior
             ipilimumab treatment is allowed as is the use of topical steroids and
             anti-inflammatory eye drops.

          -  Symptomatic CNS metastases requiring steroid use.

          -  No active second malignancy

          -  Pregnant or breast feeding

          -  Mean QTc interval > 450 (triplicate ECGs) or history congenital prolonged QT interval

          -  Any of the following within 3 months prior to study drug administration: myocardial
             infarction, unstable angina, symptomatic congestive heart failure, cerebrovascular
             accident or transient ischemic attack, or pulmonary embolism

          -  Inability to swallow pills

          -  Ongoing cardiac dysrhythmia >2 (per NCI CTCAE, v4.0)

          -  Unwillingness to practice birth control

          -  Inability to comply with requirements of the protocol

          -  Uncontrolled medical illness such as infection requiring intravenous antibiotics.

          -  Known allergy to treatment medication (vemurafenib)

          -  Known active or chronic infection with HIV.