Clinical Trials /

The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma

NCT01942993

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

The Effects of Treatment With Vemurafenib on the Immune System in Advanced <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma
  • Official Title: The Effect of BRAF Inhibition With Vemurafenib On The Innate and Adaptive Immune Systems in Patients With Unresectable Stage III or Stage IV Melanoma Expressing a V600 BRAF Mutation
  • Clinical Trial IDs

    NCT ID: NCT01942993

    ORG ID: GCO 13-0427

    Trial Conditions

    Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Vemurafenib Vemurafenib

    Trial Purpose

    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.

    Detailed Description

    Approximately 40-60 % of cutaneous melanomas select for a mutation in the BRAF protein
    which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK)
    pathway. Over 90% of mutations in BRAF occur at position V600 with the most common being a
    V600E mutation. Mutation at position V600 of BRAF activates the MAPK pathway which
    facilitates melanoma proliferation and growth. The response rate to treatment with
    vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is
    approximately 50%. A phase III study comparing first line treatment with vemurafenib
    compared to standard dacarbazine chemotherapy demonstrated a statistically significant
    overall survival benefit in this patient population. Based on this survival benefit
    vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF
    mutation. Vemurafenib is administered at a dose of 960 milligrams orally twice daily.

    While targeting BRAF can lead to survival benefits in patients with melanoma expressing BRAF
    mutation it is becoming increasingly apparent that the immune system is important in
    modulating the growth of melanoma. As such there are immune therapies FDA approved for the
    treatment of stage IV melanoma including ipilimumab which confers an overall survival
    benefit by activating the immune system through inhibition of the CTLA-4 protein expressed
    on certain T-cells. Little is known about how the exposure of different classes of immune
    cells to vemurafenib modulates the activity of the immune system. We do know that many
    melanomas express differentiation antigens which could potentially be recognized by the
    immune system. This recognition could potentially be utilized in the development of novel
    immunotherapeutic treatment approaches. The pharmacologic inhibition of the MAPK pathway
    does lead to increased expression of various melanoma differentiation antigens along with
    improved recognition by antigen-specific T-lymphocytes. Evaluation of a limited number of
    tumor biopsy specimens suggest that the infiltration of melanomas by CD4+ and CD8+
    T-lymphocytes markedly increases following treatment with a BRAF inhibitor. Furthermore the
    viability and function (determined using assays for cytokine release assays and cytotoxic
    activity) of T-lymphocytes was not negatively affected by exposure to vemurafenib at
    concentrations known to cause anti-tumor effects.

    The MAPK pathway is a pathway utilized by many cell types including immune cells and cells
    in the tumor microenvironment. As such vemurafenib could potentially modulate the activity
    of the MAPK pathway in the melanoma cells, immune cells, and components of the tumor
    microenvironment. Effects of vemurafenib on tumor cells may directly lead to changes in
    antigen presentation and effects on the innate and adaptive immune systems could potentially
    alter recognition of tumor cells and modulate positively or negatively immune recognition
    and antitumor activity. Therefore, a better understanding of immune modulation induced by
    anti-BRAF therapy should provide data to model and develop in a more rational fashion
    therapies which combine BRAF targeted and immune modulatory agents potentially using such
    agents as ipilimumab or anti-PD1 or anti-PDL1 antibodies.

    Trial Arms

    Name Type Description Interventions
    Vemurafenib Experimental 960 mg (four tablets of 240 mg each) of vemurafenib PO BID Vemurafenib

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Changes in the immune cellular signature in the blood circulation

    Changes in the immune cellular signature in the blood circulation

    Secondary Outcome Measures

    Changes in the immune cellular signature in the tumor

    Changes in Transcriptional Profile in the blood

    Changes in Transcriptional Profile in the blood

    Change in Transcriptional Profile in Tumor

    Changes in Dendritic Cell function in Blood

    Changes in Dendritic Cell function in Blood

    Changes in Dendritic Cell function in Tumor

    Changes in Macrophage Function in Blood

    Changes in Macrophage Function in Blood

    Changes in Macrophage Function in Tumor

    Changes in Global T cell function in Blood

    Changes in Global T cell function in Blood

    Changes in Global T cell function in Tumor

    Changes in Tumor Antigen Specific T cell Function in blood

    Changes in Tumor Antigen Specific T cell Function in blood

    Changes in Tumor Antigen Specific T cell Function in blood

    Changes in Histocytometry of tumor

    response to vemurafenib treatment

    Development of Cutaneous Squamous Cell Carcinomas

    Trial Keywords

    melanoma

    unresectable

    mutation

    BRAF protein