Clinical Trials /

The Effects of Vemurafenib + Cobimetinib on Immunity in Patients With Melanoma

NCT01813214

Description:

This study is for patients with malignant melanoma which has spread beyond the local area and cannot be surgically removed, and who have melanoma tumors that are accessible for repeat biopsies. This research study is a way of gaining new knowledge about treatment options for metastatic melanoma. This research study is evaluating the effects of the drugs vemurafenib and cobimetinib on the immune system. Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma that harbors a B-RAF mutation. Vemurafenib works by blocking a protein called B-RAF. Researchers have found that a large number of melanomas have mutations (changes) in the BRAF gene. Genes are specific parts of your DNA that contain information on hereditary characteristics such as hair color and eye color. The BRAF gene codes for a protein called B-RAF, which is involved in sending signals in cells that can lead to cell growth. Research has determined that mutations in the BRAF gene at the V600 position cause a change in the B-RAF protein that can drive the growth and spread of melanoma cells. Cobimetinib (GDC-0973, XL518) is a potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway. The purpose of this research study is to determine how vemurafenib and cobitmetinib may alter the immune system's reaction to melanoma, in order to learn how best to combine immune therapies with vemurafenib in the future.

Related Conditions:
  • Melanoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

The Effects of Vemurafenib on Immunity in Patients With <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: The Effects of Vemurafenib on Immunity in Patients With Melanoma
  • Official Title: Analysis of the Kinetics and Effects of Vemurafenib on Intratumoral and Host Immunity in Patients With Advanced BRAFV600 Mutant Melanoma: Implications for Combination With Immunotherapy
  • Clinical Trial IDs

    NCT ID: NCT01813214

    ORG ID: MLN28305

    Trial Conditions

    Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Vemurafenib Zelboraf, R05185426 (PLX4032) Vemurafenib

    Trial Purpose

    This study is for patients with malignant melanoma which has spread beyond the local area
    and cannot be surgically removed, and who have melanoma tumors that are accessible for
    repeat biopsies. This research study is a way of gaining new knowledge about treatment
    options for metastatic melanoma. This research study is evaluating the effects of a drug
    called vemurafenib on the immune system.

    Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma
    that harbors a B-RAF mutation. Vemurafenib works by blocking a protein called B-RAF.
    Researchers have found that a large number of melanomas have mutations (changes) in the BRAF
    gene. Genes are specific parts of your DNA that contain information on hereditary
    characteristics such as hair color and eye color. The BRAF gene codes for a protein called
    B-RAF, which is involved in sending signals in cells that can lead to cell growth. Research
    has determined that mutations in the BRAF gene at the V600 position cause a change in the
    B-RAF protein that can drive the growth and spread of melanoma cells.

    The purpose of this research study is to determine how vemurafenib may alter the immune
    system's reaction to melanoma, in order to learn how best to combine immune therapies with
    vemurafenib in the future.

    Detailed Description

    This is a single-arm, multicenter study of vemurafenib in patients with biopsy-accessible
    advanced metastatic melanoma.

    The trial will consist of a screening period, a treatment phase, and one post-study
    follow-up visit occurring about 30 days after the last dose of vemurafenib. Day 1 of the
    study will be defined as the first day a subject receives vemurafenib. During the treatment
    phase, all study assessments will be conducted on Day 1 ( 3 days) of each cycle, with the
    exception of computed tomography (CT) and/or magnetic resonance imaging (MRI), which should
    occur every 6 weeks (+/- 7 days).

    All subjects will have biopsies performed of safely accessible tumors before starting
    treatment and at 1, 2, and 4 weeks later (days 8, 15, 29). In addition, any patient with
    accessible tumor at the time of progression will have a tumor biopsy performed at that time.

    Mixed-effects models will be used to study the change in CD8 T cell counts per mm2 of
    tissue, changes in expression of immunoinhibitory proteins (B7-H1/PD-L1, IDO, arginase), and
    changes in endothelial homing receptor ligands and tumor associated chemokines at
    pre-treatment at pre-treatment and at weeks 1, 2, and 4 after vemurafenib therapy. Subjects
    will be treated as random effects to account for individual variability. Potential
    covariates are age, gender, and ECOG performance status.

    60 ml of blood for lymphocytes will be drawn on days 1, 8, 15, and 29.

    Trial Arms

    Name Type Description Interventions
    Vemurafenib Experimental Vemurafenib 960 mg po BID until unacceptable toxicity or progression of disease Vemurafenib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histological or cytological confirmed melanoma that is metastatic
    or unresectable stage IIIc and clearly progressive.

    - Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved
    laboratory

    - Age >/= 18 years

    - ECOG performance status 0, 1, or 2

    - Participants must have measurable melanoma

    - Women must not be pregnant

    - Breastfeeding must be discontinued prior to treatment Day 1 of the study.

    - Subjects may have received any number of prior systemic treatment regimens for
    distant metastatic disease or advanced regional disease. The following prior therapy
    is permitted in either the adjuvant or metastatic disease setting:

    - No prior therapy

    - Immunotherapy consisting of interferon-alpha, interleukin-2, GM-CSF, ipilimumab,
    anti-PD1, cancer vaccines, or other experimental agent

    - Cytotoxic chemotherapy consisting of dacarbazine, temozolomide, carboplatin, or
    paclitaxel alone or in combination

    - Targeted therapy with temsirolimus, bevacizumab, or sorafenib

    - Subjects must have discontinued cytotoxic therapy agents at least 4 weeks, cytokine
    based immunotherapy at least 6 weeks and immunoregulatory antibody therapy at least
    12 weeks prior to entering the study and have recovered from adverse events due to
    those agents.

    - Subjects must have completed radiation therapy at least 4 weeks previously

    - Subjects must have the following baseline laboratory values:

    - White blood count >/= 3000/mm3

    - Absolute granulocyte count >/= 1500/mm3

    - Platelet count >/= 100,000/mm3

    - Serum creatinine /= 40 ml/min

    - AST/ALT

    - Alkaline Phosphatase

    - INR

    - Total bilirubin

    - Subjects must not receive any other investigational agents during the period on study
    or the four weeks prior to entry.

    - Subjects must have no clinical evidence of active brain metastasis.

    - Subjects who have had brain metastases will be eligible only if all of the following
    are true:

    - The total number of brain metastases ever is - All are less than or equal to 2 cm

    - They have been resected surgically or have been treated with gamma-knife or
    stereotactic radiosurgery

    - The patient has not taken any steroids

    - Subjects must not have a serious intercurrent illness including, but not limited to:

    - Ongoing or active infection requiring parenteral antibiotics on Day 1

    - History of congenital long QT syndrome or mean corrected QTc interval > 450 msec
    at baseline

    - Clinically significant cardiovascular disease:

    i. Myocardial infarction within 6 months ii. Unstable angina iii. New York heart
    association grade II or greater congestive heart failure iv. Serious cardiac
    arrhythmia requiring medication

    - Serious non-healing wound, active ulcer, or untreated bone fracture

    - Psychiatric illness/ social situations that would limit compliance with study
    requirements.

    - Subjects must be HIV negative

    - Subjects must be Hepatitis C negative

    - Subjects must have the ability to understand and the willingness to sign a written
    informed consent document.

    Exclusion Criteria:

    - Prior therapy with a MEK inhibitor or an inhibitor of mutant BRAF

    - Patients on warfarin therapy due to the requirement for multiple biopsies

    - Subjects who have another cancer diagnosis, except that the following diagnoses will
    be allowed:

    - Squamous cell cancer of the skin without known metastasis. Subjects with
    suspected cuSCCs should have them excised prior to study registration

    - Basal cell cancer of the skin without known metastasis

    - Carcinoma in situ of the breast (DCIS or LCIS)

    - Carcinoma in situ of the cervix

    - Any cancer without distant metastasis that has been treated successfully,
    without evidence of recurrence or metastasis over 3 years

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Time course by which vemurafenib increases T cell infiltration

    Secondary Outcome Measures

    Activation state tumor-infiltrating T cells

    Expression of immunoinhibitory proteins

    Lysis of tumor cells

    Presence of tumor associated immune signatures

    Changes in endothelial homing receptor ligands and tumor associated chemokines

    Presence of immune/inflammatory expression pattern

    Presence of tissue-specific destruction and IFN-gamma upregulation

    IFN-gamma upregulation and TSD expression patterns relative to baseline

    Trial Keywords

    melanoma

    vemurafenib