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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

Phase 2
18 Years
Open (Enrolling)

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Trial Information

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

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.

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

- 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


- Alkaline Phosphatase


- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time course by which vemurafenib increases T cell infiltration

Outcome Description:

CD8 T cell count per mm2 of tumor

Outcome Time Frame:

4 weeks

Safety Issue:


Principal Investigator

Michael B Atkins, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Georgetown Lombardi Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2013

Completion Date:

December 2015

Related Keywords:

  • Melanoma
  • melanoma
  • vemurafenib
  • Melanoma



Georgetown Lombardi Comprehsnive Cancer CenterWashington, District of Columbia  20007