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A Phase I/II Trial of Leflunomide in Combination With Vemurafenib in Patients With V600 Mutant Metastatic Melanoma

Phase 1/Phase 2
18 Years
Open (Enrolling)

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Trial Information

A Phase I/II Trial of Leflunomide in Combination With Vemurafenib in Patients With V600 Mutant Metastatic Melanoma

In this study we are looking for the highest dose of the study drug that can be administered
safely without severe or unmanageable side effects in participants that have metastatic
melanoma. For this reason, not everyone who participates in this research study will receive
the same dose of the study drug. The dose you get will depend on the number of participants
who have been enrolled in the study before you and how well they have tolerated their doses.

Both leflunomide and vemurafenib will be given as a pill to take by mouth. We will instruct
you to take leflunomide pills once a day and vemurafenib pills twice a day. We will give you
a study drug dosing calendar for each treatment cycle. Each treatment cycle lasts 28 days (4

At the start of the study you will take leflunomide alone for the first 14 days of cycle 1.
For the first 3 days of cycle 1, you will receive a dose of leflunomide larger than you will
be receiving for the rest of the research study (loading dose). These first few larger doses
will introduce a certain amount of leflunomide into your body. The doses you receive after
Day 3 will be lower but will be used to maintain that level of leflunomide in your body.
Starting on Day 15, you will begin the twice-a-day Vemurafenib treatment while you continue
to take leflunomide once daily.

During all cycles you will have routine blood tests, a physical exam and you will be asked
questions about your general health and specific questions about any problems that you might
be having and any medications you may be taking. These procedures will be performed once
every cycle throughout the study.

If you have a skin lesion that can be surgically removed, the study doctor may ask you to
undergo additional skin punch biopsies as part of this research study. These samples will be
taken at three times throughout the study: before you begin the study treatment, after the
initial 2-week study treatment of leflunomide alone, and then 2 weeks after starting the
leflunomide and vemurafenib combination. We will assess your tumor by either CT scan or MRI
scan once every eight weeks while you are in this research study.

After you have completed participation in this study we would like to keep track of your
medical condition for the rest of your life. We would like to do this by calling you on the
telephone once every 4 weeks to see how you are doing. Keeping in touch with you and
checking your condition every year helps us to look at the long-term effects of the research

Inclusion Criteria:

- Histological or cytological confirmation of metastatic or unresectable melanoma

- Melanoma must be documented to contain a BRAF V600 mutation by a CLIA approved assay

- Measurable disease

- Less than or equal to 2 prior systemic treatment regimens for distant metastatic

Exclusion Criteria:

- Pregnant or breastfeeding

- Chemotherapy or radiation therapy within 4 weeks

- Prior therapy with a BRAF inhibitor or MEK inhibitor or leflunomide

- Receiving other study agents

- Known brain metastases that are symptomatic and require corticosteroids

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vemurafenib or leflunomide

- Uncontrolled intercurrent illness

- HIV-positive

- History of a different malignancy

Type of Study:


Study Design:

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

Outcome Measure:

Phase I: Determine maximum tolerated dose of Vemurafenib + Leflunomide

Outcome Description:

To determine the maximum tolerated dose of vemurafenib plus leflunomide in patients with metastatic melanoma with V600 mutation with a requirement that fewer than one third of patients have dose-limiting toxicities. The goal of the study is to combine vemurafenib and leflunomide at their respective FDA approved doses and schedules.

Outcome Time Frame:

3 months

Safety Issue:



United States: Institutional Review Board

Study ID:




Start Date:

July 2012

Completion Date:

Related Keywords:

  • Melanoma
  • Metastatic
  • Unresectable
  • Clearly progressive
  • BRAF mutation
  • Melanoma



Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Brigham and Women's HospitalBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617