Leflunomide+Vemurafenib in V600 Mutant Met. Melanoma

Status:	Recruiting
Conditions:	Skin Cancer
Therapuetic Areas:	Oncology
Healthy:	No
Age Range:	18 - Any
Updated:	11/30/2013
Start Date:	July 2012
Contact:	Keith Flaherty, MD
Email:	kflaherty@partners.org
Phone:	6177244000

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

This research study is a Phase I/II clinical trial. Phase I clinical trials test the safety
of an investigational combination of drugs. Phase I studies also try to define the
appropriate dose of the investigational drug combination to use for the Phase II portion of
the study, which will enroll more participants and continue to study the effects of the drug
and the safest dose. "Investigational" means that the combination of vemurafenib and
leflunomide is still being studied and that research doctors are trying to find out more
about it. It also means that the FDA has not approved this drug combination for your type of
cancer.

Genes are a specific part of your cell materials which send code messages to determine what
the investigators bodies look like, such as eye color, and instruct cells to control growth
and development of the body. Researchers have found that a large number of melanoma cells
have mutations in the BRAF gene. Normally, the BRAF gene helps to control how cells grow.
Mutations in the BRAF gene may disrupt this control and allow cells in the skin to change
into cancer cells, in which case, the cells keep dividing and growing out of control.
Specifically, it has been shown that vemurafenib blocks the effects of these mutations in
the BRAF gene, and, as a result, may help to prevent cancer growth. The FDA has approved
vemurafenib for use in patients with BRAF mutation positive melanoma that is unable to be
removed by surgery (unresectable) or that has spread (metastatic).

Leflunomide is in a class of medications called disease-modifying antirheumatic drugs
(DMARDs). It is FDA approved for the treatment of rheumatoid arthritis and it is believed to
decrease inflammation in that setting. However it is not approved for treatment of melanoma.
The researchers of this study believe this agent may help prevent cancer growth as well as
enhance the properties of drugs that target the BRAF gene (such as vemurafenib) based on
recently published laboratory research, and would like to learn more about any effects this
combination may have on your disease.

The main purposes of this study are to determine the highest dose of vemurafenib and
leflunomide that can be given in combination without causing severe side effects, to see
whether the combination of vemurafenib and leflunomide is safe in participants with BRAF
mutant metastatic melanoma and to learn if the combination of vemurafenib and leflunomide
shows any signs of effectively treating your disease.

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
weeks).

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
study.

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
disease

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

We found this trial at

sites

Brigham and Women's Hosp

75 Francis street
Boston, Massachusetts 02115

(617) 732-5500