Trial Information

Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma

This study uses cell transfer therapies to treat patients with metastatic melanoma. Immune
cells, also called T cells, can recognize and kill melanoma cells. These tumor fighting
immune cells are taken and grown in the laboratory and given back to the patient. A vaccine
prepared from special blood cells, known as dendritic cells, will be studied to determine
whether it will help the immune cells to work better at fighting the melanoma. Patients in
this study will also be treated with chemotherapy and high dose IL-2.

A T-cell is a type of lymphocyte. Lymphocytes are a type of white blood cell that protect
you from viral infections; help other cells fight bacterial and fungal infections; produce
antibodies; fight cancers; and coordinate the activities of other cells in the immune
system.

Dendritic cells are cells that specialize in presenting antigens to the T-cells. An antigen
is any substance capable of triggering an immune response. The cells in this study capable
of presenting the antigens are called dendritic cells, and the T-cells are cells in the
immune system responsible for coordinating the destruction of foreign antigens.

Dendritic Cells are able to attach to their surface small portions of the melanoma molecule
which are recognized by the immune system and may be responsible for causing lymphocytes to
attack the tumor. Besides attaching or binding this part of the antigen, called peptide, to
their surface, dendritic cells can, with the help of specialized molecules present on their
surface, boost the immune system. The purpose of this experimental protocol is, therefore,
to enhance the immune response against the cancer cells in your body.

Chemotherapy is used to greatly reduce the number of normal lymphocytes circulating in your
body, so that there will be more "space" for the cancer fighting lymphocytes (T-cells) that
will be infused.

IL-2 was recently approved by the FDA for the treatment of metastatic melanoma. IL-2 is a
hormone naturally found in the body that boosts the immune system. It is made in the lab,
but from a normal human gene.

A biopsy procedure of the tumor will be performed. A whole or part of your tumor will be
cut and removed using high enough pain medication. This biopsy is being done to help
attempt to grow the T-cells necessary for the treatment. Your T-cells will be grown in the
laboratory with the help of radiation-exposed cells from other blood donors. These donor
cells are tested to be negative for currently screened infectious diseases. Although
precautions have been taken to lower the chance of you receiving infectious diseases from
the cells, the use of these donor cells may cause an unwanted and unexpected immune response
and/or viral infection, which could affect your health and/or well being. If researchers
are unable to grow enough cells or if your tumor does not have enough of the necessary
components, you will not continue on study and other treatment options will be discussed
with you. If the growth of these cells is successful, you will be continued on the study.
There is up to a 6 week waiting period between the biopsy and continuing to the next phase
of this study. You will be allowed to participate in other treatment plans during this time
period.

You will either receive T-cells alone or be randomized (as in the toss of a coin) to one of
two three groups. Participants in one group will receive chemotherapy and IL-2 plus
T-cells. Participants in the second group will receive chemotherapy and IL-2 plus T-cells
and the vaccine of dendritic cells. Participants in the third group will receive
Vemurafenib and IL-2 plus T-cells and the vaccine of dendritic cells.

If you are randomized to receive dendritic cells, researchers will take some of your blood
through a procedure called apheresis. During the apheresis procedure, white blood cells are
removed from you using a serum cell separator machine. This requires putting a needle into
your arm or a temporary central venous catheter to collect blood to go into the machine.
The machine divides whole blood into red cells, plasma (the serum part) and lymphocytes (or
white cells). The lymphocytes will be taken out, and the plasma and red cells returned to
you through a second needle in your other arm or the central venous catheter. A single
apheresis procedure takes about 3-4 hours to complete. If enough cells are not collected,
then additional apheresis procedures may need to be performed. The collected cells will be
used to make the dendritic cells. A stress cardiac test (stress thallium, stress MUGA,
dobutamine echocardiogram) within 6 months of lymphodepletion to rule out cardiac ischemia.
A pulmonary function tests, (FEV1 > 65% or FVC >65% of predicted) within 6 months of
lymphodepletion. You will also have a CT scan of chest, abdomen and pelvis (a PET/CT may
also be used), an MRI/CT of brain, an EKG, and a pregnancy test will be administered.

You are expected to stay in the Houston area for at least 14 days in order to participate in
the chemotherapy and cell infusion phase of the study. After researchers have grown your
cells from the samples collected, you will be given two chemotherapy medicines to decrease
your immune system so the cells given back to you can work without any interference from the
cells in your immune system. This chemotherapy will be given for seven days prior to
receiving your cells. The two chemotherapy medicines are called cyclophosphamide and
fludarabine. The cyclophosphamide will be given for two days (on Days -7 and -6) and the
fludarabine for five days (on Days -5 through -1) immediately before the cells are infused.
On Days -7 and -6, cyclophosphamide will be given by vein over about 2 hours. A drug called
Mesna will also be infused by vein over about 24 hours starting on Day -7. Mesna is given to
protect the bladder from side effects of the cyclophosphamide. On Days -5 to -1,
fludarabine will be given by vein once a day over about 15-30 minutes.

The chemotherapy treatment will be followed by the infusion of the T-cells (Day 0). A
catheter (a thin flexible tube inserted into the body to permit introduction or withdrawal
of fluids) will be put in place to give you the cells. The catheter may be placed into a
vein in your arm or in a large vein in your neck. If the cells need to be given through a
large vein either in your upper chest or in your neck, the area will be numbed with medicine
before the catheter is put in. Other catheters may be needed in one or both of your arms
for additional routes to give you fluids, medicines, or extra nutrition. If you are
assigned to the vaccine group, you will receive the vaccine by vein about 4 hours after the
T-cells are given and again on Day 21 (+/- 7 days) if your platelet count is high enough.
If your platelet count is not high enough, the infusion will be delayed for up to day 49
until Day 35-42 and the second course of high dose IL-2 will be given.

On Days 1-5 and 22-26 (+/- 7 days) you will receive high dose IL-2 by catheter for up 10
days for up to 15 doses as an inpatient if your platelet count is high enough on Day 21.
Each infusion of IL-2 should take about 15 minutes.

You will be monitored closely during this study for any side effects of treatment. During
the T-cell and dendritic cell infusion, your vital signs will be measured every 15 minutes
and then one time an hour for 4 hours after the infusion. Blood samples (about 3 teaspoons
each) will be taken for routine blood tests every 1 to 2 days of treatment.

In order to help decrease the risk of infection during this study, you will be given some
antibiotics. You will be given levofloxacin once a day by mouth or vein until your white
blood cell level returns to an acceptable level. You will also take trimethoprim and
sulfamethoxazole (SMX) by mouth twice a day, beginning on Day -7 and continuing for at least
6 months after chemotherapy.

It is possible that you will receive a 2nd treatment (re-treatment) that will be identical
to your first schedule of therapy (an entire repeat cycle of chemotherapy, IL-2, and T-cells
with or without vaccine). If the disease gets worse, you experience any intolerable side
effects, or your doctor feels it is in your best interest, you will be taken off the study
and your doctor will discuss other treatment options with you.

You will have blood samples collected to evaluate the activity of the T-cells and their
ability to attack the tumor. Blood samples (about 4 1/2 tablespoons each time) will be
taken before surgery to remove your tumor or tumor biopsy, before chemotherapy starts and
again on Days 7, 14, 21, 28, 35, 42 (+7 days) and at each followup visit (+/- 7 days).

At about 6 weeks (+ 7 days) and at 12 weeks (+ 7 days) after you receive the T-cell and/or
vaccine infusion (for each cycle), you will return to the clinic for a physical exam and for
repeat scans to evaluate the size of your tumors.

If possible, you will also have blood samples (about 4 1/2 tablespoons) drawn on all
follow-up visits to check the effects of the T-cells on your blood cells.

If the doctor thinks it is needed, you will receive pentamidine by vein over 1 hour every 21
days for 6 months after lymphodepletion. If you cannot receive pentamidine, you will take
atovaquone by mouth.

This is an investigational study. The medications being used in this study are FDA
approved. The chemotherapy agents and IL-2 are commercially available drugs. However, their
use together in this study is experimental. The T-cell and vaccine therapy are authorized
for use only in research. A total of up to 159 patients will take part in this study. All
will be enrolled at MD Anderson.