Clinical trial: NCT01369875
Section: Alternatives
Subsections: Alternative Approaches Or Treatments What Other Choices Do I Have If I Do Not Take Part In This Study?

Instead of being in this study, you have these options:
- Getting treatment or care for your cancer without being in a study o One of the few therapies that have been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma is interleukin-2 (IL-2), also called aldesleukin. IL-2 can shrink tumors in approximately 16% of patients with metastatic melanoma.  
o Chemotherapy, such as dacarbazine or temozolomide, is also used to treat melanoma.  
- Taking part in another study - Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.  
Please talk to your doctor about these and other options.  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 6 of 12 pages
Clinical trial: NCT01369875
Section: Duration of Study Involvement
Subsections: How Many People Will Take Part In This Study?|Recovery

As many as 63 patients may participate in this study. If you decide to participate, you will undergo a series of tests to make sure you are eligible, including blood tests and scans as described below.

After your last dose of IL-2, you will recover in the hospital until you are well enough to go home. This usually takes 5 to 10 days; however, you may need to stay in the hospital for longer than 10 days before you are well enough to go home. We will continue to give you support medications, do laboratory tests, and watch you closely for any side effects until we feel your condition is stable. In addition to the laboratory tests to monitor your condition, we will remove approximately 9 teaspoons of blood three times per week to study the effects of this regimen on your immune system. The maximum amount of blood for research is approximately 2.3 cups in 8 weeks.  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 5 of 12 pages Optional Biopsy We may ask you to allow us to perform a biopsy (remove a small piece) of your tumor or lymph node after receiving the treatment to look at the effects of the treatment on the immune cells in your tumor. The biopsy to be performed is exclusively for research purposes and will not benefit you. It might help other people in the future. Even if you sign "yes" to have the biopsy you can change your mind at any time. Please read each sentence below and think about your choice. After reading each sentence, circle and initial the answer that is right for you. The decision to participate in this part of the research is optional, and no matter what you decide to do, it will not affect your care. I agree to have the tumor or lymph node biopsy for the research tests in this study.
Clinical trial: NCT01369875
Section: Participant's Rights
Subsections: Research Subject'S Rights

You should understand that this study involves research and that your participation is voluntary. Unexpected or unforeseeable side effects may also occur. Your participation in this protocol may be terminated without your consent if  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 9 of 12 pages your physician feels that it would not be safe for you to continue. Any significant new findings that relate to this protocol will be discussed with you. The sponsor of this study is Dr. Steven A. Rosenberg. Your records may be reviewed by NIH organizations and by organizations outside the National Institutes of Health, such as representatives of the US Food and Drug Administration. Every effort will be made to protect your privacy in any recording or reporting of this information.
Clinical trial: NCT01369875
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Risks Or Discomforts Of Participation|Potential Benefits Of Participation Are There Benefits To Taking Part In This Study?|What Are The Costs Of Taking Part In This Study?

The major side effects of this treatment (described in detail below) that are most severe include:
- Infection and low blood counts caused by the chemotherapy - Confusion and changes in mental status caused by the IL-2 - Fluid retention, low blood pressure, shortness of breath, and high heart rate caused by the IL-2. Other side effects of IL-2 are listed below.  
We will discuss the side effects of this experimental treatment with you. You will be given medicines, transfusions, and treatments to prevent or treat the side effects including drugs to prevent and/or treat different types of infections. We will try to make you as comfortable as possible.  
During the leukapheresis procedure, you may have some tingling in your face and lips due to the medicine used to keep your blood from clotting during the procedure. The nurses may give you a calcium-containing antacid to chew that takes away this tingling. Rarely, people may experience lightheadedness or dizziness. We ask that you eat prior to the procedure to prevent this. Rare complications of this procedure are lowered blood pressure, bleeding or bruising where the needles are put in your arms. Discomfort due to a biopsy may include pain at the site of the biopsy, swelling, bruising, and infection. When IL-2 is given through a catheter, it can make you feel like you have the flu. It can also cause confusion and mental status changes making you unable to make sound decisions. Prior to beginning treatment, we will ask you to complete a Durable Power of Attorney so that a person of your choosing can make health care decisions for you in case you develop these side effects. In our experience giving IL-2 to over 2,000 patients we have found that these side effects go away within a few days of stopping the IL-2.

One aim of this study is to see if this experimental young TIL will cause your tumors to shrink. We hope that you will get personal medical benefit from taking part in this study, but we cannot be certain. These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer.

If you choose to take part in the study, the following will apply, in keeping with the NIH policy:
- You will receive study treatment at no charge to you. This may include surgery, medicines, laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health (NIH), or arranged for you by the research team to be done outside the Clinical Center, NIH if the study related treatment is not available at the NIH.  
- There are limited funds available to cover the cost of some tests and procedures performed outside the Clinical Center, NIH. You may have to pay for these costs even if they are not covered by your insurance company.  
- Medicines that are not part of the study treatment will not be provided or paid for by the Clinical Center, NIH.  
- Once you have completed taking part in the study, medical care will no longer be provided by the Clinical Center, NIH.
Clinical trial: NCT01369875
Section: Procedures
Subsections: What Will Happen If You **Take Part In This Research Study?** Cell Harvest And Growth|Work Up|Catheter Insertion|Leukapheresis|Chemotherapy Regimen (Day -7 Through Day -1)|Cell Infusion And Il-2 Regimen (Day 0 To Day 4)|Til Cell Infusion

You will first have some tumors removed from your body so we can grow the TIL cells contained in the tumor in the laboratory. We will be obtaining the cells from a biopsy of your tumor or during surgery. Based on our previous experience growing Young TIL without the help of ECCE cells, at approximately 20% of the time we are unable to successfully grow the cells needed for this procedure. However, we have used ECCE cells in laboratory experiments and have shown that these ECCE cells help TIL have a better chance at growing. For this study, after obtain the cells from your tumor, we will try to grow them using two different methods. If your cells grow well using the original method to generate Young TIL, these are the TIL we will use to grow more cells for therapy. If your cells do not grow this way, we will check to see if your Young TIL are growing in the presence of ECCE cells. If your cells do not grow with either method, you will not be able to receive the cell infusion, you will be taken off this study, and we will look at alternative treatments for you or return you to the care of your referring physician. We usually know after about 2-4 weeks whether the cells will grow well enough to be used as an experimental treatment on this protocol. At the time we determine that your cells are not growing, we will inform you and discuss your options with you. The procedure for converting your normal cells into cells that are able to recognize your tumor has been studied in the laboratory and although these cells can destroy tumor cells in the test tube, it is not clear that they will be able to destroy them inside a patient's body. We have grown young TIL cells similar to these and treated over 50 patients. The Young TIL cells in this study are different from others that we have given patients because they are grown in the presence of special ECCE cells that help stimulate the cells to grow. In previous studies we have used other cells from the patient's own blood or from a normal volunteer to stimulate the Young TIL to grow, but the process of collecting these extra cells is expensive, time-consuming and sometimes does not generate enough cells to help grow the Young TIL. This experimental study will test whether growing young TIL cells this way is effective in shrinking your cancer tumor(s). In our initial experience with Young TIL cells, of 45 patients treated and evaluated for response, 11 had some shrinkage.

Prior to receiving the experimental treatment you will undergo many tests. These include imaging procedures, heart and lung function tests, and laboratory tests. If you are a woman, you will undergo a pregnancy test. You will also have a large catheter inserted into a vein and leukapheresis (see description below) will be performed. You may be admitted to the hospital for these tests. However, you will be allowed to leave on pass on the days that you are not having tests performed.

Prior to beginning the experimental therapy, you will have an intravenous (IV) catheter placed in your upper chest. The area will be numbed with an anesthetic before the catheter is put in. Although rare, putting these catheters in can sometimes cause collapse of a lung or cause bleeding. Lung collapse is treated by putting a tube into your chest for a few days to allow your lung to expand. Pressure is placed on any area that might bleed. Other IVs may be needed in one or both of your arms if we to give you extra fluids, medicines, or nutrition.  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 4 of 12 pages

Leukapheresis is a procedure that allows us to remove certain types of blood cells from you and return the rest of your blood. It is a very common procedure that is done routinely here at the NIH with very few risks. During leukapheresis, blood is removed from you through a needle in your arm, circulated through a machine that divides whole blood into red cells, plasma (the serum part), and lymphocytes (or white cells), and then the plasma and red cells are returned to you through a second needle in your other arm. The white blood cells may be used to help grow the Young TIL and after the experimental therapy, you will have leukapheresis so that we can test your cells.

You will be admitted to the hospital. For the seven days prior to receiving your cells you will be given two chemotherapy medicines to suppress your immune system so the cells we give you can work without any interference from the cells in your immune system. There is evidence in animal experiments and human studies that this can increase how effective the cells we give are in fighting cancer cells, but it is not known whether this is true for your cells. The two chemotherapy medicines are called cyclophosphamide and fludarabine. The cyclophosphamide will be given into your IV over 1 hour for two days and the fludarabine will be given into your IV for 30 minutes every day for the five days following the cyclophosphamide. These chemotherapies will not treat the tumor and are given only to see if the suppression of the immune system improves the functioning of the experimental cells we will be giving you.

One to four days after the last dose of chemotherapy, you will be given the TIL. The TIL will be given in your catheter over 20-30 minutes. Within 24 hours after the TIL infusion, you will be given high dose aldesleukin (IL-2) through your catheter. IL-2 is approved by the FDA for treatment of metastatic melanoma and metastatic renal cell cancer. The purpose of giving the IL-2 with this therapy is to help the cells live longer in your body. The IL-2 will be given as a 15minute infusion every 8 hours for up to five days after the cell infusion (maximum number of doses is 15). Doses may be skipped or delayed depending on how well you tolerate the doses. The risks of the cells and IL-2 are described on the following pages. The day after you receive the TIL, we will give you G-CSF (filgrastim) as a shot or injection under the skin. This will continue until your white blood cell counts begin to return to normal.

All TIL cells will be given through your catheter while we keep you in the patient care unit so we can watch you closely.  
Potential risks include:
- shortness of breath, or
- an autoimmune reaction such as loss of skin pigment (known as vitiligo) or inflammation of the eye (uveitis)
which may require the use of steroid eye drops.  
- As this is a new experimental therapy, side effects that we do not anticipate that may cause your condition to deteriorate may be encountered. Any new information that becomes available during the course of this study will be shared with you.  
In the first 24 patients treated on the initial Young TIL study, we have observed an increase in the number of patients who have experienced some of the side effects of cells and aldesleukin. One out of three these patients were intubated (a tube was placed in the throat to help them breath), and two patients were put on dialysis due to abnormalities in kidney function.  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 7 of 12 pages Medications The side effects of cyclophosphamide, fludarabine, IL-2 and some of the other medications you will receive are listed in below.  
| Cyclophosphamide and Fludarabine side effects Common Less Common                                                                                                                                                                                                                    | Rare                                                                                                                                                                                                                                                                                                          |                                                                      |              |                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|--------------|---------------------------|
|                                                                                                                                                                                                                                                                                    | Changes in blood counts  including: low red cell count  (causing fatigue and  shortness of breath), low  platelet count (increasing the  risk of bleeding and  bruising), decrease in white  blood cells (increasing the  risk of infection and the need  for treatment with antibiotics  or other treatment) |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Loss of appetite, nausea,  vomiting,                                                                                                                                                                                                                                                                          |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Diarrhea, stomach pain                                                                                                                                                                                                                                                                                        |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Mouth sores                                                                                                                                                                                                                                                                                                   |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Hair loss                                                                                                                                                                                                                                                                                                     |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Fatigue                                                                                                                                                                                                                                                                                                       |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Muscle or joint aches                                                                                                                                                                                                                                                                                         |                                                                     | Bleeding     |                           |
|                                                                                                                                                                                                                                                                                    | Infection                                                                                                                                                                                                                                                                                                     |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Bladder irritation with  bloody urine                                                                                                                                                                                                                                                                         |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Severe allergic reaction  (difficulty  breathing/swelling)                                                                                                                                                                                                                                                    |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Headache or dizziness                                                                                                                                                                                                                                                                                         |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Sweating                                                                                                                                                                                                                                                                                                      |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Swelling of arms or legs                                                                                                                                                                                                                                                                                      |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Skin changes, rash,  blisters                                                                                                                                                                                                                                                                                 |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Weakness                                                                                                                                                                                                                                                                                                      |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Hearing loss                                                                                                                                                                                                                                                                                                  |                                                                     | Heart damage |                           |
|                                                                                                                                                                                                                                                                                    | Lung damage                                                                                                                                                                                                                                                                                                   |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Kidney damage                                                                                                                                                                                                                                                                                                 |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Inflammation of the eye resulting in  blindness                                                                                                                                                                                                                                                               |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Inflammation of nervous system resulting  in death                                                                                                                                                                                                                                                            |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Epstein Barr Virus Lymphoma. This can  be fatal (Two patients on other studies in  the Surgery Branch developed EBV  lymphoma, and one died as a result of  this disease.)                                                                                                                                    |                                                                      |              |                           |
|                                                                                                                                                                                                                                                                                    | Loss of fertility                                                                                                                                                                                                                                                                                             |                                                                      |              |                           |
| Support Medications - side effects Common Less common                                                                                                                                                                                                                               | Rare                                                                                                                                                                                                                                                                                                          |                                                                      |              |                           |
| Filgrastim (To increase production of white blood cells)  Bone Pain  Severe headache                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                              | Severe breathing problems                                            |              |                           |
|                                                                                                                                                                                                                                                                                    | Rupture of your spleen                                                                                                                                                                                                                                                                                        |                                                                      |              |                           |
| Bactrim (To prevent a specific type of pneumonia)  Fever  Nausea, vomiting,   Skin rash with itching  reduced number of white  blood cells   Allergic reaction Fluconazole: (To prevent fungal infections)   Headache  Nausea, vomiting, diarrhea,  abdominal pain  Itching |                                                                                                                                                                                                                                                                                                              | A skin disorder called Stevens Johnson  Syndrome, which can be fatal |              |                           |
|                                                                                                                                                                                                                                                                                    | Liver damage which may be permanent                                                                                                                                                                                                                                                                           |                                                                      |              |                           |
| Acyclovir and Valacyclovir                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                              | Temporary decrease in                                                |             | Skin rash, hives, itching |
| kidney function which may                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                              | Tremors, dizziness, Confusion, seizures                              |              |                           |  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 8 of 12 pages  
| not cause any symptoms                 |                                                                                                                                                                                                                  |      |                                                                                     |
|----------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------------------------------------------------------------------------------------|
|                                       | Nausea, vomiting,  diarrhea, constipation                                                                                                                                                                        |      |                                                                                     |
|                                       | Pain and irritation at place  of injection                                                                                                                                                                       |     | Fatigue                                                                             |
|                                       | Blood in the urine                                                                                                                                                                                               |      |                                                                                     |
| IL-2 (aldesleukin) side effects Common | Less common                                                                                                                                                                                                      | Rare |                                                                                     |
|                                       | Fever, chills, and fatigue                                                                                                                                                                                       |      |                                                                                     |
|                                       | Lowered platelet and red blood  cell levels that may require  transfusions                                                                                                                                       |      |                                                                                     |
|                                       | Significant fluid retention causing  weight gain (as much as 20  pounds).                                                                                                                                        |      |                                                                                     |
|                                       | Low blood pressure                                                                                                                                                                                               |      |                                                                                     |
|                                       | Increased heart rate                                                                                                                                                                                             |      |                                                                                     |
|                                       | Low urine output                                                                                                                                                                                                 |      |                                                                                     |
|                                       | Swelling in your extremities,                                                                                                                                                                                    |      |                                                                                     |
|                                       | Fluid in your lungs that can  require oxygen                                                                                                                                                                     |      |                                                                                     |
|                                       | Dry mouth, nausea, vomiting and  diarrhea;                                                                                                                                                                       |      |                                                                                     |
|                                       | Rash, itching; and changes in  skin or hair pigmentation, called  vitiligo;                                                                                                                                      |      |                                                                                     |
|                                       | Changes in mental status,  including confusion, difficulty  sleeping or vivid dreams; this can be severe and require sedation  and monitoring in the ICU                                                         |     | Decrease in thyroid  function that may  require daily thyroid  hormone replacement; |
|                                       | Abnormal kidney and  liver function that can be  severe;                                                                                                                                                         |      |                                                                                     |
|                                       | Abnormal heartbeats or  low blood pressure that  may require treatment in  the ICU.                                                                                                                              |      |                                                                                     |
|                                       | Breathing problems  which may need  monitoring in ICU and  insertion of a breathing  tube                                                                                                                        |     | Bowel perforation (a hole) requiring  longer hospitalization or surgery.            |
|                                       | Autoimmune disease, where your  immune system attacks cells in  organs of your body. Should this  occur, you will be treated with  steroids to stop the immune  response.                                        |      |                                                                                     |
|                                       | Damage to the heart muscle or heart  attack                                                                                                                                                                      |      |                                                                                     |
|                                       | Loss of blood flow to the extremities  due to medicines used to treat very  low blood pressure and shock. In one  instance a patient had to have her  lower arm amputated after treatment  with these medicines. |      |                                                                                     |
|                                       | IL-2 is mixed with human albumin  which could cause an allergic reaction  or potentially transmit viral infections,  although we have not had this occur.                                                        |      |                                                                                     |
Clinical trial: NCT01369875
Section: Purpose of Research
Subsections: Introduction|Why Is This Study Being Done?|Why Are You Being Asked To Take Part In This Study?|Description Of Research Study

We invite you to take part in a research study at the National Institutes of Health (NIH). First, we want you to know that:
Taking part in NIH research is entirely voluntary. You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking part in a study or be under evaluation for study participation. You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.  
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH doctors or research team before you agree to the study. Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other health professional.

The purpose of this study is to determine whether we can treat melanoma by taking blood cells called lymphocytes from patients' tumors, and grow them in the laboratory in large numbers to then give the cells back to the patient. These cells are called Young Tumor Infiltrating Lymphocytes, or Young TIL and these Young TIL were prepared in the presence of another type of cell called Engineered Cells for Costimulation Enhancement (ECCE) that we hope will help us make the Young TIL cells grow easier and faster. We will test whether this experimental regimen can cause your tumor to shrink, as well as test the safety of this regiment and the effects on the immune system. Before giving the cells back to you, we will suppress (make it less able to fight) your immune system with two chemotherapy agents in order to create room for your cells and to prevent the immune system cells from working against the cells we give to you. After giving you the cells, we will give you aldesleukin (IL-2) for up to 5 days to help keep the cells alive.  
PATIENT IDENTIFICATION **CONSENT TO PARTICIPATE IN A CLINICAL**  
RESEARCH STUDY  
- Adult Patient or - Parent, for Minor Patient NIH-2514-1 (7-09) P.A.: 09-25-0099 File in Section 4: Protocol Consent (1)  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 2 of 12 pages

Your doctor has told you that you have been diagnosed with melanoma. The only treatment available at this time that has been shown to cure melanoma is aldesleukin. We invite you to take part in this research study that is trying to find effective treatments for patients with melanoma.

| Stage          | Timeframe                            | Location           | Comments & Instructions                                                                                                              |
|----------------|--------------------------------------|--------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| Work up        | 1-2 weeks                            | Inpatient and      | Scans, x-rays, labs, leukapheresis other tests as                                                                                    |
| outpatient     | needed                               |                    |                                                                                                                                      |
| Chemotherapy   | 1 week                               | Inpatient          | Receive IV chemotherapy to prepare your                                                                                              |
| (day -7 to -1) | immune system for the cells          |                    |                                                                                                                                      |
| Cells and IL-2 | 1-5 days                             | Inpatient and      | Receive Young TIL, and then IL-2 every 8 hours                                                                                       |
| (Day 0)        | possibly ICU                         | for up to 15 doses |                                                                                                                                      |
| Recovery       | 1-2 weeks                            | Inpatient unit     | Recover from the effects of chemotherapy and  IL-2                                                                                   |
| Follow -up     | Ongoing  unless disease  progression | Outpatient         | Return to clinic for physical exam, review of side  effects, labs, scans every 1-4 months for the first  year then every 3-4 months. |  
STUDY NUMBER: 11-C-0163 CONTINUATION: page 3 of 12 pages
Clinical trial: NCT01369875
Section: Withdrawal from Study
Subsections: Stopping Therapy

Your doctor may decide to stop your therapy for the following reasons:
- if he/she believes that it is in your best interest - if your disease comes back during treatment - if you have side effects from the treatment that your doctor thinks are too severe - if new information shows that another treatment would be better for you In this case, you will be informed of the reason therapy is being stopped.  
You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like you to talk to the study doctor and your regular doctor first.