Clinical trial: NCT01993719
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 for treatment:
.  
Getting treatment or care for your cancer without being in a study  
•
Taking part in another study
.  
Getting no treatment; or getting comfort care which is also called palliative care. This type of care helps reduce pain, tiredness, appetite problems, and other problems caused by 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.
Clinical trial: NCT01993719
Section: Confidentiality
Subsections: Will Your Medical Information Be Kept Private?|Certificate Of Confidentiality

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:  
The National Cancer Institute (NCI) and other government agencies, like the Food and
.  
Drug Administration (FDA), which are involved in keeping research safe for people.  
NIH Intramural Institutional Review Board
.  
The study Sponsor, Center for Cancer Research or their agents
.  
| PATIENT        |
|----------------|
| IDENTIFICATION |  
Iovance Biotherapeutics, Inc.
A description of this clinical trial will be available on http://www.Clinicaltrials.gov , as required by U.S. Law. This Web site will not include information that can identify you. At most the Web site will include a summary of the results. You can search this Web site at any time.  
| CONTINUATION SHEET for either:       |
|--------------------------------------|
| NIH-2514-1 (07-09)                   |
| NIH-2514-2 (10-84)                   |
| P.A.: 09-25-0099                     |
| File in Section 4:  Protocol Consent |  
| Study   |
|---------|  
STUDY NUMBER: 14-C-0022 CONTINUATION: page 15 of 18 pages

To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers can use this Certificate to legally refuse to disclose information that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, if there is a court subpoena. The researchers will use the Certificate to resist any demands for information that would identify you, except as explained below.  
You should also know that there are several circumstances in which the Certificate does not provide coverage. These include when information:
.  
will be used for auditing or program evaluation internally by the NIH; or
•  
must be disclosed to meet the legal requirements of the federal Food and Drug Administration (FDA).
.  
is necessary for your medical treatment and you have consented to this disclosure;
.  
is for other research.
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or other person obtains your written consent to receive research information, then the researchers will not use the Certificate to withhold that information.  
The Certificate of Confidentiality will not protect against the required reporting by hospital staff of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others.
Clinical trial: NCT01993719
Section: Participant's Rights
Subsections: Research Subject'S Rights What Are The Costs Of Taking Part In This Study?

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 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: NCT01993719
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Risks Or Discomforts Of Participation What Side Effects Or Risks Can I Expect From Being In This Study?|Common, Some May Be Serious

The risks and discomforts of this research study can be significant. This experimental treatment can lead to long-term decrease in your immune function. It is also possible that you may lose your fertility following this experimental treatment. It is possible, although unlikely, that this experimental treatment may cause your death.  
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. You should talk to your study doctor about any symptoms that you experience while taking part in the study.

In 100 people receiving MK-3475 (pembrolizumab), more than 20 and up to 100 may have:
•
Tiredness PATIENT IDENTIFICATION  
| CONTINUATION SHEET for either:       |
|--------------------------------------|
| NIH-2514-1 (07-09)                   |
| NIH-2514-2 (10-84)                   |
| P.A.: 09-25-0099                     |
| File in Section 4:  Protocol Consent |  
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Clinical trial: NCT01993719
Section: Procedures
Subsections: Cell Harvest And Growth|Work-Up|Leukapheresis|Catheter Insertion|Follow Up And Evaluation Of Experimental Regimen|Retreatment|Cell Infusion|Aldesleukin (Il-2)|Medications

You underwent a procedure to take a piece of your tumor either from a biopsy or during surgery, so we can grow TIL from your tumor cells in the laboratory while enrolled on our companion protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols). Sometimes we are unable to successfully grow the cells needed for this procedure. If your cells do not grow, you will not be able to receive the cell infusion. We usually know after about 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. Several medications are used during the preparation of your cell product, be sure to tell your doctor if you are allergic to any antibiotics.

Prior to receiving the experimental treatment, you will undergo many tests. We will evaluate you for eligibility for participation on this trial with a physical examination, CT and/or MRI scans, xrays, EKG, heart and lung function tests, and blood tests. Patients who have a positive HIV blood test will not be eligible for this protocol because it may put them at higher risk of developing infections. If you are a woman, you will undergo a pregnancy test. 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.

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 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 procedure takes between 4-5 hours to complete. Rarely, people may experience lightheadedness or dizziness. We ask that you eat prior to the procedure to prevent this. The white blood cells collected before treatment may be used to help grow the cells and after the treatment, can be tested to see how the therapy has affected your immune system.

| IDENTIFICATION   |
|------------------|  
Prior to beginning the experimental cell treatment, 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.  
PATIENT  
| CONTINUATION SHEET for either:       |
|--------------------------------------|
| NIH-2514-1 (07-09)                   |
| NIH-2514-2 (10-84)                   |
| P.A.: 09-25-0099                     |
| File in Section 4:  Protocol Consent |  
1HIJKILMN/O!PP !QHI-HQO,(R%"ST,(R%$

You will need to continue to take Bactrim, an antibiotic, for at least 6 months following your treatment to prevent you from catching a certain type of pneumonia seen in patients who have low white blood cell counts. You will also need to take Valtrex, an anti-viral, for at least 6 months following your treatment to prevent any type of herpes simplex virus, like shingles. We will ask you to return to the NIH Clinical Center frequently after you are discharged approximately 6 and 12 weeks following treatment and then if you are responding to the treatment, every 3 months x3, then every 6 months x5 years and then as determined by your physician. The follow up visits will take up to 2 days. At each visit you will have lab tests, imaging studies and a physical examination. At some of your follow up visits, you may undergo leukapheresis or have about 8 tubes of blood drawn (4 tablespoons) so that we can see the effect this therapy has had on your immune system and if the cells we gave you are still alive. If you are unwilling or unable to travel to the NIH Clinical Center we will contact you by phone or email and we may ask you to send us lab, imaging, and physical exam reports. If your tumor appears to be growing, we will look for other investigational therapies you may be eligible for, or refer you back to the care of your local physician.

If your tumor does not shrink or shrinks and then recurs following the initial treatment and you have previously received pembrolizumab or nivolumab, you may receive one additional treatment.  
The second treatment may start at least 6- 8 weeks after your last dose of IL-2. In the retreatment arm we want to see if patients whose tumor has not responded to either pembrolizumab or TIL therapy might respond to the combination of these 2 therapies. We think that the pembrolizumab may help the cells that we give you last longer. You will receive the high dose chemotherapy regimen described above and you will receive pembrolizumab the prior to receiving your cells and then every three weeks for a total of 4 doses. The side effects of pembrolizumab are listed below and the research nurse will give you a hand out describing the side effects as well. We do not anticipate that the pembrolizumab will increase the side effects from the TIL or the aldesleukin but as we have not given these agents together before, we do not know if this will be true. We will monitor you very carefully for any increase in side effects and provide treatment as needed.

Based on our experience giving similar types of TIL cells grown in the laboratory, you may experience the following side effects:
Fever, chills and shortness of breath, which may last for a few hours (common)
.  
.  
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. You may also experience other side effects that we don't yet know about

| PATIENT        |
|----------------|
| IDENTIFICATION |  
When IL-2 is given through an intravenous 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  
| CONTINUATION SHEET for either:       |
|--------------------------------------|
| NIH-2514-1 (07-09)                   |
| NIH-2514-2 (10-84)                   |
| P.A.: 09-25-0099                     |
| File in Section 4:  Protocol Consent |  
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study NIH 2514-2, Minor Patient's Assent to Participate In A Clinical Research  
  
Study STUDY NUMBER: 14-C-0022 CONTINUATION: page 7 of 18 pages 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.

The side effects of cyclophosphamide, fludarabine, high dose IL-2 and some of the other medications you will receive are listed below:
Cyclophosphamide and Fludarabine side effects:  
| Common                   | Less Common                         | Rare                                 |                                   |
|--------------------------|-------------------------------------|--------------------------------------|-----------------------------------|
| Changes in blood         | Bleeding                            | Heart damage                         |                                   |
| .                        | .                                   | .                                    |                                   |
| counts including: low    | .                                   | Infection                            | Lung damage                       |
| red cell count (causing  | Bladder irritation                  | Kidney damage                        |                                   |
| .                        | .                                   |                                      |                                   |
| fatigue and shortness    | with bloody urine                   | Inflammation of the eye resulting in |                                   |
| .                        |                                     |                                      |                                   |
| of breath), low platelet | .                                   | Severe allergic                      | blindness                         |
| count (increasing the    | reaction (difficulty                | Inflammation of nervous system       |                                   |
| .                        |                                     |                                      |                                   |
| risk of bleeding and     | breathing/swelling)                 | resulting in death                   |                                   |
| bruising), decrease in   | .                                   | Headache or                          | Epstein Barr Virus Lymphoma. This |
| white blood cells        | dizziness                           | can be fatal (Two patients on other  |                                   |
| (increasing the risk of  | Sweating                            | studies in the Surgery Branch        |                                   |
| .                        |                                     |                                      |                                   |
| infection and the need   | .                                   | Swelling of arms                     | developed EBV lymphoma, and one   |
| for treatment with       | died as a result of this disease.)  |                                      |                                   |
| or legs                  |                                     |                                      |                                   |
| antibiotics or other     | Skin changes, rash,                 | Loss of fertility                    |                                   |
| .                        | .                                   |                                      |                                   |
| treatment)               | blisters                            | Two out of the first 81 patients     |                                   |
| .                        |                                     |                                      |                                   |
| Loss of appetite,        | .                                   | Weakness                             | enrolled on the initial young TIL |
| nusea, vomiting,         | Hearing loss                        | study died from complications        |                                   |
| .                        |                                     |                                      |                                   |
| .                        | Diarrhea, stomach                   | resulting from suppression of the    |                                   |
| pin                      | immune function which resulted in a |                                      |                                   |
| Mouth sores              | severe infection (one of these      |                                      |                                   |
| .                        |                                     |                                      |                                   |
| .                        | Hair loss                           | patients also received radiation as  |                                   |
| .                        | Fatigue                             | part of their treatment regimen).    |                                   |
| Muscle or joint aches    |                                     |                                      |                                   |
| .                        |                                     |                                      |                                   |  
Pembrolizumab - side effects (retreatment only)
Clinical trial: NCT01993719
Section: Purpose of Research
Subsections: Why Is This Study Being Done?

Your doctor has told you that you have been diagnosed with metastatic melanoma. We have developed an experimental therapy that involves taking cells called lymphocytes from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Young Tumor Infiltrating Lymphocytes, or Young TIL and the therapy is called cell therapy. Before receiving the cells, the patients receive 2 chemotherapy drugs to temporarily suppress the immune system to improve the chances that the tumor fighting cells PATIENT IDENTIFICATION  
| CONSENT TO PARTICIPATE IN A CLINICAL     |                             |
|------------------------------------------|-----------------------------|
| RESEARCH STUDY                           |                             |
| Adult Patient or                         | - Parent, for Minor Patient |
| .                                        |                             |
| NIH-2514-1 (07-09)                       |                             |
| P.A.: 09-25-0099                         |                             |
| File in Section 4:  Protocol Consent (1) |                             |  
| CONTINUATION SHEET for either:                                           |
|--------------------------------------------------------------------------|
| NIH 2514-1, Consent to Participate in A Clinical Research Study          |
| NIH 2514-2, Minor Patient's Assent to Participate In A Clinical Research |
| Study                                                                    |  
STUDY NUMBER: 14-C-0022 CONTINUATION: page 2 of 18 pages will be able to survive in the body. After the cells are given, the patients receive aldesleukin (IL- 2) to help the tumor fighting cells stay alive longer. The purpose of this study is to see if these tumor fighting cells (young TIL) with the administration of aldesleukin can cause metastatic melanoma tumors to shrink and to evaluate the toxicity of this treatment.
Clinical trial: NCT01993719
Section: Withdrawal from Study
Subsections: Stopping Therapy

Your doctor may decide to take you off this study under the following circumstances:  
if he/she believes that it is in your best interest
.  
if your disease comes back during treatment
.  
if you become pregnant
. .
if you experience side effects from the treatment that are considered too severe  
if new information becomes available that shows that another treatment would be better for
.  
you
In this case, you will be informed of the reason for that decision.  
You can stop participating at any time. However, if you decide to stop participating in the study, we encourage you to talk to the study doctor and your regular doctor first. If you refuse to participate or withdraw from the protocol or at the completion of the protocol, we will attempt to offer you participation in other NIH protocols if these are available, or will refer you to your home physician for further management.  
If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines,  
| PATIENT        |
|----------------|
| IDENTIFICATION |  
information collected on you up to that point may still be provided to the Sponsor. If you withdraw your consent and leave the trial, any samples of yours that have been obtained for the study and stored at the NCI can be destroyed upon request. However, any samples and data generated from