Clinical trial: NCT01610570
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 - 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.
Clinical trial: NCT01610570
Section: Confidentiality
Subsections: Will My Medical Information Be Kept Private?

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. Your personal information may be  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 13 of 16 pages given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:
- Representatives of the National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in overseeing research
- The Institutional Review Board (IRB) of this hospital
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."
Clinical trial: NCT01610570
Section: Duration of Study Involvement
Subsections: Before You Begin The Study|How Long Will I Be In The Study?

You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.  
- A medical history
- Physical exam
- Vital signs (blood pressure, pulse, temperature)
- Blood tests
- Urine tests
- Pregnancy test (if you are a woman who could have children)
- Echocardiogram or MUGA and an EKG, tests that checks the function of your heart
- We will also do whatever X-rays, CT scans, or other tests are needed to check your tumor
- Review of your tumor tissue to confirm your diagnosis  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 3 of 16 pages

You may be in the study until one of the following occur:  
- Your tumor gets worse
- The side effects of mithramycin are too harmful for you
- You need a treatment that is not allowed on this study
- You are not able to follow study-related treatment instructions
- New information becomes available that suggests this is not the best treatment for you
- The study is not in your best interest
- The study is stopped
Your doctor may decide to take you off the study drug if any of these occur; you will be told the reason you are being taken off the mithramycin.  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 6 of 16 pages
Clinical trial: NCT01610570
Section: Participant Responsibilities
Subsections: Birth Control|Other Medications

Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. If you become pregnant on the study, you will be taken off of mithramycin immediately. Further, if the pregnancy is taken to term, the outcome will also be recorded in study records. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study and for at least two months after finishing treatment with mithramycin. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study.

There are several medications, such as aspirin or ibuprofen, which are not allowed during participation in this study, as these medications may increase the risk for mithramycin side effects, such as bleeding. It is very important that you contact your doctor prior to starting a new medicine (including herbal or over the counter medications) to check if it is OK to take it. The study team will provide you and your home doctor with a list of medicines, which you should not take.
Clinical trial: NCT01610570
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 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: NCT01610570
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?**|Side Effects From Mithramycin Likely|Rare But Serious|Side Effects From Dexamethasone|Potential Benefits Of Participation Are There Benefits To Taking Part In This Study?

You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don't know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the mithramycin. In some cases, side effects can be serious, long lasting, or may never go away. Rarely there is a risk of death from a serious side effect. We will tell you if we learn any new information that may affect your health, welfare, or decision to stay in this study.  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 10 of 16 pages You should talk to your study doctor about any side effects that you have while taking part in the study.

- Decreased blood level of calcium - Nausea or vomiting
- Diarrhea - Loss of appetite
- Mouth sores - Increase blood levels of liver enzymes, which may indicate damage to the liver (which may be severe)
- Increase in LDH, which is an indicator of damage to your cells.
Less Likely  
- Bleeding including nose bleed
- Fever
- Drowsiness
- Weakness - Tiredness
- Pain, redness, soreness or swelling of the area where the IV goes in the skin
- Skin changes, blushing of the face
- Headache
- Mental depression, restlessness, irritability - Decreased platelets (the blood cell that helps blood clot)
- Decreased red blood cells (the blood cells that carry oxygen)
- Abnormal levels of white blood cells (the cells that prevent infection)
- Muscle or stomach cramps, possibly due to a low blood level of calcium
- Abnormal levels of blood elements including phosphorus or potassium. - Increased blood levels of kidney function tests, such as creatinine, urea or protein  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 11 of 16 pages

- Bleeding that may require a transfusion of blood or blood products. Bleeding may result in bloody or black stools or vomiting blood, or blood nose, or small broken blood vessels under the skin.  
- A significant rash called toxic epidermal necrolysis characterized by widespread and severe skin irritation has been reported with mithramycin.  
While receiving mithramycin, you should avoid any drugs that contain salicylates, a component of aspirin, such as Aspirin, Bufferin, Ascriptin, Aspergum, Anacin, and some Alka-Seltzer products and some cold preparations, as they may increase the risk of bleeding. When the WBC is low (neutropenia), fever may be a sign of significant infection. When fever and neutropenia is present, hospitalization for administration of intravenous antibiotics may be necessary. Because mithramycin may decrease the production of red cells (the part of the blood that carries oxygen and gives energy) and platelets (the part of the blood that helps prevent bleeding), it is possible that you will require transfusions with red cells or platelets. When these transfusions are required will vary from participant to participant and can be discussed with your doctor. Most transfusions have no side effects. However, you may have an allergic reaction (a rash, hives or very rarely, difficulty breathing that can be so severe as to result in death). In addition, although the blood bank that services our patients is excellent, there is at least a theoretic possibility of infections such as AIDS or hepatitis being transmitted by blood. The blood bank is very good at screening for these diseases and the chance of these problems is very small. A separate informed consent would be obtained should you need a blood transfusion.

- High blood pressure  
- High Blood glucose
- Stomach upset,
- Burning in stomach from excess stomach acid
- Increased risk of infection - Increased appetite
- Weight gain
- Thinning of bones
- Increase pressure in eyes
- Personality changes, e.g., irritability, euphoria, mania  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 12 of 16 pages  
- Feelings of depression
- Pulmonary tuberculosis - Vision problems
- Acne, allergic dermatitis, dry scaly skin
- Destruction of bone tissue

The potential benefit of the treatment with mithramycin is that it may cause your cancer to stop growing or to shrink for a period of time. It may lessen the symptoms, such as pain, that are caused by the cancer. It is extremely unlikely that this treatment will cure your cancer. Because there is not much information about the mithramycin effect on cancers in humans, we do not know if you will benefit from taking part in this study. Information learned from this study may help future patients with cancer.
Clinical trial: NCT01610570
Section: Procedures
Subsections: During The Study|Research Study Tests And Procedures|Pharmacokinetic Studies (Pks)|Pharmacodynamic Studies|Archival Tumor Tissue|Review Of Scans

If the exams, tests and procedures show that you can be in the study, and you choose to take part, you will be admitted to the hospital at NIH and given mithramycin through an IV (intravenous - small plastic tube put in a vein in your arm or neck) over about 6 hours. You will receive mithramycin every day for 7 days. If you do not have unacceptable side effects or worsening of your cancer, this treatment can be repeated every 28 days. This is called a cycle. You will receive the first cycle of mithramycin as an inpatient in the hospital so that we can monitor you carefully for side effects and treat them. You will also be given dexamethasone every day in order to prevent mithramycin liver toxicity. You may receive subsequent cycles as an outpatient if your doctor believes this is safe for you. The dose for the first children enrolled on the study will be based on the side effects seen in adults. Between 3 and 6 children will receive mithramycin at each dose. There will be two doses tested in this study. If the side effects are not too severe, the next group of children will receive a higher dose. This is called 'dose escalation'. Whatever dose you start at, your dose will not be increased. If you have bad side effects, the drug will be stopped or delayed. You will be given medicines to help treat any side effects that you might have. While you are receiving cycles of mithramycin, you will be watched closely for any untoward effects. You will need to have the following procedures and tests:
- Physical exam every week
- Blood tests daily during mithramycin treatment and then twice a week for the rest of the cycle Between doses we will ask you to fill out forms to help keep track of any symptoms you may experience and any medications you may take. Scans and x-rays to evaluate your tumor will be done after every 2 cycles (about 2 months, 4 months, etc).

We would also like to do some extra research tests. These tests will help us learn more about mithramycin and may help children who receive this drug in the future. The information learned from these tests will not change the way you are treated, and the results of these tests will not be returned to you. You can still be a part of the main study even if you say 'no' to taking part in any of the optional biology studies. The maximum amount of blood taken from you is based on your age and will not be more than the blood volume limit set for research by the NIH. We will not draw more than 1 teaspoon of blood for every kilogram (2.2 pounds) of your body weight in a single day and not more than 2 teaspoons of blood for every kilogram (2.2 pounds) of your body weight in an 8 week period. For example, if you weigh 85 pounds (weight of some 12 year olds), your weight in kilograms is about 38 kg; therefore we would not draw more 38 teaspoons (12.5 tablespoons) in one day and not more than 76 teaspoons (or 25 tablespoons) of blood in an 8 week period.  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 4 of 16 pages A check box for your decision about taking part in each optional test is provided at the end of this consent form. The following is a description of each of the optional tests.

We want to find out how mithramycin is processed and then cleared from the body. These tests are called pharmacokinetic (PK) tests. They will measure the amount of mithramycin in the blood at different time points during treatment. If you agree, we would like to obtain blood samples from you. These samples are about 3 mL (about ½ teaspoon) of blood each and will be taken before the drug begins, and at the middle and end of the first mithramycin infusion (on day 1), and then just before and at the completion of the mithramycin infusion on days 2, 4 and day 7 of your first cycle. A sample will also be obtained 24 and 48 hours after the day 7 dose. A total of 24 mL of blood will be drawn (approximately 4-5 teaspoons) will be drawn for PK studies. Please read the sentence below and think about your choice. After reading the sentence, circle and initial the answer that is right for you. I agree to have the pharmacokinetic studies performed in this study.  
Yes No Initials_________

We would also like to take a small amount of blood for research tests called pharmacodynamic studies (PD). These tests will help us learn more about mithramycin and may help children who receive this drug in the future. The information learned would not change the way you are treated, and the results of these tests will not be given to you. A total of 1 mL of blood will be drawn (approximately 1/5 teaspoon) at the following time points: before the first dose of mithramycin, before the dose at the start of every other cycle. Prior to this blood sample you will need to not eat or drink anything for 10-12 hours. You should also avoid antacids or any medication that helps you have a bowel movement like Reglan, Metamucil, Miralax, for 48 hours prior to the blood test. The amount of blood we are drawing for research studies is safe to draw even from small children. Please read the sentence below and think about your choice. After reading the sentence, circle and initial the answer that is right for you. I agree to have research blood drawn for pharmacodynamic studies performed in this study.  
Yes No Initials_________  
| 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   |
|--------------------------|-----------------------------------------------------------------------------------------------------------------------------|  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 5 of 16 pages

One of the tests we would like to perform is done on tissue previously obtained from your tumor. It is called immunohistochemistry or IHC and is used to evaluate for NR0B1 expression. NR0B1 is a gene which gives directions (or encodes) for a protein normally found in the body. Mutations or changes in the NR0B1 gene may result in mishappen or nonfunctional proteins, which may lead to certain disorders. We plan to test tumor tissue that was previously obtained during surgery or a biopsy. We will not ask you to have a biopsy to do this test. This is a research test and the information learned will not change the way you are treated, and the results of these tests will not be given to you.  
I agree to allow previously obtained tumor tissue to be used for research tests in this study.  
Yes No Initials_________

Copies of the scans used to diagnose your tumors and scans taken to see if your tumor is responding to treatment will be sent to a central review center as part of our quality control program. We will also have a radiologist review the scans of your tumor to study a new method of measuring the volume of tumors in patients with Ewing Sarcoma. Currently we measure tumor size by two common methods: one method measures the longest length of the tumor, and the second method measures the length and the width, or two dimensions of the tumor. In the proposed scan review, we will compare these two methods with a new method that measures the volume, or 3 dimensions, of the tumor to see which method gives us the best information for determining tumor size.
Clinical trial: NCT01610570
Section: Purpose of Research
Subsections: Why Are You Being Asked To Take Part In This Study?

You are being invited to participate in this study because you have advanced cancer that is not responding to known effective therapies. How many people will take part in this Study? Up to 18 children and adolescents will take part in phase I of the study.
Clinical trial: NCT01610570
Section: Withdrawal from Study
Subsections: When **You Are Finished Taking The Drugs (Treatment)**|Stopping Therapy

Once the mithramycin is stopped, you will need to come back to NIH for evaluation (physical exam and blood work) until you recover from any side effects, and at least 30 days after the last dose of mithramycin. Afterwards, the study doctor will refer you back to your local health care provider.  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 7 of 16 pages  
| Study Chart                                                                                                                                                                                                                                                                                                                                                                    | Cycle 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Subsequent Cycles                                                                                                                                                                                                                                                                                           |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| DAY                                                                                                                                                                                                                                                                                                                                                                            | WHAT YOU DO                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | DAY                                                                                                                                                                                                                                                                                                         | WHAT YOU DO |
| Come into the clinic and do the  following: - Routine blood tests - Urine tests - Pregnancy test if you are able to  have children - Physical exam by your doctor - MRI, PET or CT scan - EKG - Get a disease evaluation that will be  done by your doctor. Depending on  the results of this evaluation, your  doctor will tell you whether or not  you may begin this study. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                             |             |
| Before  starting  study                                                                                                                                                                                                                                                                                                                                                        | Receive oral/IV dexamethasone (12  hours before study drug) Come to NIH hospital and do the  following: - Routine blood tests - Physical exam  - EKG - Prior to first dose of study drug  receive oral/IV dexamethasone - Get the study drug mithramycin  - Twice daily for 24 hours after the  last dose of study drug receive  oral/IV dexamethasone - Blood drawn before and after  mithramycin infusion for PKs  - Blood drawn for PD studies if you  have Ewing sarcoma (Phase I and II) | Come to NIH hospital and do  the following: - Routine blood tests - Physical exam  - EKG - Get the study drug  mithramycin - Twice daily for 24 hours  after the last dose of  study drug receive  oral/IV dexamethasone - Blood drawn for PD  studies (Phase I and II)  on Cycles 3, 5, 7, 9, 11,  and 13. |             |
| Day 1                                                                                                                                                                                                                                                                                                                                                                          | Day 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                             |             |  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 8 of 16 pages  
| -                                  | Routine blood tests                                                                                                                                                                                                                                                                                   |              |                                                                                                                                                                                                      |                                    |
|------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| -                                  | Get the study drug mithramycin                                                                                                                                                                                                                                                                        |              |                                                                                                                                                                                                      |                                    |
| -                                  | Twice daily for 24 hours after the  last dose of study drug receive  oral/IV dexamethasone                                                                                                                                                                                                            |              |                                                                                                                                                                                                      |                                    |
| -                                  | EKG on days 4 & 7                                                                                                                                                                                                                                                                                     | Days 2- 7    | -                                                                                                                                                                                                    | Routine blood tests  (cycles 2, 3) |
| -                                  | Routine blood tests twice  weekly (cycles 4 to the  end)                                                                                                                                                                                                                                              |              |                                                                                                                                                                                                      |                                    |
| -                                  | Get the study drug  mithramycin                                                                                                                                                                                                                                                                       |              |                                                                                                                                                                                                      |                                    |
| -                                  | Twice daily for 24 hours  after the last dose of study  drug receive oral/IV  dexamethasone                                                                                                                                                                                                           |              |                                                                                                                                                                                                      |                                    |
| -                                  | EKG on day 7                                                                                                                                                                                                                                                                                          |              |                                                                                                                                                                                                      |                                    |
| Days 2- 7  Days 1,  2, 4, 7,  8, 9 | Blood drawn for mithramycin PKs  Come into the clinic and do the  following: - Routine blood tests twice per week - Physical exam by your doctor every  week                                                                                                                                          | Day 9 to  28 | Come into the clinic and do  the following: - Routine blood tests twice  per week (cycles 2 and 3) - Routine blood tests  weekly for cycles 4 to the  end - Physical exam by your  doctor every week |                                    |
| Day                                | 9                                                                                                                                                                                                                                                                                                     |              |                                                                                                                                                                                                      |                                    |
| to 28                              | Come into the clinic and do  the following: - Routine blood tests - Physical exam by your  doctor - MRI or CT scan - Disease evaluation that  will be done by your  doctor. Depending on the  results of this evaluation,  your doctor will tell you  whether or not you may  continue the next cycle |              |                                                                                                                                                                                                      |                                    |
| Every 2  cycles                    |                                                                                                                                                                                                                                                                                                       |              |                                                                                                                                                                                                      |                                    |  
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  
STUDY NUMBER: 12-C-0135 CONTINUATION: page 9 of 16 pages

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.