Clinical trial: NCT04201457
Section: Alternatives
Subsections: What Is The Usual Approach To My Low-Grade Glioma Or High-Grade Glioma?

The usual approach for patients who are not in a study is treatment with surgery, radiation, or drugs but there is not a Food and Drug Administration (FDA) approved treatment. Sometimes, combinations of these treatments are used. Your doctor can explain which treatment may be best for you. These treatments can reduce symptoms and may stop the tumor from growing for a few months or longer.  
What are my choices if I decide not to take part in this study?  
- You may choose to have the usual approach described above. - You may choose to take part in a different research study, if one is available. - You may choose not to be treated for cancer. - You may choose to only get comfort care to help relieve your symptoms and not get treated for your cancer.
Clinical trial: NCT04201457
Section: Confidentiality
Subsections: Who Will See My Medical Information?|How Will Information About Me Be Kept Private?

Your privacy is very important to us. The study doctors will make every effort to protect it. The study doctors have a privacy permit to help protect your records if there is a court case. However, some of your medical information may be given out if required by law. If this should happen, the study doctors will do their best to make sure that any information that goes out to others will not identify who you are. Some of your health information, such as your response to cancer treatment, results of study tests, and medicines you took, will be kept by the study sponsor in a central research database. However, your name and contact information will not be put in the database. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. There are organizations that may look at or receive copies of some of the information in your study records. Your health information in the research database also may be shared with these organizations. They must keep your information private, unless required by law to give it to another group.  
Some of these organizations are:
- The study sponsor and any company supporting the study agents now or in the future. This would include any organization helping the sponsor with the study
- The NCI Central IRB, which is a group of people who review the research with the goal of protecting the people who take part in the study.  
- Federal agencies such as the Food and Drug Administration, the Office of Human Research Protections (OHRP) and the National Cancer Institute in the U.S.  
- Governmental agencies in other countries where the study drug may be considered for approval.  
- Laboratories performing the required and optional research studies of blood and tumor samples.  
- The pharmaceutical company that supplies dabrafenib and trametinib and any company supporting the study or the study agent now or in the future.  
- Your insurance company or other health benefits plan (if charges are billed to these plans).
Coded patient data and images from brain scans will be transmitted over the internet to be analyzed by other PBTC researchers. The PBTC has procedures (data encryption) in place to make electronic transmission of research information as secure as possible. The data security involves coding the data in a way that only the authorized receiver can decode the data. The method used to transfer information is more secure than many methods used by financial institutions when conducting business over the internet. In addition to storing data in the study database, data from studies that are publicly funded may also be shared broadly for future research with protections for your privacy. The goal of this data sharing is to make more research possible that may improve people's health. Your study records may be stored and shared for future use in public databases. However, your name and other personal information will not be used. Some types of future research may include looking at your information and information from other patients to see who had side effects across many studies or comparing new study data with older study data. However, right now we don't know what research may be done in the future using your information. This means that:  
- You will not be asked if you agree to take part in the specific future research studies using your health information.  
- You and your study doctor will not be told when or what type of research will be done. - You will not get reports or other information about any research that is done using your information.
There are laws that protect your genetic information. However, there is a risk that someone could get access to your genetic information and identify you by name. In some cases, employers could use your genetic information to decide whether to hire or fire you. The study doctors believe the risk of this happening is very small. However, the risk may increase in the future as people find new ways of tracing information. For more information about the laws that protect you, ask your study doctor.

Your privacy is very important to the study researchers and biobank. They will make every effort to protect it. Here are just a few of the steps they will take:  
1. They will remove identifiers, such as your initials, from your sample and information.  
They will replace them with a code number. There will be a master list linking the code numbers to names, but they will keep it separate from the samples and information.  
2. Researchers who study your sample and information will not know who you are. They also must agree that they will not try to find out who you are.  
3. Your personal information will not be given to anyone unless it is required by law. 4. If research results are published, your name and other personal information will not be used.
Clinical trial: NCT04201457
Section: Participant Responsibilities
Subsections: What Am I Being Asked To Do?|What Are My Responsibilities In This Study?

We are asking you to take part in a research study. This study has public funding from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United States Department of Health and Human Services. We do research studies to try to answer questions about how to prevent, diagnose, and treat diseases like cancer.  
We are asking you to take part in this research study because you have a low-grade glioma or highgrade glioma with a certain tumor marker that has grown or has come back after receiving a similar drug.

If you choose to take part in this study, you will need to:
- Keep your study appointments.  
- Tell your doctor about:
o all medications and supplements you are taking o any side effects o any doctors' visits or hospital stays outside of this study o if you have been or are currently in another research study
- Write down in your medication diary when you take the study drugs at home For women: Do not get pregnant or breastfeed while taking part in this study. **For men:** Do not father a baby while taking part in this study. **For all:** Tell your study doctor right away if you think that you or your partner have become pregnant during the study or within 4 months after your last dose of study drug.  
What are the costs of taking part in this study?  
You and/or your insurance plan will need to pay for other costs of medical care you get as part of the study, just as you would if you were getting the usual care for your cancer. This includes:
- the costs of tests, exams, procedures, and drugs that you get during the study to monitor your safety and prevent and treat side effects.  
- the costs of getting the dabrafenib, trametinib and hydroxychloroquine ready and giving it to you.  
- your insurance co-pays and deductibles.
Talk to your insurance provider and make sure that you understand what your insurance pays for and what it doesn't pay for if you take part in this clinical trial. Also, find out if you need approval from your plan before you can take part in the study. Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs will be billed to you or your insurance provider. You or your insurance provider will not have to pay for the dabrafenib, trametinib or hydroxychloroquine while you take part in this study. Taking part in this study may mean that you need to make more visits to the clinic or hospital than if you were getting the usual approach to treat your cancer. You may:
- Have more travel costs.  
- Need to take more time off work.  
- Have other additional personal costs.  
You will not be paid for taking part in this study. The research may lead to new tests, drugs, or other products for sale. If it does, you will not get any payment.
Clinical trial: NCT04201457
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: What Are The Risks And Benefits Of Taking Part In This Study?|Risks|Benefits|What Possible Risks Can I Expect From Taking Part In This Study? General Risks|Side Effect Risks|Drug Risks|Possible Side Effects Of Dabrafenib Common, Some May Be Serious In 100 People Receiving Dabrafenib (Gsk2118436B), More Than 20 And Up To 100 May Have:|Possible Side Effects Of Trametinib Common, Some May Be Serious|Occasional, Some May Be Serious|Rare, And Serious|Additional Drug Risks|What Happensif I Am Injured Because I Took Part In This Study?|What Are The Risks In This Optional Sample Collection?|What Are The Benefits To Taking Part In This Optional Sample Collection?

There are both risks and benefits to taking part in this study. It is important for you to think carefully about these as you make your decision.

We want to make sure you know about a few key risks right now. There is more information in the "What possible risks can I expect from taking part in this study?" section.  
If you choose to take part in this study, there is a risk that the study drugs may not be as good as the usual approach for your cancer at shrinking or stabilizing your cancer. There is also a risk that you could have side effects from the study drugs. These side effects may be worse and may be different than you would get with the usual approach for your cancer. Some of the most common side effects that the study doctors know about are:
- Nausea
- Fatigue
- Diarrhea
- Rash
- Eye problems There may be some risks that the study doctors do not yet know about.

There is some evidence in people with another cancer that giving hydroxychloroquine with dabrafenib and trametinib can shrink or stabilize cancer However, we do not know if this will happen in people with your type of cancer. It is unlikely that it will work in everyone with your cancer or help you live longer. This study may help the study doctors learn things that may help other people in the future.

If you choose to take part in this study, there is a risk that the study drugs may not be as good as the usual approach for shrinking or stabilizing your cancer.  
You also may have the following discomforts:
- Spend more time in the hospital or doctor's office.  
- Be asked sensitive or private questions about things you normally do not discuss.  
- May not be able to take part in future studies.
The study drugs used in this study could be very harmful to an unborn or newborn baby. There may be some risks that doctors do not yet know about. It is very important that you check with your study doctor about what types of birth control or pregnancy prevention to use during the study and for 4 months after you have completed the study.

The study drugs used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will test your blood and let you know if changes occur that may affect your health. There is also a risk that you could have other side effects from the study drugs. Here are important things to know about side effects:
1. The study doctors do not know who will or will not have side effects. 2. Some side effects may go away quickly, some may last a long time, and some may never go away.  
3. Some side effects may make it hard for you to have children. 4. Some side effects may be mild. Other side effects may be very serious and even result in death.  
You can ask your study doctor questions about side effects at any time. Here are important ways to make side effects less of a problem:
- If you notice or feel anything different, tell your study doctor. He or she can check to see if it is a side effect.  
- Your study doctor will work with you to treat your side effects.  
- Your study doctor may adjust the study drugs to try to reduce side effects.

The tables below show the most common and most serious side effects doctors know about. Keep in mind that there might be other side effects doctors do not yet know about. If important new side effects are found, the study doctor will discuss these with you. The different combination of these study drugs may increase your side effects or may cause new side effects.

- Nausea - Tiredness - Fever *(Fever and complications of fever are more frequent and severe when dabrafenib* mesylate is used together with trametinib dimethyl sulfoxide.)
- Pain
- Headache
- Hair loss - Skin changes including rash OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving dabrafenib (GSK2118436B), from 4 to 20 may have:  
- Anemia which may require blood transfusion
- Constipation, diarrhea, vomiting
- Chills
- Swelling of arms, legs - Flu-like symptoms including body aches
- Cold symptoms such as stuffy nose, sneezing, sore throat
- Bleeding *(The risk of bleeding is increased when dabrafenib mesylate is used together with* trametinib dimethyl sulfoxide.)
- Infection, especially when white blood cell count is low
- Loss of appetite
- A new skin cancer resulting from treatment of earlier cancer
- Wart - Dizziness - Cough
- Dry skin
- Change in hair
- Increased sweating
- Redness, pain or peeling of palms and soles
- Itching
- High blood pressure which may cause headaches, dizziness, blurred vision - Blood clot which may cause swelling, pain, shortness of breath (The risk is increased when dabrafenib mesylate is used together with trametinib dimethyl sulfoxide.)

In 100 people receiving trametinib (GSK1120212B), more than 20 and up to 100 may have:
- Diarrhea, nausea - Tiredness
- Swelling of the body
- Skin changes including rash, acne

In 100 people receiving trametinib (GSK1120212B), from 4 to 20 may have:
- Swelling and redness of the eye
- Changes in the eyes that may cause blurred vision or blindness - A tear or hole in the bowels that may require surgery
- Pain in belly (pancreas) that may require hospitalization
- Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
- Fainting - Kidney damage which may require dialysis (The risk is increased when dabrafenib mesylate is used together with trametinib dimethyl sulfoxide.)
- Skin rash developing 1-8 weeks after a drug is given which may be accompanied by fever, lymph node swelling and organ failure
- Swelling and redness of the skin
- Severe skin rash with blisters and peeling which can involve mouth and other parts of the body
- Anemia which may require blood transfusion - Abnormal heartbeat
- Blurred vision or other visual disturbances - Dry eye, mouth, skin
- Swelling of the eye - Pain - Constipation, heartburn, vomiting
- Sores in the mouth which may cause difficulty swallowing - Chills, fever - Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
- Infection - Change in heart function - Loss of appetite, dehydration - Dizziness, headache
- Cough, shortness of breath
- Hair loss, itching - Change in or loss of some or all of the finger or toenails - High blood pressure which may cause headaches, dizziness, blurred vision - Bleeding

In 100 people receiving trametinib (GSK1120212B), 3 or fewer may have:
- Heart failure which may cause shortness of breath, swelling of ankles, and tiredness
- Changes in the eyes (blood clot or retinal detachment) which may cause blindness
- Blood clot which may cause swelling, pain, shortness of breath
- A tear or hole in the bowels that may require surgery
- Damage to muscle which may cause muscle pain, dark red urine
- Damage to the lungs which may cause shortness of breath - Redness, pain or peeling of palms and soles - Skin rash developing 1-8 weeks after a drug is given which may be accompanied by fever, lymph node swelling and organ failure
- Severe skin rash with blisters and peeling which can involve mouth and other parts of the body  
Possible Side Effects of Hydroxychloroquine Sulfate  
Very Common  
Out of 100 people receiving hydroxychloroquine, more than 10 people may have:  
- Abdominal Pain  
- Nausea  
Common  
Out of 100 people receiving hydroxychloroquine, between 1 and 10 people may have:  
- Headache - Dizziness  
- Blurry vision  
- Changes in mood  
- Diarrhea  
- Vomiting  
- Loss of appetite  
- Skin rash  
- Itching  
Rare **and Serious**  
Out of 100 people receiving hydroxychloroquine, less than 1 person may have:  
- Dizziness  
- Nervousness  
- Ringing of the ears  
- Liver damage - Damage to the retinas of the eyes, which may cause a loss or change in vision, such as  
seeing spots or halos, abnormal colors, sensitivity to light, night blindness  
- Sensory motor disorders, such as decreased coordination and balance, difficulties with  
taste, speech, touch, repetitive movements  
- Pigmentary changes in skin and mucous membranes - Bleaching of hair - Alopecia

The study drug could interact with other drugs. Certain types of anti-seizure medications are not allowed while taking the study drugs. Your study doctor will review your current anti-seizure medication and if you are taking a medication that is not allowed, they can change your anti-seizure medication to another type that is allowed. Your study doctor will give you a drug information handout and wallet card that lists these possible interactions. Share this information with your family members, caregivers, other health care providers, and pharmacists.

If you are injured as a result of taking part in this study and need medical treatment, please talk with your study doctor about treatment options. The study sponsor will not pay for medical treatment for injury. Your insurance company may not be willing to pay for study-related injury. If you have no insurance, you would be responsible for any costs. Novartis, the pharmaceutical company providing the study drugs, will not provide payment for any medical expenses which you may incur because of your participation in this study. No other type of compensation will be provided by Novartis. If you feel this injury was a result of medical error on the part of the study doctors or others involved in the study, you have the legal right to seek payment even though you are in a study. Agreeing to take part in this study does not mean you give up these rights

- The most common risks related to drawing blood from your arm are brief pain and maybe a bruise.  
- Generally, hospitals will keep some of your tissue. This tissue may be used to help treat your cancer in the future. There is a small risk that when this tissue sample is submitted to the biobank for this optional sample collection, your tissue could be used up.  
- Your medical and genetic information is unique to you. There is a risk that someone outside of the research study could get access to your study records or trace information in a database back to you. They could use that information in a way that could harm you. Researchers believe the chance that someone could access and misuse your information is very small. However, the risk may increase in the future as people find new ways of tracing information.  
- In some cases, this information could be used to make it harder for you to get or keep a job and get or keep health insurance. There are laws against the misuse of genetic information, but they may not give full protection. For more information about the laws that protect you, ask your study doctor or visit: https://www.genome.gov/10002328/

You will not benefit from taking part. The researchers, using the samples from you and others, might make discoveries that could help people in the future.
Clinical trial: NCT04201457
Section: Procedures
Subsections: What Will Happen If I Decide To Take Part In This Study?|What Exams, Tests, And Procedures Are Involved In This Study?|What Is Involved In This Optional Sample Collection? If You Agree To Take Part, Here Is What Will Happen Next:

If you decide to take part in this study, you will take dabrafenib and plus hydroxychloroquine twice a day and trametinib once a day for a 28-day course. You will continue to repeat these 28-day courses for up to 2 years as long as your brain tumor doesn't grow.  
After you finish taking dabrafenib and trametinib plus hydroxychloroquine, your doctor and study team will watch you for side effects up to 5 years from the start of treatment. They will check you every 3 months during the follow-up.

Before you begin the study, your doctor will review the results of your exams, tests, and procedures. This helps your doctor decide if it is safe for you to take part in the study. If you join the study, you will have more exams, tests, and procedures to closely monitor your safety and health. Most of these are included in the usual care you would get even if you were not in a study. Listed below are exams, tests, and procedures that need to be done as part of this study to monitor your safety and health but may not be included in the usual care. We will use them to carefully follow the effects of the study treatment, including preventing and managing side effects.  
These exams, tests, and procedures to monitor your safety and health include:
- An Electrocardiogram (EKG) will be done prior to starting treatment, between 2-6 hours after the first dose and then every 3 months during treatment and at the end of treatment
- An Echocardiogram (ECHO) will be done prior to starting treatment, every 3 months during treatment and at the end of treatment
- Eye exams (assessing how well you see, looking at the back of your eye and measuring the thickness of the nerve that helps you see) will be done prior to starting treatment, every 3 months during treatment and at the end of treatment.
Your study doctor may recommend additional exams later during treatment if you have symptoms of heart or eye problems Some exams, tests, and procedures are a necessary part of the research study but would not be included in usual care. Listed below are lab procedures that will be done for research purposes only.  
- Autophagy Inhibition You will need to have blood samples taken at specific time points for the study. These blood samples will be drawn from your arm or existing line before you start treatment, on Day 1 and Day 15 of Course 1, and at each time you have an MRI (if you have low-grade glioma, your MRIs will be at the end of courses 2,4,6, then every 3 months; if you have high-grade glioma, your MRIs will be every 2 months) and at the end of therapy. Autophagy inhibition looks at how your tumor cells are responding to the treatment. The study doctor will draw 12-15 ml or about 2 ½ to 3 teaspoons at each time point. You and your study doctor will not get the results of this testing.

1. About 2 teaspoons of blood will be collected from a vein in your arm A sample from the tissue that was collected at the time of your previous surgery will be sent to the biobank.  
2. There is no limit on the length of time we will keep your samples and research information.  
The samples will be kept until they are used for research or destroyed.  
3. Researchers can only get samples from the biobank after their research has been approved by experts. Researchers will not be given your name or contact information.  
4. Some of your genetic and health information may be placed in central databases for researchers to use. The databases will not include your name or contact information.
Clinical trial: NCT04201457
Section: Purpose of Research
Subsections: Why Is This Study Being Done?|What Is The Purpose Of This Study?

This study is being done to answer the following question:
Is the combination of dabrafenib and trametinib plus hydroxychloroquine safe and tolerated without severe side effects in children?  
We are doing this study because we want to find out if this approach is better or worse than the usual approach for your recurrent or progressive brain tumor. The usual approach is defined as care people get for recurrent or progressive glioma..

The purpose of this part of the study is to test the safety of adding hydroxychloroquine to dabrafenib and trametinib. This study tests different doses of the drug Hydroxychloroquine to see which dose is safer for children. The combination of dabrafenib and trametinib has been approved by the FDA to treat other cancers in adults. Hydroxychloroquine has been approved by the FDA to treat malaria, a form of arthritis and a similar disease called Lupus. There will be about 75 people total taking part in this study.
Clinical trial: NCT04201457
Section: Voluntary Participation
Subsections: Taking Part In This Study Is Your Choice.|My Signature Agreeing To Take Part In The Study

You can choose to take part, or you can choose not to take part in this study. You also can change your mind at any time. Whatever choice you make, you will not lose access to your medical care or give up any legal rights or benefits. This document has important information to help you make your choice. Take time to read it. Talk to your doctor, family, or friends about the risks and benefits of taking part in the study. It's important that you have as much information as you need and that all your questions are answered. See the "Where can I get more information?" section for resources for more clinical trials and general cancer information.

I have read this consent form, or had it read to me. I have discussed it with the study doctor and my questions have been answered. I will be given a signed and dated copy of this form. I agree to take part in the main study. I also agree to take part in any additional studies where I circled and initialed "yes".  
Participant's signature Date of signature Parent or Legal Guardian Signature Date of Signature 2nd Parent or Legal Guardian If permission by both parents is required, both signatures should be completed unless one parent is deceased, unknown, incompetent, not reasonably available, or only one parent has legal responsibility for the care and custody of the child. Date of Signature Signature of person(s) conducting the informed consent discussion Date of signature  
| Appendix A: Study Calendar for Phase I                           | Completion/                  |                         |           |                |    |
|------------------------------------------------------------------|------------------------------|-------------------------|-----------|----------------|----|
| Discontinuation Of Treatment  (within 30 days  of the last dose) |                              |                         |           |                |    |
| Courses  2- Course  13 (+/- 7  days)                             | Courses  14-26 (+/- 7  days) |                         |           |                |    |
| Course  1 Day  15                                                |                              |                         |           |                |    |
| Pre                                                                  |                              |                         |           |                |    |
| treatment                                                        | Course  1                    |                         |           |                |    |
| Physical Assessments Medical history                             | X                            | Weekly                  | X         | X              | X  |
| Physical  exam/height/weight/skin                                | X                            | Weekly                  | X         | X              | X  |
| exam Vital signs                                                 | X                            | Weekly                  | X         | X              | X  |
| Performance status                                               | X                            | X                       | X         | X              |    |
| Neurologic exam                                                  | X                            | Weekly                  | X         | X              | X  |
| Laboratory Evaluations Blood Counts                              | X                            | Weekly                  | XA        | Every 8  weeks | X  |
| Blood Chemistries  including liver enzymes                       | X                            | X                       | XA        | Every 8  weeks | X  |
| Serum or Urine pregnancy  test (for females of                   | X                            | X                       | X         | X              |    |
| childbearing potential) CSF cytology (if clinically  indicated)  | X                            |                         |           |                |    |
| Evaluations Echocardiogram (ECHO)                                | X                            | X                       | X         | X              |    |
| Electrocardiogram (ECG)                                          | X                            | X                       | X         | X              |    |
| Eye Exam                                                         | X                            | X                       | X         | X              |    |
| Imaging Assessments                                              | Every 8 weeks (end of        |                         |           |                |    |
| Brain MRI low-grade  glioma                                      | X                            | courses 2,4,6) and then | X         |                |    |
| every 12 weeks.                                                  |                              |                         |           |                |    |
| Brain MRI high-grade  glioma                                     | X                            | Every 8 weeks           |           |                |    |
| Spinal MRI (only if  clinically indicated)                       | X                            | X                       | X         | X              |    |
| Research Samples Biomarkers                                      | X                            | X                       | With each | With each      |    |
| MRI                                                              | MRI                          |                         |           |                |    |
| Pharmacogenetics and  Pharmacokinetics                           | X                            | X                       |           |                |    |
Clinical trial: NCT04201457
Section: Withdrawal from Study
Subsections: If I Decide To Take Part In This Study, Can I Stop Later? Yes, You Can Decide To Stop Taking Part In The Study At Any Time.|What If I Change My Mind About This Optional Sample Collection?

If you decide to stop, let your study doctor know as soon as possible. It's important that you stop safely. If you stop, you can decide if you want to keep letting the study doctor know how you are doing. Your study doctor will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study.  
Are there other reasons why I might stop being in the study?  
Yes. The study doctor may take you off the study if:
- Your health changes and the study is no longer in your best interest.  
- New information becomes available and the study is no longer in your best interest.  
- You do not follow the study rules.  
- If you become pregnant while on the study.  
- The study is stopped by the National Cancer Institute (NCI), Institutional Review Board
(IRB), Food and Drug Administration (FDA)or the Pediatric Brain Tumor Consortium (PBTC). The study sponsor, (PBTC)is the organization who oversees the study.
It is important that you understand the information in the informed consent before making your decision. Please read, or have someone read to you, the rest of this document. If there is anything you don't understand, be sure to ask your study doctor or nurse.

If you decide you no longer want your samples to be used, you can call the study doctor, insert name of study doctor for main trial, at *insert telephone number of study doctor for main trial*, who will let the biobank know. Then, any sample that remains in the biobank will be destroyed or returned to your study doctor. This will not apply to any samples or related health information that have already been given to or used by researchers.