Clinical trial: NCT02942264
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:  
You could have a different treatment for your relapsed brain tumor. Possible alternative treatments include Optune, procarbazine, Gliadel® wafer, lomustine, carmustine, carboplatin, irinotecan, bevacizumab, etoposide. Enrolling in this trial means you will be foregoing available treatments that are approved based on studies demonstrating some clinical benefit in patients with your disease. You do not have to join this 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: NCT02942264
Section: Confidentiality
Subsections: Confidentiality Protections Provided In This Study|Will Your Medical Information Be Kept Private?|Certificate Of Confidentiality|Privacy Act

If we share your specimens or data with other researchers, in most circumstances we will remove your identifiers before sharing your specimens and data. You should be aware that there is a slight possibility that someone could figure out the information is about you.

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 NIH and other government agencies, like the Food and Drug Administration
(FDA), which are involved in keeping research safe for people.  
National Institutes of Health Intramural Institutional Review Board Qualified representatives from Adastra Pharmaceuticals, the pharmaceutical company who produces Zotiraciclib (TG02)
When results of an NIH research study are reported in medical journals or at scientific meetings, the people who take part are not named and identified. In most cases, the NIH will not release any information about your research involvement without your written permission. However, if you sign a release of information form, for example, for an insurance company, the NIH will give the insurance company information from your medical record. This information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. Further, the information collected for this study is protected by NIH under a Certificate of Confidentiality and the Privacy Act.

To help us protect your privacy, the NIH Intramural Program has received a Certificate of Confidentiality (Certificate). With this certificate, researchers may not release or use data or information about you except in certain circumstances. NIH researchers must not share information that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a court. The Certificate does not protect your information when it:
1. is disclosed to people connected with the research, for example, information may be used for auditing or program evaluation internally by the NIH; or 2. is required to be disclosed by Federal, State, or local laws, for example, when information must be disclosed to meet the legal requirements of the federal Food and Drug Administration (FDA);
3. is for other research; 4. is disclosed with your consent.  
The Certificate does not prevent you from voluntarily releasing information about yourself or your involvement in this research. The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or others including, for example, child abuse and neglect, and by signing below you consent to those disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice and Acknowledgement of Information Practices consent.

The Federal Privacy Act generally protects the confidentiality of your NIH medical records we collect under the authority of the Public Health Service Act. In some cases, the Privacy Act protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy Act allows release of information from your medical record without your permission, for example, if it is requested by Congress. Information may also be released for certain research purposes with due consideration and protection, to those engaged by the agency for research purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is involved in a lawsuit. However, NIH will only release information from your medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
Clinical trial: NCT02942264
Section: Duration of Study Involvement
Subsections: Before You Begin The Study|During The Study

Before you can start this protocol, we will do an evaluation to see if you are eligible to participate in this study. You may be enrolled in a screening study to determine your eligibility. This will include a physical examination and blood laboratory studies. You will also need to have an MRI of the brain if you have not had one in 14 days and an EKG will be done. We must also be certain we have complete information about your history any past treatments, including surgeries. You will need to provide surgical tissue samples from prior surgeries. Women who are capable of having children will have a pregnancy test. You cannot take part in this study if you are pregnant. Any concerns you or your clinician may have can be further explored, and you may be referred to a specialist for further evaluation or treatment if necessary.

You will also complete a questionnaire about the severity of your symptoms and the interference these symptoms have in your daily life over the last 24 hours. You will complete this symptom burden questionnaire before you start study therapy and whenever you have a CT scan or MRI. You will also complete a questionnaire related to symptoms associated with treatment on day 2, 8, 14, 21, and 28 of each cycle as described in the study visit table below. These questionnaires related to symptoms associated with treatment will not be done for some patients.
Clinical trial: NCT02942264
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Birth Control|Risks Or Discomforts Of Participation What Side Effects Or Risks Can I Expect From Being In This Study?|Zotiraciclib (Tg02) Risks In Humans|Temozolomide Risks Common, Some May Be Serious|Rare, And Serious|Other Risks|Risks For Gadolinium Enhanced Mri Scans: Procedure|Potential Benefits Of Participation Are There Benefits To Taking Part In This Study?

If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don't know how this medicine would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the partner of a woman who can become pregnant, you will need to practice an effective form of birth control before starting study treatment, during study treatment and for 30 days after the last dose of study medication. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once. Effective forms of birth control include:
- abstinence - intrauterine device (IUD)
- hormonal [birth control pills, injections, or implants]
- tubal ligation - vasectomy Other forms of birth control require the use of more than 1 method:
Latex condom Diaphragm Cervical Cap

While on the study, you are at risk for these side effects. You should discuss these with your doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make side effects less serious and uncomfortable.  
| COMMON, SOME MAY BE SERIOUS                                                                                                                                                                                                                                                                                                                                                                                                          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| In 100 people receiving Zotiraciclib (TG02), more than 20 and up to 100 may have:  Diarrhea  Nausea (urge to vomit)  Vomiting  Upset stomach  Constipation  Decreased appetite  Abdominal pain  Moderate to severe low white blood cell  count  Low potassium and phosphorus in the blood  Shortness of breath and cough  Elevated blood sugar  Dizziness  Elevated blood pressure  Muscle aching  Low platelet count |

| In 100 people receiving Zotiraciclib (TG02), from 4 to 20 may have:  Pneumonia  rash  Elevated liver enzyme  confusion  Severe infection  fever  Kidney failure   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Please tell the study doctor or study staff right away if you have any side effects. Please tell them if you have any other problems with your health or the way you feel during the study, whether or not you think they are related to the study drug. Zotiraciclib (TG02) citrate may affect the electrical activity of the heart that coordinates the heart's beating. Medications that affect this electrical activity of the heart, taken with Zotiraciclib (TG02) citrate should be avoided. Your study doctor will make decisions about your medications on a case by case basis and discuss this with you.  
You should inform the study doctor before you start any new medications, including prescription, over-the-counter, or herbal products. If you are having stomach upset, consult with your physician for recommended medications.

In 100 people receiving Temozolomide, more than 20 and up to 100 may have:
Constipation, nausea, vomiting, diarrhea Dizziness Muscle weakness, paralysis, difficulty walking Trouble with memory Tiredness Difficulty sleeping Hair loss OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Temozolomide, from 4 to 20 may have:
Headache, seizure Infection, especially when white blood cell count is low Low platelet count Moderate to severe low white blood cell count Anemia which may cause tiredness Bruising, bleeding

In 100 people receiving Temozolomide, 3 or fewer may have:
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat Cancer of bone marrow caused by chemotherapy Damage to the bone marrow (irreversible) which may cause infection, bleeding, may require blood transfusions Rash Severe skin rash with blisters and can involve inside of mouth and other parts of the body

Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection may cause anemia (low red blood cell count), which may create a need for blood transfusions.  
Questionnaires may contain questions that are sensitive in nature. You may refuse to answer any question that makes you feel uncomfortable. The primary use of the information you provide is to assess the severity of your symptoms. Submission of this information is voluntary. If you have concerns after completing the questionnaire, you are encouraged to contact your doctor or the study doctor. MRI scans cannot be done on people who have a cardiac pacemaker, neural pacemaker, surgical metal clips in the brain or on blood vessels, cochlear implants, or foreign metal objects within the eye. At the time of your MRI, you will be asked about these things. When you are in the scanning machine, a feeling of claustrophobia may come over you, and there will be a repetitive thumping noise. Cool air will surround you, and the room is lit so you will not feel like you are in a cave or underground. It is important to remain still during the MRI scan. If you are very claustrophobic in MRI scanners, you may ask your physician for a mild sedative for the procedure. If you do this, you must not drive a vehicle after the MRI. You can notify the MRI technologist of any discomfort you feel. The medicine that is used for the injection may rarely (1:2000) cause an allergic reaction such as hives, shortness of breath, or low blood pressure. The medical personnel in the MRI room are prepared to treat you for this kind of reaction. The MRI study will be stopped.  
This study may involve unpredictable risks to the participants.

During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (iv) catheter. It will be done for medical purposes. Risks The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with pain and swelling. Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and usually go away quickly. Mild symptoms that may occur include: coldness in the arm at injection, a metallic taste, headache, and nausea. In an extremely small number of patients, fewer than one in 300,000 people, more severe symptoms have been reported including: shortness of breath, wheezing, lowering of blood pressure. You should not receive gadolinium if you previously had an allergic reaction to it. You will be asked about such allergic reactions before gadolinium is given.  
People with kidney disease are at risk for a serious reaction to gadolinium contrast called
"nephrogenic systemic fibrosis (NSF)". This condition always involves the skin and can also involve the muscles, joints and internal organs. NSF has resulted in a very small number of deaths. A blood test of your kidney function may be done within the month before an MRI scan with gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney function is below the safe level. Most of the gadolinium contrast leaves the body in the urine. However, the FDA has issued a safety alert that indicates small amounts of gadolinium may remain in the body for months to years. The effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been linked to health risks in people whose kidneys work well. Some types of gadolinium contrast drugs are less likely to remain in the body than others. In this study, we will use the gadolinium contrast drugs that are less likely to remain in the body. We use gadobutrol which is a form of gadolinium contrast that is less likely to accumulate in the body than older types of gadolinium. You will receive additional information called a medication guide about the contrast medication you will receive. Please tell your research team if you have had any MRI scans in the past 12 months. We will also give you additional information called a "Medication Guide." Upon request, we will give you individual information about retained gadolinium we see on your studies.

The aim of this study is to determine a safe dose and to see if this experimental treatment will cause your tumors to shrink. We do not know if you will receive personal medical benefit from taking part in this study. These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer. Because there is not much information about the drug's effect on your cancer, we do not know if you will benefit from taking part in this study, although the knowledge gained from this study may help others in the future who have cancer.
Clinical trial: NCT02942264
Section: Procedures
Subsections: Zotiraciclib (Tg02) Dosing|Pre-Medications:|Study Visits:|Additional Research Blood And Tissue Samples:

You will take the first 200 mg dose of Zotiraciclib (TG02) 3 days prior to Day1 of cycle 1. You will take a 200 mg dose of Zotiraciclib (TG02) on days 1, 12, 15, and 26 of every 28day cycle in all the cycles. The 12 participants treated at the TG02 200 mg dose level will be followed to determine the progression free survival at 4 months.

Due to the possibility of nausea, vomiting and diarrhea with Zotiraciclib (TG02) treatment, participants will receive treatment to prevent vomiting and diarrhea before and for 24 hours following Zotiraciclib (TG02) administration. These may be tailored to the individual participant.

| Screen  Baseline                                                                                                  | Cycle 1   | Cycle 2   | Subsequent  Odd  numbered cycles   | Subsequent  Even  numbered cycles   | Off    |    |    |    |    |    |
|--------------------------------------------------------------------------------------------------|-----------|-----------|------------------------------------|-------------------------------------|----|----|----|----|----|----|
| therapy                                                                                          |           |           |                                    |                                     |    |    |    |    |    |    |
| Procedure                                                                                        | Wk        | Wk        | Wk                                 | Wk                                  | Wk | Wk | Wk | Wk |    |    |
| 2                                                                                                | 4         | 2         | 4                                  | 2                                   | 4  | 2  | 4  |    |    |    |
| Office visit                                                                                     | X         | X         | X                                  | X                                   | X  |    |    |    |    |    |
| Brain MRI                                                                                        | X         | X         | X                                  | X                                   |    |    |    |    |    |    |
| Blood work                                                                                       | X         | X         | X                                  | X                                   | X  | X  | X  | X  | X  | X  |
| EKG                                                                                              | X         | X         | X                                  | X                                   |    |    |    |    |    |    |
| Questionnaires*                                                                                  | X         | X         | X                                  | X                                   |    |    |    |    |    |    |
| Pregnancy                                                                                        | X         | X         | X                                  | X                                   | X  | X  |    |    |    |    |
| Test * Questionnaires: Symptom Burden Questionnaire will be done at baseline and with MRI scans. |           |           |                                    |                                     |    |    |    |    |    |    |  
At cycle 1, 2 and every 4 weeks:
You will have a physical exam in NOB clinic You will have a pregnancy test (if appropriate) and an EKG at cycle 1, 2 and every 8 weeks Every other week:
You will have blood collected for routine blood tests every other week Every 8 weeks:
You will have an MRI of the brain. With each MRI:
You will also be asked to complete a symptom burden questionnaire to  
Consent to Participate in a Clinical Research Study  
NIH-2977 (4-17) File in Section 4: Protocol Consent (2) Version Date: 06/01/2020 Page 4 of 16  
determine if you have symptoms of depression, anxiety, and general well-being or function. This will take only a few minutes to complete.

Research blood will be collected in the final 12 patients enrolled in Phase I at the following times: pre-dose, 1 hour, 2 hours, 4 hours, 24 hours and 48 hours after the dose. This set of blood samples will only occur in the first cycle of the protocol. Tumor sample will be needed to confirm the diagnosis before you start the study. Should you need surgery for your cancer during the study, we may collect tissue for research purposes.
Clinical trial: NCT02942264
Section: Purpose of Research
Subsections: Why Is This Study Being Done?|Description Of Research Study

This study will test an investigational drug called Zotiraciclib (TG02) citrate. An "investigational drug" is a drug that is being tested and is not approved for sale in the United States by the Food and Drug Administration (FDA). The purpose of this research study is to find out what effects (good and bad) Zotiraciclib (TG02) citrate has on you and your cancer. You will also receive temozolomide which is FDA approved and commonly used for recurrent high-grade astrocytoma. This study has two parts: a phase I part and a phase II part. In the phase I part, the main purpose is to learn about the safety of the study drug, Zotiraciclib (TG02). The study Consent to Participate in a Clinical Research Study NIH-2977 (4-17) File in Section 4: Protocol Consent (2) Version Date: 06/01/2020 Page 1 of 16 investigators have given Zotiraciclib (TG02) citrate to people in this study and found the highest dose of Zotiraciclib (TG02) citrate that people can tolerate when given in combination with temozolomide in two different treatment schedules. It was also found that one temozolomide treatment schedule was better than the other. However, we want to make sure that the highest dose that people tolerated is also the dose you need. Providing direct medical benefit to you is not the purpose of this part of the study. In the phase II part, the dose of Zotiraciclib (TG02) in combination temozolomide chosen in phase 1 will be compared to temozolomide alone. The dosing schedule of temozolomide used in this part of the study will depend on the response to each phase I part. The purpose of this part of the study is to find out if Zotiraciclib (TG02) citrate in combination temozolomide is as effective as temozolomide alone for people with the brain tumors.

You will also be enrolled in the Neuro Oncology Branch Natural History protocol to assess molecular markers of your brain tumor. If you agree to be in this study, we will ask you to do the following things:
Clinical trial: NCT02942264
Section: Voluntary Participation
Subsections: It Is Your Choice To Take Part In The Study

You may choose not to take part in this study for any reason. If you join this study, you may change your mind and stop participating in the study at any time and for any reason. In either case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you must be taking part in a study or are being considered for a study. If you do choose to leave the study, please inform your study team to ensure a safe withdrawal from the research.
Clinical trial: NCT02942264
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 and you cannot or choose not to cross over to TMZ+ Zotiraciclib (TG02)
if you have side effects from the treatment that your doctor thinks are too severe  
Consent to Participate in a Clinical Research Study  
NIH-2977 (4-17) File in Section 4: Protocol Consent (2) Version Date: 06/01/2020 Page 9 of 16  
if new information shows that another treatment would be better for you if you become pregnant 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. 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, information collected on you up to that point may still be provided to Adastra Pharmaceuticals or designated representatives. 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 the samples that have already been distributed to other researchers or placed in the research databases cannot be recalled and destroyed.