A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients with Newly Diagnosed Glioblastoma Multiforme
Protocol Version: November 20, 2006
| Purpose of Study | Eligibility Criteria | Treatment Schedule | Sample Informed Consent | Patient Information |
Primary Objectives
Study Arm I: To determine the Maximum Tolerated Dose (MTD) of AT-101 in patients with newly diagnosed glioblastoma multiforme when given in conjunction with radiation therapy and concomitant temozolomide.
Study Arm II: To determine the Maximum Tolerated Dose (MTD) of AT-101 in patients with newly diagnosed glioblastoma multiforme when given with adjuvant temozolomide after the completion of standard radiation therapy and concomitant temozolomide.
Secondary Objectives
To assess the toxicity associated with the two treatment settings.
To assess and describe the pharmacokinetics of AT-101 in the Study Arm I, the first three patients of each cohort will require blood sampling for determination of plasma concentrations of AT-101.
To explore preliminary evidence of therapeutic activities with respect to AT-101 concurrently treatment with TMZ and RT in patients with newly diagnosed GBMF who have not received prior chemotherapy and with adjuvant TMZ patients who have received concomitant RT and TMZ.
To explore the relationships between treatment with the combination of AT-101, RT and TMZ and cellular/molecular features identified in tumor biopsy specimens.
Inclusion Criteria
1. Patients must be at least 18 years of age.
2. Patients must have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme).
3. Study Arm I Patients ONLY: Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor. Glucocorticoid therapy is allowed.
4. Study Arm II Patients ONLY: Patients must have received planned treatment with radiation therapy and concomitant temozolomide at least 4 weeks (28 days) but no more than 7 weeks (49 days) prior to starting treatment on this study.
5. Patients must have a Karnofsky performance status ³ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
6. Patients must have the following hematologic, renal and liver function (i.e. hemoglobin ≥ 10gm/dl, absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, creatinine £ 1.5 mg/dl, total bilirubin ≤ 1.5 mg/dl, ALT and AST £ 2.5 times above the upper limits of the institutional norm.
7. Patients must be able to provide written informed consent.
8. Study Arm I Patients ONLY: Patients should have completed surgery ≤ 6 weeks from the start of AT-101 treatment.
9. Patients must have recovered from the immediate post-operative period and be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the start of treatment.
10. Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative serum pregnancy test. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
11. Patients must have a Mini Mental State Exam (MMSE) score of ³ 15.
12. Patients must have tumor tissue form completed and signed by a pathologist.
13. Patients must be able to swallow and retain oral medication.
14. Patients must have willingness and ability to comply with study procedures and follow-up examination.
Exclusion Criteria
1. Patients with serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
2. Patients who are pregnant or breast-feeding. All patients (both men and women) must be willing to practice birth control during and for 2 months after treatment with AT-101. Women of childbearing potential (WCBP) must have a negative serum pregnancy test. In addition, sexually active WCBP must agree to use two forms of adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner). Men should also protect their partner from becoming pregnant through use of condoms with spermicide, vasectomy or abstinence.
3. Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents).
4. Study Arm I Patients ONLY: Patients who have received Gliadel wafers are not eligible. Patients accrued to Study Arm II may have received Gliadel wafers.
5. Patients with a concurrent or prior malignancy, unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for ³ five years are eligible for this study.
6. Patients with ≥ Grade 2 sensory neuropathy based on the NCI CTCAE v.3.0.
7. Patients receiving cytochrome p450 enzyme-inducing anticonvulsant drugs (EIADs).
8. Patients who have been previously treated with gossypol, or have allergies to gossypol.
9. Patients who have received radiosurgery or brachytherapy.
10. Patients who participated in Study Arm I are NOT eligible for Study Arm II.
11. Patients who are taking iron supplements.
12. Patients with symptomatic hypercalcemia or hypercalcemia that is > Grade 2 (according to CTCAE).
13. Patients with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel are excluded. Patients with ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction are also excluded.
This is an open label, dose escalation, non-randomized, limited institution, phase I study to determine the MTD of oral AT-101 administered in combination with RT and TMZ. This study will also determine the MTD of oral AT-101 when administered in combination with adjuvant TMZ.
· Study Arm I: Dose escalation of AT-101 administered concurrently with RT and TMZ through the completion of RT.
· Study Arm II: Dose escalation of AT-101 administered concurrently with adjuvant TMZ.
Clinical and laboratory parameters will be assessed to evaluate toxicity of AT-101 administered in combination with RT and TMZ. In addition, PK blood samples of the first three patients of each cohort during Study Arm I will be analyzed for plasma concentrations of AT-101.
Study ARM I:
The MTD of AT-101 will be established when administered concurrently with RT and TMZ. Patients will be enrolled into open label sequential cohorts. Patients will receive AT-101 starting at 20 mg once daily for 5 of 7 days (Monday-Friday) in conjunction with radiation therapy and concomitant TMZ. AT-101 will be taken within 2-4 hours prior to receiving radiation therapy. Patients will begin AT-101 on the first day of RT and TMZ treatment and continue to receive AT-101 on a Monday- Friday schedule matching their radiation schedule until radiation therapy is completed (6 weeks). AT-101 should not be taken if RT is not administered. If RT is extended beyond 6 weeks (due to missed doses) then AT-101 administration may be extended until the last day of RT administration. Patients will receive daily TMZ continually every day for 6 weeks during their radiation. There is no need to coordinate the administration of AT-101 with the daily TMZ.
Study ARM II:
Patients will be enrolled in this arm of the study following treatment with radiation therapy and concomitant TMZ. Patients must be enrolled in this arm of the study prior to beginning adjuvant TMZ treatment cycles.
Three patients will be treated at the starting dose of 20mg/day for 21 of 28 days (3 weeks on, 1 week rest). Treatment with AT-101 will begin on the first day of adjuvant TMZ treatment. Each treatment cycle is 28 days. Patients will be evaluable for the cohort if they have completed 80% of their expected dose of AT-101 for two treatment cycles.
A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients with Newly-Diagnosed Glioblastoma Multiforme
Study Arm I
This is a clinical trial (a type of research study). Clinical trials include only patients who choose to take part. Please take your time to make your decision. Discuss it with your family and friends.
You are being asked to take part in this research study because you have been diagnosed with a type of brain cancer called glioblastoma multiforme.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to test the safety and side effects of AT-101 when it is added to currently standard treatment, which is radiation combined with an approved medication, temozolomide (TMZ). AT-101 is an investigational drug, which means that AT-101 is not approved by the United States Food and Drug Administration (FDA) for general use. The FDA does permit its use in studies like this one to determine whether it is safe and effective.
AT-101 is a form of a drug called gossypol. Gossypol has been studied extensively in more than 9,000 people, mostly in China, as a male contraceptive (form of birth control) and for treating endometriosis (a condition in the tissues of the uterus or “womb”) and myoma (tumors of the uterus). Gossypol has also been studied as a treatment for cancer. Four (4) studies in the United States and Britain were done, which included about 100 patients. Those studies identified safe doses of gossypol that could be given to cancer patients. Some patients with brain cancer or cancer of the adrenal gland had their tumors shrink in size when they received treatment with gossypol. Laboratory studies suggest that the form of gossypol in AT-101 may be a more effective form in treating cancer.
AT-101 is in its early stage of testing on humans. Currently, AT-101 is being studied in research studies of patients with early and advanced cancers. The purpose of these studies is to find the highest dose of AT-101 that can be safely given to patients without causing severe side effects, and to see the effects AT-101 has to shrink or stop these cancers from growing.
This research is being done because currently, there are few effective treatments for this type of cancer. This drug may be active in other types of cancer and we are studying the proper dose of AT-101 to give to patients with brain tumors. This means we will give increasing doses of AT-101 until patients have major side effects. You will be assigned a dose when you enter the study. You will be told what your dose is and it will not be increased. You will be given the same or lower dose throughout your treatment. You will be given a lower dose if you experience side effects that require reduced dosing. We will also be looking at the side effects of AT-101.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 20-50 people will take part in the study.
WHAT IS INVOLVED IN THE STUDY?
If you take part in this study you will have the following tests and procedures:
Before treatment starts, you will have a complete physical exam, blood and urine tests. You will have a physical examination including measurement of your height, weight, blood pressure, pulse rate, breathing rate, performance status, which measures the degree of your ability to complete daily activities (e.g., dressing and eating). You will have a complete neurological exam to test your thinking and motor skills, and perform a test to assess your mental abilities. You will also take a brief test called a mini mental status exam, which is a series of questions that evaluate your mental abilities. Additionally, you will have an electrocardiogram (ECG) (a test that produces a graphic picture of the electric activity of your heart). To measure the extent of your brain cancer, you will a have an MRI scan, which is method of obtaining pictures of internal soft bodily tissue through the use of powerful magnets and radio waves.
About 3 tablespoons of blood will be drawn from one of your veins to conduct laboratory tests (e.g., standard blood count including a count of your platelets, and blood chemistries). You will also be asked to give a sample of urine in order to perform a standard urine test and have a pregnancy test if you are a woman that is able to have children.
AT-101 is given in the form of a pill that you take by mouth. You will take AT-101 every day you receive radiation therapy. Typically radiation is given 5 out of 7 days during the week (Monday-Friday) for 6 weeks. You will take AT-101 5 out of 7 days each week (Monday-Friday) approximately 2-4 hours before your scheduled radiation dose for 6 weeks. You will be given a drug diary and you will be required to record the time and the number of pills you take. You should swallow these pills at least 1 hour (or more) before or at least 1 hour (or more) after a meal. It is important for you to take AT-101 at about the same time every day. Your doctor will instruct you if there are any changes to this routine. If you have side effects that are too severe, your dose of AT-101 may be reduced for safety, or discontinued entirely if necessary.
Radiation will be given daily (5 days each week) in the outpatient department for about six weeks. There is nothing experimental about the radiation that will be given. During this time you will also receive temozolomide (TMZ). You will begin taking TMZ on the first day of radiation. Temozolomide is given in the form of a pill that you will take every day for 6 weeks while you are receiving radiation. The number of pills you take every day will depend on your body size. TMZ must be taken on an empty stomach. You cannot eat or drink anything except water for one hour before taking you pills and for one hour after taking your pills. You will take your pills at least one hour before you receive radiation. On days you do not receive radiation you will take your TMZ pills in the morning.
Your study doctor will give you AT-101 at the clinic. You will be given instructions on how to store your AT-101 pills and when to take them. You will return any empty bottles and/or remaining AT-101 at each visit to your study doctor.
During the study, physical exams, neurologic exams and ECGs will be repeated. Routine blood tests will be done. If at any point your blood counts are low, these blood tests will be repeated more often.
If you are one of the first three patients in a dose level, as part of this study, we will also be collecting extra blood samples in order to check the amount of AT-101 in your blood. On Day 1 of your treatment you will take your dose of AT-101 in the clinic. We will collect 7 extra blood samples. This will require you to stay in the clinic for at least 6 hours. On the 2nd day we will collect one blood sample before your dose of AT-101. Approximately 2 tablespoons of blood are drawn for each sample. These extra blood tests are for research purposes only and would not be part of your standard care. The costs associated with collecting and processing these blood samples will not be charged to you or your insurance company.
As a part of this study we will collect samples of your tumor tissue for research purposes. Some of the tumor tissue that was taken during your surgery or biopsy will be sent to a lab for analysis. The tissue samples will be used to characterize the immunochemistry and molecular biology of your tumor. Glioblastoma multiforme can be very different in each patient. We hope to learn about the characteristics of your tumor. We will use the information we collect about this kind of tumor to help us better treat patients with glioblastoma multiforme in the future.
HOW LONG WILL I BE IN THE STUDY?
AT-101 will be continued until you complete your radiation therapy (approximately 6 weeks). You will return to the clinic 1 week after you complete your radiation therapy for follow up evaluations. This means that you will be on this study for a total of 7 weeks. The researcher may decide to take you off this study if your doctor thinks it will be in your best interest, your condition worsens, or new information becomes available. Even after you stop receiving treatment as part of this study a member of the research team will contact you once every two months to see how you are doing.
Your participation in your clinical trial is completely voluntary. You can stop participating at any time. If you decide not to participate, or wish to withdraw your consent to participate in this treatment at any time, it will in no way affect your regular treatments or medical care. If you stop participating in this study you may be asked to return to the clinic for a final evaluation. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and visit your regular doctor first.
WHAT ARE THE RISKS OF THE STUDY?
While on the study, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make the side effects less serious and uncomfortable.
Many side effects go away shortly after the AT-101 is stopped, but in some cases side effects can be serious or long-lasting or permanent or fatal.
Likely Side effects include (> 20% of patients experience these):
· Nausea, vomiting, diarrhea, abdominal pain, or poor appetite. These are expected to be mild and brief but may be severe or long-lasting.
· Fatigue—expected to be mild but could be moderate worse.
· Dry skin or dry mouth
· Skin rash—some cancer patients have had a severe skin rash covering much of their bodies, after receiving gossypol. The rash went away when gossypol treatment was stopped and standard medicines were used. Admission to the hospital was not required.
· Abnormal liver function blood tests— expected to be mild to moderate, but some patients may experience a severe change in liver function blood tests that could be accompanied by episodes of nausea, vomiting, and fatigue. Severe changes in liver blood tests are expected to go back to normal when you stop taking AT-101.
· Decreased fertility—when given repeatedly for weeks or months, gossypol does reduce the ability of men to father a child. This effect was long-lasting or permanent in some men who received gossypol. It is possible that AT-101 will have similar effects. It is possible that men in particular who receive AT-101 may have long-term or permanent difficulty fathering children or even become sterile. However, it is not possible to say exactly what the chance of decreased fertility is in this trial. Tests for fertility will not be done as part of this trial.
Less Likely Side Effects include (≤ 20% of patients experience these):
· Reduced ability for the bowels to work, called “ileus” by doctors. This could lead to bloating, discomfort, inability to have a bowel movement, nausea, and vomiting. It has not been common but has happened to a few people who got gossypol OR AT-101. When it has occurred, it has not lasted long and went away when gossypol was temporarily stopped.
· Low blood potassium—some people who were studied while taking gossypol for prolonged periods developed low potassium. If this occurs, it is likely to be mild and easily treated by giving potassium pills (supplements) by mouth. However, low potassium can cause an abnormal heartbeat or muscle weakness that can be severe. The amount of potassium in your blood will be carefully monitored during the study.
· Dizziness
· Decreased libido (sex drive)
· Pain in the testicles (men)
Unlikely Side effects:
· Damage to the heart muscle or abnormal heartbeat—a rare but serious effect observed in animals treated with gossypol. In people, gossypol has not caused effects on the heart that have required treatment. However, if this unlikely problem were to occur in this trial, it could be life-threatening. You will be monitored throughout this study for any change in certain blood enzymes or heartbeat rhythm.
· Paralysis associated with very low blood potassium—a rare but serious effect observed in some Chinese men who received gossypol to prevent conception. This condition was reversible if treated with potassium supplements.
· Low blood counts— refers to decreases in the number of certain types of blood cells which are common in cancer trials, but have been rare and mild in past studies of gossypol. If low blood counts occur, they could increase your risk of bleeding or getting an infection. Mildly low blood counts may not require treatment at all.
Side effects due to blood drawing may include: pain, bruising, bleeding or other discomfort at the blood drawing site. Anemia (low red blood cells), fainting or infection at the blood drawing site may occur (very unlikely).
Temozolomide Side Effects:
Temozolomide is a chemotherapy drug that is considered standard treatment with your radiation therapy. Temozolomide may cause the following:
· Nausea and vomiting, especially on the first day of each maintenance cycle. It may be necessary to use medication to prevent this. It may also cause constipation, loss of appetite, abnormal liver tests, and diarrhea
· Lowering of your blood counts, which may result in low white blood cells, platelets, and red blood cells. If you have very low white blood cells, you are at a higher risk for infections. Lung infections have occured in patients receiving daily treatment with temozolomde combined with radiation and steroids (eg, dexamethason). To prevent this your doctor may ask you to take preventative medication during this time. Apart from this, if you develop fever it may be necessary to treat you with antibiotics. Low platelets may result in a bleeding tendency, if necessary this can be treated with platelets infusions. Low red blood cells can also be treated with transfusions. As a rule, stopping temozolomide results in recovery of your low blood counts.
· Fatigue, lethargy, insomnia, weakness
· Headache
· Hair loss and rash
· Kidney problems and high blood sugar
Reproductive risks: Because there may be a risk of birth defects if a fetus is exposed to AT-101, you should not use this drug if you and your partner are planning to have a baby during this study or two months following the end of the study. A barrier method of birth control (i.e. condom) must be used during the study and for eight (8) weeks after your last dose of study drug. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy.
Standard Radiation: Standard radiation therapy can cause reddening and tanning of the skin and blisters. Other possible toxicities include fatigue, hair loss, skin reaction in the ear canals, dry mouth, altered taste, difficulty thinking, dead cells, hormone dysfunction and cataracts. Radiation can cause brain swelling which may cause some brain tumor symptoms such as headaches, seizures, and/or weakness to be worse. Brain swelling can also cause double vision, slurred speech and other neurological problems. Brain swelling can be treated by increasing your steroid dose.
Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by the hospital or the insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
For more information about risks and side effects, ask the researcher or contact
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with brain tumors in the future.
WHAT OTHER OPTIONS ARE THERE?
You do not have to join this clinical trial to get treatment for your disease. Instead of being in this study other options are:
i Standard radiation therapy with or without chemotherapy
i Other experimental therapy
i No further anti-cancer therapy and comfort care only
Please talk to your regular doctor about these options. You may continue to get care from you physician even if you do not take part in the study.
Should your disease become worse, or if you have severe side effects, this therapy may be discontinued and other means of treating you will be discussed. Please talk to you doctor about these and other options.
WHAT ABOUT CONFIDENTIALITY?
This section tells you what information about you may be used and given out in this study and who may give and receive the information. By signing this consent form, you agree that health information that identifies you may be used and/or given out as needed in this study. _________________ has a policy to protect health information that may identify you. Federal and state laws also protect your privacy. ______________________ has procedures in place to support these policies and laws.
a. What information about you may be used or given out in this study?
Information that identifies you and relates to your health or medical condition may be used or given out in this study. Information that identifies you can include your name, address, telephone number, date of birth, Social Security number and other details about you. Information that relates to your health or medical condition includes:
Information obtained from the activities and procedures outlined in this consent form, which may include:
i) things done to see if you can join this study, such as physical examinations, blood and urine tests and any other information that you share with us, including information about your health history and your family health history; and
ii) information obtained during the study, such as how you respond to the study activities or procedures, information we learn in study visits, phone calls, surveys, physical examinations, blood and urine tests, x-rays and other tests and any other medical information we learn from you as a participant in this study.
b. Who may use and give out information about you?
Some people may see your health information and may give out your health information during this study. These include the researcher and the research staff, the institutional review boards and their staff, legal counsel, audit and compliance staff, officers of the organization and other people who need to see the information to help this study or make sure it is being done as it should.
c. Who may see your health information?
Other organizations may see your health information during this study. These include:
· Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections and the Food and Drug Administration
· Doctors and staff at other places that are participating in this study
· The pharmaceutical sponsor, Ascenta Therapeutics Inc.
· The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI (National Cancer Institute).
· The Contract Research Organization.
· The Data Safety Monitoring Board
· An outside institutional review board
· NABTT CNS Consortium
d. Why will this information be used and given out?
Your information will be used and given out to carry out this study and to evaluate the results of this study.
e. What if you decide not to give your permission to use and give out your health information?
You do not have to give your permission to use or give out your health information. However, if you do not give permission, you may not participate in this study.
f. May you withdraw or cancel your permission?
You may cancel your agreement to allow your health information to be used or given out at any time by sending a written notice to the Institutional Review Board Office, __________________________________. If you do this, you are leaving this study. If you leave this study, no new health information about you will be gathered after that date. However, information gathered before that date may be used or given out if it is needed for this study or any follow-up for this study.
g. Is your health information protected after it has been given to others?
If your health information is given to someone not covered by these policies and laws, that information may no longer be protected, and may be used or given out without your permission.
h. Does this consent form have an end date?
This authorization to use and give out health information continues until the end of this study and any necessary data analysis follow-up activities for this study.
A) What is the role of the IRB?
Research studies involving human volunteers are reviewed by an Institutional Review Board (IRB). The IRB is made up of doctors, nurses, scientists, non-scientists and people from the community. The IRB is responsible for protecting participant’s rights.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. Some of the costs of the blood tests and brain scans may not be covered by your insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
In the case of injury or illness resulting from this study, emergency medical treatment is available but will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury.
You or your insurance company will be charged for continuing medical care and/or hospitalization.
Ascenta Therapeutics, Inc. will provide you with AT-101 free of charge for this study.
You will receive no payment for taking part in this study.
WHAT ARE MY RIGHTS AS A PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. Leaving the study will not result in any penalty or loss of benefits to which you are entitled. We will talk to you about new information that may affect your health, welfare, or willingness to stay in this study.
A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients with Newly-Diagnosed Glioblastoma Multiforme
Study Arm II
This is a clinical trial (a type of research study). Clinical trials include only patients who choose to take part. Please take your time to make your decision. Discuss it with your family and friends.
You are being asked to take part in this research study because you have been diagnosed with a type of brain cancer called glioblastoma multiforme.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to test the safety and side effects of AT-101 when it is added to currently standard treatment. You should have completed part of the standard treatment which is radiation combined with an approved medication, temozolomide (TMZ). In this study we will add AT-101 to standard TMZ given after radiation therapy. AT-101 is an investigational drug, which means that AT-101 is not approved by the United States Food and Drug Administration (FDA) for general use. The FDA does permit its use in studies like this one to determine whether it is safe and effective.
AT-101 is a form of a drug called gossypol. Gossypol has been studied extensively in more than 9,000 people, mostly in China, as a male contraceptive (form of birth control) and for treating endometriosis (a condition in the tissues of the uterus or “womb”) and myoma (tumors of the uterus). Gossypol has also been studied as a treatment for cancer. Four (4) studies in the United States and Britain were done, which included about 100 patients. Those studies identified safe doses of gossypol that could be given to cancer patients. Some patients with brain cancer or cancer of the adrenal gland had their tumors shrink in size when they received treatment with gossypol. Laboratory studies suggest that the form of gossypol in AT-101 may be a more effective form in treating cancer.
AT-101 is in its early stage of testing on humans. Currently, AT-101 is being studied in research studies of patients with early and advanced cancers. The purpose of these studies is to find the highest dose of AT-101 that can be safely given to patients without causing severe side effects, and to see the effects AT-101 has to shrink or stop these cancers from growing.
This research is being done because currently, there are few effective treatments for this type of cancer. This drug may be active in other types of cancer and we are studying the proper dose of AT-101 to give to patients with brain tumors. This means we will give increasing doses of AT-101 until patients have major side effects. You will be assigned a dose when you enter the study. You will be told what your dose is and it will not be increased. You will be given the same or lower dose throughout your treatment. You will be given a lower dose if you experience side effects that require reduced dosing. We will also be looking at the side effects of AT-101.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 20-50 people will take part in the study.
WHAT IS INVOLVED IN THE STUDY?
If you take part in this study you will have the following tests and procedures:
Before treatment starts, you will have a complete physical exam, blood and urine tests. You will have a physical examination including measurement of your height, weight, blood pressure, pulse rate, breathing rate, performance status, which measures the degree of your ability to complete daily activities (e.g., dressing and eating). You will have a complete neurological exam to test your thinking and motor skills, and perform a test to assess your mental abilities. You will also take a brief test called a mini mental status exam, which is a series of questions that evaluate your mental abilities. Additionally, you will have an electrocardiogram (ECG) (a test that produces a graphic picture of the electric activity of your heart). To measure the extent of your brain cancer, you will a have an MRI scan, which is method of obtaining pictures of internal soft bodily tissue through the use of powerful magnets and radio waves.
About 3 tablespoons of blood will be drawn from one of your veins to conduct laboratory tests (e.g., standard blood count including a count of your platelets, and blood chemistries). You will also be asked to give a sample of urine in order to perform a standard urine test and have a pregnancy test if you are a woman that is able to have children.
AT-101 is given in the form of a pill that you take by mouth. You will take AT-101 every day for 21 out of 28 days (3 out of 4 weeks). Twenty-eight days is considered a treatment cycle. You should swallow these pills at least 1 hour (or more) before or at least 1 hour (or more) after a meal. It is important for you to take AT-101 at about the same time every day. You will be given a drug diary and you will be required to record the time and the number of pills you take. Your doctor will instruct you if there are any changes to this routine. If you have side effects that are too severe, your dose of AT-101 may be reduced for safety, or discontinued entirely if necessary.
You will also continue to receive temozolomide as you did during radiation therapy but on a different schedule. You will no longer take temozolomide every day. You will take several pills for only the first 5 days of each treatment cycle. TMZ must be taken on an empty stomach. You cannot eat or drink anything except water for one hour before and for one hour after taking your pills.
Your study doctor will give you AT-101 at the clinic. You will be given instructions on how to store your AT-101 pills and when to take them. You will return any empty bottles and/or remaining AT-101 at each visit to your study doctor.
After the second treatment cycle an MRI will be obtained. If this MRI shows that the tumor size is the same or smaller, you will begin another 28-day (four-week) cycle of treatment. An MRI will be obtained before every other treatment cycle (every 8 weeks) to see if your tumor is growing. During the study, physical exams, neurologic exams and ECGs will be repeated. Routine blood tests will be done. If at any point your blood counts are low, these blood tests will be repeated more often.
As a part of this study we will collect samples of your tumor tissue for research purposes. Some of the tumor tissue that was taken during your surgery or biopsy will be sent to a lab for analysis. The tissue samples will be used to characterize the immunochemistry and molecular biology of your tumor. Glioblastoma multiforme can be very different in each patient. We hope to learn about the characteristics of your tumor. We will use the information we collect about this kind of tumor to help us better treat patients with glioblastoma multiforme in the future.
HOW LONG WILL I BE IN THE STUDY?
We estimate you will be on this study for at least 8 weeks. An MRI will be obtained after you complete the second treatment cycle (8 weeks of treatment). If this MRI shows that the tumor size is the same or smaller, you will begin a third, four-week cycle of treatment. As long as your tumor does not grow and as long as you do not experience any bad side effects you may continue to receive maintenance cycles for a maximum of 6 cycles. If the MRI shows that your tumor is growing you will stop AT-101 and temozolomide treatment and you and your doctor will discuss other treatment options. Even after you stop receiving treatment as part of this study a member of the research team will contact you once every two months to see how you are doing.
Your participation in your clinical trial is completely voluntary. You can stop participating at any time. If you decide not to participate, or wish to withdraw your consent to participate in this treatment at any time, it will in no way affect your regular treatments or medical care. If you stop participating in this study you may be asked to return to the clinic for a final evaluation. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and visit your regular doctor first.
WHAT ARE THE RISKS OF THE STUDY?
While on the study, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make the side effects less serious and uncomfortable.
Many side effects go away shortly after the AT-101 is stopped, but in some cases side effects can be serious or long-lasting or permanent or fatal.
Likely Side effects include (> 20% of patients experience these):
· Nausea, vomiting, diarrhea, abdominal pain, or poor appetite. These are expected to be mild and brief but may be severe or long-lasting.
· Fatigue—expected to be mild but could be moderate worse.
· Dry skin or dry mouth
· Skin rash—some cancer patients have had a severe skin rash covering much of their bodies, after receiving gossypol. The rash went away when gossypol treatment was stopped and standard medicines were used. Admission to the hospital was not required.
· Abnormal liver function blood tests— expected to be mild to moderate, but some patients may experience a severe change in liver function blood tests that could be accompanied by episodes of nausea, vomiting, and fatigue. Severe changes in liver blood tests are expected to go back to normal when you stop taking AT-101.
· Decreased fertility—when given repeatedly for weeks or months, gossypol does reduce the ability of men to father a child. This effect was long-lasting or permanent in some men who received gossypol. It is possible that AT-101 will have similar effects. It is possible that men in particular who receive AT-101 may have long-term or permanent difficulty fathering children or even become sterile. However, it is not possible to say exactly what the chance of decreased fertility is in this trial. Tests for fertility will not be done as part of this trial.
Less Likely Side Effects include (≤ 20% of patients experience these):
· Reduced ability for the bowels to work, called “ileus” by doctors. This could lead to bloating, discomfort, inability to have a bowel movement, nausea, and vomiting. It has not been common but has happened to a few people who got gossypol OR AT-101. When it has occurred, it has not lasted long and went away when gossypol was temporarily stopped.
· Low blood potassium—some people who were studied while taking gossypol for prolonged periods developed low potassium. If this occurs, it is likely to be mild and easily treated by giving potassium pills (supplements) by mouth. However, low potassium can cause an abnormal heartbeat or muscle weakness that can be severe. The amount of potassium in your blood will be carefully monitored during the study.
· Dizziness
· Decreased libido (sex drive)
· Pain in the testicles (men)
Unlikely Side effects:
· Damage to the heart muscle or abnormal heartbeat—a rare but serious effect observed in animals treated with gossypol. In people, gossypol has not caused effects on the heart that have required treatment. However, if this unlikely problem were to occur in this trial, it could be life-threatening. You will be monitored throughout this study for any change in certain blood enzymes or heartbeat rhythm.
· Paralysis associated with very low blood potassium—a rare but serious effect observed in some Chinese men who received gossypol to prevent conception. This condition was reversible if treated with potassium supplements.
· Low blood counts— refers to decreases in the number of certain types of blood cells which are common in cancer trials, but have been rare and mild in past studies of gossypol. If low blood counts occur, they could increase your risk of bleeding or getting an infection. Mildly low blood counts may not require treatment at all.
Side effects due to blood drawing may include: pain, bruising, bleeding or other discomfort at the blood drawing site. Anemia (low red blood cells), fainting or infection at the blood drawing site may occur (very unlikely).
Temozolomide Side Effects:
Temozolomide is a chemotherapy drug that is considered standard treatment with your radiation therapy. Temozolomide may cause the following:
· Nausea and vomiting, especially on the first day of each maintenance cycle. It may be necessary to use medication to prevent this. It may also cause constipation, loss of appetite, abnormal liver tests, and diarrhea
· Lowering of your blood counts, which may result in low white blood cells, platelets, and red blood cells. If you have very low white blood cells, you are at a higher risk for infections. Lung infections have occured in patients receiving daily treatment with temozolomde combined with radiation and steroids (eg, dexamethason). To prevent this your doctor may ask you to take preventative medication during this time. Apart from this, if you develop fever it may be necessary to treat you with antibiotics. Low platelets may result in a bleeding tendency, if necessary this can be treated with platelets infusions. Low red blood cells can also be treated with transfusions. As a rule, stopping temozolomide results in recovery of your low blood counts.
· Fatigue, lethargy, insomnia, weakness
· Headache
· Hair loss and rash
· Kidney problems and high blood sugar
Standard Radiation: Standard radiation therapy can cause reddening and tanning of the skin and blisters. Other possible toxicities include fatigue, hair loss, skin reaction in the ear canals, dry mouth, altered taste, difficulty thinking, dead cells, hormone dysfunction and cataracts. Radiation can cause brain swelling which may cause some brain tumor symptoms such as headaches, seizures, and/or weakness to be worse. Brain swelling can also cause double vision, slurred speech and other neurological problems. Brain swelling can be treated by increasing your steroid dose.
Reproductive risks: Because there may be a risk of birth defects if a fetus is exposed to AT-101, you should not use this drug if you and your partner are planning to have a baby during this study or two months following the end of the study. A barrier method of birth control (i.e. condom) must be used during the study and for eight (8) weeks after your last dose of study drug. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy.
Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by the hospital or the insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
For more information about risks and side effects, ask the researcher or contact ___.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with brain tumors in the future.
WHAT OTHER OPTIONS ARE THERE?
You do not have to join this clinical trial to get treatment for your disease. Instead of being in this study other options are:
i Standard radiation therapy with or without chemotherapy
i Other experimental therapy
i No further anti-cancer therapy and comfort care only
Please talk to your regular doctor about these options. You may continue to get care from you physician even if you do not take part in the study.
Should your disease become worse, or if you have severe side effects, this therapy may be discontinued and other means of treating you will be discussed. Please talk to you doctor about these and other options.
WHAT ABOUT CONFIDENTIALITY?
This section tells you what information about you may be used and given out in this study and who may give and receive the information. By signing this consent form, you agree that health information that identifies you may be used and/or given out as needed in this study. _________________ has a policy to protect health information that may identify you. Federal and state laws also protect your privacy. ______________________ has procedures in place to support these policies and laws.
a. What information about you may be used or given out in this study?
Information that identifies you and relates to your health or medical condition may be used or given out in this study. Information that identifies you can include your name, address, telephone number, date of birth, Social Security number and other details about you. Information that relates to your health or medical condition includes:
Information obtained from the activities and procedures outlined in this consent form, which may include:
i) things done to see if you can join this study, such as physical examinations, blood and urine tests and any other information that you share with us, including information about your health history and your family health history; and
ii) information obtained during the study, such as how you respond to the study activities or procedures, information we learn in study visits, phone calls, surveys, physical examinations, blood and urine tests, x-rays and other tests and any other medical information we learn from you as a participant in this study.
b. Who may use and give out information about you?
Some people may see your health information and may give out your health information during this study. These include the researcher and the research staff, the institutional review boards and their staff, legal counsel, audit and compliance staff, officers of the organization and other people who need to see the information to help this study or make sure it is being done as it should.
c. Who may see your health information?
Other organizations may see your health information during this study. These include:
· Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections and the Food and Drug Administration
· Doctors and staff at other places that are participating in this study
· The pharmaceutical sponsor, Ascenta Therapeutics Inc.
· The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI (National Cancer Institute).
· The Contract Research Organization.
· The Data Safety Monitoring Board
· An outside institutional review board
· NABTT CNS Consortium
d. Why will this information be used and given out?
Your information will be used and given out to carry out this study and to evaluate the results of this study.
e. What if you decide not to give your permission to use and give out your health information?
You do not have to give your permission to use or give out your health information. However, if you do not give permission, you may not participate in this study.
f. May you withdraw or cancel your permission?
You may cancel your agreement to allow your health information to be used or given out at any time by sending a written notice to the Institutional Review Board Office, __________________________________. If you do this, you are leaving this study. If you leave this study, no new health information about you will be gathered after that date. However, information gathered before that date may be used or given out if it is needed for this study or any follow-up for this study.
g. Is your health information protected after it has been given to others?
If your health information is given to someone not covered by these policies and laws, that information may no longer be protected, and may be used or given out without your permission.
h. Does this consent form have an end date?
This authorization to use and give out health information continues until the end of this study and any necessary data analysis follow-up activities for this study.
A) What is the role of the IRB?
Research studies involving human volunteers are reviewed by an Institutional Review Board (IRB). The IRB is made up of doctors, nurses, scientists, non-scientists and people from the community. The IRB is responsible for protecting participant’s rights.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. Some of the costs of the blood tests and brain scans may not be covered by your insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
In the case of injury or illness resulting from this study, emergency medical treatment is available but will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury.
You or your insurance company will be charged for continuing medical care and/or hospitalization.
Ascenta Therapeutics, Inc. will provide you with AT-101 free of charge for this study. You will receive no payment for taking part in this study.
WHAT ARE MY RIGHTS AS A PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. Leaving the study will not result in any penalty or loss of benefits to which you are entitled. We will talk to you about new information that may affect your health, welfare, or willingness to stay in this study.