A Phase II Trial of Radiation plus Temozolomide followed by adjuvant Temozolomide and Poly-ICLC in Patients with Newly Diagnosed Glioblastoma Multiforme
Protocol Version: October 12, 2005
| Purpose of Study | Eligibility Criteria | Treatment Schedule | Sample Informed Consent | Patient Information |
Primary Objective
The overall objective of this study is to evaluate the safety and efficacy of radiation plus low-dose temozolomide followed by adjuvant temozolomide and Intramuscular Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) for adult patients with newly diagnosed glioblastoma multiforme.
Secondary Objective
The secondary objective of this study is to estimate the frequency of toxicity associated with this treatment regime.
Inclusion Criteria
1. Patients must be at least 18 years of age.
2. Patients must have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme). Diagnosis will have been established by biopsy or resection no more than 3 months prior to registration.
3. 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. 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).
5. Patients must have normal hematologic, renal and liver function (i.e. Absolute neutrophil count > 1500/mm3, Platelets > 100,000/mm3, creatinine £ 1.7 mg/dl, total bilirubin ≤ 1.5 mg/dl, transaminases £ 4 times above the upper limits of the institutional normal.
6. Patients must be able to provide written informed consent.
7. 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 pregnancy test. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
8. Patients must have a Mini Mental State Exam score of ³ 15.
9. Patients must have Gadolinium MRI or contrast CT scan within 14 days of starting treatment.
10. Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with poly-ICLC plus temozolomide on this protocol.
Exclusion Criteria
Patients with any of the following are ineligible for this research study:
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. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
3. Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents).
4. Patients with a concurrent or prior malignancy are ineligible 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.
5. Patients who have received Gliadel wafers are not eligible for this study.
6. Patients requiring ongoing therapy for psychoses with antipsychotic medications at the time of enrollment will be ineligible.
Patients who enroll on this study will receive 6 weeks of standard radiation therapy with concomitant TMZ treatment. Treatment with TMZ will stop for 4 weeks (rest period) following the end of RT. These 6 weeks of combined treatment and the following 4 weeks no treatment is called an initiation cycle.
After the 10 week initiation cycle, maintenance cycles will immediately follow. An MRI will be performed at the end of the initiation cycle (6 weeks of radiation + TMZ and 4 weeks rest). This MRI is not to be used to assess for tumor progression (unless the progression is outside of the radiation port).
The maintenance cycles will begin immediately after the initiation cycle and each maintenance cycle will last for 9 weeks. TMZ will no longer be given every day. It will be given orally at a dose of 200 mg/m2 daily for only the first 5 consecutive days of each cycle. Weeks 2-8 of the maintenance cycle patients will receive poly-ICLC three times every 7 days by intramuscular injection. Poly-ICLC will be dosed at 20 mcg/kg. The days of poly-ICLC administration must be at least 2 days apart and not be more than 3 injections within a 7 day period. The drug may be administered at any time of day, but it is recommended that each patient choose a consistent time for administration (patients will be given a drug diary to record each administration). After the patient has received 21 injections of poly-ICLC (encompassing a 7 week period) they will receive no treatment during week 9 (last week) of the maintenance cycle. This will begin a new maintenance cycle. Temozolomide dosing will start within seven days (± 3 days) after the last injection of poly-ICLC. Poly-ICLC will not be administered during the 5 day course of temozolomide therapy. After completing one maintenance cycle of Poly-ICLC and TMZ an MRI will be obtained. If according to this MRI the patient has progressed then the patient will stop Poly-ICLC and TMZ treatment and go off treatment. If patient has not progressed then patient will continue to receive additional maintenance cycles of Poly-ICLC and TMZ with MRIs performed prior to every maintenance cycle (every 9 weeks) until post initiation therapy progression. All patients will be followed every two months for survival.
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 study because you have a
newly diagnosed brain tumor called a glioblastoma multiforme.
WHY IS THIS STUDY BEING DONE?
You have been diagnosed with a brain tumor called
glioblastoma multiforme. This research is being done because this type of tumor
is almost never cured with surgery, radiation, or chemotherapy. For this
reason, we are trying to find new drugs to improve treatment for this tumor.
The study you are being asked to join uses an experimental drug called poly-ICLC.
Poly-ICLC is experimental because it has not been approved by the U. S. Food and
Drug Administration (FDA). Poly-ICLC is a new type of drug that may prevent
cancer cells from growing and invading healthy brain cells. Poly-ICLC has been
tested on patients with brain tumors as a single therapy. The first part of
this study combines external beam radiation, which is "standard" therapy
for this disease and with temozolomide.
Temozolomide (TMZ) is a chemotherapy. TMZ is an FDA approved drug and has
recently been found to increase the survival of patients with glioblastoma
multiforme. The combination of TMZ and radiation therapy is now being
considered the “standard of care”. In this study, you will be given both
radiation therapy and TMZ before you receive poly-ICLC. Four weeks after you
complete your radiation therapy and TMZ you will begin receiving TMZ alone
followed by poly-ICLC.
The purpose of this study is to learn whether with the addition of poly-ICLC treatment to TMZ will increase the survival of patients with glioblastoma multiforme. We also want to find out what effects (good and bad) poly-ICLC has on you and your brain tumor. We will also be looking at the safety profile of this drug.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 96 people will take part in the study.
WHAT IS INVOLVED IN THE STUDY?
If you decide to take part in this study, you
will need to have some tests and examinations before you begin. Your doctor
will perform a history and a physical examination. You will have a chest x-ray
and ECG. An ECG is a simple test that measures the rhythm of your heart and may
detect some abnormal condition. You will have an MRI scan of your brain. You
will also have laboratory tests to make sure you are not at increased risk for
side effects. If you are a woman of child bearing potential a pregnancy test
will be obtained. If the results of this test are positive you cannot take part
in this study. Some of these tests would be done even if you do not take part
in this study.
You will begin your radiation therapy with TMZ. 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 TMZ. TMZ 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. You will take your pills in the morning. TMZ must be taken on an empty stomach. You cannot eat anything except water for one hour before taking your pills and for one hour after taking your pills. TMZ capsules should be swallowed whole in rapid succession without chewing them. You will take your pills at least one hour before you receive radiation. On days you do not receive radiation you will take your pills in the morning. During the 4 weeks directly after radiation you will not take any TMZ. You will have 4 weeks of rest where you will receive no therapy. These first ten weeks (6 weeks of radiation + TMZ and 4 weeks of rest) of treatment are called an initiation cycle. An MRI of your brain will be obtained after you complete your initiation cycle. This MRI is part of your standard radiation therapy follow-up care.
After the initiation cycle you will begin your maintenance cycles. Each maintenance cycle will be 9 weeks long. TMZ and poly-ICLC treatment will be given during each maintenance cycle. You will no longer take TMZ every day. You will take several pills for only the first 5 days of each maintenance cycle. TMZ must be taken on an empty stomach. You cannot eat or drink anything except water for one hour before or for one hour after taking your pills. TMZ capsules should be swallowed whole in rapid succession without chewing them. About 2 days after your Day 5 TMZ dose (during week two of your maintenance cycle) you will begin the poly-ICLC treatment. Poly-ICLC is given as an intramuscular injection. This means you will inject the drug directly into your muscle (probably your arm or thigh). You will learn how to administer the poly-ICLC yourself. For the first injection you will need to come to the clinic so that your study doctor or study nurse can supervise the administration and monitor your vital signs. You will give yourself 3 injections every week for 7 weeks (total of 21 injections during weeks 2-8 of each maintenance cycle). We will give you a drug calendar to keep track of when to take your TMZ and poly-ICLC. We will also give you a drug diary to record the date, time, injection site and amount of drug that was administered. You will be asked to sign and date the drug diary. During the last week (week 9) of your maintenance cycle you will not receive any treatment. After the maintenance cycle another MRI will be obtained. If this MRI shows that the tumor size is the same or smaller, you will begin another nine-week cycle of treatment. An MRI will be obtained before every maintenance cycle (every 9 weeks) to see if your tumor is growing. You may continue to receive poly-ICLC and TMZ as long as your tumor is not growing and you do not experience too many bad side effects.
Blood tests, Physical/Neurological Exam and MRI will also be repeated while you are on study. Some of these tests will be done more frequently than if you were not taking part in this research study. Your blood counts will be checked at least once every week during your initiation cycle and then once a week during the first 5 weeks of each maintenance cycle. Three extra blood samples will be drawn during the first maintenance cycle (2 samples during week 2, and one sample during week 8). These samples are being drawn to measure the amount of poly-ICLC in your blood. These three blood samples are drawn for research purposes only and would not be drawn if you were not on this study.
HOW LONG WILL I BE IN THE STUDY?
We estimate you will be on this study for at least 19 weeks. An MRI will be obtained after you complete the first maintenance cycle (10 week initiation cycle + 9 week maintenance cycle). If this MRI shows that the tumor size is the same or smaller, you will begin a second, ten-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 indefinitely. If the MRI shows that your tumor is growing you will stop poly-ICLC and TMZ treatment and you and your doctor will discuss other treatment options.
Your participation in your clinical trial is completely voluntary. You can stop participating at any time. If you decide not to participate it will not affect your medical care at this institution. If you join this study you may withdraw from it at any time. However, if you decide to withdraw from 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 Poly-ICLC is
stopped, but in some cases side effects can be serious, long-lasting, permanent
or fatal.
Poly-ICLC Side Effects:
There are risks to joining this study. Some, none or all of these side effects are possible.
The most common reported side effects of poly-ICLC in brain tumor patients are:
· Mild temporary discomfort at the site of the injection
· Fatigue or a feeling of tiredness and weakness over your entire body
· Low-grade fever
· Muscle or joint aches
· Nausea
· Headache
These side effects usually decrease with subsequent injections.
Less likely side effects reported by brain tumor patients on poly ICLC are:
· Temporary decreases of the blood counts (red blood cells, white blood cells, and platelets). A decrease in your red blood cells can cause fatigue, shortness of breath. A decrease in your white blood cells may cause you to be at an increased risk for infection or infection with fever. A decrease in your platelet count can cause you to be at an increased risk for bleeding.
· Increase in swelling or inflammation around the tumor or tumor site that can cause increased pressure and require treatment with steroids.
· Mild and temporary elevation of the liver enzymes which may mean mild liver inflammation that spontaneously resolves.
· Diarrhea or loss of appetite
· Development of a high fever with chills and overall fatigue and weakness after an injection that typically will get better over 12 to 24 hours. You can be given medication to make you better if this happens. This does not usually happen again after later injections.
A few patients with a history of seizures, had seizures when they developed a fever after the poly injection.
Other drugs will be given to make side effects less serious and uncomfortable. Many side effects go away shortly after poly-ICLC is stopped, but in some cases side effects may be long lasting or permanent.
Risks associated with blood drawing for treatment include infection, bleeding and discomfort. Your physician will discuss these with you.
In order to join this study you must have a chest x-ray. The radiation exposure you will receive from getting a chest x-ray is equivalent to an exposure of 0.02 rem to your whole body. Naturally occurring radiation (cosmic radiation, radon etc.) produces whole body radiation exposures of about 0.3 rem per year. Occupationally exposed individuals are permitted to receive whole body exposures of 5 rem per year.
This study may also have risks to you that cannot be determined at this time. You will be told of any potential risks that may be discovered while you are participating in this study.
Reproductive risks: Because there may be a risk of birth defects if a fetus is exposed to Poly-ICLC, 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, dental problems, 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 having your physician increase your steroid dose.
TMZ Side Effects:
TMZ is chemotherapy drug that is considered standard treatment with your radiation therapy. TMZ may cause the following:
Likely sides effects:
· Nausea and vomiting, especially on the first day of each maintenance cycle. It may be necessary to use medication to prevent this.
· Constipation
· Loss of appetite,
· Lowering of your blood counts, which may result in a 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 occurred in patients receiving daily treatment with temozolomide 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 transfusions. Low red blood cells can also be treated with transfusions. As a rule, stopping TMZ results in recovery of your low blood counts.
· Fatigue, lethargy, insomnia, weakness
· Headache
· Hair loss and rash
Less Likely side effects:
· Kidney problems and high blood sugar
· Abnormal liver tests, and diarrhea
Note: For more comprehensive information regarding less likely and rare side effects please refer to the package insert.
Financial risks: There may be extra costs with this treatment. Some of the costs 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.
For more information about risks and side effects, ask the researcher or contact .
ARE THERE ANY BENEFITS TO TAKING PART IN THIS 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 of another type (this includes receiving TMZ alone given in monthly cycles for 6 months after radiation therapy)
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 your physician even if you do not take part in the study.
If your disease becomes worse, or should you have severe side effects, this therapy will be discontinued and other means of treating you will be discussed.
WHAT ARE THE COSTS?
The Oncovir, Inc. will
provide you with the Poly-ICLC free of charge for this study. Should this agent
become commercially available or approved for this indication during the course
of this study, you may be asked to purchase subsequent doses of the drug needed
to complete the study in the event that the company no longer provides the drug.
Taking part in this study may lead to added costs to you or your insurance company. Some of the costs of the administration of the medication, hospitalization, blood tests and brain scans may not be covered by your insurance company. You or your insurance company will be responsible for the cost of standard radiation therapy and TMZ. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study. The three extra blood samples drawn specifically for research purposes will not be charged to you or your insurance company.
TMZ is available by prescription. If your insurance company does not cover the cost of TMZ, you may seek assistance through the Schering’s Commitment to Care Program by calling 1-800-521-7157. The research nurse will have this information available for you.
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.
You will receive no payment for taking part in this study.
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:
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.
i. 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 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.