A Safety Run-In/Randomized Phase II Trial of EMD 121974 in Conjunction with Concomitant Temozolomide and Adjuvant Temozolomide with Radiation Therapy in Patients with Newly Diagnosed Glioblastoma Multiforme

Protocol Version: December 22, 2005

Treatment Schedule

Sample Informed Consent

Patient Information

Purpose of Study

Safety Run-In

To assess the safety profile of EMD 121974 (cilengitide) when administered as a one-hour infusion twice a week concurrently with concomitant and adjuvant temozolomide with radiation therapy for newly diagnosed glioblastoma multiforme.

Phase II Primary Objective

To estimate overall survival in newly diagnosed patients with glioblastoma multiforme treated with EMD 121974 concurrently with concomitant and adjuvant temozolomide with radiation therapy.

Phase II Secondary Objectives

To estimate and compare overall survival between a low dose treatment group and a high dose treatment group in newly diagnosed patients with glioblastoma multiforme treated with EMD 121974 concurrently with concomitant and adjuvant temozolomide with radiation therapy.
To determine the toxicity of EMD 121974 (cilengitide) when it is administered in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme.
To evaluate the molecular profile of individual patients and correlate molecular expression profiles with clinical outcomes.
To characterize tumor blood volume, tumor blood flow, and permeability ratios using perfusion MR in newly diagnosed glioblastoma multiforme and follow these parameters during treatment with EMD 121974 (cilengitide).

Eligibility Criteria

Inclusion Criteria

Patients must be at least 18 years of age.
Patients must have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme).
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.
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).
Patients must have normal hematologic, renal and liver function (i.e. Absolute neutrophil count > 1500/mm3, Platelets > 100,000/mm3, creatinine < 1.5 mg/dl or Cr Clearance > 60 mL/min, total bilirubin < 1.5 mg/dl, transaminases < 4 times above the upper limits of the institutional normal.
Patients must be able to provide written informed consent.
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.
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.
Patients must have a Mini Mental State Exam score of ³ 15.
Patients must have tumor tissue form completed and signed by a pathologist.

Exclusion Criteria

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.
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.
Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents).
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.
Patients who are unable to undergo an MRI evaluation.
Patients with a history of wound-healing disorders, advanced coronary disease, or with a recent history (< 1 year) of peptic ulcer disease are ineligible.

Treatment Schedule

Safety Run-In

Patients who enroll may undergo placement of a CVA line for frequent intravenous access. Six patients will be treated at the starting dose of 500mg given concurrently with radiation and concomitant temozolomide. EMD 121974 is administered intravenously as a 1 hour infusion, once per day, twice a week schedule (total daily dose may not be split and administered BID). Patients will begin treatment with EMD 121974 on the first day they receive radiation therapy and concomitant TMZ. Patients will continue to receive daily TMZ every day for 6 weeks during their radiation. There is no need to coordinate the twice weekly administration of EMD 121974 with radiation therapy and daily TMZ (See section 4.4 for instructions regarding concomitant TMZ and radiation administration). Patients must be treated with EMD 121974 on a Monday and Thursday or Tuesday and Friday dosing schedule (Dosing may not occur less than three days apart). Changes in scheduled radiation or daily TMZ treatment should not effect EMD 121974 treatments. No more than six patients will be entered at a given dose level until three patients have been followed until the end of their initiation cycle (6 weeks of radiation + TMZ + EMD 121974 and 4 weeks of EMD 121974 alone), permitting toxicity to be assessed.

After the 10 week initiation cycle, maintenance cycles will immediately follow, with no break in administration of EMD 121974. An MRI will be performed at the end of the initiation phase (6 weeks of radiation + TMZ + EMD 121974 and 4 weeks of EMD 121974 alone). This MRI is not to be used to assess for tumor progression (unless the progression is outside of the radiation port).

The maintenance phase will begin immediately after the initiation phase. Four consecutive weeks of EMD 121974 and TMZ will constitute one maintenance cycle. EMD 121974 will be given in exactly the same manner during the maintenance cycles as it was given during the initiation cycle (one-hour infusion, twice a week). TMZ, however, will not be given every day. It will be given orally at a dose of 150-200 mg/m2 for only the first 5 consecutive days of each cycle. After completing two maintenance cycles of EMD 121974 and TMZ an MRI will be obtained. If according to this MRI the patient has progressed then the patient will stop EMD 121974 and TMZ treatment and go off treatment. If patient has not progressed then patient will continue to receive additional maintenance cycles of EMD 121974 and TMZ with MRIs performed every odd maintenance cycle (every 8 weeks) until post initiation therapy progression.

Randomized Phase II

Patients who enroll on this study will receive 6 weeks of standard radiation therapy with concomitant TMZ and EMD 121974 treatment. EMD 121974 is given as a one-hour infusion, twice a week. Patients on this portion of the trial will be randomized to either Arm L and receive a “low dose” (500 mg) or to Arm H and receive a “high dose” (2000 mg) of EMD 121974, provided that an MTD was not reached at either dose during the Safety Run-In. Patients will receive 6 weeks of standard radiation therapy and concomitant TMZ with EMD 121974 therapy. There is no need to coordinate the twice weekly administration of EMD 121974 with radiation therapy or daily TMZ (See section 4.4 for instructions regarding concomitant TMZ and radiation administration). For the four weeks following the completion of radiation therapy patients will continue EMD 121974 at the same dose. Treatment with TMZ will stop for 4 weeks following the end of RT. These 6 weeks of combined treatment and the following 4 weeks of EMD 121974 alone is called an initiation cycle.

After the 10-week initiation cycle, maintenance cycles will immediately follow, with no break in administration of EMD 121974. Four consecutive weeks of EMD 121974 and TMZ will constitute one maintenance cycle. EMD 121974 will be given in exactly the same manner during the maintenance cycles as it was given during the initiation cycle (one-hour infusion, twice a week). TMZ, however, will not be given every day. It will be given orally at a dose of 150-200 mg/m2 for only the first 5 consecutive days of each cycle. Patients on both arms will remain on the same dose of EMD 121974 during their initiation cycle and during their maintenance cycles. After completing two maintenance cycles of EMD 121974 and TMZ an MRI will be obtained. If according to this MRI the patient has progressed then the patient will stop EMD 121974 and TMZ treatment and go off treatment. If patient has not progressed then patient will continue to receive additional maintenance cycles of EMD 121974 and TMZ with MRIs performed every odd maintenance cycle (every 8 weeks) until post initiation therapy progression. All patients will be followed every two months for survival.

Sample Informed Consent

Consent A: Safety Run-In

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 EMD 121974. EMD 121974 is experimental because it has not been approved by the U. S. Food and Drug Administration. EMD 121974 is a new type of drug that may prevent cancer cells from growing and invading healthy brain cells. EMD 121974 has been tested on patients with brain tumors as a single therapy. This study combines EMD 121974 with external beam radiation, which is "standard" therapy for this disease, and with temozolomide. Temozolomide is a chemotherapy. Temozolomide has recently been found to increase the survival of patients with glioblastoma multiforme. The combination of temozolomide and radiation therapy is being considered the new “standard of care”. You will be given both radiation therapy and temozolomide while you also receive EMD 121974. The purpose of this study is to find out what dose of EMD 121974 is safe to give while also receiving radiation therapy and temozolomide. We also want to find out what effects (good and bad) EMD 121974 has on 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 9-18 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.

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.

You will start taking the experimental drug, EMD 121974, on the first day of your radiation therapy and temozolomide. You will be treated with EMD 121974 intravenously (IV) (into a vein). Each infusion will be given over one hour. You will be treated twice a week on a Monday/Thursday schedule or a Tuesday/Friday schedule. Because of the frequency of treatments your doctor may suggest that you have a central venous access (CVA) device or central line placed. A central line is a broad term that includes many types of catheters (thin, flexible, hollow tubes) that are inserted into and positioned within a large vein that is near the heart. Generally this procedure is done under local anesthesia as an outpatient prior to starting treatment. This is a temporary device that will remain in place as long as your doctor thinks it is needed for your treatment. You will be taught how to care for the catheter.

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. 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 your 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 pills in the morning. You will continue to receive EMD 121974 on the same schedule for four weeks after radiation. During the 4 weeks directly after radiation you will not take any temozolomide. These first ten weeks (6 weeks of radiation + TMZ + EMD 121974 and 4 weeks of EMD 121974 alone) of treatment are called an initiation cycle. An MRI of your brain tumor will be obtained after you complete your initiation cycle. This MRI is part of your standard radiation therapy follow-up care.

Every four weeks of treatment after your initiation cycle will be called a maintenance cycle. You will continue to receive EMD 121974 on a twice a week schedule with no breaks during your maintenance cycles. You will also continue to receive temozolomide 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 maintenance cycle. TMZ must be taken on an empty stomach. You cannot eat or drink anything except water for one hour before taking your pills and for one hour after taking your pills. After the second maintenance cycle another MRI will be obtained. If this MRI shows that the tumor size is the same or smaller, you will begin a third, four-week cycle of treatment. An MRI will be obtained prior to every odd maintenance cycle (every 8 weeks) to see if your tumor is growing. After 6 5-day TMZ treatments (6 maintenance cycles) you will stop receiving TMZ. Even if you stop receiving TMZ after 6 maintenance cycles you may continue to receive EMD 121974 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. If you participate in this 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 for as long as you receive TMZ.

As part of this study we will be collecting 3 extra blood samples during week 1, week 4, week 8 of the initiation cycle for a total of 9 extra blood samples. These extra blood samples are taken so that we can measure the amount of MED 121974 in your blood. The blood samples will be collected on the first day of treatment during each of these weeks. You will need to stay in the clinic for 3-5 extra hours after receiving EMD 121974 on these days. These tests are for research purposes and would not be done if you were not on a clinical trial.

For this study a special type of MRI scan, called perfusion MRI, will be performed while you are having your standard MRI. The perfusion MRI may increase the time you spend in the MRI machine. This MRI will allow us to evaluate the amount of blood volume in the tumor. The blood volume is related to tumor blood vessels. This perfusion study will be part of each MRI that you have while on this study.

HOW LONG WILL I BE IN THE STUDY?

We estimate you will be on this study for at least 18 weeks. An MRI will be obtained after you complete the second maintenance cycle (after 18 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 indefinitely. If the MRI shows that your tumor is growing you will stop EMD 121974 and temozolomide 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 EMD 121974 is stopped, but in some cases side effects can be serious, long-lasting, permanent or fatal.

EMD121974 Side Effects:

There are risks to joining this study. Some, none or all of these side effects are possible.

Nausea, vomiting, mouth sores, loss of appetite, diarrhea, stomach pain or cramping or rectal discomfort
Headache
Fatigue or tiredness
Changes in the sense of taste and smell
Muscle aches, joint pain
Rash, itching, bruising or superficial bleeding
Temporary lowering of your red blood cell count. In extreme cases this may be corrected with blood transfusions.
Temporary lowering of your platelet count. This could increase your risk for bleeding.
Temporary lowering of your white blood cell count. This could increase your risk for infection.
Altered kidney or liver function
Swelling
Shortness of breath, and coughing
Sensory changes
Changes in vision

Other drugs will be given to make side effects less serious and uncomfortable. Many side effects go away shortly after EMD 121974 is stopped, but in some cases side effects may be long lasting or permanent.

This treatment is based on preventing new blood vessel growth. Therefore, its effect on wound healing and endometrial tissue (menstrual periods and conception) are unknown. EMD121974 may bind to blood vessels at sites of wound healing. The risk of potential interference with wound healing is unknown. These risks may be irreversible or long lasting or life threatening. Patients should discuss any elective surgery or major dental work with their physicians due to potential delayed wound healing. EMD121974 may also bind to blood vessels lining the uterus. The risk of this and the effect of binding to blood vessels in the endometrial tissues are also unknown. You will be monitored closely and treated immediately if these side effects occur.

Risks associated with blood drawing and with placement of a IV line for treatment include infection, bleeding and discomfort. There are other risks associated with having a central line placed. 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 EMD 121974, 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 increasing your steroid dose.

Temozolomide Side Effects:

Temozolomide is 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 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 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

Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by your 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:

Standard radiation therapy with or without chemotherapy of another type.
Other experimental therapy
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.

If your disease become worse, or should you have severe side effects, this therapy will be discontinued and other means of treating you will be discussed.

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 and are part of the NABTT CNS Consortium.
The pharmaceutical sponsor, Merck KgA Pharmaceuticals, Inc.
The sponsor of this study and people that the sponsor may contract with for this study. The name of the sponsor is CTEP/NCI (Cancer Therapy Evaluation Program/National Cancer Institute).
The monitoring service responsible for Clinical Data Update System (CDUS) is CTIS ( Capital Technology Information Services)
The Data Safety Monitoring Board
An outside institutional review board

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 THE COSTS?

The Division of Cancer Treatment and Diagnosis, NCI, will provide you with the EMD 121974 agent 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. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.

Temozolomide is available by prescription. If your insurance company does not cover the cost of temozolomide, you make 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 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.

WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or a research-related injury, contact the researcher __________________ (NAME{S}) at __________________ (TELEPHONE NUMBER) .

For questions about your rights as a research participant, contact the__________________ (NAME OF CENTER) Institutional Review Board (which is a group of people who review the research to protect your rights) at __________________ (TELEPHONE NUMBER ).

WHERE CAN I GET MORE INFORMATION?

You may call the NCI's Cancer Information Service at

1 800 4 CANCER (1 800 422 6237) or TTY: 1 800 332 8615

Visit the NCI's Web sites

cancerTrials: comprehensive clinical trials information

http://cancertrials.nci.nih.gov.

cancerNet: accurate cancer information including PDQ

http://cancernet.nci.nih.gov.

Consent B: Randomized Phase II

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 EMD 121974. EMD 121974 is experimental because it has not been approved by the U. S. Food and Drug Administration. EMD 121974 is a new type of drug that may prevent cancer cells from growing and invading healthy brain cells. EMD 121974 has been tested on patients with brain tumors as a single therapy. This study combines EMD 121974 with external beam radiation, which is "standard" therapy for this disease and with temozolomide. Temozolomide is a chemotherapy. Temozolomide has recently been found to increase the survival of patients with glioblastoma multiforme. The combination of temozolomide and radiation therapy is being considered the new “standard of care”. You will be given both radiation therapy and temozolomide while you also receive EMD 121974.

When EMD 121974 was given to brain tumor patients in another study, some responses were seen at both low and high doses of the drug. The purpose of this study is to learn whether there are more responses with a high or low dose of EMD 121974. For this reason patients who join this trial will be randomly assigned to a high or low dose. This means that the selection is done by chance (like flipping a coin) and that you and your doctor cannot choose which dose you will receive. You will be told what your dose is and it will not be increased while you are on the study. We also want to find out what effects (good and bad) EMD 121974 has on your brain tumor. We will also be looking at the safety profile of this drug.

HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?

94 patients will take part in this study.

WHAT IS INVOLVED IN THE STUDY?

You will begin receiving the experimental drug, EMD 121974, on the first day of your radiation therapy and temozolomide. You will be treated with EMD 121974 in the outpatient infusion center. EMD 121974 will be given intravenously (IV) (into a vein) twice each week. Each infusion will be given over one hour. You will be treated twice a week on a Monday/Thursday schedule or a Tuesday/Friday schedule. Because of the frequency of treatments your doctor may suggest that you have a central venous access (CVA) device or central line placed. A central line is a broad term that includes many types of catheters (thin, flexible, hollow tubes) that are inserted into and positioned within a large vein that is near the heart. Generally this procedure is done under local anesthesia as an outpatient prior to starting treatment. This is a temporary device that will remain in place as long as your doctor thinks it is needed for your treatment. You will be taught how to care for the catheter.

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. 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 your 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 pills in the morning. You will You will continue to receive EMD 121974 on the same schedule for four weeks after you complete radiation. During the 4 weeks directly after radiation you will not take any Temozolomide. These first ten weeks (6 weeks of radiation + TMZ + EMD 121974 and 4 weeks of EMD 121974 alone) 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. You will continue to receive EMD 121974 on a twice a week schedule with no break.

Every four weeks of treatment after your initiation cycle will be called a maintenance cycle. You will also continue to receive temozolomide 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 maintenance cycle. TMZ must be taken on an empty stomach. You cannot eat or drink anything except water for one hour before taking your pills and for one hour after taking your pills. After the second maintenance cycle another MRI will be obtained. If this MRI shows that the tumor size is the same or smaller, you will begin another four-week cycle of treatment. An MRI will be obtained before every other maintenance cycle (every 8 weeks) to see if your tumor is growing. After 6 5-day TMZ treatments (6 maintenance cycles) you will stop receiving TMZ. Even if you stop receiving TMZ after 6 maintenance cycles you may continue to receive EMD 121974 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 for as long as you receive TMZ.

HOW LONG WILL I BE IN THE STUDY?

We estimate you will be on this study for at least 18 weeks. An MRI will be obtained after you complete the second maintenance cycle (18 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 indefinitely. If the MRI shows that your tumor is growing you will stop EMD 121974 and temozolomide treatment and you and your doctor will discuss other treatment options.

WHAT ARE THE RISKS OF THE STUDY?

EMD121974 Side Effects:

There are risks to joining this study. Some, none or all of these side effects are possible.

Nausea, vomiting, mouth sores, loss of appetite, diarrhea, stomach pain or cramping or rectal discomfort
Headache
Fatigue or tiredness
Changes in the sense of taste and smell
Muscle aches, joint pain
Rash, itching, bruising or superficial bleeding
Temporary lowering of your red blood cell count. In extreme cases this may be corrected with blood transfusions.
Temporary lowering of your platelet count. This could increase your risk for bleeding.
Temporary lowering of your white blood cell count. This could increase your risk for infection.
Altered kidney or liver function
Swelling
Shortness of breath, and coughing
Sensory changes
Changes in vision

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 EMD 121974, 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.

Temozolomide Side Effects:

Temozolomide is 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 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 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

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 BENEFITS TO TAKING PART IN THE STUDY?

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:

Standard radiation therapy with or without chemotherapy of another type.
Other experimental therapy
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 ABOUT CONFIDENTIALITY?

a. What information about you may be used or given out in this study?

Information obtained from the activities and procedures outlined in this consent form, which may include:

b. Who may use and give out information about you?

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 and are part of the NABTT CNS Consortium
The drug manufacturer is MERCK KGA Pharmaceuticals, Inc.
The sponsor of this study and people that the sponsor may contract with for this study. The name of the sponsor is DCTD/NCI (Division of Cancer Treatment and Diagnosis/National Cancer Institute).
The monitoring service responsible for Clinical Data Update System (CDUS) is CTIS ( Capital Technology Information Services)
The Data Safety Monitoring Board
An outside institutional review board

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?

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?

WHAT ARE THE COSTS?

The Division of Cancer Treatment and Diagnosis, NCI, will provide you with the EMD 121974 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.

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 ARE MY RIGHTS AS A PARTICIPANT?

We will talk to you about new information that may affect your health, welfare, or willingness to stay in this study.

WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or a research-related injury, contact the researcher __________________ (NAME{S}) at __________________ (TELEPHONE NUMBER) .

WHERE CAN I GET MORE INFORMATION?

You may call the NCI's Cancer Information Service at

1 800 4 CANCER (1 800 422 6237) or TTY: 1 800 332 8615

Visit the NCI's Web sites

cancerTrials: comprehensive clinical trials information

http://cancertrials.nci.nih.gov.

CancerNet: accurate cancer information including PDQ

http://cancernet.nci.nih.gov.