Phase I study of Combined Radiotherapy and Arsenic Trioxide for the Treatment of Newly Diagnosed Malignant Glioma

Protocol Version: March 21, 2005

Purpose of Study Eligibility Criteria Treatment Schedule Sample Informed Consent Patient Information

Purpose of Study

Primary Objectives

Secondary Objectives

Eligibility Criteria

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. Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agents (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 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.
  5. Absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, creatinine < 1.5 mg/dL, total bilirubin < 2 mg/dl, transaminases < 4 times above the upper limits of the institutional normal, serum potassium > 3.0 and < 5.5mEq/l, and magnesium > 1.2 and < 2.5 mEq/l.
  6. Patients must give informed consent and understand the investigational nature of this study and its potential risks and benefits.
  7. Patients must not be pregnant or breast-feeding. All patients with the potential for pregnancy should be counseled and requested to follow acceptable birth control methods to avoid conception. Patients who are pregnant or breast-feeding will be excluded because no information on this agent exists with regard to safety for a fetus or breast-feeding infant. 
  8. Patients must have a Karnofsky performance status of > 60%.
  9. No other serious concurrent infection or other medical illness should be present which would jeopardize the ability of the patient to receive the therapy outlined in this protocol with reasonable safety.
  10. Patients must have a mini mental score > 15.

Exclusion Criteria

Patients with any of the following are ineligible for this research study:

  1. Patients with a prior malignancy. Patients with curatively treated carcinoma in situ or basal cell carcinoma of the skin or patients who have been free of disease for > five years are eligible for this study. 
  2. Patients who are pregnant or breast-feeding. These patients are excluded because no information on this agent exists with regard to safety for a fetus or breast-feeding infant.
  3. Prior therapy (surgery excluded) for the brain tumor.
  4. Patients with second-degree heart block.
  5. Patients who are being treated with Amphotericin B.
  6. Patients who cannot undergo MRI are not eligible for this study.
  7. Patients who are currently taking drugs that are known to prolong the QT interval. In order to be eligible patients will need to be off these drugs for ( 5 days prior to starting treatment. Patients may not resume these drugs for > 2 weeks after last ATO treatment. Please see Appendix III for a list of drug that are known to prolong the QT interval or torsade de pointes. If QT prolongation continues after 5 daysl post drug discontinuation, the patient is not eligible for ATO treatment.

Treatment Schedule

This study will be divided into two separate study arms.  Patients accrued to Group A will receive ATO once a week during the 6 weeks of radiation therapy.  Patients accrued to Group B will receive ATO 2 times a week during the 6 weeks of radiation therapy.

Treatment Group A

Eligible patients will receive conventional radiation therapy, 5 days a week for 6 weeks.  Radiation will begin on a Monday and patients will receive ATO on a weekly basis (every Tuesday) during the time they are receiving standard radiotherapy.  Patients will receive a total of 6 treatments with ATO.   ATO should begin as soon after radiation as possible, up to 2 hours post end of radiation therapy. 

ATO will be administered once per week.  ATO is infused over 2 hours.  The dose will start at 0.3 mg/kg in 100 ml of 5% dextrose solution.  ATO can be administered using either a peripheral IV line or a central line.

Treatment Group B

Eligible patients will receive conventional radiation therapy, 5 days a week for 6 weeks.  Radiation will begin on a Monday and patients will receive ATO twice a week (every Tuesday and Thursday) during the time they are receiving standard radiotherapy.  Patients will receive a total of 12 treatments with ATO.   ATO should begin as soon after radiation as possible, up to 2 hours post end of radiation therapy. 

ATO will be administered twice a week.  ATO is infused over 2 hours.  The dose will start at 0.2 mg/kg in 100 ml of 5% dextrose solution twice a week.  Each administration must be a minimum of 48 hours apart.  ATO can be administered using either a peripheral IV line or a central line.

Sample Informed Consent

Your doctors have found that you have a brain tumor (cancer) called glioblastoma multiforme.  Unfortunately, this tumor is not usually cured with surgery, radiation or chemotherapy.  For this reason, we are trying to find new drugs to improve the treatment of this tumor.  You are being asked to join a clinical trial (a type of research study) that will test a new drug.  You may want a friend or family member to read this consent and talk to the study doctor with you.  You can also talk to your personal doctor about what you should do.  Talking things over can help you make your choice.

WHY IS THIS STUDY BEING DONE?

The purpose of this research study is to test an investigational drug called Arsenic Trioxide (ATO).  ATO is investigational because the U.S Food and Drug Administration (FDA) has not approved it for the treatment of malignant brain tumors.  This drug will be given along with radiation therapy to the brain.  Radiation therapy is the “standard” therapy for this disease.  ATO may reduce the blood flow to the tumor.  ATO may help make the radiation therapy more effective.  The purpose of this study is to find the right dose of ATO to give patients with brain tumors who receive radiation therapy.  This means we will give increasing doses of ATO to each group of patients who enter the trial.  We will continue to do this until patients have major side effects.  You will either receive ATO once a week during your radiation or you will receive ATO twice a week during your radiation.  You will be assigned to a dose when you start the study. Your doctor will tell you what your dose will be and it will not be increased.  You will be given the same or lower dose throughout your treatment.  We will also be looking to see if this medication helps to kill brain tumor cells when given together with radiation therapy.

HOW LONG WILL I BE IN THE STUDY?

We are not sure how long you will be in this study.  The first part of the study will be the treatment phase.  During this time you will receive six weeks of radiation therapy and a weekly or twice weekly ATO treatment.  After you complete your treatments you will be in the follow up phase.  You will continue to be followed by your study doctor as long as the tumor does not grow. If the tumor begins to grow you will be taken off study. You may also be taken off study if you experience too many serious side effects. 

You may also stop participating at any time.  However, if you decide to stop participating in the study, we encourage you to talk to the researcher and your regular doctor first.

HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?

Approximately 18-30 people will take part in the study.

WHAT IS INVOLVED IN THE STUDY?

Part of this study is standard (the usual care given for this disease) and part is experimental. The radiation therapy and blood tests are standard treatment. The ATO is an experimental drug that will be given along with the standard treatment. 

Your first study visit will be a screening visit.  This visit must take place within 14 days of starting radiation treatment.  The doctor will ask you about your medical history and you will have a physical exam.  Blood and urine samples will be collected. These tests would be done before many other types of cancer treatments. A perfusion MRI (type of scan) of the brain, a chest x-ray, and electrocardiogram (a test that shows the electrical activity of the heart) will also be done.  The perfusion MRI allows us to evaluate the amount of blood volume in the tumor.  This information is related to tumor blood vessels.

All patients who join this study will receive standard radiation therapy to the brain. This type of radiation therapy is usually given once a day, five days a week for six weeks (a total of 30 treatments).  On the third day and last day that you receive radiation therapy you will also have perfusion MRIs of the brain.

ATO will be given once a week or twice a week during the 6 weeks of radiation therapy.  It will be given into one of your veins over 2 hours. You will receive a total of six treatments or 12 treatments. On the days that you receive ATO, it will be given after the radiation treatment. 

Extra blood samples will be taken once a week at the time of an ATO treatment.  These extra samples are collected to check the level of arsenic in your blood.  At the time of your very first ATO infusion a blood sample will be taken before the infusion, during the infusion, 5 minutes before your infusion is done, and then at 15 minutes, one hour, two hours, four hours, and six hours after the infusion.  One sample will be collected on day two and day 3 of radiation therapy.   Patients receiving ATO twice a week will have two extra samples collected at the time of the second ATO infusion during the first week of RT.  Extra blood samples will also be collected for all patients before and during one ATO treatment each week.  Each extra blood sample will collect about two tablespoons of blood.  You will not be charged for the cost of collecting the research blood samples.

You will be evaluated weekly for the first 10 weeks that you are on the study. For the first 6 weeks you will have lab tests and an electrocardiogram performed each week.  Patients receiving ATO twice a week will have an electrocardiogram perform before the first ATO infusion each week but will have lab tests performed twice a week (prior to each infusion). 

You will also be evaluated weekly for the first month after the completion of radiation therapy.  During these visits we will check to see what effects the ATO and radiation are having on you.  These visits will include lab tests as well. 

At your one-month follow-up visit you will also have a physical and a neurological exam and an MRI.  After this visit you will return to the clinic for MRIs and evaluations every two months. If the scans show that the tumor is the same size or smaller, you will continue to visit the clinic every 2 months. If the MRI shows that the tumor is growing you will be taken off study and your doctor will discuss other treatment options with you.

Participation in this study may be terminated by the research doctor without your consent.  You will be told if there is any new information that might make you want to stop being in this clinical trial.  The research doctor can end your part in the trial at any time.  If you are taken off study you will receive the same continuing medical care you would otherwise receive.

ARE THERE ANY BENEFITS TO TAKING PART IN THIS STUDY?

We do not know if you will benefit from taking ATO. It is possible that the ATO may make radiation therapy more effective in treating your tumor. However, no benefit is guaranteed. By taking part in this research study, you will help us to increase our overall knowledge of your disease. This will help us learn how to treat future patients.

WHAT ARE THE RISKS OF THE STUDY?

While you are on this 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 try to make the side effects less serious and uncomfortable.

Side effects associated with ATO:  

·        ATO may also affect your blood counts.  It could cause you to have a low white blood cell count. This would mean that you were at an increased risk of infection with or without a fever.  It could cause you to have a low red blood cell count.  If this happens you might feel tired or short of breath. ATO could cause low platelet count. If this happens you would be at an increased risk of bleeding.

·        ATO may cause rapid heart rate, irregular heartbeats, abnormal or prolonged changes on your electrocardiogram, and/or heart failure.

·        ATO may cause a condition where damage to the blood vessel cells causes fluid to leak into lungs and other tissues. Low blood pressure may also occur. ATO may cause fatigue, fever, shaking chills and weight gain. Some patients have experienced a syndrome that includes fever, weight gain, fluid retention, shortness of breath, lung inflammation and infection.

·        ATO may cause hair loss, skin abnormalities, hardening of the outer layer of the skin, dry skin, changes in skin color, itching and a peeling rash.

·        Patients have reported loss of appetite, diarrhea, constipation, nausea and vomiting.  Saliva changes and mouth sores have also been reported. 

·        ATO may cause bleeding into the skin.

·        Abnormal liver function tests and kidney problems and kidney failure have been reported in patients taking ATO.  

·        ATO may cause abnormal lab values.  These include high blood sugar, low blood potassium and low levels of magnesium in the blood.

·        Dizziness during the infusion has also been reported.

·        Patients taking ATO have experienced stomach pain, joint pain, muscle pain, muscle wasting and weakness.  Bone pain, headache and toothache have also been reported.

·        ATO may cause shortness of breath, fluid to collect in your lungs or infection in your lungs.  Severe lung infection could cause you to stop breathing.

·        ATO may cause swelling in your arms and legs or numbness, tingling and pain in the hands and/or feet.  ATO may also cause weakness and/or paralysis.

·        ATO may also cause inflammation in your pancreas (a large gland behind your stomach which secretes digestive enzymes and hormones).  Abnormal pancreatic function tests have also occurred.

 

Other serious side effects: 

·        ATO may cause fluid in the area around your heart. The procedure to treat fluid around the heart may cause the heart to stop.

·        Increased sweating, flushing, skin irritation, hives, bruising and fluid retention (swelling) have been reported.

·        Low blood oxygen levels, cough, bloody cough, wheezing, and abnormal lung sounds have been noted in patients taking ATO. 

·        Some patients have reported confusion, agitation, depression, anxiety, a low level of consciousness and insomnia.

·        Some patients have had an allergic reaction to ATO.  This reaction may include a fever or cold-like symptoms such as sneezing, nasal stuffiness and sore throat.

·        ATO may cause dry mouth, heartburn, weight loss and stomach distension. Urinary and anal incontinence have also been reported.

·        Patients have experienced an imbalance of chemicals in the blood.  Low blood levels of calcium, low blood sugar and high potassium have been reported in patients taking ATO.

·        ATO can cause bleeding to occur in the nose, respiratory tract or in the digestive tract.  Also vaginal bleeding has occurred.

·        Other patients taking ATO have experienced high blood pressure, tremor, seizures

·        ATO may cause eye pain, ear pain, neck pain, nerve pain, throat pain, back pain, chest pain or painful reaction at the infusion site. 

·        ATO can cause swelling of the head and neck as well as swelling of other lymph nodes.

·        Patients taking ATO have also reported hearing noises in the ear such as buzzing, clicking or thudding. 

Risks related to radiation therapy: Radiation therapy is known to cause loss of hair, and dryness, irritation or darkening of the skin in the treated area. Patients may experience fatigue, dizziness or loss of hearing. Some patients treated with radiation have developed problems with thinking, which may be permanent. Receiving ATO in addition to your standard radiation therapy may cause the side effects of radiation therapy to be worse. 

Risks to Unborn Children: We do not know what effects ATO could have on the unborn fetus. You may not participate in this study if you are pregnant or breast-feeding a baby. If you are a woman of childbearing potential, you will be given a pregnancy test before you begin the study. Whether you are a man or woman, you must use medically approved birth control while you are taking part in this study and for at least two months after completing treatment. If you become pregnant, you must notify one of the doctors listed on this form immediately.

WHAT OTHER OPTIONS ARE THERE?

You do not have to join this study to receive treatment for your brain tumor. Instead of joining this research study you could choose to receive standard radiation therapy alone. Or, you could decide to get standard radiation with chemotherapy. There may be other research studies that you are eligible for. You could choose to receive no treatment at all. Your decision on whether to participate in this study will not affect your medical care at this hospital now or in the future. If you decide to join this research study, you may withdraw from it at any time.

WHAT ARE THE COSTS? 

There may be extra costs associated with joining this research study. You will be responsible for any costs that your insurance company does not cover. Your insurance company will probably cover routine health care costs such as MRI scans, medications, radiation treatment, physician visits, and laboratory tests. The ATO will be provided to you at no cost. However, your insurance may not cover the cost of administering the ATO. You may wish to check with your health insurance company to find out exactly what is covered by your policy.

The Division of Cancer Treatment, and Diagnosis, NCI will provide you with the NCI sponsored/supplied agent free of charge for this study. Every effort will be made to ensure that there are adequate supplies of ATO for all participants. If the drug becomes commercially available for patients with your diagnosis there is a slight possibility that you may be asked to purchase subsequent supplies. Your physician will discuss this with you should this situation arise.

You will not receive cash or other gifts for taking part in this research study.

WHAT ABOUT CONFIDENTIALITY?

Your medical records are confidential. However, in connection with this study, it is important for your physician and others to have access to your medical records. This includes the time while you are on the study and for routine follow-up information afterwards. Other people who may have access to your records include New Approaches to Brain Tumor Therapy (NABTT), Cancer Therapy Evaluation Program and the National Cancer Institute (CTEP/NCI), the Federal Food and Drug Administration (FDA), Cell Therapeutics, Inc., the local institution], and the Institutional Review Board (IRB). By signing this consent you give authorization to release your medical records to these parties to be utilized only in connection with this study. Because these parties may need to see your records, we cannot guarantee complete confidentiality. The data collected for this study may also be used for medical and scientific purposes, but your identity will not be disclosed. 

You will receive a copy of this consent form.

QUESTIONS YOU MAY HAVE ABOUT THIS STUDY?

This consent form explains the research study. Please read it carefully. Ask questions about anything you do not understand. If you do not have questions now, you may ask later. During the study, you will be told any new facts that could affect whether you want to stay in the study. We will explain what other treatment could be given outside the research. You should understand those options before you sign this form. If you have questions you should call the principal investigator

PRIVACY INFORMATION:

We will keep the study information private to the extent possible by law. However, State law requires us to report certain contagious diseases and information about child abuse if we discover it. Also, under certain conditions, people responsible for making sure that the research is done properly may review your study records. All of these people are also required to keep your identity confidential. Otherwise, the information that identifies you will not be given out to people who are not working on the study, unless you give permission.

IF YOU ARE HURT BY BEING ON THIS STUDY?

If you think you have been hurt by being in the study, or not treated fairly, you should call the Joint Committee on Clinical Investigation at, to receive help or advice, including help finding medical care if needed.

The Federal government do not have any program to pay you if you are hurt or have other bad effects that are not the fault of the study doctors.

If you have a question about your rights as a patient or you feel your rights have in some way been violated please contact ________

JOINING OF YOUR OWN FREE WILL (VOLUNTEERING FOR THE STUDY)

You do not have to join this or any research study. If you do join, and later change your mind, you may quit at any time. Your participation in this study will not affect your medical care at this hospital now or in the future. All normal treatment options will still be available to you.