A Phase 2 Trial of Erlotinib (OSI-774) and Sorafenib (BAY 43-9006) for Patients with Progression or Recurrent Glioblastoma Multiforme
Protocol Version: July 17, 2006
| Purpose of Study | Eligibility Criteria | Treatment Schedule | Sample Informed Consent | Patient Information |
Primary Objective
The primary objective of this trial is to estimate the overall survival rate associated with this combined regimen in treating adult patients with recurrent glioblastoma multiforme.
Secondary Objective
1) To assess and estimate the toxicities.
2) Tumor response rate.
3) To estimate 6-month progression free survival.
4) To describe the pharmacokinetics of this route of administration.
5) For the Molecular Targeted Combinations Correlative (MTC2) Study Initiative: To determine the relationship between tumor and blood biomarkers and clinical outcome of patients treated with the combination of targeted agents.
Inclusion Criteria
1. Patients must be at least 18 years of age.
2. Patients must have histologically proven malignant glioma (anaplastic astrocytoma, anaplastic oliogodendroglioma or glioblastoma multiforme) which is progressive or recurrent after radiation therapy ± chemotherapy. Patients with previous low grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have a high grade glioma are eligible.
3. Patients must have tissue specimens available and agree to have their blood and tissue blocks (or slides) submitted for the combined correlative studies.
4. Patients must have contrast enhancing measurable progressive or recurrent glioblastoma multiforme by MRI or CT imaging. (Within 14 days before starting treatment).
5. Patients must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy, while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen. NOTE: For a non-cytotoxic, FDA approved agents (i.e. celebrex, thalidomide, etc.) therapy could be started 2 weeks after discontinuing this agent provided the patient has fully recovered from all toxicity associated with the agent. For investigational, non-cytotoxic agents a minimum of 3 weeks must have elapsed before the patient will be eligible for this study.
6. 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).
7. Patients must have the following hematologic, renal and liver function. Patients must meet the following laboratory criteria: absolute neutrophil count ³1500/mm3; hemoglobin ≥ 9 gm/dl; platelets ³ 100,000/mm3; creatinine £ 1.7mg/dl; total bilirubin £ 1.5mg/dl; transaminases £ 4 times above the upper limits of the institutional norm; PT, PTT within institutional norm or below.
8. Patients must be able to provide written informed consent.
9. Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative serum pregnancy test. (The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.)
10. Patients must have a Mini Mental State Exam score ³ 15.
Exclusion Criteria
1. Patients with serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety. (Examples of medical illnesses are [but not limited to] the following: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.)
2. Patients with uncontrolled hypertension. Hypertension with systolic blood pressure of >140 mmHg or diastolic pressure >90 mmHg. However, patients with well-controlled hypertension are eligible.
3. 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.).
4. Patients who have received more than two prior treatments.
5. Patients who have had prior therapy with erlotinib or sorafenib or any other agent targeting EGFR.
6. Patients receiving concurrent therapy for their tumor (with the exception of steroids).
7. Patients undergoing major surgery or sustaining a significant traumatic injury within 21 days prior to treatment are ineligible.
8. Patients with a concurrent malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients with a prior malignancy are ineligible unless they have been free of disease for ³ five years.
9. Patients must not have any evidence of bleeding diathesis or coagulopathy.
10. Patients with PT INR > 1.5 are excluded, unless the patient is on full dose warfarin.
11. Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met:
The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin.
The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices).
NOTE: Patients on a full dose of anticoagulants will a different schedule for PT/INR evaluations (See Section 9.1)
12. Prophylactic anticoagulation (i.e. low dose warfarin) are eligible provided their coagulation parameter levels are as follows: prothrombin time (INR; International Normalized Ratio of prothrombin time) <1.1 x institutional upper limit of normal.
13. Patients with known abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren’s syndrome), congenital abnormality (e.g., Fuch’s dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluoresein, Bengal‑Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) are excluded.
14. Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills are excluded.
15. Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine)
16. Patients may not have allergies to or a history of allergic reactions attributed to erlotinib and/or sorafenib.
17. Eligibility of patients receiving any other medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of erlotinib or sorafenib will be determined following review of their case by the Principal Investigator.
18. HIV patients receiving combination anti-retroviral therapy will be excluded.
Treatment for this protocol will be administered on an outpatient basis. Each patient will receive 150mg of erlotinib once a day and 400mg of sorafenib twice a day. Each treatment cycle is 28 days. Tumor tissue and blood samples will be obtained from each patient prior to beginning treatment with erlotinib and sorafenib. Erlotinib and sorafenib will be administered orally on a continous daily schedule with no breaks between treatment cycles. Each patient will receive 150mg of erlotinib once a day and 400mg of sorafenib twice a day for 28 days. Pharmacokinetic samples will be obtained during day 15 of the first treatment cycle. Treatment of an individual patient will continue until there is objective or clinical evidence of either disease progression or treatment-related, dose-limiting toxicity, or if the patient decides to discontinue treatment for any reason. All patients will be given both drugs to take home and a drug calendar that explicitly details how many tablets of each drug the patient will be taking each day. The patient will be asked to record the amount of erlotinib and sorafenib actually taken as well as the date and time of each dose in a pill diary.
Tissue and Blood Collection Informed Consent for the Molecular Targeted Combinations Correlative (MTC2) Study Initiative
This study is part of a series of studies sponsored by the National Cancer Institute to test combinations of investigational targeted drugs in patients with brain cancer, kidney cancer and melanoma (a type of skin cancer). One of the goals of this program is to collect and analyze tumor and blood sample markers. These markers may predict which patients may benefit from the drugs. These results may help future patients with these markers to predict that the treatment will work. To achieve this goal, tumor and blood specimens need to be obtained from patients participating in these studies. These specimens will be stored until the trials are done and then the specimens will be analyzed. The results from these laboratory marker studies will be compared to the outcomes of patients from this study and the other studies. We hope to find markers that show which patients will benefit from the drugs in the future.
To participate in the treatment part of this study tumor tissue and blood samples are required.
The research that may be done with your tissue will not help you directly. It may help people who have cancer and other diseases in the future.
Reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not affect your care.
Your agreement to allow the use of the tumor tissue and blood samples to identify markers that might find patients that benefit from the drugs is required to be part of the study. In addition, we would like to keep some of the tissue and blood that is left over for future research. If you agree, this tissue and blood will be kept and may be used in research to learn more about cancer and other diseases. This is optional. You do not have to agree to this part of the study. The sample may be stored for a long time, even after your death. You have a say in how your stored sample is used in future research.
Things to Think About
Your agreement to allow the use of the tumor tissue and blood samples to identify markers that might find patients that benefit from the drugs is required to be part of the study.
The choice to let us keep the left over tissue and blood for other future research is up to you.
No matter what you decide to do, it will not affect your care.
If you decide now that your tissue and blood can be kept for future research, you can change your mind at any time. Just contact us and let us know that you do not want us to use your tissue. Then any tissue and blood that remains will no longer be used for research.
In the future, people who do research may need to know more about your health. This may mean that reports about your health will be given to researchers in the future. However, your name, address, phone number, or any other information that will let the researchers know who you are will not be given.
Sometimes tissue and blood are used for genetic research (about diseases that are passed on in families). Even if your tissue or blood is used for this kind of research, the results will not be put in your health records.
Your tissue and blood will be used only for research and will not be sold. The research done with your samples may or may not help develop commercial products. There are no plans to provide payment to you if this happens.
Benefits
The benefit of this research is to learn more about markers that show which patients with cancer may benefit from treatment. Future research using tissues include learning more about what causes cancer and other diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. NABTT will protect your records so that your name, address, and phone number will be kept private. The chance that this information will be given to someone else is very small.
Making Your Choice
Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No". If you have any questions, please talk to your doctor or nurse, or call our research review board at the IRB's phone number. No matter what you decide to do, it will not affect your care.
1. My tissue and blood may be used for research that may identify markers that might predict who benefits from treatment. (Note: this is required to participate in the clinical trial)
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Yes |
No |
2. My tissue may be kept for use in research to learn about, prevent, or treat cancer.
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Yes |
No |
3. My tissue may be kept for use in research to learn about, prevent or treat other health problems (for example: diabetes, Alzheimer's disease, or heart disease).
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Yes |
No |
4. My tissue and blood may be used for genetic research (about diseases that are passed on in families).
|
Yes |
No |
5. Someone may contact me in the future to ask me to take part in more research.
|
Yes |
No |
Please sign your name here after you circle your answers.
Your Signature: _________________________________________
Date:_____________________
Signature of Doctor/Nurse: ________________________________
Date:_____________________
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 brain tumor (glioma), which has grown or has recurred.
WHY IS THIS STUDY BEING DONE?
This research is being done because the type of tumor you have 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. This study you are being asked to join uses two experimental drugs. One drug is called erlotinib and the other is called sorafenib. These drugs are experimental because they have not been approved by the U.S. Food and Drug Administration for treatment of brain cancer. These drugs work by preventing cancer cells from growing. The purpose of this study is to find out what effects (good and bad) these drugs have on your brain tumor.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 56 people will take part in the study.
WHAT IS INVOLVED IN THE STUDY?
If you take part in this study you will have the following tests and procedures:
Before treatment starts, you will have a complete physical exam, blood and urine tests. A chest x-ray and ECG (heart tracing) will be done. An MRI or CT scan of the brain will also be performed. Women able to have children will have a pregnancy test.
Both drugs are taken by mouth. You will start both drugs on the same day and will take 150mg of erlotinib once each day and 400mg of sorafenib twice each day. Erlotinib should be taken in the morning and on an empty stomach (either 1 hour before or 2 hours after food). Your doses of sorafenib should be taken approximately 12 hours apart once in the morning and once in the evening (preferably 8 a.m. and 8 p.m.). Sorafenib can be taken with or without food. You will be asked to record the amount of drug taken each day in a drug diary.
You will take these drugs every day for 4 weeks with no breaks. Each 4 week (28 day) period is called a treatment cycle. After the second treatment cycle (after 8 weeks of continuous treatment) another brain scan will be performed. If your scan shows that your tumor is the same size or smaller you will begin a third treatment cycle. You will continue to receive erlotinib and sorafenib as long as your tumor is not growing and you are not experiencing too many side effects from the erlotinib and/or sorafenib. Brain scans will be repeated every 8 weeks (2 cycles). If at any time your scan shows that your tumor is growing than you will stop receiving the erlotinib and sorafenib. The brain scans (MRI or CT) would be part of routine cancer care.
During the study, a physical exam and neurologic exam will be repeated. Routine blood tests will be done before each cycle of erlotinib and sorafenib. If at any point your blood counts are low, these blood tests will be repeated more often.
Extra blood samples will be drawn for research purposes. You will need to return to the clinic for the nurse to obtain these blood samples. Approximately 2 teaspoons of blood are drawn for each sample. We will use these blood samples to measure the amount erlotinib and sorafenib in your blood. These extra blood tests are for research purposes only and would not be part of your standard care. The costs associated with collecting and processing these blood samples will not be charged to you or your insurance company.
HOW LONG WILL I BE IN THE STUDY?
Treatment with erlotinib and sorafenib will be continued on the same schedule unless your tumor grows, or you have side effects that warrant discontinuation, or you desire to stop treatment. The researcher may decide to take you off this study if your doctor thinks it will be in your best interest, your condition worsens, or new information becomes available.
Your participation in your clinical trial is completely voluntary. You can stop participating at any time. If you decide not to participate, or wish to withdraw your consent to participate in this treatment at any time, it will in no way affect your regular treatments or medical care. If you stop participating in this study you may be asked to return to the clinic for a final evaluation. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and visit your regular doctor first.
WHAT ARE THE RISKS OF THE STUDY?
While on the study, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make the side effects less serious and uncomfortable.
Many side effects go away shortly after the erlotinib and/or the sorafenib is stopped, but in some cases side effects can be serious or long-lasting or permanent or fatal.
Possible Side Effect for Erlotinib
Likely Side Effects:
· Dry skin, itchy skin, rash or a peeling rash
· Diarrhea, nausea
Less Likely Side Effects:
· Fatigue, fever
· Hair loss, acne
· Loss of appetite, dry mouth, heartburn, mouth sores, changes in taste, vomiting
· Liver function abnormalities
· Dry eye syndrome
· Headache, mouth pain
· Cough, shortness of breath
Rare but Serious Side Effects:
· Inflammation of the lungs
Possible Side Effects for Sorafenib
Likely Side Effects:
· Fatigue
· Diarrhea
· Hand-foot syndrome (redness, peeling and sometimes pain of the soles on the feet and palms of the hands) and peeling rash
Less Likely Side Effects:
High blood pressure
Flu-like symptoms, fever, chills, joint pain, arthritis, muscle pain,
Allergic reactions, dry skin, flushing, hair loss, changes in nail appearance, vitiligo (skin disorder resulting in pigmentation (color) changes), itching, non-life-threatening skin cancer
· Abdominal pain/cramping, swelling of the abdomen, constipation, nausea, vomiting, excess gas, indigestion/heartburn, abnormal liver functions
· Low platelet count (which can cause small red spots on the skin and will increase your risk of bleeding), low white blood cell counts (which can increase your risk of infection), low red blood cell counts (which can cause fatigue and shortness of breath)
· Bleeding in the stomach, intestines or rectum, bleeding in the kidneys or bladder
· Pancreatitis (inflammation in your pancreas). The pancreas is a large gland behind your stomach which secretes digestive enzymes and hormones. Elevated amylase/lipase (enzymes produced by the pancreas).
· Numbness or tingling sensations
· Loss of appetite, weight loss
· Kidney failure, increase of sugar in the blood (hyperglycemia), low phosphate in the blood
· Shortness of breath, low oxygen in the blood, pneumonia, collapsed lung, fluid around the lungs
· Dehydration, difficulty swallowing, mouth sores and inflammation of the mouth
· Join paint, muscle pain
Rare but Serious Side Effects:
· A break or rupture in the gastrointestinal tract
There is the possibility that erlotinib and/or sorafenib will interact with other medications you are taking. This is particularly important if you are taking medication to control or prevent seizures. If you are taking one of these mediations (warfarin, quinidine, cyclosporine, digoxin, Depakote/valproic acid), your physician will monitor you carefully for side effects and check your drug levels carefully.
Side effects due to blood drawing may include: pain, bruising, bleeding or other discomfort at the blood drawing site. Anemia (low red blood cells), fainting or infection at the blood drawing site may occur (very unlikely).
Reproductive risks: Because there may be a risk of birth defects if a fetus is exposed to erlotinib and/or sorafenib, you should not use this drug if you and your partner are planning to have a baby during this study or two months following the end of the study. A barrier method of birth control (i.e. condom) must be used during the study and for eight (8) weeks after your last dose of study drug. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy.
Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by the hospital or the insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
For more information about risks and side effects, ask the researcher or contact .
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct medical benefit to you. The benefits of erlotinib and sorafenib treatment to patients with brain tumors is unknown. We hope the information learned from this study will benefit other patients with brain tumors in the future.
WHAT OTHER OPTIONS ARE THERE?
Should your disease become worse, or if you have severe side effects, this therapy may be discontinued and other means of treating you will be discussed. You may choose at this time, or any time in the future to have no further therapy; other than care for relief of your symptoms (supportive care). You may also consider other treatments for your disease such as further surgery, radiation therapy or chemotherapy. Other research options may also be available to you.
Please talk to you doctor about these and other options.
WHAT ABOUT CONFIDENTIALITY?
This section tells you what information about you may be used and given out in this study and who may give and receive the information. By signing this consent form, you agree that health information that identifies you may be used and/or given out as needed in this study. _________________ has a policy to protect health information that may identify you. Federal and state laws also protect your privacy. ______________________ has procedures in place to support these policies and laws.
a. What information about you may be used or given out in this study?
Information that identifies you and relates to your health or medical condition may be used or given out in this study. Information that identifies you can include your name, address, telephone number, date of birth, Social Security number and other details about you. Information that relates to your health or medical condition includes:
Information obtained from the activities and procedures outlined in this consent form, which may include:
i) things done to see if you can join this study, such as physical examinations, blood and urine tests and any other information that you share with us, including information about your health history and your family health history; and
ii) information obtained during the study, such as how you respond to the study activities or procedures, information we learn in study visits, phone calls, surveys, physical examinations, blood and urine tests, x-rays and other tests and any other medical information we learn from you as a participant in this study.
b. Who may use and give out information about you?
Some people may see your health information and may give out your health information during this study. These include the researcher and the research staff, the institutional review boards and their staff, legal counsel, audit and compliance staff, officers of the organization and other people who need to see the information to help this study or make sure it is being done as it should.
c. Who may see your health information?
Other organizations may see your health information during this study. These include:
· Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections and the Food and Drug Administration
· Doctors and staff at other places that are participating in this study
· The pharmaceutical collaborators, Bayer Corporation/Onyx Pharmaceuticals and OSI Pharmaceuticals.
· The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI (National Cancer Institute).
· The Contract Research Organization.
· The Data Safety Monitoring Board
· An outside institutional review board
· NABTT CNS Consortium
d. Why will this information be used and given out?
Your information will be used and given out to carry out this study and to evaluate the results of this study.
e. What if you decide not to give your permission to use and give out your health information?
You do not have to give your permission to use or give out your health information. However, if you do not give permission, you may not participate in this study.
f. May you withdraw or cancel your permission?
You may cancel your agreement to allow your health information to be used or given out at any time by sending a written notice to the Institutional Review Board Office, __________________________________. If you do this, you are leaving this study. If you leave this study, no new health information about you will be gathered after that date. However, information gathered before that date may be used or given out if it is needed for this study or any follow-up for this study.
g. Is your health information protected after it has been given to others?
If your health information is given to someone not covered by these policies and laws, that information may no longer be protected, and may be used or given out without your permission.
h. Does this consent form have an end date?
This authorization to use and give out health information continues until the end of this study and any necessary data analysis follow-up activities for this study.
A) What is the role of the IRB?
Research studies involving human volunteers are reviewed by an Institutional Review Board (IRB). The IRB is made up of doctors, nurses, scientists, non-scientists and people from the community. The IRB is responsible for protecting participant’s rights.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. Some of the costs of the blood tests and brain scans may not be covered by your insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
In the case of injury or illness resulting from this study, emergency medical treatment is available but will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury.
You or your insurance company will be charged for continuing medical care and/or hospitalization.
NCI (National Cancer Institute) will provide you with the investigational agents (erlotinib and sorafenib) 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 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.