Open-Label Phase I/Phase II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects with Recurrent High Grade Glioma
Protocol Version: October 16, 2006
| Purpose of Study | Eligibility Criteria | Treatment Schedule | Sample Informed Consent | Patient Information |
Phase I – Objectives
Primary Objective
To determine the maximum tolerated dose (MTD) of Tetra-O-Methyl Nordihydroguaiaretic Acid (EM-1421) administered as a daily intravenous infusion for 5 consecutive days every 28 days to adults with recurrent high grade glioma, receiving anticonvulsants that induce hepatic metabolic enzymes (Group A) or not receiving anticonvulsants or receiving anticonvulsants with modest induction or no induction of hepatic metabolic enzymes (Group B).
Phase II – Objectives
Primary Objective
To estimate the response rates of adult patients with recurrent high grade glioma treated with EM-1421 administered at the MTD.
Secondary Objectives
To assess overall survival.
To assess the safety and tolerability associated with the EM-1421 given at the MTD in patients with recurrent high grade glioma.
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 contrast enhancing measurable progressive or recurrent malignant glioma by MRI or CT imaging. (Within 14 days before starting treatment).
4. 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.
5. Patients must have a Karnofsky performance status ³ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
6. Patients must have normal 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 £ 1.5mg/dl; total bilirubin £ 1.5mg/dl; transaminases £ 4 times above the upper limits of the institutional norm; PT, PTT, INR within institutional norm or below.
7. Patients must be able to provide written informed consent.
8. 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.)
9. 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.
2. Patients who are pregnant or breast-feeding. (The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.)
3. Patients receiving concurrent therapy for their tumor (with the exception of steroids).
4. 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.
5. Patients with a known sensitivity to any of the study medication components (EM-1421 is formulated in a solution of Polyethylene glycol (PEG 300) and 2-Hydroxypropyl β-cyclodextrin).
This is a Phase I, dose escalation study of EM-1421 administered by intravenous infusion for five consecutive days. A treatment cycle is 28 days with EM-1421 being given as an infusion for the first five days of every cycle. Patients meeting all eligibility criteria will be enrolled in cohorts of 3 patients per Group A and/or B (based on whether the patient is taking anticonvulsant drugs that induce hepatic enzymes or not) to receive EM-1421 as a daily intravenous infusion for five consecutive days of each 28-day cycle. The EM-1421 dose levels to be studied include 750, 1100, 1700, 2200, 3000, 4000, 5300, 7000 and 9000 mg/day. Each patient in a cohort will be treated at the same dose and on the same schedule of daily infusions. No intra-patient dose escalation will be allowed.
Once the MTD has been described for Groups A and/or B, a standard two-stage design trial will follow. During this phase of the trial, EM-1421 will continue to be administered as an IV infusion. Treatment of an individual patient will continue until there is evidence of either disease progression or unacceptable toxicity, or if the patient decides to discontinue treatment for any reason.
Open-Label Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects with Recurrent High Grade Glioma
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?
The purpose of this study is to find the highest dose of an investigational agent called EM-1421 that can be given without causing severe side effects. This research is being done because currently, there are few effective treatments for this type of cancer. EM-1421 may be able to kill tumor cells in other types of cancer and we are studying the proper dose of EM-1421 to give to patients with brain tumors. This means we will give increasing doses of EM-1421 until patients have major side effects. You will be assigned a dose when you enter the study. You will be told what your dose is and it will not be increased. You will be given the same or lower dose throughout your treatment. We will also be looking at the side effects of EM-1421.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 6-36 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 serum pregnancy test.
This drug is given as an intravenous infusion for 5 consecutive days every 28 days. Each 4 week (28 day) period is called a treatment cycle. This means you will come to the clinic (in the outpatient department) and receive a 30 minute infusion on the first 5 days of each treatment cycle. A brain scan will be performed before starting treatment with EM-1421 and after the second cycle of drug. Brain scans will be repeated every 8 weeks (2 cycles). The brain scans (MRI or CT) would be part of routine cancer care.
During the study, a physical exam, vital signs and neurologic exam will be repeated. Routine blood tests will be done before each cycle of EM-1421 and on Day 15 of each cycle. If at any point your blood counts are low, these blood tests will be repeated more often.
As part of this study, we will also be collecting extra blood samples in order to check the amount of EM-1421 in your blood. On day 1, day 2, day 5 and day 6 of the first and second treatment cycle these extra blood samples will be drawn. On day 1 and day 5 of these 2 cycles 8 extra blood samples will be drawn. On these days you will be required to remain at the clinic for an additional 4 hours after your infusion. On day 2 and day 6 of these 2 cycles one blood sample will be drawn. Approximately 2 tablespoons of blood are drawn for each sample. These extra blood tests are for research purposes only and would not be part of your standard care. The costs associated with collecting and processing these blood samples will not be charged to you or your insurance company. These blood samples may be used for further study by Erimos Pharmaceuticals after analysis of the blood for the amount of EM-1421 is completed.
HOW LONG WILL I BE IN THE STUDY?
EM-1421 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 EM-1421 is stopped, but in some cases side effects can be serious or long-lasting or permanent or fatal.
Expected Side effects include:
Based on the information gathered from animal experiments, we can predict some, but not all, of the side effects you may have. Studies were conducted in laboratory animals (dogs) that received very high doses of EM-1421. Side effects observed in these animals that could likely occur in humans include: nausea, vomiting, diarrhea and mild ataxia (unsteadiness while walking). One patient receiving EM-1421 at a high dose experienced metabolic acidosis. This means that the pH level of the blood was dangerously low. The low pH level caused this patient to have respiratory failure (inability to breath).
There may be additional unanticipated side effects that were not seen.
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 EM-1421, you should not use this drug if you and your partner are planning to have a baby during this study or two months following the end of the study. A barrier method of birth control (i.e. condom) must be used during the study and for eight (8) weeks after your last dose of study drug. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy.
Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by the hospital or the insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
For more information about risks and side effects, ask the researcher or contact .
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with brain tumors in the future.
WHAT OTHER OPTIONS ARE THERE?
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 sponsor, Erimos Pharmaceuticals, LLC.
· The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI.
· 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.
Erimos Pharmaceuticals, LLC will provide you with the investigational 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.
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.
Open-Label Phase I/II Study of Intravenous Infusion of Tetra-o-Methyl Nordihydroguaiaretic Acid (EM-1421) in Subjects with Recurrent High Grade Glioma
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?
The purpose of this study is to find out what effects (good and bad) EM-1421 has on you and your brain tumor. This research is being done because currently, there are few effective treatments for this type of cancer. EM-1421 is an investigational drug. This drug may be able to kill cancer cells. We are trying to learn if this drug is active against the type of brain tumor you have. We will also be looking at the side effects of EM-1421.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 17-35 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 serum pregnancy test.
This drug is given as a 30 minute intravenous infusion for 5 consecutive days every 28 days. Each 4 week (28 day) period is called a treatment cycle. This means you will come to the clinic (in the outpatient department) and receive a 30 minute infusion on the first 5 days of each treatment cycle. A brain scan will be performed before starting treatment with EM-1421 and after the second cycle of drug. Brain scans will be repeated every 8 weeks (2 cycles). The brain scans (MRI or CT) would be part of routine cancer care.
During the study, a physical exam, vital signs and neurologic exam will be repeated. Routine blood tests will be done before each cycle of EM-1421 and on Day 15 of each cycle. If at any point your blood counts are low, these blood tests will be repeated more often.
As part of this study, we will also be collecting extra blood samples in order to check the amount of EM-1421 in your blood. On day 1, day 2, day 5 and day 6 of the first and second treatment cycle these extra blood samples will be drawn. On day 1 and day 5 of these 2 cycles 8 extra blood samples will be drawn. On these days you will be required to remain at the clinic for an additional 4 hours after your infusion. On day 2 and day 6 of these 2 cycles one blood sample will be drawn. Approximately 2 tablespoons of blood are drawn for each sample. These extra blood tests are for research purposes only and would not be part of your standard care. The costs associated with collecting and processing these blood samples will not be charged to you or your insurance company. These blood samples may be used for further study by Erimos Pharmaceuticals after analysis of the blood for the amount of EM-1421 is completed.
HOW LONG WILL I BE IN THE STUDY?
EM-1421 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 EM-1421 is stopped, but in some cases side effects can be serious or long-lasting or permanent or fatal.
Expected Side effects include:
Based on the information gathered from animal experiments, we can predict some, but not all, of the side effects you may have. Studies were conducted in laboratory animals (dogs) that received very high doses of EM-1421. Side effects observed in these animals that could likely occur in humans include: nausea, vomiting, diarrhea and mild ataxia (unsteadiness while walking). One patient receiving EM-1421 at a high dose experienced metabolic acidosis. This means that the pH level of the blood was dangerously low. The low pH level caused this patient to have respiratory failure (inability to breath).
There may be additional
unanticipated side effects that were not seen.
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 EM-1421, you should not use this drug if you and your partner are planning to have a baby during this study or two months following the end of the study. A barrier method of birth control (i.e. condom) must be used during the study and for eight (8) weeks after your last dose of study drug. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy.
Financial risks: There may be extra costs with this treatment. Some of the costs may not be covered by the hospital or the insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.
For more information about risks and side effects, ask the researcher or contact .
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with brain tumors in the future.
WHAT OTHER OPTIONS ARE THERE?
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 sponsor, Erimos Pharmaceuticals, LLC.
· The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI.
· 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.
Erimos Pharmaceuticals, LLC will provide you with the investigational 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.
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.