Clinical trial NCT03137888
Conditions: Glioblastoma Gliosarcoma
Sponsor: Emory University
Start date: 2017-09-20; Completion date: 2024-09-09
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies the side effects of spectroscopic magnetic resonance imaging (MRI)-guided radiation therapy and how well it works in treating patients with newly-diagnosed glioblastoma or gliosarcoma. Spectroscopic MRI can show doctors where the extent of tumor is in the brain beyond current clinical MRI scans by mapping areas of high tumor metabolism. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Spectroscopic MRI-guided radiation therapy may work better in treating patients with glioblastoma or gliosarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the feasibility of using spectroscopic MRI (sMRI) to guide dose-escalated radiation therapy (RT) for newly-diagnosed glioblastoma (GBM)s.

II. To determine the safety of using sMRI to guide dose-escalated RT for newly-diagnosed GBMs.

SECONDARY OBJECTIVE:

I. To determine whether the progression free survival at 1 year with sMRI-guided, dose-escalated RT is improved for newly-diagnosed GBMs.

TERTIARY OBJECTIVES:

I. To determine whether sMRI-guided, dose-escalated RT increases the overall survival of patients with newly diagnosed GBMs.

II. To determine whether sMRI data obtained after initiation of therapy (at 2 weeks after RT/TMZ start and prior to cycle 1 and 5 of adjuvant temozolomide \[TMZ\]) will provide early evidence of GBM progression not seen on standard MRIs.

III. To determine whether performance on neurocognitive and quality-of-life (QOL) assessments in newly-diagnosed GBM patients treated with sMRI-guided, dose-escalated RT differ from historical controls.

OUTLINE:

Patients undergo sMRI-guided radiation therapy daily for the first 5 days of every week (Monday - Friday) over 6 weeks. Patients also receive standard of care temozolomide orally (PO) daily during radiation therapy for up to 42 days.

After completion of study treatment, patients are followed up every 3 months for up to 2 years and then periodically.

Arms: arm 1: Patients undergo spectroscopic magnetic resonance imaging-guided dose-escalated radiation therapy daily for the first 5 days of every week (Monday - Friday) over 6 weeks. Patients also receive standard of care temozolomide PO daily during radiation therapy for up to 42 days.
Interventions: intervention 1: Dose-Escalated Radiation Therapy intervention 2: Spectroscopic Magnetic Resonance Imaging intervention 3: Temozolomide
Intervention descriptions: intervention 1: Undergo sMRI-guided radiation therapy, dose painted to maximum of 75 Gy over six weeks intervention 2: Patients will undergo sMRI scans within a 14 day window prior to starting treatment intervention 3: Given PO

Protocol documents:
ICF_001.pdf: 
 
 
 
 
 
Informed Consent Form 
 
 
RAD 3383-17: Pilot study of spectroscopic MRI-guided, dose-escalated 
radiation therapy for newly-diagnosed glioblastoma 
 
NCT Number: NCT03137888 
 
 
Document IRB Approval Date: 3/13/19 


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IRB Form 04152016 
  
 
 
You Are Being Asked to Be in a Research Study 
 
What Is a Research Study? 
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.   
 
Do I Have to Do This? 
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study.  
 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.   
 
What Is This Document? 
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you. 
 
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom. 
 
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used. 
 
What Should I Do Next? 
1. Read this form, or have it read to you. 
2. Make sure the study doctor or study staff explains the study to you. 
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)  
4. If there will be medical treatment, know which parts are research and which are 
standard care. 
5. Take time to consider this, and talk about it with your family and friends. 
 
 


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IRB Form 04152016 
Emory University 
Consent to be a Research Subject / HIPAA Authorization  
 
 
Title: Rad3383-17 Pilot study of spectroscopic MRI-guided, dose-escalated radiation therapy for newly-
diagnosed glioblastoma 
 
Principal Investigator/Sponsor:  Hui-Kuo G. Shu, MD, PhD 
 
Study-Supporter: National Cancer Institute (NCI) 
 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you everything you need to 
think about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to 
take part, you can change your mind later on and withdraw from the research study. The decision to join 
or not join the research study will not cause you to lose any medical benefits.  If you decide not to take part in 
this study, your doctor will continue to treat you. 
 
Before making your decision: 
• Please carefully read this form or have it read to you 
• Please listen to the study doctor or study staff explain the study to you  
• Please ask questions about anything that is not clear 
 
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would 
like to participate. You may wish to discuss your decision with family or friends. Do not sign this consent form 
unless you have had a chance to ask questions and get answers that make sense to you.  By signing this form 
you will not give up any legal rights. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. 
This Web site will not include information that can identify you. At most the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
Why is this research being done? 
You are asked to participate in this research because you have a gliosarcoma or glioblastoma (GBM) of the 
brain.  This research uses a type of MRI scan that detects your brain’s natural metabolism, an imaging technique 
called Spectroscopic magnetic resonance imaging (sMRI). This sMRI scan can map areas of high tumor 
metabolism without using any injection of contrast agent.  There is a significant difference in metabolism 
between normal brain tissues and brain tumors, which can show where the extent of tumor is in your brain 
beyond the current clinical MRI scans.  The purpose of this study is to determine if higher dose localized 
radiotherapy [75 Gray (Gy), as compared to 60 Gy currently used as standard of care] guided by sMRI can 
improve patient outcome. It will also be investigated how this type of treatment affects mood, function and 
quality-of-life compared to standard therapy.  Researchers do not yet know whether this will improve tumor 
control.  There may be risks associated with an increased dose of radiation treatment. 
 
The current standard care starts with removing as much of it as can be safely removed. Radiotherapy and 
temozolomide chemotherapy are used to treat the remaining tumor. This treatment usually does not control the 


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IRB Form 04152016 
tumor for the long term.  This study seeks to identify the most active areas of the tumor based on the sMRI and 
increases the dose of radiation therapy to those areas in hopes of improving tumor control. 
  
Radiotherapy is given for approximately 30 sessions over about 6 weeks.  The radiation is aimed at the areas of 
the brain where there is likely to be tumor after surgery.  Standard diagnostic MRI scan with contrast agent is 
used to target the radiation.  Standard MRI shows areas where the shape of the brain is altered and areas where 
the brain is disturbed or injured.  The targeting of radiation is also guided by your doctor’s knowledge of the 
likely pattern of extension of the tumor. 
 
Your doctors will target radiation using the location of metabolically active tumors in addition to the standard 
abnormalities normally targeted based on standard diagnostic MRI.  These areas of biochemical abnormalities 
will receive extra radiation beyond the standard dose.  We do not know whether this is safe or will improve 
your tumor control outcome. 
 
Patients getting standard therapy are treated with radiation to a dose of 60 Gy to the highest risk regions and a 
lower dose (45-54 Gy) to lower risk regions.  Even with this therapy, the tumor will generally regrow within the 
area that got 60 Gy of radiotherapy treatment.  Higher radiation doses may result in better control.  This has 
been tested in studies before.  Increasing the dose of radiation based on standard diagnostic MRI was safe but 
did not improve outcome.     
 
This research is being done to ultimately determine whether giving additional radiation to these areas of high 
tumor metabolism will improve results of treatment.  We will test whether targeting radiation this way is safe.  
Tumor outcome will be monitored.  You will also have tests of mood, neurocognitive function and quality-of-
life to monitor the benefit of more aggressive treatment from the aspect of patients’ quality-of-life.   
 
How many people will be in this study? 
Up to 52 people will take part in this study, with 25 expected to take part at Emory. 
 
What will I be asked to do (procedures)? 
If you agree to be in this study, we will ask you to do the following things: 
 
Before the research starts (screening): 
After signing this consent form, you will be asked to have some screening tests or procedures to find out 
if you can be in the research study. These tests and procedures are part of regular cancer care and are 
routinely done even if it turns out that you do not take part in the research study. If you have had some 
of these tests or procedures recently, they may not have to be repeated.   
• A medical history (questions about your health, current medications, and any allergies) will be taken.   
• A physical examination including height and weight will be performed.   
• Your performance status or how your disease affects your daily activities will be assessed.   
• An assessment of your tumor will be made by MRI (magnetic resonance imaging).   
• A pregnancy test for women of childbearing potential will be obtained.     
 
If these tests show that you are eligible to participate in the research study, you will begin the study 
treatment.  If you do not meet the eligibility criteria, you will not be able to participate in this research 
study.   
 
After the screening procedures confirm that you are eligible to participate in the research study: 


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You will have the following tests and procedures:  
 
Radiation therapy: 
You will have radiation therapy (RT) about 5 days/week for about 6 weeks.  The treatment involves a 
higher dose to a selective volume based on sMRI [75 Gray (Gy), as compared to 60 Gy currently used as 
standard of care] guided by sMR. 
 
Medications during radiation therapy:  
Temozolomide (TMZ) chemotherapy (standard care) 
TMZ chemotherapy will be given as a pill by mouth. It is started on the first day of radiation.  It will be 
given daily (7 days/week) for the duration of RT (about 6 weeks).  The dose of TMZ that is used in this 
phase of treatment will be based on your height and weight.  TMZ must be taken at least one hour before 
or two hours after eating.  Prior to receiving TMZ, you will be given a medicine to prevent nausea.   
 
Rest period:  
Following radiation treatments, there will be a four-week break in which you will not take any study 
medications.   
 
Adjuvant Phase which is the treatment given after radiotherapy is done (standard care) 
After the 4-week rest period, you will re-start Temozolomide chemotherapy – dose, duration, and 
number of cycles will be determined by your doctor.  This is standard therapy for your type of tumor.   
 
Spectroscopic MRS (sMRI) scans (research activity):  
sMRI scan will be performed on a normal MRI machine without intravenous contrast.  These studies 
will take less than an hour and may be done with or separate from normal diagnostic MRIs.  These are 
extra scans that happen because you are participating in this study. 
 
The timing for the two sMRI scans is as follows: 
1) 
Within 2 weeks before the start of RT/TMZ (for RT planning) 
2) 
Two weeks after the start of RT/TMZ (during the third week of treatment)  
 
It is possible that the sMRI scan will not function properly due to technical reasons or that it will 
identify an area within your brain of high tumor metabolism that is too large to safely treat with the 
increased dose of radiation. If this happens, you will be removed from the study and treated as per 
standard of care or considered for an alternative research protocol.   
 
Neurocognitive, mood, and quality-of-life studies (research activities):  
We want to know how your life has been affected by your brain tumor and its treatment.  Your memory 
and thinking ability (neurocognitive function), mood (depression survey), and general sense of well-
being (quality-of-life) will be evaluated by a tests and questionnaires. These will be done in your 
doctor’s office.  It takes about 40 minutes to complete these tests and questionnaires.   
 
The timing of these tests is as follows:  
1) 
Within 14 days before to the day of starting therapy (may be performed anytime on first 
day of therapy),   
2) 
10 weeks after starting therapy (4 weeks after completion of RT/TMZ)  


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3) 
Every 6 months thereafter. Tests are repeated until either tumor progression or 2 years 
without progression after completion of RT/TMZ.   
 
This information may help doctors better understand what effects this treatment has on patients and may 
eventually help patients and doctors decide which treatment to use for these brain tumors.  As always, 
we will do our best to make sure that your personal information will be kept private.   
 
MRI scans (standard care):  
A diagnostic MRI scan with and without intravenous contrast will be done 1-2 weeks before the start of 
therapy if the immediate post-operative MRI scan was done > 28 days from registration. This is for RT 
treatment planning and establishment of a pre-treatment baseline.  
  
About 10 weeks after the start of therapy, you will have another diagnostic MRI scan with and without 
intravenous contrast. This is to look at the status of your tumor. The follow-up diagnostic MRI scans 
will ordered by your doctor according to the standard care schedule of your type of tumor. 
 
Physical exams (standard care):  
Physical exams will be performed every other week during RT/TMZ treatment.   
 
How long will you be in the study? 
You will be in the study for 2 years.  We will monitor the records of you long term outcome after this.  
The treatment with radiation and chemotherapy lasts for six weeks.  One month after this, chemotherapy 
will start again according to your doctor’s instruction as standard care therapy for your type of tumor.   
 
What are the possible risks and discomforts? 
Risks and Discomforts  
 
There are risks to taking part in any research study.   
 
Please notify your doctor if any of the following occur:  
• A fever of 100.5 F or above.   
This could be a sign of an infection.  If you have a low white blood cell count, this can be serious, 
life-threatening or fatal.  You may have to take antibiotics or be admitted to the hospital.   
• Low energy or shortness of breath.    
This could be a sign of anemia (not enough red blood cells).  If this becomes severe, you may need 
to come into the clinic or hospital to have a transfusion of red blood cells.   
 
This study changes the way radiation is aimed.  More radiation will also be given to some areas of 
your brain.  This may increase the risks and side effects related to the radiation therapy.  Ask 
your doctors about how these risks apply to you.  Your doctors will discuss any extra risks in your 
situation. 
 
Risks of Radiation Therapy:   
  
Likely (events occurring greater than 20% of the time): 
• Tiredness  
• Hair loss   


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• Redness or irritation of your skin 
• Dry skin  
  
Less Likely (events occurring less than or equal to 20% of the time):  
• Headaches  
• Worsening of your current symptoms  
• Swelling of your brain requiring steroids 
• Ear pain or discomfort  
• Decreased Hearing 
 
Rare but serious (events occurring less than 2-3% of the time):  
• Seizures.   
• Coma.   
• Lower white blood cell and platelet counts raising the risk of infection and bleeding.   
• Radiation therapy at these dose levels also may cause damage to normal brain, but this is rare.   
• Specific effects depend upon the location of the area(s) of damage but may be a decrease in 
judgment, memory, emotions, vision, hearing, sensation, or ability to control movement.   
• Another brain tumor or cancer caused by radiation 
  
 
Risk associated with temozolomide (standard care) 
 
Likely risks of TMZ (events occurring more than 20% of the time):  
• Feeling sick to your stomach (nausea).   
• Throwing up (vomiting).   
• Decreased appetite (anorexia).   
• Difficulty in passing stools (constipation).   
• Headache.   
• Fatigue.   
• Fever (pyrexia).   
 
Less likely risks of TMZ (events occurring less than or equal to 20% of the time): 
• Fall in the white blood cell counts that leads to a higher risk of infection (neutropenia).   
• Fall in the platelet count leading to a higher risk of bleeding (thrombocytopenia).   
• Fall in the red blood cell count leading to anemia (feeling tired and low energy) (anemia).   
• A low number of a particular white blood cell, which is important to the immune system 
(lymphopenia).   
• Sores in the mouth (stomatitis).   
• Loose stools (diarrhea).   
• Pain in the belly (abdomen).   
• Change in liver function tests (tests that show how the liver is working).   
• Rash (psoriasis).   
• Itchiness (pruritis).   
• Lack of interest in or ability to carry out daily activities.   


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• Weakness (asthenia).   
• Dizziness.   
• Anxiety.   
• Depression.   
• Memory loss.   
• Muscle pain (myalgia).   
• Joint pain (arthralgia).   
• Tingling or burning in your arms or legs.   
• Shortness of breath (dyspnea).   
• Cough.   
• Swelling in your arms or legs (edema).   
• Increased need to pass urine.   
 
Rare but serious risks of TMZ (events occurring less than 2-3% of the time):  
• Problem with the bone marrow that causes decreased production of red cells, white cells, or 
platelets that can sometimes turn into blood cancer called Myelodysplastic syndrome.   
• Convulsions.   
• Weakness on one side of your body (hemiparesis).   
• Abnormal coordination.   
• Inability to move an arm or leg (paralysis).   
• Severe skin reaction.   
• Fever, chills, swelling of body, shortness of breath (allergic reaction).   
• Re-activation of hepatitis infection (if you have previously been diagnosed with Hepatitis-A type of 
infection in the liver).   
• A blood disorder in which the body’s bone marrow does not make enough new blood cells (Aplastic 
Anemia).   
• Inflammation in the lungs (pneumonitis).   
• Change in kidney function tests (tests that show the kidneys are working).   
• Later development of secondary leukemia, lymphoma or other cancers.   
• Liver damage which may cause yellowing of eyes and skin, swelling and may result in liver failure. 
 
Risks and side effects related to spectroscopic MRI (research activity) 
Less Likely:  
• Some people who are claustrophobic (have a fear of enclosed places) might feel anxiety or 
nervousness during MR scan.  
• Increased discomfort from the noise that the MRI instrument makes 
• This will involve up to an extra hour in the MRI scanner each time spectroscopy is done.  
 
Risks and side effects of study questionnaires (research activity) 
Less Likely:  
• You may get tired or bored when we are asking you questions or you are completing questionnaires. 
You do not have to answer any question you do not want to answer. 
 
For more information about risks and side effects, ask your study doctor.  


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Risks and side effects related to radiation 
• In addition to radiation therapy you may receive additional radiation from procedures to evaluate 
your condition. The principal risk associated with a radiation dose is the possibility of developing a 
radiation-induced cancer later in life. However, the additional risk of radiation-induced cancer from 
these diagnostic procedures is low compared to the risks from the radiation therapy.  
 
Are there risks related to pregnancy? 
You should not become pregnant or father a baby while on this study because the radiation and 
chemotherapy in the standard care of your tumor type can affect an embryo or fetus.    
  
Women should not breastfeed a baby while on this study.    
  
It is important you understand that you need to use birth control while on this study.  Check with your 
study doctor about what kind of birth control methods to use and how long to use them.  Some methods 
might not be approved for use in this study.   
  
The treatments used in the standard care (TMZ) of your tumor type may make you unable to have 
children in the future.    
  
Women will need to have pregnancy testing prior to enrolling in the study.  
 
Additional risks   
The sMRI results and copies of your MRI scans will be shared with researchers outside of Emory, after 
all identifying information will be removed from these data.  Despite significant precautions that will be 
taken to maintain confidentiality for study subjects, there remains a small possible risk for breach of 
confidentiality. 
 
It is possible that we will discover that you have a medical issue that is unrelated to the purpose of this 
sMRI study. If we believe that the information is of urgent medical importance, we will share this 
information with you. You should not assume that if you are not contacted, that you do not have any 
medical issue might be related to a disease. 
 
There may be side effects and discomforts that are not yet known. 
 
 
 
 
 
Will I benefit directly from the study?  
You may or may not benefit from being a part of this study. Your brain tumor may improve while you are in 
this study but you may feel worse (headache and pressure) with more aggressive treatment that could cause 
significant tumor cell death with accompanying brain swelling triggered by cancer death with accompanying 
edema.  This study is designed to learn whether or not more aggressive radiation therapy is beneficial for 
patients with your type of brain tumor. Especially for treating brain tumor patients, the balance between 
aggressive treatment and preserving quality of life is critically important to see the real benefit in patients with 
your type of brain tumor.  The change in the amount of radiation and how it is aimed may have increased risks. 
We do not know if it improves the outcome. 
 
If you take part in this study, you may help others in the future based on information gained by this study. 
 


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Will I be compensated for my time and effort? 
You will not be compensated for your time and effort. 
 
What are my other options? 
If you decide not to join this study, other options are available.  You do not have to join this study to get 
treatment.   
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another investigational study  
• Getting no treatment  
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries 
to improve how you feel.  Comfort care tries to keep you as active and comfortable as long as possible.    
  
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Why might we take you out of the study early?  
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, the study team may use your health information that it has 
already collected if the information is needed for this study or any follow-up activities. 
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and 
other identifying information will not appear when we present or publish the study results. 
 
Study records can be opened by court order.  They also may be provided in response to a subpoena or a request 
for the production of documents.  
 
Storing and Sharing your Information 
Your samples and health information will be stored and shared with other researchers. The samples and 
information will be available for any research question, such as research to understand what causes certain 
diseases (for example heart disease, cancer, or psychiatric disorders), development of new scientific methods, or 
the study of where different groups of people may have come from. 
 
Medical Record 
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare medical 
record.  If you have never been an Emory Healthcare patient, you do not have one.   An Emory Healthcare 


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medical record will be made for you if an Emory provider or facility gives you any services or procedures for 
this study.   
 
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare medical 
record you have now or any time during the study.   
 
Emory Healthcare may create study information about you that can help with your care.  For example, the 
results of study tests or procedures.  These study results will be put in your Emory Healthcare medical record. 
Anyone who has access to your medical records will be able to have access to all the study information placed 
there.  The confidentiality of the study information in your medical record will be protected by laws like the 
HIPAA privacy rule.  State and federal laws may not protect the research information from disclosure.  
 
The results of some study tests and procedures will be used only for research purposes and will not be placed in 
your medical record.  For this study, those items include: research activities (spectroscopic MRI and 
neurocognition tests) 
 
Tests and procedures done at non-Emory places may not become part of your Emory medical record. Also, if 
you decide to be in this study, it is up to you to let your other health providers know.  
 
In Case of Injury 
If you get ill or injured from being in the study, Emory would help you to get medical treatment.   Emory and 
the sponsor have not, however, set aside any money to pay you or to pay for this medical treatment. The only 
exception is if it is proved that your injury or illness is directly caused by the negligence of an Emory or sponsor 
employee.  “Negligence” is the failure to follow a standard duty of care.  
 
If you become ill or injured from being in this trial, your insurer will be billed for your treatment costs.  If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs.   
 
If you believe you have become ill or injured from this research, you should contact Dr. Hui-Kuo Shu at 
telephone number 
. You should also let any health care provider who treats you know that you 
are in a research study.  
 
Cost 
The study sponsor will pay for certain items and services that you may receive if you take part in this study.  
These study-related costs provided by the study sponsor will include but are not limited to the following:  
1) 
spectroscopic MRI scans,  
2) 
administration of neurocognitive/quality-of-life/mood tests and assessments.   
 
As indicated above, spectroscopic MRI scans will be provided to you free of charge for this study.  However, 
diagnostic MRI studies are part of the standard-of-care assessment and follow-up for patients with your type of 
tumor.  Therefore, the cost of these diagnostic MRIs will be billed as part of the normal management of your 
type of tumor.   
 
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor will not 
pay for your regular medical care. If you have insurance, Emory will submit claims to your insurance for items 
and services that the sponsor does not cover.  Emory will send in only those claims for items and services that it 
reasonably believes your insurance will pay and that the sponsor has not paid.  
 


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Generally, insurance companies will not pay for items and services that are required just for a research study. 
How much you will have to pay for any co-payments, deductibles or co-insurance depends on your plan.  
Emory and the sponsor will not pay for these costs.  
 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask 
them what they will pay for and what they will not pay for.  You can also ask the study team for help in figuring 
out what you will have to pay. 
 
Withdrawal from the Study 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to have some 
of the final steps done.   
 
 
Authorization to Use and Disclose Protected Health Information 
 
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your “protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy 
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The PHI that we will use or share for the main research study includes: 
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Rad3383-17 
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Version Date: 01/30/2019 
PI: Hui-Kuo Shu, MD 
 
 
IRB Form 04152016 
Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this document. 
You do not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign 
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may still receive non-research related treatment.   
 
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normal business operations.  
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make sure the research is done correctly and to collect and analyze the results of the research.  
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Clinical Research.  
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you want to do this, you must contact: 
 
Dr. Hui-Kuo Shu 
Winship Cancer Institute, Emory University 
1365 Clifton Road NE 


Study No.: «ID» 
 
Emory University IRB 
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Document Approved On: «ApproveDate» 
 
 
Rad3383-17 
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Version Date: 01/30/2019 
PI: Hui-Kuo Shu, MD 
 
 
IRB Form 04152016 
Atlanta, GA 30322 
 
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Contact Information 
Contact Dr. Hui-Kuo Shu at 
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IRB Form 04152016 
Consent and Authorization 
 
 
TO BE FILLED OUT BY SUBJECT ONLY 
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form, you will not give up any of your legal rights. We will give you a copy of the signed form to keep. 
 
 
 
Name of Subject  
 
 
 
 
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Signature of Subject (18 or older and able to consent) 
Date              Time    (please circle) 
 
 
TO BE FILLED OUT BY STUDY TEAM ONLY 
 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
 
 
 
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Prot_SAP_002.pdf: 
Protocol Version date: 09-15-2020
1
Pilot study of spectroscopic MRI-guided, dose-escalated radiation therapy for 
newly-diagnosed glioblastoma  (RAD 3383-17)
Principal Investigators (Clinical)
Hui-Kuo G. Shu, MD, PhD
Dept. of Radiation Oncology
Emory University-School of Medicine
Phone: 
404-778-2161
Fax: 
404-778-4139
E-Mail: 
hgshu@emory.edu
Principal Investigator (Scientific)
Hyunsuk Shim, PhD
Dept. of Radiology and Imaging Sciences
Emory University-School of Medicine
Phone: 
404-778-4564
Fax:  
404-778-5550
E-Mail:  
hshim@emory.edu
Johns Hopkins
Principal Investigators (Clinical)
Larry Kleinberg, MD (Clinical)
Dept. of Radiation Oncology
Johns Hopkins University-School of Medicine
Phone:
410-614-2597
Fax:
410-502-1419
E-Mail:
kleinla@jhmi.edu
Principal Investigator (Scientific)
Peter B. Barker, D.Phil. (Scientific)
Dept. of Radiology
Johns Hopkins University-School of Medicine
Phone:
410-955-1740
Fax:
410-502-6076
E-Mail:
pbarker2@jhmi.edu
University of Miami
Principal Investigators (Clinical)
Eric A. Mellon, MD, PhD (Clinical)
Dept. of Radiation Oncology
University of Miami
Phone:
305-243-5470
E-Mail:
eric.mellon@med.miami.edu
Principal Investigator (Scientific)
Andrew Maudsley, PhD (Scientific)
Dept. of Radiology
University of Miami
Phone:
305-243-8080
E-Mail:
amaudsley@med.miami.edu
Emory University
Co-Investigators
Neuroradiology


Protocol Version date: 09-15-2020
2
Brent Weinberg, MD, PhD
Dept. of Radiology
Emory University-School of Medicine
Phone:
404-778-4564
Fax:
404-712-5813
E-Mail:
brent.d.weinberg@emory.edu
Radiation Oncology
Eduard Schreibmann, PhD
Dept. of Radiation Oncology
Emory University-School of Medicine
Phone:
404-778-5667
Fax:
404-778-4139
E-Mail:
eschre2@emory.edu
Statistics
Ying Guo, PhD
Dept. of Biostatistics and Bioinformatics
Emory University-School of Public Health
Phone:
404-712-8646
Fax:
404-727-1370
E-Mail:
yguo2@emory.edu
Multi-Site Coordinator
Latrisha Moore, CCRC
Clinical Trials Office
Emory University, Winship Cancer Institute
Phone:
404-778-5809
Fax:
404-778-5033
E-Mail:
latrisha.moore@emoryhealthcare.org
Saumya Gurbani, MS
MD/PhD Student, Study Coordinator for imaging study
Emory University-School of Medicine
Phone: 909-800-9153
Fax:  
404-778-5550
E-Mail:  
saumya.gurbani@emory.edu
Karthik Ramesh, BS
PhD Student, Study Coordinator for imaging study
Emory University-School of Medicine
Phone: 425-512-3406
Fax:  
404-778-5550
E-Mail:  
karthik.ramesh@emory.edu
University of Miami
Clara Morales
Department of Radiology
University of Miami
1150 NW 14th St, Suite 713
Phone:
305-243-3404
Fax: 
305-243-3405
E-mail:
c.marales1@med.miami.edu
Raymond S. Vado


Protocol Version date: 09-15-2020
3
Clinical Research Coordinator
Sylvester Comprehensive Cancer Center
University of Miami
Phone:
305-243-6809
Fax:
305-243-0312
E-mail
rxv307@med.miami.edu
Johns Hopkins University
Michal Povazan, PhD
Study Coordinator for imaging study
Johns Hopkins School of Medicine
Phone:  
443-743-8455
E-mail:
mpovaza1@jhmi.edu
Aiana Cerezo
Study Coordinator
Johns Hopkins School of Medicine
E-Mail:
arodri47@jhu.edu


Protocol Version date: 09-15-2020
4
TABLE OF CONTENTS
Item
Page
TITLE AND INVESTIGATORS
1
TABLE OF CONTENTS
4
ABSTRACT
5
STUDY SCHEMA
6
1.0
INTRODUCTION AND BACKGROUND
7
2.0
OBJECTIVES
8
3.0
PATIENT ELIGIBILTY
9
4.0
PATIENT SAFETY
11
5.0
PHARMACEUTICAL INFORMATION
13
6.0
REGISTRATION PROCEDURES
19
7.0
STUDY EVALUATIONS
20
8.0
TREATMENT PLAN
22
9.0
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS
25
10.0
ANCILLARY TREATMENT/SUPPORTIVE CARE
28
11.0
TREATMENT EVALUATION
29
12.0
ADVERSE EVENT REPORTING
31
13.0
DATA AND SAFETY MONITORING PLAN (DSMP)
33
14.0
STATISTICAL CONSIDERATIONS AND METHODOLOGY
36
15.0
DATA COLLECTION
38
16.0
REFERENCES
38
APPENDIX 1.
KARNOFSKY PERFORMANCE SCALE
41
APPENDIX 2.
NEUROCOGNITIVE TESTS
42
APPENDIX 3.
QOL QUESTIONNAIRES
49
APPENDIX 4.
Neuro-Oncology article by Cordova et al.
54


Protocol Version date: 09-15-2020
5
ABSTRACT
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults.  The current 
standard of care is maximal safe resection followed by radiation therapy (RT) with concurrent and adjuvant 
temozolomide (TMZ) chemotherapy.  Despite this aggressive management, GBMs invariably progress 
resulting in significant morbidity and mortality for patients.  Overall, the single most effective adjuvant 
treatment for this disease is RT.  Patients are generally treated with focal radiation to a dose of 60 Gy to 
the highest risk regions and a lower dose (45-54 Gy) to lower risk regions.  However, despite this therapy, 
tumor will generally regrow within the high dose volume suggesting that GBMs are relatively radioresistant 
and that increasing radiation doses may be beneficial for patients with this tumor. However, dose escalation 
studies that treat beyond the 60 Gy standard have not been shown, to date, to improve patient outcomes.  
It is important to note that most of these dose escalation studies were conducted in the pre-temozolomide 
era.  Interestingly, one study utilizing proton therapy with doses up to 90 cobalt gray equivalent (CGE) did 
change the pattern of recurrence from within the high dose volume to the margins of this region, particularly 
where doses fall below 70 CGE.  This result suggests that current MRI-based approaches for defining tumor 
volume/margin may not fully identify all regions at highest risk for recurrence and that better identification 
of the high risk regions will now allow realization of the benefits of dose escalation in this disease.  
Indiscriminate increases in treatment margin may allow delivery of dose-escalated radiation to the needed 
region(s) at the cost of irradiating wide areas of the brain with these higher doses significantly increasing 
the likelihood of unacceptable morbidities.  Thus, improved definition of the regions at highest risk for 
recurrence will allow dose escalation to be targeted to a more limited volume that would be better tolerated 
by patients. 
Currently, MRI using T1-weighted (T1w) post-contrast and T2/FLAIR sequences is used to define 
treatment volumes for radiation planning; however, these sequences may not identify all regions in the brain 
at highest risk for tumor recurrence.  Proton magnetic resonance spectroscopic imaging (MRSI) is an 
alternative modality that is able to map certain metabolite levels within the brain. This may allow for more 
accurate characterization of regions with significant tumor involvement than would be achievable with 
conventional MRIs.  Several reports demonstrate that a high choline (Cho) to N-acetyl apartate (NAA) ratio 
(Cho/NAA) correlates with areas of high tumor cell density and, after treatment, areas of tumor recurrence.  
However, MRSI is not widely used in clinical practice due to relatively low resolution, long acquisition time, 
and inefficient data analysis and visualization in commercially available packages.  The first two limitations 
have now been overcome with state-of-the-art technology utilizing EPSI (echo planar spectroscopic 
imaging) with GRAPPA (parallel imaging) for the spectroscopic imaging.  High resolution, three dimensional 
(3D), whole brain metabolite maps can now be obtained in relatively short (12-15 minute) scan times and 
in a form that can be registered with other conventional MR images by utilizing an advanced analysis and 
visualization tool. We have now termed this advanced imaging modality spectroscopic MRI (sMRI).  Based 
on a recently completed early phase clinical study sponsored by NCI, “combining high resolution MRSI with 
5-ALA to improve complete resection in GBM surgery” (NCI R21 CA186169; Emory IRB00051663), we 
learned that sMRI Cho/NAA showed significant correlations with tumor cell density in histological results (ρ 
= 0.82, p < 0.001). Based on early data from the control arm of on-going clinical study, “Quantitative MRSI 
to predict early response to histone deacetylase inhibitor therapy in new GBM management” (NCIU01 
CA172027; Emory IRB00055973) and an institutional study “MRSI in the treatment planning and 
assessment of glioblastoma” (Emory IRB0006545), sMRI metabolic abnormalities predated contrast-
enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free 
survival (Cordova et al. This Neuro-Oncology article is enclosed in Appendix).
We believe that the combination of sMRI and conventional MRI scans can be used to guide radiation 
therapy target definition and dose-escalated treatment planning, significantly improving outcomes for 
patients with this highly aggressive brain tumor.  


Protocol Version date: 09-15-2020
6
 STUDY SCHEMA
Registration
Confirm patient eligibility.  30 patients will be treated with dose-escalated RT.  May consent >30 patients 
due to exclusion criteria identified by baseline imaging.
Baseline imaging
 sMRI in 14 day window prior to start of treatment
Concurrent chemoradiation phase of therapy 
RT dose painted to maximum of 75 Gy over six weeks (5x/week, Mon-Fri, 30 total treatments) with 
concomitant daily TMZ (75mg/m2/day, 7x/week, Mon-Sun, 42 total doses).  
[2 week imaging]
[sMRI after 2 weeks from the baseline imaging (after 10 fractions, but up to 15 fractions of RT)]
Rest period (4-5 weeks)
Standard MRI (with gadolinium) within one week prior to starting adjuvant TMZ (4-5 weeks after 
completion of RT).
Adjuvant phase of therapy (every 28 days, at physician’s discretion)
Follow up schedule
Standard MRI (with gadolinium) and clinical assessment one week prior to every odd-numbered adjuvant 
cycle (every 2 months x up to 1 year) then 4 weeks ± one week after completion of adjuvant TMZ then 
every 3 months ± 2 weeks up to approximately 2 years after completion of RT/TMZ.  
Subsequent follow up schedule will be determined by patient’s physician.  After 2 years, patients will only 
be followed to assess survival and disease control, if patient remains without evidence of progression.  
Standard MRIs will be obtained in follow-up at discretion of treating physician.  


Protocol Version date: 09-15-2020
7
1.0
INTRODUCTION AND BACKGROUND
Glioblastomas (GBMs) are aggressive primary brain tumors of astrocytic origin. Approximately ten 
thousand new cases are diagnosed each year in the U.S., making it the most common primary 
malignant brain tumor in adults. While radiation therapy (RT) has long been used in the treatment of 
GBMs and will delay their progression, it generally will not control these tumors long term. Incremental 
progress has been made in the management of GBMs, most recently with the addition of 
temozolomide (TMZ) chemotherapy to RT; however, outcomes remain poor, with a median survival 
of only 14-15 months [1, 2]. Recurrence is largely due to the inherently infiltrative nature of GBM, with 
tumor cells migrating to regions distant from the central contrast-enhancing regions. Because of this, 
regions of nonenhancing signal abnormality on fluid-attenuated inversion recovery (FLAIR) or T2-
weighted (T2w) images are covered in a typical RT treatment plan, albeit with moderate doses. 
However, T2w/FLAIR is not tumor-specific due to difficulties in differentiating nonenhancing tumor 
from other causes of increased FLAIR or T2 signal (e.g. radiation effects, ischemic injury, edema, 
and infection) [3, 4]. T1-weighted -contrast-enhancing (T1w-CE) MRI displays the leaky 
neovasculature associated with these tumors, indicating well-perfused tumor lesions with excellent 
oxygen and chemotherapeutic drug delivery.  Despite the constant effort of tumor cells to recruit new 
blood vessels (neoangiogenesis), there is a significant gradient of oxygen. Hypoxia occurs in tumors 
100 µm away from the blood supply, and tends to be widespread in GBMs. The viable hypoxic cells 
existing in solid tumors are associated with the failure of radiation and certain chemotherapy 
regimens [5]. Obviously, IV contrast agents cannot effectively reach all the tumor cells beyond the 
contrast-enhancing border; therefore, it is unreasonable to use conventional T1w-CE MRI alone as 
the basis for RT treatment planning. Newer imaging methods are desperately needed to identify the 
actively proliferating tumor beyond the T1w-CE area. This could potentially make a significant impact 
on improving tumor control.  
Based on retrospective analysis of successive Brain Tumor Study Group trials, a fractionated dose 
of 60 Gy was determined to be optimal for GBMs [6]. A typical RT dosing regimen for the treatment 
of GBM involves treating a wide volume, including nonenhancing T2w/FLAIR-hyperintense regions 
with margin, to a moderate dose (45-54 Gy), followed by a boost to the resection cavity plus any 
residual T1w-CE abnormality with margin to a higher dose (60 Gy). A study using proton therapy for 
GBM found that patients not only tolerated doses up to 90 cobalt-gray equivalent (CGE), but also 
started to display a change in the pattern of recurrence with nearly all failures in regions receiving < 
70 CGE [7]. Of note, TMZ was not used for this study. This result suggests that tumoricidal doses (in 
the 70+ Gy range) may have finally been achieved, with marginal failures now being due to growth 
of disease that had infiltrated into brain surrounding the initial contrast-enhancing portion of the tumor. 
This study also suggests that better definition of the brain volume most at risk for tumor recurrence 
may allow better targeting of these regions with higher doses leading to improved local control and 
overall patient outcomes.  Combining RT dose escalation with concurrent/adjuvant TMZ may produce 
more toxicities, especially since the incidence of pseudoprogression after concurrent RT/TMZ is 
significantly higher than after RT alone. Pseudoprogression is the phenomenon where an early 
increase in volume of contrast enhancement is seen following treatment with RT/TMZ (usually within 
3 months post-RT). This effect is indistinguishable from early true tumor progression by standard MR 
imaging, and is generally only distinguished by serial imaging over time, when this change either 
stabilizes/improves (pseudoprogression) or continues to worsen (true progression) without 
alterations in the therapy. Brandes et al. have reported that the overall incidence of 
pseudoprogression is on the order of 30% in patients treated with the Stupp regimen [8]; therefore, it 
follows that TMZ may also alter tolerance to dose-escalated RT. This concern has been somewhat 
allayed by Tsien et al. with their report that TMZ could be safely paired with dose-escalated intensity 
modulated RT [9]. Of note, no late grade III or greater CNS toxicities were seen with doses up to 75 
Gy, and for doses above 75 Gy (7 pts at 78 Gy and 9 pts at 81 Gy), only 3 patients developed ≥ grade 
III late CNS toxicities. Thus, it is appears that dose-escalated RT may be safely paired with TMZ. 
Since previous results also suggest that very high radiation doses (70+ Gy range) shift the pattern of 
recurrence to the margins of the high dose irradiation zone [7], there is now a greater premium on 
defining further areas that may be at increased risk of recurrence that can potentially be boosted by 
these higher doses.


Protocol Version date: 09-15-2020
8
Currently, GBMs are imaged with conventional MRI sequences, including T2w, FLAIR, and pre- and 
post-contrast T1w sequences, and some advanced MRI techniques, including diffusion-weighted 
imaging (DWI), and dynamic susceptibility contrast (DSC) and/or dynamic contrast-enhanced (DCE) 
perfusion-weighted imaging (PWI). DWI and PWI MRIs have been used to follow response of GBMs 
to therapy, but have not proven particularly useful for RT planning [10-12].  Similarly, diffusion tensor 
imaging (DTI), a MR technique that describes the movement of water molecules using metrics, such 
as mean diffusivity (MD), and fractional anisotropy (FA), which represent the magnitude and 
directionality of water diffusion, respectively [13, 14], did not have value for predicting recurrences 
outside the high dose irradiated regions of brain when analyzing a cohort of GBM patients treated at 
the University of Pennsylvania (Dr. Verma, personal communications).  Overall, the most common 
advanced MRI techniques have proven disappointing at identifying high risk regions that can be better 
targeted with radiation. 
Proton magnetic resonance spectroscopic imaging (MRSI), which can characterize regions of brain 
based on levels of various metabolites and other substances, is a candidate imaging modality for 
defining high risk regions that are not identified by standard MRI.  Metabolites that can be evaluated 
include choline (Cho), a peak reflecting cell membrane synthesis that is elevated in highly 
proliferating, non-necrotic gliomas; creatine (Cr), an energy metabolite; and N-acetyl aspartate 
(NAA), a healthy neuronal biomarker. Early studies established that the MR spectra of GBMs differ 
significantly from normal brain, with increased levels of Cho, and decreased levels of NAA [14, 15]. 
MRSI has even been evaluated as a guide for RT planning when registered with the conventional 
MRI scans and treatment-planning CT scans [16-19]. Park et al. correlated the pattern of recurrence 
after RT with pre-treatment MRSI findings and noted that 8 of 9 patients with a growing enhancing 
lesion post-RT had recurrence in regions with high Cho/NAA [20]. Stadlbauer et al. demonstrated in 
gliomas that MRSI-derived Cho/NAA ratios frequently identified regions at higher risk of tumor beyond 
the T2w signal abnormalities, and concluded that MRSI may be useful for delineating infiltrating 
nonenhancing tumor (beyond contrast enhancing tumor), which has clear implications for therapeutic 
planning [21, 22]. These previous studies have shown that MRSI can help identify GBMs, and 
potentially provide guidance for RT management.  However, with poor resolution and limited field-of-
views among a host of other difficulties, it has not been possible to exploit current clinical 
implementations of MRSI for use in RT treatment planning.   
We have been using an advanced spectroscopic technique we have termed spectroscopic MRI 
(sMRI) which combines advanced technologies, such as 3D echo-planar spectroscopic imaging 
(EPSI), parallel acquisition (GRAPPA), and elliptical k-space encoding, with a 32-channel head coil. 
This acquisition obtains metabolite maps over approximately 65% of the brain coverage with high 
resolution in 15 minutes. This sMRI sequence was developed 10 years ago by Dr. Andrew Maudsley 
(University of Miami) and has been adapted in multiple clinical studies by numerous investigators in 
the world.  We have been using sMRI in various clinical studies at Emory. Based on a recently 
completed early phase clinical study sponsored by NCI, “combining high resolution MRSI with 5-ALA 
to improve complete resection in GBM surgery” (IRB00051663), we learned that sMRI Cho/NAA 
showed significant correlations with tumor cell density in histological results (ρ = 0.82, p < 0.001). 
Based on early data from the control arm of on-going clinical study, “Quantitative MRSI to predict 
early response to SAHA therapy in new GBM management” (IRB00055973) and an institutional study 
“MRSI in the treatment planning and assessment of glioblastoma” (IRB0006545), sMRI Cho/NAA 
metabolite ratio map before RT treatment initiation matched well with contrast-enhancement at sites 
of tumor recurrence and exhibited an inverse relationship with progression-free survival (Cordova et 
al. This Neuro-Oncology article is enclosed in Appendix).  Here, we will use our high-resolution, 
volumetric sMRI combined with standard MRIs that are routinely performed in the clinic for focal 
radiotherapy planning with escalated doses to select regions for the potential benefit of newly-
diagnosed GBM patients.  
2.0
OBJECTIVES
Our main goal is to establish the use of sMRI in addition to standard contrasted MRIs to guide dose-
escalated radiation therapy for newly-diagnosed GBM patients.  We have demonstrated that sMRI 


Protocol Version date: 09-15-2020
9
has reached a level of technical development and validation where it is now feasible to use it for 
mapping regions of brain at high risk for tumor recurrence that may not have otherwise been 
appreciated by contrast-enhanced MRIs.  In addition, the safety of this dose-escalated treatment 
approach will need to be demonstrated before it can be more widely adopted.  Finally, we will also 
assess the efficacy of selectively targeting RT dose escalation with sMRI guidance in comparison to 
historical controls.  
2.1
Primary Objectives
2.1.1
To determine the feasibility of using sMRI to guide dose-escalated RT for newly-
diagnosed GBMs.  
2.1.2
To determine the safety of using sMRI to guide dose-escalated RT for newly-diagnosed 
GBMs.  
2.2
Secondary Objectives
2.2.1
To determine whether the progression free survival at 1 year with sMRI-guided, dose-
escalated RT is improved for newly-diagnosed GBMs.  
2.3
Exploratory Objectives
2.3.1
To determine whether sMRI-guided, dose-escalated RT increases the overall survival 
of patients with newly-diagnosed GBMs.  
2.3.2
To determine whether sMRI data obtained after initiation of therapy (at 2 weeks after 
RT/TMZ start and prior to cycle 1 and 5 of adjuvant TMZ) will provide early evidence 
of GBM progression not seen on standard MRIs.  
2.3.3
To determine whether performance on neurocognitive and quality-of-life (QOL) 
assessments in newly-diagnosed GBM patients treated with sMRI-guided, dose-
escalated RT differ from historical controls.
3.0
PATIENT ELIGIBILTY
3.1
Minorities and Women:  Subjects will be approximately representative of the demographics 
of the patient population at Emory University, Johns Hopkins, and University of Miami.  This 
study is designed to include women and minorities, but is not designed to measure differences 
of intervention effects.  While males and females will be recruited with no preference to gender, 
and based on the results of previous studies, we expect 50% of our accrual to be female.  No 
exclusion to this study will be based on race.  Minorities will actively be recruited to participate.  
However, based on previous enrollment, we expect about 27% of subjects to be minorities.  
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
3
+
3
=
6
Not Hispanic or Latino
12
+
12
=
24
Ethnic Category: Total of all 
subjects
15
+
15
=
30
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
2
+
2
=
4
Black or African American
3
+
3
=
6


Protocol Version date: 09-15-2020
10
Native Hawaiian or other Pacific 
Islander
0
+
0
=
0
White
10
+
10
=
20
Racial Category: Total of all 
subjects
15
+
15
=
30
(A1 = A2)
(B1 = B2)
(C1 = C2)
Accrual 
Rate:
1
pts/month/site
Total Expected 
Accrual: 
30
Min
43
Max
Projected Start 
Date of Study:
July 1, 2017
3.2
Subject Enrollment
Subjects will be recruited from newly-diagnosed GBM patients referred by neurosurgery, 
neuro-oncology or radiation oncology.  Initial screening will be conducted/reviewed by clinical 
investigators and/or their trained designee (e.g. research nurse, research coordinator, etc.).  
Cases will be identified from the neurosurgery, neuro-oncology and radiation oncology 
outpatient clinics and neurosurgery inpatient service.  
3.3
Patient Selection - Inclusion Criteria: 
3.3.1
Patients must have a newly-diagnosed glioblastoma or gliosarcoma that has been 
confirmed pathologically by a board-certified neuropathologist.  
3.3.2
Patients must be ≥ 18 years of age.  
3.3.3
Patients must be able to have MRI scans.  
3.3.4
Patient must have the following lab values ≤ 14 days prior to registration:  

WBC ≥ 3,000/μL

ANC ≥ 1,500/μL

platelet count of ≥ 75,000/μL

hemoglobin ≥ 9.0 gm/dL (transfusion is allowed to reach minimum level)

SGOT ≤ 2.0x UNL

bilirubin ≤ 2 x UNL

creatinine ≤ 1.5 mg/dL
3.3.5
Patients must have a life expectancy of ≥ 12 weeks.  
3.3.6
Patients must have a Karnofsky Performance Status (KPS) ≥ 60.  
3.3.7
Patients who are women of childbearing potential must have a negative pregnancy test 
documented ≤ 14 days prior to registration. This is not specific to dose escalation and 
is mandatory for standard care for patients being treated with radiation therapy. The 
cost of this test will be covered by standard of care.   
3.3.8
Patients must be able to understand and provide written informed consent.  
3.3.9
Both men and women, and members of all races and ethnic groups are eligible for this 
trial.  Subjects will be approximately representative of the demographics of the referral 
base for the participating institutions.  
3.3.10
Patient must be able to swallow capsules.
3.3.11
Patients must be willing to forego other cytotoxic and non-cytotoxic therapies against 
the tumor while being treated on this protocol.  


Protocol Version date: 09-15-2020
11
3.4
Patient Selection - Exclusion Criteria: 
3.4.1
Patients with pacemakers, aneurysm clips, neurostimulators, cochlear implants, metal 
in ocular structures, history of being a steel worker, or other incompatible implants 
which makes MRI safety an issue are excluded.  
3.4.2
Patients that have any significant medical illnesses that in the investigator’s opinion 
cannot be adequately controlled with appropriate therapy or would compromise the 
patient’s ability to tolerate this therapy are excluded.  
3.4.3
Patients with a history of any other invasive cancer (except non-melanoma skin cancer 
and excluding carcinoma in-situ), unless in complete remission and off of all therapy 
for that disease for ≥ 3 years, are ineligible.  
3.4.4
Patients with an active infection or serious intercurrent medical illness are ineligible.  
3.4.5
Patients receiving any other investigational agents are excluded.  
3.4.6
Patients who have received prior cytotoxic, non-cytotoxic or experimental drug 
therapies for brain tumor are excluded.  
3.4.7
Patients with a history of prior cranial radiation are ineligible.  
3.4.8
Patients may not be enrolled on any other therapeutic trial for which they are receiving 
an anti-tumor therapy.  
3.4.9
Patients with GBMs located in the following anatomical regions known to have 
magnetic susceptibility or poor signal will be excluded:  mesial temporal lobe, 
orbitofrontal cortex, prefrontal cortex, medial frontal gyrus, brainstem, and cerebellum.
3.4.10
The maximum radiation target volume for 75 Gy is 65 cc (per NRG Oncology Guide). 
Patient may be excluded after the first sMRI scan if the 75 Gy volume is greater than 
65 cc [we anticipate that contrast-enhancing tumor volume (residual tumor volume 
following tumor resection) would be less than 20 cc]. 
4.0
PATIENT SAFETY
4.1
Risks associated with dose-escalated RT (research-related).  The risks of dose-escalated 
RT are expected to be similar to the risks of standard dose RT for newly-diagnosed GBMs 
although the incidence may be slightly increased.  Incidence of serious toxicities will be 
carefully monitored in treated patients and is a primary objective of this study. Potential 
toxicities are listed below:
Acute 
Expected adverse events include hair loss, fatigue, and erythema or soreness of the scalp. 
Potential acute toxicities include nausea and vomiting as well as temporary aggravation of brain 
tumor symptoms such as headaches, seizures, and weakness. Reactions in the ear canals and 
on the ear should be observed and treated symptomatically; these reactions could result in 
short-term hearing impairment. Dry mouth or altered taste has been occasionally reported. 
Early Delayed 
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1-3 months after radiotherapy treatment. 
Late Delayed 
Possible late delayed effects of radiotherapy include radiation necrosis, leukoencephalopathy, 
endocrine dysfunction, and radiation-induced neoplasms. In addition, neurocognitive deficits, 
which could lead to mental slowing and behavioral change, are possible. Permanent hearing 
impairment and visual damage are rare. Cataracts can be encountered.


Protocol Version date: 09-15-2020
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4.2
Risks associated with temozolomide (standard care).  The risks related to the use of 
temozolomide are outlined in the information below regarding this drug.  
4.3
Risks associated with sMRI (research-related).  The risks of undergoing sMRIs are the same 
as those with conventional MRI.  Movement or heating of metallic implants is a potential risk, 
and so subjects will be screened to exclude people with metallic implants, fragments, or 
pacemakers.  Some individuals experience claustrophobic reactions in the scanner.  Subjects 
will be informed of this prior to the study, but because it is difficult to predict who will have such 
a reaction, this is not a specific exclusion criterion.  Any subject experiencing claustrophobia or 
discomfort during the study will be removed from the scanner immediately.  There is no invasive 
component to this study and so discomfort, bruising, or infection is not a risk.  Of note, there is 
NO injection of contrast agent.
There may be additional risks associated with scanning at 3T, which are addressed here: 
1.
Effect of the static field.  The FDA has approved, for routine clinical use, scanners up to 
4.0 T.  The scanners that we will be using are FDA approved.  However, the sMRI software 
package being used is experimental and has been provided through a master research 
agreement with the University of Miami.  The software has been used for 10 years in 
numerous clinical studies all over the world. The 3D whole brain MR spectroscopic imaging 
sequence (EPSI/GRAPPA) and the analysis program MIDAS (Metabolic Imaging Data 
Analysis System) was developed by Dr. Andrew Maudsley (scientific PI of U of Miami) in 
2006 [31-42]. The scan will be done in a 3T Siemens MR scanner (TIM/TRIO, Prisma, 
Skyra) or equivalent.  Metabolite maps and their ratio maps will be calculated. Due to some 
degree of variability of Cho/NAA ratio between subjects, we will use the signal from each 
patient’s contralateral normal-appearing white matter for normalization. The sMRI 
measurement has been validated in several previous studies including a recent Neuro-
Oncology article (enclosed in Appendix). Dr. Shim (Emory) has used sMRI to guide tumor 
resection in GBM patients (NCI R21 CA186169; Emory IRB00051663), and has four on-
going clinical studies (Emory IRB00055973, IRB0006545, IRB00073702, and 
IRB00086047) using sMRI.  Dr. Maudsley ran several clinical studies (e.g., Miami 
IRB20020513, IRB20130481, IRB20020513, IRB20020787, IRB20090847, IRB20061005) 
with hundreds of human subjects (normal volunteers and patients). In addition, sMRI has 
been used worldwide by numerous investigators. Since 2016, we began to use a web-
based sMRI clinical interface to extract information from MIDAS to visualize the metabolite 
maps for easier clinical workflow of the MIDAS results for busy clinicians. In addition, this 
web-based tool allows efficient data sharing among imaging scientists and clinicians for 
consultation and storage of de-identified data sets. sMRI studies will be obtained at the 
schedule outlined in section 7.1. There is no conclusive evidence for irreversible or 
hazardous bioeffects to acute, short-term exposures of humans up to 3.0 T.  Studies have 
indicated some mild side-effects at 7.0 T, including nausea, vertigo, and metallic taste 
when moving into or out of the scanner.  However, there is no evidence that this is either 
irreversible or harmful.  If subjects experience unusual sensations, they will be withdrawn.
2.
Effect of the gradient field.  MRI operates by rapidly changing small additional fields, called 
gradients.  By Faraday’s induction law, a changing magnetic field will induce electrical 
currents in any conductor.  Thus, rapid cycling of the gradient field can induce peripheral 
nerve stimulation.  However, this is not substantially different at higher magnetic fields 
since the gradients are separate from the main magnet.  If subjects experience peripheral 
nerve stimulation, e.g. tingling or twitching, they will be withdrawn.  
3.
Effect of the RF electromagnetic field.  The fundamental principle of MRI is that protons 
are excited by sending in an RF pulse at their resonant frequency for the magnetic field.  
The FDA provides guidelines for the safe use of MR systems, which includes specific 
recommendations for how much RF power is safe.  The “specific absorption rate”, or SAR 
is the mass normalized rate at which RF power is coupled to biologic tissue and is typically 
indicated in units of watts per kilogram (W/kg) (NRCP, 1986).  The FDA provides 
recommendations for two alternative safe levels of exposure to RF radiation during MR 


Protocol Version date: 09-15-2020
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procedures, primarily to control the risk of systematic thermal overload (heating) and local 
thermal injury.  These are (FDA, 1988): 
a.
The exposure to RF energy below the level of concern is an SAR of 0.4 W/kg or less 
averaged over the body, and 8.0 W/kg or less spatial peak in any 1 g of tissue, and 3.2 
W/kg or less average over the head; or 
b.
The exposure to RF energy that is sufficient to produce a core temperature increase 
of 1oC and localized heating to no greater extent than 38oC in the head, 39oC in the 
trunk, and 40oC in the extremities, except for patients with impaired systemic blood 
flow and/or perspiration.  
We will adhere to the recommendations for the head, which is also monitored by Siemens’ built 
in monitor.  
5.0
PHARMACEUTICAL INFORMATION
5.1
Temozolomide (NSC# 362856) (Standard Care)
5.1.1
Chemical 
Name: 
3.4-Dihydro-3-methyl-4-oxoimidazo-[5,1-d]-1,2,3,5-tetrazin-8-
carboxamide. (Former name includes 8 carbamoyl-3-methylimidazo-5,1-d] 1.2.3.5-
tetrazin-4-(3H)-one.  
5.1.2
Other Names: Temodar 
5.1.3
Mechanism of Action: Temozolomide is not directly active but undergoes rapid non-
enzymatic conversion at physiologic pH to the reactive compound MTIC.  The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA.  Alkylation 
(methylation) occurs mainly at the O6 and N7 positions at guanine.  
5.1.4
Pharmacokinetics: Temozolomide is rapidly and completely absorbed after oral 
administration; peak plasma concentrations occur in 1 hour.  Food reduces the rate 
and extent of temozolomide absorption.  Mean peak plasma concentration and AUC 
decreased by 32% and 9%, respectively, and Tmax increased 2-fold (from 1.1 to 2.25 
hours) when temozolomide was administered after a modified high-fat breakfast.  
Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hours and 
exhibits linear kinetics over the therapeutic dosing range.  Temozolomide has a mean 
apparent volume of distribution of 0.4 L/kg (%CV=13%).  It is weakly bound to human 
plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.  
5.1.5
Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at 
physiologic pH to the active species MTIC and to temozolomide acid metabolite.  MTIC 
is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be 
an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which 
is believed to be the active alkylating species.  Cytochrome P450 enzymes play only a 
minor role in the metabolism of temozolomide and MTIC.  Relative to the AUC of 
temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.  
Approximately 38% of the administered temozolomide total radioactive dose is 
recovered over 7 days: 37% in urine and 0.8% in feces.  The majority of the recovery 
of radioactivity in urine is as unchanged temozolomide (5.6%), AIC (12%), 
temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). 
Overall clearance of temozolomide is ~5.5 L/hr/m.  
5.1.6
Pharmaceutical Data: Temozolomide (Temodar®) is supplied in white, opaque, 
preservative free, 2-piece, hard gelatin capsules in the following p.o. dosage strengths: 
5 mg, 20 mg, 100 mg, and 250 mg.  Capsules should not be opened or chewed. If 
capsules are accidentally opened or damaged, inhalation or contact with the skin 
should be avoided.  Each capsule contains drug substance in combination with lactose, 
anhydrous NF, colloidal silicon dioxide NF, sodium starch glycolate NF, tartaric acid 


Protocol Version date: 09-15-2020
14
NF, and stearic acid NF.  The capsule shells contain gelatin NF, titanium dioxide USP, 
and sodium lautyl sulfate NF.  
5.1.7
Storage and Stability: Temozolomide should be stored at room temperature.  The 
capsules are packaged in 30 cc 28 mm-48-Type I amber glass bottles (30 
capsules/bottle) and should be stored between 2 and 30 degrees Centigrade.  
Capsules are stable for at least 30 months when stored in amber glass bottles at this 
temperature.  
5.1.8
Route of Administration: Temozolomide should be taken by mouth after fasting from 
solid food for 2 hours.  
5.1.9
Drug Source: Temozolomide has been approved by the FDA for refractory anaplastic 
astrocytomas and newly-diagnosed glioblastoma.  Patients or third party payers must 
pay for the Temozolomide.  If the patient is unable to pay for the drug, he/she may 
seek assistance through Schering-Plough Pharmaceutical’s Commitment to Care 
Program.  
5.1.10
Adverse Reactions: The most common reactions to temozolomide include nausea, 
vomiting, headache, fatigue and hematologic effects.  These events are usually mild 
to moderate.  Nausea and vomiting is usually readily controlled with antiemetics. 
Myelosuppression (thrombocytopenia and neutropenia) is the dose-limiting side effect.  
It usually occurs within the first few cycles of therapy and is not cumulative.  In prior 
studies, myelosuppression occurred late in the treatment cycle and returned to normal, 
on average, within 14 days of nadir counts.  Other less common side effects may 
include somnolence or insomnia, anorexia, constipation, diarrhea, weight loss, 
abdominal pain, rash, pruritis, anxiety, depression, pain when swallowing, 
hyperglycemia, epistaxis, empyema, pulmonary edema, respiratory insufficiency, 
respiratory arrest, cardiac arrest, toxic hepatitis, liver or kidney abnormalities and/or 
breast tumors.  
The information provided in the consent includes the following:
Likely side effects:

Nausea and vomiting, especially on the first day of each cycle.  It may be necessary to use 
medication to prevent this.

Constipation 

Loss of appetite

Lowering of your blood counts, which may result in 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 (e.g., dexamethasone).  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 platelet transfusions.  Low red blood cells can also be treated with transfusions.  

Fatigue, lethargy, insomnia, weakness

Headache

Hair loss and rash
Less Likely side effects:

Kidney problems and high blood sugar

Abnormal liver tests and diarrhea


Protocol Version date: 09-15-2020
15

Recently, cases of hepatic injury, including fatal hepatic failure, have been observed in patients 
enrolled in clinical studies utilizing the agent temozolomide. In addition, it was noted that liver 
toxicity may occur several weeks or more after initiation of treatment or after temozolomide 
discontinuation. Refer to the package insert for additional information on adverse events observed 
to date.
A tabular summary of side effects follows:
Concomitant 
Phase RT Alone
(n=285)
Concomitant Phase 
RT+TMZ 
(n=288)*
Maintenance Phase 
TNZ
(n=224)
 
All
Grade ≥ 
3
All
Grade ≥ 3
All
Grade ≥ 3
Subjects Reporting 
any Adverse 
Reaction
258 (91) 74
(26)
266 (92)
80
(28)
206 (92)
82
(37)
Body as a Whole - General Disorders
  Anorexia
25
(9)
1
(< 1)
56
(19)
2
(1)
61
(27)
3
(1)
  Dizziness
10
(4)
0
 
12
(4)
2
(1)
12
(5)
0
 
  Fatigue
139 (49) 15
(5)
156 (54)
19
(7)
137 (61)
20
(9)
  Headache
49 (17) 11
(4)
56
(19)
5
(2)
51
(23)
9
(4)
  Weakness
9
(3)
3
(1)
10
(3)
5
(2)
16
(7)
4
(2)
Central and Peripheral Nervous System Disorders
  Confusion
12
(4)
6
(2)
11
(4)
4
(1)
12
(5)
4
(2)
  Convulsions
20
(7)
9
(3)
17
(6)
10
(3)
25
(11)
7
(3)
  Memory Impairment
12
(4)
1
(< 1)
8
(3)
1
(< 1)
16
(7)
2
(1)
  Disorders of the Eye
 
 
 
 
 
 
 
 
 
 
 
 
  Vision Blurred
25
(9)
4
(1)
26
(9)
2
(1)
17
(8)
0
 
Disorders of the Immune System
  Allergic Reaction
7
(2)
1
(< 1)
13
(5)
0
 
6
(3)
0
 
Gastrointestinal System Disorders
  Abdominal Pain
2
(1)
0
 
7
(2)
1
(< 1)
11
(5)
1
(< 1)
  Constipation
18
(6)
0
 
53
(18)
3
(1)
49
(22)
0
 


Protocol Version date: 09-15-2020
16
  Diarrhea
9
(3)
0
 
18
(6)
0
 
23
(10)
2
(1)
  Nausea
45 (16)
1
(< 1) 105 (36)
2
(1)
110 (49)
3
(1)
  Stomatitis
14
(5)
1
(< 1)
19
(7)
0
 
20
(9)
3
(1)
  Vomiting
16
(6)
1
(< 1)
57
(20)
1
(< 1)
66
(29)
4
(2)
Injury and Poisoning
  Radiation Injury NOS
11
(4)
1
(< 1)
20
(7)
0
 
5
(2)
0
 
Musculoskeletal System Disorders
  Arthralgia
2
(1)
0
 
7
(2)
1
(< 1)
14
(6)
0
 
  Platelet, Bleeding and 
Clotting Disorders
3
(1)
0
 
11
(4)
8
(3)
19
(8)
8
(4)
Thrombocytopenia Psychiatric Disorders
  Insomnia
9
(3)
1
(< 1)
14
(5)
0
 
9
(4)
0
 
Respiratory System Disorders
  Coughing
3
(1)
0
 
15
(5)
2
(1)
19
(8)
1
(< 1)
  Dyspnea
9
(3)
4
(1)
11
(4)
5
(2)
12
(5)
1
(< 1)
Skin and Subcutaneous Tissue Disorders
  Alopecia
179 (63)
0
 
199 (69)
0
 
124 (55)
0
 
  Dry Skin
6
(2)
0
 
7
(2)
0
 
11
(5)
1
(< 1)
  Erythema
15
(5)
0
 
14
(5)
0
 
2
(1)
0
 
  Pruritus
4
(1)
0
 
11
(4)
0
 
11
(5)
0
 
  Rash
42 (15)
0
 
56
(19)
3
(1)
29
(13)
3
(1)
Special Senses Other, Disorders
  Taste Perversion
6
(2)
0
 
18
(6)
0
 
11
(5)
0
 
*One patient who was randomized to RT only arm received RT+temozolomide.
RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified.
Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥ 3 column. 
Source:  http://www.rxlist.com/temodar-drug.htm
Please refer to the package insert for additional information.  
5.1.12
Summary of Background: Temozolomide (TMZ, Temodar®) is an orally administered 
alkylating agent with activity against malignant gliomas.  It is a prodrug that 


Protocol Version date: 09-15-2020
17
spontaneously converts at physiologic pH to the active alkylating agent 5-(3-
methyltriazen-1-yl)imidazole-4-carboximide (MTIC) under physiologic conditions. The 
cytotoxicity of temozolomide is principally mediated through methylation of DNA at the 
O6 position of guanine (Investigational Brochure-Temozolomide).  
5.1.13
Effects of Temozolomide on Glioma Cells: The alkylating agents temozolomide and 
BCNU are mainstays of adjuvant therapy for malignant glioma.  Temozolomide 
functions primarily as an alkylating agent inducing methylation of the O-6 residues of 
guanine, generating mismatch pairing and leading to futile DNA mismatch repair 
possibly with strand breaks [22].  The biologic consequences of these molecular effects 
of the agent include alterations in the cell cycle kinetics and induction of apoptosis.  
These effects have been demonstrated in a variety of malignant cells particularly in 
hematopoietic malignancies in vitro and are believed to be the mechanisms of action 
of the agent in humans as well.  Studies focusing on the effects of this agent against 
gliomas are fewer but have shown that mechanisms similar to those for hematogenous 
malignancies are operative in this tumor type as well.  The cell cycle changes induced 
by temozolomide are of particular relevance to the rationale for this trial proposal.  In 
vitro studies have shown that temozolomide induces a prolonged G2/M arrest 
associated with an increase in p53 and p21 protein levels [23].  The cells showed 
decreased proliferation by a clonogenic assay and exhibited features of senescence 
in cells with wild type p53; in cells with deficient p53, a transient G2/M arrest was 
followed by induction of apoptosis possibly by mitotic catastrophe.  The induction of 
G2/M arrest in glioma cells has been associated with Chk1 activation and inhibitory 
phosphorylation of cdc25c and cdc2 inactivating the cyclin B1/cdc2 complex necessary 
for progression of the cell cycle from G2 to M phase [23].  Pharmacologic inhibition of 
Chk1 or of the p38MAPK pathways sensitized glioma cells to temozolomide-induced 
apoptosis.  These data suggest the biologic effects of temozolomide are related to the 
cell cycle changes and apoptosis induced by this agent.  
5.1.14
Temozolomide Clinical Experience:
5.1.14.1
Adult Phase I/II Studies of Temozolomide: As a result of the encouraging 
preclinical data, a phase I trial with temozolomide was conducted by the 
Cancer Research Campaign (CRC) Phase I-II Clinical Trials Unit in the 
United Kingdom (UK).  This trial was conducted in two phases. The first 51 
patients were treated with temozolomide administered either orally or 
intravenously, using a single-dose schedule.  The subsequent 133 patients 
received a 5-day oral schedule.  Cycles of temozolomide were repeated 
every 28 days.  The total doses administered over 5 days were 750, 900, 
1000, and 1200 mg/m2.  Dose-limiting toxicity was myelosuppression and 
the maximum tolerated dose (MTD) was defined at 1000 mg/m2.  Only one 
course was administered at 1200 mg/m2 and resulted in Grade 4 
myelotoxicity.  The nadir for hematologic parameters of neutropenia or 
thrombocytopenia usually occurred at 21 days or later following the first dose 
of each cycle with recovery to at least Grade 1 by 28 days.  Overall, Grades 
1 to 4 anemia, leukopenia and thrombocytopenia occurred in 17%, 12% and 
9% of the evaluable courses, respectively.  Grade 3 and 4 thrombocytopenia 
and leukopenia occurred in 4% and 3% of the evaluable courses, 
respectively, and were primarily seen at doses >1000 mg/m2.  Mild to 
moderate (Grades 1 and 2) nausea and vomiting were reported in 28% of 
the evaluable courses at doses up to 750 mg/m2, inclusive.  These events 
were usually limited to day 1 and were readily controlled with standard 
antiemetics.  At higher doses (>750-1200 mg/m2), Grades 3 and 4 nausea 
and vomiting were seen in 9% of the evaluable courses.  The percentages 
of adverse events reported included: constipation (10%), headache (5%), 
rash (4%), renal disorders (3%), elevated hepatic enzymes (3%), alopecia 


Protocol Version date: 09-15-2020
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(2%), diarrhea (2%), itching and burning (<1%), lethargy (<1%), altered 
consciousness (<1%), and esophagitis (<1%).  
Based on this study, the recommended starting dose of temozolomide for 
Phase II trials was 150 mg/m2/day, orally, once a day for 5 days (total dose 
750 mg/m2) for the first cycle with subsequent dose escalation to 200 
mg/m2/day, once a day for 5 days (total dose 1000 mg/m2) in the absence 
of myelotoxicity.  The CRC subsequently conducted three Phase II trials of 
temozolomide in patients with documented progression who had either high-
grade glioma, advanced malignant melanoma, or low-grade non-Hodgkin’s 
lymphoma (Investigator's Brochure -Temozolomide. Schering Plough) [24].  
Activity in these tumor types was reported in all three studies.  
5.1.14.2
Temozolomide for Recurrent Malignant Gliomas:  A randomized trial was 
conducted to compare the efficacy of temozolomide with procarbazine in 
patients with GBM at first relapse [25].  Patients were randomized to 
temozolomide administered orally once daily for 5 days at a starting dose of 
either 200 mg/m2/day (no prior chemotherapy) or 150 mg/m2/day (prior 
chemotherapy) every 28 days, or procarbazine 150 mg/m2/day for 28 days 
every 56 days.  Temozolomide performed better than procarbazine in terms 
of progression free survival (PFS), overall survival and objective response 
to treatment, although the differences were modest.  The 6-months 
progression free survival (6M-PFS) was 21% in the temozolomide group 
compared to 8% in the procarbazine group (p=0.008).  In comparison, the 
6M-PFS for GBM patients in 8 negative phase II trials from MD Anderson 
Cancer Center was only 15% (Wong et al, 1999).  Median PFS was 2.89 
months with temozolomide compared to 1.97 months with procarbazine.  
The median overall survival for the intent-to-treat population of 
temozolomide recipients with GBM (7.34 months) was longer than for 
procarbazine recipients (5.82 months).  5.4% of TMZ patients and 5.3% of 
procarbazine patients had a PR, while 40.2% of temozolomide patients and 
27.4% of procarbazine patients had SD.  The overall response rate (PR + 
SD) was 45.6% in the temozolomide group and 32.7% in the procarbazine 
group [25].  The most common grade 3 or 4 toxicities in the temozolomide 
group were headache (10%), thrombocytopenia (7%), neutropenia (4%), 
fatigue (3%), vomiting (4%) and nausea (4%).  Quality of life was significantly 
better in the temozolomide group.  
In another trial, the efficacy of temozolomide for AA at first relapse was 
evaluated in a phase II study consisting of 162 patients [24].  Temozolomide 
was administered once daily for 5 days every 28 days at a starting dose of 
either 200 mg/m2/day in patients who had received no prior chemotherapy 
or 150 mg/m2/day in patients who had received prior chemotherapy.  8% of 
patients experienced a CR, 27% had a PR and 26% had SD, producing an 
overall response rate of 61%. 6M-PFS was 46% compared to 31% from the 
MD Anderson database of 8 negative phase II trials for recurrent AA [26].  
The MTP was 5.4 months and the median survival was 14.6 months.  Both 
overall response and maintenance of progression-free status were 
associated with health-related quality-of-life benefits, independent of steroid 
use [27].  Based on these results, temozolomide was approved by the FDA 
for the treatment of recurrent AA in 1999.  Over the past few years TMZ has 
become the treatment of choice for patients with recurrent malignant 
gliomas.  However, the responses tend to be modest and short-lived. 
Several different schedules have been evaluated but none have been clearly 
superior to the standard regimen [28].  There is significant interest in 
combining temozolomide with other agents to increase its effectiveness.  


Protocol Version date: 09-15-2020
19
5.1.14.3
Temozolomide for Newly Diagnosed Glioblastomas: Based on 
preclinical evidence that temozolomide has additive activity when combined 
with radiation therapy (RT) [29], Stupp et al., conducted a phase II study in 
which 64 patients with newly-diagnosed GBM were treated with 
temozolomide 75 mg/m2/d x 6 weeks with concomitant fractionated RT (60 
Gy; 2 Gy x 5d/wk for 6 weeks) followed by temozolomide adjuvant therapy 
(200 mg/m2/d x 5 days every 28 days for 6 cycles) [30].  This regimen was 
well-tolerated and the median survival of 16 months was significantly better 
than the historic median survival of GBM of 9-12 months.  As a result of 
these promising results, the European Organization for Research and 
Treatment of Cancer (EORTC) and the National Cancer Institute of Canada 
(NCIC) conducted a randomized phase III trial (EORTC Study 26981) of 573 
patients comparing this regimen of concomitant and adjuvant temozolomide 
and radiation therapy to radiation therapy alone in patients with newly-
diagnosed GBM [1, 2].  This study showed that the combination of 
temozolomide with radiation therapy was well-tolerated and resulted in a 
survival benefit.  The median survival of patients treated with temozolomide 
+ radiation therapy was increased compared to radiation therapy alone (14.6 
mo v.12.1 mo; p< .0001).  In addition, patients receiving temozolomide with 
radiation therapy had a significantly higher percentage of patients surviving 
at two years (26%) than patients receiving radiation therapy alone (10%).  
This study conclusively demonstrated for the first time that adjuvant 
chemotherapy is of benefit in patients with GBM.  
6.0
REGISTRATION PROCEDURES
6.1
Patient registration
6.1.1
Pre-registration: Emory: Pre-registration must be completed and sent to the Central 
Subject Registrar and to the Office of Clinical Research.  After receipt of the pre-
registration form and confirmation of a valid, signed informed consent form/HIPAA 
authorization form, the Winship Clinical Trials office will assign a patient study number.
Participating site(s): After each subject signs consent, the Central Subject 
Registration form is to be completed and sent to Winship Clinical Trial Office within 48 
hours of consent. This form, along with the valid, signed informed consent form/HIPAA 
authorization form, is to be faxed or emailed to Winship’s Central Subject Registrar per 
instructions on the form. The Winship Clinical Trials office will assign a patient study 
number to these patients.
6.1.2
Patient study number assignment/confidentiality: Subjects will be assigned a 
coded designation according to the site at which the subject signs consent. (QTR01, 
the site initials, and enrollment number entered on study will be assigned 
QTR01EM001).  Actual names, contact information and relationship to this code will 
be kept secure in the Winship Clinical Research Office.  
6.1.3
Registration: Participating site(s): The Eligibility checklist is to be printed from OnCore 
and verified by 2 people, of which one must be a clinical investigator or co-investigator. 
The completed and signed eligibility checklist along with all redacted supporting source 
documentation must be submitted to the Winship Multi-site Coordinator or designee 
(fax 404-778-5033) within 14 days after pre-registration but no later than 2 business 
days from scheduled treatment visit.  Eligibility will be confirmed by a clinical principal 
or co-investigator and the Multi-site Coordinator or designee within 2 business days of 
receipt of all eligibility documentation and confirmation will be sent to the participating 
site along with cohort assignment, if subject meets criteria. Once eligibility is confirmed, 
then patient will be registered and scheduled for appropriate appointments.
6.2
Investigator registration/requirements: Prior to recruitment of subjects to this trial, 


Protocol Version date: 09-15-2020
20
investigators must complete training as required per institutional IRB for participation on clinical 
trials along with protocol specific training.  Each investigator must be registered (FDA Form 
1572 with original signature, current CV, Supplemental Investigator Data Form with signature, 
and Financial Disclosure Form with original signature) and maintain an “active” registration 
status.  
6.3
Site registration/requirements
6.3.1
IRB: IRB approval for this study will be obtained and maintained for the duration of the 
study treatment and follow up times.  Documentation of initial and continued IRB 
approval will be submitted to the Winship Clinical Research Office.  
6.3.2
Radiation Therapy: All institutions participating on this trial will need to be credentialed 
to use IMRT on the study.  Previous credentialing for cooperative group and/or 
consortium trials (eg. RTOG/NRG, ABTC, etc.) is acceptable.  
6.3.3
Neurocognitive certification: All study staff that will be administering neurocognitive 
testing will need to be certified as specified in section 7.2.1.  Previous certification for 
administering these tests on other studies is acceptable after submission of 
documentation to the Winship Clinical Research Office.  
7.0
STUDY EVALUATIONS
7.1
Summary of Active Monitoring Schedule
Chemoradiation
(RT+TMZ, 6 weeks)
Tests and 
procedures
Pre-
reg
21 days 
prior to 
start of 
therapy
1
2
3
4
5
6
Adjuvant TMZ 
Cycles 1-129
7 days 
before each 
cycle 
After 
completion of 
adjuvant TMZ 
Path diagnosis
X
H&P, weight, 
KPS
X
X7
X7
X7
X
X12
Height
X
Neuro exam
X
X7
X7
X7
X
X12
Adverse event 
assessment
X
X5
X5
X5
X5
X5
X5
X
X12
Rad Onc consult
X3
Neuro Onc 
consult
X3
CBC w/diff
X
X5
X5
X5
X5
X5
X5
X
CMP1
X
X5
X5
X5
X5
X5
X5
X
MRI w/contrast2
X
X10
X12
sMRI
(Research)
X
X8
Steroid/anti-
Sz/chemo med 
documentation
X
X6
X6
X6
X6
X6
X6
X
Neurocognitive 
and QOL 
assessments
(Research)
X
X11
X11
Pregnancy test
X4


Protocol Version date: 09-15-2020
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1 Comprehensive Metabolic Panel (CMP) - Sodium, potassium, bicarbonate, chloride, BUN, creatinine, 
calcium, glucose, total bilirubin, SGOT (AST), SGPT (ALT), alkaline phosphatase, albumin, total protein 
(Standard care). The frequency of CMP will be up to the treating physician’s discretion.  
2 Standard diagnostic brain MRI w/ & w/o contrast.
3 Either Rad Onc or Neuro Onc consultation needs to be completed at pre-registration.  The other 
consultation can be completed  21 days before initiation of therapy. (Standard care) 
4 To be completed only in women of childbearing potential.  Test obtained  21 days prior to registration.  
May use a test result obtained for other clinically warranted indications if the test date is within the 
above time window. (Standard care)
5 To be assessed during chemoradiation.  (Standard care)
6 Document steroids, anti-seizure, and temozolomide meds weekly during cycle 1.  (Standard care)
7 To be performed every other week starting on week 2 of chemoradiation.  (Standard care)
8 sMRI should be performed during the 3rd week of chemoradiation (after 10 fractions up to 15 fractions, 
or prior to receiving the 16th fraction).  (Research)
9 TMZ cycles will be determined at treating physician’s discretion. (Standard care)
10 Standard diagnostic brain MRI w/ & w/o contrast to be completed  7 days prior to starting each odd 
number cycles.  (Standard care)
11 To be performed every 6 months (± 1 month) after pre-cycle 2 assessment until progression (will 
attempt be obtain final assessment only if date of progression is > 3 months from previous 
assessment) or until approximately 2 years after pre-cycle 2 assessment (maximum of 4 additional 
assessments).  (Research activity)
12 Follow-ups and standard diagnostic brain MRI w/ & w/o contrast to be completed 1 month (± 2 weeks) 
after completion of adjuvant TMZ chemotherapy and then every 3 months (± 2 weeks) (until 
approximately 2 years after RT).  Subsequent followups/MRIs will be determined by treating physician.  
(Standard care)
7.2
Neurocognitive Testing (Research)
7.2.1
Certification: All members of the study team that will be administering the 
neurocognitive tests will need to be certified.  Previous certification in the prior two 
years is acceptable. If necessary, refresher certification will be provided to any study 
personnel that are uncertain about test administration even if they have undergone 
certification within the past two years.  This certification process will be under the 
direction of Dr. Drenna Waldrop-Valverde (404-712-9487). 
7.2.2
Timing of Assessments: Evaluations will be performed  21 days before starting 
chemo radiation (may complete as late as day 1 of RT/TMZ), ≤ 7 days prior to initiation 
of cycle 1 of adjuvant TMZ, and every 6 months (± 1 month) thereafter for 
approximately 2 years after RT completion.  (See Table in section 7.1)  In case of 
disease progression within 2 years from cycle 1, patients will be re-tested for the final 
time only if previous assessment was > 3 months from date of progression.  
7.2.3
Tests to be administered: Hopkins Verbal Learning Test – Revised (HVLT-R), 
Controlled Oral Word Association test from the Multilingual Aphasia Examination 
(COWA), Trail Making Test A and B, and Recall and Recognition of Word List encoded 
from the HVLT-R. 
7.3
Quality-of-Life (QOL) Testing (Research): These questionnaires have been validated in the 
brain tumor population and used in other large, prospective studies for this patient population, 
providing a good potential comparison group for patients on this study.  Subjects can opt out 
of this assessment if they so choose.
7.3.1
Timing of Assessments: Evaluations will be performed  21 days before starting 
chemo radiation (may complete as late as day 1 of RT/TMZ), ≤ 7 days prior to initiation 
of cycle 1 of adjuvant TMZ, and every 6 months (± 1 month) thereafter for 


Protocol Version date: 09-15-2020
22
approximately 2 years after RT completion.  (See Table in section 7.1)  In case of 
disease progression within 2 years from cycle 1, patients will be re-tested for the final 
time only if previous assessment was > 3 months from date of progression.    
7.3.2
QOL Questionnaires: EORTC Quality of Life Questionnaire-Core 30/Brain Cancer 
Module-20 (EORTCQLQ30/BN20); M. D. Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT) 
8.0
TREATMENT PLAN
8.1
Radiation Therapy
8.1.1
Timing of Radiotherapy: RT must begin ≤ 50 days from resection. Daily oral 
temozolomide will start together with the first day of radiation.  RT may start on M-Th.  
Temozolomide is given every day during course RT (M-Su) up to a total of 42 doses 
(may halt as early as 40 doses if RT is completed prior to 42 dose course). 
8.1.2
Certification: IMRT or VMAT technique will be used for all cases. To utilize IMRT or 
VMAT on this study, proper credentials are required.  Previous certification by the 
Radiological Physics Center (RPC) for use of IMRT or VMAT on another protocol is 
acceptable.  
8.1.3
Radiation Energy: Minimum photon energy is 6 MV with IMRT or VMAT plans 
designed and verified by simulation.  Minimum SSD or SAD is 80 cm. 
8.1.4
Target Volume Definitions
8.1.4.1
ICRU Definitions: ICRU terminology defines the gross tumor volume (GTV) 
and clinical tumor volume (CTV) as the extent of gross and microscopic 
disease, respectively. The planning target volume (PTV) is geometrically, 
not anatomically, defined and is an expansion of the CTV intended to 
account for uncertainty in patient positioning.
8.1.4.2
GTV1: This volume encompasses the edema and T2 hyper-intensity 
surrounding the main tumor mass as estimated from the T2-weighted or 
FLAIR postoperative MRI scan.  By definition, this volume will also include 
all of GTV2 and GTV3.
8.1.4.3
GTV2: This volume encompasses the post-operative resection cavity (as 
seen on both T1 post-contrast and T2 sequences) plus any contrast 
enhancing volume or mass that is considered likely to represent residual 
enhancing tumor.  Fusion of the pre-operative T1-weighted, contrast 
enhanced MRI is also encouraged to allow comparison with RT planning 
MRI to ensure inclusion of the pre-operative localized contrast-enhancement 
or mass within the GTV2. GTV2 may be modified to account for anatomic 
changes post-operatively to respect the anatomic structures within which the 
tumor was initially bound.  For example, if a large tumor with mass effect has 
been resected, anatomically distant brain parenchyma may post-operatively 
be within the fusion-generated GTV2.  GTV2 may be modified to exclude 
geographically distant brain parenchyma in this situation.  By definition, this 
volume will also include all of GTV3.  
8.1.4.4
GTV3: This volume will encompass the volume of Cho/NAA ratio ≥ 2x 
contralateral normal brain from the pre-RT sMRI scan plus any T1 contrast 
enhancing residual seen on the post-operative and pre-RT diagnostic brain 
MRIs. This can be modified at discretion of treating physician(s) with 
consultation with other investigator(s), as needed. 
8.1.4.5
CTV1: This volume includes GTV1 plus a 5 mm margin (at discretion of 
treating radiation oncologist).  CTV1 may be anatomically confined, for 


Protocol Version date: 09-15-2020
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example, to within the calvarium.  However, high grade gliomas can invade 
most intracranial structures and should not be confined by the tentorium or 
an arbitrary midline.  This expansion can be excluded from the brainstem 
and optic chiasm/nerves at the treating physician’s discretion if there is not 
felt to be risk of extension into these regions.  By definition, this volume will 
completely encompass CTV2 and CTV3
8.1.4.6
CTV2: This volume includes GTV2 plus a 5 mm margin cropped to be 
completely encompassed by CTV1.  By definition, this volume will also 
completely encompass CTV3.  
8.1.4.7
CTV3: This volume includes GTV3 with no margin cropped to be completely 
encompassed by CTV1 and CTV2.
8.1.4.8
PTV1, PTV2 and PTV3: These volumes are uniform 3 mm expansions of 
CTV1, CTV2 and CTV3, respectively, to account for set-up uncertainty.  It is 
not confined anatomically, with the exception of cases that would otherwise 
exceed normal tissue tolerance (see below for normal tissue dose 
constraints). 
8.1.5
Prescription Isodose: The prescription isodose surface (100% dose curve) shall 
encompass a minimum of 95% of the PTV.  In addition, the entire PTV shall be 
encompassed by the 95% isodose surface.  The dose uniformity guidelines below must 
be met for all PTVs. 
8.1.6
Tissue Heterogeneity: Calculations to take into account the effect of tissue 
heterogeneities are required.  
8.1.7
Target Dose
8.1.7.1
Prescription dose for IMRT or VMAT techniques: Patients will be treated 
with a simultaneous in-field boost plan.  PTV1 will receive 5010 cGy in 30 
fractions of 167 cGy per day. PTV2 will simultaneously receive 6000 cGy in 
30 fractions of 200 cGy per day.  PTV3 will simultaneously receive 7500 cGy 
in 30 fractions of 250 cGy per day.
8.1.8
Dose Uniformity: The entire PTV shall be encompassed within the 95% isodose 
surface as evaluated by dose volume histogram.  Does plan should try to achieve 99% 
of PTVs receive at least 95% of prescription dose unless coverage needs to be 
compromised to meet OAR constraints. In addition, no part of PTV3 shall receive more 
than 110% of the prescription dose (8250 cGy) and ≤ 10% of PTV3 shall receive more 
105% of the prescription dose (7875 cGy).  
8.1.9
Time Considerations: Patients will receive one treatment per day, five days per week.  
All fields will be treated each day.  At least two fractions must be given during the first 
week of treatment.  
8.1.10
Simulation: A conventional CT or MRI simulator will be used for patient simulation.  
The patient shall be treated in the supine position with a head-holding device that is 
transparent to x-rays (thermoplast masks, bite-block, etc.) to ensure adequate 
immobilization and reproducible daily setup of the treatment position.  
8.1.11
Organs at Risk (OARs): When possible, without shielding GTV/CTV/PTV, the listed 
OARs should not receive more than the following doses: 
brainstem  6000 cGy (95% of volume  5400 cGy)
optic nerves and optic chiasm  5500 cGy (99% of volume   5400 cGy)
retina  4000 cGy
cervical spinal cord  5000 cGy


Protocol Version date: 09-15-2020
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lens  500 cGy  
No more than 1% or 1 cc of unspecified tissue outside of the PTV should receive > 
110% of the prescribed dose.  Planning organ at risk volumes (PRVs) are 
recommended such that the spinal cord should have 3-dimensional expansion by 5 
mm while the optic nerves, optic chiasm, and brainstem should have a 3-dimensional 
expansion by at least 1 mm.  The dose constraints to the PRVs will be the same as for 
their respective OARs as outlined above.  Higher priority OARs (higher priority than 
PTV coverage) include: brainstem, cervical spinal cord, optic nerves and optic chiasm 
as defined above.  In these cases, PTV coverage will be compromised to keep OARs 
dosing within the above constraints.  Lower priority OARs (lower priority than PTV 
coverage) include: parotids (entire volume) ≤ 10 Gy; oral cavity/lips/nasal cavity mean 
dose  20 Gy and < 1% receiving > 40 Gy; inner/middle ear mean dose  30 Gy and < 
1% receiving > 50 Gy; and lens/retina as defined above.  For example (for the lower 
priority OARs), typically 100% of the parotids should receive  10 Gy, but tumor 
coverage is of higher priority leading to cases where this dose may exceed 10 Gy.  
8.1.12
IMRT or VMAT Plan Verification: The monitor units used for the IMRT or VMAT plan 
must be independently checked prior to the patient’s first treatment.  Measurements in 
a QA phantom can suffice for a check as long as the plan’s fluence distribution can be 
re-computed for a phantom geometry.  
8.1.14
Verification of treatment set-up: Orthogonal pair of reference films is sufficient for 
the initial and subsequent ports.  While setup checks using orthogonal pairs are 
required at least weekly, use of daily kV OBI equipment to check and reset the 
isocenter is encouraged.  
8.2
Treatment schedule
Concurrent RT/TMZ (~42 days + 4-6 week break)
Agent
Dose level
Route
Schedule
RT
75 Gy
Ext. beam
1x/day on M-F for 30 txs, may start M-Th
TMZ
75 mg/m2
Oral
1x/day, 7 days/week on M-Su during RT1
4-5 week treatment break after completion of RT2
Adjuvant TMZ, Cycles 1-12 (28 days) at the discretion of the treating physician (Standard)
1  TMZ will start with 1st RT treatment.  If RT is extended due to holidays or unplanned breaks, up to 
7 additional doses of TMZ can be given (up to 49 days).  While a typical TMZ course will involve 
42 days, the last dose will be on the last day of RT.  This may result in as few as 40 days of TMZ 
if the first day of RT falls on a Monday and there are no breaks resulting in completion of RT on 
Friday of the 6th week of therapy.  
2 Rest period may extend longer depending on dose limiting toxicity.  
8.2.1
Administration of temozolomide (Standard care): TMZ dosing will be based on 
actual body weight.  The smallest TMZ capsules are 5 mg.  Therefore, patient doses 
of TMZ will be rounded to the nearest interval of 5 mg.  TMZ capsules should be taken 
preferably in the morning for the concurrent RT/TMZ course with up to 200 mL of water 
on an empty stomach one hour before or two hours after food.  Evening/night dosing 
of TMZ right before bedtime can be used during adjuvant TMZ therapy (cycles 1-12).  
If possible, TMZ should be taken 2-3 hours before RT but the timing of the dose is left 
to the discretion of the treating physician.  Since TMZ may cause nausea, an 


Protocol Version date: 09-15-2020
25
appropriate anti-emetic (e.g., 1 mg dose of granisetron or 4-8 mg of ondansetron) 
should be given once a day before the TMZ.  On days when patients do not have 
radiation, they should continue to take temozolomide in the morning on an empty 
stomach at approximately the same time as radiation days.  
8.2.2
Pneumocystis jirovecii pneumonia [PJP (PCP)] prophylaxis: Since low dose TMZ 
is immunosuppressive and associated with an increased risk of PJP, all subjects must 
receive prophylaxis during RT with concomitant TMZ.  Prophylaxis must be continued 
for at least two weeks after the completion of RT.  The choice of prophylactic 
medications will be left to the discretion of the treating physician.  Options include 
atovaquone 
and 
dapsone. 
 
Based 
on 
NABTC 
experience, 
trimethoprim/sulfamethoxazole (Bactrim) appears to contribute to myelosuppression in 
patients on chemotherapy.  Thus, this agent is not preferred.  It may be used in patients 
who cannot tolerate other options listed above, although the final decision will be left 
to the discretion of the treating physician.  The decision to continue PJP prophylaxis 
beyond the time points noted is left to the discretion of the treating physician.  Subjects 
who continue to demonstrate lymphopenia after the continuous daily dosing of TMZ 
has been discontinued should be considered for ongoing prophylaxis.  
8.2.3
Treating physician: Subjects will be treated as outpatients.  All treatments are 
prescribed/given by study physicians.  During RT, subjects will be evaluated on a 
weekly basis.  During the adjuvant TMZ phase, subjects will be evaluated on a q28 
day basis.  
9.0
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS
Follow modifications based information given below until individual treatment tolerance can be 
ascertained.  If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed.  If an adverse event is not covered below, doses 
may be reduced or held at the discretion of the treating physician for the subject’s safety.  Dose 
adjustments for hematological adverse event are based on the blood counts obtained in preparation 
for the day of treatment.  
9.1
Radiation therapy: While interruption due to acute radiation adverse events is unlikely given 
the type of radiation planned, individual reasons, such as major worsening of neurological or 
mental status or any other medical condition may preclude the continuation of radiotherapy.  
Resuming RT in this setting will be at the discretion of the treating physician.  For example, 
cranial irradiation can be withheld for CNS adverse events or toxicity ≥ grade 3 attributable to 
radiotherapy.  The overall time of interruption and overall time of radiotherapy must be 
recorded.  If radiotherapy is interrupted, actions regarding dosing on concomitant 
temozolomide are described below:

If administration of TMZ is interrupted, RT will proceed normally and no catch up days 
of TMZ will be given after end of RT.  

If RT extends beyond 42 days because of delays, TMZ may be extended to a maximum 
of 49 days (at discretion of treating physician).  If RT is still not completed, additional 
TMZ beyond 49 days is not permitted.  

If RT is stopped for an adverse event felt clearly related to radiation and not TMZ, 
concomitant TMZ should be continued as per protocol unless PD occurs.  
9.2
Concomitant treatment: If the attribution of the adverse event can be clearly linked to TMZ, 
these dose modifications should be followed.  
9.2.1
Dose modification criteria for TMZ during RT (chemoradiation phase): Concurrent 
TMZ dose for cycle 1 is 75 mg/m2 given every day (including weekends) over the RT 
course (up to a maximum of 49 days).  Maximum dose reduction is 50% of the starting 
dose.  If significant toxicity is still experienced at 50% of the starting dose, TMZ will be 


Protocol Version date: 09-15-2020
26
discontinued.  
Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless 
otherwise specified
Dose modification criteria for TMZ (during concurrent RT/TMZ phase)
CTCAE Category
Adverse Event
Dosage Change
Grade 2 - ANC<1500-
1000 or 
PLTS<100,000-50,000
Continue RT but omit TMZ until 
ANC1500 and PLTS100,000, 
TMZ dose by 15%.  
Grade 3 - ANC<1000-500 
or PLTS<50,000-
25,000
Continue RT but omit TMZ until 
ANC1500 and PLTS100,000, 
TMZ dose by 25%.  
Blood/bone 
marrow
Grade 4 - ANC<500 or 
PLTS<25,000
Hold RT and TMZ.  Resume RT 
when ANC 500 & PLTS25,000 
and TMZ when ANC 1500 & 
PLTS100,000, TMZ dose by 
50%.  
Grade 2 - 
Nausea/vomiting on 
optimal anti-emetics
TMZ may be held until recovery 
to grade 0-1 at physician’s 
discretion.  
Grade 3 - 
Nausea/vomiting on 
optimal anti-emetics
Omit TMZ until grade 0-2 (or ≤1 
grade of baseline), TMZ dose by 
25%.  
Gastrointestinal
Grade 4 - 
Nausea/vomiting on 
optimal anti-emetics
Omit TMZ until grade 0-2 (or ≤1 
grade of baseline), TMZ dose by 
50%.  
Grade 2
TMZ may be held until recovery 
to grade 0-1, TMZ dose by 15% 
at physician’s discretion.  
Grade 3
Omit TMZ until grade 0-2 (or ≤1 
grade of starting value for pre-
existing abnormalities), TMZ 
dose by 25%.
Non-hematologic
   Other
Grade 4
Omit TMZ until grade 0-2 (or ≤1 
grade of starting value for pre-
existing abnormalities), TMZ 
dose by 50%.
Development of alopecia does not require dose modification
9.3
Adjuvant treatment: If the attribution of the adverse event can be clearly linked to TMZ, these 
dose modifications should be followed.  
During adjuvant therapy only, patients who require resection for radiation necrosis without 
evidence of recurrent tumor may continue to receive protocol therapy as long as they are not 
off study drug for >6 consecutive weeks.  
9.3.1
Dose modification criteria for adjuvant TMZ after RT (cycles 1-12): Adjuvant TMZ 
dose for cycle 1 is 150 mg/m2 given days 1-5 of 28 day cycle.  This dose is used even 
if TMZ dose reductions or treatment delays were necessary during concurrent RT/TMZ 


Protocol Version date: 09-15-2020
27
as long as other criteria at time of starting cycle 1 do not preclude beginning adjuvant 
TMZ therapy.  If tolerated, subsequent cycles will increase dose to 200 mg/m2 given 
days 1-5 of 28 day cycles.  Maximum dose reduction is 50% of the starting dose (75 
mg/m2 if dose reduction required after cycle 1 or 100 mg/m2 if dose reduction required 
after cycle 2 or later).  If significant toxicity is still experienced at 50% of the starting 
dose, TMZ will be discontinued.  
Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless 
otherwise specified
Dose modification criteria for TMZ at time of retreatment
CTCAE Category
Adverse Event
Dosage Change
Blood/bone 
marrow
ANC<1500 or 
PLTS<100,000 
Hold TMZ until ANC1500 and 
PLTS100,000, TMZ dose 
based on nadirs (see table 
below based on interim AEs).  If 
no recovery for > 4 weeks then 
discontinue TMZ.  
Non-hematologic
   Other
Grade 3/4 
Hold TMZ until recovery to 
grade 0-1, TMZ based on 
interim AEs (see table below).  If 
no recovery for > 4 weeks then 
discontinue TMZ.  
Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless 
otherwise specified
Dose modification criteria for TMZ based on interim adverse events
CTCAE Category
Adverse Event
Dosage Change
Grade 3 - ANC<1000-
500 or PLTS<50,000-
25,000
TMZ dose by 25%.  (Hold TMZ 
based on above table’s criteria)  
Blood/bone 
marrow
Grade 4 - ANC<500 or 
PLTS<25,000
TMZ dose by 50%.  (Hold TMZ 
based on above table’s criteria)  
Grade 3 - 
Nausea/vomiting on 
optimal anti-emetics
TMZ dose by 25%. 
Gastrointestinal
Grade 4 - 
Nausea/vomiting on 
optimal anti-emetics
TMZ dose by 50%.  
Grade 3
TMZ dose by 25%.  (Hold TMZ 
based on above table’s criteria)  
Non-hematologic
   Other
Grade 4
TMZ dose by 50%.  (Hold TMZ 
based on above table’s criteria)  
10.0 ANCILLARY TREATMENT/SUPPORTIVE CARE
10.1 Antiemetics: Since TMZ may cause nausea, it is suggested that an appropriate antiemetic 
(e.g., 1 mg dose of granisetron, or 4 mg of ondansetron, or other) be given one hour before 


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TMZ.  As an alternative, antiemetic may be used on the first 3 days of concomitant RT/TMZ 
and the first 3 days of adjuvant TMZ, with any further need determined by the treating physician 
based on perception of clinical need.  Additional symptoms will be managed as per standard 
antiemetic guidelines.  
10.2 Antidiarrheals: Use of loperamide (Imodium) for treatment-induced diarrhea is strongly 
encouraged.  Treat diarrhea promptly with appropriate supportive care, including loperamide.  
Instruct patients to begin taking loperamide at the first signs of: 1) poorly formed or loose stool, 
2) occurrence of more bowel movements than usual in one day, or 3) unusually high volume 
of stool.  Loperamide should be taken in the following manner: 4 mg at first onset of diarrhea, 
then 2 mg after each unformed stool.  Daily dose should not exceed 16 mg/day.  Loperamide 
should not be taken prophylactically.  Advise patients to drink plenty of clear fluids to help 
prevent dehydration caused by diarrhea.  Avoid loperamide if there is the presence of blood or 
mucus in the stool or if diarrhea is accompanied by fever. 
10.3 Supportive care: Patients should receive full supportive care while on this study.  This includes 
blood product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications (i.e., 
antidiarrheals, analgesics, antiemetics) received from the first day of treatment until 30 days 
after the final dose will be recorded on the concomitant medication form.  Adequate hydration 
should be maintained in the setting of dysgeusia (popsicles and Gatorade have been found to 
be useful by some investigators).  
10.4 Colony stimulating factors: These factors should not be used prophylactically to prevent 
granulocytopenia.  Growth factors are not permitted to induce elevations in neutrophil count for 
the purposes of (1) administration of TMZ on the scheduled dosing interval, or (2) allowing 
treatment with TMZ at a higher dose, or (3) avoiding interruption of the treatment during 
concomitant radiotherapy.  The therapeutic use of colony stimulating factors will be based on 
clinical judgment and may be appropriate in patients with a documented infection in the 
presence of severe granulocytopenia (granulocyte count less than 500/mm3).  Use of colony 
stimulating factors in clinically indicated situations should be consistent with product labeling 
and recorded on the concomitant medication form.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based 
Clinical Practice Guideline. J Clin Oncol 24(19): 1-19 AND American Society of Clinical 
Oncology/American Society of Hematology 2007 Clinical Practice Guideline Update on the Use 
of Epoetin and Darbepoetin J Clin Oncol 25(34): 1-17. (See www.asco.org web site)  
10.5 Erythropoietin: RBC support with erythropoietin can be used at the physician’s discretion.  
10.6 Pneumocystis jirovecii pneumonia (PJP [PCP]) prophylaxis: Pneumocystis jirovecii 
pneumonia has developed in patients when taking concomitant TMZ and steroids.  This is of 
concern especially for lymphopenic patients.  Prophylactic treatment is required for the 
concomitant RT/temozolomide of the study (cycle 1).  See section 8.2.3 for details.  
10.7 Surgery: If neurosurgical management is required for reasons not due to tumor progression, 
these procedures must be documented, including the indications for surgery, the surgical 
operative note and pathology report.
10.8 Corticosteroid treatment: Dosages and evaluation date of dexamethasone use must be 
recorded on concomitant steroid, anticonvulsant, and antiemetic medication form.  
Corticosteroids should be used in as low a dose as possible.  At progression of disease, 
corticosteroid choice and dosages are at the discretion of the patient’s physician.  
10.9 Treatment of fatigue: Patients experiencing profound fatigue may use medications such as 
modafinil at the discretion of the treating physician.  
11.0 TREATMENT EVALUATION


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11.1 Objectives – (see section 2.1-3)  
11.2 Imaging assessment
11.2.1
Conventional MRI scans (Standard care): Diagnostic MRI scans with and without 
contrast will be utilized to assess for response.    
11.2.2
sMRI (Research, 2 scans at week 0 (before treatment) and week 2): 3-D whole 
brain MR spectroscopic imaging sequence (EPSI/GRAPPA) and the analysis program 
MIDAS (Metabolic Imaging Data Analysis System) were developed by Dr. Andrew 
Maudsley (scientific PI of U of Miami) in 2006 [31-42]. The scan will be done in 3T 
Siemens MR scanner (TIM/TRIO, Prisma, Skyra) or equivalent.  Metabolite maps and 
their ratio maps will be calculated in MIDAS. Due to some degree of variability of 
Cho/NAA ratio between subjects, we will use the signal from contralateral normal white 
matter for normalization. We will use a web-based sMRI clinical interface to extract 
information from MIDAS to visualize the metabolite maps for efficient clinical workflow 
of the MIDAS results for busy clinicians and non-MRS experts. In addition, this web-
based tool allows effective data sharing among imaging scientists and clinicians for 
consultation and storage of de-identified data sets (this sMRI clinical interface has been 
used at Emory (NCI U01 CA172027 & NCI R21 NS100244; Emory IRB00055973). 
sMRI studies will be obtained at the schedule outlined in section 7.1.  
11.3 Response criteria
11.3.1
Measurable Disease: Measurable lesions with clearly defined margins by contrast-
enhanced MRI scan beyond pseudoprogression period. We anticipate an extended 
period of pseudoprogression with dose escalation. 
11.3.2
Objective Status, To Be Recorded at Each Evaluation: Unless progression is 
observed, objective status can only be determined when ALL measurable sites and 
lesions are assessed.  
11.3.3
Response Definitions
11.3.3.1
Complete Response (CR): Complete disappearance of all measurable 
disease in contrast-enhancing MRI.  No new lesions. No evidence of non-
evaluable disease.  All measurable lesions and sites must be assessed 
using the same techniques as baseline.  Patients must be on no steroids.  
11.3.3.2
Partial Response (PR): (Measurable disease only) Greater than or equal to 
50% decrease under baseline in tumor volume [43] of all measurable lesions.  
No progression of evaluable disease.  No new lesions.  All measurable 
lesions and sites must be assessed using the same techniques as baseline.  
The steroid dose at the time of the scan evaluation should be no greater than 
the maximum dose used in the first 8 weeks from initiation of therapy.  
11.3.3.3
Stable Disease (SD): Does not qualify for CR, PR, or progression.  The 
designation of SD requires a minimum of 8 weeks duration (2 assessment 
of stable disease 8 weeks apart).  All measurable sites must be assessed 
using the same techniques as baseline.  The steroid dose at the time of the 
scan evaluation should be no greater than the maximum dose used in the 
first 8 weeks from initiation of therapy.  
11.3.3.4
Progressive Disease (PD): 50% increase in the tumor volume of all 
measurable lesions over previous exam (over baseline if no decrease) using 
the same techniques as baseline, OR clear appearance of any new 
lesion/site, OR clear clinical worsening or failure to return for evaluation due 
to death or deteriorating condition (unless clearly unrelated to this cancer).  
NOTE: Increasing contrast enhancing disease in months 1-3 (potentially up 
to month 6) post-RT may represent pseudoprogression.  For the current 
study, we anticipate that incidence of this phenomenon will be increased. 


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30
Because of difficulties in the interpretation of pseudo-progression on MRI, 
the first three post-RT/TMZ scans should NOT be used to declare 
progression.  Progressive worsening on subsequent imaging studies usually 
distinguishes true progression from pseudoprogression.  In particular, DSC 
perfusion 
imaging 
may 
be 
helpful 
at 
distinguishing 
true 
and 
pseudoprogression. If the rCBV map does not show evidence of increased 
perfusion in regions with increasing contrast-enhanced lesion(s), then 
pseudoprogression is favored and patient may be maintained on study.  
Subsequent increases up to 6 months post-RT will be evaluated on a case-
by-case at a multi-disciplinary tumor board of the respective institution to 
assist in making a determination regarding true versus pseudoprogression 
and whether pathologic sampling would be beneficial. The date of 
progression will be backdated to when the changes were first observed in 
the case that the patient is later determine to have true progression.    
11.3.3.5
Regressive Disease (REGR): (Evaluable disease only) Unequivocal 
reduction in extent of contrast as compared to baseline-enhancement or a 
decrease in mass effect as agreed upon independently by primary physician 
and quality control physicians; no new lesions.  
11.3.3.6
Unknown: Progression has not been documented and one or more 
measurable sites have not been assessed.  
11.4 Best Response: This will be calculated from the sequence of objective statuses.  For patients 
with all disease sites assessed every evaluation period, the best response will be defined as 
the best objective status as measured according to section 11.5.  
11.5 Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, as compared with the baseline assessment, that should 
coincide with objective measurement of tumor size.  
NEURO EXAM STATUS (compared to pre-treatment exam)
Better
Must be on stable or decreasing dose of steroids
Same
Failure to qualify for better or worse
Worse
Include patients requiring increasing steroid doses 
to remain stable
11.6 Performance Status: Patients will be graded according to Karnofsky Performance Status (see 
Appendix 3).  
11.7 Time to Treatment Failure: From date of registration to the date of first observation of PD (as 
defined in section 11.5), non-reversible neurologic progression or permanently increased 
steroid requirement (applies to SD only), death due to any cause, or early discontinuation of 
treatment.  
11.8 Overall Survival Time: From date of definitive surgery or biopsy to date of death due to any 
cause.  
11.9 Progression Free Survival Time: From date of definitive surgery or biopsy to date of 
progression (defined in section 11.3.3.4) or death.  Once the real progression is confirmed from 
the subsequent scans, the first date exhibiting PD will be noted as the PFS time.
12.0 ADVERSE EVENT REPORTING 
12.1 Definitions


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12.1.1
Adverse Event Definition - An adverse event (AE) is any untoward medical 
occurrence in a patient administered a pharmaceutical product, which does not 
necessarily have a causal relationship with the treatment.  An adverse event can be 
any unfavorable and unintended sign (eg, including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the drug, whether or not it 
is considered to be drug related.  This includes any newly occurring event or previous 
condition that has increased in severity or frequency since the administration of drug.
12.1.2
Serious Adverse Event Definition - A serious adverse event (SAE) is any adverse 
event, occurring at any dose and regardless of causality that:

Results in death.

Is life-threatening.  Life-threatening means that the patient was at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form.

Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered AEs if the 
illness or disease existed before the patient was enrolled in the trial, provided that 
it did not deteriorate in an unexpected manner during the trial (eg, surgery 
performed earlier than planned).

Results in persistent or significant disability/incapacity.  Disability is defined 
as a substantial disruption of a persons’ ability to conduct normal life functions.

Is a congenital anomaly/birth defect.

Is an important medical event.  An important medical event is an event that may 
not result in death, be life-threatening, or require hospitalization but may be 
considered an SAE when, based upon appropriate medical judgment, it may 
jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definitions for SAEs.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.  
Clarification should be made between the terms “serious” and “severe” since they ARE 
NOT synonymous.  The term “severe” is often used to describe the intensity (severity) 
of a specific event (as in mild, moderate, or severe myocardial infarction); the event 
itself, however, may be of relatively minor medical significance (such as a severe 
headache).  This is NOT the same as “serious,” which is based on patient/event 
outcome or action criteria described above and are usually associated with events that 
pose a threat to a patient’s life or functioning.  A severe adverse event does not 
necessarily need to be considered serious.  For example, persistent nausea of several 
hours duration may be considered severe nausea but not an SAE.  On the other hand, 
a stroke resulting in only a minor degree of disability may be considered mild, but would 
be defined as an SAE based on the above noted criteria.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.
12.2 Procedures for AE and SAE Reporting
All serious adverse events (SAEs) will be assessed in a timely fashion and, if deemed 
reportable, SAE reports will be forwarded to its institutional IRB per IRB reporting requirements 
(e.g., Hopkins events get reported to Hopkins IRB and notify Emory PIs). 
Assessing Causality:


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Investigators are required to assess whether there is a reasonable possibility that dose 
escalated RT caused or contributed to an adverse event.  The following general guidance may 
be used.
Yes: if the temporal relationship of the clinical event to dose-escalated RT makes a causal 
relationship possible, and other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event.
No:
if the temporal relationship of the clinical event to dose-escalated RT makes a causal 
relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event.
12.3 Attribution
The clinical Principal Investigator (PI) at each site or his designee will document his opinion 
and any supporting laboratory and clinical information of the potential attribution of the study 
treatment to any grade 3 or greater toxicity based on the following guidelines: 
12.3.1
Unrelated
This category applies to those toxicities that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.)
12.3.2
Unlikely (must have any two criteria)
In general, this category can be considered applicable to those toxicities that are 
judged to be unrelated to the test treatment. A toxicity may be considered unlikely if or 
when:
1.
It does not follow a reasonable temporal sequence from administration of the test 
treatment;
2.
It could readily have been produced by the subject’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the subject;
3.
It does not follow a known pattern of response to the test treatment;
4.
It does not reappear or worsen when the test treatment is re-administered.
12.3.3
Possible (must have any two criteria)
This category applies to those toxicities for which a connection with the test treatment 
administration appears unlikely but cannot be ruled out with certainty.  A toxicity may 
be considered possibly related if and when:
1.
It follows a reasonable temporal sequence from administration of the test 
treatment;
2.
It could not readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject;
3.
It does follow a known pattern of response to the test treatment.
12.3.4
Probable (must have any two criteria)
This category applies to those toxicities that are felt with a high degree of certainty to 
be related to the test treatment.  A toxicity may be considered probably related if and 
when:
1.
It follows a reasonable temporal sequence from administration of the test 
treatment;


Protocol Version date: 09-15-2020
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2.
It could not reasonably be explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject;
3.
It disappears or decreases on cessation or reduction in test treatment.  There are 
important exceptions when a toxicity does not disappear upon discontinuation of 
the test treatment, yet treatment-relatedness clearly exists (e.g. bone marrow 
depression, fixed drug eruptions, tardive dyskinesia);
4.
It follows a known pattern of response to the test treatment.
12.3.5
Definite (must have all four criteria)
This category applies to those toxicities that are felt to be incontrovertibly related to the 
test treatment.  A toxicity may be considered definitely related if and when:
1.
It follows a reasonable temporal sequence from administration of the test 
treatment;
2.
It could not reasonably be explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject;
3.
It disappears or decreases on cessation or reduction in dose with re-exposure to 
drug. (Note: this is not to be construed as requiring re-exposure of the subject, 
however, a category of definitely related can only be used when a recurrence is 
observed.)
4.
It follows a known pattern of response to the test treatment.
The Emory IRB, Johns Hopkins University IRB and University of Miami IRB will be notified of 
the event happened at each site promptly per each IRB requirements.
Intensity for each adverse event, including any lab abnormality, will be determined by using 
the NCI CTCAE, version 4.0, as a guideline.
12.4 Monitoring of Adverse Events and Period of Observation
Adverse events, both serious and non-serious, and deaths that occur during the subject’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until 
they are resolved or are clearly determined to be due to a patient’s stable or chronic condition 
or intercurrent illness(es).
13.0 DATA AND SAFETY MONITORING PLAN (DSMP) 
13.1 Good Clinical Practice
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.  
13.2 Winship Cancer Institute Data Safety Monitoring Committee: 
The study will also be followed by the Winship Cancer Institute Data Safety Monitoring 
Committee to allow for local review and confirmation of proper study execution and safety 
measures.  
13.2.1
Patient safety, study efficacy and compliance will be reviewed at the Neuro-oncology 
Working Group meeting. The Data and Safety Monitoring Committee (DSMC) of the 


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Winship Cancer Institute will also oversee the conduct of this study (annually or semi-
annually – depending on the risk level assigned to the protocol by the Winship Cancer 
Institute Clinical and Translational Research Committee). The DSMC will review 
pertinent aspects of study conduct including patient safety, compliance with protocol, 
data collection and efficacy. The committee will review the charts of 10% of patients 
enrolled to the study and two of the first 5 patients entered to the study. The Committee 
reserves the right to conduct additional audits if necessary. The clinical Principal 
Investigator (PI) at each site or his designee is responsible for notifying the DSMC 
about the accrual of patients when the first 5 have been entered to the study. The PI 
or designee will also notify the DSMC of study status within 2 months before the next 
scheduled review is due.
13.2.2
Procedures to assure data integrity and protocol adherence 
13.2.2.1
Imaging and clinical data will be analyzed in a quarterly meeting of 
investigators, clinical research coordinators and regulatory personnel.
13.2.2.2
Adverse event reporting will utilize NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 and is detailed in section 12.0 
above.
13.2.2.3
Study Team Oversight:  The study progress in terms of enrollment, activity 
of current patients under active treatment, observed toxicities will be 
reviewed in the monthly Emory Neuro-oncology Working Group.  Here 
there will be random and selected case report form and chart review.  
Special and problematic items requiring additional attention will be 
addressed in separate sessions of the Neuro-oncology Working Group 
occurring up to weekly including selected study investigators, clinical 
research coordinators and regulatory personnel.  
13.2.2.4
Training of investigators, clinical research coordinators and regulatory 
personnel at all sites will be performed by one of the principal investigators 
utilizing the written protocol and a summary of pertinent treatment 
activities.  Completion of the training of investigators, clinical research 
coordinators and regulatory personnel will be documented on a study 
training log. 
13.2.2.5
External Site Management:  Enrollment will occur at Johns Hopkins 
University and University of Miami
•
Monitoring of Study Activity:  Monitoring of study activity will occur by 
monthly review of enrollment activity of current patients under active 
treatment, observed toxicities by the investigator, clinical research 
coordinator and regulatory personnel at Johns Hopkins and University of 
Miami.  The results of this review will be summarized and shared and 
logged monthly in written form (and verbal form when needed) with the 
Emory investigators. 
•
Investigator Communication:  Verbal investigator communication among 
three sites will occur and be logged quarterly to discuss the content 
mentioned above.  
•
Reporting of Adverse Events Occurring at Johns Hopkins and University 
of Miami:  The criteria and methods of collecting adverse event data 
outlined in section 12.0 will apply at Johns Hopkins and U of Miami also.  
o
Each site Principal Investigators (PI) are responsible for review 
and assessment of all adverse events at their site as specified in 
the protocol. AEs, SAEs (initial and follow ups), and UPs will be 
reported to the  each site IRB as per protocol requirements 


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including reporting SAEs and UPs within 24 hours of the 
participating site becoming aware of the event.
o
Johns Hopkins and University of Miami sites are also responsible 
for the following: 

Report events, as applicable, to their IRB. 

Submit all acknowledgements of reports submitted 
promptly to their IRB to the Winship multisite coordinator 
or Emory PIs. 

Resolve all queries related to the SAE report in a timely 
manner. 

Maintain copies of each event reported in the subject’s 
study records.

Enter AEs into Oncore® in a timely manner.

Enter SAEs and UPs into Oncore® or equivalent 
(depending on the institution) in the SAE category, in a 
timely manner.
o
Winship multisite coordinator will inform all three sites of adverse 
events that require expedited reporting to local IRBs.
o
Emory Lead investigator will review SAE data summary reports on 
a regular basis, at least annually
o
Emory Lead investigator will submit SAE data summary reports to 
the Data Safety Monitoring Committee for review as per their 
guidelines.
13.3 On-site Audits
Regulatory authorities and the IRB may request access to all source documents, data capture 
records, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support given 
reasonable notice at all times for these activities.  
The following applies for monitoring of Sub-sites:  
At the study initiation, the PI, regulatory specialist, and research coordinators will perform a site 
initiation teleconference.  During this teleconference, the Emory team will review the study, 
enrollment, reporting, and regulatory compliance. The participating site will have internal monitoring 
meetings.  These meetings will include the investigators, the clinical research coordinator and the 
regulatory affairs coordinator and will meet at least on a monthly basis to review and discuss study 
data to ensure subject safety.  The research coordinators will maintain one spread sheet which will 
summarize all the patient data for patients actively being treated on the trial as well as a roadmap 
detailing pending tests/treatments for each individual patient.  The spread sheet will be shared with 
the Emory PIs.  Teleconferences will be conducted monthly among the PIs and the research team 
with the participating sites.  The purpose of the meetings is to discuss the enrollment, regulatory 
updates, monitor toxicities, and evaluate the progress of the trial.  The minutes from the 
teleconference will be maintained in the regulatory binder for the study.  In addition, electronic 
copies will be sent via email to the PIs at each site.  Chart reviews will be performed on selected 
cases from the participating site to confirm that the data collection is accurate. 
Winship’s Multisite Coordinator will perform remote quarterly monitoring of participating sites’ data 
and will perform an annual on-site monitoring visit as necessary per site enrollment.  Monthly 


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reviews of data in OnCore will be conducted to ensure compliance or identify discrepancies
14.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY
14.1 Primary Objectives
14.1.1
To determine the feasibility of using sMRI to guide dose-escalated RT for newly-
diagnosed GBMs.  Feasibility of this approach will be determined by whether treatment 
volumes based on sMRI can be co-registered with clinical images and transferred into 
the radiation treatment execution platform in a seamless manner, so that sMRI 
information can be efficiently applied to the patient treatment.  
14.1.2
To determine the safety of using sMRI to guide dose-escalated RT for newly-diagnosed 
GBMs.  The safety of this approach will be confirmed by assessing toxicity potentially 
attributable to the dose-escalated RT.  Toxicity will be determined by CTCAE v4.0 
criteria.  If > 6 of 30 patients (> 20% of subjects) experience a grade 3 or greater toxicity 
by 6 months after completion of RT/TMZ that is ruled as at least possibly attributable 
to the dose-escalated RT, then the safety of this treatment approach will be questioned 
and require further review by the study team.  Interim analyses with stopping rules are 
described later in this Section.  
14.2 Secondary Objectives
14.2.1
To determine whether the progression free survival at 1 year sMRI-guided, dose-
escalated RT increases with newly-diagnosed GBMs.  Subjects on this study will be 
followed for progression free survival (PFS) which is defined from the time of surgical 
resection to the time of either radiographic progression or death, whichever occurs 
first.  While PFS actuarial curves will be assessed and compared to historical controls, 
we are particularly interested in comparing the 1-year PFS rate which, based on the 
control arm (receiving standard dose RT with TMZ) of recent GBM trials, is 
approximately 30% in historical cohorts [44-46].  
14.3 Exploratory Objectives
14.3.1
To determine whether sMRI-guided, dose-escalated RT increases the overall survival 
of patients with newly-diagnosed GBMs.  Subjects on this study will also be followed 
for overall survival (OS) which is defined from the time of surgical resection to the time 
of death.  The OS actuarial curve and 1-year OS rate will be assessed and compared 
to historical controls. The 1-year OS rate of control arm patients on recent trials is 
approximately 66%
14.3.2
To determine whether sMRI data obtained after initiation of therapy (at 2 weeks after 
RT/TMZ start and prior to cycle 1 and 5 of adjuvant TMZ) will provide early evidence 
of GBM progression not seen on standard MRIs.  Changes in sMRI parameters over 
time will be assessed to determine whether they will be able to predict development of 
recurrence.  Global changes in sMRI parameters including to absolute metabolite 
concentrations or metabolic ratios will be examined to see if these factors may be an 
early marker of tumor recurrence.  In addition, further assessments will be made on a 
voxel-wise basis to determine whether individual changes may be predictive of ultimate 
recurrence within particular voxels.  
14.3.3
To determine whether performance on neurocognitive and quality-of-life (QOL) 
assessments in newly-diagnosed GBM patients treated with sMRI-guided, dose-
escalated RT differ from historical controls.  We will compare performance on 
neurocognitive and QOL assessments in our 30 subject cohort with performance by 
historical control cohorts from recent GBM trials (eg. RTOG 0525 and 0825) [45, 46].  
Better performance may be attributable to better control of disease while worse 
performance may imply increased toxicity from the study treatment regimen.  


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14.3 Accrual rate and numbers: The anticipated rate of accrual will be 2-3 patients/month among 
three sites.  This will allow consenting of 30 patients over a period of 1.5 years.  
14.3 Criteria for removal from trial: All reasons for discontinuation of treatment must be 
documented.  
14.3.1
Progression of disease will be hard to determine due to pseudoprogression as defined 
in section 11.3.  The final progression free survival will be determined at year 1, which 
is beyond pseudoprogression possibility.  
14.3.2
Patient may withdraw from study at any time for any reason.  
14.4 Adverse event stopping rule: Safety assessments will be performed throughout treatment, 
at two week intervals during RT and prior to each odd number adjuvant TMZ cycle following 
completion of RT. Toxicity will be carefully assessed using CTCAE v4.03 criteria, and the rate 
of radiation necrosis development will be determined. While we expect this regimen to be 
tolerated based on the previous experience reported by Tsien et al. [9], we will still employ an 
interim safety analysis with a special stopping rule if neurotoxicity is greater than expected.  
Because the expected incidence of late grade 3+ neurotoxicity with standard-of-care 
chemoradiation is ~5%, or 2 of 30 patients in our planned cohort, we will employ the following 
interim analysis and stopping rule after 10 subjects have completed treatment and have been 
followed for 6 months after completion of chemoradiation: if more than 2 subjects (out of 10) 
develop CTCAE v4.03 grade III or greater neurotoxicity (> 20% incidence) judged to be at least 
possibly due to RT by 6 months from completion of RT/TMZ, study accrual will halt and await 
assessment of toxicities by the DSMC to review attribution of toxicities before a decision will 
be made about either permanent closure or re-opening with continuation/completion of study 
accrual.  
 
14.5 Statistical analysis for survival endpoints:  The primary objectives are to determine the 
feasibility of this escalated protocol and the safety of increased doses in patients with GBM. 
We anticipate that 30 patients will provide us sufficient data to make these conclusions. Since 
survival analyses are exploratory objectives of this study, these endpoints are not used to 
determine accrual numbers for this study.  The PFS of patients in this protocol will be compared 
with historical controls, and that data will be used to estimate the effect size for future power 
analyses. With a planned accrual of 30 subjects, the following power to detect potential 
improvements in 1 year PFS is as follows: 1-year PFS rate is expected to be 30-35% based 
on historical controls [44-46].  Our study will have 82% power to detect an improvement to a 
rate of 60% at α=0.05 using a two-sided test. Cox's proportional hazard regression model will 
be applied to model 1-year PFS outcome to test whether subjects treated with escalated RT 
doses guided by the sMRI demonstrate significantly higher PFS as compared to historical 
controls receiving standard treatment, controlling for other potential risk factors. Of note, 
calculations to determine the power to detect a certain PFS effect size based the number of 
patients we needed to determine feasibility and safety were presented above.  However, this 
study was not actually powered based on PFS improvement.
14.6 Statistical analysis of sMRI scans: This study is mainly using pre-RT sMRI parameters to 
help define a region at high risk for recurrence that can be treated with higher doses of RT.  
Exploratory objectives will involve examining changes in absolute metabolite levels and 
metabolic ratios during RT that may be useful for adaptive radiation therapy (changing dose 
plan during early phase of RT).  sMRI data will be evaluated both on a patient-wise basis and 
on a voxel-wise basis with utilization of deformable registration technique, as needed, to 
achieve good matching of maps across serially acquired scans.
14.7 Statistical analysis of neurocognitive function and QOL scores: Linear mixed effects 
models will be applied to model the repeatedly measured score from each assessment and/or 
test over time.  We hypothesize that changes in individual and/or composite metabolite levels 
will be predictive of the temporal changing patterns in the scores on the neurocognitive 
functional tests and QOL assessments.  Changes in individual and multiple metabolite levels 


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within normal brain surrounding the region of the tumor as well as in tumor-bearing regions of 
brain will be evaluated with scores on these assessments using logistic regression models.  
14.8 Interim analysis and stopping rule for efficacy/futility: While there will be stopping rules for 
toxicity/adverse events (see Section 14.4), there will not be stopping rules for efficacy/futility.  
The primary goal of the study is to determine the feasibility and safety of sMRI-guided, dose-
escalated RT and TMZ for newly diagnosed GBM patients.  At the time we anticipate 
performing interim analysis for toxicity assessment in the first 10 patients with adequate follow-
up, approximately 20 patients will have already initiated therapy allowing up to 10 patients to 
avoid enrollment if this treatment regimen is determined to be too toxic.  
15.0 DATA COLLECTION
15.1 Data submission forms: A copy of the eligibility/registration form will be completed and kept 
at the Emory Winship Cancer Institute Clinical Research Office.  

The clinical management system being used for this study is The Online Collaborative 
Research Environment (OnCore). OnCore will be used to record all study related 
information for all registered patients. All data must be entered no later than 30 days 
following each visit completion. All queries are to be resolved within 4 weeks of issue.
15.2 Imaging and RT data: Imaging data will be collected with masked patient identification.  All 
diagnostic imaging data sets will be electronically transferred under the study ID to a secure 
server at Emory University.  In addition, patient treatment plans, including isodose clouds and 
all structure including tumor volumes and OARs under the study ID, will be similarly transferred 
and stored.  For instructions on how to transfer each data set, please contact Edi Schreibmann 
at 404-778-5667. 
15.3 REDCap data:  To be able to accurately determine/analyze the progression (date and 
recurrence patterns) and outcomes/benefits of the new treatment strategy, we need the 
following information uploaded to the REDCap database set up for this trial. Our REDCap for 
this study is set up under Study ID, rather than patients’ identity. The following documents will 
be collected to REDCap after masking patient’s name or hospital ID number. Those include all 
reports from neuro-oncologists (to monitor the condition of the patients and any new 
interventions that are prescribed to the patients) and pathology reports that are generated after 
surgical interventions. The initial pathology report has genomic/histological information of the 
tumor subtype while the follow up pathology reports contain the tumor/necrosis proportion of 
sampling to determine progression/treatment effect. For instructions on how to upload data to 
the REDCap, please contact Karthik Ramesh at 425-512-3406.  
16.0 REFERENCES
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Stupp, R., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of 
the EORTC-NCIC trial. Lancet Oncol, 2009. 10(5): p. 459-66.
2.
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N 
Engl J Med, 2005. 352(10): p. 987-96.
3.
Pope, W.B., J.R. Young, and B.M. Ellingson, Advances in MRI assessment of gliomas and 
response to anti-VEGF therapy. Curr Neurol Neurosci Rep, 2011. 11(3): p. 336-44.
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Tsuchiya, K., Y. Mizutani, and J. Hachiya, Preliminary evaluation of fluid-attenuated inversion-
recovery MR in the diagnosis of intracranial tumors. AJNR Am J Neuroradiol, 1996. 17(6): p. 1081-
6.
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Knisely, J.P. and S. Rockwell, Importance of hypoxia in the biology and treatment of brain tumors. 
Neuroimaging Clin N Am, 2002. 12(4): p. 525-36.
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Walker, M.D., T.A. Strike, and G.E. Sheline, An analysis of dose-effect relationship in the 
radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys, 1979. 5(10): p. 1725-31.


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7.
Fitzek, M.M., et al., Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent 
for glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg, 1999. 91(2): p. 251-
60.
8.
Brandes, A.A., et al., MGMT promoter methylation status can predict the incidence and outcome 
of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma 
patients. J Clin Oncol, 2008. 26(13): p. 2192-7.
9.
Tsien, C.I., et al., Concurrent temozolomide and dose-escalated intensity-modulated radiation 
therapy in newly diagnosed glioblastoma. Clin Cancer Res, 2012. 18(1): p. 273-9.
10.
Nelson, S.J., Assessment of therapeutic response and treatment planning for brain tumors using 
metabolic and physiological MRI. NMR Biomed, 2011. 24(6): p. 734-49.
11.
Wang, L.L., et al., Critical role of imaging in the neurosurgical and radiotherapeutic management 
of brain tumors. Radiographics, 2014. 34(3): p. 702-21.
12.
Wang, S., et al., Diagnostic utility of diffusion tensor imaging in differentiating glioblastomas from 
brain metastases. AJNR Am J Neuroradiol, 2014. 35(5): p. 928-34.
13.
Go, K.G., et al., Localised proton spectroscopy and spectroscopic imaging in cerebral gliomas, with 
comparison to positron emission tomography. Neuroradiology, 1995. 37(3): p. 198-206.
14.
Lu, S., et al., Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain 
tumors. AJNR Am J Neuroradiol, 2003. 24(5): p. 937-41.
15.
Nelson, S.J., D.B. Vigneron, and W.P. Dillon, Serial evaluation of patients with brain tumors using 
volume MRI and 3D 1H MRSI. NMR Biomed, 1999. 12(3): p. 123-38.
16.
Chang, J., et al., Image-fusion of MR spectroscopic images for treatment planning of gliomas. Med 
Phys, 2006. 33(1): p. 32-40.
17.
Graves, E.E., et al., Registration of magnetic resonance spectroscopic imaging to computed 
tomography for radiotherapy treatment planning. Med Phys, 2001. 28(12): p. 2489-96.
18.
Narayana, A., et al., Use of MR spectroscopy and functional imaging in the treatment planning of 
gliomas. Br J Radiol, 2007. 80(953): p. 347-54.
19.
Pirzkall, A., et al., 3D MRSI for resected high-grade gliomas before RT: tumor extent according to 
metabolic activity in relation to MRI. Int J Radiat Oncol Biol Phys, 2004. 59(1): p. 126-37.
20.
Park, I., et al., Patterns of recurrence analysis in newly diagnosed glioblastoma multiforme after 
three-dimensional conformal radiation therapy with respect to pre-radiation therapy magnetic 
resonance spectroscopic findings. Int J Radiat Oncol Biol Phys, 2007. 69(2): p. 381-9.
21.
D'Atri, S., et al., Involvement of the mismatch repair system in temozolomide-induced apoptosis. 
Mol Pharmacol, 1998. 54(2): p. 334-41.
22.
Stadlbauer, A., et al., Magnetic resonance spectroscopic imaging for visualization of the infiltration 
zone of glioma. Cen Eur Neurosurg, 2011. 72(2): p. 63-9.
23.
Hirose, Y., M.S. Berger, and R.O. Pieper, Abrogation of the Chk1-mediated G(2) checkpoint 
pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human 
glioblastoma cells. Cancer Res, 2001. 61(15): p. 5843-9.
24.
Yung, W.K., et al., A phase II study of temozolomide vs. procarbazine in patients with glioblastoma 
multiforme at first relapse. Br J Cancer, 2000. 83(5): p. 588-93.
25.
Yung, W.K., Temozolomide in malignant gliomas. Semin Oncol, 2000. 27(3 Suppl 6): p. 27-34.
26.
Wong, E.T., et al., Outcomes and prognostic factors in recurrent glioma patients enrolled onto 
phase II clinical trials. J Clin Oncol, 1999. 17(8): p. 2572-8.
27.
Osoba, D., et al., Health-related quality of life in patients with anaplastic astrocytoma during 
treatment with temozolomide. Eur J Cancer, 2000. 36(14): p. 1788-95.
28.
Khan, R.B., et al., A phase II study of extended low-dose temozolomide in recurrent malignant 
gliomas. Neuro Oncol, 2002. 4(1): p. 39-43.
29.
van Rijn, J., et al., Survival of human glioma cells treated with various combination of temozolomide 
and X-rays. Int J Radiat Oncol Biol Phys, 2000. 47(3): p. 779-84.
30.
Stupp, R., et al., Promising survival for patients with newly diagnosed glioblastoma multiforme 
treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin 
Oncol, 2002. 20(5): p. 1375-82.
31.
Maudsley, A.A., et al., Mapping of brain metabolite distributions by volumetric proton MR 
spectroscopic imaging (MRSI). Magn Reson Med, 2009. 61(3): p. 548-59.
32.
Ogg, R.J., P.B. Kingsley, and J.S. Taylor, WET, a T1- and B1-insensitive water-suppression 
method for in vivo localized 1H NMR spectroscopy. J Magn Reson B, 1994. 104(1): p. 1-10.


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33.
Ebel, A. and A.A. Maudsley, Comparison of methods for reduction of lipid contamination for in vivo 
proton MR spectroscopic imaging of the brain. Magn Reson Med, 2001. 46(4): p. 706-12.
34.
Hetherington, H.P., et al., Evaluation of cerebral gray and white matter metabolite differences by 
spectroscopic imaging at 4.1T. Magn Reson Med, 1994. 32(5): p. 565-71.
35.
Zhu, X., et al., Spectral phase-corrected GRAPPA reconstruction of three-dimensional echo-planar 
spectroscopic imaging (3D-EPSI). Magn Reson Med, 2007. 57(5): p. 815-20.
36.
Sabati, M. and A.A. Maudsley. SNR-optimized, fast, and high-resolution mapping of whole brain 
tissue water content. in ISMRM. 2011. Montreal, Canada.
37.
Zhang, Y., M. Brady, and S. Smith, Segmentation of brain MR images through a hidden Markov 
random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging, 2001. 
20(1): p. 45-57.
38.
Maudsley, A.A., C. Domenig, and S. Sheriff, Reproducibility of serial whole-brain MR spectroscopic 
imaging. NMR Biomed, 2010. 23(3): p. 251-6.
39.
Maudsley, A.A., et al. Towards standardization of volumetric MRSI. in ISMRM. 2011. Montreal, 
Canada.
40.
Maudsley, A.A., et al., Comprehensive processing, display and analysis for in vivo MR 
spectroscopic imaging. NMR Biomed, 2006. 19(4): p. 492-503.
41.
Soher, B.J., et al., Automated spectral analysis III: application to in vivo proton MR spectroscopy 
and spectroscopic imaging. Magn Reson Med, 1998. 40(6): p. 822-31.
42.
Cordova, J.S., et al., Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in 
glioblastoma patients. Neuro Oncol, 2016.
43.
Cordova, J.S., et al., Quantitative tumor segmentation for evaluation of extent of glioblastoma 
resection to facilitate multisite clinical trials. Transl Oncol, 2014. 7(1): p. 40-7.
44.
Chinot, O.L., et al., Bevacizumab plus radiotherapy-temozolomide for newly diagnosed 
glioblastoma. N Engl J Med, 2014. 370(8): p. 709-22.
45.
Gilbert, M.R., et al., A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl 
J Med, 2014. 370(8): p. 699-708.
46.
Gilbert, M.R., et al., Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized 
phase III clinical trial. J Clin Oncol, 2013. 31(32): p. 4085-91.


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APPENDIX 1 - Karnofsky Performance Scale
100 Normal no complaints; no evidence of 
disease.
90 Able to carry on normal activity; minor signs 
or symptoms of disease.
Able to carry on normal activity and to work; no special 
care needed.
80 Normal activity with effort; some signs or 
symptoms of disease. 
70 Cares for self; unable to carry on normal 
activity or to do active work.
60 Requires occasional assistance, but is able 
to care for most of his personal needs.
Unable to work; able to live at home and care for most 
personal needs; varying amount of assistance needed.
50 Requires considerable assistance and 
frequent medical care. 
40 Disabled; requires special care and 
assistance.
30 Severely disabled; hospital admission is 
indicated although death not imminent.
20 Very sick; hospital admission necessary; 
active supportive treatment necessary.
10 Moribund; fatal processes progressing 
rapidly.
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
0
Dead


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APPENDIX 2 - NEUROCOGNITIVE TESTS
NEUROCOGNITIVE TEST INSTRUCTIONS AND ADMINISTRATION PROCEDURES
1. Testing must be completed in one session. Test instructions must be followed verbatim with every 
patient at every study visit. All tests should be completed in black pen.
2. Tests should be administered in the following order to every patient and at every study visit: 
HVLT-R Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWAT; HVLT-R 
Part B (Delayed Recall); and the HVLT-R Part C (Delayed Recognition).
3. You may fill the delay interval between COWAT and HVLT-R Part B (Delayed Recall) with QOL 
questionnaires.
4. Patients should not be given copies of their tests to avoid learning the material between test 
administrations.
1.
HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
This test has three parts and six alternate forms:
Part A - Free Recall: Complete the three learning trials first
Part B - Delayed Recall: Complete after a 20 minute delay that includes administration of Trail Making 
Tests and COWAT as well as QOL assessments and symptom self-report measures, if appropriate
Part C - Delayed Recognition: Complete immediately after Delayed Recall
Part A – Free Recall: Trial 1
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, 
I’d like you to tell me as many of the words as you can remember. You can tell them to me in any 
order. Are you ready?”
•
Read the words at the rate of one word every 2 seconds.
Examiner: “OK. Now tell me as many of those words as you can remember.”
•
Check off the words the patient recalls on the form.
•
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list.
•
There is no time limit for each recall trial. However, if the patient does not produce any words for 
10-15 seconds, ask the patient if he/she can remember any more words.
•
If not, move on to trial 2. Later, you can record the number of words that were correctly repeated on 
the summary form.
Part A – Free Recall: Trial 2
Examiner: “Now we are going to try it again. I am going to read the same list of words to you. Listen 
carefully, and tell me as many of the words as you can remember, in any order, including the words 
you told me the first time.”


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•
Read the words at the rate of one word every 2 seconds.
•
Check off the words the patient recalls on the form.
•
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list.
•
There is no time limit for each recall trial. However, if the patient does not produce any words for 
10-15 seconds, ask the patient if he/she can remember any more words.
•
If not, move on to trial 3. Later, you can record the number of words that were correctly repeated on 
the summary form.
Part A – Free Recall: Trial 3
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of 
the words as you can remember, in any order, including all the words you’ve already told me.”
•
Read the words at the rate of one word every 2 seconds.
•
Check off the words the patient recalls on the form.
•
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list.
•
There is no time limit for each recall trial. However, if the patient does not produce any words for 
10-15 seconds, ask the patient if he/she can remember any more words.
•
Do not tell the respondent that recall of the words will be tested later.
•
Record the time on the clock that you complete ‘Part A – Free Recall’ (for example, 10:00 am) on the 
designated space on the HVLT-R form.
2. TRAIL MAKING TEST [Timed Test]
Part A – Sample: The Sample for Part A must be completed/attempted by each patient and every 
assessment. Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom of 
the worksheet should be approximately six inches from the edge of the table). Give the patient a black pen 
and say:
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line 
from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the 
end (point to the circle marked END). Draw the lines as fast as you can. Ready, begin.”
If the patient completes Sample A correctly and in a manner demonstrating that s/he understands what to 
do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and 
explain it. The following explanations of mistakes serve as illustrations:
•
“This is where you start (point to number 1)”
•
“You skipped this circle (point to the circle omitted)”


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•
“You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END”
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind 
the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample A, take 
his/her hand and guide him/her through the trail using the opposite end of the pen, lightly touching the 
worksheet to avoid making marks on the copy. Then say:
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3 
(point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do 
not skip around, but go from one number to the next in proper order. Remember to work as fast as 
you can. Ready, begin.”
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A 
correctly and appears to understand what to do, proceed immediately to Part A.
Part A – Test: After the patient has completed Sample A, place the Part A test worksheet directly in front 
of the patient and say:
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same 
way. Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point 
to 4) and so on, in order, until you reach the circle marked END (point). Do not skip around, but go 
from one number to the next in proper order. Remember to work as fast as you can. Ready, begin.”
•
Start timing as soon as the instruction is given to “begin”
•
Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, 
call it to his/her attention immediately and have him/her proceed from the point the mistake occurred
•
The patient must complete the test in 3 minutes or less
•
DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”
•
If the patient does not complete the test within 3 minutes, terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the 
worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated 
and the last correct number reached on the test.
•
If the patient successfully completes the test, collect the worksheet and record the time to completion 
on the Trail Making Data Sheet in minutes and seconds. Then say, “That’s fine. Now we’ll try 
another one.”
Part B – Sample: The Sample for Part B must be completed/attempted by each patient and every 
assessment. Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom of 
the worksheet should be approximately six inches from the edge of the table) and say:
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point to 1) and 
draw a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point 
to C) and so on, in order, until you reach the end (point to the circle marked END). Remember, first 
you have a number (point to 1), then a letter (point to A), then a number (point to 2), then a letter 
(point to B), and so on. Draw the lines as fast as you can. Ready, begin.”


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If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what to 
do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and 
explain it. The following explanations of mistakes serve as illustrations:
•
“You started with the wrong circle. This is where you start (point to number 1)”
•
“You skipped this circle (point to the circle omitted)”
•
“You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 
3 (point to 3) and so on, until you reach the circle marked END (point)”
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the 
patient, however, to be sure to touch the circles. If the patient still cannot complete Sample B, take their 
hand and guide them through the trail using the opposite end of the pen, lightly touching the worksheet to 
avoid making marks on the copy. Then say:
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 to A 
(point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in order, until you 
reach the circle marked END (point). Ready, begin.”
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Test Data Sheet. If the patient completes Sample 
A correctly and appears to understand what to do, proceed immediately to Part A.
Part B – Test:
After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and 
say:
Examiner: “ Good! Let’s try the next one. On this page are both numbers and letters. Do this the 
same way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 (point to 2), 2 to 
B (point to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, until you reach the circle 
marked END (point). Remember, first you have a number (point to 1), then a letter (point to A), then 
a number (point to 2), then a letter (point to B), and so on. Do not skip around, but go from one circle 
to the next in the proper order. Draw the lines as fast as you can. Ready, begin.”
•
Start timing as soon as the instruction is given to “begin”
•
Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, 
call it to his/her attention immediately and have him/her proceed from the point the mistake occurred 
- do NOT start from the beginning
•
The patient must complete the test in 5 minutes or less
•
DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”
•
Collect the worksheet and record the time to completion on the Trail Making Test Data Sheet in 
minutes and seconds
•
If the patient does not complete the test within 5 minutes, terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the 
worksheet and complete the Trail Making Test Data Sheet indicating the reason the test was 
terminated and the last correct number or letter reached on the test.


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•
At the top of both Sample forms and both Test forms please write: subject ID number, date of 
evaluation, institution name, name of certified tester, and the certified tester’s phone number.
3. CONTROLLED ORAL WORD ASSOCIATION TEST (COWAT) [Timed Test]
This test has three parts (letters) and two alternate forms.
Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can 
all of the words that you can think of that begin with that letter. You may say any words at all, except 
proper names such as the names of people or places. So you would not say ‘Rochester’ or ‘Robert’. 
Also, do not use the same word again with a different ending, such as ‘Eat,’ and ‘Eating.’
“For example, if I say ‘s,’ you could say ‘son’, ‘sit,’ ‘shoe,’ or ‘slow.’ Can you think of other words 
beginning with the letter ‘s’?”
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word 
beginning with the letter “s”. If a second appropriate word is given, proceed to the test itself.
If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the instructions. 
If the patient then succeeds, proceed to the test.
If the patient fails to respond, repeat the instructions. If it becomes clear that the patient does not understand 
the instructions or cannot associate, stop the procedure, and indicate the reason(s) on the scoring sheet 
and the Neurocognitive Evaluation Summary Form (CS).
If the patient has succeeded in giving two appropriate words beginning with the demonstration letter, say:
Examiner: “That is fine. Now I am going to give you another letter and again you say all of the words 
beginning with that letter that you can think of. Remember, no names of people or places, just 
ordinary words. Also, if you should draw a blank, I want you to keep on trying until the time limit is 
up and I say STOP.”
“You will have a minute for each letter. The first letter is ‘___’” (see scoring sheet).
**Allow exactly one minute for each letter**
•
If the patient discontinues before the end of the time period, encourage him/her to try to think of more 
words.
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If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the 
words you can think of that begin with a “c”).
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No extension on the time limit is made in the event that instructions are repeated.
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Continue the evaluation with the remaining two letters, allowing one minute for each.


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Recording and Scoring:
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The record sheet provides lines on which the patient’s responses can be entered (e.g., write in the 
word that is said by the patient). Record all patient responses verbatim. If his/her speed of word 
production is too fast to permit verbatim recording, a “+” should be entered to indicate a correct 
response.
•
Incorrect responses should be struck through with a line and then initial and date in the margin next 
to the error.
•
If the patient provides more responses than there are lines on the record sheet, place check marks 
in the boxes to indicate correct responses only.
•
Count all the correct responses. The number of correct words should be indicated below each column 
on the recording sheet and on the Neurocognitive Evaluation Summary Form (CS) that is sent to the 
RTOG.
Comments on scoring:
•
Note: It can be helpful for the first several patients and for patients known to be fast with their word 
production to tape record the session for transcription at a later time.
•
The instructions include a specific prohibition against giving proper names or different forms of the 
same word. Therefore, inflections of the same word (e.g., eat-eating; mouse-mice; loose-loosely; ran-
run-runs) are not considered correct responses.
•
Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-funny; sad-
sadness). These are not considered correct responses. On the other hand, if the word refers to a 
specific object (e.g., foot-footstool; hang-hanger), it would be counted as a correct answer.
•
Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the word is 
acceptable IF the patient definitely indicates the alternative meaning to you.
•
Slang terms are OK if they are in general use.
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Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be 
considered part of the lexicon of the relevant language, the criterion being their listing in a standard 
dictionary of that language. All incorrect and repeated responses MUST be crossed out with one 
single line, initialed and dated. Additionally, all duplicate entries that have been verified to have 
different meanings must be marked “ok”, initialed and dated. Refer to the descriptions above for 
guidelines for acceptability. Add the total number of correct responses in each column and input the 
totals where indicated on the COWAT worksheet.
•
If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the 
reason on the Neurocognitive Evaluation Summary Form (CS)
4. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
Part B – Delayed Recall
•
DO NOT READ THE WORD LIST AGAIN.
•
Record the time on the clock that you start ‘Part B – Delayed Recall’ (for example, 10:20 am) on the 
designated space on the HVLT-R form.


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•
Administer ‘Part B – Delayed Recall’ after completing all Trail Making Tests and the COWAT. There 
should be at least 20 minutes between ‘Part A’ and ‘Part B’ of the HVLT-R. If the time is too short, 
allow the patients to complete a questionnaire.
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those 
words as you can remember.”
•
Check the box on the corresponding line of the HVLT-R worksheet for each word the patient 
accurately recalls.
•
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and 
say nothing to the patient about the word not being on the list.
•
There is no time limit for each recall trial. However, if the patient does not produce any words for 
10-15 seconds, ask the patient if he/she can remember any more words.
•
If not, record the number of words that were correctly recalled on the summary form.
Part C – Delayed Recognition
Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the 
original list, and some are not. After I read each word, I’d like you to say “Yes” if it was on the 
original list or “No” if it was not. Was [word] on the list?”
•
Read the words from the top of the columns down.
•
Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response.
•
Guessing is allowed.
•
If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the 
reason on the Neurocognitive Evaluation Summary Form (CS).
•
The score for this portion of the HVLT-R is the number of list words (i.e., words that in CAPS) correctly 
identified (“yes” response) minus the number of non-list words (i.e., words in lower case) incorrectly 
identified (“yes” response). Therefore, the actual score can range from –12 (no list words identified 
and all non-list words identified) to +12 (all list words identified and no non-list words identified).


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APPENDIX 3 – QOL QUESTIONNAIRES


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APPENDIX 4 – Cordova et al. 2016


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