Conditions: High Grade Glioma Astrocytoma, Grade III Glioblastoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 177
Healthy volunteers: no

Brief summary:
This is a Phase 2 study of newly diagnosed patients with high grade glioma (HGG) undergoing standard radiation therapy and temozolomide treatment. BMX-001 added to radiation therapy and temozolomide has the potential not only to benefit the survival of high grade glioma patients but also to protect against deterioration of cognition and impairment of quality of life. BMX-001 will be given subcutaneously first with a loading dose zero to four days prior to the start of chemoradiation and followed by twice a week doses at one-half of the loading dose for the duration of radiation therapy plus two weeks. Both safety and efficacy of BMX-001 will be evaluated. Impact on cognition will also be assessed. Eighty patients will be randomized to the treatment arm that will receive BMX-001 while undergoing chemoradiation and 80 patients randomized to receive chemoradiation alone. The sponsor hypothesizes that BMX-001 when added to standard radiation therapy and temozolomide will be safe at pharmacologically relevant doses in patients with newly diagnosed high grade glioma. The sponsor also hypothesizes that the addition of BMX-001 will positively impact the overall survival and improve objective measures of cognition in newly diagnosed high grade glioma patients.

Detailed description:
160 patients will be enrolled and randomized with a treatment arm allocation ratio of 1:1 in the Phase 2 study. At enrollment, patients will be assessed with medical history, physical/neurological examinations, standard laboratory evaluations (CBC with differential and comprehensive metabolic panel (CMP)), baseline brain MRI with and without gadolinium, cognitive testing and patient-reported outcome questionnaires of HRQoL. On the first day of BMX-001 (loading dose), patients will be evaluated with medical history, patient physical/neurological examinations, and standard laboratory evaluations (CBC with differential and CMP), and ECG. Patients in Arm A will be administered BMX-001 subcutaneously first as a loading dose before the start of chemoradiation and then at maintenance dose (50% of the loading dose) twice a week for 8 weeks. Because oxidative stress continues to occur for up to several weeks following RT, the proposed protocol includes administering BMX-001 both before the start of RT and continuing for 2 weeks after the completion of RT and TMZ. TMZ will be dosed at 75 mg/m2 orally daily for 42 days and RT will be delivered in daily fractions of 1.8-2 Gy given 5 days a week for 6 weeks for a total of 59.4-60 Gy. During standard RT and TMZ, CBC with differential and CMP will be obtained weekly. Two weeks after the completion of standard RT and TMZ and every 8 weeks during adjuvant TMZ, patients will be evaluated with the following: medical history, physical/neurological examinations, Brain MRI with and without gadolinium, cognitive testing and patient-reported outcome questionnaires of HRQoL. Two weeks after the completion of chemoradiation, patients will transition to adjuvant chemotherapy with TMZ dosed at 150-200 mg/m2 orally for 5 days of a 28-day cycle for a total of 12 cycles. In light of the findings that BMX-001 can spare radiation-induced hair loss in a mouse model \[41\], we will evaluate and describe hair loss as an exploratory outcome in HGG patients by evaluating hair at baseline and then every 8 weeks. Patients will be discontinued from the study if they experience progression of disease, death or withdraw informed consent.

Arms:
arm 1: Patients will receive standard of care radiation therapy plus temozolomide (TMZ). BMX-001 will be given by subcutaneous injection with a loading dose of 28 mg/subject given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses at half the loading dose for a total of 8 weeks. A total of 80 subjects will receive BMX-001 in this phase. arm 2: In this arm, one-half of the study subjects will not receive BMX-001 but will undergo all components of standard therapy (radiation therapy plus temozolomide \[TMZ\]). A total of 80 subjects will be in this study arm. arm 3: All subjects enrolled will receive BMX-001 at one of 4 different dose levels. BMX-001 will be given by subcutaneous injection with a loading dose given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses (half the dosing dose) for a total of 8 weeks. Subjects will also undergo standard therapy (radiation therapy plus temozolomide \[TMZ\])

Interventions: intervention 1: BMX-001 intervention 2: Radiation Therapy intervention 3: Temozolomide
Intervention descriptions: intervention 1: BMX-001 consists of a porphyrin ring with pyridyl groups attached at each of the four methane bridge carbons. The nitrogen in the pyridyl ring is at the 2 position and has a side chain consisting of six carbons with an ether linkage. A manganese atom is chelated into the porphyrin ring and is the active center of the molecule. This molecule is an enzymatic scavenger of free radical species operating at close to diffusion-limited rates. intervention 2: RT will be delivered in daily fractions of 1.8-2 Gy given 5 days a week for 6 weeks for a total of 59.4-60 Gy. intervention 3: Initially, temozolomide (TMZ) will be dosed at 75 mg/m2 orally daily for 42 days. Two weeks after the completion of chemoradiation, patients will transition to adjuvant chemotherapy with TMZ dosed at 150-200 mg/m2 orally for 5 days of a 28-day cycle for a total of 12 cycles.

Protocol document:
ICF_002.pdf: 
 
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RESEARCH SUBJECT CONSENT FORM 
 
TITLE: 
A Phase 1/2 Trial for Patients with Newly Diagnosed High Grade 
Glioma Treated with Concurrent Radiation Therapy, 
Temozolomide, and BMX-001 
 
PROTOCOL NO.: 
BMX- HGG-001- Phase 2 
WIRB® Protocol #20151095 
 
SPONSOR: 
BioMimetix JV, LLC 
 
INVESTIGATOR: 
Name 
Address 
City, State, Zip Code 
Country  
 
STUDY-RELATED 
PHONE NUMBER(S): 
Name 
Number(s) (24 Hours) 
[24-Hour Number Required] 
 
You are being invited to take part in a research study.  A person who takes part in a research 
study is called a research subject, or research participant.  
 
Concise Summary 
 
Your consent is being sought for a research study.  Your participation is voluntary.   
 
The purpose of the study is to test the effect of the investigational study drug (BMX-001) in 
combination with radiation therapy and temozolomide.  This is a combination Phase 1/ Phase 
2 study.  The Phase 1 portion of the study was conducted to help determine the safety of the 
drug as given in humans for the first time as well as to establish the best dose to be given for 
the Phase 2 portion of the study.   Phase 1 is completed, if you decide to participate you will be 
taking part in Phase 2.  Phase 2 is a randomized study.  You will be randomly assigned (like 
the flip of a coin) to receive either BMX-001 and participate in Arm A or participate in Arm B 
(without BMX-001). Overall survival will be measured and side effects will be evaluated.  
This study will also assess the effect of BMX-001 in terms of protecting your brain from the 
worsening of cognitive (thinking) abilities and quality of life that is sometimes experienced 
when undergoing treatment with radiation therapy and temozolomide (Temodar®) for high 
grade glioma.  It is thought BMX-001 may be effective in preventing memory and thinking 
problems after radiation therapy, although there is no proof of this yet.  In this study, subjects 
are randomized to get either the investigational agent BMX-001 with radiation therapy and 
temozolomide or just temozolomide and radiation therapy alone.  BMX-001 is injected under 
the skin. The first dose is given a couple of days before radiation therapy (RT) starts, and then 
twice a week for 8 weeks. You will continue to be part of this study for as long as you are 
receiving care for your high grade glioma.  There are risks to this study drug that are described 
in this document.  Some risks include irritation at the injection site, feeling tired, a temporary 


 
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drop in blood pressure and in rare incidences a skin reaction. 
 
The study will also collect information on your quality of life, side effects of the treatment, 
survival and neurocognitive effects before and after temozolomide and radiation therapy is 
given.  You have other options instead of being in this study such as receiving alternative 
investigational drugs, choosing an alternative chemotherapy treatment, you could also choose 
to receive the standard therapy for this disease, and you can also choose to receive no therapy 
at this time and receive care to help you feel more comfortable.   
 
If you are interested in learning more about this study, please continue reading below. 
 
What should I know about this research? 
 
• Someone will explain this research to you. 
• This form sums up that explanation. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• You can choose not to take part. There will be no penalty or loss of benefits to which you 
are otherwise entitled. 
• You can agree to take part and later change your mind. There will be no penalty or loss of 
benefits to which you are otherwise entitled. 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 
 
Why is this research being done? 
 
The purpose of this research is to study the effect of the investigational study drug (BMX-001) in 
combination with radiation therapy and temozolomide.  BMX-001 is investigational, which 
means that it is not approved by the Food and Drug Administration (FDA).  BMX-001 is an 
investigational new class of compound that would be termed "a redox-active metalloporphyrin."  
This drug was designed to mimic the body's most powerful antioxidant enzymes and is a potent 
anti-inflammatory that acts by blocking multiple steps in the inflammatory cascade. By 
inhibiting the inflammatory cascade BMX-001 is expected to protect normal tissues from the 
inflammatory side-effects of radiation and chemotherapy while at the same time acting as an 
antioxidant that will have an inhibitory effect on the growth of tumor. Overall survival will be 
measured and side effects will be evaluated.  This study will also assess the effect of BMX-001 
in terms of protecting your brain from the worsening of cognitive (thinking) abilities and quality 
of life that is sometimes experienced when undergoing treatment with radiation therapy and 
temozolomide (Temodar®) for high grade glioma.  BMX-001 is thought to reduce the toxicities 
(bad side effects) of radiation therapy to the brain. 
 
You are being asked to take part in this research study because you have been newly diagnosed 
with a malignant (cancerous) brain tumor.   
 
Research studies are voluntary and include only people who choose to take part.  Please read this 
consent form carefully and take your time making your decision. As your study doctor or study 
staff discusses this consent form with you, please ask him/her to explain any words or 


 
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information that you do not clearly understand.  We encourage you to talk with your family and 
friends before you decide to take part in this research study.  The nature of the study, risks, 
inconveniences, discomforts, and other important information about the study are listed below. 
 
Providing direct medical benefit to you is not the main purpose of this study.  The purpose of the 
Phase 2 is to see if adding the study drug, BMX-001 will provide benefit as compared to the 
standard of care treatment alone.  Please carefully read the sections on risk and benefits below. 
 
This is a combination Phase 1/ Phase 2 study.  The Phase 1 portion of the study was conducted to 
help determine the safety of the drug as given in humans for the first time as well as to establish 
the best dose to be given for the Phase 2 portion of the study.   Phase 1 is completed, if you 
decide to participate you will be taking part in Phase 2.   
 
Please tell the study doctor or study staff if you are taking part in another research study. 
 
About 160 subjects will take part in this research at up to 10 clinical centers.   
 
How long will I be in this research? 
 
If you receive the study drug, BMX-001 (subjects in Arm A), you will first receive it a few days 
before, or on the day you start radiation therapy.  You will then continue to receive the study 
drug twice a week for the next 8 weeks, approximately 6 weeks during your radiation therapy, 
and then for 2 more weeks afterwards.  Subjects who do not receive the study drug (Arm B) will 
have a few study visits less than the subjects in Arm A.  All subjects will be followed after 8 
weeks of being in the study, every 8 weeks for up to 12 cycles of adjuvant temozolomide.  We 
expect that your taking part in this research will last as long as you are receiving treatment for 
your high grade glioma at [Institution].   You may remain in this study, as long as your tumor 
does not get larger (progresses) or there are no bad side effects. 
 
The study doctor may also take you off the study if new scientific developments occur that 
indicate the treatment is not in your best interest, or he/she feels that this treatment is no longer 
in your best interest. 
 
We will tell you about new information that may affect your health, welfare, or willingness to 
stay in this study. 
 
You can choose to stop participating at any time without penalty or loss of any benefits to which 
you are entitled. However, if you decide to stop participating in the study, we encourage you to 
talk to your doctor first. 
 
What happens to me if I agree to take part in this research? 
 
Screening 
If you agree to be in this study, you will be asked to sign and date this consent form.  Many of 
these procedures will take place up to three weeks before you start the study drug or before you 
start radiation treatment.  You will have the following tests and procedures to make sure that you 
are eligible: 


 
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§ Vital signs, including blood pressure 
§ History and physical exam including a full neurological exam (brain and nervous system 
function)  
§ Blood draw (by needlestick) for hematology (blood counts), blood chemistry tests, and 
blood clotting ability  
§ Blood pregnancy test, if you are female of childbearing potential, within 2 days of 
starting the study drug 
§ Tumor measurement using MRI (scan that uses magnets) 
§ An Electrocardiogram (ECG) 
§ Assessments of Quality of Life (used to evaluate the general well-being of individuals) 
§ Neurocognitive Testing (used to evaluate the ability to think and reason). You will be 
evaluated for neurocognitive performance using computerized and paper standard 
neurocognitive testing. 
§ Pictures of your hair to evaluate for possible hair loss associated with radiation therapy. 
These pictures are not required and will only be done with your consent. 
 
After completion of the screening process, the doctor will determine whether you are eligible to 
participate in the treatment part of the study.  If you are eligible and you choose to participate, 
you will be enrolled in the study.  If you do not meet the eligibility requirements, you cannot take 
part in this study, in which case your doctor will inform you of other options that are available to 
you. 
 
The tests during screening and throughout the study are explained in more detail below: 
 
Magnetic Resonance Imaging Scans (MRIs)/Diffusion Tensor Imaging (DTI):  MRIs use a 
magnet and radio waves to make diagnostic medical images of the body. As this test uses a 
magnet, it is possible that the magnet could attract certain types of metal within your body.  
Therefore, we will carefully ask you about metal within your body (this includes certain dyes 
found in tattoos).  If there is any question about potentially hazardous metal within your body, 
you will be excluded from the study.  The MRI involves entering a large room in which a magnet 
is present. You will be placed on a narrow bed and then slid into a small tunnel approximately 6 
feet in length and 25 inches in diameter.  You will be asked to lie still for about one hour on this 
bed. You will hear a loud machine-like noise. You may be asked to have a harmless monitoring 
device applied during the study. During the study, you can have voice contact and physical 
contact with someone in attendance if you desire.  You may be given a dye intravenously 
(through a vein) in order enhance the MRI image. 
 
As part of this trial, the MRI performed will be modified (called Diffusion Tensor Imaging or 
DTI), in order to study improved ways to evaluate your condition. Your MRI scans as part of this 
trial will be slightly longer (less than 10 minutes) than routine MRIs. There will be no extra 
injections or cost to you that comes from this modified scan.  We use MRIs to study tumor 
progression and DTIs to study white matter protection.   
 
Electrocardiogram (ECG): ECG is a diagnostic tool that is routinely used to assess the electrical 
and muscular functions of the heart. This will be done at the screening visit (for all subjects) and 
for subjects in Arm A also on the first day you receive the study drug and during weeks 1 and 4, 


 
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before and about 60 minutes after the initial study drug injection.   
 
Blood Tests:  In total, 18 ml approximately 4 teaspoons of blood will be drawn from your arm by 
a needlestick for the evaluations before starting study drug during the screening period.  During 
the course of the study, complete blood count (CBC) tests will be drawn (approximately 
1 teaspoon) weekly, beginning at Week 2, while you are receiving radiation therapy and 
temozolomide and for 2 weeks afterward, and then on days 21 and 28 while you are receiving 
adjuvant (added) temozolomide (that is, temozolomide the first 5 days of each 28-day cycle).  
Blood chemistry (CMP) tests also will be drawn (approximately 1 teaspoon of blood) weekly 
beginning at Week 2, while you are receiving radiation therapy and temozolomide and for 
2 weeks afterward, and then at day 21 of each cycle while you are receiving adjuvant 
temozolomide (that is, temozolomide the first 5 days of each 28-day cycle). 
 
A blood test to determine how well your blood clots will be drawn during the screening period 
(less than 1 teaspoon of blood [3 mL]). 
 
For women of childbearing potential, a blood test to rule out pregnancy will be done during the 
screening period within 48 hours prior to starting the study drug.  Approximately 1 teaspoon of 
blood will be taken to perform this test. 
 
In total, approximately 14 teaspoons (70 mL) of blood will be drawn during the study period 
when you are receiving radiation therapy and temozolomide for standard clinical blood tests such 
as CBC and CMP tests.  In total approximately 36 teaspoons (180 mL) will be drawn over a 
12-month period while you will be receiving adjuvant temozolomide for standard clinical blood 
tests, such as CBC and CMP tests. 
 
Quality of Life:  Assessed by using patient report outcomes (PROs).  PROs refer to the subjective 
report of symptoms, concerns, and feelings.  This will be evaluated using questionnaires.  These 
questionnaires will ask questions about your mood, sleep, thoughts, feelings, physical function, 
thinking, and overall well-being.  Questionnaires will be on paper and will be completed with 
pen. 
 
Neurocognitive Testing: Testing will be performed on the computer, with a tester, and/or on 
paper.  For the computer testing, the program consists of verbal and visual memory tests, 
attention tests, reasoning tests and speed of processing tests.   You will use a laptop computer or 
iPad to complete these tests.  No previous exposure to computers, tablets or computer testing is 
needed to complete the test.  For the tests that you complete on an iPad, the verbal responses you 
provide during the tests will be audio recorded.   These audio recordings will be used by the 
representatives of the sponsor to make sure that your responses are recorded correctly.  The 
audio recordings will be retained for the period of time specified for all other study data or as 
required by law.    
 
Please see the chart in the “Study Procedure” section below for the frequency of Quality of Life 
and Neurocognitive Testing evaluations you will have while participating in this study. 
 
It will take approximately two hours to complete neurocognitive testing and to fill out the 
questionnaires. 


 
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You will not receive the results of the neurocognitive testing you perform during the study. 
 
Additional tests may be done at the discretion of your physician as part of your regular care 
throughout the study. These exams and tests will be done to monitor the effects of study drugs. 
 
Optional Photographs to Assess Hair Loss: In order to assess potential hair loss from radiation 
therapy, photographs may be taken of your scalp. The photographs will be taken of the 
craniotomy surgical incision site and surrounding area. The camera will be held approximately 
6-48 inches from the incision. There will be no identifiers on the photographs. Up to 6 
photographs may be taken at any one time-point. Photographs will not include your entire face 
(will not include your eyes, nose, mouth). The photographs will be taken by the PI or trained 
staff and may be uploaded to the electronic medical record, kept in a separate electronic research 
file or on paper. The photographs may be uploaded to the electronic medical record by using 
electronic applications for iPhones or for iPads or tablets.   These applications allow for the 
photograph to be uploaded directly and are not stored on the device taking the picture. If you 
agree to have your photograph taken, the study team will take the photograph of your craniotomy 
incision site at baseline (when you go on study), after you complete radiation and temozolomide 
(2-4 weeks after completion) and approximately every 8 weeks while you are on the study. 
 
Whether or not you decide to have these pictures taken you can still participate fully in all other 
aspects of the study as described in this consent form. While the photographs will not include 
your face, (eyes, nose or mouth) and will not have your name or other personal identifiers, there 
is a risk that the photo could be left on the individual employee or work Phone or the institution 
device.   
 
I consent to have pictures of my scalp as described above:  
 (initials)  
 Date 
 
I do NOT consent to have pictures taken my scalp as described above:  
 (initials)  
 Date 
 
Study Procedures 
This is a randomized study.  You will be randomly assigned (like the flip of a coin) to receive 
either BMX-001 and participate in Arm A or participate in Arm B (without BMX-001).  You 
have a 1 in 2 chance of receiving the study drug (BMX-001).  You cannot choose your study 
group. If you are randomized to receive BMX-001, less than 12 weeks after surgery for your 
malignant brain tumor, you will receive a loading dose (which is a higher dose given in two 
injections) of BMX-001 injected under your skin (on your torso, upper leg or upper arm) the day 
before you start radiation therapy and temozolomide.  Thereafter, you will receive a lower dose 
(given in one injection) injection of BMX-001 under your skin twice each week for the 
approximately 6 weeks that you will be receiving radiation therapy and temozolomide, along 
with 2 weeks after chemoradiation.  This will be the end of your treatment with BMX-001. The 
total planned number of doses of BMX-001 that you will receive will be 17 doses. 
 
If your malignant brain tumor does not appear to get worse 2-4 weeks after radiation therapy, but 
not greater than 8 weeks, you will begin standard of care adjuvant (added) temozolomide per 
standard dosing.  The temozolomide will be daily for 5 days, days 1-5 of each cycle.  Each cycle 
will be 4 weeks. The dose of temozolomide will be reduced if you have an adverse event (bad 


 
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effect) that the study doctor attributes to temozolomide. You will receive the drug temozolomide 
by mouth in a fasting state (nothing to eat for one hour prior to each dose and for two hours after 
each dose).  The actual number of temozolomide capsules you take will vary depending upon 
your height and weight. 
 
The charts below show what evaluations you will have during this study.  The left-hand column 
tells you which evaluations will be done and the right-hand column shows the relative time 
frame within the part of the study. 
 
Evaluations Prior to the start of RT and TMZ/ Loading Day (First BMX-001 Dose for subjects 
in Arm A) 
Medical History and Physical with full Neurological Examinations 
Toxicity Assessment 
Vital signs, including blood pressure 
Electrocardiogram (ECG) – Arm A only 
MRI (DTI/Susceptibility Imaging) 
 
Evaluations During Radiation Therapy/Temozolomide +/- BMX-001 
Medical History and Physical with full Neurological Examinations 
Every 2 weeks 
ECG -Arm A only 
 
First day of BMX-
001, Week 1 and 
Week 4 before and 60 
minutes after the 
injection. 
Vital signs, including blood pressure 
Every week 
Complete Blood Count (CBC) with differential (blood count test) 
Weekly 
Comprehensive Metabolic Panel (CMP)- blood chemistry test 
Weekly  
Toxicity assessment 
Continuous 
 


 
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Evaluations During Adjuvant Temozolomide 
History and Physical with Neurological Examination 
Every 8 weeks 
CBC with differential 
About at days 21 and 
28 of each 28 day 
cycle 
CMP 
About on day 21 of 
each 28 day cycle 
MRI of the brain 
Every 8 weeks 
Toxicity (adverse event or bad effect) assessment 
Continuous a 
Quality of Life Assessments 
Every 8 weeks 
Neurocognitive Testing 
Every 8 weeks b 
MRI (DTI/Susceptibility Imaging) 
Before starting 
adjuvant 
temozolomide and 
6 months after 
completion of 
radiation therapy 
a You should contact your study doctor at any time to let him or her know of any bad side effects 
that you might be having. 
 
b. Some additional neurocognitive tests will be performed before the start of the first cycle of 
adjuvant temozolomide, and about 6 and 12 months after you complete radiation therapy. 
 
Optional Photographs for Hair Loss Evaluation 
Photographs of your scalp (optional) 
Baseline 
2-4 weeks after 
radiation therapy 
Approximately every 
8 weeks while on the 
study 
 
After the completion of treatment, we will continue to contact you to see how you are doing.   
 
What are my responsibilities if I take part in this research? 
 
If you take part in this research, you will be responsible for following the guidelines included in 
this informed consent form.    
 


 
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Could being in this research hurt me? 
 
Side effects of study drugs and procedures may be mild or they may severe enough to be life 
threatening.  They may resolve (stop) after you stop the study drug or procedure or they may 
continue.  Adding BMX-001 to standard of care therapy may interfere with the effectiveness of 
radiation or chemotherapy. 
 
As a result of your participation in this study, you are at risk for the following side effects: 
 
BMX-001 may cause some, all or none of the side-effects listed below.  BMX-001 has only been 
given to animals before.  Side effects are dose-dependent and the relatively low doses of this 
drug planned in this study have not been associated with side effects in animals other than those 
related to the color of the injected drug. 
 
The most common side effects (expected to occur in more than 30% of subjects) are: 
 
• Red to brown discoloration of the skin at the injection site which may take up to several 
weeks to resolve 
• Irritation at the site of the injection of the drug under the skin 
• Transient tachycardia (fast heart beat) after receiving the study drug  
 
Less common side effects (expected to occur in 10-30% of subjects) are: 
 
• Pain at the site of the injections of the drug under the skin 
• Local histamine release which could be caused by the study drug. This could cause 
pruritus (itching), erythema (redness), edema (swelling), urticaria (welts).  This is 
expected to resolve within a couple of hours of injection.   
 
Rare side effects (expected to occur in less than 10% of subjects) are: 
 
• Temporary hypotension (low blood pressure) 
• Malaise or “not feeling well” for a few hours 
• Prolongation of the QT interval after the loading dose.  This is a condition in which your 
heart muscle takes slightly longer than normal to recharge between beats. This can be 
seen on an ECG, and is called a prolonged QT interval. We will monitor this by 
performing ECGs before and after study drug administration the first day you receive the 
drug and then twice (or more if indicated by your doctor) during BMX-001 treatment.  
Many drugs are known to cause this.  For more information about this please discuss with 
your study doctor.   
 


 
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Additional possible side effects are: 
 
• Red to dark color of urine 
• Light-activated skin rash in response to sun exposure 
• It is also possible that previously unobserved and unexpected side effects could occur. 
 
Temozolomide may cause some, all or none of the side effects listed below (Arm A and Arm B). 
 
The most common side effects (occurring in more than 30% of subjects) were: 
 
• Fatigue 
• Nausea 
• Hair loss 
 
Less common side effects (occurring in 10-30% of subjects) were: 
 
• Thrombocytopenia (low platelets) 
• Loss of appetite 
• Headache 
• Constipation 
• Diarrhea 
• Vomiting 
• Rash 
• Swelling in extremities 
 
Rare side effects (occurring in less than 10% of subjects) were: 
 
• Abdominal and/or breast pain 
• Dry skin, skin redness, and/or itching 
• Inflammation of the mouth, throat and/or sinuses 
• Dizziness, weakness 
• Confusion, memory impairment 
• Anxiety, depression 
• Joint and muscle pain 
• Trouble sleeping 
• Change in sense of taste 
• Blurred vision 
• Coughing or shortness of breath 
• Urinary incontinence/frequency, urinary tract infection 
• Weight increase 
• Seizures/convulsions 
• Adrenal hypercorticisim (elevated hormone levels) 
• Low white blood cell (WBC) count 
• Allergic reaction, sometimes severe 
• Anemia (decreased number of red blood cells), which may cause symptoms of shortness 


 
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of breath, weakness, and fatigue. 
 
Rare and Serious 
 
• Liver damage which may cause yellowing of eyes and skin and swelling and may result 
in liver failure 
 
Rarely, unusual (“opportunistic”) infections have occurred.  Rare cases of erythema multiforme 
(skin condition) have been reported which got better after temozolomide was stopped and, in 
some cases, recurred upon restarting treatment with temozolomide. 
 
Very rare side effects have included secondary cancers including leukemia and myelodysplastic 
syndrome (MDS).  MDS is a disorder of the bone marrow in which blood cells that do not 
function normally are produced. 
 
Reproductive studies have not been done with temozolomide.  Immature sperm and testicular 
atrophy (wasting away) occurred in studies with rats and dogs, using doses of temozolomide 
¼ and 5/8 of the recommended human doses.  In animal studies temozolomide caused death and 
multiple malformations of unborn young in rats and rabbits exposed during pregnancy. 
 
Risks and Side Effects of Radiation Therapy: The radiation you will receive is considered 
standard of care for your tumor. The amount of radiation you will receive by participating in this 
study is the same as for patients with the same disease who are not taking part in this study. 
 
Early side effects of radiation that may start while you are receiving radiation include hair loss, 
scalp redness, inflammation of the ear canals, and fatigue. In a few patients, radiation contributes 
to headaches or nausea. Rarely, tumors may swell during radiation causing neurological 
symptoms such as weakness on one side, visual loss, or changes in mental function. There is a 
small chance of long-term effects from radiation, occurring months or years after completion. 
These may include worsening of mental function, hearing, vision, strength and coordination. 
Rarely, radiation may cause the development of benign or malignant tumors around the brain or 
skull. It is unknown whether temozolomide increases the risk of any of the early or late side 
effects of radiation. 
 
MRI:  There have been no ill effects reported from exposure to the magnetism or radio waves 
used in this test. However, it is possible that harmful effects could be recognized in the future. A 
known risk is that the magnet could attract certain kinds of metal. Therefore, we will carefully 
ask you about metal within your body (this includes certain dyes found in tattoos). If there is any 
question about potentially hazardous metal within your body, you will be excluded from the 
study. We will also keep the examining room locked so that no one carrying metal objects can 
enter while you are in the scanner. 
 


 
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The most common side effects of the MRI contrast agents are local warmth/pain at the injection 
site, nausea and/or vomiting.  Serious allergic reactions are very rare, may occur and may be life-
threatening.  A rare but serious adverse reaction has been observed in patients that received a 
gadolinium-based contrast material during MRI examinations, a reaction called nephrogenic 
systemic fibrosis (NSF). Patients with kidney disease are at increased risk of developing NSF. 
NSF may cause skin thickening, joint pain and/or swelling. In rare cases NSF can lead to lung 
and heart problems and cause death. To minimize the likelihood that you will be affected, you 
will have a blood test to measure your kidney function. If your blood test is abnormal, you will 
not be permitted to receive gadolinium. 
 
Blood Draws:  The collecting of blood samples to monitor your health and do PK throughout 
this study may cause mild discomfort or pain from the needle puncture and possible bruising or 
mild bleeding.  The risk of infection is slight and will be further reduced by keeping the puncture 
site clean and dry. 
 
Drug and Food Interactions: For your safety, you must tell the study doctor or nurse about all 
the prescribed medical food and drugs, herbal products, over-the-counter (OTC) drugs, vitamins 
and natural remedies that you are taking before you start the study and before taking any of these 
products while you are on the study. 
 
Neuro-Cognitive Testing: There are few physical risks associated with this type of testing. 
Frustration with completing the mental tasks is the most common risk of this testing. Some 
individuals can feel stressed and anxious during testing. You should discuss these feelings with 
your physician if you are concerned. 
 
Confidentiality: There is also the potential risk of loss of confidentiality. Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed. Some of the 
questions we will ask you as part of this study may make you feel uncomfortable. You may 
refuse to answer any of the questions and you may take a break at any time during the study. You 
may stop your participation in this study at any time. 
 
There may be risks, discomforts, drug interactions or side effects that are not yet known. 
 
For those of Reproductive Potential 
 
Female 
Being a part of this study while pregnant may expose the unborn child to significant risks, some 
of which may be currently unforeseeable.  Therefore, pregnant women will be excluded from the 
study.  If you are a woman of childbearing potential, a blood pregnancy test will be done (using 
1 teaspoon of blood drawn from a vein by needle-stick), and it must be negative before you can 
continue in this study.  If sexually active, you must agree to use appropriate contraceptive 
measures for the duration of the study and for 12 months afterwards. Medically acceptable 
contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), 
(2) approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or 
(4) an intrauterine device (IUD). Contraceptive measures such as Plan B(TM), sold for emergency 
use after unprotected sex, are not acceptable methods for routine use.  If you do become pregnant 


 
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during this study or if you have unprotected sex, you must inform your study physician 
immediately. 
 
Male 
Your participation in this research may damage your sperm, which could cause harm to a child 
that you may father while on this study.  Such harm may be currently unforeseeable.  If you are 
sexually active, you must agree to use a medically acceptable form of birth control in order to be 
in this study and for 12 months afterward. Medically acceptable contraceptives include: 
(1) surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide.  
Contraceptive measures such as Plan B(TM), sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. You should inform your partner of the potential for harm to 
an unborn child.  She should know that if pregnancy occurs, you will need to report it to the 
study doctor, and she should promptly notify her doctor. 
 
Will it cost me money to take part in this research? 
 
There will be no additional costs to you as a result of being in this study.  However, routine 
medical care for your condition (care you would have received whether or not you were in this 
study) will be charged to you or your insurance company.  You may wish to contact your 
insurance company to discuss this further.  In order to make sure that tests and studies done 
solely for research purposes are charged correctly, we will carefully monitor your charges as 
long as you are participating in this study.  These tests and studies are not a part of routine care, 
and people who are not part of the study do not usually have them performed.  Please talk to the 
research team if you would like to know more about which tests and studies are being done 
solely for research purposes. 
 
BMX-001 is provided free of charge by BioMimetix, JV LLC while you are on study.  
Temozolomide is commercially available and will not be supplied free of charge. Radiation 
therapy is standard of care and will not be supplied free of charge. 
 
1. The ECGs are research-related costs and will not be charged to you or your insurance.  
The MRI for DTI/Susceptibility Imaging may or may not be covered, please discuss with 
your study doctor.   
 
If you do not sign this consent form, you will continue to receive care, but not as a part of this 
study. 
 
Will being in this research benefit me? 
 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits to you may include protection against cognitive decline caused by radiation 
therapy and/or reduction and/or remission of your high grade glioma. Additionally, a potential 
benefit may include protection against development of thrombocytopenia (a condition in which 
you have a low blood platelet count) which is caused by treatment with TMZ. About 15% of the 
subjects receiving TMZ as part of standard therapy for HGG develop thrombocytopenia. These 
subjects are at risk for a bleeding complication and may have their cancer therapy interrupted to 
allow recovery of the bone marrow. However, because this clinical protocol is experimental, it 


 
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cannot be guaranteed that subjects will receive any benefit as a result of participating in this 
research study. 
 
We hope that in the future the information learned from this study will benefit other people with 
your condition. 
 
During this research project, new information regarding the risks and benefits of the study may 
become known to the investigators.  If this occurs, they will tell you about this new information.  
New information may show that you should no longer participate in the research.  If this occurs, 
the persons supervising the research will stop your participation in it.  In either case, you will be 
offered all available care that suits your needs and medical conditions. 
 
What other choices do I have besides taking part in this research? 
 
Instead of being in this study, you have these options: 
 
• You could choose to receive alternative investigational drugs. 
• You could choose to receive an alternative chemotherapy treatment. 
• You could choose to receive the standard therapy for this disease. 
• You could choose to receive no therapy at this time and receive care to help you feel 
more comfortable.  If you choose this option, you may reconsider at any time, and this 
decision will in no way affect the regular care that you receive. 
 
Please talk to your doctor about these and other options. 
 
What happens to the information collected for this research? 
 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
 
• The research sponsor, BioMimetix JV, LLC 
• People who work with the research sponsor 
• Government agencies, such as the Food and Drug Administration 
• The Institutional Review Board (IRB) that reviewed this research 
• The Data Safety Monitoring Board 
 
Study records that identify you will be kept confidential as required by law. Federal Privacy 
Regulations provide safeguards for privacy, security, and authorized access. Except when 
required by law or for your care, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records disclosed 
outside of [Institution].  An exception to this is that your date of birth, the dates that you 
complete the questionnaires, your audio recorded neurocognitive testing sessions, and other 
study procedures and computer internet protocol (IP) addresses will be included in the 
information sent to VeriSci (previously called NeuroCog), a group outside of [Institution] that 
collects this data on our behalf. The results of the neurocognitive tests conducted on the iPad and 
the audio recordings included with them will be stored on a secure cloud based server maintained 


 
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by VeraSci.  The electronic files, including the audio files, will be retained for the period of time 
specified for all other study data or as required by law.  For all records disclosed outside of the 
clinical center, you will be assigned a unique code number. The key to the unique code number 
will be maintained electronically on a secure network, which is accessible only to key personnel 
for the study and is password protected. 
 
As part of the study, the study team will report the results of your study-related laboratory tests 
and imaging to BioMimetix JV, LLC.  Additionally, tests used to diagnose your cancer will be 
reported to the sponsor.  Tests to be provided to the sponsor would include laboratory tests such 
as your blood counts and tests to measure the function of your liver and kidneys, pathology 
reports, neurological tests, and radiographic studies including MRI scans of your head.  As part 
of the study, your date of birth, dates of procedures and initials may also be reported to 
BioMimetix JV, LLC and people working with BioMimetix JV, LLC. In addition, your records 
may be reviewed in order to meet federal or state regulations.  Reviewers may include 
representatives from the Food and Drug Administration, representatives of BioMimetix JV, LLC, 
the Western Institutional Review Board [and the [Institution IRB]]. In addition, the data and 
conduct for this study will be monitored by an outside committee called a Data Safety 
Monitoring Board (DSMB). Data about your participation will be shared with the DSMB 
members for their review of overall safety of the study drug. Data shared may have dates of 
treatment, test/procedures, diagnosis, and your initials and study ID.  
 
If any of these groups review your research record, they may also need to review your entire 
medical record. 
  
The images from the modified MRI scans and any MRI scan obtained to follow your brain tumor 
performed within three months of the modified scans may be sent outside of the clinical center to 
research collaborators located at Duke University (the imaging analysis center for this study), or 
others such as neuroimaging researchers, grant funding agencies and/or foundations, such as the 
National Institutes of Health, and/or to other databases organized by the National Cancer 
Institute, such as the National Cancer Imaging Archive. For tests to be useful, limited identifiers 
like test dates and diagnosis are necessary. By signing this consent form you authorize 
[Institution] to send out these specific identifiers in any MRI images that are sent outside of 
[Institution]. 
 


 
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As part of this study, [Name] and his or her study team will ask you to have certain tests and 
radiographic studies.  Some of these blood and radiographic studies would have been done as 
part of your regular care.  These test results will be used both to treat you and to complete this 
research.  These test results will be recorded in your medical record and will be reported to 
BioMimetix JV, LLC. Results of tests and studies done solely for this research study and not as 
part of your regular care will also be included in your medical record. 
 
The study results may be retained in your research record forever.  Any research information in 
your medical record will also be kept indefinitely. 
 
This information may be further disclosed by the sponsor of this study, BioMimetix JV, LLC.  If 
disclosed by the sponsor, the information is no longer covered by the federal privacy regulations.  
We protect your information from disclosure to others to the extent required by law. We cannot 
promise complete secrecy. 
 
If this information is disclosed to outside reviewers for audit purposes, it may be further 
disclosed by them and may not be covered by the federal privacy regulations. While the 
information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your identity will not be revealed. 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential. 
 
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. 
 
Data or specimens collected in this research might be deidentified and used for future research or 
distributed to another investigator for future research without your consent. 
 
Who can answer my questions about this research? 
 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed above on the first page. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of 
people who perform independent review of research studies. You may talk to them at (800) 562-
4789, help@wirb.com if: 
 
• You have questions, concerns, or complaints that are not being answered by the research 
team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 


 
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• You want to talk to someone else about the research. 
• You have questions about your rights as a research subject. 
 
What if I am injured because of taking part in this research? 
 
Immediate necessary medical care is available at [Institution] in the event that you are injured as 
a result of your participation in this research study. However, there is no commitment by 
[Institution], BioMimetix, JV, LLC or your physicians to provide monetary compensation or free 
medical care to you in the event of a study-related injury. 
 
For questions about the study or research-related injury, contact [Name] at [Number].   
 
Can I be removed from this research without my approval? 
 
Your doctor may decide to take you off this study if your condition gets worse, if you have 
serious side effects, or if your study doctor determines that it is no longer in your best interest to 
continue.  The sponsor or regulatory agencies may stop this study at any time without your 
consent. A reason why this might occur includes new identification of an unexpected problem 
with the study drug.  If this occurs, you will be notified and your study doctor will discuss other 
options with you. 
 
What happens if I agree to be in this research, but I change my mind 
later? 
 
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw 
from the study at any time. If you withdraw from the study, no new data about you will be 
collected for study purposes unless the data concern an adverse event (a bad effect) related to the 
study.  If such an adverse event occurs, we may need to review your entire medical record.  All 
data that have already been collected for study purposes, and any new information about an 
adverse event related to the study, will be sent to the study sponsor. 
 
Your decision not to participate or to withdraw from the study will not involve any penalty or 
loss of benefits to which you are entitled, and will not affect your access to health care. If you do 
decide to withdraw, we ask that you contact [Name] in writing and let him/her know that you are 
withdrawing from the study.  The mailing address is [address].   
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in this research. 
 


 
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Will I be paid for taking part in this research? 
 
Subjects who agree to be in this study will have their external beam radiation treatment at 
[Institution]. The study sponsor will provide a travel stipend up to the amount of $1,000, to help 
compensate you for travel expenses associated with undergoing external beam radiation 
treatment at [Institution] while on this study. The travel stipend will be provided as follows: 
 
$100 for each week of radiation treatment (pro-rated for visits completed up to 6 weeks, for a 
total of $600), followed by $400 provided at the completion of week 8.  Payments will be 
provided after you have completed the 3rd week of standard radiation treatment here at 
[Institution].  At that time a check for $300 will be requested and mailed to your home. After you 
complete week 8, a second check for $700 will be requested and mailed to your home.   
 
In order to receive this stipend, an additional form needs to be completed and a social security 
number will have to be collected. 
 
Payment received as compensation for participation in research is considered taxable income to 
the research subject. If payment to an individual exceeds $600 in any one calendar year, 
[Institution] is required to report this information to the Internal Revenue Service (IRS). 
Research subject payments to a non-employee of [Institution] exceeding $600 during any 
calendar year will result in a 1099 (Miscellaneous Income) form being issued to the individual 
and a copy sent to the IRS. 
 
Statement of Consent:  
 
All subjects unable to consent are required to assent, unless the investigator determines that 
the capability of the subject is so limited that the subject cannot reasonably be consulted.  
 
Your signature documents your permission for you or the individual named below to take part in 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of subject 
Date 
 
(not required if subject personally provided consent) 
 
 
 
 
 
 
 
Signature of person obtaining consent 
Date 
 


 
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My signature below documents that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the subject, and that 
consent was freely given by the subject. 
 
 
 
 
 
 
 
Signature of witness to consent process 
Date 


 
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**For Sites in California** 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
RESEARCH PURPOSES  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research information 
with [enter SMO company name], an agent for the study doctor. delete if the site 
does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported, and 
• Western Institutional Review Board® (WIRB®)  
 
Why will this information be used and/or given to others? 
• to do the research,  
• to study the results, and  
• to make sure that the research was done right.   
 
If the results of this study are made public, information that identifies you will not 
be used. 
 
What if I decide not to give permission to use and give out my health 


 
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information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
This permission will be good until December 31, 2060. 
 
You may withdraw or take away your permission to use and disclose your health 
information at any time.  You do this by sending written notice to the study doctor.  
If you withdraw your permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you 
will be gathered after that date.  Information that has already been gathered may 
still be used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your 
permission. 
 
Authorization: 
I have been given the information about the use and disclosure of my health 
information for this research study.  My questions have been answered. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
AUTHORIZATION SIGNATURE: 
 
 
 
 
 
 
Signature of Subject 
 
Date 

Prot_000.pdf: 
Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 1 of 137 
Protocol #: BMX-HGG-001 
 
A Phase 1/2 Study 
 
A Phase 1/2 Trial for Patients with Newly Diagnosed High Grade Glioma 
Treated with Concurrent Radiation Therapy, Temozolomide, and  
BMX-001 
 
 
 
 
Sponsor: 
BioMimetix JV, LLC  
Funding Source: 
BioMimetix JV, LLC 
WIRB (Central IRB) 
Study #: 
20151095 
IND# 
124640 
 
 
Medical Monitor: 
Elizabeth A. Regan, MD, PhD 
BioMimetix JV, LLC 
303-921-1880 (cell) 
elizabeth.regan@bmxpharma.com 
 
 
 
Coordinating Center for Biostatistics and Imaging 
Duke University 
 
Coordinating Principal Investigator 
 
Katherine Peters, MD, PhD, FAAN 
The Preston Robert Tisch Brain Tumor Center 
Duke University Medical Center 
Box 3624 
Durham, NC 27710 
 
 
 
 
 
 
 
 
 
 
 


May 28, 2021


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 3 of 137 
2 PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I acknowledge that I have read and understand the BMX-HGG-001 protocol named above and agree 
to carry out all of its terms in accordance with applicable regulations and laws. 
I assure that the study drug supplied by the sponsor will be used only as described in the protocol 
named above. 
 
 
 
Principal Investigator Name Signed 
 
 
 
Date 
Principal Investigator Name Printed 
 
 
 
 
Clinical Center Name 
 
 
 
 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 4 of 137 
 
3 Table of Contents 
1 
SPONSOR SIGNATURE PAGE ......................................................................................................................... 2 
2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................................................ 3 
4 
LIST OF ABBREVIATIONS ............................................................................................................................... 9 
5 
PROTOCOL SYNOPSIS ..................................................................................................................................11 
5.1 
Purpose ............................................................................................................................................11 
5.2 
Phase 1 ............................................................................................................................................11 
5.2.1 
Primary Objective ........................................................................................................................11 
5.2.2 
Secondary Objectives ...................................................................................................................11 
5.2.3 
Exploratory Objectives .................................................................................................................11 
5.3 
Phase 2 ............................................................................................................................................11 
5.3.1 
Primary Objective ........................................................................................................................11 
5.3.2 
Secondary Objectives ...................................................................................................................11 
5.3.3 
Exploratory Objectives .................................................................................................................12 
5.4 
Design and Procedure.......................................................................................................................12 
5.4.1 
Phase 1 (Enrollment Complete) ....................................................................................................12 
5.4.2 
Phase 2 ........................................................................................................................................13 
5.5 
Selection of Subjects.........................................................................................................................13 
5.5.1 
Inclusion Criteria ..........................................................................................................................13 
5.5.2 
Exclusion Criteria .........................................................................................................................14 
5.5.3 
BMX-001 Specific Concerns ..........................................................................................................14 
5.6 
Risk/Benefit Assessment ...................................................................................................................15 
5.6.1 
Potential Benefits ........................................................................................................................15 
5.6.2 
Risks of BMX-001 .........................................................................................................................15 
5.6.3 
Risks of TMZ ................................................................................................................................16 
5.6.4 
Radiation Treatment Side Effects .................................................................................................17 
5.6.5 
Risks of Phlebotomy .....................................................................................................................17 
5.6.6 
Risks of MRI .................................................................................................................................17 
5.6.7 
Unknown Risks.............................................................................................................................18 
5.7 
Data Analysis and Statistical Considerations ......................................................................................18 
6 
STUDY SCHEMA ...........................................................................................................................................19 
7 
BACKGROUND AND SIGNIFICANCE ..............................................................................................................20 
7.1 
Study Disease ...................................................................................................................................20 
7.2 
Radiation-Induced Damage during Brain Tumor Treatment ...............................................................20 
7.3 
Cognition and HRQoL in HGG ............................................................................................................20 
7.4 
Thrombocytopenia ...........................................................................................................................22 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 5 of 137 
7.5 
BMX-001 ..........................................................................................................................................24 
7.6 
Study Rationale ................................................................................................................................25 
8 
OBJECTIVES AND ENDPOINTS ......................................................................................................................26 
9 
INVESTIGATIONAL PLAN ..............................................................................................................................29 
9.1 
Study Design ....................................................................................................................................29 
9.1.1 
Phase 1 Specific Design ................................................................................................................29 
9.1.2 
Phase 2 Specific Design ................................................................................................................31 
9.1.3 
Safety Considerations ..................................................................................................................31 
9.1.4 
Prolongation of QTc Interval and Management ............................................................................32 
9.1.5 
Missed Doses ...............................................................................................................................32 
9.1.6 
Concomitant Medications ............................................................................................................33 
9.1.7 
TMZ Treatment Plan ....................................................................................................................33 
9.1.8 
Radiation Treatment Plan.............................................................................................................33 
9.1.9 
Randomization .............................................................................................................................34 
9.2 
Rationale for Selection of Dose and Regimen ....................................................................................35 
9.3 
Rationale for Correlative Studies.......................................................................................................35 
9.4 
Definition of Evaluable Subjects ........................................................................................................35 
9.5 
Data collection for subjects unable to come to clinical center ...........................................................35 
9.6 
Early Study Termination....................................................................................................................35 
10 
STUDY DRUG (BMX-001) ..............................................................................................................................36 
10.1 
Names, Classification, and Mechanism of Action ...............................................................................36 
10.2 
Packaging and Labeling .....................................................................................................................36 
10.2.1 
Drug Product Formulation and Manufacture ................................................................................36 
10.2.2 
Labels for BMX-001 for Injection, 10 mg/mL .................................................................................37 
10.2.3 
Syringe and Label for Administration of BMX-001 for Injection, 10 mg/mL ....................................37 
10.2.4 
Multi-Dose Kits ............................................................................................................................37 
10.3 
Supply, Receipt, and Storage ............................................................................................................38 
10.4 
Compliance and Accountability .........................................................................................................38 
10.5 
Disposal and Destruction ..................................................................................................................38 
11 
STUDY DRUG (TMZ) .....................................................................................................................................39 
11.1 
Description .......................................................................................................................................39 
11.2 
Formulation .....................................................................................................................................39 
11.3 
Storage.............................................................................................................................................39 
11.4 
Administration .................................................................................................................................39 
11.5 
Toxicities ..........................................................................................................................................39 
11.6 
Packaging and labeling .....................................................................................................................39 
12 
SUBJECT ELIGIBILITY ....................................................................................................................................39 


Protocol #: BMX-HGG-001 
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Page 6 of 137 
13 
SCREENING AND ON-STUDY TESTS AND PROCEDURES .................................................................................40 
13.1 
Screening Examination .....................................................................................................................41 
13.2 
Run-In Period ...................................................................................................................................42 
13.3 
Chemoradiation Treatment Period (with and without BMX-001) .......................................................42 
13.4 
BMX-001 Treatment Criteria .............................................................................................................42 
13.4.1 
Phase 2 - Criteria for holding BMX-001 .........................................................................................42 
13.4.2 
Phase 2- Re-treatment Criteria for BMX-001 ................................................................................42 
13.4.3 
Phase 2- Discontinuation Criteria for BMX-001 .............................................................................43 
13.5 
End of Study .....................................................................................................................................43 
13.6 
Overall Study Completion .................................................................................................................43 
13.7 
Withdrawal of Subject(s) ..................................................................................................................43 
13.7.1 
Criteria for Early Withdrawal ........................................................................................................43 
13.7.2 
Follow-up Requirements for Early Withdrawal .............................................................................44 
13.8 
Study Assessments ...........................................................................................................................44 
13.8.1 
Medical History ............................................................................................................................44 
13.8.2 
Physical and Neurological Examinations .......................................................................................44 
13.8.3 
Electrocardiogram (ECG) ..............................................................................................................44 
13.8.4 
Radiographic Response ................................................................................................................45 
13.8.5 
HRQoL .........................................................................................................................................46 
13.8.6 
Cognitive Testing .........................................................................................................................47 
13.8.7 
Hair Integrity and Hair Loss ..........................................................................................................49 
13.8.8 
Medical and Demographic Information ........................................................................................49 
13.8.9 
Bone Marrow Assessments ..........................................................................................................49 
13.8.10 
MRI Diffusion Tensor/Susceptibility Imaging.................................................................................49 
13.8.11 
Drug Levels and Pharmacokinetic Assessment ..............................................................................50 
14 
SAFETY MONITORING AND REPORTING .......................................................................................................51 
14.1 
Adverse Events .................................................................................................................................51 
14.1.1 
Reporting of AEs ..........................................................................................................................51 
14.2 
Serious Adverse Events .....................................................................................................................51 
14.2.1 
Reporting of SAEs.........................................................................................................................52 
14.3 
External Data and Safety Monitoring Board (DSMB) ..........................................................................52 
15 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................................54 
15.1 
Monitoring .......................................................................................................................................54 
15.1.1 
DSMB-Plus ...................................................................................................................................54 
15.2 
Audits...............................................................................................................................................55 
15.3 
Data Management and Processing ....................................................................................................55 
15.3.1 
Study Documentation ..................................................................................................................55 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
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15.3.2 
Data Management Procedures and Data Verification ...................................................................55 
15.3.3 
Coding .........................................................................................................................................55 
15.3.4 
Study Closure ...............................................................................................................................55 
16 
STATISTICAL METHODS AND DATA ANALYSIS ...............................................................................................56 
16.1 
Analysis Sets .....................................................................................................................................56 
16.2 
Patient Demographics and Other Baseline Characteristics .................................................................56 
16.3 
Treatments.......................................................................................................................................56 
16.4 
Phase 1 Dose Escalation....................................................................................................................56 
16.4.1 
Primary Objective ........................................................................................................................56 
16.5 
Phase 2 ............................................................................................................................................60 
16.5.1 
Primary Objective for Phase 2 ......................................................................................................60 
16.5.2 
Secondary Objectives for Phase 2 .................................................................................................61 
16.5.3 
Exploratory Objectives for Phase 2 ...............................................................................................62 
16.5.4 
Interim Analysis for Phase 2 .........................................................................................................63 
16.5.5 
Sample Size Calculation for Phase 2 ..............................................................................................64 
17 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .......................................................................................65 
17.1 
Regulatory and Ethical Compliance ...................................................................................................65 
17.2 
Institutional IRBs and Research Committees .....................................................................................65 
17.3 
Informed Consent.............................................................................................................................65 
17.4 
Privacy, Confidentiality, and Data Storage .........................................................................................66 
17.5 
Data and Safety Monitoring ..............................................................................................................66 
17.6 
Protocol Amendments ......................................................................................................................67 
17.7 
Records Retention ............................................................................................................................67 
17.8 
Conflict of Interest ............................................................................................................................67 
18 
REFERENCES ................................................................................................................................................68 
19 
APPENDICES ................................................................................................................................................72 
19.1 
Appendix A: RANO (Radiographic Assessment in Neuro-Oncology) Criteria for Newly Diagnosed 
Patients 72 
19.2 
Appendix B: Pharmacokinetic Analysis ..............................................................................................76 
19.2.1 
Phase 1 Pharmacokinetic Analysis ................................................................................................76 
19.2.2 
Phase 2 Pharmacokinetic Analysis ................................................................................................77 
19.3 
APPENDIX C: Statistical Tables ..........................................................................................................78 
19.3.1 
PROBABILITY OF MTD SELECTION WITH A LOGISTIC MODEL IN THE SECOND STAGE WITH VARIOUS 
TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 2 AFTER FIRST STAGE WITH COHORTS OF 3 .........78 
19.3.2 
PROBABILITY OF MTD SELECTION WITH AN EMPIRIC MODEL IN THE SECOND STAGE WITH VARIOUS 
TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 2 AFTER FIRST STAGE WITH COHORTS OF 3 .........82 
19.3.3 
PROBABILITY OF MTD SELECTION WITH A LOGISTIC MODEL IN THE SECOND STAGE WITH VARIOUS 
TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 3 AFTER FIRST STAGE WITH COHORTS OF 3 .........86 


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19.3.4 
PROBABILITY OF MTD SELECTION WITH A EMPIRIC MODEL IN THE SECOND STAGE WITH VARIOUS 
TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 3 AFTER FIRST STAGE WITH COHORTS OF 3 .........90 
19.4 
Appendix D Cytochrome P450 Drug Interaction Table .......................................................................93 
19.5 
Appendix E Copy of BAC App screenshots .........................................................................................94 
 
94 
19.6 
Appendix F:  Beck Depression Inventory- II (BDI-II) .......................................................................... 103 
19.7 
Appendix G:  FACIT-Fatigue............................................................................................................. 109 
19.8 
Appendix H:  Fact-BR ...................................................................................................................... 110 
19.9 
Appendix I:  FACT-Cog..................................................................................................................... 115 
19.10 
Appendix J:  Godin Leisure-Time Exercise Questionnaire ................................................................. 118 
19.11 
Appendix K:  Trails Making Test (TMT) Parts A & B .......................................................................... 120 
19.12 
Appendix L:  HVLT-R Forms 1, 2 and 3 ............................................................................................. 125 
19.1 
Appendix M:  COWA ....................................................................................................................... 137 
 
 
 


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4 LIST OF ABBREVIATIONS 
AE  
Adverse Event 
ALT  
Alanine Aminotransferase 
ALC  
Absolute Lymphocyte Count 
AST  
Aspartate Aminotransferase 
BAC  
Brief Assessment of Cognition 
BDI-II 
Beck Depression Inventory-II 
BUN 
Blood Urea Nitrogen 
CBC  
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CPC  
Cancer Protocol Committee 
CR  
Complete Response 
CRM 
Continual Reassessment Method 
CT  
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT  
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-Br 
Functional Assessment of Cancer Therapy-Brain 
FDA  
Food and Drug Administration 
GBM 
Glioblastoma 
Gy  
Gray 
HIF-1 
Hypoxia-inducible factor-1 
HGG 
High Grade Glioma 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
HRQoL 
Health-Related Quality of Life 
ICS  
Investigational Clinical Site 
IRB  
Institutional Review Board 
KPS  
Karnofsky Performance Scale 
MDS 
Myelodysplastic Syndrome 
MnSOD 
Manganese Superoxide Dismutase 
MOS 
Median Overall Survival 
MRI  
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI  
National Cancer Institute 
NFĸB  
Nuclear Factor Kappa B 
ORR 
Overall Response Rate 
OS  
Overall Survival 
PD  
Progressive Disease 
PFS  
Progression-free Survival 
PFS-6 
Progression-free Survival at 6 months 
p.o.  
per os/by mouth/orally 
PR  
Partial Response 
PRO 
Patient-Reported Outcome 
PRT-BTC 
Preston Robert Tisch Brain Tumor Center 
QTc  
Corrected QT Interval 
RIO  
Research Integrity Office 
RT  
Radiation Therapy 
SAE  
Serious Adverse Event 
SD  
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 


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SOC  
Standard of Care 
SOD 
Superoxide Dismutase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SQ  
Subcutaneous 
TdP  
Torsades de pointes 
TMZ 
Temozolomide 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WIRB 
Western Institutional Review Board 
 
 


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5 PROTOCOL SYNOPSIS  
5.1 
Purpose 
This is a Phase 1/2 study of BMX-001 in combination with standard radiation therapy (RT) and 
temozolomide (TMZ) in the treatment of newly diagnosed high grade glioma (HGG) patients. Phase 1 
was conducted as a single site study at the Preston Robert Tisch Brain Tumor Center at Duke (PRT-
BTC). Phase 2 will be conducted as a multi-center study and will include up to 10 additional sites 
besides the PRT-BTC at Duke. 
5.2 
Phase 1  
5.2.1 
Primary Objective 
1. To determine the maximum tolerated dose (MTD) of BMX-001 in combination with standard RT 
and TMZ in newly diagnosed HGG patients.  
5.2.2 
Secondary Objectives 
1. To assess the safety and tolerability of BMX-001 in combination with standard RT and TMZ in 
newly diagnosed HGG patients.  
2. To assess the efficacy of BMX-001 in combination with standard RT and TMZ in newly diagnosed 
HGG patients based upon overall survival (OS) and progression free survival (PFS). 
3. To examine the impact on cognition of BMX-001 in combination with standard RT and TMZ in 
treatment of newly diagnosed HGG patients. 
4. To describe radiographic response in newly diagnosed HGG patients treated with BMX-001 in 
combination with standard RT and TMZ. 
5. To characterize the pharmacokinetic profile of BMX-001 when delivered in combination with RT 
and TMZ in newly diagnosed HGG patients. 
5.2.3 
Exploratory Objectives 
1. To describe patient-reported outcomes of health-related quality of life (HRQoL) in newly 
diagnosed HGG patients treated with BMX-001 in combination with standard RT and TMZ. 
2. To describe changes in hair loss during BMX-001 in combination with standard RT and TMZ in 
newly diagnosed HGG patients. 
5.3 
Phase 2 
5.3.1 
Primary Objective 
1. To assess the effect on overall survival (OS) of standard RT and TMZ in combination with BMX-
001 compared to standard RT and TMZ alone in newly diagnosed HGG patients.  
5.3.2 
Secondary Objectives 
1. To assess the impact on cognition of standard RT and TMZ in combination with BMX-001 
compared to standard RT and TMZ alone in newly diagnosed HGG patients. 
2. To assess protection of bone marrow against chemotherapy-induced thrombocytopenia of 
standard RT and TMZ in combination with BMX-001 compared to standard RT and TMZ alone in 
newly diagnosed HGG patients. 
3. To assess the safety and tolerability of standard RT and TMZ in combination with BMX-001 
compared to standard RT and TMZ alone in newly diagnosed HGG patients.  
4. To assess the effect on progression-free survival (PFS) of standard RT and TMZ in combination 
with BMX-001 compared to standard RT and TMZ alone in newly diagnosed HGG patients.  


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5. To assess radiographic response in newly diagnosed HGG patients treated with standard RT and 
TMZ in combination with BMX-001 compared to standard RT and TMZ alone. 
6. To characterize the repeated-dose pharmacokinetic profile of BMX-001 when delivered in 
combination with RT and TMZ in newly diagnosed HGG patients. 
5.3.3 
Exploratory Objectives 
1. To describe patient-reported outcomes of HRQoL in newly diagnosed HGG patients treated with 
standard RT and TMZ in combination with BMX-001 compared to standard RT and TMZ alone. 
2. To describe changes in hair loss in newly diagnosed HGG patients treated with standard RT and 
TMZ in combination with BMX-001 compared to standard RT and TMZ alone. 
3. To describe change in white matter integrity in newly diagnosed HGG patients treated with 
standard RT and TMZ in combination with BMX-001 in comparison to standard RT and TMZ 
alone. 
5.4 
Design and Procedure 
5.4.1 
Phase 1 (Enrollment Complete) 
In the Phase 1 component of this protocol, we will conduct a dose-escalation study of the 
combination of BMX-001 with standard dosing of daily TMZ and RT in patients with newly diagnosed 
HGG (WHO grade III or IV). The dose escalation will be guided by a CRM design to determine the MTD 
of BMX-001 in combination with concurrent daily TMZ and RT. Subjects will be administered BMX-001 
subcutaneously first as a loading dose given 0 to 4 days before the start of chemoradiation and then 
at a subsequent dose (50% of the loading dose) twice a week for eight weeks. There will only be two 
doses per week regardless of whether the dose is a loading or maintenance dose. TMZ will be dosed 
at 75 mg/m2 orally daily for 42 days and RT will be delivered in daily fractions of 1.8-2 Gy given 5 days 
a week for 6 weeks for a total of 59-60 Gy. 
 
Cohorts of 3 subjects will be accrued and treated until the MTD is defined. Following the treatment of 
the first 3 subjects at the initial dose level of 0.1 mg/kg dose level, the rules provided in Section 
9.1.1.1 will be used to determine dose assignments for subsequent subjects and whether dose can be 
escalated. If a subject terminates protocol treatment without experiencing a DLT and before 
completing standard chemoradiation, then the subject will not be evaluable for the determination of 
DLT and will be replaced. 
 
It is estimated that a maximum of 18 subjects will be required for Phase 1. The maximum tolerated 
dose (MTD), defined as the dose that has an estimated DLT rate nearest to 0.25, will be the dose used 
in the future Phase 2 study.  
 
In order to evaluate the pharmacokinetics of BMX-001 in combination with current chemoradiation, 
blood samples will be drawn for analysis. The first dose of BMX-001 will be administered 
subcutaneously in the morning as a loading dose. Blood will be drawn on the following days: loading 
dose day, Day 8 or the next date on which drug is administered, and Day 36 or the next date on which 
drug is administered. Measures will be obtained at the following times: Predose, 0.5 hour, 1 hour, 2 
hours, 6 hours, and 24 hours. Samples will be analyzed for BMX-001 using validated analytical 
methods at a laboratory identified by the sponsor. See Appendix B for details (Section 19.2). 
 
With accrual in Phase I complete, a total of 17 subjects were enrolled. Enrollment numbers for Phase 
1 broken down by dose escalation groups are as followed: 
 


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Dosing Group 
Loading Dose 
Maintenance Dose 
Number of Subjects Treated 
1 
7 mg/subject 
3.5 mg/subject b.i.w. 
4 
2 
14 mg/subject 
7 mg/subject b.i.w. 
3 
3 
28 mg/subject 
14 mg/subject b.i.w. 
6 
4 
42 mg/subject 
20 mg/subject b.i.w. 
4 
 
5.4.2 
Phase 2 
The Phase 2 portion of this study will be a randomized study comparing the impact of concurrent 
daily TMZ and RT with BMX-001 (Arm A) versus concurrent daily TMZ and RT alone (Arm B) on 
survival in patients with newly diagnosed HGG (WHO grade III and IV). The loading dose for Arm A 
determined from the Phase 1 component of this protocol is 28 mg/subject with a 14 mg/subject 
maintenance dose given twice weekly. Subjects will be randomized with a treatment arm allocation 
ratio of 1:1 and there will be 160 patients enrolled in this phase of the study (80 subjects per arm). 
Subjects in Arm A will be administered BMX-001 subcutaneously first as a loading dose given 0 to 4 
days before the start of chemoradiation and then at subsequent dose twice a week for eight weeks. 
Subjects in Arm A and Arm B will receive TMZ dosed at 75 mg/m2 orally daily for 42 days and RT 
delivered in daily fractions of 1.8-2 Gy given 5 days a week for 6 weeks for a total of 59.4-60 Gy. 
Cognitive performance will be measured at the time of enrollment and 2 weeks after the completion 
of RT, and standard of care (SOC) clinic visits (approximately 8 weeks apart +/- 2 weeks) until death, 
or patient’s choice to discontinue study measures.  Cognitive testing should continue after noted 
progression until the 12 month follow up timepoint is reached (testing may be done at a visit 
following the 12 month timepoint).   
 
In order to characterize the repeated dose pharmacokinetic profiles of BMX-001 in combination with 
RT and TMZ in newly diagnosed HGG patients, pharmacokinetic blood samples will be drawn from six 
patients in the Phase 2 portion of the study on Days 8 and 36 only (see Section 19.2.2). The first 6 
patients enrolled and assigned to Arm A at PRT-BTC at Duke will participate in the PK portion. 
Measures will be obtained at approximately the following times: Pre-dose, then 0.5 hour, 1 hour, 2 
hours, 6 hours and 24 hours post-dose. Samples will be analyzed for BMX-001 using validated 
analytical methods at a laboratory identified by the sponsor. See Appendix B for details (Section 
19.2). 
5.5 
Selection of Subjects 
The inclusion/exclusion criteria for the Phase 1 and 2 component of this protocol are identical. 
5.5.1 
Inclusion Criteria 
1. Subjects must have histologically confirmed diagnosis of WHO grade III or IV malignant glioma  
2. Subjects must be planning to start standard of care radiation therapy and chemotherapy 
(temozolomide) 
3. Subjects must be within 12 weeks of last major neurosurgical procedure for the high-grade 
glioma (craniotomy, open biopsy, or stereotactic biopsy) 
4. Subjects must have had a definitive resection with residual radiographic contrast enhancement 
on post-resection CT or MRI of less than or equal to 3 cm in any two perpendicular planes on any 
images   
5. Age ³ 18 years 
6. Karnofsky Performance Status (KPS) ≥ 70% 
7. Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 cells/µl, platelets ≥ 125,000 cells/µl 
8. Serum creatinine ≤ 1.5 mg/dl, serum SGOT and bilirubin ≤ 1.5 times upper limit of normal 
9. Signed informed consent approved by the Institutional Review Board  


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10. If sexually active, patients must agree to use appropriate contraceptive measures for the 
duration of the study and for 12 months afterwards as stated in the informed consent 
11. If using corticosteroids:  stable and/or decreasing dose of corticosteroids for greater than or 
equal to 7 days  
12. Subjects must be fluent in English (due to the neurocognitive testing and the Brief Assessment of 
Cognition (BAC) application only being available in English)  
5.5.2 
Exclusion Criteria 
1. Pregnancy or breast-feeding 
2. Active infection requiring IV antibiotics within 7 days before enrollment 
3. Signs of wound-healing problems or infection at the craniotomy/biopsy site 
4. Prior, unrelated malignancy requiring current active treatment with the exception of cervical 
carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin 
5. Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than 
corticosteroids 
6. Prior treatment with radiotherapy for a brain tumor, irrespective of the grade of the tumor 
7. Prior allergy to temozolomide 
8. Prior progression on adjuvant temozolomide dosed at 150 mg/m2 to 200 mg/m2 on Days 1-5 of a 
28-day cycle 
9. Evidence of > grade 1 CNS hemorrhage on MRI or CT scan  
10. Systemic treatment with inducers or strong inhibitors of cytochrome P450 within four days 
before enrollment or planned treatment during the study drug treatment period of the study 
(see Appendix D).  
11. Metal in the body that is not compatible with MRI 
12. Severe allergy to contrast agents 
5.5.3 
BMX-001 Specific Concerns 
Subjects meeting any of the following criteria are ineligible for study entry:  
1. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or 
diastolic blood pressure > 100 mmHg) within 28 days of first study treatment 
2. Active or history of postural hypotension and autonomic dysfunction 
3. Clinically significant (i.e. active) cardiovascular disease or cerebrovascular disease, for example 
cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 
months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II 
or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by 
medication or potentially interfering with protocol treatment  
4. History or evidence upon physical/neurological examination of central nervous system disease 
(e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially 
interfering with protocol treatment 
5. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial 
thrombosis) within 6 months prior to start of study treatment 
6. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc 
interval >480 milliseconds (ms) (CTCAE grade 1) using the specific/usual choice by clinical center 
for correction factor. 
7. A known history of additional risk factors for Torsades de Pointes (TdP) (e.g., congestive heart 
failure, hypokalemia, known family history of Long QT Syndrome). 
 
 
For inclusion criteria (Section 5.5.1) #4 and exclusion criteria (Section 5.5.2) #9, final review and 
determination will be made centrally.  The baseline CT or MRI scan will be uploaded to the Duke 
coordinating center for final confirmation of eligibility.  Review the sponsor provided Imaging Manual 


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for more details about this transfer.  Once eligibility is confirmed the site will be notified.  Subjects 
will not be randomized until final eligibility is confirmed. 
5.6 
Risk/Benefit Assessment 
5.6.1 
Potential Benefits 
The potential benefits may include protection against cognitive decline caused by RT and/or 
reduction and/or remission of the subject’s HGG. Additionally, a potential benefit may include 
protection against development of thrombocytopenia caused by treatment with TMZ. From prior 
study of HGG, roughly 15% of patients will develop grade 3 or 4 thrombocytopenia [1]. These subjects 
are at risk for a bleeding complication and may have their cancer therapy interrupted to allow 
recovery of the bone marrow. If this can be prevented it would be a major advance in therapy for 
HGG.  
 
Because this clinical protocol is experimental, it cannot be guaranteed that subjects will receive any 
benefit as a result of participating in this research study. The information collected in this research 
may help scientists better understand the mechanisms involved in oxidative stress as it pertains to 
treatment of brain cancer. If such an understanding emerges from this research, it may benefit 
society by furthering the development of improved treatment methods for newly diagnosed HGG in 
the future. 
5.6.2 
Risks of BMX-001 
Studies have been performed using intravenous infusions of a related metalloporphyrin in multiple 
models including rats, mice, dogs, guinea pigs, and baboons with the finding of dose-related 
hypotension [2]. Metalloporphyrin compounds being evaluated are potent, catalytic antioxidants and 
have the potential to scavenge superoxide within the vascular system and thereby change the 
balance of superoxide and nitric oxide in the microvasculature. This would augment the vasodilating 
activity of nitric oxide and lead to hypotension [2]. This has been found in animal models to be a 
significant, but transient side effect and therefore blood pressure monitoring is essential in this 
clinical trial of a metalloporphyrin compound. Studies of rats, mice, and monkeys have been 
performed with BMX-001 and have shown transient, dose-related hypotension. Hypotension is 
related to plasma Cmax levels and subcutaneous administration significantly reduces the risk of this 
toxicity in mice and primates (unpublished data per BioMimetix JV, LLC). This hypotensive effect was 
also found in primates. We have designed this protocol to monitor blood pressure closely.  
A summary of the possible adverse side effects that could be associated with BMX-001 administration 
is below. These possible side effects are dose-dependent, and the relatively low doses of this drug 
planned in this study have not been associated with side effects in animals other than those related 
to the color of the injected drug. 
The most common side effects (expected to occur in more than 30% of subjects) are: 
• 
Red to brown discoloration of the skin at the injection site which may take up to several 
weeks to resolve 
• 
Irritation at the site of the injection of the drug under the skin 
• 
Transient tachycardia from study drug  
 
Less common side effects (expected to occur in 10-30% of subjects) are: 
• 
Transient pain at the injection site.  This is expected to be related to the concentration of 
administered drug and the volume administered, rather than subject body size   
• 
Local histamine release which could be caused by study drug. This could cause pruritus 
(itching), erythema (redness), edema (swelling), urticaria (welts).  This is expected to resolve 
within a couple of hours of injection   


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Rare side effects (expected to occur in less than 10% of subjects) are: 
• 
Temporary hypotension (low blood pressure) 
• 
Malaise or “not feeling well” for a few hours 
• 
Prolongation of the QTc interval  
 
Additional possible side effects: 
• 
Light-activated skin rash in response to sun exposure (not yet reported in humans) 
• 
Red to dark color of urine (not yet reported in humans) 
• 
It is also possible that previously unobserved and unexpected side effects could occur. 
Human safety data for BMX-001 in combination with TMZ and RT has been studied in Phase 1 of this 
clinical trial. BMX-001 at 42 mg/subject loading dose and 20 mg/subject subsequent doses given 
twice weekly was the maximum administered dose and 28 mg/subject loading dose and 14 mg 
/subject for subsequent twice weekly doses was the MTD. Sinus tachycardia (grade 3) was the dose-
limiting toxicity at 42 mg/subject loading dose (n=1). The only other related grade ≥ 3 event seen was 
hypotension (grade 3) (n=1). The most common related toxicity was grade 1 injection site reaction 
(n=7). There is no apparent toxicity to end organ tissues or bone marrow. 
5.6.3 
Risks of TMZ 
Most common side effects (occurring in more than 30% of subjects): 
• 
Fatigue  
• 
Nausea 
• 
Hair loss 
 
Less common side effects (occurring in 10-30% of subjects): 
• 
Thrombocytopenia (low platelets), which may result in easy bruising or bleeding for a longer 
time. 
• 
Loss of appetite 
• 
Headache 
• 
Constipation 
• 
Diarrhea 
• 
Vomiting 
• 
Rash 
• 
Swelling in extremities 
 
Rare side effects (occurring in less than 10% of subjects): 
• 
Abdominal and/or breast pain 
• 
Dry skin, skin redness, and/or itching 
• 
Inflammation of the mouth, throat and/or sinuses 
• 
Dizziness, weakness 
• 
Confusion, memory impairment 
• 
Anxiety, depression 
• 
Joint and muscle pain 
• 
Trouble sleeping 
• 
Change in sense of taste 
• 
Blurred vision 
• 
Coughing or shortness of breath 
• 
Urinary incontinence/frequency, urinary tract infection 
• 
Weight increase 
• 
Seizures/convulsions 
• 
Adrenal hypercorticisim (elevated hormone levels) 


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• 
Low white blood cell (WBC) count, which may lead to infection. 
• 
Allergic reaction, sometimes severe 
• 
Anemia (decreased number of red blood cells), which may cause symptoms of shortness of 
breath, weakness, and fatigue. 
 
Rarely, unusual (“opportunistic”) infections have occurred. Rare cases of erythema multiforme (skin 
condition) have been reported, which got better after TMZ was stopped and, in some cases, recurred 
upon restarting treatment with TMZ. 
 
Very rare side effects have included secondary cancers including leukemia and myelodysplastic 
syndrome (MDS). MDS is a disorder of the bone marrow in which blood cells that do not function 
normally are produced. 
 
There have been reports of hepatotoxicity or liver injury in patients receiving TMZ. TMZ may cause 
elevations in liver enzymes, which measure liver function, elevation of bilirubin levels, which may 
lead to jaundice or a yellowing of the skin and mucous membranes, cholestasis, which results from a 
decreased flow of bile from the liver, and hepatitis, an inflammation of the liver. 
 
Reproductive studies have not been done with TMZ. Immature sperm and testicular atrophy (wasting 
away) occurred in studies with rats and dogs, using doses of TMZ 1/4 and 5/8 of the recommended 
human doses. In animal studies, TMZ caused death and multiple malformations in rats and rabbits 
exposed during pregnancy. 
5.6.4 
Radiation Treatment Side Effects 
Possible side effects include swelling of the brain, hair loss, localized skin irritation, low blood counts, 
fatigue, memory loss, hearing loss, nausea and/or vomiting, loss of appetite, headaches, RT necrosis 
(death of tissue or skin), and secondary cancer. 
5.6.5 
Risks of Phlebotomy 
Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or swelling 
in the area of the insertion, bleeding at the site of the needle puncture, light headedness, fainting and 
very rarely, local infection, which may be severe. These risks are reduced by the fact that the blood 
will be drawn by a qualified physician, nurse or phlebotomist (a professional trained to draw blood). 
5.6.6 
Risks of MRI 
Risks and/or discomforts associated with MRI scans include anxiety produced from being in a tight, 
enclosed space (claustrophobia). In addition, the machine operates using a large and powerful 
magnet, which attracts certain metals. Therefore, people with metals in their bodies that are not 
compatible with MRI will be excluded from the study. Patients will also be checked to make sure that 
they do not bring any metal objects into the MRI facility. Dental fillings are less affected by the 
magnetic fields generated and are therefore permitted. It will be asked that patients let the 
physicians conducting this study know of any metal in their bodies other than dental fillings. During 
the MRI, patients will be given a contrast agent. The agent is given routinely to obtain enhanced MRI 
scans of the brain. The agent is administered through the vein and requires the placement of an IV 
catheter. The catheter placement is similar to drawing blood except that the catheter remains in the 
vein during the time the agent is actively delivered. The risks of a blood draw and insertion of a 
catheter are similar. There have been a few, rare cases of allergies to the agent used in MRI contrast 
enhanced scans. Patients with any known severe allergies to contrast agents will be excluded from 
the study. Patients with mild allergies (i.e., rash only) may be pretreated with Tylenol and Benadryl 
prior to injection of the contrast agent. A rare but serious adverse reaction has been observed in 
patients that received a gadolinium-based contrast material during MRI examinations, a reaction 
called nephrogenic systemic fibrosis (NSF). Patients with kidney disease are at increased risk of 


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developing NSF. NSF may cause skin thickening, joint pain and/or swelling. In rare cases NSF can lead 
to lung and heart problems and cause death. 
5.6.7 
Unknown Risks 
The overall risk classification of this research is unknown.  
5.7 
Data Analysis and Statistical Considerations 
Within the Phase 1 portion of this study, the MTD for BMX-001 administered in conjunction with 
temozolomide and radiation treatment will be determined for patients newly diagnosed with high 
grade glioma. A CRM model as described in section 16.4.1.2 will be used to determine the dose with 
the estimated DLT rate closest to the target DLT rate of 0.25. This Phase 1 study will be conducted in 
two stages. The first stage involves dose escalation in successive cohorts of 3 patients until a DLT is 
observed. The second stage commences with the observation of a DLT. Within the second stage, all 
accumulated data will be used within the context of a one-parameter model to determine the 
appropriate dose for each subsequent cohort of 3 patients. When the toxicity outcomes associated 
with patients within a cohort within the second stage are known, the one-parameter logistic model 
will be re-estimated by the study’s statistical team using all available data. Based upon this re-
estimated model, the dose level that results in a DLT rate nearest to the target DLT rate will be 
determined, and used to treat the next patients, subject to a dose escalation restriction. That 
restriction requires that the dose for the next patient cannot be more than one level higher than that 
of the current patient. 
 
In Phase 2, the study’s primary endpoint is overall survival, defined as the time between 
randomization and death. A logrank test will be used to compare the survival experience of the two 
treatment arms. An intent-to-treat philosophy will be used in the analysis of survival by including all 
patients who are randomized in the analysis. Among the secondary endpoints are two that are of 
particular interest: cognitive function and thrombocytopenia. The mean change in cognitive 
functioning between baseline (enrollment) and week 24 within each treatment arm will be 
computed, and analysis of covariance will be conducted to compare groups with respect to that 
change. Treatment group assignment will be included in the model as a predictor, and the baseline 
measure of cognitive function will be included as a covariate. The proportion of patients who 
experience grade 3 or 4 thrombocytopenia during concurrent temozolomide and radiation, a period 
that terminates 2 weeks after completion of radiation treatment, will be summarized. A chi-square 
test will be conducted to compare the prevalence of such thrombocytopenia observed in patients 
with and without BMX-001 [1]. 
 
 
 


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6 STUDY SCHEMA 
 
 
Figure 1: Study Schema for Phase 2 Portion of the Study.  Review the table in Section 13 for a complete list of 
study procedures.   
 
 


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7 BACKGROUND AND SIGNIFICANCE 
7.1 
Study Disease 
Primary brain tumors represent 1% of all diagnosed cancers, but are among the most lethal [3]. 
Median survival for adults with HGG (WHO grade III and IV) is poor and ranges from 9-15 months 
after diagnosis. Most high grade CNS tumors are highly resistant to current available therapies. The 
standard of care for newly diagnosed high-grade gliomas (HGGs) involves surgical resection, followed 
by standard RT with concurrent TMZ, and subsequent adjuvant TMZ. Patients with HGG not only 
contend with oncologic diagnosis but also a neurologic one that can lead to cognitive dysfunction. 
7.2 
Radiation-Induced Damage during Brain Tumor Treatment 
During the disease treatment course, the nervous system can be damaged by all parts of the 
multimodal approach. In particular, RT can lead to the generation of reactive oxygen species which in 
turn leads to oxidative stress [4]. The oxidative stress is not only responsible for the damaging of the 
DNA and killing of the tumor cells but also leads to damage of the white matter [5]. Central nervous 
system toxicity from RT is defined as acute, early delayed, and late delayed [6]. Acute form can occur 
during RT and is more apparent with doses > 60 Gy. This is rarely seen with the modern approach to 
standard chemoradiation in adult glioma patients. Early delayed encephalopathy and late delayed 
encephalopathy are still seen with some frequency in the HGG population. Early delayed 
encephalopathy is characterized clinically by somnolence, attention deficits, and gait impairment. 
This occurs between one to six months after RT and is thought to be due to transient demyelination. 
Late delayed encephalopathy occurs months to years after RT and, clinically, patients demonstrate a 
pattern of subcortical dementia (short-term memory loss, problems with gait and attention). 
Mechanism of action involves damage to the supporting vasculature, which in turn leads to 
demyelination and, in severe cases, RT necrosis. The impact to patients is cognitive impairment and 
subsequent degradation of HRQoL. In fact, 50-90% of brain tumor patients that received RT 
demonstrated cognitive impairment, if they survived >6 months from RT [7-10]. In summary, the 
oxidative stress produced by RT in brain tumor patients leads to white matter damage, subsequent 
cognitive impairment, and finally quality of life impairment.  
7.3 
Cognition and HRQoL in HGG 
Cognitive dysfunction, whether it develops due to the underlying tumor, treatment, or use of 
medications such as anti-epileptics and corticosteroids, usually comes in concert with a reduction in 
HRQoL. In both newly diagnosed and recurrent HGGs, reduction in cognitive function was associated 
with a reduction in reported HRQoL [11-13]. When compared to healthy controls or patients with 
other malignancies, high-grade glioma patients experience a great degree of cognitive impairment 
and related reduction in HRQoL [13]. 
 
Before and during treatment for HGG, adult patients experience a decline in perceived HRQoL[14,15]. 
Liu defines HRQoL as “a concept that encompasses the multidimensional well-being of a person and 
reflects an individual’s overall satisfaction with life” [15]. For brain tumor patients, focal neurological 
dysfunction, whether cognitive or physical, fatigue associated with treatment, symptoms such as 
nausea and anorexia associated with treatment, and other common symptoms such as insomnia, 
seizures, and headaches all have negative impacts on HRQoL. Overall, functionality and HRQoL are 
particularly important in brain tumor patients since these patients have more dysfunction in these 
areas than age-matched controls with non-small lung cancer [13]. In a large prospective study by 
Budrukkar and colleagues of HRQoL in brain tumor patients, they found that HRQoL, as rated by 
scores from questionnaires, was low before starting any type of treatment, and factors associated 
with poorer HRQoL included patients with poor performance status, illiteracy, and a more aggressive 
nature of the tumors [16]. Moreover, HRQoL is dependent upon the physical function and cognition 
of the brain tumor patient such that patients with better physical function and better cognitive 


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function reported having a higher level of HRQoL [11]. Liu and colleagues discuss how these 
symptoms and signs are interrelated and should not be studied alone because cognitive decline/
dysfunction were associated with increased fatigue and poorer performance status [15,17,18]. During 
concurrent chemoradiation, brain tumor patients experience a decline in relative HRQoL particularly 
due to fatigue and changes in cognition [7,19].  
 
In order to capture fully the many aspects of cognition and HRQoL, we have utilized both objective 
and subjective measures to evaluate issues with cognition, fatigue, HRQoL, and mood. Cognition can 
be measured objectively with standardized cognitive testing. One testing model is CNS Vital Signs®, a 
computerized battery. CNS Vital Signs® has been validated and is being used extensively in our 
research, not only primary brain tumor patients, but also patients with other forms of cancer [20]. 
Modalities within CNS Vital Signs® assess cognitive flexibility, complex attention, executive 
functioning, psychomotor speed, processing speed, verbal and visual memory. We published the 
cognitive performance of newly diagnosed HGG using this battery and showed that they had 
measurable cognitive dysfunction in all domains [21,22]. After diagnosis, newly diagnosed HGG 
patients exhibit deficits in all tested cognitive domains with standardized scores ranging from 90.1 to 
72.7 (a score of 100 represents mean standardized score for normative age-matched subjects). These 
deficits continue throughout the treatment and disease trajectory with lower performances present 
after radiotherapy and 24 weeks after initial diagnosis. Importantly, performance on neurocognitive 
testing is independent of education, grade, gender, and tumor location, but Karnofsky Performance 
Scale (KPS) and surgery extent are important predictors of neurocognitive performance. Moreover, 
long-term survivors of primary HGG (WHO grade IV) continued to exhibit cognitive dysfunction 
despite having achieved an improved survival [23]. Therefore, there is an unmet need to improve the 
cognitive outcomes in patients with newly diagnosed HGG, irrespective of survival outcomes. Another 
testing model called The Brief Assessment of Cognition (BAC) is a battery of tests is implemented 
through an iPad-based app (VeraSci). The BAC was created by Richard Keefe, Jim Gold, Terry 
Goldberg, and Philip Harvey as a pen-and-paper measure for the repeated assessment of cognition in 
clinical trials for schizophrenia (referred to as BACS) [24]. With published normative data [25] and 
over a decade of use, the BACS is the subject of approximately 100 peer-reviewed papers and has 
been used in over 30 multisite clinical trials across a range of patient groups. To reduce rater burden 
and promote standardization of neurocognitive testing in clinical trials, the BAC is now implemented 
as an iPad-based app [26]. The BAC App assists raters in administration and scoring of all subtests 
included in the original pen-and-paper instrument. 
 
Subjectively, HRQoL is measured using patient-reported outcome questionnaires known as PROs. A 
commonly used instrument is the Functional Assessment of Cancer Therapy-Brain (FACT-Br) which 
has been used extensively and has been documented to identify key QoL problems for brain tumor 
patients [27]. Other standardized questionnaires will include Functional Assessment of Cancer 
Therapy-Fatigue, Functional Assessment of Cancer Therapy-Cognition, and Beck Depression 
Inventory. 
 
RT in patients with HGG causes oxidative stress in brain tissue, which can lead to white matter 
damage, subsequent cognitive impairment, and HRQoL impairment. White matter damage due to RT 
can be detected using serial MRI diffusion tensor/susceptibility imaging [28-30]. This damage is 
evident and detectable using serial MRI diffusion tensor/susceptibility imaging both immediately and 
subsequently after the completion of RT in HGG patients [31-33]. Therefore, MRI diffusion tensor/
susceptibility imaging can serve as a biomarker of white matter damage caused by RT in HGG 
patients. In fact, early changes in the parahippocampal white matter seen on MRI diffusion tensor/
susceptibility imaging have been linked to late decline in verbal memory in patient that received RT 
[34].  
 
Interventions to improve cognition and HRQoL in brain tumor patients have included stimulants such 
as methylphenidate and modafinil. Clinical trials with methylphenidate in brain tumor patients 


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undergoing RT were discontinued in early stages because interim analysis did not show any evidence 
of effectiveness [35]. Studies with modafinil did show some positive effects on HRQoL in brain tumor 
patients, but the study was not placebo-controlled [36]. Medications to treat Alzheimer’s disease are 
being explored in the glioma population. Donepezil, a reversible acetylcholinesterase inhibitor used in 
mild to moderate Alzheimer’s dementia, has been studied in primary brain tumor patients. In this 
Phase 2 study, donepezil improved cognition, mood, and HRQoL in irradiated brain tumor patients 
[37]. More rigorous Phase 2 studies are needed to evaluate the effectiveness of anti-Alzheimer’s 
agents in glioma patients and side effects from these medications have limited their usefulness. 
Therefore, new approaches and more clinical studies are needed to evaluate interventions in regards 
to cognition and HRQoL in primary brain tumor patients.  
 
In Phase 1, all fifteen subjects have completed quality of life evaluations and cognitive evaluations for 
the time points before concurrent chemoradiation and after concurrent chemoradiation. Cognitive 
testing included Hopkins Verbal Learning Test-Revised (HVLT-R), Trails Making A and B Tests, and 
Controlled Oral Wood Association Test (COWA). While it is early to assume cognitive protection of 
BMX-001, we have early findings that there is improvement of verbal memory as demonstrated by 
improved scores on HVLT-R, and no degradation in performance on Trails Making B Test (Figure 2) 
and COWA. This is notable because these arethe primary cognitive tests that reveal poorer 
performance in HGG patients after RT.  
 
Figure 2. Performance on cognitive testing in 15 subjects in Phase 1 study of newly diagnosed high-grade 
glioma utilizing BMX-001 in combination with concurrent chemoradiation. Left panel: HVLT-R (higher scores = 
better performance). Right panel: Trails Making B Test (faster/shorter times = better performance) (note, only 
13 subjects completed the second Trails Making B Test) 
While promising, these results, along with the quality of life data, will need to be considered more 
fully after more subjects are treated with BMX-001 in Phase 2. 
 
7.4 
Thrombocytopenia  
Another key observation made in the Phase 1 portion of this study is that none of our patients have 
experienced bone marrow suppression secondary to radiation and temozolomide outside of two 
instances of grade 1 thrombocytopenia in week 6 of radiation and chemotherapy.  
 
In Phase 1, marked bone marrow protection has been observed as shown in Figure 3 below. In 
patients receiving temozolomide the standard of care is to stop therapy for patients developing a 
platelet count below 100,000. None of the fifteen evaluable subjects receiving BMX-001 + 
temozolomide developed platelet counts below 100,000. We compared this to patients that were not 
on protocol but had a diagnosis of glioblastoma (GBM) and were receiving radiation and TMZ and 
were being treated at the Duke Cancer Institute. In this control cohort, 9 out of 20 patients who 


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received concurrent TMZ and radiation therapy developed thrombocytopenia with platelet counts 
below 100,000. While these groups cannot be directly compared, the observation that subjects that 
received BMX-001 along with concurrent chemoradiation did not develop platelet counts below 
100,000/mm3 is compelling. 
 
 
 
Figure 3. Platelet counts in high-grade glioma patients receiving temozolomide with and without 
BMX-001. Each line represents a separate patient. N=20 for patients receiving chemoradiation alone 
(left panel). N=15 for patients receiving BMX-001 + chemoradiation (right panel). 
 
The data supports the conclusion that BMX-001 may be beneficial in preventing chemotherapy-
induced bone marrow suppression at administered doses between 7 mg and 42 mg/subject load 
followed by one-half the loading dose administered biweekly. 
 
Of note, there are now current studies underway with BMX-001 in radiation protection for mucositis 
and xerostomia in irradiated head and neck cancer patients, as well as a therapeutic for patients with 


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multiple brain metastases. With the information from these studies, we are confident in our toxicity 
pattern for BMX-001 in cancer patients and in the doses chosen for Phase 2 evaluation. 
 
7.5 
BMX-001 
It is well-established that induction of oxidative stress after RT and chemotherapy plays a major role 
in tumor and normal tissue therapy responses [38,39]. Ironically, the responses in tumor tend to 
protect vascular endothelium and tumor cells from RT damage [40], whereas these same stresses 
after RT promote normal tissue damage [38,41]. A variety of approaches have been investigated to 
mitigate oxidative stress post irradiation, including the free radical scavenger, amifostine [42-44]. 
Although this agent is approved for this use, its daily use is limited by side effects [42,44]. Other 
agents that have been tested pre-clinically and clinically include nitroxides and genistein, but these 
are not currently approved for protection against normal tissue injury post irradiation, and neither 
provides catalytic inactivation of reactive species responsible for oxidative stress [42]. Over the past 
20 years, Dr. Ines Batinic-Haberle and colleagues have developed a class of manganese (Mn) 
porphyrin-based compounds that: 1) are potent anti-inflammatory agents and 2) catalytically 
inactivate a range of reactive oxygen species, including peroxynitrite and superoxide anion [45-47]. 
These properties give this class of compound the unique function of protecting normal tissues while 
also augmenting tumor killing in patients undergoing radiation and chemotherapy. In addition to 
inactivation of reactive oxygen species, these drugs inhibit transcriptional activity of stress-induced 
transcription pathways by either eliminating reactive oxygen species that activate stress responses or 
by indirectly preventing activation. Transcription factors known to be inhibited by this class of 
metalloporphyrin include HIF-1 [48,49], NFĸB [50], SP-1 [51] and AP-1 [45]. The most recently 
developed compound, BMX-001 (MnTnBuOE-2-PyP5+), is among the most highly potent in a series of 
well over two dozen metalloporphyrins that have been evaluated thus far [52]. BMX-001 is lipophilic 
and crosses the blood brain barrier. This drug has been licensed for commercial development and will 
be the lead compound for this project. 
 
In normal brain, oxidative stress incites inflammatory responses that contribute to white matter 
degradation and cognitive deficits. Metalloporphyrins have been shown to protect against a range of 
CNS conditions associated with inflammation, including stroke [53] and spinal cord damage [54-56]. 
Furthermore, metalloporphyrins have been shown to protect mice from total body irradiation toxicity 
[57] and xerostomia following parotid gland irradiation [58]. Radiation-induced lung injury was 
protected against by administration of metalloporphyrins in rhesus macaques [59]. Relevant to this 
application, Weitzel and colleagues showed protection against hippocampal stem cell loss and white 
matter degradation after whole brain RT therapy [58]. In this study, C57BL/6J mice were exposed to 8 
Gy of whole brain irradiation with and without concurrent BMX-001. In mice that had been treated 
with BMX-001 and RT, there was preservation of myelin in the corpus callosum and anterior 
commissure in comparison to mice that received only RT without BMX-001. Moreover, the mice that 
received BMX-001 and RT performed better on rotorod tests and running wheel tests, both tests of 
cognitive function, in comparison to the RT alone group. It is well-established that oxidative stress 
and cognitive losses are a consequence of brain irradiation [6]. Therefore, there is ample evidence to 
suggest that BMX-001 will reduce the magnitude of oxidative stress after RT therapy and TMZ; this 
will lead to protection against cognitive losses and improvement in HRQoL. 
 
In tumors, Dr. Dewhirst and colleagues showed that RT and chemotherapy increase oxidative stress, 
driving upregulation of HIF-1 [40,60], a transcription factor that promotes endothelial and tumor cell 
survival and increases tumor aggressiveness [61]. Radiation creates persistent oxidative stress in 
surviving cells, which upregulates NFkB [62]; this transcription factor also drives treatment resistance 
[63]. Treatment with this new class of metalloporphyrin prevents HIF-1 and NFkB upregulation in 
tumors after RT and chemotherapy and improves tumor treatment responses [57]. Using LN-18 and 
LN-229 HGG cell lines, BMX-001 showed no significant protective effect on clonogenic survival when 


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cells were also exposed to RT [64]. The effect of BMX-001 has been studied on mouse flank HGG 
xenografts. In this study by Weitzel and colleagues, while RT did lead to a reduction in GBM tumor 
growth in comparison to saline alone, the combination of BMX-001 and RT demonstrated a greater 
and significant degree of tumor reduction [64]. This demonstrated that BMX-001 has a differing effect 
in tumor tissue in comparison to normal tissues with BMX-001 showing potential to protect normal 
tissues and sensitize tumors to RT. Thus, the rationale for this protocol is based on the demonstrated 
dual activity of BMX-001 to protect normal tissue while sensitizing tumors to therapy.  
7.6 
Study Rationale 
BMX-001 added to RT and TMZ has the potential not only to enhance the survival of HGG patients but 
also to protect against deterioration of cognition, impairment of HRQoL, and bone marrow 
suppression. We have performed a Phase 1 trial of BMX-001 at escalating doses in combination with 
standard RT, 33 fractions to 59-60 Gy, plus daily TMZ at the standard dosing of 75 mg/m2. We have 
confirmed that BMX-001, when added to standard RT and TMZ, will be safe at pharmacologically 
relevant doses in patients with newly diagnosed HGG. Safety and MTD have been determined in the 
Phase 1 portion of this study, thus we will now move to a Phase 2 study comparing concurrent daily 
TMZ and standard RT alone to the same regimen in combination with BMX-001 to assess the impact 
of BMX-001 on the survival of newly diagnosed HGG patients. We hypothesize that BMX-001, when 
added to standard RT and TMZ, will be safe and will sensitize the malignancy resulting in enhanced 
patient survival. In addition, BMX-001 will protect normal brain tissue from the effects of radiation 
and chemotherapy and will protect bone marrow from chemotherapy-induced thrombocytopenia. 
 
 


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8 OBJECTIVES AND ENDPOINTS 
Table 1: Phase 1 Objectives and Endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
To determine the maximum 
tolerated dose (MTD) of BMX-001 in 
combination with standard RT and 
TMZ in newly diagnosed HGG 
patients 
MTD is defined as the dose level that has an 
estimated DLT rate nearest to 0.25 
See Section 16.4.1 
Secondary  
To assess the safety and tolerability 
of BMX-001 in combination with 
standard RT and TMZ in newly 
diagnosed HGG patients 
Proportion of patients with DLT 
See Section 16.4.1.4 
Secondary 
To examine the impact on cognition 
of BMX-001 in combination with 
standard RT and TMZ in treatment of 
newly diagnosed HGG patients 
Mean change between baseline and week 24 
in normalized scores for cognition using 
standardized cognitive tests and computerized 
battery CNS Vital Signs®. This includes Hopkins 
Verbal Learning Test-Revised, Trails Making 
Test Parts A and B, and Controlled Word 
Association Test and CNS Vital Signs® battery 
consisting of seven tests that measure verbal 
and visual memory, finger tapping, symbol 
digit coding, the Stroop Test, a test of shifting 
attention, and continuous performance test.  
See Section 16.4.1.4 
Secondary 
To assess the efficacy of BMX-001 in 
combination with standard RT and 
TMZ in newly diagnosed HGG 
patients based upon overall survival 
(OS) and progression free survival 
(PFS)  
Median OS, where OS is defined as the time to 
death from the time of protocol treatment is 
initiated 
Median PFS, where PFS is defined as the time 
between initiation of protocol treatment and 
the first recurrence of disease or death 
 
See Section 16.4.1.4 
Secondary 
To describe radiographic response in 
newly diagnosed HGG patients 
treated with BMX-001 in 
combination with standard RT and 
TMZ 
Proportion of patients with radiographic 
response 
See Section 16.4.1.4 
Secondary 
To characterize the pharmacokinetic 
profile of BMX-001 when delivered in 
combination with RT and TMZ in 
newly diagnosed HGG patients 
Plasma concentrations and calculated 
pharmacokinetic parameters (maximum 
concentration, time to reach maximum 
concentration, area under the curve, half-life, 
total body clearance, and volume of 
distribution) will be determine for BMX-001 
See Section 19.1 
Exploratory 
To describe patient-reported 
outcomes of HRQoL in newly 
diagnosed HGG patients treated with 
BMX-001 in combination with 
standard RT and TMZ 
Mean change from baseline at each follow-up 
assessment for subscales of the following 
PROs include Functional Assessment of Cancer 
Therapy-Brain Cancer (FACT-BR) version 4, 
Functional Assessment of Cancer Therapy-
Fatigue (FACIT-Fatigue) subscale, version 4, 
Functional Assessment of Cancer Therapy-
Cognition (FACT-Cog) subscale, Beck 
depression inventory (BDI-II), revised version, 
Godin Leisure questionnaire 
See Section 16.4.1.5 
Exploratory 
To describe changes in hair loss 
during BMX-001 in combination with 
standard RT and TMZ in newly 
diagnosed HGG patients 
Subjective investigator and patient 
assessment, photographs 
See Section 16.4.1.5 
 
 
 


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Table 2: Phase 2 Objectives and Endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
To assess the efficacy of standard RT 
and TMZ in combination with BMX-
001 compared to standard RT and 
TMZ alone in newly diagnosed HGG 
patients based upon overall survival 
(OS).  
Median OS, where OS is defined as the time to 
death from randomization. 
See Section 16.5.1 
Secondary 
To examine the impact on cognition 
of BMX-001 in combination with 
standard RT and TMZ in treatment of 
newly diagnosed HGG patients. 
Mean change between baseline and week 24 
in normalized scores for cognition using 
standardized cognitive tests and BAC This 
includes Hopkins Verbal Learning Test-Revised, 
Trails Making Test Parts A and B, and 
Controlled Word Association Test and BAC 
(VeraSci) consisting of seven tests that 
measure verbal memory and learning, working 
memory, motor function, verbal fluency, 
speed of processing, and executive function.  
See Section 16.5.2 
Secondary 
To assess protection of bone marrow 
against chemotherapy induced 
thrombocytopenia in patients being 
treated with standard RT and TMZ in 
combination with BMX-001 
compared to standard RT and TMZ 
alone in newly diagnosed HGG 
patients. 
Proportion of patients with thrombocytopenia 
grade 3 or 4 adverse event during standard RT 
and TMZ treatment. 
 
Proportion of patients with a platelet count 
below 100,00 during standard RT and TMZ 
treatment and who had suspension of TMZ 
therapy.  
See Section 16.5.2.2 
Secondary 
To assess the safety and tolerability 
of standard RT and TMZ in 
combination with BMX-001 
compared to standard RT and TMZ 
alone in newly diagnosed HGG 
patients.  
Proportion of subjects who experience grade 3 
or 4 adverse event during standard RT and 
TMZ treatment.  
 
Proportion of subjects who experience grade 3 
or 4 adverse event that are definitely, possibly, 
or probably related to BMX-001 treatment. 
See Section 16.5.2 
Secondary 
To assess the efficacy of standard RT 
and TMZ in combination with BMX-
001 compared to standard RT and 
TMZ alone in newly diagnosed HGG 
patients based upon progression-free 
survival (PFS). 
Median PFS, where PFS is defined as the time 
between initiation of protocol treatment and 
the first recurrence of disease or death. 
See Section 16.5.2 
Secondary 
To assess radiographic response in 
newly diagnosed HGG patients 
treated with standard RT and TMZ in 
combination with BMX-001 
compared to standard RT and TMZ 
alone. 
Proportion of subjects with complete or partial 
radiographic response. 
See Section 16.5.2 
Secondary 
To characterize the repeated-dose 
pharmacokinetic profile of BMX-001 
when delivered in combination with 
RT and TMZ in newly diagnosed HGG 
patients. 
Plasma concentrations and calculated 
pharmacokinetic parameters (maximum 
concentration, time to reach maximum 
concentration, area under the curve, half-life, 
total body clearance, and volume of 
distribution) will be determined for BMX-001. 
See Section 16.5.2 
Exploratory 
To describe patient-reported 
outcomes of HRQoL in newly 
diagnosed HGG patients treated with 
standard RT and TMZ in combination 
with BMX-001 compared to standard 
RT and TMZ alone. 
Mean change from baseline at each follow-up 
assessment for subscales of the following 
PROs include Functional Assessment of Cancer 
Therapy-Brain Cancer (FACT-BR) version 4, 
Functional Assessment of Cancer Therapy-
Fatigue (FACIT-Fatigue) subscale, version 4, 
Functional Assessment of Cancer Therapy-
Cognition (FACT-Cog) subscale, Beck 
depression inventory (BDI-II), revised version, 
Godin Leisure questionnaire.  
See Section 16.5.3 


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Exploratory 
To describe changes in hair loss in 
newly diagnosed HGG patients 
treated with standard RT and TMZ in 
combination with BMX-001 
compared to standard RT and TMZ 
alone.  
Subjective investigator and patient 
assessment, photographs.  
See Section 16.5.3 
Exploratory 
To describe change in white matter 
integrity in newly diagnosed HGG 
patients treated with standard RT 
and TMZ in combination with BMX-
001 compared to standard RT and 
TMZ alone.  
MRI Brain Diffusion Tensor /Susceptibility 
Imaging (white matter integrity).  
See Section 16.5.3 
 
 


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9 INVESTIGATIONAL PLAN 
9.1 
Study Design  
As this study is a Phase 1/2 study, this protocol includes a Phase 1 Dose Escalation portion and a 
randomized Phase 2 portion. In the Phase 1 Dose Escalation portion of the study, the dose of BMX-
001 will be escalated, while the dose of daily TMZ and RT (chemoradiation phase) will remain fixed 
and will be followed by adjuvant TMZ (adjuvant phase). The randomized Phase 2 study component 
will assess the impact of BMX-001 in combination with daily TMZ and standard RT in comparison to 
daily TMZ and standard RT in newly diagnosed HGG patients on overall survival and, as secondary 
endpoints, impact on cognition and on bone marrow suppression. 
 
A clinical research coordinator will schedule all of the appointments and the calendar will be provided 
to the patients. For study schema, please see Section 6 and Figure 1. 
9.1.1 
Phase 1 Specific Design 
This Phase 1 study will be a single-site study of escalating doses of BMX-001 in combination with RT 
and TMZ (chemoradiation phase), followed by adjuvant TMZ (adjuvant phase). In the chemoradiation 
phase, external beam RT therapy will be given over less than seven weeks in 30-33 fractions for a 
total dose of 59-60 Gy. TMZ (75 mg/m2 po daily) will be started on the first day of RT and will be 
administered for 42 days. TMZ will be given before RT daily. In line with Brain Tumor Center standard 
of care, adjuvant TMZ therapy will begin 2 to 4 weeks after the completion of RT. Adjuvant TMZ could 
be administered for up to 12 scheduled 28-day cycles. TMZ will be given orally at night on days 1-5 of 
28-day cycle. During the chemoradiation phase and 2 weeks thereafter, CBC with differential and a 
CMP will be obtained weekly. A minimum of 3 subjects and a maximum of 18 subjects with newly 
diagnosed HGG who are patients at The Preston Robert Tisch Brain Tumor Center clinic at Duke 
University Medical Center will be enrolled into this study during a 12-month period. We will aim to 
enroll 3 subjects every eight to ten weeks. Once 3 patients have undergone treatment without 
experiencing a DLT after a monitoring period of four weeks following completion of all doses of BMX-
001, the dose of the subsequent group of 3 patients will be escalated. 
9.1.1.1 Dose Escalation for BMX-001 in Phase 1 
BMX-001 will be administered subcutaneously as a loading dose before starting concurrent 
chemoradiation (days -5 through 0 depending on patient/radiotherapy scheduling). After the loading 
dose, the dose levels will be given two times per week for 8 weeks. The starting dose level will be 7 
mg loading dose. BMX-001 dose escalation will be 7 mg loading dose, 14 mg loading dose, 28 mg 
loading dose, and 42 mg loading dose in four dose levels. After the loading dose, the BMX-001 dose 
will be administered at the amounts listed below twice a week (see Table 3 below). The 
corresponding volumes of BMX-001, Injection Solution 10 mg/mL associated with the loading doses 
are as follows (the equivalent dose for a 70 kg adult is also given): 
0.7 mL/subject loading dose = 7 mg/subject and is equivalent to 0.1 mg/kg for 70 kg subject 
1.4 mL/subject loading dose = 14 mg/subject and is equivalent to 0.2 mg/kg for 70 kg subject 
2.8 mL/subject loading dose = 28 mg/subject and is equivalent to 0.4 mg/kg for 70 kg subject 
4.2 mL/subject loading dose = 42 mg/subject and is equivalent to 0.6 mg/kg for 70 kg subject 
The corresponding maintenance doses would be equivalent to the following:  
0.35 mL/subject dose = 3.5 mg/subject and is equivalent to 0.05 mg/kg for 70 kg subject 
0.7 mL/subject dose = 7 mg/subject and is equivalent to 0.1 mg/kg for 70 kg subject 
1.4 mL/subject dose = 14 mg/subject and is equivalent to 0.2 mg/kg for 70 kg subject 
2 mL/subject dose = 20 mg/subject and is equivalent to 0.3 mg/kg for 70 kg subject 


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BMX-001 will be administered by subcutaneous injection of a sterile 10 mg/mL solution in saline. 
Syringes will be either 1 mL or 3 mL with a 25 gauge X 5/8 inch needle depending on the volume of 
injection. The subcutaneous injections may be at any optimum site on the torso, the upper leg or 
upper arm. Sites of injection should be alternated. Subsequent (maintenance) doses will be one-half 
the size of the loading dose (except Group IV where the subsequent dose is rounded down to 20 mg) 
and should be administered twice weekly. The first dose should be delivered 3 to 5 days after the 
loading dose and further doses delivered at 3 to 4 day intervals to average 2 doses per week. The 
BMX-001 doses other than the loading dose will be delivered within 12 hours before or after RT. 
Schedule of subsequent doses will be dependent on the day of the loading dose and radiation 
schedule. For each week the doses are given, the days will either be Monday and Thursday for 
injections or Tuesday and Friday for injections. BMX-001 will not be administered on Saturday or 
Sunday.  
 
Table 3: Loading Doses and Subsequent Doses for BMX-001 in Phase 1 Study 
 
Subject Group 
 
I 
II 
III 
IV 
 
Loading Dose1 
 
7 mg 
14 mg 
28 mg 
42 mg 
Week 
Subsequent Doses1 
1 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
2 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
3 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
4 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
5 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
6 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
7 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
8 
3.5 mg b.i.w. 
7 mg b.i.w. 
14 mg b.i.w. 
20 mg b.i.w. 
1Dose of BMX-001 for Injection, 10 mg/mL administered to subject. 
9.1.1.2 Definition of Dose-Limiting Toxicity (DLT) 
Toxicities will be graded according to the NCI CTCAE version 4.03 criteria. DLTs will be defined as any 
of the following events that are possibly, probably, or definitely attributable to BMX-001 during dose 
escalation. 
 
A dose limiting toxicity is defined as an adverse event or laboratory abnormality that is: a. assessed as 
unrelated to disease progression, intercurrent illness, or concomitant medications; b. occurs during 
and/or following the first dose of BMX-001; and c. meets any of the following criteria: 
9.1.1.2.1    Non-hematologic 
1. The occurrence of non-hematologic grade 3 or greater adverse events considered to be 
possibly, probably, or definitely related to BMX-001 during treatment with BMX-001, 
excluding grade ³ 3 alopecia and elevation in alkaline phosphatase, grade ³ 3 nausea or 
vomiting unless occurring despite the use of standard anti-emetics; and grade 3 
hypertriglyceridemia or hypercholesterolemia unless occurring despite standard lipid-
lowering agents. 
2. > 14 day delay to re-treat due to failure to resolve any grade 3 or greater non-hematologic 
drug-related toxicity to re-treatment criteria or pre-treatment baseline. 
3. Grade ≥ 2 neurological toxicity that impairs activities of daily living and persists ≥ 7 days. 
4. Inability to complete > 75% of the planned RT treatments.  
9.1.1.2.2    Hematologic 
Occurrence of any of the following hematologic adverse events will be defined as a DLT: 
1. Grade 4 neutropenia (ANC, including bands, ≤0.5 x 109 /l); 


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2. Grade 3 thrombocytopenia (platelet count of ≤ 50x109/l); 
3. > 14 day delay to re-treat due to failure to resolve hematologic toxicity to re-treatment 
criteria. 
9.1.1.2.3    Other Considerations 
Not applicable 
9.1.1.3 Dose Modification 
There are no reductions in the BMX-001. If adverse events occur that require holding BMX-001, the 
dose will remain the same once treatment resumes. 
 
Any toxicity possibly, probably, or definitely associated with BMX-001 should be managed according 
to standard medical practice. There is no available antidote for BMX-001.  
 
Subjects should be assessed clinically for toxicity prior to, during, and after each injection. If an 
unmanageable toxicity, i.e. in the opinion of the subject and treating physician, occurs because of 
BMX-001 at any time during the study, treatment with BMX-001 should be discontinued.  
 
Injection of BMX-001 should be interrupted for subjects who develop dyspnea or clinically significant 
hypotension and it may be re-started at the following scheduled injection, if the treating physician 
considers it safe for the subject to proceed on study. Subjects who experience a Grade 3 or 4 allergic 
reaction / hypersensitivity, adult respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from BMX-001 treatment.  
 
Regardless of the reason for holding study drug treatment, the maximum allowable length of 
treatment interruption is 3 weeks. If BMX-001 is held for greater than 3 weeks, BMX-001 will be 
discontinued. 
9.1.2 
Phase 2 Specific Design 
The Phase 2 portion of this study will be a randomized, multi-center study comparing Arms A and B. 
Arm A will consist of daily TMZ and RT with BMX-001 and Arm B will include daily TMZ and RT alone. 
 
For the Phase 2 Study, BMX-001 will be administered subcutaneously as a loading dose before 
starting concurrent chemoradiation (days -5 through 0 depending on patient/MRI scheduling), during 
treatment, and after treatment concludes. After the loading dose, the subsequent doses will be given 
two times per week for 8 weeks. The BMX-001 doses other than the loading dose will be delivered 
within 12 hours before or after RT. Patients will be randomized with a treatment arm allocation ratio 
of 1:1 to receive BMX-001 or to proceed with RT and TMZ alone. There will be 160 patients enrolled 
in this phase of the study (80 subjects per arm). The Phase 1 trial has confirmed the safe RP2D for 
BMX-001. The loading dose determined safe from Phase 1 and being studied in Phase 2 is 28 
mg/subject and the maintenance doses are each 14 mg/subject.  
BMX-001 will be administered by subcutaneous injection of a sterile 10 mg/mL solution in saline. The 
subcutaneous injections may be at any optimum site on the torso, the upper leg or upper arm. The 
first subsequent dose should be delivered 1 to 5 days after the loading dose and subsequent doses 
delivered at 3 to 4 day intervals to average 2 doses per week.  The Phase 2 criteria for holding, re-
treating and discontinuing BMX-001 is captured in Section 13.4 BMX-001 Treatment Criteria.   
9.1.3 
Safety Considerations 
In Phase 1, no hypotension was found in the dose chosen for Phase 2. However, because of the 
development of transient hypotension in rat models, patients will undergo monitoring before and at 
5 (+/-2), 15 (+/-3), 30 (+/-5) , and 60 minutes (+/- 5) minutes after the BMX-001 injections on the 
loading dose day and 5 (+/-2), 15 (+/-3), 30 (+/-5) on all other days of BMX-001 injections. This will 


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include the following vital signs: heart rate, oxygen saturation, and blood pressure. Injection site 
reaction will also be reviewed. In summary, patients will be observed for at least 60 (+/-5) minutes 
after the subcutaneous injection of BMX-001 on the loading dose day and at least 30 (+/- 5) minutes 
on the maintenance dose days.   This observation will include collection of heart rate, oxygen 
saturation, blood pressure, as well as injection site reaction.  
 
In primate studies, the primary toxicity seen was skin reaction/irritation and/or transient skin 
discoloration due to subcutaneous injection. Excretion of the drug was also associated with a 
red/purple color of urine. Care will be taken to limit the volume of the injections to no more than 1.4 
mL per site. Thus a 28 mg/subject (2.8 mL @ 10 mg/mL) or 20 mg/subject (2 mL @ 10 mg/mL) dose 
will be administered in two equal portions at two different sites. A 42 mg/subject (4.2 mL @ 10 
mg/mL) dose will be administered in three equal portions at three different sites. A separate drug 
product vial, syringe and needle will be used for each injection. Before patients are initiated on any 
treatments (radiation, TMZ, or BMX-001), patient must be at least 2 weeks from neurosurgical 
procedure (craniotomy, open biopsy, or stereotactic biopsy). Moreover, there can be no signs of 
wound-healing problems or infection at the craniotomy/biopsy site.  
9.1.4 
Prolongation of QTc Interval and Management 
There have been reports of human subjects with a QT prolongation present after a BMX-001 loading 
dose (28 mg/subject) that was not present at baseline.  Prolongation of QTc interval has not been 
observed in preclinical studies of BMX-001.   
 
In all cases Electrocardiogram QT corrected interval prolonged did not exceed a grade 2 (average QTc 
481 - 500 ms) according to CTCAE. 
 
No action with regards to BMX-001 was taken due to these events and subjects continued on the 
study and the QT prolongation appears to have resolved.  These cases have been reviewed in detail 
by BioMimetix.     
 
If a subject develops prolonged QT after receiving a dose of BMX-001, the case should be reviewed 
with the BioMimetix Medical Monitor to determine further dosing of BMX-001 and inclusion in the 
study.  Additionally, levels of electrolytes (potassium, calcium, and magnesium) should be checked 
and supplementation given to correct any values outside the normal range.  Finally, concomitant 
therapies should be reviewed and adjusted as appropriate for medications with known QT-prolonging 
effects. 
 
If the cause is not identified and the investigator believes it is appropriate, particularly if QTc remains 
elevated, study drug may be interrupted, and an ECG should be re-checked in approximately 1 week 
after the QTc prolongation was first observed or more frequently as clinically indicated. If QTc has 
recovered or improved and the investigator believes it is safe to do so, continuing BMX-001 therapy 
should be considered if previously held. 
 
9.1.5 
Missed Doses 
Regardless of the reason for withholding study drug treatment, the maximum allowable length of 
treatment interruption is 3 weeks. If BMX-001 is withheld for greater than 3 weeks, BMX-001 will be 
discontinued. If BMX-001 is discontinued for missed doses, the patient will remain on the study and 
all planned study endpoints will be assessed. Any missed doses should be made up at the end of 
treatment, so that the subjects complete the planned number of doses (which is 17).  Any missed 
doses of BMX-001 should be documented with the reason included.   


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9.1.6 
Concomitant Medications 
Because corticosteroids are anti-inflammatory and could interrupt oxidative stress, patients will be 
required to be on stable or decreasing corticosteroids dose at the time of the study enrollment. If a 
patient is required to have additional systemic steroids such as to treat an allergic reaction, adrenal 
insufficiency, increased neurological symptoms, and/or increased intracranial pressure, then systemic 
corticosteroids can be added to control symptoms at the discretion of the treating physician and at 
the minimal effective dose deemed medically appropriate. Dexamethasone use is allowed in this 
study.  Topical steroids are not a contraindication. 
 
Standard anti-emetics, such as ondansetron, will be able to be used during TMZ therapy. 
Ondansetron is typically administered 30 minutes before TMZ. 
 
Use of drugs known to lengthen QT intervals should be avoided or minimized when possible. 
 
9.1.7 
TMZ Treatment Plan 
TMZ is an oral alkylating agent which has demonstrated anti-tumor activity as a single agent in the 
treatment of recurrent glioma. As stated previously, Stupp et al.[65] have demonstrated an increase 
in efficacy of TMZ in combination with RT in the adjuvant treatment of primary malignant gliomas. In 
addition, the regimen was considered safe. Non-hematological grade 2 toxicities included: Fatigue 
(26%), other constitutional symptoms (7%), rash and dermatologic side effects (9%), infection (1%), 
vision (14%), and nausea and vomiting (13%). Grade 3 / 4 non-hematological toxicities occurred 
<10%: Fatigue (7%), other constitutional symptoms (2%), rash and dermatologic side effects (1%), 
infection (3%), vision (1%), and nausea and vomiting with a 5HT3-RA (<1%). Thus, this safe and 
standard regimen will be utilized in this protocol. During the chemoradiation phase, daily TMZ 
therapy will be calculated at a dose of 75 mg per square meter of body surface area per day and be 
administered 7 days a week from the first until the last day of RT therapy or a total of 42 days. 
Weekly CBC with differential and CMP will begin at week 2 and continue through week 8. Platelet 
count is part of CBC with differential count. Additional clinical and laboratory assessments will be at 
the discretion of the RT therapist. During the adjuvant phase, 5-day TMZ therapy will be calculated at 
a dose of 150 or 200 mg/m2 and be administered the first 5 days of a 28 day cycle. One cycle will 
consist of 28 days. If a subject cannot tolerate the 5-day TMZ and is switched to metronomic TMZ 
(low-dose, continuous TMZ), they will remain on the study and will complete all planned study 
endpoints. Use of Optune device will be allowed during the adjuvant phase with TMZ per NCCN 
guidelines and subjects will complete all planned study endpoints. If a subject completes only 6 cycles 
of temozolomide (vs. 12 cycles), they will remain in the study and subjects will complete all planned 
study endpoints through the planned 12 cycle timeframe.  After that they will be continued to be 
followed for vital status.    
9.1.8 
Radiation Treatment Plan 
As detailed by the Stupp [65] regimen, RT therapy will be administered as fractionated focal 
irradiation in daily fractions of 1.8-2 Gy given 5 days a week for 6 weeks for a total of 59-60 Gy. 
Patients will be followed closely by the RT therapist throughout treatment. The RT therapist and 
oncologist will conduct the standard physical exams and obtain the lab work necessary for the 
eligibility. Additional clinical and laboratory assessments will be at the discretion of the RT therapist 
and oncologist. All RT will be planned and performed at the clinical center as part of standard of care.   
9.1.8.1 Dose Definition and Schedule  
The external beam RT therapy (RT) plan will be determined at the discretion of the local RT therapist 
dependent on tumor size and location. It should begin 2-12 weeks after surgery. One treatment of 
1.8-2.0 Gy will be given daily, 5 days per week, (30-33 fractions over less than seven weeks) for a total 


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of 59-60 Gy. All portals shall be treated during each treatment session. Doses are prescribed at the 
maximum dose line encompassing > 95% of the target volume. 
9.1.8.2 Physical Factors  
Treatment shall be delivered on megavoltage machines of energy ranging from 4 to 18 MV photons. 
Selection of the appropriate photon energy(ies) should be based on optimizing the RT dose 
distribution within the target volume and minimizing dose to non-target normal tissue. Photon 
energies > 10 MV should be utilized only in dual energy beam arrangements using at least one beam 
with energy < 10 MV. Source skin distance for SSD techniques or source axis distance for SAD 
techniques must be at least 80 cm.  
9.1.8.3 Localization, Simulation, and Immobilization  
The patient shall be treated in the supine or another appropriate position for the location of the 
lesion. A head-holding device that is transparent to x-rays and provides adequate immobilization 
must be utilized at all times during planning and therapy to ensure reproducibility. 
 
The initial target volume shall include the contrast-enhancing lesion and surrounding edema (if it 
exists) demonstrated on the pre-operative MRI plus a 2.0-cm margin. If no surrounding edema is 
present, the initial target volume should include the contrast-enhancing lesion plus a 2.5-cm margin. 
This primary target volume will be treated to 45-46 Gy in 23-25 daily fractions, at 1.8-2.0 Gy per 
fraction.  
 
The boost volume will be based on the post-operative MRI performed during treatment planning. 
After 45-46 Gy, the boost volume will include the contrast-enhancing lesion plus a 1.5-cm margin or, 
if minimal contrast-enhancing lesion is present at a portion of the resection cavity on MRI, the 
surgical defect plus a 2.0-cm margin, whichever is greater at that segment of the MRI image. The 
boost volume will be treated to an additional 14-14.4 Gy in 7-8 daily fractions, 1.8-2.0 Gy per fraction. 
This will bring the total target dose to 59-60 Gy in 30-33 fractions. All parts of the target volumes are 
to receive at least 100% but no more than 110% of the dose at the prescription isodose line. 
 
All RT will be planned and performed by the clinical center as part of standard of care.   
9.1.8.4 Treatment Planning and Safety  
Treatment plans may include opposed lateral fields, a wedge pair of fields, rotation, or multiple-field 
techniques, including intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc 
therapy (VMAT). MRI-guided 3D treatment planning is necessary to assure accuracy in the selection 
of field arrangements. Isodose distributions for the primary and boost target volume are required on 
all patients, including those treated with parallel-opposed fields. A composite plan is required 
showing the respective target volumes. The inhomogeneity across the target volume shall be kept to 
a minimum. The maximum dose should be no higher than 112% of the prescription. Possible side 
effects include swelling of the brain, hair loss, localized skin irritation, low blood counts, fatigue, 
memory loss, hearing loss, nausea and/or vomiting, loss of appetite, headaches, RT necrosis (death of 
tissue or skin), and secondary cancer.  
9.1.8.5 Dose Limitations to Critical Structures 
The lens and cervical spine must be shielded from the direct beam at all times. The maximum dose to 
the optic apparatus (optic chiasm, optic nerves, eyes) must be limited to 54 Gy, and the brain stem 
limited to 60 Gy. 
9.1.9 
Randomization 
Within the Phase 2 portion of this study, patients will be randomized using a 1:1 allocation ratio to 
receive standard of care treatment consisting of TMZ and RT with BMX-001 (Arm A) or without BMX-


Protocol #: BMX-HGG-001 
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001 (Arm B). A permuted block randomization algorithm stratified by grade (III / IV) and by institution 
will be used. 
9.2 
Rationale for Selection of Dose and Regimen 
We have additional safety data from the completion of this Phase 1 trial in humans. In Phase 1, the 
DLT for BMX-001 administered at 42 mg loading dose and 20 mg maintenance dose was sinus 
tachycardia (grade 3) in one subject. The only other toxicity related grade > 3 event seen was 
hypotension (grade 3) in one patient. The most common related toxicity was grade 1 injection site 
reaction in 7 patients. The volume of subcutaneous injection will be limited to 1.4 mL per site. Thus a 
28 mg/subject (2.8 mL @ 10 mg/mL) dose will be administered in two equal portions at two different 
sites. A separate drug product vial, syringe and needle will be used for each injection.  
9.3 
Rationale for Correlative Studies 
Not applicable. 
9.4 
Definition of Evaluable Subjects  
Within the Phase 1 portion of this protocol, a patient who terminates protocol treatment before 
completion of the standard RT and TMZ without experiencing DLT will not be considered evaluable 
for the purpose of determining the MTD.  
 
Within the Phase 2 portion of this protocol, all patients who are randomized will be included in 
primary analyses for the primary objective of survival regardless of treatment compliance. An intent-
to treat approach will be used in statistical analyses. 
9.5 
Data collection for subjects unable to come to clinical center 
In the event that subjects are unable to visit the clinical center we request that the clinical center 
staff either mail, email, or conduct the following HrQoL assessments by phone: 
 
-FACT-BR  
-FACT-Cog  
-FACIT-Fatigue 
-Beck Depression Inventory  
-Godin Leisure Questionnaire 
 
Mailed questionnaire will be sent with a cover letter and will be pre-labeled with the Subject’s Study 
ID Number.  Subjects will be asked not to include their names or return addresses on the package in 
order to limit the PHI sent by mail. 
9.6 
Early Study Termination 
This study can be terminated at any time for any reason by the sponsor. If this occurs, all subjects on 
study should be notified as soon as possible. Additional procedures and/or follow up should occur in 
accordance with Section 13.7.1, which describes procedures and processes for prematurely 
withdrawn patients and in accordance with Section 13.7.2.  
 
 
 


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10 STUDY DRUG (BMX-001) 
10.1 Names, Classification, and Mechanism of Action 
BMX-001, also known as MnTnBuOE-2-PyP5+ (manganese butoxyethyl pyridyl porphyrin), is a 
metalloporphyrin antioxidant that has anti-inflammatory, anti-oxidant and anti-tumor functions. A 
series of metalloporphyrins have undergone preclinical evaluation and BMX-001 represents one with 
increased catalytic potency along with high lipophilicity. This class of metalloporphyrins leads to 
inactivation of reactive oxygen species and in turn leads to reduction of oxidative stress. The 
lipophilicity of BMX-001 leads to its accumulation in the brain parenchyma and it has been shown to 
cross the blood-brain barrier. Because the vasculature of most mammalian species is highly sensitive 
to an oxidative shift, there is a concern for blood pressure monitoring in studies of the 
metalloporphyrin compounds. Studies in Sprague-Dawley rats showed that intravenous delivery of 
metalloporphyrin could lead to transient hypotension [2]. In this same study, mice, guinea pigs, dogs, 
and baboons receive intravenous delivery of metalloporphyrins with less effect on blood pressure. 
BMX-001 was patented by Duke University and has been licensed to BioMimetix JV, LLC. Molecular 
structure is depicted in Figure 4.  
Figure 4: BMX-001 Structure 
10.2 Packaging and Labeling 
10.2.1 
Drug Product Formulation and Manufacture 
The drug will be supplied by BioMimetix JV, LLC. The drug substance (1.2 kg of solid) was 
manufactured and stored according to cGMP by Albany Molecular Research, Inc. (AMRI). 
BioMimetix has contracted with AMRI (Glasgow) Ltd. to manufacture single dose vials of sterile BMX-
001 for injection. Manufacturing will be conducted on AMRI's Flexicon FPC50W filling machine, which 
is dedicated for aseptic GMP manufacturing within a clean room suite. Manufacturing will include 
batch pre-filtration and aseptic filtration and filling in accordance with AMRI Glasgow's validated 
process. 
BMX-001 will be formulated as a solution in 0.9% saline at 10 mg/mL, aseptically filtered and filled to 
2 mL in a 5 mL Type 1 clear glass vial, sealed with a 20 mm Flurotec serum stopper and flip off 
aluminum overseal.  A nitrogen overlay will be applied to each vial following filling and prior to 
stoppering.  
 


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In-process testing will include pre-filtration bioburden, post-use filter integrity test, and in-process 
weight checking. Release tests and specifications for BMX-001 for injection are currently under 
development, but will be established before manufacturing of the clinical batch commences. These 
will include sterility (USP <71>), bacterial endotoxins (USP <85>), particulate matter (USP <788>), 
appearance, color and clarity, pH, osmolality, assay and purity. 
The clinical batch of drug product will be placed on stability and tested for the duration of its use 
during the clinical trials. 
10.2.2 
Labels for BMX-001 for Injection, 10 mg/mL 
An exemplary label for the BMX-001 for Injection, 10 mg/mL is reproduced in Figure 5.  
BMX-001 for Injection, 10 mg/mL 
Lot # P07715 
Administer SQ, ≤1.4 mL/site. 
Caution:  New Drug – Limited by Federal Law to 
Investigational Use 
Emergency contact:  Dr. Shayne Gad, cell 919-618-0523 
Store at Room Temperature 
Figure 5: Exemplary Label for BMX-001 for Injection, 10 mg/mL 
10.2.3 
Syringe and Label for Administration of BMX-001 for Injection, 10 mg/mL 
A pharmacist will prepare the loaded syringe(s) and needle(s) that will be used for subcutaneous 
administration of the appropriate dose of BMX-001 for Injection, 10 mg/mL to the clinical subject.   In 
Phase 2, the loading dose is 28 mg/subject and the maintenance doses are 14 mg/subject biw. The 
drug product is shipped to the clinical centers as a sterile solution of BMX-001 in saline packaged in 
single use vials.  The pharmacist at the clinical center needs to draw the appropriate volume into a 
syringe.   
The syringe should be stored at room temperature until use, which will occur within 4 hours of 
preparation. Appropriate procedures for drug accountability must be followed.  
 
No more than 1.4 mL is to be administered at a single injection site. Thus a 28 mg or 20 mg dose will 
be administered in two equal portions (14 mg or 10 mg, respectively), taken from different vials and 
injected via separate syringes and needles at two different sites. A 42 mg dose will be administered in 
three 14 mg portions taken from three different vials and injected via separate syringes and needles 
at three different sites. 
10.2.4 
Multi-Dose Kits 
Multi-dose kits containing vials labeled as described in Section 10.2.2 are packaged in paperboard 
cartons. The carton label includes the information indicated in Figure 6, where "XXX" is replaced by 
the number of vials contained in the carton. 
Lot # P07715 
 
Store at Room Temperature 
BMX-001 for Injection, 10 mg/mL Multi-Dose Kit 
Contents:  XXX Single-Dose Units @ 20 mg each 
Caution:  New Drug – Limited by Federal Law to 
Investigational Use 
Emergency contact:  Dr. Shayne Gad, cell 919-618-0523 


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Figure 6: Exemplary Label for Multi-Dose Kits 
10.3 Supply, Receipt, and Storage 
The multi-dose kits described in Section 10.2.4 will be shipped by overnight delivery to the clinical 
center pharmacy. These kits will be stored at room temperature per the Certificate of Analysis 
provided in the BMX-001 Investigator Brochure, in a locked, physically secure environment, according 
to the pharmacy's standard procedures for storage of investigational drug products. Drug 
accountability records will be maintained by the clinical center for all clinical trial supplies. 
10.4 Compliance and Accountability 
Drug accountability records will be maintained for all clinical trial supplies. 
10.5 Disposal and Destruction 
All empty and partially used clinical trial supplies will be destroyed in accordance with the 
institution’s requirements for an investigational agent.  Unused supplies must not be destroyed until 
after drug accountability is performed by the sponsor and instructions are provided regarding 
destruction or return. Disposition of all unused boxes of study drug will be carried out according to 
instructions provided by BioMimetix JV, LLC, at the end of the study after drug accountability is 
performed. The pharmacy will maintain detailed documentation of the number and identification of 
BMX-001 vials which are destroyed, and copies of these documents will be provided to BioMimetix 
JV, LLC. 
 
 


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11 STUDY DRUG (TMZ) 
11.1 Description 
8-Carbamoyl-3-methylimidazol[5,1-d]-1,2,3,5-tetrazine-4-(3H)-one, CCRG 81045, M&B 39831)-
Temozolomide is commercially available and not provided in this study.  
11.2 Formulation 
TMZ is available in 250 mg, 180 mg, 140 mg, 100 mg, 20 mg, and 5 mg strengths. Refer to package 
insert for contents of the formulation.  
11.3 Storage 
TMZ capsules should be stored between 2oC to 30oC. Commercial supply and packaging will be used. 
11.4 Administration 
TMZ is administered orally on an empty stomach. The drug is approximately 100% bioavailable.  
The dose will be rounded to the nearest 5 mg when possible.  Final dose will be determined by the 
subject’s primary neuro-oncologist and the following can be taken into account: number of pills per 
day and number of co-payments required. Effects of food on product absorption are not yet known. 
DO NOT OPEN CAPSULES. DO NOT MIX WITH FOOD. DO NOT CHEW CAPSULES. 
 
TMZ at a dose of 75mg/m2 po daily will be started with external beam RT (+/- 5 days). TMZ will be 
held according to standard of care for the institution (typically when platelets drop below 100,000 
cells/uL), grade 4 neutropenia, or grade 4 non-hematologic toxicity secondary to TMZ. TMZ will be re-
started at 50 mg/m2 after resolution of the toxicity, or < grade 1. If the grade 3 thrombocytopenia, 
grade 4 neutropenia, or grade 4 non-hematologic toxicity secondary to TMZ recurs at 50 mg/m2, TMZ 
will be held during RT therapy, but may resume after RT therapy if the patient meets the treatment 
criteria.  
11.5 Toxicities 
TMZ has been well tolerated by both adults and children with the most common toxicity being mild 
myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, 
headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, and 
hepatotoxicity. Hypersensitivity reactions have not yet been noted with TMZ. As is the case with 
many anti-cancer drugs, TMZ may be carcinogenic. Rats given TMZ have developed breast cancer. 
The significance of this finding for humans is not presently known. 
11.6 Packaging and labeling 
TMZ is manufactured by multiple sources and commercial drug will be used is in this study. 
12 SUBJECT ELIGIBILITY 
Please see Section 5.5 for a complete list of inclusion and exclusion criteria. 
 
 


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13 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
Table 4: Screening and On-Study Tests and Procedures 
On-Study Tests and Procedures 
 
 
 
Week 
1  
Arm 
A 
only r 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 q 
Week 
8 q 
Weeks 9 and 
Forward 
Evaluation 
Screeninga  
Day -5 
to 0 p 
 
 
 
  
 
 
 
 
Adjuvant Phaseb, 
g, v 
Informed consent 
and Demographics w 
X 
 
 
 
 
 
 
 
 
 
 
Randomization o 
X 
 
 
 
 
 
 
 
 
 
 
History and physical 
exam, including full 
neurologic exam & 
KPS c 
X 
X 
 
X 
 
X 
 
X 
 
X 
Xb 
Vital signs, including 
blood pressure m 
X 
Xl 
Xl 
X 
Xl 
X 
Xl 
X 
Xl 
X 
Xb 
CBC with 
differential d 
X 
 
 
X  
X 
X 
X 
X 
X 
X  
Xb 
CMP  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Xb 
PT, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
Beta-HCG, if 
applicable, within 
48 hours prior to 
start of study 
treatment 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
Xe 
Xe 
 
 
Xe 
 
 
 
 
 
PK sampling serum f 
 
X 
 
X 
 
 
X 
 
 
 
 
MRI of the brain 
X 
 
 
 
 
 
 
 
 
 
Xb 
MRI (DTI/
Susceptibility 
Imaging) in Phase 2 
only 
 
X 
 
 
 
 
 
 
 
 
Xh 
BAC App Cognitive 
Testing s 
X (baseline) 
 
 
 
 
 
 
 
 
 
Xb, s 
Additional Cognitive 
Testingg , t 
X (baseline) 
 
 
 
 
 
 
 
 
 
Xb 
HRQoL 
Measurementsg 
X (baseline) 
 
 
 
 
 
 
 
 
 
Xb 
Hair Loss 
Evaluationu 
X (baseline) 
 
 
 
 
 
 
 
 
 
Xb 
Toxicity Assessment 
X 
Ongoing 
Xi 
Radiation 
 
 
Continuous Dosing Monday-Friday for 6 weeks 
 
 
TMZ 
 
 
Continuous Dosing at 75 mg/m2 for 42 days 
 
Will start 
adjuvantb 
BMX-001 
 
Xj 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
 
a Within 3 weeks of starting BMX-001.  
b Will transition to 5-day TMZ dosed at 150-200 mg/m2 po daily for the 1st 5 days in 28-day cycle (Adjuvant Phase). Study 
assessments for HRQoL Measurements, and Hair Loss Evaluation will be obtained approximately every 8 weeks (+/- 2 
weeks) when a subject returns for a Standard of Care visit, until tumor progression, death, or patient comes off of study.  
Cognitive testing will also be completed every 8 weeks and at SOC visits; Cognitive testing will continue after tumor 
progression.  CBC with differential will be obtained approximately on Days 21 or 28 of each 28-day cycle, and CMP will be 
obtained approximately on Day 21 of each 28-day cycle, or per the ordering physicians Standard of care practice, during 
the adjuvant phase, until the subject comes off the study. If subject is transitioned to metronomic temozolomide because 
of poor tolerance to 5-day temozolomide, then they will continue to be on study. Moreover, if Optune is used during the 
adjuvant phase, then they will continue to be on study. Adjuvant temozolomide can start up to 4 weeks after radiation 
therapy has completed.   
c Starting at Loading dose day or Day -5 to 0, this will occur once every other week during weeks 1-8.   This may be 
modified to meet standard of care scheduling for patient visits. 


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d Weekly CBCs and CMPs will begin at week 2 and continue through week 8. Platelet count is part of CBC with differential 
count.  
e ECG will be done at screening for all subjects.  For subjects in Arm A, ECG will also be obtained before the loading dose is 
administered (within 5 to 60 minutes before the dose), and at 60 (+/- 15 min) minutes after the loading dose.  Pre-dose 
(within 5 to 60 minutes before the dose), and Post-dose ( 60 +/- 15 min) ECGs will also be collected at the Week 1 first 
maintenance dose and on either one of the BMX-001 injection days in Week 4. 
f See Appendix B for timing of PK sampling, Day 8 and Day 36 only. Phase 1- all subjects, Phase 2- 6 subjects at Duke.  
g HRQoL measurements will be completed during Screening as a baseline and then approximately every 8 weeks when a 
subject returns for a Standard of Care visit during the Adjuvant Phase. These assessments should be completed prior to 
other study-related evaluations at study visits, if at all possible.  
h DTI/Susceptibility Imaging is for clinical centers selected by the sponsor and completed at baseline, during the Adjuvant 
Phase before the start of the first cycle of adjuvant temozolomide, as well as 6 months (approximately 24 weeks, +/- 2 
weeks) after radiotherapy/chemotherapy  
i Toxicity assessment will continue to be obtained at every SOC clinic visit during the Adjuvant Phase for a minimum of 30 
days after last BMX-001 treatment for subjects receiving BMX-001 or last chemo/RT for subjects not receiving BMX-001, 
and also followed for any unresolved adverse events considered related to study therapy.  
j For BMX-001, this dose will be the loading dose. In Phase 2- Applicable only for patients in Arm A. 
k For BMX-001, doses (50% of the loading dose) will be twice a week subcutaneously weeks 1-8. There will only be two 
doses per week regardless of being a loading or maintenance dose. In Phase 2- Applicable only for patients in Arm A. 
l For patients in Phase 2 Arm B (standard RT + TMZ without BMX-001), vital sign evaluation will only be required on days of 
the History and Physical assessment.  
m Arm A:  Patients will be monitored at drug administration with vital signs and injection site reaction at pre dose, at 5 (+/-
2), 15 (+/-3), 30 (+/-5), and 60 (+/- 5) minutes post administration on the BMX-001 loading dose. Patients will be monitored 
at drug administration with vital signs and injection site reaction at pre dose, at 5 (+/-2), 15 (+/-3) and 30 (+/-5) minutes 
post administration on BMX-001 maintenance injection days. See Section 0.  
o Phase 2 only, subjects will be randomized after all eligibility criteria is confirmed.   
p For Phase 2: For subjects in Arm A, this column is the day of the BMX-001 Loading Dose. For Subjects in Arm B, these 
items should occur -5 to 0 days prior to the start of RT.  The procedures for this visit should not take place until final 
eligibility is confirmed and randomization has occurred.   
q In Phase 2, subjects randomized to Arm B will NOT have a Week 7 or Week 8 research study visit.    
r In Phase 2, subjects randomized to Arm B do not have a Week 1 study visit, although they will be in the clinic for the start 
of RT and TMZ.   
s These assessments should be completed prior to other study-related evaluations at study visits, if at all possible.  CNS 
Vital Signs®(Phase 1) /NeuroCog BAC App (Phase 2) will be done screening (baseline), and then approximately every 8 
weeks when a subject returns for a Standard of Care visit during the Adjuvant Phase.   
t.   Hopkins Verbal Learning Test-Revised (Forms 1, 2, and 3), Trails Making Test Parts A and B, and Controlled Word 
Association Test will be performed only at baseline, the standard of care visit before the start of the first cycle of adjuvant 
temozolomide, and the standard of care visit that is 6 and 12 months from the completion of radiotherapy/chemotherapy.   
See appendices for appropriate versions of these forms to use.   
u  Hair loss evaluation includes subjective description and photos. 
v Patients will continue to complete visits in the adjuvant cycle for up to the 12 planned cycles, as long as they do not have 
progression on MRI (even if they stop taking adjuvant TMZ).  Cognitive testing will be completed even after progression is 
noted.   
w Collection of Gender, Race, Ethnicity, Education completed, employment, and smoking status to be obtained at 
screening. 
 
13.1 Screening Examination 
The screening examination will take place between Day -21 and -1. An informed consent must be 
signed by the patient before any study specific screening procedures take place. Information 
collected prior to the signing of informed consent according to standard of care for procedures such 
as KPS, labs, history and physical, and MRI, etc.  may be used to determine eligibility.  Subject data to 
be collected at the Screening Examination is listed in the table above and includes physical and 
neurological examination; vital signs and weight; ECG, laboratory studies (complete blood count with 
differential, complete metabolic panel, PT/aPTT, and beta-HCG); past medical history; and 
concomitant medications (including but not limited to steroids and anticonvulsants).  Additional 


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baseline testing will be completed for the following:  cognitive testing, HRQoL Measurements, and 
hair loss evaluation.   
 
The screening MRI or CT scan will be uploaded to the Duke central core for final review of eligibility.  
This will be required for all subjects. The clinical centers will be notified of the final determination of 
eligibility prior to the subject completing any study visit.      
 
The pathology report used to determine eligibility, which includes any tumor markers will be 
redacted and uploaded to the sponsor electronic data capture system.   
 
If a subject is found to be ineligible to participate in the study, the patient will not be randomized to a 
treatment arm and minimal records regarding the subject and the reason for screen failure will be 
retained. 
13.2 Run-In Period 
Not applicable. 
13.3 Chemoradiation Treatment Period (with and without BMX-001) 
The treatment period for BMX-001 is eight weeks.  This consists of treatment prior to start of 
chemotherapy- RT, during the six weeks of concurrent daily TMZ and standard RT with BMX-001 
(Phase 1 and Phase 2 (Arm A)) followed by 2 weeks of BMX-001 (Phase 1 and Phase 2 (Arm A)).  For 
subjects in Arm B, this period is six weeks of concurrent daily TMZ with standard RT followed by 2 
weeks of no treatment.   For subjects in Arm B, they do not need to return to the clinical center for a 
study visit once TMZ and RT is complete for visits at Week 7 and Week 8.   
13.4 BMX-001 Treatment Criteria 
 
If adverse events occur that require holding BMX-001, the dose will remain the same once treatment 
resumes.  Missed doses should be made up at the end of treatment to achieve the total number of 
planned doses (17). 
 
13.4.1 
Phase 2 - Criteria for holding BMX-001 
Non-Hematologic Criteria 
1. The occurrence of non-hematologic grade 3 or greater adverse events considered to be 
possibly, probably, or definitely related to BMX-001 during treatment with BMX-001, 
excluding grade ≥ 3 alopecia and elevation in alkaline phosphatase, grade ≥ 3 nausea or 
vomiting unless occurring despite the use of standard anti-emetics; and grade ≥ 3 
hypertriglyceridemia or hypercholesterolemia unless occurring despite standard lipid 
lowering agents. 
2. Intolerable ≥ Grade 2 Injection Site Reactions 
3. ≥ Grade 2 electrocardiogram prolonged QTc interval 
 
Hematologic Criteria 
1. Grade 4 neutropenia (ANC, including bands, ≤ 500 cells /μl); 
2. Grade 3 thrombocytopenia (platelet count of ≤ 50,000 cells/μl); 
 
13.4.2 
Phase 2- Re-treatment Criteria for BMX-001 
Non-Hematologic 


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1. Resolution of any grade 3 or greater toxicity felt to be possibly, probably or definitely 
attributable to BMX-001 to grade 1 or pre-treatment baseline. 
2. Resolution of Intolerable ≥ Grade 2 Injection Site Reactions to < Grade 1 
3. Resolution of Grade 2 electrocardiogram prolonged QTc interval to baseline, or after review 
by sponsor. 
 
Hematologic 
1. ANC ≥ 1,000 cells/μl 
2. Platelets ≥ 50,000 cells/μl 
 
13.4.3 
Phase 2- Discontinuation Criteria for BMX-001 
Inability to resolve any grade 3 or greater toxicity felt to be possibly, probably or definitely 
attributable to BMX-001 to grade 1 or pre-treatment baseline within 21 days.   
 
For both non-hematologic and hematologic events, if any event requires holding BMX-001 > 21 
days without retreatment, BMX-001 would not be started again.  In these cases, subjects should 
continue to be followed for survival without the completion of study treatment visits.   
 
13.5 End of Study 
The end of study for a subject will occur when the subject comes off study for the following reasons: 
completion of all study tests/procedures, progressive disease, unacceptable toxicity, allergic reaction 
to TMZ, allergic reactions to BMX-001, non-compliance with study follow-up, or withdrawal of 
consent. Patient death due to progressive disease will not be reported as a SAE. It is the intent that all 
patients will be followed as long as possible for survival. See Section 13.7.2 for follow-up 
requirements after the patient comes off study. 
13.6 Overall Study Completion 
The study will be considered complete once enrollment has been met, follow-up procedures on all 
subjects have been conducted, and data analysis is concluded. The study may also be terminated 
early for any reason by the sponsor. In order to terminate the study with the external IRB, all data 
extraction and analysis must be complete. Therefore, if any articles for publication are derived from 
the current study, they must be submitted and accepted with no further need for additional data 
review prior to termination with the IRB. 
 
Subjects that are lost to follow-up will be documented in the patient record and in the database.  
13.7 Withdrawal of Subject(s) 
13.7.1 
Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject 
from the study at any time based on his/her discretion. Reasons for PI-initiated withdrawal may 
include, but is not limited to the following: 
- 
Adverse events 
- 
Abnormal laboratory values 
- 
Abnormal test procedure results 
- 
Protocol deviation 
- 
Administrative issues 
- 
Disease progression- Patients will still complete cognitive testing (HVLT-R, COWA, TMT, BAC App) 
after coming off for disease progression.  All other assessments will stop at the point of 


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progression.  If a patient came off study for disease progression prior to this protocol 
amendment, and is still having study visits or is within 3 months from their 12 month visit, they 
should be contacted and asked to complete the cognitive testing at their next visit.   
- 
Pregnancy 
13.7.2 
Follow-up Requirements for Early Withdrawal 
Subjects who are withdrawn due to toxicity or progressive disease will be followed for as long as they 
are receiving treatment for their HGG at the clinical center. Study visits will cease, however data 
collection for survival should continue at a minimum of three month intervals.   For subjects who 
voluntarily withdraw, there is not an end of study visit, unless deemed appropriate by the PI. Early 
withdrawal subjects will be followed for survival where possible, except for subjects that specifically 
request not to have any further follow up. 
13.8 Study Assessments 
13.8.1 
Medical History 
Standard medical history assessments will be conducted and recorded per institutional and sponsor 
guidelines.  
13.8.2 
Physical and Neurological Examinations 
Physical and neurologic examinations, vital signs (temperature, respiratory rate, blood pressure and 
pulse), height (screening only), weight and KPS must be performed at: 
 
- 
screening 
- 
day of loading dose (Arm A in Phase 2) 
- 
two weeks after the completion of RT and TMZ 
- 
every standard of care (SOC) clinic visit (approximately every 8 weeks) during adjuvant TMZ 
- 
at the time of study completion 
 
Additional physical and neurological examination may be performed every two weeks during 
standard RT and TMZ per the standard of care practice. More frequent examinations may be 
performed at the investigator’s discretion, if medically indicated.  
 
a. Physical examination, vital signs, weight and height 
A complete Physical Examination (PE) will include a general physical examination of major body 
systems, temperature, respiratory rate, blood pressure, heart rate, body weight and height. 
 
Height will be measured and documented at screening only. 
 
Blood pressure should be measured per institutional guidelines.  
 
b. Neurologic examination 
A complete neurologic examination will include assessment of level of consciousness, mental 
status, speech, cranial nerves, motor, sensory, coordination, reflexes, and gait. Follow-up 
evaluation of the neurologic examination will be based on any changes in the neurologic clinical 
examination from the previous exam. Changes should be unrelated to postictal state or other 
unrelated events such as infection. 
13.8.3 
Electrocardiogram (ECG) 
ECG will be done for screening purposes for all subjects.  For subjects in Arm A, a baseline ECG prior 
to BMX-001 administration will be completed and at 60 (±15) minutes after dosing on the loading day 
of BMX-001 and on the first BMX-001 maintenance dose administration day during Week 1 and any 


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dose in Week 4 pre-dose and at 60 (±15) minutes after dosing.   Results will be filed in the source for 
each subject and redacted tracings will be uploaded to the sponsor electronic database.   
 
13.8.4 
Radiographic Response 
The guidelines and criteria for radiographic response will be based on the RANO criteria. MRI brain 
with and without contrast will be obtained at baseline after standard RT and TMZ (within 2 to 4 
weeks) and every standard of care (SOC) clinic visit (approximately every 8 weeks) during adjuvant 
TMZ. Institutional standard operating procedure will be followed (see Protocol Appendix A, Section 
19.1). The clinical centers will be provided with a Clinical Trial Radiographic Assessment Form (CTRAF) 
to aid them with the data collection required for the study.  A different form may be used with 
approval from the sponsor.  RANO criteria will be utilizing based on the modifications from Ellingson 
et al. [66]. In these criteria, particularly in regards to newly diagnosed subjects, the areas considered 
in determining comprehensive objective status in RANO criteria are target lesions (enhancing 
disease), new sites of measurable disease, neurological examination status, and corticosteroid usage 
and dose. 
 
Complete Response (CR): Requires all of the following: 
1. Disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 
weeks. The first scan exhibiting disappearance of all enhancing measurable and non-measurable 
disease is considered “preliminary CR”. If the second scan exhibits measurable enhancing disease 
with respect to the “preliminary CR” scan, then the response is not sustained, noted as 
“pseudoresponse”, PsR, and is now considered “preliminary PD” (note confirmed PD requires at 
least two sequential increases in tumor volume). If the second scan continues to exhibit 
disappearance of enhancing disease or emergence of non-measurable disease (less than 
10mm bidimensional product), it is considered a durable CR and the patient should continue on 
trial until confirmed PD is observed. 
2. Patients should be either off of corticosteroids or on physiologic replacement doses only. 
3. Stable or improved neurological examinations.  
 
Partial Response (PR): Requires all of the following 
1.  Greater than or equal to a 50% reduction in the size (products of the largest perpendicular 
diameters) for all enhancing lesions compared with baseline, sustained for at least 4 weeks. The 
first scan exhibiting greater than or equal to a 50% decrease in the sum of the products of the 
perpendicular diameters of all measurable enhancing lesions compared with the baseline is 
considered “preliminary PR”. If the second scan exhibits PD with respect to the “preliminary PR” 
scan, then the response is not sustained, noted as pseudoresponse, PsR, and is now considered 
“preliminary PD” (note confirmed PD requires at least two sequential increases in tumor 
volume.) If the second scan exhibits SD, PR, or CR, it is considered a durable PR and the patient 
should continue on trial until confirmed PD is observed. 
2. Patients should have either the same corticosteroid doses or on lower corticosteroid dose 
compared with baseline scan. 
3. Stable or improved neurological examinations 
 
Stable Disease: Evaluations that do not meet criteria for CR, PR or PD. 
 
Progressive Disease: Defined as the following 
1.  Greater than or equal to a 25% increase in the product of the largest perpendicular diameters of 
any enhancing lesion or any new enhancing tumor on MRI scans. The first scan exhibiting greater 
than or equal to a 25% increase in the sum of the products of perpendicular diameter of the 
enhancing lesions should be compared to the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response (on stable or increasing corticosteroid dose) and is 


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noted as “preliminary PD”. If the second scan at least 4 weeks later exhibits a subseqeuent 
greater than or equal to 25% increase in the sum of products of perpendicular diameters of the 
enhancing lesions relative to the “preliminary PD” scan, it is considered “confirmed PD” and the 
patient should be discontinued from the study. If the second scan at least 4 weeks later exhibits 
SD or, PR/CR, this scan showing “preliminary PD” is noted as “pseudoprogression”, PsP, and the 
subject should remain on study until a second increase in tumor size relative to the PsP scan is 
observed. Of note, any new measurable (> 10 mm X 10 mm) enhancing lesion should not be 
immediately considered PD, but instead should be added to the sum of the bidimensional 
products representing the entire enhancing tumor burden.  
2. In the case where the baseline or best response demonstrates no measurable enhancing disease 
(visible or not visible), then any new measurable (>10mm x 10mm) enhancing lesions are 
considered PD after confirmed by a subsequent scan ≥4 weeks exhibiting greater than or equal to 
a 25% increase in sum of products of perpendicular diameters relative to the scan first illustrating 
new measurable disease. The first scan exhibiting new measurable disease is noted as 
“preliminary PD”. If the second scan at least 4 weeks later exhibits a subsequent greater than or 
equal to a 25% increase in sum of products of perpendicular of enhancing lesions relative to the 
“preliminary PD” scan it is considered “confirmed PD” and the patient should discontinue 
therapy. If the second scan at least 4 weeks later exhibits SD, CR, PR, or becomes non-
measurable, this scan showing “preliminary PD” is noted as “pseudoprogression”, PsP, and the 
subject should continue on study until a second increase in tumor size relative to the 
“preliminary PD”, or PsP, scan is observed. Note that any new measurable (>10mm x 10mm) 
enhancing lesions on the subsequent scan following the “preliminary PD” scan should not be 
immediately considered “confirmed PD”, but instead should be added to the sum of 
bidimensional products representing the entire enhancing tumor burden. 
3.  Unequivocal and significant worsening neurological examination not attributable to other 
causes. 
4. Of note, if there has been a major reduction in steroid dosage in the interval and the patient is 
felt to be clinically stable or improved, the proper assessment may be “indeterminate” and the 
therapy could be continued pending the next evaluation. 
5. Failure to return for evaluation as a result of death or deteriorating condition. 
 
Not Evaluable (NE): Progression has not been documented and one or more sites have not been 
assessed. 
13.8.5 
HRQoL 
HRQoL will be assessed by the Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale. The 
FACT-BR (version 4) contains subscales for physical (7-items), functional (7-items), emotional (6-
items), and social/family (7-items) well-being. In addition, this instrument contains an 23-item brain 
cancer subscale (BCS) which assess symptoms commonly reported by brain cancer patients [27]. 
Cancer-related fatigue will be assessed by the 13-item Fatigue Scale using the Functional Assessment 
of Cancer Therapy-Fatigue (FACIT-Fatigue) subscale, version 4 [67]. Cognitive problems will be 
assessed using version 3 of the Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) 
subscale [68]. This includes subscales for perceived cognitive impairments (20 items), comments from 
others (4 items), perceived cognitive abilities (9 items), and impact of quality of life (4 items). Beck 
depression inventory (BDI) will be used to evaluate for underlying depressive symptoms. We will use 
the revised version (BDI-II) and the scores will range from 0 (no depression) to 63 (severe depression) 
[69]. The BDI contains 21 questions in regards to mood symptoms and is multiple-choice and self-
reported. Exercise behavior will be assessed using the Godin Leisure questionnaire [70]. HRQoL PROs 
questionnaires will be obtained at screening, after standard RT and TMZ (within 2 to 4 weeks), and 
approximately every 8 weeks when a subject returns for a Standard of Care visit during adjuvant TMZ.  


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13.8.6 
Cognitive Testing  
Cognitive testing will include the performance on the following testing using a computerized battery 
CNS Vital Signs® [22] (Phase 1) and Brief Assessment of Cognition (BAC) through the NeuroCog app 
(Phase 2). The CNS Vital Signs® battery consists of seven tests that measure verbal and visual 
memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, continuous 
performance test. Verbal memory test will assess verbal learning, memory for words, immediate 
recall, and delayed recall. Visual memory tests will assess visual learning, memory for geometric 
shapes, immediate recall, and delayed recall. Finger tapping test will assess motor speed and fine 
motor control. Symbol digit coding test will evaluate complex attention, visual-perceptual speed, and 
information processing speed. Stroop Test will assess executive function, simple and choice reaction 
time, speed-accuracy trade-off, information processing speed, and inhibition/disinhibition. Shifting 
attention test will assess executive function, reaction time, and information processing speed. 
Continuous performance test will assess sustained attention and choice reaction time. Normative 
data is available for this testing through CNS Vital Signs® and patients’ performance will be compared 
to this normative data. In Phase 2, the BAC battery of tests is implemented through an iPad based 
app called the BAC App (the vendor that provides this is called VeraSci, previously called NeuroCog) 
[22]. The table below shows a description of the BAC App Subtests. Examples are included in 
Appendix E.  The verbal responses provided during the tests conducted with the iPad will be audio 
recorded.   These audio recordings will be used by the representatives of the site and sponsor to 
make sure that your responses are recorded correctly.  The audio recordings will be stored and van 
be viewed later using VeraSci’s proprietary portal, which appropriate credentials are needed to 
access.  They will be retained for the period of time specified for all other study data or as required by 
law.    Cognitive testing with the BAC App will be obtained at screening (for the baseline assessment), 
after standard RT and TMZ (within 2 to 4 weeks), and approximately every 8 weeks when a subject 
returns for a Standard of Care visit during adjuvant TMZ.  If a subject comes off study for disease 
progression before the approximate 6 and 12 months post completion of treatment timepoint, 
cognitive testing should still be collected at those timepoints. Additional cognitive testing (HVLT-R, 
COWA, and TMT) will be performed at these selected times: baseline, standard of care visit before 
the start of the first cycle of adjuvant temozolomide, and standard of care visits that are 6 and 12 
months from the completion of radiotherapy/chemotherapy. These tests will be performed by a 
trained neuropsychologist or delegate at the clinical center. The tests will include Hopkins Verbal 
Learning Test-Revised to assess learning, total recall, and memory [71], Trails Making Test Parts A and 
B to assess attention and executive function [72], and Controlled Oral Word Association Test to assess 
verbal fluency [73]. 
 


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Table 5: Description of the BAC App Subtests. Traditional BAC App Battery. List of tests, the domains of cognition 
they assess, a description of the methodology for assessment and the total time for test administration. 
Domain 
BAC Subtest 
Summary 
Duration (mins) 
Verbal Memory 
& Learning 
Verbal Memory 
  
Subject is presented with 15 words and 
asked to recall as many as possible. This 
procedure is repeated 5 times. 
Outcome measure: Number of words 
recalled  
7 
Working 
Memory 
Digit Sequencing  
Subject is presented with auditory 
clusters of numbers (e.g. 9, 3, 6) of 
increasing length and asked to tell the 
rater the numbers in order from lowest to 
highest.  
Outcome measure: Number of correct 
responses 
5 
Motor Function 
Token Motor  
Subject is presented with tokens and 
asked to drag them to a center container 
as quickly as possible for 60 seconds.  
Outcome measure: Number of tokens 
correctly dragged into the container  
3 
Verbal Fluency 
Semantic Fluency 
Subject is given 60 seconds to verbally 
generate as many words as possible in a 
given category. 
Outcome measure: Number of words 
generated 
5 
Letter Fluency 
In two separate trials, subject is given 60 
seconds to verbally generate as many 
words as possible beginning with a given 
letter of the alphabet.  
Outcome measure: Number of words 
generated  
Speed of 
Processing 
Symbol Coding 
Subject is provided a key and asked to fill 
in the corresponding numbers beneath a 
series of symbols as quickly as possible 
within 90 seconds.  
Outcome measure: Number of correct 
items  
3 
Executive 
Function 
Tower of London  
Subject is asked to give the minimum 
number of times the balls in one picture 
would need to be moved in order to make 
the arrangement of balls identical to that 
in the opposing picture. 
Outcome measure: Number of correct 
responses 
7 
 


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13.8.7 
Hair Integrity and Hair Loss 
Subjective assessments of hair loss will be obtained by the treating provider for subjects at screening 
(baseline), after standard RT and TMZ finishes (within 2 to 4 weeks), and standard of care (SOC) clinic 
visit (approximately every 8 weeks) during adjuvant TMZ.  
 
The photographs will be taken of the craniotomy scar (surgical incision site) and can be taken at any 
angle or background approximately 6-48 inches from the scalp. There will be no identifiers on the 
photographs. Up to 6 photographs may be taken at any one time point. Photographs will not include 
the subjects entire face (will not include eyes, nose, mouth). The photographs will be taken by the PI 
or trained staff and may be uploaded to the electronic medical record, kept in a separate electronic 
research file or on paper. One photo per timepoint will also be uploaded to the sponsor electronic 
database.  Participation in these pictures is optional for the patient and they can decline the picture 
taking at any time. Hair loss will be subjectively described and evaluated clinically by the providers 
treating the patient and later by the sponsor. If the patient is bald, the photos and descriptions may 
be omitted.   
13.8.8 
Medical and Demographic Information 
Medical and demographic information will consist of general demographic information (e.g., race, 
ethnicity, education, employment, smoking status). Demographic information should be collected at 
the time of screening.  Medical information will be abstracted from medical records and study 
questionnaires.  
13.8.9 
Bone Marrow Assessments  
Bone marrow function will be assessed by CBC with differential (which includes platelet counts) as 
described in the table in Section 13 Screening and On-Study Tests and Procedures. 
13.8.10 MRI Diffusion Tensor/Susceptibility Imaging 
MRI diffusion tensor/susceptibility imaging during Phase 2 involves the application of standard MRI 
imaging of the brain to evaluate white matter integrity. This will be done before contrast injection on 
subjects enrolled at clinical centers as indicated by the sponsor in Phase 2. All images will be acquired 
on state-of-the-art 3T scanners.  
 
Imaging should include T1-weighted 3D imaging before and after single dose contrast agent injection 
as specified in the standardized brain tumor imaging protocol (BTIP, 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588759/, Table 1).  T2 and FLAIR imaging should 
also be performed as specified in this publication.  
 
For susceptibility images, images will be acquired using a multi-echo 3D gradient echo sequence.   
 
 
For Siemens scanners, use the following parameters:  
 
TE1 
=min 
TR 
=60 ms 
flip angle 
= 12º 
FOV 
= 220x220 mm2 
matrix size 
= 256x256, 2mm slice thickness with no gaps, 
parallel imaging acceleration factor 2. 
 
 
For GE scanners, use the following parameters:  


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TE1 
=min 
TR 
=45 ms 
flip angle 
= 12º 
FOV 
= 220x220 mm2 
matrix size 
= 256x256, 2mm slice thickness with no gaps, 
parallel imaging acceleration factor 2.   
 
Obtain maximum number of echoes (at least 9).  Sites should reconstruct and save both magnitude 
and unfiltered phase images from this sequence. 
 
Diffusion tensor images will be acquired before contrast injection using a multi-channel head coil (at 
least 8-channels) and a standard single-shot EPI sequence with a parallel-imaging acceleration factor 
of 2. The parameters will be as follows: TE = 82 ms, TR = 8 s, FOV = 220x220 mm2, matrix size = 
128x128, slice thickness = 2 mm without gap, b-value = 1000 s/mm2, 5 non-diffusion weighted images 
and 25 diffusion encoding directions. 75 slices will be acquired to cover the whole brain.  
 
These images will be obtained three times during the study: on day -5 to 0, after standard RT and 
TMZ (within 2 to 4 weeks), and 24 weeks after the start of standard RT and TMZ (within 2 to 4 weeks).  
 
Images will be cleaned of identifiers (except for the date of the scan which is needed for analysis), 
encrypted and transferred to the Duke Imaging center for analysis.  Please see the sponsor provided 
Imaging Manual for specifics.   
13.8.11 Drug Levels and Pharmacokinetic Assessment 
See Appendix B, Section 19.2.  In Phase 2, only 6 subjects enrolled in Arm A (at Duke) will have PK 
samples drawn.  
 
 


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14 SAFETY MONITORING AND REPORTING 
The Principal Investigator is responsible for the identification and documentation of adverse events 
and serious adverse events, as defined below. The Principal Investigator will review and sign off on all 
adverse events and problems as they occur and will report them to the IRB in accordance with HRPP 
policies and to the Sponsor, BioMimetix JV, LLC. At each study visit, the Principal Investigator or 
designee must assess, through non-suggestive inquiries of the subject or evaluation of study 
assessments, whether an AE or SAE has occurred. 
14.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject which does not 
necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition. An AE can therefore be any unfavorable 
and unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease 
that occurs in any subject enrolled in this clinical trial. It may or may not be related to use of the 
BMX-001. Abnormal laboratory findings without clinical significance (based on the Principal 
Investigator’s judgment) should not be recorded as AEs. But laboratory value changes that require 
therapy or adjustment in prior therapy are considered adverse events. 
 
From the time the subject signs the informed consent form through 30 days after completion of the 
final BMX-001 treatment (for subjects in Arm A, this will be 30 days after the last chemo/RT for 
subjects in Arm B), all AEs must be recorded in the subject medical record and adverse events case 
report form. 
 
AEs will be assessed according to the CTCAE version 4.03. If CTCAE grading does not exist for an AE, 
the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal 
(5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite: The AE is clearly related to the BMX-001 
- 
Probably: The AE is likely related to the BMX-001 
- 
Possible: The AE may be related to the BMX-001 
- 
Unlikely: The AE is doubtfully related to the BMX-001 
- 
Unrelated: The AE is clearly NOT related to the BMX-001 
14.1.1 
Reporting of AEs 
BioMimetix JV, LLC should be notified of all treatment-related adverse events on a regular basis (to be 
agreed upon by the study team and BioMimetix JV, LLC).  
14.2 Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
- 
Fatal 
- 
Life-threatening 
- 
Constitutes a congenital anomaly or birth defect 
- 
A medically significant condition (defined as an event that compromises subject safety or may 
require medical or surgical intervention to prevent one of the three outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to conduct normal life 
functions. 


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14.2.1 
Reporting of SAEs 
Only adverse events that the Sponsor and/or Principal Investigator determines to be serious, 
unanticipated, and related or possibly/probably (i.e., more likely than not) related to the research 
must be reported to the sponsor. Those adverse events will be submitted, according the following 
guidelines: 
• 
Report within 24 hours of learning about any subject’s death that was unanticipated and 
more likely related to the research than unrelated; 
• 
Report within 5 business days of learning about any serious, unanticipated, and related or 
possibly/probably related adverse event; 
or other unanticipated problem or event that was more likely related to the research than 
unrelated. 
• 
Report within 10 business days of learning about any other SAE not meeting the above 
criteria.   
 
Refer to sponsor Standard Operating Procedures for SAE Reporting specifics.   
 
The Principal Investigator is responsible for compliance with all applicable regulations pertaining to 
the reporting of adverse events to the IRB. Follow-up information on these events shall also be 
reported to BioMimetix JV, LLC, and the IRB as required as soon as follow up information is available. 
Follow-up information may include hospital admission records, discharge summaries and autopsy 
reports, where applicable.  
 
The Sponsor must report to the FDA, in an IND safety report, any suspected adverse reaction that is 
both serious and unexpected. Before submitting this report, the sponsor needs to ensure that the 
event meets all three of the definitions contained in the requirement:  
• 
Suspected adverse reaction (i.e. there is a reasonable possibility that the drug caused the adverse 
event) 
• 
Serious  
• 
Unexpected  
 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
 
The Sponsor is required to report to the FDA all IND Safety reports in writing within 15 days (7 days 
for unexpected fatal or life-threatening suspected adverse reaction). The FDA Form 3500A can be 
found on the FDA website, www.fda.gov. All other adverse events will be reported to the FDA in the 
IND Annual Report. 
 
In addition to the above mentioned reporting responsibilities, after discontinuation of the study, all 
SAEs considered to be drug related will be reported to BioMimetix JV, LLC, by the Principal 
Investigator. 
14.3 External Data and Safety Monitoring Board (DSMB) 
The DSMB-Plus established for Phase 1 will be used for Phase 2 during the period that Duke Cancer 
Center is the only participating clinical center. When additional clinical centers are added to the 
Phase 2 study, the DSMB-Plus will be modified to become a DSMB-Plus which has oversight for all 
clinical centers.  This will involve approval of a new charter.   
 
The sponsor and Principal Investigators are responsible for overseeing the safety and efficacy of the 
trial, executing the DSMB plan, and complying with all reporting requirements to local and federal 
authorities. Additional oversight will be carried out by an external DSMB In Phase 2. 
 


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An external DSMB-Plus will be utilized to monitor Phase 2 when this becomes a multi-center study. 
This DSMB will be organized to meet requirements of Western IRB, the institutional IRBs, and the NCI. 
We anticipate a charter with a minimum of 3 members, which may include: a radiation oncologist 
with experience in high grade glioma, a medical oncologist with expertise in high grade glioma, a 
biostatistician, and/or an ethicist or patient advocate. The responsibilities of the DSMB will be to 
review safety of study procedures, to maintain study integrity, to review adverse events and to 
review efficacy of the outcome data. The DSMB will meet either face to face or by teleconference or 
with electronic communication at least semi-annually and on an ad hoc basis as indicated by any 
adverse events. Minutes will be kept of both open and closed meetings of the DSMB. At the end of 
the study, all minutes taken will be available to the clinical trial principal investigators, the NCI, and 
BioMimetix JV, LLC. 
 
The DSMB’s responsibilities will include evaluation of treatment outcome for evidence of tumor 
protection by the study drug. The DSMB will have authority to recommend closure of the clinical trial 
for either efficacy or futility. 
 
 


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15 QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 Monitoring 
BioMimetix JV, LLC personnel will monitor this study. The Clinical Center Principal Investigator and 
Study Coordinator should be available to the clinical trial monitor during monitoring visits and ensure 
that access to all documents and records is provided. This local Principal Investigator agrees to 
cooperate with the clinical trial monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. For this study, the expected average monitoring frequency is at least 
one visit approximately every 10 weeks, while the study is enrolling and subjects are receiving 
treatment.  
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of the 
clinical center institution, the Sponsor, the Clinical Center Principal Investigator, or the IRB. All study 
documents must be made available upon request to the clinical trial monitor and other authorized 
regulatory authorities, including but not limited to the National Institute of Health, National Cancer 
Institute, and the FDA. Every reasonable effort will be made to maintain confidentiality during study 
monitoring. 
15.1.1 
DSMB-Plus 
Per the recommendation of the Duke School of Medicine Research Integrity Office (RIO), a data safety 
monitoring board DSMB-Plus has been formed and a charter has been established for periodic review 
and assessment of data and outcomes to assure continuing safety of research participants in this trial. 
The committee will participate in decisions regarding reports or publications to ensure there is no 
bias as a result of conflict of interest questions. Because of Duke University’s potential for conflict of 
interest with BMX-001, the Duke RIO has recommended use of a DSMB-Plus for review of the study 
for bias in the protocol design, performance of the study, and assessment of endpoints and ongoing 
periodic assessment of adverse events and study conduct. 
 
Members of the DSMB-Plus will be approved by the ROI office and a DSMB-Plus charter established. 
For Phase 1 narrative summaries will be prepared by the study coordinator or research nurse and 
reviewed and signed by the PI. Of note, this DSMB-Plus will be involved in the Phase 1 portion of this 
study. Narrative summaries of subjects from each dose level will be prepared four weeks after the 
last dose of BMX-001. These summaries will include a review of safety data, Adverse Event 
assessments with attention paid to endpoint assessments and data in the protocol. PK data may also 
be reviewed at this timepoint. The DSMB-Plus committee will review narrative summaries and offer a 
recommendation about dose escalation or discontinuation of enrollment to the PI. Policies of the 
DSMB-Plus will be described in the DSMB-Plus Charter, which will be signed by the DSMB-Plus 
members and PI.  
 
In Phase 1 DSMB-Plus meetings will be convened after the 3rd subject on a cohort (dose level) has 
reached 4 weeks after the last dose of BMX-001. DSMB-Plus review will be prior to each dose 
escalation.   In Phase 2, the DSMB-Plus will meet twice a year.  The DSMB-Plus will review safety and 
data reports which will be provided by the sponsor prior to the meetings.  Review of data can be via 
WEBEX or teleconference. Copies of DSMB-Plus meeting minutes will be provided to RIO office (Dr. 
Gregory Samsa) within 30 days of the DSMB-Plus review.  
 
This DSMB-Plus committee will also consider conflict of interest questions related to this research. 
The DSMB-Plus will evaluate whether financially-linked biases have affected the design, conduct, or 
reporting of the research related to BMX-001.  
 


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Policies of the DSMB-Plus will be described in the DSMB-Plus Charter, and signed by the DSMB-Plus 
members. 
15.2 Audits 
The study may be audited by an audit team originating from the sponsor or its designee. The 
Investigator agrees to cooperate with the auditor to ensure than any problems detected in the course 
of the audit visits are resolved.  
15.3 Data Management and Processing 
15.3.1 
Study Documentation 
In Phase 1- Duke Brain Tumor Center has developed the study database.   Phase 1 data will be 
provided to BioMimetix JV, LLC in either paper format or downloaded documents from Title 21 CFR 
Part II Compliant Clinical database. All documentation transmitted to BioMimetix JV, LLC will be de-
identified in the appropriate manner required to be HIPAA compliant.  
 
In Phase 2, BioMimetix JV, LLC, will develop the electronic Data Capture system and database for the 
study. Electronic records of subject data will be maintained using a Title 21 CFR Part 11 Compliant 
Clinical database called REDCap Cloud. Access to electronic databases will be limited to the Principal 
Investigator, biostatisticians, data manager and key personnel.  
 
15.3.2 
Data Management Procedures and Data Verification 
The Clinical Center Principal Investigator is responsible for maintaining adequate records to enable 
the conduct of the study to be fully documented. Subsequent electronic review of the data may result 
in queries being generated that will be forwarded simultaneously to the Investigator or designee for 
resolution. All data modifications resulting from review or querying of the data will be electronically 
tracked. Any errors detected by either the monitor or the Investigator should be communicated to 
the Sponsor.  
 
Copies of all regulatory documents such as the protocol, study approval letters, all CRFs, drug 
dispensing and accountability logs, all original patient consent forms, and all correspondence 
pertaining to the conduct of the study should be kept by the Clinical Center Principal Investigator for 
the maximum period of time permitted by local regulations. 
15.3.3 
Coding 
All medical terms will be coded using CTCAE v.4.03, which has been harmonized to MedDRA (Medical 
Dictionary for Regulatory Activities) coding.  
15.3.4 
Study Closure 
Following completion of the study, the Clinical Center Principal Investigator will be responsible for 
ensuring the following activities: 
• 
Data clarification and/or resolution of queries 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 
 
 


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16 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key 
personnel. Any data analysis carried out independently by the investigator must be approved by the 
statistician before publication or presentation. 
16.1 Analysis Sets 
 
MTD Analysis Set: Patients who complete concurrent chemoradiation with scheduled treatments 
with BMX-001 or terminate treatment during that period of time due to DLT will be considered 
evaluable and included in the analysis of MTD.  
 
Adverse Experience Analysis Set: All patients who receive BMX-001 will be included in any overall 
summary of adverse experienced. 
 
Survival Analysis Data Set: All patients who receive BMX-001 will be included in analyses of survival 
and progression-free survival. 
 
PRO / Cognition Analysis Set: All patients who receive BMX-001 and provide a follow-up assessment 
will be included in statistical analyses of HRQoL and cognition. 
 
The MTD Analysis dataset as described above is applicable to the Phase 1 portion of this study; 
whereas, the other datasets are applicable to both the Phase 1 and Phase 2 portions of this study.  
16.2 Patient Demographics and Other Baseline Characteristics 
For each phase of this study, the clinical and socio-demographic characteristics of all patients treated 
will be summarized using descriptive statistics (e.g. means/standard deviations, percentiles, 
frequencies). Patient characteristics within patient subgroups defined by dose level may also be 
generated for the Phase 1 portion of this protocol. Within the Phase 2 portion, patient characteristics 
will be summarized by treatment group assignment. 
16.3 Treatments 
Within the Phase 1 portion of this study, the number of patients treated at each dose level will be 
summarized. 
 
Within the Phase 2 portion of this study, a CONSORT diagram will be generated that displays the 
number of patients treated within each treatment arm, as well as the number of cycles of adjuvant 
treatment received. 
16.4 Phase 1 Dose Escalation 
16.4.1 
Primary Objective 
The primary objective of this Phase 1 study is to determine the maximum tolerated dose (MTD) of 
BMX-001 administered with standard radiotherapy and daily TMZ among patients with newly 
diagnosed HGG. Four dose levels are planned and are described in Section 9.1.1.  
16.4.1.1 
Variable 
Based upon all available data and the CRM model described in Section 16.4.1.2, the MTD will be the 
dose with the estimated DLT rate closest to the target DLT rate of 0.25. 


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16.4.1.2 
CRM Design Considerations 
Though 3+3 study designs are commonly used to determine MTD, we propose to adopt a Phase 1 
dose escalation strategy that avoids the following shortcomings of the standard 3+3 design. 
Specifically, the 3+3 design suffers from the problem of “memory loss” that occurs as dose is 
escalated. In addition, the 3+3 algorithm allows many patients to be treated at low and ineffective 
doses due to conservative dose escalation, does not have a statistical justification, and does not 
involve an explicit target DLT rate [74].  
 
A two-stage CRM design will be used to determine the MTD of BMX-001 where the first stage 
involves dose escalation in successive patients until an initial dose-limiting toxicity (DLT) is observed. 
Within the second stage, all accumulated data will be used within the context of a one-parameter 
logistic model to determine the appropriate dose for each subsequent patient. Maximum likelihood 
estimation will be used. This modeling process will determine the dose with a DLT rate closest to the 
target DLT rate of 0.25. Cohorts of 3 patients will be accrued to this study within both stages of the 
trial.  
 
The remaining portion of this section provides information about the development of the CRM model 
that is to be used specifically for this study. R software developed by Cheung [75] aided in its 
development. 
 
MTD: No dose-limiting toxicities (DLTs) were observed in monkey toxicity studies for BMX-001 within 
the range of doses being planned for these human studies. Hence, we do not expect DLTs to occur 
within the range of doses that will be used in this Phase 1 study. 
 
One-stage versus two-stage CRM: With no expectation that DLTs will be observed among the doses 
that will be investigated in this study, the use of a one-parameter CRM model is inappropriate as such 
a model assumes that the initial patient is treated at the prior or expected MTD. Rather, a two-stage 
CRM with dose escalation restriction will be used. The first stage involves a predetermined dose 
escalation scheme that starts at dose level 1 and terminates once the first DLT is observed. 
Thereafter, a model-based CRM will be used in the second stage to define patient dose assignment.  
 
Whenever a dose assignment is needed during the second stage, all available data will be used with 
maximum likelihood estimation to generate the CRM model. The dose that results in a DLT rate 
nearest to the target rate will be determined from this model, and used to treat the next patient 
subject to a dose escalation restriction. That restriction requires that the dose for the next patient 
cannot be more than one level higher than that of the current patient. 
 
Target DLT rate (θ): CRM designs used for oncology therapeutic trials are often designed with a target 
DLT rate (θ) between 0.2 and 0.3. This study is designed to detect a target DLT rate of 0.25. 
 
Sample size: Cheung [75] suggests that the fixed sample size used in one-stage CRM designs be 
constrained so that 
 
!"# (# '()* +*,*+)"-)
-
  >  
/
0123*4 560 714* 
 
If this study was a one-stage study, the implication of this constraint is that N > 14. For the two-stage 
design, Cheung [75] recommends that the number of observations reserved for the highest dose level 
in case of no toxicity should be greater than 1.5/target DLT rate, or 6 for this study. The simulations 
described below consider a fixed sample size ranging between 16 and 20 patients. 
 


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Functional form of model: The logistic and empiric models are commonly used as the underlying 
functional form describing the relationship between the probability of DLT and dose. The one-
parameter logistic model has the following form where β is an unknown parameter to be estimated:  
 
Probability of DLT = 
89:( #;89:(<)'()* )
/;89:( #;89:(<)'()* ) 
 
The one-parameter model has the following functional form: 
 
Probability of DLT = doseexp(β) 
 
Simulations reported below examine the impact of functional form (logistic and empiric) on model 
inference. 
 
Initial guess of toxicity probability: Within the second stage of the CRM model, there is a need to 
specify a set of initial guesses for the dose-specific probability of DLT. Referred to as the skeleton of 
the CRM, this initial guess at toxicity probability is increasing with dose. Even with good clinical 
guesses for the skeleton, the resulting CRM model may fail regularity conditions required for the 
study to have good operating characteristics. As an alternative, an initial toxicity probability 
distribution can be generated so that the CRM is δ-sensitive. A δ-sensitive CRM will eventually select 
a dose as the MTD with toxicity falling between θ±δ [74]. 
 
The GETPRIOR function available within the R-package DFCRM was used to estimate the skeleton 
assuming δ was 0.03, 0.05, 0.07 [74,76,77]. Though we expect that DLT will not be encountered at 
any dose level, we will assume that the prior MTD is dose level 5. Tabulated below are the initial 
guesses generated by the GETPRIOR function regardless of underlying functional form (logistic or 
empiric). 
 
Initial Guess of Toxicity Probability with Empiric Model 
Delta (δ) 
Dose Level 1 
Dose Level 2 
Dose Level 3 
Dose Level 4 
0.03 
0.097 
0.141 
0.192 
0.250 
0.05 
0.036 
0.084 
0.157 
0.250 
0.07 
0.009 
0.043 
0.124 
0.250 
 
 
Initial Guess of Toxicity Probability with Logistic Model 
Delta (δ) 
Dose Level 1 
Dose Level 2 
Dose Level 3 
Dose Level 4 
0.03 
0.101 
0.143 
0.193 
0.250 
0.05 
0.044 
0.089 
0.158 
0.250 
0.07 
0.016 
0.051 
0.127 
0.250 
 
Initial design: The GETINIT function within the R-package DFCRM was used to identify compatible and 
coherent initial designs given the identified initial guesses of toxicity probability and the model’s 
functional form (logistic or empiric) [74,75]. The algorithm started the search for an initial design with 
the most aggressive initial design that started the trial at the second highest dose. More conservative 
designs were subsequently tested for compatibility if the current design compatible.  
 
Compatible designs exist that involve treating cohorts of 2 or 3 patients with increasing dose until at 
least one DLT is observed. Given the expectation that DLT will not be observed, a rapid escalation 
would be appropriate with the treatment of cohorts of 3 patients. However, an important secondary 
outcome of the Phase 1 study is pilot data concerning the impact of dose on cognition. Hence, an 
initial design with cohorts of 3 patients will be used to garner additional information about the 
cognitive effects of BMX-001 treatment. 


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Cohort size during the second stage: With an accrual rate of approximately 3 patients per month, the 
observation period for the determination of DLT is 4 weeks. Cohort sizes of 3 will be considered for 
the second stage.  
 
Study Simulations: The performance of the two-stage design CRM design was examined under a 
variety of conditions, including functional form [logistic vs empiric], initial guess of DLT toxicity 
probabilities, cohort size, overall sample size [17,19,21]), and various true underlying toxicity 
probability profiles using the CRMSIM function within the R-package DFCRM [74,75,78]. Results 
based upon 500 simulations are summarized in Appendix C. These simulations suggest the following: 
• 
The majority of simulations identify the correct MTD dose, or a contiguous dose. 
• 
The probability of selecting a dose as the MTD is comparable with the two different functional 
forms. 
• 
When the MTD is at a higher dose, the probability of declaring that dose as the MTD is greatest 
when the initial guess of toxicity probability assumes δ=0.03. 
• 
Increasing the maximum number of subjects from 16 to 20 does not increase the probability of 
correctly choosing the MTD substantially. 
 
Therefore, the following design elements will be used in the conduct of this study: 
• 
Logistic functional form 
• 
Initial guess of toxicity probability that assumes δ=0.03, i.e. (0.101, 0.143, 0.193, 0.250) 
• 
The maximum number of patients evaluable for the determination of MTD that will be enrolled is 
18. 
• 
Cohorts of 3 patients will be accrued to this study within both stages of the trial.  
16.4.1.3 
Implementation of Phase 1 Study 
Initial Design / Stage 1: As described above, this Phase 1 study will be conducted in two stages. In the 
first stage, cohorts of 3 patients will be treated starting with dose level #1. Once 3 patients have been 
undergone treatment without experiencing DLT after a monitoring period of four weeks after 
completion of all doses of BMX-001, the dose of the subsequent group of 3 patients will be escalated. 
This process will continue until a patient experiences a DLT. 
 
Model-Based Escalation / Stage 2: Within stage 2, patients will be accrued to the study in cohorts of 3 
patients. Whenever the toxicity outcomes associated with patients within a cohort are known, the 
one-parameter logistic model will be re-estimated by the study’s statistical team using all available 
data. Based upon this re-estimated model, the dose level that results in a DLT rate nearest to the 
target DLT rate will be determined, and used to treat the next patient subject to a dose escalation 
restriction. That restriction requires that the dose for the next patient cannot be more than one level 
higher than that of the current patient.  
 
Study Termination: A maximum of 18 patients evaluable for the determination of MTD will be 
accrued to the study. Though simulations demonstrating properties of this design assumed a fixed 
sample size, accrual termination will also be allowed once 6 or more consecutive patients have been 
treated at a dose level without any indication that the dose should be escalated or de-escalated [74]. 
16.4.1.4 
Secondary Objectives of Phase 1 Study 
Adverse events will be tabulated in a different manner for the manuscript summarizing the results of 
this study, annual reports for the Safety Oversight Committee, and the final report included within 
ClinicalTrials.gov. 
 


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For the manuscript, adverse events that are possibly, probably, and definitely treatment-related will 
be summarized. For each type of toxicity, the maximum grade experienced by each patient will be 
summarized with frequency distributions within each treatment group.  
 
Two tabulations will be generated for review by the Duke Cancer Institute Safety Oversight 
Committee including one that includes all toxicities regardless of attribution, and another that 
includes only toxicities that are possibly, probably, and definitely related to study regimen. For each 
of these tabulations, the maximum grade of each type of toxicity experienced by each patient will be 
summarized with frequency distributions within each treatment group. 
 
The mean change between baseline and each follow-up assessment for cognitive function will be 
computed. Baseline will be the last assessment obtained before initiation of standard of care 
treatment consisting of temozolomide and RT. Analyses will be sub-divided in terms of WHO grade 
and histological subtype.  
 
Kaplan-Meier methods will be used to graphically describe the distribution of overall survival (OS) and 
progression-free survival. OS is defined as the time interval between initiation of protocol treatment 
and death, with overall survival censored at last follow-up if the patient remained alive. PFS is defined 
as the time between initiation of protocol treatment and disease progression or death. If the patient 
remains alive without disease progression, then PFS will be censored at last follow-up. Median OS 
and PFS, as well as 6- and 12-month estimates of OS and PFS will be estimated from the Kaplan-Meier 
curve. Because OS and PFS can differ in HGG based on grade (WHO grade III vs IV) and histological 
subtype (e.g. anaplastic oligodendroglioma vs. anaplastic astrocytoma), analyses will be sub-divided 
in terms of WHO grade and histological subtype. 
 
The radiographic response rate will be calculated as the proportion of patients with a complete or 
partial response for all patients and within subgroup of patients defined by grade. Exact binomial 
confidence intervals will be computed. 
 
Pharmacokinetics will be done as described in Appendix B (Section 19.2). 
16.4.1.5 
Exploratory Objectives of Phase 1 Study 
The mean change between baseline and each follow-up assessment for HRQoL will be computed as 
was computed for cognitive function outcome variables. Analyses will be sub-divided in terms of 
WHO grade and histological subtype. Hair loss is a descriptive measure and will be defined and 
analyzed using pictures.  
16.4.1.6 
Interim Analysis of Phase 1 Study 
See Sections 16.4.1.2 and 16.4.1.3. 
16.4.1.7 
Sample Size Calculation 
See Section 16.4.1.2. 
16.5 Phase 2 
16.5.1 
Primary Objective for Phase 2 
The primary goal of this randomized open-label Phase 2 study is to examine the impact of BMX-001 on 
overall survival, among patients newly diagnosed with HGG who are receiving standard of care (SOC) 
treatment consisting of daily TMZ and RT.  
16.5.1.1 
Variable 
The study’s primary endpoint is OS as defined by the time between randomization and death, or the 
last follow-up if the patient remains alive. 


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16.5.1.2 
Statistical Hypothesis, Model, and Method of Analysis 
 
As stated in section 7.6, this study will assess the hypothesis that BMX-001, when added to standard 
RT and TMZ, will sensitize the malignancy and result in enhanced patient survival. 
 
All randomized patients will be included in the analysis of survival and included in their assigned 
treatment arm regardless of compliance. This approach to analysis is consistent with an intent-to-
treat analysis approach. 
 
Kaplan-Meier methods will be used to graphically describe the distribution of overall survival (OS) 
among patients within the BMX group and within the control group. Median OS and PFS, as well as 6- 
and 12-month estimates of OS and PFS will be estimated from the Kaplan-Meier curve. A logrank test 
will compare arms with respect to the survival outcome. 
 
Because OS can differ in HGG based on grade (WHO grade III vs IV) and histological subtype (e.g. 
anaplastic oligodendroglioma vs. anaplastic astrocytoma), the survival of patient subgroups of patients 
defined by grade and histological subtype will be described. 
16.5.2 
Secondary Objectives for Phase 2 
This study has 6 secondary objectives that include an assessment the impact of BMX-001 on 
cognition, thrombocytopenia, adverse events, progression free-survival, radiographic response, and 
pharmacokinetics. 
16.5.2.1 
Secondary Objective #1 for Phase 2: Cognition 
The key secondary objective includes an evaluation and comparison of cognition among patients 
newly diagnosed with HGG and whether the addition of BMX-001 to standard RT and TMZ impacts 
cognition. This secondary endpoint is the mean change in cognitive functioning between baseline and 
week 24 within each treatment arm. The baseline measure is the last assessment obtained before 
initiation of standard chemoradiation.  
 
Analysis of covariance will be conducted to compare treatment groups with respect to the change in 
cognitive function. The outcome of this model is change in cognitive function. Treatment group 
assignment will be included in the model as a predictor, and the baseline measure of cognitive 
function will be included as a covariate. Additional analyses will explore the impact of BMX-001 on 
cognition within patient subgroups defined by WHO grade and histological subtype.  
 
Measurement of cognition will continue after initiation of adjuvant temozolomide. Longitudinal 
analyses will compare treatment arms with respect to the pattern of cognitive change observed over 
time. Initially a repeated measures analysis will be conducted. However, a significant amount of the 
follow-up cognitive assessments may be missing due to health decline, disease progression, and 
death. The patterns of “drop-out” in the two treatment arms may also differ. To address these 
problems, additional analyses will be conducted. These analyses may focus on only assessments with 
relative complete data, or may consider alternative analytic methods such as pattern mixture models. 
16.5.2.2 
Secondary Objective #2 for Phase 2: Thrombocytopenia 
The proportion of patients who experience grade 3 or 4 thrombocytopenia during concurrent 
temozolomide and radiation will be estimated within each treatment group. The proportion of 
patients who experience a platelet count less than 100K during concurrent temozolomide and 
radiation will also be estimated within each treatment group. The period of observation for these 
events will extend until 2 weeks after completion of radiation treatment. For both endpoints, a chi-
square test will be conducted to compare the prevalence of such thrombocytopenia observed in 
patients with and without BMX-001. 
 


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In addition, the longitudinal patterns of platelet count over time will be explored in mixed linear 
models that account for within patient correlation. These longitudinal patterns will focus on the time 
period during BMX-001 treatment administration that continues for 2 weeks after radiation 
treatment is completed. 
16.5.2.3 
Secondary Objective #3 for Phase 2: Adverse Events 
The phase 2 portion of this study has two adverse event endpoints: (1) The proportion of patients 
who experience any grade 3 or 4 adverse event during radiation and temozolomide treatment, and 
(2) The proportion of patients who experience a grade 3 or 4 adverse event that is definitely, possibly, 
or probably related to BMX-001 treatment during this same period. Adverse events occurring 
between baseline through 2 weeks after discontinuation of radiation will be the focus of these 
analyses. 
 
Adverse Event Monitoring and Tabulations: Adverse events will be tabulated in a different manner for 
semi-annual reports to the DSMB-Plus / DSMB, the manuscript summarizing the results of this study, 
and the final report included within ClinicalTrials.gov.  
 
DSMB-Plus / DSMB Monitoring: Two tabulations of adverse events occurring during concurrent 
chemoradiation will be generated for DSMB-Plus / DSMB review including one that includes all 
toxicities regardless of attribution, and another that includes only toxicities that are possibly, 
probably, and definitely related to BMX-001 treatment. For each of these tabulations, the maximum 
grade of each type of toxicity experienced by each patient will be summarized with frequency 
distributions within each treatment group. The period of observation that will be the focus of these 
tabulations will extend 2 weeks after termination of radiation treatment. Additional tabulations will 
summarize adverse events experienced during adjuvant treatment. 
 
For the manuscript, similar summaries of adverse events will be generated.  
 
For ClinicalTrials.gov, serious adverse events and other adverse events will be summarized separately. 
These tabulations will reflect the number of patients who experience each type of toxicity regardless 
of grade or attribution.  
16.5.2.4 
Secondary Objective #4 for Phase 2: Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the time between initiation of protocol treatment and 
disease progression or death. If the patient remains alive without disease progression, then PFS will 
be censored at last follow-up. Analyses similar to those described for OS will be generated for PFS.  
16.5.2.5 
Secondary Objective #5 for Phase 2: Radiographic Response 
Radiographic response will be determined by brain MRI evaluations for assessment based on the 
RANO criteria. The radiographic response rate is defined as the proportion of patients of with a 
complete or partial response. The response rate within each arm will be calculated, and compared 
using an exact chi-square test. Additional analyses will describe the response rate within patient 
subgroups defined by arm, WHO grade and histological subtype. Exact binomial confidence intervals 
will be generated for each response rate estimate. 
16.5.2.6 
Secondary Objective #6 for Phase 2: Pharmacokinetics 
Pharmacokinetics will be done as described in Appendix B (Section 19.2).   
16.5.3 
Exploratory Objectives for Phase 2 
Three exploratory objectives will be pursued within this protocol. This includes an assessment of 
health-related quality of life, a description of hair loss, and an examination of changes in white matter 
integrity. 
 


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Many of the proposed exploratory analyses assume methods for normally distributed data are 
appropriate. If underlying assumptions for planned analyses are violated, plans will be modified. 
Alternative analytic methods may also be considered to assess the robustness of inferences. 
 
Additional statistical analyses may be conducted besides those described in this protocol. These 
additional analyses may be motivated by evolving research outside of this protocol, or they may be 
suggested by statistical analyses pre-specified in this protocol. 
16.5.3.1 
Exploratory Objective #1 for Phase 2: Health-Related Quality of Life 
Methods described in section 13.8.5 will be used to analyze HRQoL data. Given that numerous 
endpoints will be examined in these exploratory analyses, adjustments for multiple comparisons (e.g. 
false discovery rate methods or Bonferroni) may be considered. 
16.5.3.2 
Exploratory Objective #2 for Phase 2: Hair Loss 
Qualitative assessments of hair loss depicted in longitudinal subject photographs will be conducted 
and summarized. Changes observed in Arm A will be compared to those observed in Arm B. 
16.5.3.3 
Exploratory Objective #3 for Phase 2: White Matter Integrity 
The mean change between baseline and each follow-up assessment for white matter integrity, as 
measured by MRI diffusion tensor/susceptibility imaging will be computed. Assuming normality, 
analysis of variance or a repeated measures analysis may be used to compare change in Arms A and 
B. Additional analyses will be sub-divided in terms of WHO grade and histological subtype.  
16.5.4 
Interim Analysis for Phase 2 
Interim analyses using an O’Brien-Fleming boundary will be conducted with the goal of terminating 
accrual early to accept or reject the null hypothesis of no difference in survival. Given the inflated 
type I error rate for this Phase 2 study, early termination will only be considered if it appears that the 
addition of BMX-001 treatment to radiation and temozolomide is decreasing survival. The interim 
analysis will be conducted to determine whether the addition of BMX-001 is possibly detrimental to 
the survival of patients.  
 
Interim analyses for the primary endpoint (survival) will be conducted annually beginning June 2021. 
The decision rule for accrual suspension will be defined by the O’Brien-Fleming spending function and 
is dependent upon the number of deaths that will have been reported by the time of the interim 
analysis. If the boundary is crossed, accrual will be suspended while all other data (e.g. cognitive 
function data) is reviewed to determine whether accrual should be permanently terminated. 
 
Though not part of the formal interim decision-making described above, additional interim analyses 
of secondary and exploratory outcomes will be conducted for multiple purposes, including 
assessment of data completeness and program planning.  Currently, the planned time of these 
analyses is as follows: 
 
Date 
Planned Analysis 
June 2020 
Among the initial 80 patients treated, changes in platelet counts  during 
radiation and temozolomide treatment and ending 2 weeks after termination of 
radiation will be examined.  The consistency of these counts with AE reports will 
also be assessed. 
December 2020 
Among the initial 80 patients treated on the study, changes in neurocognition 
and quality of life PROs through week 24 will be examined.  Patterns of data 
missingness will be assessed, including reasons for missed assessments. 
June 2021 
Among the initial 80 patients treated on the study, changes in neurocognition 
and quality of life PROs through week 52 will be examined.  Patterns of data 
missingness will be assessed, including reasons for missed assessments. The 


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conduct of this interim analysis may be dependent upon any issues occurring in 
the December 2020 analysis. 
 
16.5.5 
Sample Size Calculation for Phase 2 
Though the primary outcome of this study as currently design is overall survival, an important 
secondary outcome is the change in cognition. Power calculations will be presented for both 
outcomes. 
16.5.5.1 
Power of Survival Comparisons 
The primary goal of the Phase 2 portion of this study is to assess the effect of BMX-001 treatment in 
conjunction with standard of care treatment consisting of temozolomide and radiation on the survival 
of patients newly diagnosed with grade III or IV glioma. A permuted block randomization stratified by 
histologic grade (grade III / IV) and institution will be used to assign patients to treatment with or 
without BMX-001. 
 
With standard treatment, the median survival of Grade IV patients is 14.6 months, and the median 
survival of Grade III is approximately 36 months. Given that we anticipate that approximately 10% of 
patients to be Grade III, we estimate that the overall median survival with standard treatment to be 
roughly 16.7 months. 
 
Though this Phase 2 study is comparative, the goal is to determine whether BMX-001 is worthy of 
further investigation in combination with standard RT and TMZ treatment, and not to make definitive 
statements about the effect of BMX-001. Many aspects of the new treatment will be considered in 
the decision-making concerning further investigation, including relative toxicity and ease of 
treatment administration. As a Phase 2 study, there is a need to constrain the sample size 
requirements at the expense of either an increased false negative or false positive rate. A false-
positive rate of 0.2 will be used to test the primary statistical hypothesis while maintaining 
reasonably high power [80-82].  
 
The power of a statistical comparison of survival is a function of the number of deaths observed. In 
order that a 1-tailed logrank test conducted at the 0.2 level to have 90% power to detect a hazard 
ratio of 0.63, 84 deaths need to be observed among the 160 randomized patients. Under the 
assumption that survival is exponentially distributed, this hazard ratio represents an increase in 
median survival from 16.7 to 26.5 months.  
 
With an accrual goal of 160 patients and an expected randomization rate of approximately 6 patients 
per month, we anticipate that accrual will be completed within approximately 27 months. It is 
estimated that approximately 10 months after accrual completion are needed to observe 
approximately 84 deaths among randomized patients.  
16.5.5.2 
Cognition as Outcome 
Changes in cognition is an important issue with treatment of HGG patients with radiation. As such, an 
important secondary objective of this study is to determine whether treatment with BMX-001 in 
conjunction with standard RT and TMZ mitigates the reduction in cognitive function due to the 
radiation. The endpoint that is of interest is the change in cognitive function between baseline and 
week 24.  
 
We focus on the week 24 assessment of cognitive function in this power calculation given that the 
study is a randomized study, even though we are interested in comparing groups with respect to 
change in cognitive function between baseline and week 24. Studies recently conducted at Duke 


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suggest that the standard deviation associated with a one-time assessment of executive function, a 
component of cognitive function, is approximately 30 units. 
 
We anticipate that 120 of the 160 patients will have pre- and post-measurements of cognitive 
function. A two-tailed t-test conducted at the 0.05 level of significance (two-tailed) will have 80% 
power to detect a difference of 15.5. 
16.5.5.3 
Thrombocytopenia as Outcome 
Platelet counts will be obtained during radiation and temozolomide treatment and ending 2 weeks 
after termination of radiation. The percentage of patients within each treatment group that 
experience grade 3 or 4 thrombocytopenia will be estimated. Gerber [1] reports that 15% of patients 
who receive standard radiation and temozolomide experience grade 3 or 4 thrombocytopenia. With 
80 patients per arm, there is 80% power with a one-tailed chi-square test (α=0.05) to detect a 
reduction in grade 3 or 4 thrombocytopenia from 15% in Arm B (without BMX-001) to 4% in Arm A 
(with BMX-001). 
 
17 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
17.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
17.2 Institutional IRBs and Research Committees 
It is expected that the protocol, informed consent form, advertising material (if applicable), and 
additional protocol-related documents must be submitted to the local clinical center Institutional 
Review Board’s (IRB) and internal committees in addition to the external Central IRB (WIRB for this 
study) for review. The study will first be submitted to WIRB by the sponsor and then, after WIRB 
approval, to the local IRBs, if required. The study may be initiated only after the Principal Investigator 
has received written and dated approval from all required IRBs and Committees. 
 
The Principal Investigator will have the responsibility to submit and obtain approval from the local IRB 
for all subsequent protocol amendments and changes to the informed consent form, continuing 
review, as well as informing any appropriate committee about protocol amendments that potentially 
affect research design or data analysis (i.e. amendments affecting subject population, inclusion/
exclusion criteria, agent administration, statistical analysis, etc.). 
 
The sponsor will handle study level submissions to the Central IRB, and the site will be responsible for 
handling site-specific submissions to the Central IRB. 
17.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject 
population. Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other study-
related matters. This discussion will occur in a location that ensures subject privacy and in a manner 
that minimizes the possibility of coercion. Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as 
needed to make an informed decision about participation in the study. 


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Before conducting any study-specific procedures, the Principal Investigator must obtain written 
informed consent from the subject or a legally acceptable representative. The original informed 
consent form (including any updated consent (re-consent) documents) will be stored with the source 
documents, and a copy of the informed consent form will be provided to the subject. The Principal 
Investigator and the study team are responsible for asking the subject whether the subject wishes to 
notify his/her primary care physician about participation in the study. If the subject agrees to such 
notification, the Principal Investigator will inform the subject’s primary care physician about the 
subject’s participation in the clinical study. 
17.4 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will 
be maintained.  
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study. Prospective participants will be consented in an exam room where it is just 
the research staff, the patient and his family, if desired. For all future visits, interactions with research 
staff (study doctor and study coordinators) regarding research activities will take place in a private 
room. All research related interactions with the participant will be conducted by qualified research 
staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff. Subjects will be identified only by a unique study 
number and subject initials. Electronic records of subject data will be maintained using a dedicated 
compliant database, which is housed in an encrypted and password-protected file on a secure 
network drive. Access to electronic databases (without edit rights) will be limited to the Principal 
Investigator, the study coordinator, and the statistical team. The only personnel with both access and 
edit rights to the electronic databases are the data management team, including the clinical trials 
manager.  
 
For the diffusion tensor images, information that would directly identify the patient will be removed 
from the DICOM image datasets to produce a limited imaging dataset (for the purposes of this scan, a 
limited dataset has the 16 direct identifying information removed from the DICOM header, but may 
include information about the date/time of imaging and the imaging location).  The limited imaging 
dataset will then be transferred to Duke University for review and analysis.  The process of cleaning 
(removing patient identifiers from the images) and transferring the images is done by the clinical 
center staff.  The sponsor has provided an Imaging Manual for specific instructions on this process.   
 
The results of the BAC App tests conducted on the iPad and the audio recordings included with them 
will be stored on a secure cloud based server maintained by the sponsor’s representative 
(VeraSci).  The electronic files, including the audio files, will be retained for the period of time 
specified for all other study data or as required by law. 
 
Upon completion of the study, research records will be archived and handled per institutional policy. 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
17.5 Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the Data and Safety Monitoring 
Plan. For a more detailed description of the DSMP for this protocol, refer to refer to the Safety 
Monitoring and Reporting section and the Quality Control and Quality Assurance section.  


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17.6 Protocol Amendments 
All protocol amendments must be initiated by the Sponsor and approved by the IRB prior to 
implementation. IRB approval is not required for protocol changes that occur to protect the safety of 
a subject from an immediate hazard. However, the Principal Investigator must inform the Sponsor 
and the IRB and all other applicable regulatory agencies of such action immediately. 
17.7 Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
- 
at least two years after the date on which a New Drug Application is approved by the FDA, if an 
IND is involved 
- 
at least two years after formal withdrawal of the IND associated with this protocol, if an IND is 
involved 
- 
at least six years after study completion (Duke policy) or longer if required by another 
participating institution 
17.8 Conflict of Interest 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflicts of interest. Conflicts of interest may arise 
from situations in which financial or other personal considerations have the potential to compromise 
or bias professional judgment and objectivity. Conflicts of interest include but are not limited to 
royalty or consulting fees, speaking honoraria, advisory board appointments, publicly-traded or 
privately-held equities, stock options, intellectual property, and gifts. 
 
 
 


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52. 
Batinic-Haberle, I., J.S. Reboucas, and I. Spasojevic, Superoxide dismutase mimics: chemistry, pharmacology, 
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Bao, F. and D. Liu, Hydroxyl radicals generated in the rat spinal cord at the level produced by impact injury 
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19 APPENDICES 
19.1 Appendix A: RANO (Radiographic Assessment in Neuro-Oncology) 
Criteria for Newly Diagnosed Patients 
 
RANO was published in April 2010 for the evaluation of HGG [79] and modified in 2017 [66]. 
For newly diagnosed HGG studies, the post radiation therapy MRI scan is required and is used as the 
baseline scan for which response will be determined. The post-operative MRI scan and pre-entry MRI scan 
are also desired and will vary based on the requirements of clinical protocols. In these criteria, particularly 
in regards to newly diagnosed subjects, the areas considered in determining comprehensive objective 
status in RANO criteria are target lesions (enhancing disease), new sites of measurable disease, 
neurological examination status, and corticosteroid usage and dose. 
 
Definitions 
Measurable lesions  
• 
Contrast enhancing  
• 
Two perpendicular diameters ≥10mm  
• 
If slice + gap > 5mm, minimum is 2 x total  
• 
Do not include cavity, cyst, or necrosis in the measurement  
 
Non-measurable lesions  
• 
Do not enhance (seen only on T2/FLAIR)  
• 
Too small, e.g. 12 x 8 mm  
• 
Poorly defined margin  
 
 


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Choosing a target lesion (2) 
 
Target Lesions: 
Take products of diameters and add them up → Sum of products of diameters (SPD)  
 
A1 x B1 + A2 x B2 + … = SPD 
 
Complete Response (CR): Requires all of the following: 
§ 
Disappearance of all enhancing measurable and non-measurable disease sustained 
for at least 4 weeks. The first scan exhibiting disappearance of all enhancing 
measurable and non-measurable disease is considered “preliminary CR”. If the 
second scan exhibits measurable enhancing disease with respect to the “preliminary 
CR” scan, then the response is not sustained, noted as “pseudoresponse”, PsR, and is 
now considered “preliminary PD”. If the second scan continues to exhibit 
disappearance of enhancing disease or emergence of non-measurable disease (less 
than 10mm bidimensional product), it is considered a durable CR and the patient 
should continue on therapy until confirmed PD is observed. 
§ 
Patients should be either off of corticosteroids or on physiologic replacement doses 
only. 
§ 
Stable or improved neurological examinations 
 
Partial Response (PR): Requires all of the following 
§ 
Greater than or equal to a 50% reduction in the size (products of the largest 
perpendicular diameters) for all enhancing lesions compared with baseline, 
sustained for at least 4 weeks. The first scan exhibiting greater than or equal to a 
50% decrease in the sum of the products of the perpendicular diameters of all 
measurable enhancing lesions compared with the baseline is considered 
“preliminary PR”. If the second scan exhibits PD with respect to the “preliminary PR” 
scan, then the response is not sustained, noted as pseudoresponse, PsR, and is now 
considered “preliminary PD” (note confirmed PD requires at least two sequential 
increases in tumor volume.) If the second scan exhibits SD, PR, or CR, it is 
considered a durable PR and the patient should continue on therapy until confirmed 
PD is observed.  
 
§ 
Patients should have either the same corticosteroid doses or on lower corticosteroid 
dose compared with baseline scan. 
 
§ 
Stable or improved neurological examinations 
 
Stable Disease (SD): Evaluations that do not meet criteria for CR, PR or PD  
 
Progressive Disease (PD): Defined as the following 
§ 
Greater than or equal to a 25% increase in the product of the largest perpendicular 
diameters of any enhancing lesion or any new enhancing tumor on MRI scans. The first 
scan exhibiting greater than or equal to a 25% increase in the sum of the products of 
perpendicular diameter of the enhancing lesions should be compared to the smallest 
tumor measurement obtained either at baseline (if no decrease) or best response (on 
stable or increasing corticosteroid dose) and is noted as “preliminary PD”. If the second 
scan at least 4 weeks later exhibits a subsequent greater than or equal to 25% increase 
in the sum of products of perpendicular diameters of the enhancing lesions relative to 
the “preliminary PD” scan, it is considered “confirmed PD” and the patient should be 
discontinued from the study. If the second scan at least 4 weeks later exhibits SD or, 
PR/CR, this scan showing “preliminary PD” is noted as “pseudoprogression”, PsP, and 
the subject should remain on study until a second increase in tumor size relative to the 
PsP scan is observed. Of note, any new measurable (> 10 mm X 10 mm) enhancing lesion 


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should not be immediately considered PD, but instead should be added to the sum of the 
bidimensional products representing the entire enhancing tumor burden.  
 
§ 
In the case where the baseline or best response demonstrates no measurable enhancing 
disease (visible or not visible), then any new measurable (>10mm x 10mm) enhancing 
lesions are considered PD after confirmed by a subsequent scan ≥4 weeks exhibiting 
greater than or equal to a 25% increase in sum of products of perpendicular diameters 
relative to the scan first illustrating new measurable disease. The first scan exhibiting 
new measurable disease is noted as “preliminary PD”. If the second scan at least 4 weeks 
later exhibits a subsequent greater than or equal to a 25% increase in sum of products of 
perpendicular of enhancing lesions relative to the “ preliminary PD” scan it is considered 
“confirmed PD” and the patient should discontinue therapy. If the second scan at least 4 
weeks later exhibits SD, CR, PR, or becomes non-measurable, this scan showing 
“preliminary PD” is noted as “pseudoprogression”, PsP, and the subject should continue 
on study until a second increase in tumor size relative to the “preliminary PD”, or PsP, 
scan is observed. Note that any new measurable (>10mm x 10mm) enhancing lesions on 
the subsequent scan following the “preliminary PD” scan should not be immediately 
considered “confirmed PD”, but instead should be added to the sum of bidimensional 
products representing the entire enhancing tumor burden. 
 
§ 
Unequivocal and significant worsening neurological examination not attributable to 
other causes. 
 
§ 
Of note, if there has been a major reduction in steroid dosage in the interval and the 
patient is felt to be clinically stable or improved, the proper assessment may be 
“indeterminate” and the therapy could be continued pending the next evaluation. 
 
§ 
Failure to return for evaluation as a result of death or deteriorating condition. 
 
Not Evaluable (NE): Progression has not been documented and one or more sites have not been 
assessed. 
 


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Response Evaluation:  
 
 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease, 
PsP=pseudoprogression, NE=not evaluable 
 
 Algorithm for Newly Diagnosed Glioblastoma (2) 
 
 
MRI (0)= pre-entry MRI, MRI (N)=additional required MRI scan, MRI (N+1)=follow-up confirmatory 
MRI scan. Please note that while this figure references volumetric analysis, our standard operating 
procedure is to use bi-dimensional measures.  
 
 
 


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19.2 Appendix B: Pharmacokinetic Analysis 
19.2.1 
 Phase 1 Pharmacokinetic Analysis 
The major goal of the pharmacokinetic studies conducted in conjunction with this protocol will be to 
determine pharmacokinetics of BMX-001 in combination with RT and TMZ. These samples will be 
collected from patients during chemoradiation phase only. 
 
Pharmacokinetic Assessment of BMX-001:. A series of blood samples will be taken for the 
measurement of the compound in order to define pharmacokinetics in these patients. Patients 
should have their dose administered on the same time of day. Instructions for the handling and 
shipping of plasma samples collected for pharmacokinetic analysis of BMX-001 are provided below. 
Blood sample volumes and schedule of samples are specified below. 
 
Pharmacokinetic Blood Sample Collection and Handling: Blood samples (4 ml) will be collected into 
pre-cooled (ice bath) heparinized tubes and gently inverted 8-10 times and immediately placed in the 
ice bath. Within 30 minutes, plasma will be prepared by centrifugation (2000 x g, 40C, 10 min). 
Following centrifugation, 1 mL plasma will be transferred by polypropylene disposable pipette to a 2-
mL polypropylene cryogenic vial containing 20 µL of 50% citric acid, inverted 8-10 times, and stored 
frozen at -800C until shipment and analysis.  
Blood Sampling Time Schedule for BMX-001: Drug pharmacokinetics will be obtained on loading dose 
day, Day 8 or the next date on which drug is administered, and Day 36 or the next date on which drug 
is administered during the chemoradiation phase. Measures will be obtained at the following time-
points: Pre Dose, 0.5 hour, 1 hour, 2 hours, 6 hours and 24 hours. Day 8 and Day 36 are intended to 
be the first maintenance dose of the second week and the first maintenance dose of the sixth week 
following initiation of radiation therapy. 
PK Labelling: PK samples will labelled such that they are blinded to Dr. Ivan Spasojevic’s labs. The 
cyro-vials provided to his lab will labelled with random numbers generated by statisticians and kept in 
a master file maintained by the study team. Samples will not be identified by patient, timepoint, dose 
level or cohort prior to being analysed by Dr. Spasojevic. Data generated by the samples will be 
evaluated after each enrolled cohort. Labelling and blinding procedures will be specified in the Blood 
Collection and Plasma Separation Storage SOP.  
Analytical Method: Concentrations of BMX-001 will be determined using a high-pressure liquid 
chromatography – tandem-mass spectrometry (LC/MS/MS) by laboratory personnel designated by 
BioMimetix JV, LLC.  
 
Samples will be taken/shipped to Dr. Ivan Spasojevic at the following address: 
Ivan Spasojevic, PhD 
Pharmacology Lab 
Duke Hospital South 
Orange Zone, Room 5317 
200 Trent Drive 
Durham, NC 27710 
Tel: 919-684-8311 
Cell: 919-323-5927 
Fax: 919-684-8380 
 


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Pharmacokinetic Sample Collection for BMX-001 in Combination with Current Chemoradiation 
Phase 1 Study Day 
Timing 
Range of time to be 
collected within 
Loading Dose Day 
Pre-dose 
N/A 
30 minutes post-dose 
+/- 2 minutes 
1 hour post-dose 
+/- 5 minutes 
2 hours post-dose 
+/- 5 minutes 
6 hours post-dose 
+/- 5 minutes 
24 hours post-dose 
+/- 10 minutes 
Day 8 or the next day 
when drug is 
administered 
Pre-dose 
N/A 
30 minutes post-dose 
+/- 2 minutes 
1 hour post-dose 
+/- 5 minutes 
2 hours post-dose 
+/- 5 minutes 
6 hours post-dose 
+/- 5 minutes 
24 hours post-dose 
+/- 10 minutes 
Day 36 or the next day 
when drug is 
administered 
Pre-dose 
N/A 
30 minutes post-dose 
+/- 2 minutes 
1 hour post-dose 
+/- 5 minutes 
2 hours post-dose 
+/- 5 minutes 
6 hours post-dose 
+/- 5 minutes 
24 hours post-dose 
+/- 10 minutes 
 
19.2.2 
Phase 2 Pharmacokinetic Analysis 
In order to provide a wider population sample for pharmacokinetics, we will obtain sparse sampling 
from 6 patients in the Phase 2 Arm A portion of the study.  
 
The major goal of the pharmacokinetic studies conducted in conjunction with this protocol will be to 
determine pharmacokinetics of BMX-001 in combination with RT and TMZ. These samples will be 
collected from patients during chemoradiation phase only. 
 
Pharmacokinetic Assessment of BMX-001: A series of blood samples will be taken for the 
measurement of the compound in order to define pharmacokinetics in these patients. Patients 
should have their dose administered on the same time of day. Instructions for the handling and 
shipping of plasma samples collected for pharmacokinetic analysis of BMX-001 are provided below. 
Blood sample volumes and schedule of samples are specified below. 
 
Pharmacokinetic Blood Sample Collection and Handling: Blood samples (4 ml) will be collected into 
pre-cooled (ice bath) heparinized tubes and gently inverted 8-10 times and immediately placed in the 
ice bath. Within 30 minutes, plasma will be prepared by centrifugation (2000 x g, 40C, 10 min). 
Following centrifugation, 1 mL plasma will be transferred by polypropylene disposable pipettes to 
create two 2-mL polypropylene cryogenic vial aliquots containing 20 µL of 50% citric acid, inverted 8-
10 times, and stored frozen at -800C until shipment and analysis. One aliquot is acceptable if samples 
are not being shipped. 
Blood Sampling Time Schedule for BMX-001: Drug pharmacokinetics will be obtained on Day 8 or the 
next day when drug is administered and Day 36 or the next day when drug is administered during the 
chemoradiation phase. Measures will be obtained at the following time-points: Pre Dose, 0.5 hour, 1 
hour, 2 hours, 6 hours and 24 hours. 


Protocol #: BMX-HGG-001 
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Analytical Method: Concentrations of BMX-001 will be determined using a high-pressure liquid 
chromatography – tandem-mass spectrometry (LC/MS/MS) by laboratory personnel designated by 
BioMimetix JV, LLC.  
 
Samples will be taken/shipped to Dr. Ivan Spasojevic at the following address: 
Ivan Spasojevic, PhD 
Pharmacology Lab 
Duke Hospital South 
Orange Zone, Room 5317 
200 Trent Drive 
Durham, NC 27710 
Tel: 919-684-8311 
Cell: 919-323-5927 
Fax: 919-684-8380 
 
Pharmacokinetic Sample Collection for BMX-001 in Combination with Current Chemoradiation 
Phase 2 Study Day 
Timing 
Range of time to be 
collected within 
Day 8 or the next day 
when drug is 
administered 
Pre-dose 
N/A 
30 minutes post-dose 
+/- 2 minutes 
1 hour post-dose 
+/- 5 minutes 
2 hours post-dose 
+/- 5 minutes 
6 hours post-dose 
+/- 5 minutes 
24 hours post-dose 
+/- 10 minutes 
Day 36 or the next day 
when drug is 
administered 
Pre-dose 
N/A 
30 minutes post-dose 
+/- 2 minutes 
1 hour post-dose 
+/- 5 minutes 
2 hours post-dose 
+/- 5 minutes 
6 hours post-dose 
+/- 5 minutes 
24 hours post-dose 
+/- 10 minutes 
 
19.3 APPENDIX C: Statistical Tables 
19.3.1 
PROBABILITY OF MTD SELECTION WITH A LOGISTIC MODEL IN THE SECOND STAGE 
WITH VARIOUS TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 2 AFTER FIRST 
STAGE WITH COHORTS OF 3 
Initial Guess of Toxicity Probability=0.101 / 0.143 / 0.193 / 0.25 (delta=0.03; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0020 
0.0060 
0.0250 
0.9670 
21 
0.0020 
0.0060 
0.0145 
0.9775 
24 
0.0000 
0.0035 
0.0095 
0.9870 
 


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True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0220 
0.0815 
0.8920 
21 
0.0030 
0.0200 
0.0830 
0.8940 
24 
0.0010 
0.0140 
0.0790 
0.9060 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0050 
0.0290 
0.1270 
0.8390 
21 
0.0050 
0.0305 
0.1420 
0.8225 
24 
0.0010 
0.0210 
0.1770 
0.8010 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.2395 
0.3665 
0.2455 
0.1485 
21 
0.2315 
0.3970 
0.2645 
0.1070 
24 
0.2390 
0.4285 
0.2600 
0.0725 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3230 
0.1915 
0.2470 
0.2385 
21 
0.3010 
0.2430 
0.2285 
0.2275 
24 
0.2920 
0.2590 
0.2715 
0.1775 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4900 
0.2455 
0.1705 
0.0940 
21 
0.4775 
0.2945 
0.1605 
0.0675 
24 
0.5050 
0.2935 
0.1595 
0.0420 
 


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Initial Guess of Toxicity Probability=0.044 / 0.089 / 0.158 / 0.25 (delta=0.05; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0030 
0.0205 
0.0465 
0.9300 
21 
0.0015 
0.0125 
0.0475 
0.9385 
24 
0.0015 
0.0095 
0.0280 
0.9610 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0305 
0.1335 
0.8315 
21 
0.0020 
0.0255 
0.1390 
0.8335 
24 
0.0015 
0.0180 
0.1315 
0.8490 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0030 
0.0375 
0.2020 
0.7575 
21 
0.0015 
0.0335 
0.2160 
0.7490 
24 
0.0015 
0.0225 
0.2215 
0.7545 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.2040 
0.4325 
0.2820 
0.0815 
21 
0.1855 
0.4765 
0.2810 
0.0570 
24 
0.1840 
0.5280 
0.2490 
0.0390 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3200 
0.2405 
0.2740 
0.1655 
21 
0.3050 
0.2650 
0.2900 
0.1400 
24 
0.2935 
0.2770 
0.3040 
0.1255 
 


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True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4685 
0.3100 
0.1735 
0.0480 
21 
0.4635 
0.3370 
0.1680 
0.0315 
24 
0.4555 
0.3760 
0.1410 
0.0275 
 
Initial Guess of Toxicity Probability=0.016 / 0.051 / 0.124 / 0.250 (delta=0.07; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0030 
0.0410 
0.0905 
0.8655 
21 
0.0020 
0.0250 
0.1070 
0.8660 
24 
0.0020 
0.0160 
0.0730 
0.9090 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0030 
0.0690 
0.2005 
0.7275 
21 
0.0035 
0.0470 
0.2170 
0.7325 
24 
0.0025 
0.0310 
0.2010 
0.7655 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0030 
0.0530 
0.2710 
0.6730 
21 
0.0015 
0.0330 
0.3205 
0.6450 
24 
0.0020 
0.0245 
0.2920 
0.6815 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.1765 
0.5295 
0.2385 
0.0555 
21 
0.1605 
0.5580 
0.2480 
0.0335 
24 
0.1525 
0.5875 
0.2400 
0.0200 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 82 of 137 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3240 
0.3060 
0.2420 
0.1280 
21 
0.3320 
0.3135 
0.2730 
0.0815 
24 
0.2905 
0.3320 
0.2795 
0.0980 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4800 
0.3505 
0.1350 
0.0345 
21 
0.4900 
0.3540 
0.1345 
0.0215 
24 
0.4725 
0.3790 
0.1350 
0.0135 
 
19.3.2 
PROBABILITY OF MTD SELECTION WITH AN EMPIRIC MODEL IN THE SECOND STAGE 
WITH VARIOUS TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 2 AFTER FIRST 
STAGE WITH COHORTS OF 3 
 
Initial Guess of Toxicity Probability=0.097 / 0.141 / 0.192 / 0.25 (delta=0.03; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0020 
0.0060 
0.0250 
0.9670 
21 
0.0020 
0.0060 
0.0170 
0.9750 
24 
0.0000 
0.0035 
0.0100 
0.9865 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0185 
0.0835 
0.8935 
21 
0.0035 
0.0200 
0.0820 
0.8945 
24 
0.0010 
0.0130 
0.0705 
0.9155 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 83 of 137 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0050 
0.0265 
0.1280 
0.8405 
21 
0.0050 
0.0305 
0.1395 
0.8250 
24 
0.0015 
0.0210 
0.1540 
0.8235 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.2465 
0.3540 
0.2525 
0.1470 
21 
0.2285 
0.4025 
0.2600 
0.1090 
24 
0.2340 
0.4285 
0.2570 
0.0805 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3260 
0.1860 
0.2480 
0.2400 
21 
0.3000 
0.2420 
0.2355 
0.2225 
24 
0.2920 
0.2555 
0.2585 
0.1940 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4935 
0.2360 
0.1780 
0.0925 
21 
0.4760 
0.2960 
0.1605 
0.0675 
24 
0.5025 
0.2955 
0.1545 
0.0475 
 
Initial Guess of Toxicity Probability=0.036 / 0.084 / 0.157 / 0.25 (delta=0.05; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0050 
0.0160 
0.0430 
0.9360 
21 
0.0020 
0.0155 
0.0430 
0.9395 
24 
0.0010 
0.0120 
0.0330 
0.9540 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 84 of 137 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0055 
0.0260 
0.1335 
0.8350 
21 
0.0020 
0.0255 
0.1250 
0.8475 
24 
0.0015 
0.0190 
0.1205 
0.8590 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0305 
0.2050 
0.7600 
21 
0.0020 
0.0325 
0.2090 
0.7565 
24 
0.0010 
0.0185 
0.2275 
0.7530 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.1755 
0.4645 
0.2600 
0.1000 
21 
0.1835 
0.4690 
0.2955 
0.0520 
24 
0.1430 
0.5430 
0.2700 
0.0440 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3030 
0.2635 
0.2635 
0.1700 
21 
0.2920 
0.2850 
0.2750 
0.1480 
24 
0.2805 
0.2875 
0.3020 
0.1300 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4520 
0.3415 
0.1520 
0.0545 
21 
0.4705 
0.3325 
0.1680 
0.0290 
24 
0.4415 
0.3755 
0.1560 
0.0270 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 85 of 137 
Initial Guess of Toxicity Probability=0.009 / 0.043 / 0.124 / 0.25 (delta=0.07; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0040 
0.0400 
0.0880 
0.8680 
21 
0.0015 
0.0285 
0.1100 
0.8600 
24 
0.0015 
0.0255 
0.0820 
0.8910 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0605 
0.1770 
0.7580 
21 
0.0020 
0.0450 
0.2385 
0.7145 
24 
0.0025 
0.0410 
0.2030 
0.7535 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.0045 
0.0500 
0.2560 
0.6895 
21 
0.0015 
0.0445 
0.3085 
0.6455 
24 
0.0015 
0.0330 
0.3060 
0.6595 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.1845 
0.5150 
0.2400 
0.0605 
21 
0.1655 
0.5685 
0.2305 
0.0355 
24 
0.1460 
0.6090 
0.2215 
0.0235 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.3185 
0.3260 
0.2375 
0.1180 
21 
0.3185 
0.3200 
0.2720 
0.0895 
24 
0.3010 
0.3435 
0.2830 
0.0725 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 86 of 137 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
18 
0.4655 
0.3775 
0.1200 
0.0370 
21 
0.4770 
0.3755 
0.1260 
0.0215 
24 
0.4635 
0.4060 
0.1160 
0.0145 
 
 
19.3.3 
PROBABILITY OF MTD SELECTION WITH A LOGISTIC MODEL IN THE SECOND STAGE 
WITH VARIOUS TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 3 AFTER FIRST 
STAGE WITH COHORTS OF 3 
 
Initial Guess of Toxicity Probability=0.101 / 0.143 / 0.193 / 0.25 (delta=0.03; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.008 
0.020 
0.032 
0.940 
18 
0.004 
0.006 
0.030 
0.960 
20 
0.000 
0.010 
0.016 
0.974 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.016 
0.032 
0.106 
0.846 
18 
0.004 
0.024 
0.116 
0.856 
20 
0.002 
0.036 
0.118 
0.844 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.014 
0.062 
0.128 
0.796 
18 
0.004 
0.036 
0.162 
0.798 
20 
0.004 
0.042 
0.160 
0.794 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 87 of 137 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.266 
0.304 
0.260 
0.170 
18 
0.250 
0.378 
0.254 
0.118 
20 
0.262 
0.374 
0.262 
0.102 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.372 
0.170 
0.198 
0.260 
18 
0.328 
0.190 
0.260 
0.222 
20 
0.348 
0.204 
0.258 
0.190 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.502 
0.228 
0.162 
0.108 
18 
0.500 
0.252 
0.180 
0.068 
20 
0.508 
0.262 
0.176 
0.054 
 
Initial Guess of Toxicity Probability=0.044 / 0.089 / 0.158 / 0.25 (delta=0.05; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.024 
0.072 
0.898 
18 
0.006 
0.022 
0.060 
0.912 
20 
0.008 
0.014 
0.050 
0.928 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.008 
0.050 
0.154 
0.788 
18 
0.008 
0.036 
0.162 
0.794 
20 
0.008 
0.034 
0.134 
0.824 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 88 of 137 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.062 
0.222 
0.710 
18 
0.008 
0.042 
0.228 
0.722 
20 
0.008 
0.038 
0.204 
0.750 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.202 
0.450 
0.256 
0.092 
18 
0.194 
0.472 
0.254 
0.080 
20 
0.180 
0.504 
0.252 
0.064 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.290 
0.308 
0.216 
0.186 
18 
0.310 
0.282 
0.252 
0.156 
20 
0.284 
0.302 
0.268 
0.146 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.454 
0.326 
0.156 
0.064 
18 
0.464 
0.322 
0.164 
0.050 
20 
0.446 
0.362 
0.154 
0.038 
 
Initial Guess of Toxicity Probability=0.016 / 0.051 / 0.124 / 0.250 (delta=0.07; logistic)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.024 
0.034 
0.078 
0.864 
18 
0.010 
0.038 
0.088 
0.864 
20 
0.012 
0.026 
0.090 
0.872 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 89 of 137 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.028 
0.064 
0.188 
0.720 
18 
0.012 
0.056 
0.202 
0.730 
20 
0.014 
0.036 
0.226 
0.724 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.230 
0.480 
0.226 
0.064 
18 
0.190 
0.510 
0.246 
0.054 
20 
0.224 
0.486 
0.236 
0.054 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.392 
0.262 
0.192 
0.154 
18 
0.348 
0.302 
0.216 
0.134 
20 
0.374 
0.234 
0.272 
0.120 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.514 
0.300 
0.160 
0.026 
18 
0.488 
0.330 
0.142 
0.040 
20 
0.478 
0.346 
0.144 
0.032 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 90 of 137 
19.3.4 
PROBABILITY OF MTD SELECTION WITH A EMPIRIC MODEL IN THE SECOND STAGE 
WITH VARIOUS TRUE UNDERLYING TOXICITY PROFILES AND COHORTS OF 3 AFTER FIRST 
STAGE WITH COHORTS OF 3 
 
Initial Guess of Toxicity Probability=0.097 / 0.141 / 0.192 / 0.25 (delta=0.03; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.018 
0.022 
0.954 
18 
0.010 
0.012 
0.022 
0.956 
20 
0.004 
0.012 
0.024 
0.960 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.012 
0.038 
0.078 
0.872 
18 
0.010 
0.030 
0.086 
0.874 
20 
0.006 
0.028 
0.108 
0.858 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.010 
0.040 
0.124 
0.826 
18 
0.010 
0.040 
0.116 
0.834 
20 
0.006 
0.046 
0.184 
0.764 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.250 
0.336 
0.276 
0.138 
18 
0.280 
0.350 
0.240 
0.130 
20 
0.244 
0.448 
0.222 
0.086 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.322 
0.222 
0.188 
0.268 
18 
0.312 
0.216 
0.222 
0.250 
20 
0.342 
0.218 
0.264 
0.176 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 91 of 137 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.498 
0.244 
0.170 
0.088 
18 
0.480 
0.268 
0.164 
0.088 
20 
0.498 
0.322 
0.122 
0.058 
 
Initial Guess of Toxicity Probability=0.036 / 0.084 / 0.157 / 0.25 (delta=0.05; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.008 
0.022 
0.062 
0.908 
18 
0.002 
0.016 
0.048 
0.934 
20 
0.000 
0.024 
0.032 
0.944 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.010 
0.048 
0.156 
0.786 
18 
0.002 
0.034 
0.140 
0.824 
20 
0.000 
0.036 
0.146 
0.818 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.008 
0.046 
0.192 
0.754 
18 
0.002 
0.034 
0.230 
0.734 
20 
0.000 
0.036 
0.188 
0.776 
 
True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.188 
0.472 
0.246 
0.094 
18 
0.220 
0.456 
0.254 
0.070 
20 
0.170 
0.530 
0.252 
0.048 
 


Protocol #: BMX-HGG-001 
Version 9.0, 25 May 2021 
Page 92 of 137 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.304 
0.282 
0.240 
0.174 
18 
0.308 
0.278 
0.250 
0.164 
20 
0.294 
0.296 
0.264 
0.146 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.456 
0.342 
0.158 
0.044 
18 
0.488 
0.306 
0.178 
0.028 
20 
0.436 
0.394 
0.144 
0.026 
 
Initial Guess of Toxicity Probability=0.009 / 0.043 / 0.124 / 0.25 (delta=0.07; empiric)  
 
True Probability of DLT=0.05 / 0.055 / 0.06 / 0.065 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.036 
0.158 
0.800 
18 
0.006 
0.042 
0.084 
0.868 
20 
0.006 
0.018 
0.084 
0.892 
 
True Probability of DLT=0.05 / 0.07 / 0.11 / 0.2 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.076 
0.262 
0.656 
18 
0.010 
0.064 
0.234 
0.692 
20 
0.006 
0.046 
0.218 
0.730 
 
True Probability of DLT=0.05 / 0.05 / 0.15 / 0.25 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.006 
0.054 
0.326 
0.614 
18 
0.006 
0.054 
0.316 
0.624 
20 
0.006 
0.034 
0.302 
0.658 
 


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True Probability of DLT=0.1 / 0.25 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.218 
0.488 
0.224 
0.070 
18 
0.198 
0.522 
0.224 
0.056 
20 
0.180 
0.544 
0.238 
0.038 
 
True Probability of DLT=0.2 / 0.2 / 0.3 / 0.4 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.366 
0.278 
0.240 
0.116 
18 
0.364 
0.286 
0.244 
0.106 
20 
0.344 
0.306 
0.254 
0.096 
 
True Probability of DLT=0.2 / 0.3 / 0.4 / 0.5 
n 
Dose 
Level 1 
Dose 
Level 2 
Dose 
Level 3 
Dose 
Level 4 
16 
0.510 
0.318 
0.134 
0.038 
18 
0.508 
0.334 
0.126 
0.032 
20 
0.472 
0.374 
0.138 
0.016 
 
 
19.4 Appendix D Cytochrome P450 Drug Interaction Table 
 
Please see the following website for known cytochrome P450 inducers and strong inhibitors. The website is 
updated frequently as new information becomes available (Flockhart, 2007) 
 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
Dexamethasone is listed on this table, but is allowed in this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19.5 Appendix E Copy of BAC App screenshots 
 
 


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19.6 Appendix F:  Beck Depression Inventory- II (BDI-II) 
 


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19.7 Appendix G:  FACIT-Fatigue 
 


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19.8 Appendix H:  Fact-BR 
 


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19.9  Appendix I:  FACT-Cog 
 


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19.10 Appendix J:  Godin Leisure-Time Exercise Questionnaire 
 
 


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19.11 Appendix K:  Trails Making Test (TMT) Parts A & B 
 


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-Total time to complete in seconds: ____________ 
- Number of errors: ____________ 
 


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-Total time to complete in seconds: ____________ 
- Number of errors: ____________ 
 


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19.12 Appendix L:  HVLT-R Forms 1, 2 and 3 
 
 


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19.1 
Appendix M:  COWA 
 
 
 

SAP_001.pdf: 
Page 1 of 21 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
FOR THE PHASE 2 COMPONENT 
OF THE PROTOCOL ENTITLED 
“A Phase 1 / 2 Trial for Patients with 
Newly Diagnosed High Grade Glioma 
Treated with Concurrent Radiation 
Therapy, Temozolomide, and BMX-001”  
Protocol #: BMX-HGG-001 
 
Adapted from the Statistical Section included in the Research Protocol 
 
Version Date:  June 1, 2023 
 
 


Page 2 of 21 
 
1 
List of Abbreviations ____________________________________________________________________________ 4 
2 
SIGNATURES ______________________________________________________________________________________ 5 
3 
INTRODUCTION __________________________________________________________________________________ 6 
4 
OVERVIEW OF STUDY DESIGN _________________________________________________________________ 6 
5 
PATIENT CHARACTERISTICS ___________________________________________________________________ 7 
6 
ANALYSIS POPULATIONS _______________________________________________________________________ 7 
7 
TREATMENT AND SUBJECT DISPOSITION ___________________________________________________ 8 
8 
PRIMARY OBJECTIVE: SURVIVAL ______________________________________________________________ 8 
8.1 
ENDPOINT _________________________________________________________________________________________ 8 
8.2 
METHOD OF PRIMARY ENDPOINT ANALYSIS ________________________________________________ 8 
8.3 
INTERIM ANALYSES ______________________________________________________________________________ 9 
 
INTERIM ANALYSIS #1 _______________________________________________________________________ 9 
 
INTERIM ANALYSIS #2 _______________________________________________________________________ 9 
 
PRIMARY ENDPOINT ANALYSIS _____________________________________________________________ 9 
8.4 
POWER OF SURVIVAL COMPARISONS & FINAL ANALYSIS__________________________________ 9 
 
ORIGINAL POWER ANALYSIS ________________________________________________________________ 9 
 
REVISED POWER ANALYSIS _______________________________________________________________ 10 
8.5 
ADDITIONAL ANALYSES, INCLUDING SUBGROUP ANALYSES ____________________________ 10 
9 
SECONDARY OBJECTIVE: COGNITION _______________________________________________________ 11 
9.1 
DROP-OUT PATTERNS _________________________________________________________________________ 12 
9.2 
ENDPOINT _______________________________________________________________________________________ 12 
9.3 
METHOD OF ANALYSIS ________________________________________________________________________ 12 
9.4 
POWER FOR COGNITIVE COMPARISONS ____________________________________________________ 13 
 
ORIGINAL POWER ANALYSIS ______________________________________________________________ 13 
 
REVISED POWER ANALYSIS _______________________________________________________________ 13 
9.5 
ADDITIONAL ANALYSES _______________________________________________________________________ 13 
10 
SECONDARY OBJECTIVE: THROMBOCYTOPENIA _______________________________________ 13 
10.1 
ENDPOINT _____________________________________________________________________________________ 14 
10.2 
METHOD OF ANALYSIS ______________________________________________________________________ 14 
10.3 
POWER FOR THROMBOCYTOPENIA ENDPOINT _________________________________________ 14 
 ORIGINAL POWER ANALYSIS ______________________________________________________________ 14 
 REVISED POWER ANALYSIS _______________________________________________________________ 14 


Page 3 of 21 
11 
SECONDARY OBJECTIVE: ADVERSE EVENTS (AE) _______________________________________ 14 
11.1 
ENDPOINTS ___________________________________________________________________________________ 14 
11.2 
METHOD OF SUMMARIZATION AND ANALYSIS _________________________________________ 15 
 ADVERSE EVENTS DURING CHEMORADIATION _________________________________________ 15 
 SERIOUS ADVERSE EVENTS DURING CHEMORADIATION ______________________________ 15 
 ADVERSE EVENTS DURING CHEMORADIATION ATTRIBUTABLE TO BMX-001 ______ 15 
 OTHER SAFETY MEASURES AND TABULATIONS ________________________________________ 16 
12 
SECONDARY OBJECTIVE:  PROGRESSION-FREE SURVIVAL ____________________________ 16 
12.1 
ENDPOINT _____________________________________________________________________________________ 16 
12.2 
METHOD OF ANALYSIS ______________________________________________________________________ 16 
12.3 
ADDITIONAL ANALYSES _____________________________________________________________________ 16 
13 
SECONDARY OBJECTIVE: RADIOGRAPHIC RESPONSE _________________________________ 16 
13.1 
ENDPOINT _____________________________________________________________________________________ 17 
13.2 
METHOD OF ANALYSIS ______________________________________________________________________ 17 
13.3 
ADDITIONAL ANALYSES _____________________________________________________________________ 17 
14 
SECONDARY OBJECTIVE: PHARMACOKINETICS ________________________________________ 17 
15 
EXPLORATORY OBJECTIVE: HEALTH-RELATED QUALITY OF LIFE (HRQoL) _______ 17 
15.1 
ENDPOINT _____________________________________________________________________________________ 18 
15.2 
METHOD OF PRIMARY ANALYSIS __________________________________________________________ 18 
15.3 
ADDITIONAL ANALYSES _____________________________________________________________________ 18 
16 
EXPLORATORY OBJECTIVE: HAIR LOSS __________________________________________________ 19 
17 
EXPLORATORY OBJECTIVE: WHITE MATTER INTEGRITY _____________________________ 19 
17.1 
ENDPOINT _____________________________________________________________________________________ 19 
17.2 
METHODS OF ANALYSIS _____________________________________________________________________ 19 
18 
PROTOCOL DEVIATIONS ___________________________________________________________________ 19 
19 
DESCRIPTION OF TABLES FOR REPORTING _____________________________________________ 20 
20 
REFERENCES _________________________________________________________________________________ 21 
 
 
 
 


Page 4 of 21 
1 List of Abbreviations 
AE 
Adverse Events 
ANCOVA 
Analysis of covariance 
COWA 
Controlled Oral Word Association 
CSR 
Clinical Study Report 
FDA 
Food and Drug Administration 
Gy 
Gray 
HGG 
High Grade Glioma 
HRQoL 
Health related Quality of Life 
HVLT-R 
Hopkins Verbal Learning Test - Revised 
ICH 
International Conference on Harmonization 
ITT 
Intent to Treat 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PRO 
Patient Reported Outcome 
RANO 
Response Assessment in Neuro-Oncology 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of Care 
TEAE 
Treatment-Emergent Adverse Event 
TMT 
Trails Making Test 
TMZ 
Temozolomide 
WHO 
World Health Organization 
 
 
 




Page 6 of 21 
3 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (version 9.0 dated 
25 May 2019).  If statistical methods differ substantially between the SAP and the protocol, 
refer to the SAP. 
The SAP describes the datasets and the statistical methods to be used for reporting and 
analysis of all data collected during the trial. 
If a future protocol amendment necessitates a substantial change to the statistical analysis 
of the trial data, the SAP will be amended.  If, after the database is locked, additional 
analyses are required to supplement the planned analyses described in this SAP, those 
unplanned analyses will not be described in an amended SAP, but they will be identified 
in the final Clinical Study Report (CSR). 
We have considered the following guidelines when writing this SAP: 
• 
International Conference on Harmonization (ICH) E9, Guidance for Industry:  
Statistical Principles for Clinical Trials  
• 
ICH E3, Guidance for Industry:  Structure and Content of Clinical Study Reports.   
Statistical analysis will primarily be conducted using SAS version 9.4, with additional 
analyses and data visualization performed using the R software (version 4.2.1 or later). 
4 OVERVIEW OF STUDY DESIGN 
The Phase 2 portion of this protocol is a multi-
center randomized open-label study comparing 
the impact of concurrent daily Temozolomide 
(TMZ) and Radiation Therapy (RT) with BMX-
001 (Arm A) versus concurrent daily TMZ and RT 
alone (Arm B) on survival in patients among 
patients with newly diagnosed high grade glioma 
(HGG - WHO grade III and IV).  Subjects were 
randomized with a treatment arm allocation ratio 
of 1:1, with a goal of enrolling 160 patients in this phase of the study (80 subjects per arm). 
A permuted block randomization stratified by histologic grade (grade III / IV) and institution 
will be used to assign patients to treatment with or without BMX-001. 
Subjects in Arm A were administered BMX-001 subcutaneously first as a loading dose (28 
mg) given 0 to 4 days before the start of chemoradiation and then at subsequent dose (14 
mg) twice a week for eight weeks. Subjects in Arm A and Arm B received TMZ dosed at 
75 mg/m2 orally daily for 42 days and RT delivered in daily fractions of 1.8-2 Gy given 5 
days a week for 6 weeks for a total of 59.4-60 Gy.  
In all subjects, cognitive performance was measured at the time of enrollment and 2 weeks 
after the completion of RT, and standard of care (SOC) clinic visits (approximately 8 weeks 
apart +/- 2 weeks) until death, or patient’s choice to discontinue study measures.  
Cognitive testing was to continue after noted progression until the 12 month follow up 
timepoint is reached.   
In order to characterize the repeated dose pharmacokinetic (PK) profiles of BMX-001 in 
combination with RT and TMZ in newly diagnosed HGG patients, PK blood samples were 
drawn on Days 8 and 36 only from the first 6 patients enrolled and assigned to Arm A at 
a single center (Duke). Measures were obtained at approximately the following times: Pre-
TREATMENT ARMS 
Arm A: Concurrent daily TMZ and 
RT with BMX-001 
Arm B: Concurrent daily TMZ and 
RT alone 


Page 7 of 21 
dose, then 0.5 hour, 1 hour, 2 hours, 6 hours and 24 hours post-dose. Samples will be 
analyzed for BMX-001 using validated analytical methods at the Duke PK lab.   
The study’s primary phase 2 endpoint is overall survival (OS), defined as the time between 
randomization and death. A logrank test will be used to compare the survival experience 
of the two treatment arms. An intent-to-treat philosophy will be used in the analysis of 
survival by including all patients who are randomized in the analysis.   Other analysis sets 
are defined in this document. 
Among the secondary endpoints are two that are of particular interest: cognitive function 
and thrombocytopenia. The mean change in cognitive functioning between baseline 
(enrollment) and week 24 within each treatment arm will be computed, and analysis of 
covariance will be conducted to compare groups with respect to that change. Treatment 
group assignment will be included in the model as a predictor, and the baseline measure 
of cognitive function will be included as a covariate.  
The proportion of patients who experience grade 3 or 4 thrombocytopenia during 
concurrent temozolomide and radiation, a period that terminates 2 weeks after completion 
of radiation treatment, will be summarized. A chi-square test will be conducted to compare 
the prevalence of such thrombocytopenia observed in patients with and without BMX-001. 
5 PATIENT CHARACTERISTICS 
The clinical and socio-demographic characteristics of all randomized patients will be 
summarized using descriptive statistics (e.g., means/standard deviations, percentiles, 
frequencies). Patient characteristics will be summarized by treatment group assignment. 
Characteristics that will be summarized include: 
 
• 
Institution 
• 
Race 
• 
Ethnicity 
• 
Gender 
• 
Tumor Grade, according to WHO grade at time of enrollment and WHO 20211* 
• 
Performance Status (KPS) 
• 
Histology  
• 
Disease Description (Unifocal / Multifocal) 
• 
MGMT Status (Methylated / Unmethylated) 
• 
IDH:  mutated or wildtype 
• 
Extent of Resection (Gross total Resection / Subtotal Resection / Biopsy Only) 
• 
Age  
6 ANALYSIS POPULATIONS 
The following populations will be identified: 
• 
Intent to Treat Population (ITT):  All patients randomized into the clinical trial, 
regardless of compliance.  
                                               
1 During study accrual, a new WHO classification system for CNS tumors was published [1]. Though 
the classification system in use at the time of study activation was used throughout the conduct of 
the study, the classification of all patients under the new WHO 2021 system will also be described. 


Page 8 of 21 
• 
Safety Population:  All patients who received at least one dose of  BMX-001 or 
temozolomide 
• 
Treated Population:  All patients who completed chemoradiation with or without 
BMX-001.  BMX-001 must be given for at least 6 weeks (or 13 doses). 
• 
PK Population:  Subjects who participated in the PK portion of the study (n=6). 
7 TREATMENT AND SUBJECT DISPOSITION 
A CONSORT diagram will be generated that displays the number of patients randomized 
within each treatment arm, the number of patients within each arm who are treated with 
chemoradiation, as well as the number of cycles of adjuvant treatment received. For 
treatment during chemoradiation, the total dose of BMX-001 administered will be 
summarized, as well as the total dose of TMZ and RT administered.   
 
All subjects who withdrew or were withdrawn from the study will be listed by treatment arm 
with the reason for withdrawal. 
8 PRIMARY OBJECTIVE: SURVIVAL 
The primary goal of this randomized, open-label Phase 2 study is to examine the impact 
of BMX-001 on overall survival among patients newly diagnosed with HGG who are 
receiving SOC treatment consisting of daily TMZ and RT.  After the primary endpoint 
analysis at 84 deaths, we will continue following patients for survival and disease 
progression even after the primary endpoint analysis.  Per protocol, patients will be 
followed indefinitely.   
8.1 
ENDPOINT   
The study’s primary endpoint is overall survival (OS) which is defined by the time 
between randomization and death, or the last follow-up if the patient remains alive. 
8.2 
METHOD OF PRIMARY ENDPOINT ANALYSIS  
This study will assess the hypothesis that BMX-001, when added to standard RT 
and TMZ, will sensitize the malignancy and result in enhanced patient survival as 
well as protect normal tissues from RT, resulting in better quality of life.   
The primary analysis of survival will be done with the ITT population.   
Kaplan-Meier methods will be used to graphically describe the distribution of 
overall survival (OS) among patients within the BMX-001 treatment group (Arm A) 
and within the control group (Arm B). Median OS, as well as 6-, 12-, 24-, and 36-
month estimates of OS will be estimated from the Kaplan-Meier curve. A logrank 
test will compare arms with respect to the survival outcome. 
As an additional descriptive statistic, the mean overall survival over a time interval 
chosen to maintain reasonable coverage of observed survival will be calculated. 
If the underlying assumptions for the planned analyses are not satisfied,  
alternative methods of analysis depending on the observed distribution of the data 
will be explored. 


Page 9 of 21 
8.3 
INTERIM ANALYSES   
Interim analyses using an O’Brien-Fleming boundary will be conducted with the 
goal of terminating accrual early to accept or reject the null hypothesis of no 
difference in survival. Given the inflated type I error rate for this Phase 2 study, 
early termination will only be considered if it appears that the addition of BMX-001 
treatment to radiation and temozolomide is decreasing survival. The interim 
analysis will be conducted to determine whether the addition of BMX-001 is 
possibly detrimental to the survival of patients.  
 INTERIM ANALYSIS #1 
The study was originally designed with one interim survival analysis after 
approximately 42 deaths. The decision rule for accrual suspension was defined by 
the O’Brien-Fleming spending function and is dependent upon the number of 
deaths that will have been reported by the time of the interim analysis. If the 
boundary was crossed, accrual was to be suspended while all other data (e.g., 
cognitive function data) is reviewed to determine whether accrual should be 
permanently terminated. 
The first interim analysis was conducted in December 2021 when 46 deaths had 
been observed in the ITT population (20 in Arm A and 26 in Arm B). The study was 
not terminated early as a result of the first interim analysis. 
 INTERIM ANALYSIS #2 
An unplanned interim analysis was conducted in March 2022 to support an FDA 
application for breakthrough therapy designation.  That analysis was conducted 
when 54 deaths had been observed among treated subjects (22 in Arm A and 30 
in Arm B). The study was not terminated early as a result of the first interim 
analysis. 
 PRIMARY ENDPOINT ANALYSIS 
After these 2 interim analyses, no further interim analysis will be conducted until 
the primary endpoint analysis.  The primary endpoint analysis is scheduled to 
occur after 84 deaths have been observed. 
8.4 
POWER OF SURVIVAL COMPARISONS & FINAL ANALYSIS 
The primary goal of the Phase 2 portion of this study is to assess the effect of BMX-
001 treatment in conjunction with standard of care treatment consisting of 
temozolomide and radiation on the survival of patients newly diagnosed with grade 
III or IV glioma.  
 ORIGINAL POWER ANALYSIS 
With standard treatment, the median survival of Grade IV patients is 14.6 months, 
and the median survival of Grade III is approximately 36 months. Before study 
activation, we anticipated that approximately 10% of patients to be Grade III.  With 
10% of patients as grade III, we estimated that the overall median survival with 
standard treatment to be roughly 16.7 months 


Page 10 of 21 
Though this Phase 2 study is comparative, the goal is to determine whether BMX-
001 is worthy of further investigation in combination with standard RT and TMZ 
treatment.  Many aspects of the new treatment will be considered in the decision-
making concerning further investigation, including relative toxicity and ease of 
treatment administration. As a Phase 2 study, there is a need to constrain the 
sample size requirements at the expense of either an increased false negative or 
false positive rate. A false-positive rate of 0.2 will be used to test the primary 
statistical hypothesis while maintaining reasonably high power [3-5].  
The power of a statistical comparison of survival is a function of the number of 
deaths observed. In order that a 1-tailed logrank test conducted at the 0.2 level to 
have 90% power to detect a hazard ratio of 0.63, 84 deaths need to be observed 
among the 160 randomized patients. Under the assumption that survival is 
exponentially distributed, this hazard ratio represents an increase in median 
survival from 16.7 to 26.5 months.  
 REVISED POWER ANALYSIS 
In actuality, approximately 20% of patients enrolled were Grade III.  With 20% of 
patients to be grade III, we estimate that the median overall survival with standard 
of care treatment to be roughly 18.9 months. 
With these modifications the power analysis has been revised: 
The power of a statistical comparison of survival is a function of the number of 
deaths observed. In order that a 1-tailed logrank test conducted at the 0.2 level to 
have 90% power to detect a hazard ratio of 0.63, 84 deaths need to be observed 
among the 160 randomized patients. Under the assumption that survival is 
exponentially distributed, this hazard ratio represents an increase in median 
survival from 18.9 to 30.0 months.  
8.5 
ADDITIONAL ANALYSES, INCLUDING SUBGROUP 
ANALYSES 
The analyses described in Section 8.2 will be repeated within the treated 
population. 
Within the ITT and treated patient populations, various subgroups analyses will be 
conducted.  Subgroups will be defined by the following factors: 
• 
Original histologic WHO grade (III or IV) 
• 
New histologic WHO grade (III or IV) 
• 
MGMT (present or absent) 
• 
IDH status 
• 
19q FISH 
• 
Age:  subjects > 65 at time of consent 
• 
Others as needed 
The Kaplan-Meier estimator will describe the survival within each combination of 
histologic grade and treatment arm. Several analyses may be conducted: 
1. Within each subgroup defined by the variables above, Cox proportional 
hazards model will assess the effect of treatment on survival.  
  


Page 11 of 21 
2. The Cox model will explore the joint effect of the clinical predictor and treatment 
assignment, and possibly their interaction.  Such an analysis will explore 
whether the effect of BMX-001 treatment is consistent across levels of the 
clinical predictors. 
 
3. The Cox model may also explore the joint effects of age, gender, histologic 
grade, MGMT, and other prognostic factors on survival.      
9 SECONDARY OBJECTIVE: COGNITION 
The first secondary objective involves an assessment of whether the addition of BMX-001 
to standard RT and TMZ treatment for patients newly diagnosed with HGG has an impact 
upon cognition. The BAC App (provided by VeraSci) and paper forms (HVLT-R, COWA, 
TMT) were used to assess patient cognition.   
BAC App (i-Pad based testing) 
The BAC battery of tests was implemented through an iPad-based app called the BAC 
App (the vendor that provides this is called VeraSci, previously called NeuroCog). 
Subtests included:  
• 
Verbal Memory 
• 
Digit Sequencing 
• 
Token Motor 
• 
Semantic Fluency 
• 
Letter Fluency 
• 
Symbol Coding 
• 
Tower of London 
Beginning at baseline, the BAC will be obtained longitudinally: 
• 
Screening (for the baseline assessment), 
• 
After standard RT and TMZ (within 2 to 4 weeks), and  
• 
Approximately every 8 weeks when a subject returns for a Standard of Care visit 
during adjuvant TMZ.  
Paper cognitive testing  
Paper forms were used to assess patient cognition using the following instruments: 
• 
Hopkins Verbal Learning Test-Revised (HVLT-R) 
• 
Trails Making Test Parts A and B (TMT), and  
• 
Controlled Oral Word Association Test (COWA)  
Timepoints completed:  
• 
Baseline (prior to the start of RT) 
• 
Standard of care visit before the start of the first cycle of adjuvant temozolomide,  
• 
Standard of care visits that are 6 and 12 months from the completion of radiotherapy/
chemotherapy.  
When a subject came off study for disease progression before the approximate 6 and 12 
months post completion of treatment timepoint, cognitive testing was supposed to 
continue and be collected at those timepoints and if present will be included. 


Page 12 of 21 
The analysis of Cognition data will focus on the cohort of patients who were treated.  
Typically, patients who were not treated did not provide any cognitive data follow-up. 
9.1 
 DROP-OUT PATTERNS 
The ultimate goal of this objective is to compare groups with respect to longitudinal 
changes in cognition over time.  Unfortunately, due to the patient population that 
are eligible to participate in this study, a significant amount of the follow-up 
cognitive assessments may be missing due to health decline, disease progression, 
and death.  Some of the missing data may be intermittently missing (i.e., missing 
observations between observed assessments); however, much of the missing data 
will be “drop-out” (i.e., subject permanently drops out of longitudinal assessment).  
The pattern of “drop-out” in the two treatment arms will be assessed. 
The proportion of patients within each treatment arm who lack assessments after 
the baseline assessment will be determined and compared using a chi-square test.  
We will also explore whether there are subgroups defined by clinical, cognitive, or 
HRQoL data that are predictive of a subject lacking a post-baseline assessment. 
Drop-out may also occur after one or more follow-up assessments are completed.  
The relationship between the time of the last completed assessment and treatment 
group will be assessed via a contingency table and chi-square test. 
9.2 
 ENDPOINT 
Though the study is a longitudinal analysis, the initial focus of the analyses of this 
objective is an examination of the mean change in cognitive functioning between 
baseline and week 24 (occurs after completion of RT) within each treatment arm. 
The baseline measure is the last assessment obtained before initiation of standard 
chemoradiation. 
There is variability in the timing of follow-up measurements.  For the purpose of 
this analysis a +/- 4 week window will define the 24 week assessment. 
Clearly a patient without an assessment post-baseline will not be included in these 
analyses. Analyses described in Section 9.1 explore how the patients excluded 
from analyses differ from those who are included in analyses. 
9.3 
  METHOD OF ANALYSIS 
For the analysis of change in cognition between baseline and week 24, an analysis 
of covariance (ANCOVA) will be conducted to compare treatment groups within 
the treated patient cohort. The outcome of this model is change in cognitive 
function. Treatment group assignment will be included in the model as a predictor, 
and the baseline measure of cognitive function will be included as a covariate.   
As noted earlier, a significant amount of the follow-up cognitive assessments may 
be missing due to health decline, disease progression, and death.  Much of the 
missing data is due to a subject permanently dropping out of the longitudinal 
assessment. A linear random coefficient model stratified by drop-out pattern will 
assess whether cognitive changes over time are consistent across treatment 
groups and drop-out patterns.  This pattern-mixture model accounts for within 
subject correlation of longitudinal assessments. 


Page 13 of 21 
If assumption for conducting either the ANCOVA model or the pattern mixture 
model are not satisfied, alternative approaches to analyses may be conducted. 
Options include transformation of the outcome data, as well as use of 
nonparametric methods. 
Given that numerous endpoints will be examined that relate to cognition, 
adjustments for multiple comparisons (e.g., false discovery rate methods or 
Bonferroni) may be considered. 
9.4 
POWER FOR COGNITIVE COMPARISONS 
 ORIGINAL POWER ANALYSIS 
We focus on the week 24 assessment of cognitive function in this power calculation 
given that the study is a randomized study, even though we are interested in 
comparing groups with respect to change in cognitive function between baseline 
and week 24. Studies recently conducted at Duke suggest that the standard 
deviation associated with a one-time assessment of executive function, a 
component of cognitive function, is approximately 30 units. 
We anticipate that 120 of the 160 patients will have pre- and post-measurements 
of cognitive function. A two-tailed t-test conducted at the 0.05 level of significance 
(two-tailed) will have 80% power to detect a difference of 15.5. 
 REVISED POWER ANALYSIS 
Collection of measures of health-related quality of life and cognition is plagued with 
mistiming and drop-outs due to factors described in Section 9.1. 
For the purpose of the analyses that focus on the change in cognition between 
baseline and week 24, the follow-up assessment should have occurred within +/- 
4 week window of the scheduled week 24 assessment. 
With this adjustment, there are 94 patients (52 in Arm A and 42 in Arm B) that has 
pre- and post-measurements of cognitive function. Assuming a standard deviation 
of 30 units, a two-tailed t-test conducted at the 0.05 level of significance (two-tailed) 
will have 80% power to detect a difference of 17.6. 
9.5 
ADDITIONAL ANALYSES 
The analyses described in Section 9.3 will also be conducted within subgroups 
defined by WHO grade (original or revised), and tumor markers which have been 
captured in the study database.  Additionally, the joint effect of these clinical 
predictors, treatment assignment, and their interaction will be explored in the 
context of these models. 
10   SECONDARY OBJECTIVE: THROMBOCYTOPENIA 
The second secondary objective is to assess protection of bone marrow against 
chemotherapy-induced thrombocytopenia of standard RT and TMZ in combination with 
BMX-001 compared to standard RT and TMZ alone in newly diagnosed HGG patients. 


Page 14 of 21 
10.1  ENDPOINT 
The proportion of patients who experience grade 3 or 4 thrombocytopenia during 
concurrent temozolomide and radiation will be estimated within each treatment 
group. The proportion of patients who experience a platelet count less than 100K 
during concurrent temozolomide and radiation will also be estimated within each 
treatment group. The period of observation for these events will extend until 2 
weeks after completion of radiation treatment.  
10.2  METHOD OF ANALYSIS 
For both endpoints described in Section 10.1, a chi-square or Fisher’s exact test 
will be conducted to compare the prevalence of such thrombocytopenia observed 
in patients with and without BMX-001. 
10.3  POWER FOR THROMBOCYTOPENIA ENDPOINT 
 ORIGINAL POWER ANALYSIS 
Platelet counts will be obtained during radiation and temozolomide treatment and 
ending 2 weeks after termination of radiation. The percentage of patients within 
each treatment group that experience grade 3 or 4 thrombocytopenia will be 
estimated. Gerber [2] reports that 15% of patients who receive standard radiation 
and temozolomide experience grade 3 or 4 thrombocytopenia. With 80 patients 
per arm, there is 80% power with a one-tailed chi-square test (α=0.05) to detect a 
reduction in grade 3 or 4 thrombocytopenia from 15% in Arm B (without BMX-001) 
to 4% in Arm A (with BMX-001). 
 REVISED POWER ANALYSIS 
For this endpoint to have relevance, a patients must have received some treatment 
with temozolomide and radiation in either Arm A or B.  At this point, analyses 
suggest that 78 patients in Arm A and 71 patients in Arm B received protocol 
treatment. With 78 and 71 patients in Arms A and B, respectively, there is 80% 
power with a one-tailed chi-square test (α=0.05) to detect a reduction in grade 3 or 
4 thrombocytopenia from 15% in Arm B (without BMX-001) to 3.7% in Arm A (with 
BMX-001). 
11  SECONDARY OBJECTIVE: ADVERSE EVENTS (AE) 
The third secondary objective is to assess the safety and tolerability of standard RT and 
TMZ in combination with BMX-001 compared to standard RT and TMZ alone in newly 
diagnosed HGG patients.  The collection of adverse events was stopped 30 days after 
completion of chemoradiation treatment +/- BMX-001. Adverse events were coded by 
clinical center staff.   
11.1 ENDPOINTS 
The phase 2 portion of this study has two adverse event endpoints:  
(1) The proportion of patients who experience any grade 3 or 4 adverse event 
during radiation and temozolomide treatment, and  


Page 15 of 21 
(2) The proportion of patients who experience a grade 3 or 4 adverse event that 
is definitely, possibly, or probably related to BMX-001 treatment during this same 
period.  
Adverse events occurring between baseline through 2 weeks after discontinuation of 
radiation will be the focus of these analyses and will be summarized. 
11.2  METHOD OF SUMMARIZATION AND ANALYSIS 
 ADVERSE EVENTS DURING CHEMORADIATION 
Each participating institution coded adverse events with their preferred term and 
organ class using MedDRA system organ class. Whether or not the adverse event 
was related to BMX-001 was determined for each event. 
The initial summary of adverse events will consider all Treatment Emergent AE 
(TEAE) occurring during chemoradiation regardless of attribution to BMX-001. A 
TEAE is an event emerging during treatment having been absent pre-treatment or 
having worsened relative to pre-treatment. The period of observation that will be 
the focus of this tabulation will extend 2 weeks after termination of radiation 
treatment. 
The population for these summaries will be the safety population as defined in 
Section 6. 
For each study arm, the number of subjects with at minimum one Treatment 
Emergent AE (TEAE) will be tabulated by preferred term and MedDRA system 
organ class. Subjects with more than one TEAE will be counted only once, at 
casualty, for each system organ class /preferred term.  Multiple TEAEs in a subject 
will be counted once per system organ class and preferred term.  Summaries will 
be sorted by system organ class and decreasing total incidence of preferred term. 
 SERIOUS ADVERSE EVENTS DURING CHEMORADIATION 
Serious Adverse Events (SAEs) will be summarized by system organ class and 
preferred term.  A listing of the reasons for considering a SAE will be provided.  
Narratives of SAEs will be included.   
 ADVERSE EVENTS DURING CHEMORADIATION 
ATTRIBUTABLE TO BMX-001 
Given that this is an open-label treatment study, adverse events attributable to 
BMX-001 will only occur in patients within Arm A who receive BMX-001. 
For Arm A, the number of subjects with at least one BMX-001 related Treatment 
Emergent AE (TEAE) will be tabulated by preferred term and MedDRA system 
organ class. Subjects with more than one BMX-001 related TEAE will be counted 
only once, at casualty, for each system organ class /preferred term.  Multiple 
TEAEs in a subject will be counted once per system organ class and preferred 
term.  This summary will be sorted by system organ class and decreasing total 
incidence of preferred term. 


Page 16 of 21 
 OTHER SAFETY MEASURES AND TABULATIONS 
All AEs will be listed.  A listing of the relationship between system organ class and 
verbatim text will also be presented.   
Listings of the following data will be generated: 
• 
Clinical Laboratory Evaluations:  all laboratory values of clinical significance 
(as defined by site principal investigator) will be listed. 
• 
Vital signs:  Vital signs pre and post BMX-001 injection will be summarized.  
Only vital signs of clinical significance as defined by the site principal 
investigator will be summarized and listed.   
• 
Physical Examinations:  Abnormal physical examination findings of clinical 
significance will be summarized and listed.   
12  SECONDARY OBJECTIVE:  PROGRESSION-FREE 
SURVIVAL 
The fourth secondary objective is to assess the effect on progression-free survival (PFS) 
of standard RT and TMZ in combination with BMX-001 compared to standard RT and TMZ 
alone in newly diagnosed HGG patients. 
12.1   ENDPOINT 
Progression-Free Survival (PFS) is defined as the time between initiation of 
protocol treatment and disease progression or death. If the patient remains alive 
without disease progression, then PFS will be censored at last follow-up. Analyses 
similar to those described for OS will be generated for PFS.  
12.2    
METHOD OF ANALYSIS 
The primary analysis of PFS will consider all patients, and consider them in their 
assigned treatment arm regardless of compliance. This approach to analysis is 
consistent with an intent-to-treat analysis approach. 
As with survival, Kaplan-Meier methods will be used to graphically describe the 
distribution of PFS among patients within the BMX-001 treated group (Arm A) and 
within the control group (Arm B). Median PFS, as well as 6- and 12-month 
estimates of PFS will be estimated from the Kaplan-Meier curve. A logrank test will 
compare arms with respect to the PFS outcome. 
12.3 ADDITIONAL ANALYSES 
Analyses similar to those described in Section 8.5 will be conducted for PFS, 
including analyses within subgroups of patients defined by grade, histological 
subtype, and tumor markers which have been captured in the study database.  
Analyses will also explore the interaction between clinical factors and treatment 
assignment on the PFS outcome. 
13  SECONDARY OBJECTIVE: RADIOGRAPHIC RESPONSE 
The fifth secondary objective is to assess radiographic response in newly diagnosed HGG 
patients treated with standard RT and TMZ in combination with BMX-001 compared to 
standard RT and TMZ alone.  


Page 17 of 21 
13.1 ENDPOINT 
Radiographic response will be determined by brain MRI evaluations for 
assessment based on the RANO criteria. The radiographic response rate is 
defined as the proportion of patients of with a complete or partial response.  
13.2 METHOD OF ANALYSIS 
The response rate within each arm will be calculated and compared using a chi-
square test or an exact chi-square test. Exact binomial confidence intervals will be 
generated for each response rate estimate. 
The initial analysis of response rate will focus on the ITT patient population.  Those 
patients who did not receive treatment, or did not have a follow-up radiographic 
assessment will be included in the denominator for the calculation of response 
rate. These patients will not be counted a responders.   
13.3 ADDITIONAL ANALYSES 
Additional analyses will describe the response rate within patient subgroups 
defined by arm and WHO grade.  Response rate will also be summarized within 
the treated patient population. 
14  SECONDARY OBJECTIVE: PHARMACOKINETICS 
The sixth secondary objective is to characterize the repeated-dose pharmacokinetic profile 
of BMX-001 when delivered in combination with RT and TMZ in newly diagnosed HGG 
patients. 
Samples were obtained from the first 6 patients at Duke that are randomized to Arm A. 
Drug pharmacokinetics were obtained on Day 8 or the next day when drug is administered 
and Day 36 or the next day when drug was administered during the chemoradiation phase. 
Measures were obtained at the following time-points will be summarized: Pre-Dose, 0.5 
hour, 1 hour, 2 hours, 6 hours and 24 hours. 
15 EXPLORATORY OBJECTIVE: HEALTH-RELATED 
QUALITY OF LIFE (HRQoL) 
The first exploratory objective is to describe patient-reported outcomes of HRQoL in newly 
diagnosed HGG patients treated with standard RT and TMZ in combination with BMX-001 
compared to standard RT and TMZ alone. 
HRQoL was assessed by the Functional Assessment of Cancer Therapy-Brain (FACT-
BR) scale. The FACT-BR (version 4) contains subscales for  
• 
Physical well-being (7-items)  
• 
Functional well-being (7-items)  
• 
Emotional well-being (6-items) 
• 
Social/family well-being (7-items) 
• 
Brain cancer subscale (BCS; 23-items) which assess symptoms commonly 
reported by brain cancer patients [27].  
Cancer-related fatigue was assessed by the 13-item Fatigue Scale using the Functional 
Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) subscale, version 4 [67].  


Page 18 of 21 
Cognitive problems was assessed using version 3 of the Functional Assessment of 
Cancer Therapy-Cognition (FACT-Cog) subscale [68]. This includes subscales for: 
• 
Perceived cognitive impairments (20 items) 
• 
Comments from others (4 items) 
• 
Perceived cognitive abilities (9 items) 
• 
Impact of quality of life (4 items).  
Beck depression inventory (BDI) was used to evaluate for underlying depressive 
symptoms. We used the revised version (BDI-II) and the scores will range from 0 (no 
depression) to 63 (severe depression) [69]. The BDI contains 21 questions in regards to 
mood symptoms and is multiple-choice and self-reported.  
Exercise behavior was assessed using the Godin Leisure questionnaire [70].  
HRQoL PROs questionnaires were obtained at screening, after standard RT and TMZ 
(within 2 to 4 weeks), and approximately every 8 weeks when a subject returned for a 
Standard of Care visit during adjuvant TMZ. 
15.1 ENDPOINT 
Though the study is a longitudinal analysis, the initial focus of the analyses of this 
objective is an examination of the mean change in HRQoL between baseline and 
week 24 (occurs after completion of RT) within each treatment arm of the treated 
subjects.  
There is variability in the timing of follow-up measurements.  For the purpose of 
this analysis a +/- 4 week window will define the 24 week assessment. 
15.2 METHOD OF PRIMARY ANALYSIS 
The analyses that will be conducted are similar to those described in Section 9.3.  
For the analysis of change in HRQoL between baseline and week 24, an analysis 
of covariance will be conducted to compare treatment groups. The outcome of this 
model is change in cognitive function. Treatment group assignment will be included 
in the model as a predictor, and the baseline measure of HRQoL function will be 
included as a covariate.   
A linear random coefficient model stratified by drop-out pattern will assess whether 
HRQoL changes over time are consistent across treatment groups and drop-out 
patterns.  This pattern-mixture model accounts for within subject correlation of 
longitudinal assessments. 
If assumption for conducting these analyses fail, alternative analytic approaches 
will be considered include, a transformation of the outcome data, or nonparametric 
methods. 
Given the number of HRQoL tests that will be conducted, p-values will be adjusted 
for multiple comparisons. 
15.3 ADDITIONAL ANALYSES 
Additional analyses will explore the impact of BMX-001 on HRQoL within patient 
subgroups defined by WHO grade and histological subtype.  


Page 19 of 21 
16  EXPLORATORY OBJECTIVE: HAIR LOSS 
The second exploratory objectives is to describe changes in hair loss in newly diagnosed 
HGG patients treated with standard RT and TMZ in combination with BMX-001 compared 
to standard RT and TMZ alone. 
Subjective assessments of hair loss were obtained by the treating provider for subjects at 
screening (baseline), after standard RT and TMZ finishes (within 2 to 4 weeks), and 
standard of care (SOC) clinic visit (approximately every 8 weeks) during adjuvant TMZ.  
Qualitative assessments of hair loss depicted in longitudinal subject photographs will be 
conducted and summarized. Changes observed in Arm A will be compared to those 
observed in Arm B. 
The analyses group for this exploratory objective will include all treated patients who have 
both assessments of their hair at baseline and at one or more follow-up assessments. 
17 EXPLORATORY OBJECTIVE: WHITE MATTER 
INTEGRITY 
The third exploratory objective is to describe change in white matter integrity in newly 
diagnosed HGG patients treated with standard RT and TMZ in combination with BMX-001 
in comparison to standard RT and TMZ alone. 
17.1 ENDPOINT 
The mean change between baseline and each follow-up assessment for white 
matter integrity, as measured by MRI diffusion tensor/susceptibility imaging will be 
computed.  
These images will be obtained three times during the study: on day -5 to 0, after 
standard RT and TMZ (within 2 to 4 weeks), and 24 weeks after the start of 
standard RT and TMZ (within 2 to 4 weeks).  
17.2 METHODS OF ANALYSIS 
Assuming normality, analysis of variance or a repeated measures analysis may be 
used to compare change in Arms A and B. Additional analyses will be sub-divided 
in terms of WHO grade and histological subtype.  
18  PROTOCOL DEVIATIONS 
Before closing the database, data listings will be reviewed to determine whether data 
should be excluded from any of the analysis populations.   
As a part of this review, there may be a need to conduct sensitivity analyses that assess 
the impact on inferences when select patients are included or excluded from analyses. 
A summary of important protocol deviations such as the following will be generated: 
• 
Patient entered the study even though they did not meet inclusion/exclusion criteria 
• 
Met criteria for withdrawal but were not withdrawn (reason to be documented) 
• 
Patient received the wrong treatment or dose 
• 
Patient received an excluded concomitant medication 
 
 


Page 20 of 21 
19  DESCRIPTION OF TABLES FOR REPORTING 
The following tables and figures will be produced, source data listings will be provided 
 
Description 
Population 
Summary of Subject Disposition 
ITT, Safety, 
Treated 
Summary of Important Protocol Deviations* 
Safety 
DEMOGRAPHICS 
Summary of Demographic Characteristics 
ITT, Treated 
SAFETY DATA 
Summary of All AEs 
Safety 
Summary of TEAEs 
Safety 
Summary of BMX-001 Related TEAEs 
Safety 
Summary of Baseline AEs 
Safety 
Summary of all AEs 
Safety 
Summary of SAEs/Deaths 
Safety 
Narratives of SAEs 
Safety 
Summary of Pre and Post dosing Vital Signs 
Safety 
Listing of Abnormal ECG findings post BMX-001 
treatment 
Safety 
Summary of clinically significant: 
• 
Clinical Laboratory Evaluations 
• 
Physical Examinations:  Abnormal 
physical examination findings  
 
Safety 
Safety 
PK* 
PK 
OUTCOMES 
OS 
ITT, Treated 
PFS 
ITT, Treated 
Thrombocytopenia 
ITT, Treated 
Cognitive Testing 
ITT, Treated 
HRQoLs 
ITT, Treated 
OTHER 
Treatment Disposition:  TMZ, RT, BMX-001 
Safety 


Page 21 of 21 
Treatment Exposure:  TMZ, RT, BMX-001 
Safety 
Concomitant Medications 
Treated 
Analysis Sets, including subjects excluded from 
analysis 
All 
List of Withdrawals 
All 
*= BioMimetix will provide 
20  REFERENCES 
1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng 
HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO 
Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 
Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106. PMID: 34185076; PMCID: 
PMC8328013. 
2. Gerber DE, Grossman SA, Zeltzman M, Parisi MA, Kleinberg L. The impact of 
thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-
grade gliomas. Neuro Oncol 2007 Jan; 9(1):47-52. PMID: 17108062, PMC1828105. 
3. Ratain, M.J. and D.J. Sargent , Optimising the design of phase II oncology trials: the 
importance of randomisation. Eur J Cancer, 2009. 45(2): p. 275-80. 
4. Rubinstein, L.V., et al., Design issues of randomized phase II trials and a proposal for 
phase II screening trials.J Clin Oncol, 2005. 23(28): p. 7199-206. 
5. Rubinstein, L., et al., Randomized phase II designs. Clin Cancer Res, 2009. 15(6): p. 
1883-90.