Clinical trial NCT03168919
Conditions: Glioma
Sponsor: University of Alabama at Birmingham
Start date: 2016-10-06; Completion date: 2018-06-12
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The overall goal of this study is to determine if quantitative imaging techniques can be used to detect dynamic changes of morphology and different physiologic properties of the tumor during and after completion of radiation treatment and to predict site and time of radiation.

Detailed description:
Once eligibility criteria have been assessed and the informed consent is obtained, participants will undergo a screening process to further ensure eligibility. Screening prior to registration will comprise a review of pathology reports, postoperative magnetic resonance Imaging (MRI) images, operative reports, and medical history; general physical and neurologic exams; routine blood work; and urine pregnancy test for women of childbearing age.

The study is intended to evaluate the response of radiation treatment (RT). The consent process will be performed between the surgery and the start of RT. RT will be prescribed as per the discretion of the treating radiation oncologist as per the University of Alabama at Birmingham Department of Radiation Oncology treatment protocol in combination with temozolomide.

MRIs will be obtained before start of RT, after completion of 20 +/- 4 Gy. after completion of 40+/- 4 Gy and after the entire radiation treatment. Conventional MRIs including perfusion sequences and whole brain spectroscopy will be performed as a part of the research study. The data obtained from this research studies will not be used for clinical management.

Volumes of the enhancing component, non enhancing component, choline/N-acetyl aspartate (Cho/NAA) will be measure before, during and after RT as described before. Cerebral blood volume (CBV) of the tumor will also be calculated from perfusion imaging at each time point. Apparent diffusion co-efficient (ADC) of the tumor will be calculated from the diffusion imaging.

All the patients will be followed up with imaging and will be treated as per the standard of care. Patients will return for clinical evaluation and standard of care imaging approximately 4 weeks from the completion of the radiation therapy. After that, all the patients will be treated with standard of care maintenance temozolomide therapy and will return every 2-3 months for clinical evaluation and standard of care imaging.

At the time of recurrence, the recurrence site will be assessed and will be compared with the imaging parameters obtained during radiation treatment. Time to recurrence will also be calculated and will be correlated with the imaging parameters.

Arms: arm 1: This study has only one arm. The eligible subjects will receive standard of care fractionated radiation therapy along with concomitant temozolomide, which will NOT be changed based on the MRI scans obtained as a part of this study. There is no control or sham group.
Interventions: intervention 1: Fractionated Radiation intervention 2: Temozolomide intervention 3: MRI
Intervention descriptions: intervention 1: Standard of care fractionated radiation therapy will be given to the tumor. intervention 2: Standard of care temozolomide will be given along with radiation therapy intervention 3: Four MRI scan will be performed according to the protocol. The first one will be obtained before start of radiation therapy, the second MRI will be obtained after completion of 20 +/- 4 Gy, the third MRI will be obtained after completion of 40 +/- 4 Gy, and the final MRI will be obtained after completion of the radiation therapy.

Protocol documents:
Prot_SAP_000.pdf: 
Image-Based Quantitative Assessment of Acute Radiation-
Induced Changes in Glioblastoma Multiforme 
 
     Study Protocol & Statistical Analysis Plan  
 
 
 
 
   
 
 
 
 
        NCT03168919 
 
 
 
 
 
 
 
March 14, 2016 
 
 
 
 
Asim Bag, M.D., Principal Investigator 
 
 
  University of Alabama at Birmingham 
 
 
 
 
Birmingham, AL 35294 
 
 
 


[March 6, 19 
 
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Comprehensive Cancer Center 
University of Alabama at Birmingham 
Birmingham, Alabama 
 
Protocol UAB: 
[Image-Based Quantitative Assessment of Acute 
Radiation-Induced Changes in Glioblastoma Multiforme] 
 
 
 
Principal Investigator: 
Asim K. Bag, 
 
 
 
 
Assistant Professor of Radiology 
 
 
 
 
Department of Radiology 
 
 
 
 
619 19Th ST S; JT #N342 
 
 
 
 
Birmingham, AL 35249 
 
 
 
 
abag@uabmc.edu 
 
Co-investigators: 
Markus Bredel 
 
Professor of Radiation Oncology, 
 
University of Alabama at Birmingham Medical Center 
 
Birmingham AL, 35233 
 
mbredel@uab.edu,  
 
 
Louis Burt Nabors 
 
Professor of Neurology, 
 
University of Alabama at Birmingham Medical Center 
 
Birmingham AL, 35294 
 
bnabors@uab.edu 
 
 
John Fiveash 
 
Professor of Radiation Oncology, 
 
University of Alabama at Birmingham Medical Center 
 
Birmingham AL, 35233 
 
jfiveash@uab.edu 
 
Statistician: 
Bradford Jackson 
 
Instructor of Epidemiology, 
 
University of Alabama at Birmingham  
 
Birmingham AL, 35233 
 
bjackson@uabmc.edu 
 
Study-Coordinator 
Marianne Veterano 
 
University of Alabama at Birmingham Medical Center 
 
Birmingham AL, 35249-6830 
 
mvetrano@uabmc.edu 


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TABLE OF CONTENT 
 
 
1.0 
Introduction and Study Rationale ............................................. 
4 
2.0 
Objectives ................................................................................... 
6 
3.0 
Study Design Overview ............................................................. 
7 
3.1 
Study Design .............................................................................. 
7 
3.2 
Endpoints .................................................................................... 
9 
3.3 
Study Duration and Dates ......................................................... 
10 
3.4 
Safety and Efficacy Monitoring ................................................. 
10 
3.5 
Ethical Considerations .............................................................. 
11 
3.6 
Informed Consent ...................................................................... 
11 
3.7 
Confidentiality ............................................................................ 
11 
4.0 
Selection of Patients .................................................................. 
12 
4.1 
Number of Patients .................................................................... 
12 
4.2 
Inclusion Criteria ........................................................................ 
12 
4.3 
Exclusion Criteria ....................................................................... 
12 
4.4 
Patients of Reproductive Potential ........................................... 
12 
5.0 
Study Treatments ....................................................................... 
12 
6.0 
Study Procedures and Schedule .............................................. 
12 
6.1 
Screening Phase ........................................................................ 
12 
6.2 
Study Days .................................................................................. 
13 
6.3 
Follow-up .................................................................................... 
13 
6.4 
Enrollment and Randomization Procedures ............................ 
14 
7.0 
Efficacy and Safety .................................................................... 
14 
8.0 
Statistical Methods .................................................................... 
15 
8.1 
Sample Size ................................................................................ 
15 
9.0 
Protocol Amendments and Legal Aspects .............................. 
16 
9.1 
Protocol Amendments ............................................................... 
16 
9.2 
Approval of the Clinical Study Protocol and Amendments .... 
16 
9.3 
Closure of the Study .................................................................. 
16 
9.4 
Record Retention ....................................................................... 
16 
9.5 
Financial Disclosure .................................................................. 
17 
10.0 
Study Monitoring and Auditing ................................................. 
17 
11.0 
Documentation and Use of Study Findings ............................. 
17 
12.0 
Declaration of Sponsor and Investigator ................................. 
18 
13.0 
References .................................................................................. 
19 
 
 


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1.0 
INTRODUCTION AND STUDY RATIONALE 
 
 
 
Glioblastoma multiforme (GBM) is an extremely heterogeneous tumor with a 
rapidly fatal outcome with a median overall survival of 14.3 months from 
diagnosis. In spite of intense basic science research and numerous clinical 
trials, no therapy has emerged in the last decade that has prolonged the overall 
survival of GBM patients. Newly diagnosed GBM is currently treated with 
maximally safe resection followed by radiation therapy (RT) with concurrent 
temozolomide therapy followed by temozolomide maintenance therapy. 
Standard of care RT is prescribed to the tumor volume determined by magnetic 
resonance imaging (MRI) obtained before or immediately after tumor resection.  
No tumor physiologic information or adaptive tumor changes during RT are 
currently incorporated into the radiation treatment plan.  Standard fractionation 
(46 Gy in 23 fractions) RT is delivered to the peritumoral abnormal FLAIR 
volume followed by a sequential boost (14 Gy in 7 fractions) to the T1 contrast-
enhancing tumor volume. This approach disregards the biological complexity 
and intratumoral heterogeneity of this neoplasm in terms of angiogenesis, 
cellularity, and even the methylation status of the promoter of the O6-
methylguanine-DNA-methyltransferase (MGMT) gene, which has been shown 
to be predictive biomarker of response to conventional RT. In addition, the 
prescribed radiation dose is delivered to the tumor and peritumoral areas over 
6 weeks without monitoring response of the tumor during this treatment period. 
As a consequence, opportunities to readjust radiation dose, for example during 
the boost phase, to more radio-resistant areas in order to potentially prolong RT 
response of this extremely heterogeneous tumor are missed. Additionally, if the 
tumor becomes smaller in volume in response to RT, unnecessarily larger dose 
is given to potentially normal brain areas. 
 
 
 
The study is designed to assess the time course and magnitude of dynamic 
changes of morphology and distinct physiologic properties of GBM during and 
after completion of hypo-fractionated RT. MRIs obtained during therapy will be 
used to quantify during therapy patterns of dynamic changes of distinct 
physiological properties in response to RT. MRI obtained at completion will be 
used to quantify total effect of radiation to the tumor. Combined with follow-up 
evaluations of site of recurrence, progression time and overall survival, this 
study can establish quantitative imaging based biomarker of favorable treatment 
response and treatment resistance. These quantitative imaging biomarkers can 
be utilized to adopt a more scientific, quantitative tumor physiology based 
dynamic adaptive radiation planning compared to the current practice of pre-
treatment anatomy-based fixed dose RT. This approach of adaptive radiation 
can potentially allow dynamic readjustment of the dose to the relatively less 
responding tumor areas with simultaneous integrated boost, readjusting the 
target volumes or opt for an alternative radiation techniques and use of 
radiosensitizers as 6-week long RT progresses. In addition, our proposed 


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quantitative techniques can identify tumors poorly responding to RT that can 
allow institution of early additional or alternative therapy rather than waiting the 
tumors to recur, the current clinical standard. In addition to significant impact in 
planning RT, these quantitative imaging biomarkers can be used to predict 
response to RT, progression time, site of recurrence and overall survival. 
 
 
 
As no imaging is performed during the 6 weeks long course of hypo-fractionated 
RT of GBM, imaging changes of the contrast enhancing tumor volume and peri-
enhancing abnormal FLAIR volume related to RT are currently not known. There 
is no documentation of progressive change in tumor volume as therapy 
progresses. Neither is it known if there are progressive changes of tumor 
physiology with continued RT. It is also not known if the entire enhancing tumor 
volume and the entire non-enhancing tumor volume of this extremely 
heterogeneous tumor responds similarly to the prescribed radiation dose. We 
want to evaluate the morphologic as well as physiologic changes in response to 
radiation therapy in combination with temozolomide as described below:  
 
Morphologic changes: There are progressive changes of the size as RT 
progresses in cancers of other organ. As for example, in head and neck 
cancers with hypo-fractionated RT causes reductions of 51% in the clinical 
target volume and 48% in the planning target volume after a partial course (45-
Gy dose) of RT.1 However, we expect that there may be actual worsening of 
both the enhancing volume and the peritumoral abnormal FLAIR volume 
secondary to radiation induced release of cytokines and vasodilation.2 
 
Post contrast 3DT1 weighted sequence and 3d FLAIR sequence is routinely 
used to calculate different target volumes and can be used to quantify 
morphologic changes of the enhancing tumor volume and peri-enhancing 
abnormal FLAIR volume as therapy progresses.  
 
Physiologic changes:  
Diffusion-weighted MRI (DWI) is an MRI method that produces in vivo 
images of biologic tissues based on the detection of a change in the random 
motion of water protons.3,4 Free and random diffusion of water is impeded by 
cell membrane that is an integral part of the cellular architecture.5 Apparent 
diffusion coefficient (ADC) map, one of the many different parameters 
calculated from diffusion imaging, represents a measure of average water 
diffusion for each voxel.6 As tumor cellularity increases with increasing grade 
of a tumor, the impeding effect of cell membranes on water diffusion is 
expected to increase, resulting in lower total diffusion in a given voxel and thus 
decreasing the ADC value. An inverse correlation exists between tumor 
cellularity and ADC value.7 Lower ADC value has been associated with poor 
survival independent of the WHO grading status of the astrocytomas.5 During 
routine follow-up of GBM patients after completion of RT, an ADC value of 


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≤1.09 10-3mm2s-1 has been shown to differentiate radiation related changes 
from recurrent tumor.8  
Perfusion MRI is a technique that can provide physiologic information about 
vascular endothelial proliferation, vascular density, and angiogenesis.9 
Vascular proliferation is an important factor in the biology of GBM, and degree 
of new blood vessel formation increases with higher grades of tumor. Since 
DSC perfusion MRI can assess new vessel formation, it has been successfully 
used to assess grading of the astrocytomas10 and prediction of survival. In fact 
higher normalized CBV, a parameter generated from DSC perfusion MRI 
correlates with survival regardless of WHO grading status of the tumor. 
Tumors with a high initial relative CBV have more rapid progression than those 
who have gliomas with a low relative CBV.11 Fractional tumor burden can be 
calculated from the perfusion MRI that can reliably differentiate radiation 
related changes from residual tumor.12  
 
MR spectroscopy is a powerful tool in in investigating tumor biology.13 
Specifically, elevation in choline (Cho) with depression of N-acetylaspartate 
(NAA) is a reliable indicator of tumor. Metabolite ratios of Cho/creatine (Cr), 
NAA/Cr, and Cho/NAA are useful in grading tumors and predicting tumor 
malignancy.14 In addition, there is direct correlation between Cho level and 
cellular proliferative index.15,16 MR spectroscopy has also been used to 
differentiate radiation related changes from recurrent tumor in the post-
treatment setting. CNI >1.8 has been shown to reliable differentiate tumor from 
radiation related changes with sensitivity of 84%, specificity of 75% and 
diagnostic accuracy of 81%.17 
 
 
 
2.0 
OBJECTIVES 
 
 
Primary: 
 
Determine the time course and magnitude of MRI measures of enhancing volume, 
(with 3DT1), non-enhancing abnormal FLAIR volume (with 3D FLAIR), tumor 
cellularity (with ADC), tumor angiogenesis (with nCBV), and chemical environment 
of enhancing and non-enhancing tumor during the course of hypofractionated RT. 
 
 
Secondary: 
 
Determine whether multi-parametric imaging assessment during RT and 
immediately after completion of RT can predict time to recurrence, site of 
recurrence and overall survival. 
 
 
Determine whether imaging changes in tumor with methylated MGMT promoter 
region differs from tumors with unmethylated MGMT promoter region. 
 
 


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3.0 
STUDY DESIGN OVERVIEW 
 
 
3.1 
Study Design 
 
 
 
Patient source: Once the study is funded, consecutive 20 patients with newly 
diagnosed GBM patients scheduled to have RT will be included in the study with the 
following inclusion and exclusion criteria. The patients will be screened from the 
radiation oncology department schedule.  
 
Patient selection 
Inclusion criteria:  
1) Newly diagnosed primary GBM, based on pathology confirmation;  
2) At least 8 cm3 of residual enhancing tumor after surgery (As seen on immediate 
postoperative scan);  
3) Scheduled to receive standard fractionated RT with concomitant temozolomide 
therapy;  
4) Karnofsky Performance Score > 60.  
 
Exclusion criteria: 
 1) Scheduled to receive investigational chemotherapy, immunotherapy, or any other 
investigational agents;  
2) Placement of GLIADEL® wafer in the resection cavity;  
3) Significant amount of hemorrhage within the resection cavity (seen on immediate 
post-operative scan);  
4) A large peritumoral infraction related to surgery (identified by new confluent diffusion 
restriction);  
5) Not suitable to undergo MRI or use the MRI contrast agent (GFR<30 mL/min/1.73 
m2); or the patient has known anaphylactic reaction to gadolinium based contrast 
agents. 
6) Presence of serious systemic illness, including: uncontrolled infection, uncontrolled 
malignancy, significant renal disease, or psychiatric/social situations, which might 
impact the survival endpoint of the study or limit compliance with study requirements. 
 
 
Patient Accrual Process: Once eligibility criteria have been assessed and the 
informed consent is obtained, participants will undergo a screening process to further 
ensure eligibility. Screening prior to registration will comprise a review of pathology 
reports, postoperative MR images, operative reports, and medical history; general 
physical and neurologic exams; routine blood work; and urine pregnancy test for women 
of childbearing age.  
 


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Radiation Treatment: RT will be prescribed as per the discretion of the treating 
radiation oncologist as per the University of Alabama at Birmingham Department of 
Radiation Oncology treatment protocol in combination with temozolomide. The target 
volumes will be contoured in the conventional way based on the pre-surgery standard of 
care MRI in combination with the immediate post surgery MRI obtained within 1-2 days 
after surgery. Enhancing volume will be treated with 60 gray and non-enhancing tumor 
volume will be treated with 46 Gy with daily 2 Gy hypo-fractionated regimes. The margin 
of the abnormal FLAIR volume will be decided at the discretion of the prescribing 
radiation oncologist. Multiple MRIs obtained, as a part of this research project will not be 
used in clinical decision-making. Precisely, there will be no change in the prescribed 
radiation dose, or the radiation planning based on the MRIs obtained during 
treatment. The patient will be taken care of and followed as per the department 
protocol. 
Figure 1 – Study Design 
 
 
 
 
 
Timing   of acquisitions: The following MRI sequences will be obtained at the baseline 
(scan#1) (the previous day or on the day of starting RT) after completion of 20 Gy 
(scan#2), after completion of 40 Gy (scan#3) and after completion of 60 Gy (scan#4).  
All the following imaging sequences will be with a 3T Siemens MRI system (Siemens 
Prisma, Siemens AG, Erlangen, Germany).  
 
Imaging parameters:  


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Precontrast 3DT1 sequence: 3D spoiled gradient echo T1 weighted sequence will be 
performed using the standard parameters.  
 
3D FLAIR sequence: A 3D FLAIR imaging will be obtained in the sagittal plane using 
the standard parameters.  
 
Diffusion Imaging: Routine diffusion weighted imaging will be obtained with B1000 using 
three diffusion gradients in the three orthogonal planes using standard parameters. 
 
Echoplanar spectroscopy imaging: We will obtain point resolved echo-planar 
spectroscopy using a 20 channel head coil with TE/TR 70/1550 ms with acquisition time 
of 16 minutes as described by Ding et al.18 After correction for oversampling in the 
readout spatial and spectral dimensions, the resultant images were equivalent to 50 x 
50 voxels in-plane and 18 slices, over a field-of-view of 280 x 280 x 180 mm, with 
selection of a slab of 140 mm covering the whole brain. Subsequent to spatial 
smoothing, the effective voxel volume will be approximately 1 ml. The acquisition will 
also include a second dataset obtained in an interleaved manner without water 
suppression and using excitation and gradient-echo observation. This data will provide 
a water reference signal with identical spatial parameters.   
 
Dynamic contrast enhanced susceptibility weighted perfusion imaging: The dynamic 
contrast enhanced T1 weighted perfusion imaging will be obtained first to use as 
proposing. The dynamic contrast enhanced susceptibility weighted perfusion imaging 
will be obtained during the bolus injection of additional 0.05 mmol/kg Prohance at 4ml/s, 
followed by a 20 ml saline flush with the following parameters: TR/TE in ms: 1900/40; 
192 x 128 acquisition matrix, flip angle of 72°, slice thickness 3 mm, total of 20-24 
slices. A total of 60 dynamics will be obtained. 
 
Postcontrast 3DT1 sequence: 3D spoiled gradient echo T1 weighted sequence (exactly 
similar to the precontrast 3DT1 weighted sequence will be obtained after the 2 perfusion 
sequences will be performed using the standard parameters.  
 
Image archiving: 
All the acquired raw images will be permanently saved in the Department of Radiology 
PACS system. The post-processed images will be saved in the primary investigator’s 
office computer, which has access only the primary investigator, rather than to the 
PACS because clinical significance of the processed images is not known at the current 
time. Additionally, post-processing of the raw data takes significant amount of time and 
the end result may not be available before completion of radiation therapy.  
 
 
Patient follow-up 
All the patients will be followed up and treated as per the standard of care. Patients will 
return for clinical evaluation and standard of care imaging approximately 4 weeks from 


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the completion of the radiation therapy. After that, all the patients will be treated with 
standard of care maintenance temozolomide therapy and will return every 2 months for 
clinical evaluation and standard of care imaging. The follow up has been detailed below 
in the section 6.3.  
 
3.2 
Endpoints 
 
 
 
Primary: 
The primary endpoint for this analysis is based on CNI, which is a continuous variable 
and will be calculated MR spectroscopy from the 4 scans during radiation. We want to 
demonstrate how change in CNI correlates with time to progression and overall survival. 
CNI of GBM is typically very high due to high cellularity. As tumor cellularity is expected 
to decline with continued radiation therapy, we expect that the CNI will decrease over 
time as radiation therapy progresses. Pattern of change of CNI from baseline to the end 
of radiation therapy is expected to correlate time progression and overall survival. The 
patients will be followed up for 24 months from the diagnosis or until death for the 
progression data and the overall survival data.  
  
Secondary: 
Secondary endpoints include change of volume, change of ADC, and change of CBV. 
These endpoints including the primary endpoints are anticipated to change 
simultaneously in response to radiation. Change of tumor volume will be measured using 
3D T1 sequence, Change of ADC, a continuous variable, is calculated from diffusion 
imaging, change of CBV, also a continuous variable, is measured from perfusion MRI. 
We want to demonstrate how changes in these parameters correlate with time to 
progression and overall survival. 
 
Exploratory: 
The exploratory objectives of this study are to examine the time to first recurrence, 
evaluate the location of the recurrence, as well as the overall survival. Time to first 
recurrence is defined as the time from diagnosis to the date of the first documented tumor 
recurrence. The location of the recurrence will be assessed on the follow-up MRI. Overall 
survival is defined as the time between the date of diagnosis and the date of death due 
to any cause. Any subjects who have not died will be censored at the last known alive 
date.  
 
3.3 
Study Duration and Dates 
 
 
 
Study Inclusion: 9 months 
Study duration:  3 years 
 
 
 
3.4 
Safety and Efficacy Monitoring 
 
 
 


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We will perform 4 MRIs during the course of the radiation therapy as a part of this research 
study. Each of these 4 research MRIs possesses no additional risk compared to the 
standard MRI techniques. Each MRI will be obtained with gadolinium based contrast 
administration approved for clinical usage. We will use gadoteridol (Prohance, Bracco 
Diagnostics Inc. NJ) 
 
As described above, risks associated with the research MRIs are no different from the 
risks associated with a routine clinical MRI. If any adverse event occurs, the patient will 
be excluded from the study for the subject’s best interest. Additionally, the subject may 
withdraw himself/herself his/her consent at any point of time. All the standard MRI safety 
precaution will be taken before the image acquisition. As we do not anticipate any adverse 
event related to the research sequences, no specific precaution related to this study is 
needed. We will closely monitor the patient during the scanning. Appropriate patient care 
will be taken should there any adverse event. 
 
This study is aimed to quantify response of standard clinical treatment using advanced 
MRI technique and has NO therapeutic component. The change seen on the imaging 
during therapy will not be used for any clinical decision making as we do not know the 
clinical significance of these changes. 
 
The included subjects will be monitored for potential side effects of contrast injection as 
per clinical standards. Any side effects, which has been described in <1% of patients, will 
be managed as per clinical standards.  
 
In addition, gadolinium contrast agents have been associated with nephrogenic systemic 
fibrosis in patients with severe renal functions. We will not include any subject in this study 
with chronic severe kidney disease (GFR<30 mL/min/1.73 m2) or acute kidney injury.  
 
3.4.1 Independent Data Monitoring Committee 
 
 
 
NA 
 
 
 
3.5 
Ethical Considerations 
 
                     This study will be conducted in accordance with Good Clinical Practice, the 
Declaration of Helsinki, and 21CFRPart50 – Protection of Human Patients, Part 56 
–Institutional Review Boards, and the other applicable local ethical and legal 
requirements. 
 
 
The Ethics Review Committee/Institutional Review Board (IRB) must be constituted 
according to Code of Federal Regulations (CFR).  


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The IRB will be informed by the principal Investigator of all subsequent protocol 
amendments and of serious or unexpected AEs occurring during the study, which 
are likely to affect the safety of the patients or the conduct of the study. 
 
3.6 
Informed Consent 
 
 
The principles of informed consent in the current edition of the Declaration of 
Helsinki will be implemented in this study.  A written informed consent will be 
obtained in accordance with 21CFR50.25 and 21CFR50.27 before the protocol – 
specified procedures are carried out.  Patients, their relatives, guardians or, if 
necessary, legal representatives must be given ample opportunity to inquire about 
details of the study.  
 
 
The consent form generated by the Principal Investigator must be approved (along 
with the protocol) by the applicable IRB.  Consent forms must be in a language 
fully comprehensible to the prospective patient.  The consent form should be 
signed and dated by the patient or the patient’s legally authorized representative, 
and the investigator.  Each patient’s signed informed consent form must be kept 
on file by the investigator for possible inspection by Regulatory Authorities and 
sponsor (UAB). 
 
3.7 
Confidentiality 
 
 
Patient names will not be supplied in the sponsor data.  Only the patient number 
and patient initials will be recorded in the CRF, and if the patient name appears 
on any other document (e.g., laboratory report), it must be obliterated on the copy 
of the document to be supplied by the sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The 
patients will be informed that representative of the sponsor, independent IRB, or 
regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
 
 
The investigator will maintain a personal patient identification list (patient numbers 
with the corresponding patient names) to enable records to be identified. 
 
 
4.0 
SELECTION OF PATIENTS 
 
4.1 
Number of Patients 
 
 
Approximately 20 patients should be enrolled and treated in this study.  It is 
planned to recruit this sample in 9 months. 
 


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4.2 
Inclusion Criteria 
 
 
 
See above. 
4.3 
Exclusion Criteria 
 
 
 
 
 
See above. 
 
4.4 
Patients of Reproductive Potential 
 
 
The patient must not be pregnant or breast-feeding at enrollment in the study.  
Absence of pregnancy must be demonstrated by serum or urine testing prior to 
radiation therapy. 
 
 
Female patients of child bearing potential (i.e., ovulating, premenopausal, not 
surgical sterile) must use a medically accepted contraceptive regimen.  Male 
patients must agree to use a medically approved method of contraception. 
 
 
If a female patient becomes pregnant during the study, the subject will be 
withdrawn from the study. 
 
 
5.0 
STUDY TREATMENTS 
 
 
This is an observational study attempting quantification of imaging changes related 
to STANDARD radiation treatment given with temozolomide.  No investigational 
therapy will be given to the study subjects.  
 
 
6.0 
STUDY PROCEDURES AND SCHEDULE 
 
6.1 
Screening Phase 
 
 
Each potential patient will be examined before the start of the study to determine 
their eligibility for participation by the investigators. Vital signs and complete blood 
count will be obtained during radiation treatment as per the clinical standard of 
care. Female patients of childbearing age will be tested for serum beta-hCG. 
 
 
6.2 
Study Days 
 
 
 
 
The following tests/procedures will be completed prior to each MRI: 


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(1) 
Vital signs: The research coordinator will take the vital signs before the 
MRI.  
 
6.3 
Follow-up 
 
The final intervention as a part of this research study is to acquire the 4th MRI, 
which we plan to obtain at the completion of the current clinical standard of care 
radiation therapy. No therapy is part of this study. However, all included subjects 
will be followed-up for 24 months from the time of diagnosis. During the follow-up 
period each patient will be imaged and evaluated according to clinical standard of 
care.  We will document the followings: 
 
 
Progression: We will assess time to progression as well as site progression. 
 
 
Progression will be determined by the RANO19 criteria as described in the Table 
1: 
 
Criteria for Determining First Progression Depending on Time From Initial 
Chemoradiotherapy 
 
First Progression 
Definition 
Progressive 
disease < 12 weeks 
after completion of 
chemoradiotherapy 
Progression can only be defined using diagnostic imaging if 
there is new enhancement outside of the radiation field (beyond 
the high-dose region or 80% isodose line) or if there is 
unequivocal evidence of viable tumor on histopathologic 
sampling (eg, solid tumor areas [ie, > 70% tumor cell nuclei in 
areas], high or progressive increase in MIB-1 proliferation index 
compared with prior biopsy, or evidence for histologic 
progression or increased anaplasia in tumor). Note: Given the 
difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of 
radiographic or histologic confirmation of progression, will not 
be sufficient for definition of progressive disease in the first 12 
weeks after completion of concurrent chemoradiotherapy. 
Progressive 
disease ≥ 12 weeks 
after 
chemoradiotherapy 
completion 
• New contrast-enhancing lesion outside of radiation field on 
decreasing, stable, or increasing doses of 
corticosteroids. 
• Increase by ≥ 25% in the sum of the products of 
perpendicular diameters between the first 
postradiotherapy scan, or a subsequent scan with 
smaller tumor size, and the scan at 12 weeks or later on 
stable or increasing doses of corticosteroids.  
• Clinical deterioration not attributable to concurrent medication 


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or comorbid conditions is sufficient to declare 
progression on current treatment but not for entry onto a 
clinical trial for recurrence.  
• For patients receiving antiangiogenic therapy, significant 
increase in T2/FLAIR nonenhancing lesion may also be 
considered progressive disease. The increased 
T2/FLAIR must have occurred with the patient on stable 
or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy 
and not be a result of comorbid events (eg, effects of 
radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other 
treatment effects).  
Abbreviation: FLAIR, fluid-attenuated inversion recovery. 
 
 
  
 
Time to progression and the site of recurrence will be documented. 
 
Survival: After the first recurrence, the study will ONLY document the survival time. No 
other patient parameter will be recorded for this study. 
 
6.4 
Enrollment and Randomization Procedures 
Eligible patients will be enrolled into the study through the UAB Department of Radiology 
Research Administration office (Phone: (205) 934-4080). After the patient is scheduled to 
have the radiation therapy, the investigators will evaluate for inclusion and exclusion 
criteria. When a subject meets the inclusion and exclusion criteria, one of the investigators 
will communicate with the potential subjects describing the study. If a subject is interested, 
a consent form will be sent the patient using UAB Patient Portal. The research coordinator 
from the Radiology Research Administration office will consent the subjects.   
 
 
This study is not a RANDOMIZED study. 
 
 
 
7.0 
EFFICACY AND SAFETY 
 
 
 
No investigational drug will be administered as a part of this trial. We are not 
measuring any efficacy of any treatment modality either as a part of this research 
study.  
 
 
8.0 
STATISTICAL METHODS  


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Based on the number of subjects (n=20), our statistical analysis will be largely descriptive 
and explanatory. Descriptive summary statistics tabulations will be generated for each 
time point. Means, standard deviations, median, and interquartile ranges will be 
generated for continuous variables, and frequency and percentages will be generated for 
categorical variables. For the primary outcome variable, in order to evaluate the within-
subjects changes over time we will assess the pair-wise differences between time points 
using paired t-test, and may also perform repeated measures analysis of variance 
(ANOVA) on the continuous outcomes and account for the correlative nature of the 
repeated measurements with the caution and understanding of the limited sample size.  
 
The Kaplan-Meier approach will be used to produce survival curves as well as the median 
and corresponding 95% confidence limits for time to first recurrence as well as overall 
survival. Subjects who have not had an event will be censored at the last known date 
available.  
 
The location of recurrence will be reviewed and classified to then be presented in terms 
of frequencies and percentages to determine if there can be any dichotomization scheme 
created.  Based on the potential dichotomization, we may use chi-square tests and logistic 
regression to examine how other factors may be potentially associated with the site of 
recurrence. 
 
Distributional assumptions of the statistical analysis will be verified, and if the 
assumptions are not met, then non-parametric analogs will be considered. Statistical 
significance will be determined based on the two-sided level of significance at the 0.05 
level. All analyses will be performed using statistical analysis software SAS version 9.4. 
 
 
8.1 Sample size 
There were no formal sample size calculations performed for this study, however based 
on the anticipated number of subjects (n=20), if we assume the largest changes in volume 
to be between the first and fourth time points, and consider the paired difference in means 
with correlation ranging from weak to moderate (rho=0.1 – 0.6) we anticipate having 66-
88% power to detect statistically significant differences at the 0.05 two sided level of 
significance.  
 
 
 
 
9.0 
PROTOCOL AMENDMENTS AND LEGAL ASPECTS 
 
 
 
9.1. 
Protocol Amendments 
 


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Once the study has started, amendments should be made only in 
exceptional cases.  The changes then become part of the clinical study 
protocol. 
 
 
9.2 
Approval of the Clinical Study Protocol and Amendments 
 
 
 
Before the start of the study, the clinical study protocol, informed consent 
document, and any other appropriate documents will be submitted to the 
IRB with a cover letter for a form listing the documents submitted, their dates 
of issue, and the site (or region or area of jurisdiction, as applicable) for 
which approval is sought.  If applicable, the documents will also be 
submitted to the authorities, in accordance with local legal requirements. 
 
 
 
 
 
 
9.3 
Closure of the study  
 
 
The study must be closed at the site on completion.  Furthermore, the 
sponsor or the investigator has the right to close this study site at any time.  
As far as possible, premature closure should occur after mutual 
consultation.   Depending on local legislation, it may be necessary to inform 
IRB and the regulatory authorities when the study site is closed. 
 
 
Study materials must be returned, disposed of or retained as directed by 
the sponsor. 
 
 
9.4 
Record Retention 
 
 
The investigator must obtain approval in writing from the sponsor before 
destruction of any records. 
 
 
Essential documents should be retained until at least 5 years after the 
closure of the study. 
 
 
Essential documents include: 
 Signed informed consent documents for all patients. 
 Patient identification code list and enrollment log. 
 Record of all communications between the investigator and the IRB. 
 Record of all communication between the investigator and the Principal 
Investigator or Designee. 
 List of subinvestigators and other appropriately qualified person to 
whom the investigator has delegated significant trial-related duties, 
together with their roles in the study and their signatures. 


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 Copies of CRFs and of documentation of corrections for all patients. 
 All other source documents (patient medical records, laboratory records, 
etc.). 
 
 
 
9.5 
Financial Disclosure 
 
No financial disclosure.    
 
 
 
10.0 STUDY MONITORING AND AUDITING 
 
 
This is an investigator-initiated study. 
 
11.0 DOCUMENTATION AND USE OF STUDY FINDINGS 
 
 
 
11.1 Documentation of Study Findings 
 
 
All study findings will be documented in an excel file and will be saved in a 
password protected computer at the principal investigator’s office.  
 
 
11.2 Use of Study Findings 
 
 
The study findings will be used as preliminary data for application of 
extramural grant and will be also be presented in appropriate national 
meetings. Manuscripts will also be written for scientific publications. 
 
 
12.0 DECLARATION OF SPONSOR AND INVESTIGATOR 
 
 
12.1 Declaration of Sponsor 
 
 
This is an investigator-initiated study. 
 
12.2 Declaration of Investigator 
 
 
I confirm that I have read the above protocol.  I understand it, and I will work 
according to the principles of GCP as described in 21 CFR parts 50, 54, 56, 
and 312 and according to applicable local requirements. 
 
 
Investigator 
 
 
Date: 1/26/16 
 
Signature: 
 
 
 
 
 


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Name (block letters): 
Asim K Bag. MD 
 
 
 
 


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13.0 REFERENCES 
 
 
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