Accurate DCE-MRI Measurement of Glioblastoma Using Point-of-care Portable Perfusion Phantom
Phase: NA
Conditions: Glioblastoma
Sponsor: University of Alabama at Birmingham

May 11, 2023 
 
1 
 
O’Neal Comprehensive Cancer Center 
University of Alabama at Birmingham 
Birmingham, Alabama 
 
Title: Accurate DCE-MRI Measurement of Glioblastoma using Point-of-care Portable Perfusion Phantom 
 
 
TABLE OF CONTENTS 
 
 
 
 
1.0 
INTRODUCTION AND STUDY RATIONALE 
 
 
 
 
2.0 
OBJECTIVES 
 
 
 
 
3.0 
INVESTIGATIONAL PLAN 
 
 
 
 
4.0 
SELECTION OF PARTICIPANTS 
 
 
 
 
5.0 
STUDY TREATMENTS 
 
 
 
 
6.0 
STUDY PROCEDURES AND SCHEDULE 
 
 
 
 
7.0 
SAFETY 
 
 
 
 
8.0 
STATISTICAL METHOD 
 
 
 
 
9.0 
CLOSURE OF THE STUDY 
 
 
 
 
10.0 
REFERENCES 
 
 
 
 
 
Harrison Kim, Ph.D., M.B.A. 
National Cancer Institute 
 
University of Alabama at Birmingham 
Study Supported By 
O’Neal Comprehensive Cancer Center 
 
 
1670 University Blvd 
UAB 
 
Birmingham, AL  35294-3300 
Study Sponsor 
Tel (205-996-4088); Fax (205-975-6522) 
 
Principal Investigator 
 
 
 
Yufeng Li 
 
 
 
Biostatistician 
Sub-Investigators 
Mina Lobbous, MD 
Kristen Riley, MD 
Houman Sotoudeh, MD 
Burt Nabors, MD 
 
 
John, Fiveash, MD 
 
 
Research Nurse Coordinator 
April Riddle 
Quenteeria Mooney 
Sebastian Eady 
 
 
 
 
 

May 11, 2023 
 
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TABLE OF CONTENT 
 
 
1.0 
Introduction and Study Rationale ........................................................ 
3 
2.0 
Objectives................................................................................................ 
5 
2.1 
Primary ................................................................................................... 
5 
2.2 
Secondary................................................................................................ 
6 
3.0 
Investigational plan ................................................................................ 
6 
3.1 
Study Design ........................................................................................... 
6 
3.2 
Primary Endpoints................................................................................. 
7 
3.3 
Study Duration ....................................................................................... 
7 
3.4 
Safety and Efficacy Monitoring ............................................................ 
7 
3.5 
Therapy modification ............................................................................ 
7 
3.6 
Ethical Considerations........................................................................... 
7 
3.7 
Informed Consent .................................................................................. 
7 
3.8 
Confidentiality ........................................................................................ 
8 
4.0 
Selection of Participants ........................................................................ 
8 
4.1 
Number of Participants ......................................................................... 
8 
4.2 
Inclusion Criteria ................................................................................... 
8 
4.3 
Exclusion Criteria .................................................................................. 
8 
4.4 
Participants of Reproductive Potential ................................................ 
8 
5.0 
Study Treatments ................................................................................... 
9 
6.0 
Study Procedure and Schedule ............................................................. 
9 
7.0 
Safety ....................................................................................................... 
10 
8.0 
Statistical Method .................................................................................. 
11 
9.0 
Closure of the Study............................................................................... 
12 
10.0 
References ............................................................................................... 
12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

May 11, 2023 
 
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1.0 
INTRODUCTION AND STUDY RATIONALE 
Glioblastoma is the most common primary malignant type of brain tumor in adults (2).  
Surgical tumor resection followed by chemoradiation therapy is the standard of care for patients 
with glioblastoma, but its prognosis is still fairly dismal (median survival time = 15 months) (3, 
4).  One major concern that prevents effective treatment management is the difficulty of 
differentiating between pseudo-progression and true-progression (5).  Pseudo-progression occurs 
in about 20-30% of glioblastoma patients typically within 3 months after radiotherapy with or 
without chemotherapy has been completed (6). Pseudo-progression is a local inflammatory 
reaction caused by irradiation and enhanced by concurrent chemotherapy, which leads to a 
transient increase of blood brain barrier (BBB) permeability (7, 8). The BBB, however, is also 
disrupted by neoplasm (9). Therefore, both pseudo- and true-progressions appear with an increased 
contrast enhancement in MRI, and there are currently no established techniques to differentiate 
between them (5).  Pseudo-progression is typically known to be associated with better clinical 
outcomes (10). Thus, as illustrated in Fig. 1, pseudo-progression mistaken for true-progression 
results in the discontinuation of an effective therapy, while true-progression mistaken for pseudo-
progression leads to the continuation of an ineffective therapy that may induce adverse side effects.   
 
 
 
 
 
 
 
 
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has the potential to 
differentiate between pseudo- and true-progressions in glioblastoma (11-13).  The contrast-
enhancing lesions of pseudo-progression are due to inflammatory BBB disruption (7, 8), whereas 
those of true-progression are caused by neoplastic BBB disruption (9).  Therefore, true-
progression typically presents higher perfusion than pseudo-progression (11-13).  Dynamic 
susceptibility contrast (DSC) MRI is the most common technique for a non-invasive assessment 
of blood perfusion in the brain (14, 15).  However, hemorrhagic changes within the resection 
cavity after surgery causes susceptibility artifacts, which often interfere with DSC-MRI, leading 
to false interpretation (16-18).  On the other hand, DCE-MRI can assess the blood perfusion with 
minimal susceptibility artifacts (19-22), thus DCE-MRI may differentiate glioblastoma 
progression better than DSC-MRI (11).  
However, the measurement variability across different MRI scanners remains a serious 
concern, as it hinders data comparison among institutes to retrieve a reliable threshold for accurate 
prognosis and subsequent treatment optimization (23).  Each MRI vendor provides unique 
hardware configurations, pulse sequences and reconstruction algorithms, which cause variations 
in the quantitation of tissue contrast-agent concentration and, consequently, the DCE-MRI 
parameters (23).  An external phantom with a known contrast-agent concentration may allow us 
to detect and correct the variation.  Since the DCE-MRI measurement may drift due to hardware 
instability (24), it would be ideal if the phantom could be miniaturized to be imaged concurrently 
in the bore of a standard MRI scanner with a patient for real-time quality assurance.   
Fig. 1. Misdiagnosis of glioblastoma progression. Pseudo-progression mistaken for true-
progression results in the discontinuation of an effective therapy, while true-progression 
mistaken for pseudo-progression leads to the continuation of an ineffective therapy.  

May 11, 2023 
 
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The use of a static phantom comprised of multiple objects with different contrast-agent 
concentrations was originally suggested to correct the variation in quantitating contrast-agent 
concentrations of tissues (25).  However, a static phantom may not serve as a reliable standard 
for dynamically changing tissue contrast-agent concentration, because a) the movement of contrast 
agents in vivo causes additional signal reduction that cannot be replicated by a static phantom, b) 
the number of data points obtained from a static phantom is small, leading to larger fitting errors, 
and c) most B1 mapping techniques are T1 dependent, thus the nominal flip angle delivered to a 
static phantom with high contrast-agent concentration cannot be accurately measured, especially 
in high field MRI (≥3T) (26-29).  Therefore, a perfusion phantom with a varying contrast-agent 
concentration is required for accurate correction of MRI system-driven error.  A few perfusion 
phantoms have been developed (30, 31), but these phantoms are too bulky to be simultaneously 
imaged with a human subject.  In addition, these large phantoms are costly and not easily 
operable by typical MRI technologists, limiting the potential for widespread and routine clinical 
use.  We recently developed a perfusion phantom named P4 (Point-of-care Portable Perfusion 
Phantom) that significantly reduces variation in quantitating the perfusion of human tissues across 
different MRI scanners (1).  Figure 2A is a photograph of the P4 with its dimensions.  The P4 
is composed of top and bottom chambers with a semi-permeable membrane placed between them.  
Both chambers are filled with degassed/deionized water before use.  After starting DCE-MRI, an 
MRI contrast agent is infused to the top chamber at a constant rate using a syringe pump.  The 
contrast agent displaces the water in the top chamber and diffuses to the bottom chamber as shown 
in Fig. 2B.  Our lab-made software automatically segments the entire region of the bottom 
chamber (ROI), and the mean value within the ROI is calculated automatically, creating contrast 
enhancement curves (CEC) as shown in Fig. 2C.  The dynamic change of contrast concentration 
in the bottom chamber was linear for 10 minutes (0.11 mM/min), when independently measured 
using liquid chromatography-mass spectrometry detection (LC-MS) method (32).  The 
repeatability of phantom CEC measured by intra-class correlation coefficient (ICC) (33) was larger 
than 0.99 in all measurements.  Please see our paper for more details (1).  The P4 is small 
enough to be imaged with a human subject and is large enough not to suffer from the partial volume 
effect, thus MRI system-driven error can be detected during human imaging.  Before error 
correction, the within-subject coefficient of variation (wCV) of the volume transfer constant 
(Ktrans), a DCE-MRI parameter, was about 20%, but after error correction using the P4, the 
MRI images  
A 
B 
Fig. 2. Point-of-care portable perfusion phantom, P4. (A) Photograph and schematic of the 
perfusion phantom. This phantom contains two chambers separated by a semi-permeable 
membrane. Before use, both chambers are filled with degassed/deionized water.  After MRI 
contrast agent is infused to the top chamber (from the left), it diffuses to the bottom chamber 
through the semi-permeable membrane. (B) DCE-MRI images of the phantom before (baseline) 
and at 0, 4 and 8 minutes after MRI contrast infusion.  

May 11, 2023 
 
5 
 
variation was reduced to about 4% (1).  Figure 3 shows the Ktrans values averaged in each of 
the four organ regions of three volunteers (n=12) when two different 3T MRI scanners were used 
(1).  Before correction, the ICC between the two data sets was 0.89, and the ICC was not 
improved by static phantom based error correction (ICC=0.86).  However, after P4-based error 
correction, ICC was increased to 0.99.  The P4 is easily operable by MRI technologists, thus it 
has great potential to facilitate multi-site clinical trials employing quantitative DCE-MRI (qDCE-
MRI). Of note, the clinical utility of the P4 was recently demonstrated (34).  After P4-based 
error correction, the change of Ktrans in pancreatic tumors favorably responding to chemotherapy 
was able to be significantly differentiated from that in non-responding tumors (p<0.0001) (34).  
Besides, the P4 was able to improve the accuracy in risk stratification of prostate cancer when 
assessed by qDCE-MRI (35).   
 
 
 
 
 
 
 
We now hypothesize that the variability in qDCE-MRI measurement of glioblastoma across 
different scanners will be significantly reduced when MRI system-driven error is corrected using 
the P4, leading to better differentiation between pseudo- and true-progressions.  Figure 4A 
shows the Gaussian distribution of the Ktrans value of 
glioblastoma with true- or pseudo-progression in Yun et 
al’s study (13), where the area under the receiver operator 
characteristic curve (AUC) was 0.76.  Figure 4B shows 
the hypothetical result when the measurement variation is 
reduced fivefold by our method as demonstrated in Fig. 3, 
increasing the AUC drastically (0.76 vs 0.99).  The goal 
of the proposed study is to conduct the preliminary test of 
this hypothesis before validating our methodology in an 
extended multi-site clinical trial (e.g., R01 or U01 study). 
2.0 
OBJECTIVES 
2.1. Primary goal  
To determine whether the differentiation between pseudo- and true-progressions of 
glioblastoma can be improved in quantitative DCE-MRI measurement when the P4 phantom is 
used for error correction.  
 
0.44 
0.23 
min-1 
Ktrans: 
0.44 
0.23 
min-1 
Ktrans: 
A 
B 
AUC=0.76 
AUC >0.99 
Fig. 4. Hypothetical Gaussian distribution of 
glioblastoma Ktrans values of pseudo- and 
true-progression groups (A) before and (B) 
after P4-based error correction.   
Fig. 3. Ktrans maps before and after correction. Ktrans averaged in each of the four 
organs of three volunteers (n=12), when Scanner-A (Y-axis) or Scanner-B (X-axis) was 
used, (A) before or (B, C) after correction using (B) the static phantom (SP) or (C) P4 (1).
0.80x 
Before 
After SP correction 
After P4 
A 
B 
C 

May 11, 2023 
 
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2.2. Secondary goal 
To determine whether the reproducibility of quantitative DCE-MRI measurement of 
glioblastoma can be significantly increased when MRI system-driven error is corrected using the 
P4 phantom.      
 
3.0 
INVESTIGATIONAL PLAN 
3.1 Study Design 
Figure 5 is a flow chart that illustrates our overall study plan.  Each 
patient will be treated with surgery and followed by radiotherapy with or 
without chemotherapy. Then standard-of-care brain MRI will be applied 
every 2~3 months. If a newly or enlarged enhancing lesion is observed in 
one of the standard-of-care MRI and it is uncertain whether it is pseudo or 
true-progression, a clinical research coordinator will contact the patient for 
recruitment. All participants will sign an informed consent form that fully 
discloses the investigational nature of this study before enrollment.  If the 
patient agrees to participate in this study, a clinical research coordinator will 
schedule two imaging sessions with the P4 within a one-week period, 
assuming that the glioblastoma perfusion parameters will not change over a 
week.  The second imaging test will be scheduled at least 24 hours after the 
first one.  Pseudo or true progression of glioblastoma will be determined 
via histopathologic analysis after biopsy (or surgery) or via the Response 
Assessment in Neuro-Oncology (RANO) criteria (6).  In this pilot study, a 
total of 12 patients will be recruited.  The participants will be at least 18 years old, and will not 
be pregnant or lactating. Subjects with safety contraindications to MRI examination and those with 
hemodialysis or acute/chronic renal failure will be excluded.  The participants, however, will not 
be excluded on the basis of race, ethnicity or sex.   
The data reproducibility across two different scanners assesses between-scanner variability 
combined with the inaccuracy of region of interest (ROI), arterial input function (AIF) and image 
co-registration.  The tumor ROI will be determined by Dr. Sotoudeh (a neuro-radiologist; co-I) 
(see “ROI determination” section for the details).  The ROIs of two scans of each subject will be 
matched as closely as possible to minimize intra-observer variation.  We recently introduced a 
novel method to reliably measure individualized AIFs (36) which will be employed in this study.  
If the patient moves during imaging, a similarity transformation (37) will be used for 3D co-
registration. The pharmacokinetic (PK) parameters (e.g., Ktrans) within the ROI will be averaged at 
each scan after P4-based error correction, and the mean values of two scans will be compared to 
calculate the reproducibility coefficient (%RDC) using the equation, %RDC=2.77wCV, where 
wCV is the within-subject coefficient of variation (38).  The %RDC before P4-based error 
correction will also be calculated for comparison.  Data reproducibility will be assessed using the 
intra-class correlation coefficient (ICC) as well.  ICC = σ 2b / (σ 2b+ σ 2w), where σb is between-
subject standard deviation and σw is within-subject standard deviation.    
Each tumor will be classified into pseudo- or true-progression based on the histopathologic 
data or RANO criteria.  We expect approximately 40-50% of glioblastoma will be classified to 
Fig. 5. Overall study plan 
(TMZ=temozolomide). 
Surgery 
Radiotherapy 
Standard-of-care MRI 
Enhancing lesion? 
2nd DCE-MRI 
Therapy Assessment 
1st DCE-MRI 

May 11, 2023 
 
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pseudo-progression, as demonstrated in previous studies (11-13).  All PK parameter maps will 
be created within a month after image acquisition so that the image processing will not be biased 
by subsequent clinical findings. We will examine whether the difference of tumor PK parameters 
between pseudo- and true-progressions will become more statistically significant after P4-based 
error correction.  
 
3.2 Primary Endpoints 
 
The therapy response assessment based on RANO.  
 
3.3 Study Duration 
 
Two years. 
 
 
3.4 Safety and Efficacy Monitoring 
 
This protocol will utilize the University of Alabama at Birmingham O’Neal 
Comprehensive Cancer Center (CCC) Data and Safety Monitoring Plan.  UAB CCC is a National 
Cancer Institute-designated comprehensive cancer center. Monitoring will be performed by the 
UAB CCC Clinical Trials Network and Monitoring Office. Serious adverse events will be reported 
to the chair of CCC Data Safety Monitoring Board (DSMB) within 24 hours of awareness of the 
event.  
 
 
3.5 Therapy Modification 
 
Two DCE-MRI imaging will be applied for each participant in addition to his/her standard-
of-care. If any adverse is reported in the first DCE-MRI, the second DCE-MRI will not be applied 
for the participant.    
 
 
3.6 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).  
 
 
3.7 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.  
Participants, their relatives, guardians or, if necessary, legal representatives must be given ample 
opportunity to inquire about details of the study.  
 
 
3.8 Confidentiality 
 
Participant names will not be supplied in the data. Only the participant number and initials 
will be recorded in the case report form (CRF). The participants will be informed that 

May 11, 2023 
 
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representatives of the 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 the strictest confidence and in accordance with local data protection laws. The 
investigator will maintain a personal identification list of participants (participant numbers with 
the corresponding names) to enable records to be identified.  
 
4.0 SELECTION OF PARTICIPANTS 
 
 
4.1 Number of Participants 
We plan to accrue 12 patients at the University of Alabama at Birmingham (UAB). UAB 
has a total of 11 neurosurgeons for adult patients, seeing about 60 patients with recurrent 
glioblastoma annually. We presume that at least 16% of them will agree to participate in this study 
judging from our previous experience in patient enrollment.  
 
 
4.2 Inclusion Criteria  
 
Patients meeting all the following criteria will be considered for enrollment into the study. 
1. Adult patients (age 18 years or older). 
2. Patients with grade 3 or 4 brain tumors treated with surgery, followed by 
radiotherapy with or without chemotherapy.  
3. Patients with a newly or enlarged enhancing lesion inside the radiation field. 
4. Patients with signed informed consent. 
 
4.3 Exclusion Criteria 
 
Patients presenting with any of the following will not be included in the study:  
1. Participants with safety contraindications to MRI examination (determined by 
standard clinical screening). 
2. Participants on hemodialysis or with acute renal failure. 
3. Participants who are pregnant, lactating or are planning to become pregnant during 
the study. 
4. Participants who are planning to farther a child during the study. 
 
4.4 Participants of Reproductive Potential 
 
Participants must not be pregnant or lactating at enrollment in the study. UAB standard for 
screening of pregnant or lactating females is asking the participant if they are lactating, pregnant, 
or if there is a chance they may be pregnant. If the female answers that there is a chance that she 
may be pregnant, our standard is to perform an on-site urine HCG pregnancy test. The results of 
that test are then documented. Participants must also agree to continue to use an effective form of 
birth control for 6 months after taking the study. Effective birth control includes birth control pills, 
patch, IUD, condom, sponge, diaphragm with spermicide, or avoiding sexual activity that could 
cause pregnancy. If a female participant becomes pregnant during the study, she will not participate 
further in this study.    
 
5.0 STUDY TREATMENTS  

May 11, 2023 
 
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Each patient will undergo two DCE-MRI exams according to the timeline detailed in Fig. 
5. Patients will be treated by standard-of-care therapy otherwise.  
 
6.0 STUDY PROCEDURE AND SCHEDULE 
 
All participants will be asked not to have caffeinated or alcohol drinks for at least 24 hours 
prior to imaging.  The hematocrit (HCT) of each participant will be measured before imaging, 
which is an important factor to determine plasma input function (PIF) required for PK parameter 
quantification (PIF=1/(1-HCT)) (39, 40).  Each subject will be instructed to put his/her head with 
the phantoms as shown in Fig. 6.   
 
 
 
 
 
 
 
 
 
 
 
 
The phantom package will be thoroughly sanitized prior to each use.  MRI scanner is 
equipped with a dual-channel transmit RF coil for improved B1 field homogeneity.  B0 and B1 
shimming will be conducted, and B1 mapping will be followed using the vendor’s software (41, 
42).  DCE-MRI acquisition will then be carried out for 5 minutes.  Gadoteridol (0.1 mmol/kg) 
will be injected i.v. to each patient at 10 s after the start of imaging procedure and will be followed 
by a 20-ml saline flush at a constant rate of 2 ml/s.  Perfusion phantoms will be infused with 100 
mM gadoteridol (0.06 ml/s; 3 ml) at 10 s after imaging start using a syringe pump (NE-1600) that 
is separate from the contrast agent going into the patient.  Prior to DCE-MRI, T1W images with 
various flip angles will be obtained for T1 mapping (43).   
 
7.0 SAFETY 
There is minimal physical risk to undergoing the MRI test. Lying supine for 30 minutes to 
an hour with our phantoms located under the participant could make the participant uncomfortable. 
As the MRI machine obtains the images for the study, there will be loud noise.  There is also a 
small risk that the patient may be mildly claustrophobic.  When gadoteridol (MR contrast agent) 
is injected into the vein, a cool sensation in the arm or mild nausea is experienced by few patients. 
A small number of patients may have an allergic reaction to gadoteridol injected into the vein. 
Gadolinium based MR contrast agents can cause Nephrogenic Systemic Fibrosis (NSF) for 
patients with severe kidney disease.  NSF appears like a bad skin disease, and it can be fatal. 
However, gadoteridol is known to be safe even in patients with stages 4 and 5 of chronic kidney 
diseases (44).    
The risk of having NSF will be very low. Gadoteridol is classified as the one having the 
lowest risk of NSF by the European Medicines Agency (EMA) and American College of 
Fig. 6. P4 phantoms for brain DCE-MRI. 
Illustration of the P4 phantoms located above a 
patient inside the brain coil. 
 
P4 phantom 
P4 phantom
Brain coil 

May 11, 2023 
 
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Radiology (ACR). In animal studies, gadolinium retention has been found to be extremely low 
following the repeated administration of gadoteridol, and lowest in brain tissues when compared 
with gadolinium retention observed after repeated administration of other MR contrast agents (45-
47). To our knowledge, no instances of T1 hyperintensity in the brain have yet been observed 
following multiple exposure to approved doses of gadoteridol in adult or pediatric patients.  In 
Cho et al’s recent study (48), the adverse reactions of gadoteridol injection (up to a triple dose, 0.3 
mmol/kg, depending upon the clinical need) were examined in a total of 6163 patients having 
various diseases.  8 subjects (0.13%) had mild symptoms and 2 subjects (0.03%) had modest 
symptoms, but not a single serious adverse event was observed.  Therefore, the chance of serious 
adverse events following approved dose (0.1 mmol/kg) of gadoteridol is extremely low among the 
12 subjects even after two dosing.   
The risks of having significant claustrophobia affecting participation in this study will be 
low, as participants will be screened for kidney disease, claustrophobia and other conditions that 
would prevent them from getting an MRI.  The risk of pain during insertion of an IV catheter is 
100% but minimal and temporary.  The risk of nausea during intravenous injection of gadoteridol 
is less than 1%.  The risk of the patient having an allergic reaction to the MR contrast injected 
intravenously is less than 1%.  Allergic reactions to gadoteridol typically do not require 
medication for reversal. If a patient is uncomfortable during a particular sequence, the exam can 
be terminated immediately and they will be removed from the MRI machine.  During MRI test, 
earplugs will be given to damp loud noise.  Each participant will be closely monitored via 
microphone while being scanned to detect any risks. 
 
8.0 STATISTICAL METHOD 
 Sample Size Justification 
Aim 1.  The Ktrans reproducibility measured by the ICC was 0.99 in our previous 
experiment (1), when the P4 was used for error correction (3 volunteers x 4 tissues = 12 
measurements) (see Fig. 3C). For brain DCE-MRI, however, the perfusion value can only be 
assessed in the tumor region. Thus, to achieve greater than 90% power to confirm that the data 
repeatability measured by the ICC is larger than 0.9 with 5% type I error, at least 12 volunteers 
will be needed.    
Aim 2. In Yun et al’s study (13), the difference of tumor Ktrans between pseudo- and true-
progressions was 91% with the standard deviation (SD) of approximately 50% in each group 
(p=0.004).  If the mean and SD of each group in the proposed study will be the same with those 
of Yun et al’s study (0.44±0.25 vs 0.23±0.10 min-1), the sample size (n=12) will have 55% power 
at a 5% significant level to differentiate the two groups (assuming n=6 per group) using a one-side 
two-group student t-test.  However, if the SD is reduced to ≤35% using the P4, the power will 
be increased to ≥90%.   
 Statistical Analysis 
Descriptive analysis with the mean and SD will be presented for each experimental 
parameter and each time point.  Graphic presentation will be considered when appropriate.  Due 
to repeated measurement, ANOVA analysis with a mixed model will be used to estimate the 
measurement error (within error) with two-sided 95% confidence interval (49).  Data 

May 11, 2023 
 
11 
 
reproducibility will be assessed using both the ICC and %RDC (33).  Tumor PK parameters 
between pseudo- and true-progressions will be compared using two-group student t-test (50).  
Data will be transformed using natural logarithms if the variability is found to be dependent upon 
its mean value.  All data will be analyzed using SAS (SAS institute, Cary, NC) by Dr. Li (see her 
support letter).  
9.0 CLOSURE OF THE STUDY 
The study will be closed at the site upon completion.   
 
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