A Pilot Study to Evaluate PBR PET in Brain Tumor Patients Treated With Chemoradiation or Immunotherapy
Phase: NA
Conditions: Intracranial Tumors, Glioblastoma, Melanoma
Sponsor: Massachusetts General Hospital

1 
NCT #: NCT02431572 
Protocol #: 14-421 
TITLE:  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
Coordinating Center: 
DF/HCC 
*Principal Investigator (PI): 
Elizabeth Gerstner, MD
Version Date: June 20, 2018 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
Version Date: June 20, 2018 
3 
SCHEMA 
Diseases:  
Metastatic cancer to the brain (Cohort A) 
Primary brain tumors (Cohorts B) 
Diseases:  
Primary brain tumors (Cohorts C) 
 
Immunotherapy 
Assess 
inflammation 
(PBR PET) 
Assess 
inflammation 
(PBR PET) 
Chemoradiation 
Assess 
inflammation 
(PBR PET) 
Follow Patients 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
Version Date: June 20, 2018 
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
OBJECTIVES ..................................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
BACKGROUND .............................................................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
2.2 
IND Agent(s) ...........................................................................................................7 
2.3 
Other Agent(s) ..........................................................................................................7 
2.4 
Rationale ..................................................................................................................7 
2.5 
Correlative Studies Background ..............................................................................9 
PARTICIPANT SELECTION .........................................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ..................................................................................................11 
3.3 
Inclusion of Women and Minorities ......................................................................12 
REGISTRATION PROCEDURES ...............................................................................................12 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................12 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................12 
4.3 
General Guidelines for Other Investigative Sites ..................................................13 
4.4 
Registration Process for Other Investigative Sites.................................................13 
5. IMAGING PLAN ......................................................................................................................13 
5.1 
Treatment Regimen ................................................................................................13 
5.2 
Pre-MR-PET Scan Criteria ....................................................................................13 
5.3 
MR-PET Scan Procedure .....................................................................................14 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................15 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................15 
5.6 
Duration of Follow Up ...........................................................................................16 
5.7 
Criteria for Taking a Participant Off Study ...........................................................16 
DOSING DELAYS/DOSE MODIFICATIONS ...........................................................................17 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................17 
7.1 
Expected Toxicities ................................................................................................17 
7.2 
Adverse Event Characteristics ...............................................................................17 
7.3 
Expedited Adverse Event Reporting ......................................................................18 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................19 
7.5 
Expedited Reporting to Hospital Risk Management .............................................19 
7.6 
Routine Adverse Event Reporting .........................................................................19 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
Version Date: June 20, 2018 
5 
IMAGING AGENT INFORMATION ..........................................................................................19 
8.1 
PBR ........................................................................................................................19 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................21 
9.1 
Biomarker Studies ..................................................................................................21 
9.2 
Laboratory Correlative Studies ..............................................................................21 
STUDY CALENDAR ...................................................................................................................21 
MEASUREMENT OF EFFECT....................................................................................................23 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................23 
11.2 
Antitumor Effect – Hematologic Tumors ..............................................................29 
11.3 
Other Response Parameters ...................................................................................29 
DATA REPORTING / REGULATORY REQUIREMENTS .......................................................29 
12.1 
Data Reporting .......................................................................................................29 
12.2 
Data Safety Monitoring..........................................................................................30 
12.3 
Multicenter Guidelines...........................................................................................30 
12.4 
Collaborative Agreements Language .....................................................................30 
STATISTICAL CONSIDERATIONS...........................................................................................30 
13.1 
Study Design/Endpoints.........................................................................................30 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................30 
13.3 
Stratification Factors ..............................................................................................32 
13.4 
Interim Monitoring Plan ........................................................................................32 
13.5 
Analysis of Primary Endpoints ..............................................................................32 
13.6 
Analysis of Secondary Endpoints ..........................................................................33 
13.7 
Reporting and Exclusions ......................................................................................33 
PUBLICATION PLAN .................................................................................................................33 
REFERENCES ..............................................................................................................................34 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................36 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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OBJECTIVES 
 
1.1 
Study Design 
 
This is an imaging pilot study to look at changes in primary and metastatic brain tumor 
inflammation using PBR PET- a tracer that highlights inflammation. Our goal is to determine if 
this tracer can be used to detect changes in inflammation during tumor treatment. We will study 
3 populations of patients with intracranial tumors: metastatic brain tumor patients treated with 
immunotherapy, GBM patients undergoing chemoradiation, and GBM patients treated with 
immunotherapy. PBR PETs will be performed at baseline prior to therapy and then several 
weeks-months after start of therapy depending on therapy used. 
 
The PET studies will be performed using a simultaneous MR-PET imaging scanner. No 
diagnostic decisions or therapy decisions will be based on any results obtained from these PET 
scans, and we expect no change in the care of these patients. The success of these studies should 
enable methods that could be used in larger studies to more completely understand the role of 
inflammation in the treatment of cancer. 
 
 
1.2 
Primary Objectives 
 
1. To determine whether PET imaging with [11C] PBR28 can measure inflammation 
related to immunotherapy in patients with brain tumors- specifically metastatic brain 
tumors and glioblastoma. . 
 
2. To determine whether PET imaging with [11C] PBR28 can measure inflammation 
related to chemoradiation in patients with glioblastoma. 
 
 
1.3 
Secondary Objectives 
 
1. NA 
 
 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
An estimated 51,410 primary brain tumors were diagnosed in 2007, and 19% of these tumors 
were glioblastomas (CBTRUS- Central Brain Tumor Registry of the United States).  GBM is the 
most common malignant primary brain tumor and is a uniformly fatal disease with 5-year 
survival rates less than 4% despite aggressive treatment with surgery, radiation and 
chemotherapy.  There is no curative therapy for patients with GBM.  Current standard of care for 
patients with newly diagnosed GBM is concomitant involved field radiation and oral 
temozolomide chemotherapy followed by monthly temozolomide for 6-12 months.1  If patients 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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relapse, there is no standard of care treatment. Immunotherapy is increasingly being explored as 
a tool to improve outcome for these patients.  
 
Metastatic tumors which have spread to the brain are incurable diseases that recently have had 
modest success with immunotherapy. However, duration of response in the brain is limited for 
unclear reasons.  
 
2.2 
IND Agent(s) 
 
2.2.1 
IND Agent #1 
 
NA 
 
 
2.2.2 
IND Agent #2 
 
NA 
 
2.3 
Other Agent(s) 
 
NA 
  
2.4 
Rationale 
 
Cancer immunotherapy is rapidly gaining traction as an effective treatment in some forms of 
cancer. The last several years have seen FDA approval of active cellular immunotherapy for 
advanced prostate cancer and immune checkpoint blockade via CTLA-4 inhibition for patients 
with advanced melanoma.  Currently, there is great enthusiasm for PD-1 inhibition (checkpoint 
blockade) via monoclonal antibodies in patients with solid tumors; phase 2 results have yielded 
high response rates across a spectrum of cancers with relatively little toxicity.  In addition, 
adoptive T-lymphocyte transfer using ex vivo expanded tumor-infiltrating lymphocytes or 
chimeric antigen receptors (CAR’s) is showing great promise in patients with melanoma and 
CD19+ leukemia respectively.  Also, phase 2 studies have demonstrated convincing activity of 
immune-based approaches for both metastatic and primary tumors in the central nervous system.  
For instance, the response rate for intracranial melanoma metastases is roughly equivalent to that 
of peripheral lesions treated with CTLA-4 blockade, and glioblastoma peptide vaccination and 
dendritic cell vaccination approaches are currently in randomized phase 3 and phase 2b clinical 
trials.   
 
Evaluating the impact of immune-based therapies in the short term has been challenging in 
patients with solid malignancies, including those with brain tumors.  Standard imaging 
evaluation of tumor response, such as the RECIST or RANO criteria, may not accurately reflect 
what is occurring in the tumor microenvironment during immunotherapy. In essence, contrast-
enhancement may reflect therapy-induced inflammation rather than tumor progression.  The 
immunotherapy community has proposed a set of “immune-related response criteria” that may be 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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more applicable to these patients.  However, as these measures require the simultaneous 
assessment of multiple lesions, they are poorly suited for understanding response in 
glioblastoma. There is an expanding number of cases of immunotherapy-associated 
pseudoprogression in which intensely enhancing and space-occupying lesions resolve without 
other intervention after a few weeks.   The ability to distinguish between and inflammatory 
response and tumor progression (which is characterized by an immunosuppressive environment) 
is critical for providers.  There is, therefore, a need for more specific imaging of immunotherapy-
associated inflammation in patients with intracranial tumors.   
 
The 18-kDa translocator protein (TSPO) is a protein that is expressed in mitochondria and is 
particularly prominently expressed by activated microglia, infiltrating macrophages, and reactive 
astrocytes. Thus, it is a marker of neuro-inflammation. PET tracers are being developed that bind 
to this receptor as a means to measure inflammation.2 One of these tracers, [11C]PBR28, is a 
second generation PET tracer that binds to TSPO. This tracer has been used in many studies of 
CNS disease such as cocaine abuse3, neurocysticercosis4 depression5 Alzheimer’s disease6,7 
multiple sclerosis8,9, and seizures10. The tracer has also been used in animal models to look at 
ischemia related inflammation.11 These studies have shown that this tracer is increased in areas 
of inflammation in the brain and is safe to use in humans. There are no reported adverse events 
related to the PBR28 tracer and, in 2014, the Martinos Center manufactured 83 human doses of 
PBR28 and there were no reports of adverse events related to the doses. 
 
Unfortunately there is little data in human brain tumors so it is unclear if this tracer will be 
equally useful in this patient population. Conflicting data exists regarding TSPO expression in 
gliomas. One study in rats using an alternate TSPO binding PET tracer suggested increased 
uptake in tumors12 where as another human study showed a lack of TSPO expression in 
microglial associated with high grade gliomas.13 The rat study did not specify which cells 
expressed TSPO. Importantly, these studies were not designed to test the response of human 
gliomas to treatment or changes in TSPO expression that may occur during treatment. Thus, 
there is a rationale to further study the role of this tracer in human brain tumors to better 
characterize its utility in measuring inflammation.  
 
One goal with including both glioma patients and metastatic brain tumor patients is to determine 
if there are differences in PBR28 uptake based on type of cancer which may suggest differences 
in TSPO expression within different tumor microenvironments and in inflammatory response to 
treatment. Given the limited data on this tracer in cancer, it may be more useful in one type of 
cancer rather than another because of the different underlying biology of tumors. There is a high 
number of patients with metastatic melanoma to the brain and immunotherapy is commonly used 
for this patient population so we elected to start with this cohort of patients but are now 
amending the protocol to include all cancer types as there are now immunotherapy options and 
clinical trials of immunotherapy for more than just melanoma patients.  
 
Thus, we will evaluate [11C]PB28 PET as a tool for measuring inflammation associated with the 
response to immunotherapy or chemoradiation in patients with brain tumors. Having such a tool 
that distinguishes active tumor from inflammation will be an incredibly useful tool in the 
management of patients. If this tracer shows potential utility in this pilot study, we will examine 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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it further in separate planned phase II glioma vaccination studies at our center, in an effort to 
correlate PET findings with outcome. 
 
One limitation of PBR PET is that certain people can be classified as low binders because of a 
genetic polymorphism.14 These “low binders” have negligible binding to the PBR28 tracer so 
would not be informative to include in our study and will be excluded. Only about 10% of 
human subjects are low affinity binders based on prior data.14 As part of the screening process, 
after informed consent has been obtained, a simple blood test will be performed to determine 
binding affinity of consented patients. Those who are low-affinity binders will be not be 
enrolled. 
 
In summary, we our simple goal is to perform two PBR PETs in patients with metastatic brain 
cancer undergoing treatment with immunotherapy and one PBR PET in patients with GBM to 
measure inflammation. This is similar to performing FDG PETs in these patients but uses a 
different PET tracer than FDG. Since PBR28 was first used at the Martinos Center, there have 
been 11 clinical trials approved using this tracer and no adverse events reported. 
 
2.5 
Correlative Studies Background 
 
In addition to PET imaging, MRI scans will be acquired. MRI is a very useful tool to non-
invasively probe tumor response to treatment and is already part of the routine management of 
patients with GBM. The complicated relationship between tumor perfusion, vascular 
permeability, and tumor cellularity can be assessed by MRI. Dynamic susceptibility contrast 
(DSC) and dynamic contrast enhanced (DCE) MRI can measure vascular parameters such as 
cerebral blood volume (CBV), blood flow, mean transit time, vessel size, and permeability - all 
of which are impacted by immunotherapy and chemoradiation. These will be exploratory 
analyses to see if changes in tumor vasculature/cellularity can help interpret changes in PBR 
uptake. 
 
 
PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have evidence of metastatic cancer to the brain for Cohort A or 
histologically confirmed GBM for Cohorts Band C.  
 
3.1.2 Those with GBM but suspected to have pseudoprogression at any time after completion 
of chemoradiation can enroll in Cohort C. 
 
3.1.3 Participants must have measurable brain disease, defined as at least one lesion that is 10 
mm in diameter. 
 
3.1.4 Age  > 18 years.  
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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3.1.5 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.6 Life expectancy of greater than 3 months.  
 
3.1.7 Participants must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine 
within normal institutional limits 
OR 
− 
creatinine clearance 
≥55 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal. 
 
3.1.8 For Cohort A, only patients with metastatic cancer to the brain for whom their treating 
physician has planned to give immunotherapy as monotherapy are eligible for this study. 
This can be in the setting of a clinical trial or not. 
 
3.1.9 For Cohort B, only patients with GBM for whom their treating physician has planned to 
give immunotherapy are eligible for this study. This can be in the setting of a clinical trial 
or not. 
 
3.1.10 For Cohort C, patients with GBM who have completed standard temozolomide + 
radiation and have suspected pseudoprogression can enroll. There is no time frame from 
completion of chemoradiation as pseudoprogression is increasingly recognized at later 
time points.  
 
3.1.11 Patient must be able to undergo MRI and PET scans. 
 
3.1.12 Patient must be maintained on a stable corticosteroid regimen for 5 days prior each MR-
PET scan. 
 
3.1.13 High or mixed affinity binders (Ala/Ala or Ala/Thr) based on genotyping result from 
PBR affinity test. This blood test will be performed as part of the screening process after 
consent has been obtained.  
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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3.1.14 The effects of PBR on the developing human fetus are unknown.  For this reason and 
because radiopharmaceuticals agents are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Radiopharmaceutical agents are known to be teratogenic. 
 
3.1.15 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
 
3.2.1 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to PBR. 
 
3.2.2 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.3 Pregnant women are excluded from this study because PBR is a radiopharmaceutical 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to exposure of 
the mother to PBR, breastfeeding should be discontinued.  These potential risks may also 
apply to other agents used in this study. 
 
3.2.4 HIV-positive participants are excluded because their immune system is compromised and 
may affect the interpretation of the imaging data. 
 
3.2.5 Patients who are not suitable to undergo MRI or PET or use gadolinium contrast due to: 
• Claustrophobia 
• Presence of metallic objects or implanted medical devices in body (i.e. cardiac 
pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves 
with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel 
implants)  The craniotomy patients will all have titanium but this is MRI 
compatible 
• Sickle cell disease 
• Renal failure 
• Reduced renal function, as determined by creatinine clearance < 30 mL/min 
based on a serum creatinine level obtained within 28 days prior to registration 
 
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the 
initiation of any imaging. Any participant not registered to the protocol before protocol therapy 
begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the QACT Registrar of registration cancellations as soon as 
possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the QACT registration line at 
 and follow the 
instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
• Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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. For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
 
• The QACT Registrar will (a) review the eligibility checklist, (b) register the participant 
on the protocol, and (c) randomize the participant when applicable. 
 
• An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
NA 
 
4.4 
Registration Process for Other Investigative Sites 
 
NA 
  
 
5. IMAGING PLAN 
 
 
5.1 
Treatment Regimen 
 
This study does not add any additional treatment to enrolled patients. All treatment decisions will 
be at the discretion of the treating physician. There will be no change in the diagnosis or 
management of the patient based on any procedures or tests carried out as a part of this study. 
 
There are no expected toxicities and potential risks for PBR. All scans will be performed at the 
Martinos Center for Biomedical Imaging in Charlestown on the combined MR PET scanner.   
 
For GBM patients with suspected pseudoprogression, MR-PET will be performed at the time of 
suspected pseudoprogression. 
 
For GBM patients treated with immunotherapy, MR-PET will be performed prior to start of the 
immunotherapy and then 2 cycles later.  
 
For metastatic cancer patients treated with immunotherapy, MR-PET will be performed prior to 
start of the immunotherapy and then 3 cycles later.  
 
5.2 
Pre-MR-PET Scan Criteria 
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
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5.2.1 
Genotyping for the Ala147Thr TSPO polymorphism in the TSPO gene (rs6971). Venous 
blood (up to 50 ml) will be drawn during the Screening Visit for this purpose and sent 
Partners HealthCare Personalized Medicine Translational Genomics Core located at 65 
Landsdown street at Cambridge. This lab performs this testing for all other current PBR 
PET studies conducted at MGH. 
 
5.2.2 Stable dose of corticosteroids for 5 days prior to MR-PET scan as change in steroids can 
affect interpretation of the MRI scan. 
 
5.2.3 Creatinine clearance >30 mL/min based on a serum creatinine level obtained within 30 
days. 
 
5.2.4 β-HCG in woman of childbearing age (prior to each MR-PET scans). Please see 
http://healthcare.partners.org/phsirb/Guidance/Pregnancy_Testing_in_Research_Involving_Radia
tion.1.09.pdf  for Pregnancy Testing guidelines)  
 
 
5.3 
MR-PET Scan Procedure  
 
5.3.1 
MRI Scan 
 
Image Acquisition Details: 
 
MR scans will be performed including T1- and T2-weighted volumetric images, fluid 
attenuated inversion recovery (FLAIR), contrast agent enhanced T1-weighted 
permeability, diffusion imaging, T2/T2*-weighted perfusion scans, and MR 
Spectroscopy. The “Autoalign” package available from the manufacturer will be used to 
achieve the same slice prescription in the same patient at each visit. Each MRI will last 
60-75 minutes versus 45 minutes for standard brain MRIs. 
 
Gadolinium-diethylenetriaminepentaacetic acid (or gadopentetate dimeglumine, Gd 
DTPA) will be used as a contrast agent. The maximum contrast dose that could be given 
is 0.3 mmol/kg per visit, in line with the FDA-approved dosing for this class of contrast 
agents. 
 
Image Analysis Details: 
 
MRI data will be analyzed per our usual techniques as have been reported previously. 
 
Image Interpretation Details:  
 
Interpretation will be performed at the Martinos Center for Biomedical Imaging. The 
results will not be automatically relayed to the patient or treating physician as it is unclear 
how these scans should be interpreted so should not influence patient management. If 
requested, we will share the data with the patient’s physician but again, should not 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
15 
influence patient management. Patients and treating physicians may be curious to see the 
images so we want to allow for sharing of the images. The detailed analysis required for 
interpretation of the data will not be in real time so will not be able to influence treatment 
decisions. Moreover, we do not want lack of communication to be a barrier to accrual.    
 
 
 
5.3.2 PBR PET Scan 
 
Image Acquisition Details: 
 
During each visit, [11C]PBR28 (up to 15mCi, which results in ~3.7 mSv) will be injected 
intravenously with a slow bolus over a 30s period. The catheter will be flashed post-
injection of with 0.9% saline solution. Dynamic data will be collected over approximately 
90 minutes in list mode, and framed post-collection.  
 
At the beginning of the scan session, an intravenous catheter will be placed for tracer 
injection. A second line will be placed in the opposite arm from the injection site and will 
be used to draw 2mL or 12mL blood samples throughout the test, for at most 200mL of 
blood.  The blood draws will be used to assess the radioactivity levels in the blood 
necessary for dynamic imaging. The catheters will be removed at the end of the study.   
 
Image Analysis Details: 
 
PET volumes will be reconstructed using the ordinary Poisson ordered subsets 
expectation maximization (OP-OSEM) 3D algorithm. Corrections will be applied for 
variable detector dead time and efficiency, random coincidences, photon attenuation and 
scatter, and decay. 
 
Image Interpretation Details:  
 
Interpretation will be performed at the Martinos Center for Biomedical Imaging. 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
NA 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Patients may remain on study (i.e. continue with MR-PET imaging) until one of the following 
criteria applies: 
 
• 
Intercurrent illness that prevents further participation in the imaging studies 
 
• 
Unacceptable adverse event(s) 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
16 
 
• 
Participant demonstrates an inability or unwillingness to comply with the 
documentation requirements or imaging studies. 
 
• 
Participant decides to withdraw from the protocol (i.e. does not want to undergo 
further imaging studies) 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further imaging studies in the judgment of the treating investigator 
 
 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Elizabeth Gerstner, at 
.  
 
 
 
5.6 
Duration of Follow Up 
 
Participants will be followed for 3 years after removal from protocol therapy or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the QACT website or obtained from the QACT registration staff.  

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
17 
 
 
DOSING DELAYS/DOSE MODIFICATIONS 
 
 
No dose modifications will be made to the PBR dosing. 
 
 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
 
Per NCI Adverse Event Reporting Requirements related to PET tracers, adverse events related to 
the PET imaging are reportable up to 3.5 hours after injection (i.e. 10 half-lives of the C11 
tracer). 
 
 
 
7.1 
Expected Toxicities 
 
7.1.1 
Adverse Events List 
 
7.1.1.1 
Adverse Event List for PBR 
 
There are no known adverse events related to PBR. 
 
7.1.1.2 
Adverse Event List(s) for Other Agent(s) 
 
NA 
 
7.2 
 Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
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Version Date: June 20, 2018 
 
18 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
There are no known adverse events related to PBR28 but any event thought related to PBR28 
that is CTCAE grade ≥3 will be considered a serious adverse event and should be reported 
to the Overall PI and RDRC per the DFCI IRB reporting policy.  
 
7.3 
Expedited Adverse Event Reporting  
 
Per NCI Adverse Event Reporting Requirements related to PET tracers, investigators 
must report to the Overall PI any serious adverse event (SAE) related to the PET imaging 
up to 3.5 hours after injection (i.e. 10 half-lives of the C11 tracer). Thus, by 3.5 hours 
after injection the tracer should be out of a patients system and not responsible for any 
adverse events. Any SAEs related to the PET imaging will also be reported to the RDRC. 
 
 
7.3.1 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
7.3.2 
Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
NA 
 
 
7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI 
on the toxicity case report forms.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data 
submissions. Any AEs related to the PET imaging will also be reported to the RDRC. 
 
 
 
IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
PBR 
 
8.1.1 
Description 
 
The chemical name is: N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine.  
 
 
8.1.2 
Form 
 
PBR is an intravenous injection. The radiopharmaceutical product, PBR, is the only 
active ingredient and it is dissolved in a solution of ≤10 mL of 95% isotonic saline: 5% 
ethanol (v:v). PBR is provided as a ready to use isotonic, sterile, pyrogen-free, clear, and 
colorless solution. PBR is typically packaged in a glass vial and does not contain any 
preservatives. 
 
8.1.3 
Storage and Stability 
 

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Version Date: June 20, 2018 
 
20 
The PBR will be produced onsite the day of the scheduled PET scan at the Martinos 
Center under the auspicious of the Radiation Drug Review Committee (RDRC). Proper 
transportation will take place according to Martinos Center policies. The Martinos Center 
policies include standard operating procedures for the tracer. These SOP’s have been 
developed by radiochemist, nuclear medicine experts and the MGH RDRC that oversees 
all studies using novel PET tracers.  Following synthesis and quality control, the 
radiopharmaceutical will be used within 2 hours of the end of synthesis.  
 
8.1.4 
Compatibility 
 
NA 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
These personnel have undergoing training and certification in the handling of 
radiolabeled tracers (ex. qualified nuclear medicine technicians). 
 
8.1.6 
Availability 
 
PBR will be produced onsite. 
 
8.1.7 
Preparation 
 
PBR will be produced onsite as a fully prepared agent ready for intravenous 
administration.  Radioactivity dose can be adjusted by modifying the injection volume.  
No other changes in constitution should be made. Preparation will follow the SOPs of the 
Martinos center that have been developed by radiochemist, nuclear medicine experts and 
the MGH RDRC that oversees all studies using novel PET tracers. All personnel involved 
have undergoing training and any necessary certification in the handling of radiolabeled 
tracers. 
  
 
8.1.8 
Administration 
 
PBR will be administered by intravenous injection by bolus by a qualified nuclear 
medicine technician. 
 
8.1.9 
Ordering 
 
PBR will be prepared on a single injection basis as dictated by MR-PET scheduling of 
studies at the Martinos Center.   
 

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Version Date: June 20, 2018 
 
21 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
At the end of the study, unused supplies of PBR should be decayed in storage according 
to institutional policies.  This will be documented in the PBR individual batch record and 
scan log. 
 
 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 
Biomarker Studies 
 
NA 
 
9.2 
Laboratory Correlative Studies 
 
NA 
 
 
STUDY CALENDAR 
 
Screening evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  In 
the event that the participant’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
GBM Patients with suspected Pseudoprogression 
 
Pre-
Study 
 
Post-
chemoradiation 
PET + MRI 
 
 
Xa 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Physical exam 
X 
 
 

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22 
(Ht, Wt, VS) 
Steroid dose 
X 
 
Xb 
KPS 
X 
 
 
Genotyping for 
Ala/Ala or Ala/Thr 
statusc 
X 
 
 
CBC with diff 
X 
 
 
CMPd 
X 
 
 
B-HCGe 
X 
 
X 
Adverse event 
evaluationf 
 
 
3.5 hours post-PET 
scan 
Follow-upg 
 
 
 
a – at any point during therapy that a GBM patients has suspected pseudoprogression but within 4 weeks 
of consent 
b- Record steroids dose at time of PET scan 
c – this test will be performed as part of screen after informed consent is obtained. The blood will be sent 
to Partners HealthCare Personalized Medicine Translational Genomics Core located at 65 Landsdown 
street at Cambridge. This lab performs this testing for all other current PBR PET studies conducted at 
MGH. 
d - Sodium, potassium, chloride, glucose, BUN, creatinine, calcium, total protein, albumin, total 
bilirubin, SGOT [AST], SGPT [ALT], alkaline phosphatase. 
e – Serum pregnancy test (for women of childbearing potential) to be performed at baseline and prior to 
each PET. See 
http://healthcare.partners.org/phsirb/Guidance/Pregnancy_Testing_in_Research_Involving_Radiation.1.0
9.pdf 
f – Per NCI Adverse Event Reporting Requirements related to PET tracers, the window to collect 
adverse event is 3.5 hours post PET scan (i.e. 10 t½ of radiotracer). Patient will be contacted by phone 
call or clinic visit within 24 hours of scan to assess for adverse event during this window. 
g – Follow-up every 3 months will assess subsequent treatments, tumor response to treatment, and 
survival 
 
 
For patients undergoing immunotherapy 
 
Pre-Study 
Pre- 
Immunotherapy 
During-
Immunotherapy 
PET + MRI 
 
Xa 
Xb 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Physical exam (Ht, Wt, VS) 
X 
 
 
Steroid dose 
X 
Xc 
Xc 
KPS 
X 
 
 

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Genotyping for Ala/Ala or Ala/Thr statusd 
X 
 
 
CBC with diff 
X 
 
 
CMPe 
X 
 
 
B-HCGf 
X 
X 
X 
Adverse event evaluationg 
 
3.5 post-PET scan 
3.5 post-PET scan 
Follow-uph 
 
 
 
a – 1-7 days prior to surgery or immunotherapy 
b – 0-5 days prior to cycle 4 of immunotherapy for metastatic brain cancer patients or prior to cycle 3 of 
immunotherapy for GBM patients 
c- Record steroids dose at time of PET scan 
d– This test will be performed as part of screen after informed consent is obtained. The blood will be sent 
to Partners HealthCare Personalized Medicine Translational Genomics Core located at 65 Landsdown 
street at Cambridge. This lab performs this testing for all other current PBR PET studies conducted at 
MGH. 
e - Sodium, potassium, chloride, glucose, BUN, creatinine, calcium, total protein, albumin, total 
bilirubin, SGOT [AST], SGPT [ALT], alkaline phosphatase. 
f – Serum pregnancy test (for women of childbearing potential) to be performed at baseline and prior to 
each PET. See 
http://healthcare.partners.org/phsirb/Guidance/Pregnancy_Testing_in_Research_Involving_Radiation.1.0
9.pdf 
g– Per NCI Adverse Event Reporting Requirements related to PET tracers, the window to collect 
adverse event is 3.5 hours post PET scan (i.e. 10 t½ of radiotracer). Patient will be contacted by phone 
call or clinic visit within 24 hours of scan to assess for adverse event during this window. 
h – Follow-up every 3 months will assess subsequent treatments, tumor response to treatment, and 
survival 
 
 
MEASUREMENT OF EFFECT 
 
Measurement of effect will be determined by the treating physician per standard of care. The 
following is only included as reference for the treating physician. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
RANO criteria are recommended to assess response.15RECIST is recommended for the 
metastatic brain tumor patients. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 

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Version Date: June 20, 2018 
 
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Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Per RANO or RECIST guidelines as appropriate. 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol.  
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
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Version Date: June 20, 2018 
 
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as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
 
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Per RANO or RECIST guidelines as appropriate.  
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.  
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 

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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
RANO Criteria (JCO 2010; 28:1963-1972)
 
11.1.4.2 
Evaluation of Non-Target Lesions 
Per RANO or RECIST guidelines as appropriate.  
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 

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Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
No 
SD 
Documented at least once >4 
wks from baseline** 

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28 
evaluated 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 

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Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
11.1.7 Response Review 
 
NA 
 
11.2 
Antitumor Effect – Hematologic Tumors 
 
NA 
 
11.3 
Other Response Parameters 
 
NA 
 
 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
 
12.1.2 Responsibility for Data Submission 
 

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Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the QACT according to the schedule set by the QACT. 
 
12.2 
Data Safety Monitoring 
 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 
Multicenter Guidelines 
 
NA 
 
12.4 
Collaborative Agreements Language 
 
NA 
 
 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a pilot study to test the potential utility of PBR28 PET in measuring treatment 
related inflammation . We will measure if increased uptake of PBR28 in the tumor 
during treatment is associated with longer time to progression (i.e. suggesting that the 
response to therapy is inflammatory rather than tumor growth). 
 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 

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Version Date: June 20, 2018 
 
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Total sample size is anticipated to be 40 patients: 15 patients in cohort A (metastatic 
brain tumor patients) and 15 in cohort C (GBM patients suspected of having 
pseudoprogression) and 10 in cohort B (GBM patients treated with immunotherapy). 
 
Several factors influence the sample size for this study. This is a non-therapeutic study 
in a patient population which typically chooses to enroll in therapeutic trials if they are 
going to participate in a clinical trial at all so this trial will be less appealing to patients. 
In addition, since PBR PET remains investigational it is a very expensive test so 
budgetary constraints limit accrual.  
 
In order to assess if PBR PET helps to assess tumor inflammation, we will quantitate 
PBR uptake in the tumor and correlate that with tumor progression as determined by 
the treating physician or tissue histology if obtained. The hypothesis is that if tumor 
PBR retention is high, this would be consistent with a strong response to 
immunotherapy and should be associated with prolonged progression free survival. If 
PBR retention is low, indicating an immunosuppressive, active tumor 
microenvironment, PFS should be short. We selected 9 months because by this time, 
we should know who has true progression since treatment related inflammation has 
peaked by this time.  
 
The aim of this study is to demonstrate higher levels of PBR uptake in the non-
progression group. Therefore the sample size calculation is based on two group means 
comparison and the test used is a one-sided two-sample equal variance t-test (with 
mean and SD estimates as cited below). Since there is no a priory indication for the 
breakdown between progression and non-progression, we assumed equal group sizes.  
 
With 15 patients in cohort A (metastatic brain tumor patients) and 15 in cohort C (GBM 
patients suspected of having pseudoprogression), the study will have at least 80% 
power to detect a 60% difference in PBR uptake between those progression free at 9 
months and those not progression free at 9 months using a one-side hypothesis test with 
a 0.1 significance level. By 9 months, we should know who has true progression and 
who has pseudoprogression. Patients who die before nine months will be considered 
true tumor progression. Given this conservative approach we will have the power to 
detect a smaller difference in PBR uptake. 
 
For the patients who have baseline and mid treatment PET (cohort A), we will use the 
change in PBR uptake. There is limited data on PBR28 in brain tumors so this 
calculation assumes a baseline of 125 ml/cm3 and equal variance of 100 ml/cm3 (based 
on literature reported rates from healthy brain).9 PFS at 9 months was selected as most 
patients would have progressed at 9 months. All patients will also be followed for 3 
years after study completion for progression and survival. Time to event analysis will 
be used to incorporate other potential prognostic factors such as age and functional 
status.  
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
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Version Date: June 20, 2018 
 
32 
Given the small number of patients anticipated to accrue to cohort B (GBM patients 
treated with immunotherapy), these patients will be analyzed with descriptive statistics 
alone. This accrual is anticipated to be low because of the small number of GBM 
patients currently treated with immunotherapy. We anticipate enrolling a maximum of 
10 patients in this cohort.  
 
 
 
 
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
3 
+ 
8 
= 
11 
Ethnic Category: Total of all subjects 
 
5 
+ 
 
10 
= 
 
15 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
1 
= 
1 
Black or African American 
0 
+ 
1 
= 
1 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
5 
+ 
8 
= 
13 
Racial Category: Total of all subjects 
 
5 
+ 
 
10 
= 
 
15 
 
 
 
 
 
 
 
 
13.3 
Stratification Factors 
 
NA   
 
13.4 
Interim Monitoring Plan 
 
NA   
 
13.5 
Analysis of Primary Endpoints 
 
As above 
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
33 
13.6 
Analysis of Secondary Endpoints 
 
Given the small sample size, any secondary endpoint analysis will be exploratory and reported as 
descriptive. 
 
13.7 
Reporting and Exclusions 
 
 
13.7.1 Evaluation of Toxicity 
 
Patients will be evaluable for toxicity related to PBR PETs within 3.5 hours of the PET 
scan. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
NA 
 
PUBLICATION PLAN 
 
Dr. Gerstner will have sole responsibility for publishing results of this study. 
 
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
34 
REFERENCES 
 
1. 
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised 
phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66. 
2. 
Ching AS, Kuhnast B, Damont A, Roeda D, Tavitian B, Dolle F. Current paradigm of 
the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in 
neuroinflammation and neurodegenerative diseases. Insights into imaging 2012;3:111-9. 
3. 
Narendran R, Jedema HP, Lopresti BJ, et al. Imaging dopamine transmission in the 
frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study. Molecular psychiatry 
2014;19:302-10. 
4. 
Fujita M, Mahanty S, Zoghbi SS, et al. PET reveals inflammation around calcified 
Taenia solium granulomas with perilesional edema. PloS one 2013;8:e74052. 
5. 
Hannestad J, DellaGioia N, Gallezot JD, et al. The neuroinflammation marker 
translocator protein is not elevated in individuals with mild-to-moderate depression: a 
[(1)(1)C]PBR28 PET study. Brain, behavior, and immunity 2013;33:131-8. 
6. 
Kreisl WC, Lyoo CH, McGwier M, et al. In vivo radioligand binding to translocator 
protein correlates with severity of Alzheimer's disease. Brain : a journal of neurology 
2013;136:2228-38. 
7. 
Kim S, Nho K, Risacher SL, et al. gene variation and microglial activity on 
[C]PBR28 PET in older adults at risk for Alzheimer's disease. Multimodal brain image analysis : 
third International Workshop, MBIA 2013, held in conjunction with MICCAI 2013, Nagoya, 
Japan, September 22, 2013 : proceedings / Li Shen, Tianming Liu, Pew-Thian Yap, Heng Huang, 
Dingg 2013;8159:150-8. 
8. 
Takano A, Piehl F, Hillert J, et al. In vivo TSPO imaging in patients with multiple 
sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI research 2013;3:30. 
9. 
Oh U, Fujita M, Ikonomidou VN, et al. Translocator protein PET imaging for glial 
activation in multiple sclerosis. Journal of neuroimmune pharmacology : the official journal of 
the Society on NeuroImmune Pharmacology 2011;6:354-61. 
10. 
Hirvonen J, Kreisl WC, Fujita M, et al. Increased in vivo expression of an 
inflammatory marker in temporal lobe epilepsy. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine 2012;53:234-40. 
11. 
Tsukada H, Ohba H, Nishiyama S, Kanazawa M, Kakiuchi T, Harada N. PET 
imaging of ischemia-induced impairment of mitochondrial complex I function in monkey brain. 
Journal of cerebral blood flow and metabolism : official journal of the International Society of 
Cerebral Blood Flow and Metabolism 2014;34:708-14. 
12. 
Buck JR, McKinley ET, Hight MR, et al. Quantitative, preclinical PET of translocator 
protein expression in glioma using 18F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-
phenoxyaniline. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 
2011;52:107-14. 
13. 
Takaya S, Hashikawa K, Turkheimer FE, et al. The lack of expression of the 
peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas. 
Journal of neuro-oncology 2007;85:95-103. 
14. 
Kreisl WC, Jenko KJ, Hines CS, et al. A genetic polymorphism for translocator 
protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
35 
putative biomarker of neuroinflammation. Journal of cerebral blood flow and metabolism : 
official journal of the International Society of Cerebral Blood Flow and Metabolism 2013;33:53-
8. 
15. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria 
for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 
2010;28:1963-72. 
 
 

Protocol  A pilot study to evaluate PBR PET as an indicator of inflammation in brain tumor 
patients treated with chemoradiation or immunotherapy.  
 
Version Date: June 20, 2018 
 
36 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.