Clinical trial NCT03242824
Conditions: Glioma
Sponsor: Mayo Clinic
Start date: 2017-09-29; Completion date: 2021-06-16
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This proposal is for a pilot study comparing volumes of 18F-DOPA-PET avidity with contrast enhancement and T2 FLAIR on MRI. Investigators then plan to compare patterns of failure with target volumes, pre-treatment MRI changes and pre-treatment 18F-DOPA-PET.

Detailed description:

Arms: arm 1: Patients will receive 18FDOPA-PET for radiation treatment planning
Interventions: intervention 1: Fluorine F 18 Fluorodopa intervention 2: Intensity-Modulated Radiation Therapy intervention 3: Positron Emission Tomography
Intervention descriptions: intervention 1: Contrast used in PET intervention 2: Radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor intervention 3: imaging test

Protocol documents:
Prot_SAP_001.pdf: 


 
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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment 
delays/interruptions/adjustments, 
dose modifications, adverse events, 
protocol document, consent form, 
regulatory issues, 
forms completion and submission, adverse 
events, forms completion and submission 
 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
 
 
 


 
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Contents 
Study Schema ................................................................................................................................................ 4 
List of Abbreviations ..................................................................................................................................... 5 
1.0 
Background ....................................................................................................................................... 6 
2.0  
Goals ............................................................................................................................................... 10 
3.0 
Patient Eligibility ............................................................................................................................. 11 
4.0 
Test Schedule .................................................................................................................................. 12 
5.0 
Grouping/Stratification Factors: ..................................................................................................... 14 
6.0 
Registration Procedures: ................................................................................................................. 15 
7.0 
Protocol Treatment ......................................................................................................................... 16 
8.0 
Dosage Modification Based on Adverse Events .............................................................................. 21 
9.0 
Ancillary Treatment/Supportive Care: ............................................................................................ 22 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................................... 23 
11.0 
Treatment Evaluation ..................................................................................................................... 35 
12.0 
Descriptive Factors .......................................................................................................................... 40 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient ................................................................ 41 
14.0 
Body Fluid Biospecimens: None ...................................................................................................... 42 
15.0 
Drug Information ............................................................................................................................ 43 
16.0 
Statistical Considerations and Methodology .................................................................................. 44 
17.0 
Pathology Considerations/Tissue Bio specimens: .......................................................................... 51 
18.0 
Records and Data Collection Procedures ........................................................................................ 52 
19.0 
Study Finances ................................................................................................................................ 56 
20.0 
Publication Plan .............................................................................................................................. 57 
References .................................................................................................................................................. 58 
Appendix I ................................................................................................................................................... 61 
Appendix II .................................................................................................................................................. 62 
Appendix III ................................................................................................................................................. 64 
 
 
 


 
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Study Schema 
 
 
 
 
 
 
 
Baseline 
 (≤14 days prior to 
Registration) 
Standard of care CT simulation 
Pre-treatment MRI 
18F-DOPA PET   
(Research funded) 
(Must be completed ≤ 14 days prior to start 
Radiation treatment targeting 
volumes designed with both 18F-
DOPA-PET and conventional MRI 
(10 Fractions) 
Active Monitoring: 
Follow-up with standard MRI surveillance for 2 years or 
until progression 
Typical timing of scans is every 2-3 months or until 
progression. However actual timing of scans will be per 
clinicians’ discretion  
Event Monitoring 
 
See Data submission schedule Section 18.0 


 
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List of Abbreviations 
 
18F-DOPA  
3,4-dihydroxy-6-[18F] fluoro-L-phenylalanine 
AE 
 
Adverse Event/Adverse Experience 
CFR 
 
Code of Federal Regulations 
CRF 
 
Case Report Form 
CT 
 
Computed Tomography 
CTV 
 
Clinical Target Volume  
DICOM  
Digital Imaging and Communication  
DSMB  
Data and Safety Monitoring Board 
EORTC  
European Organization for Research and Treatment of Cancer 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GTV 
 
Gross Tumor Volume 
Gy 
 
Gray (radiation dosing)  
HIPAA  
Health Insurance Portability and Accountability Act 
MDASI-BT 
MD Anderson Symptom Inventory Brain Tumor Module 
MRI 
 
Magnetic Resonance Imaging 
NTD 
 
Normal Tissue Dose 
IRB 
 
Institutional Review Board 
PET 
 
Positron emission tomography 
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
PS 
 
Performance Score  
PTRAX  
Research Participant Tracking System 
PTV 
 
Planning target volume  
QOL 
 
Quality of Life 
RANO   
Response Assessment in Neuro- Oncology 
RT 
 
Radiation Therapy 
RTOG  
Radiation Therapy Oncology Group 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
SOP 
 
Standard Operating Procedure 
T/N 
 
Tumor to normal ratio 
UPIRTSO 
Unanticipated Problems Involving Risks to Subjects or Others 
VEGF-A  
Vascular endothelial growth factor- A 
 


 
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1.0  Background 
 
 
Recurrent glioblastoma remains a problem despite modern treatment techniques despite 
 
advances in modern therapy; glioblastoma continues to portend a dismal prognosis. In modern 
 
trials, median progression-free survival remains short at around 7 months, with nearly all 
 
patients experiencing tumor progression by 36 months.[1, 2]  
1.1 
Many recurrences occur outside the high-dose radiotherapy volume: 
The current standard for tumor delineation includes T1 contrast-enhanced and T2 FLAIR 
MRI. It is well established that high-grade gliomas infiltrate into peritumoral edema.[3] 
In a major prospective trial from the European Organization for Research and Treatment 
of Cancer (EORTC), the clinical target volume (CTV) included any residual tumor and 
resection cavity plus 2-cm margins.[1] Current Radiation Therapy Oncology Group 
(RTOG) protocols include the addition of postoperative edema plus 2-cm margins for 
CTV.[4] With these volumes, at least 75% of recurrences occur within the 95% isodose 
line of the 60 Gy volume.[5, 6] In addition, up to 20% of failures are located completely 
outside of the 95% isodose line.[6]   
1.2 
18F-DOPA-PET offers better localization of primary tumor than MRI alone: 
While it is well established that regions of contrast enhancement and edema are likely 
to contain tumor, it is thought that infiltration of tumor may additionally occur along 
neuronal tracts.[7] Given that up to 20% of patients may experience progression outside 
the aforementioned MRI changes, a need exists to develop a complementary imaging 
modality. While standard 18-fluoro-deoxyglucose positron emission tomography (18F-
FDG-PET) is generally insufficient in visualizing brain tumors, amino acid PET tracers, 
such as 3,4-dihydroxy-6-[18F] fluoro-L-phenylalanine (18F-DOPA) offer several 
advantages.[8]  18F-DOPA-PET shows high uptake in tumor tissue and low uptake in 
normal tissue. Unlike contrast enhancement, 18F-DOPA-PET crosses the intact blood 
brain barrier freely via an amino acid transporter.[9] In a pilot study at Mayo Clinic, 
increased 18F-DOPA-PET uptake was seen in 13 of 16 high-grade biopsy specimens, while 
MRI T1 contrast enhancement was only present in 6 of the 16 specimens.[10] With this 
knowledge, Mayo Clinic is currently enrolling patients with newly-diagnosed high-grade 
gliomas in a radiotherapy trial where dose-escalation is planned for regions of high 18F-
FDOPA uptake.  
1.3 
Pseudoprogression can be difficult to differentiate from true tumor progression:  
Following treatment with radiotherapy, inflammatory changes are often seen on MRI. 
Thus, strict criteria are used to categorize the nature of the tumor’s response. The 
historical standard criteria were published by Macdonald et al. and required >=25% 
increase in the sum of the products of perpendicular diameters of enhancing lesions, 
any new lesion, or clinical deterioration in order to declare progression.[11] These 


 
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criteria have come into question, as there can be significant interobserver variability, 
particularly in measuring irregularly shaped or cystic tumors. In addition, changes in 
contrast enhancement are typically nonspecific and simply represent a disrupted blood-
brain barrier. Thus, fluctuations in contrast enhancement may be caused by 
inflammatory changes in the treated region, anti-angiogenic agents and radiation 
necrosis.[12]  Pseudoprogression, defined as an increase in contrast enhancement that 
subsides without anti-neoplastic therapy, is common after standard treatment with 
radiotherapy and temozolomide.[13] This process is thought to be driven by radiation-
induced increased permeability of the blood brain barrier. Because pseudoprogression 
typically occurs within 12 weeks of radiotherapy inside the high-dose region, the 
updated Response Assessment in Neuro-Oncology (RANO) criteria require new 
enhancement outside the 80% isodose line or viable tumor on histopathologic sampling 
for progression to be declared less than 12 weeks after radiotherapy.[14]  These criteria 
help differentiate pseudoprogression from true progression, though challenges in 
interpreting changes in imaging after 12 weeks still remain.   
 
1.4 
Bevacizumab produces a moderately high response rate in glioblastoma:  
 
While angiogenesis is common among a spectrum of tumors, it is particularly frequent 
in glioblastoma. Commonly, the tumor parenchyma produces vascular endothelial 
growth factor A (VEGF-A), which in turn up-regulates the VEGF pathway.[4] 
Bevacizumab is a humanized monoclonal antibody with activity against the VEGF-A 
ligand, which in turn reduces VEGF pathway up-regulation.[15] A randomized study 
comparing bevacizumab with or without irinotecan in patients with recurrent 
glioblastoma demonstrated moderately high response rates in the 30-35% range as 
determined by MRI.[16] A single-arm phase II study treating recurrent glioblastoma with 
bevacizumab followed by bevacizumab and irinotecan after further progression 
produced a response rate of 35% as defined by Macdonald criteria.[17] These trials led 
to FDA approval for bevacizumab use in the treatment of recurrent glioblastoma. This 
led to RTOG 0825, a randomized placebo-controlled trial comparing standard 
radiotherapy and temozolomide with or without adjuvant bevacizumab. This study 
revealed an improvement in progression-free survival but not overall survival.[4] A 
subsequent study compared concurrent radiotherapy, temozolomide and bevacizumab 
to radiotherapy and temozolomide alone, demonstrating a similar improvement in 
progression-free but not overall survival.[18] Responses were often measured 
radiographically, which may not be the most reliable indicator of response to anti-
angiogenic agents.  
 
1.5 MRI changes after bevacizumab may not accurately reflect tumor response:  
 
While rapid responses in MRI contrast enhancement after initiation of treatment with 
VEGF pathway inhibitors are relatively common, it is not clear whether these changes 
truly reflect tumor regression or simply restoration of the blood-brain barrier.[19] 
Furthermore, increasing non-enhancing T2 FLAIR regions have been reported and may 
potentially represent tumor progression after bevacizumab.[20] This has driven 


 
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speculation that the improvement in progression-free but not overall survival with 
bevacizumab may be primarily driven by radiographic changes that do not fully correlate 
with true tumor response.   
 
1.6 
Reirradiation is often used for treatment of progression:  
 
Repeat courses of radiotherapy are often considered for progressive disease refractory 
to systemic therapy. Conventionally fractionated doses between 36 and 46 Gy have 
been used with minimal neurologic toxicity.[21-23] Hypofractionated doses of 24-50 Gy 
in 3.5-5 Gy fractions have also been used with minimal toxicity when limiting doses to 
<40 Gy.[22, 24-29] Mayer and colleagues proposed a cumulative normal tissue dose 
limit (2 Gy per fraction equivalent) of <100 Gy to limit the risk of radionecrosis.[30] In 
general, the target volume includes a minimal expansion beyond MRI contrast 
enhancement.[21, 24-27, 29] Median survival after reirradiation ranges from 7 to 10 
months.[21-27, 29] The best outcomes are seen when more time elapses between 
primary radiation and reirradiation and in patients with lower-grade histology.[24-26, 
31]  In an analysis of patterns of recurrence after reirradiation, 60-70% recurrences 
were located in-field with the remainder located out of field.[25, 32] Thus, MRI contrast 
enhancement may not accurately reflect tumor location potentially resulting in 
imprecise targeting of radiation target volumes.  
 
1.7 
18F-DOPA-PET may allow better localization of recurrent disease than MRI:  
 
Because of the shortcomings of MRI in accurately differentiating tumor progression 
from pseudoprogression, in addition to the difficulty in truly assessing the response to 
bevacizumab, a novel imaging modality would prove useful in accurately classifying 
responses to treatment. In addition, more precise target delineation in the re-irradiation 
setting is particularly attractive; so as to allow for not only better target coverage but 
potentially reduced unnecessary coverage of normal tissue.  The lack of dependence of 
18-FDOPA-PET uptake on blood-brain barrier breakdown is enticing, as many of these 
patients are currently receiving or recently received bevacizumab and may have 
alterations in the blood-brain barrier.  
 
1.71 
Preliminary results – 18F-DOPA-PET identifies glioma outside conventional MRI in 
patients with imaging findings consistent with recurrent disease. In our two 
studies (MC1078 and MC1373), 13 patients with suspected recurrent disease 
had an 18F-DOPA-PET/CT scan and MRI performed prior to stereotactic resection 
or biopsy. The PET scan  was rigidly registered to the T1-weight scan using MIM 
Maestro (MIM Software Inc, 
Cleveland, OH). The registered PET 
images  were transferred to the 
Stealth Station  Neuronavigation 
System (Medtronic Sofamor Danek, 
Memphis, TN) and stereotactic biopsy 
locations were planned based on the 
PET SUVmax and locations of PET and 
MRI discordance (Figure 1).  Of 45 
biopsy  specimens graded by Dr. 


 
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Caterina Giannini, 39 contained tumor. Fifteen samples were taken in regions of 
18F-DOPA avidity in the absence  of MRI contrast enhancement (M-P+). Of these, 
14 (93%) contained tumor and 10 (66%) were high-grade. Of the 33 specimens 
containing high-grade glioma, 20 (61%) were from regions of MRI contrast 
enhancement  and 26 (79%) were from regions of 18F-DOPA avidity. 


10 
 
2.0  
Goals 
 
 
2.1 
Primary 
 
 
2.11 
Compare the progression-free survival rate at 3 months for recurrent high-grade 
 
 
glioma patients after reirradiation targeting volumes designed with both  18F- 
 
 
DOPA-PET and conventional MRI with historical controls     
 
2.2 
Secondary 
 
 
2.21 
Compare overall survival from reirradiation and overall survival from initial  
 
 
diagnosis with historical controls 
 
2.22 
Prospectively evaluate toxicity and reoperation rates after reirradiation 
 
2.23 
Prospectively evaluate quality of life and fatigue using patient reported 
 
outcomes 
 
2.3  
Correlative Research 
 
2.31 
Compare volume of 18F-DOPA-PET uptake with MRI contrast enhancement and 
 
T2 FLAIR for patients undergoing re-irradiation for recurrent high-grade glioma 
 
2.32 
Evaluate patterns of failure after reirradiation in relation to pre-treatment MRI 
 
and 18F-DOPA-PET abnormalities 
 
 
 


 
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3.0 
Patient Eligibility 
 
 
 
3.1 
Inclusion Criteria 
3.11 
Age > 18 years 
 
3.12 
ECOG PS < 3 
 
3.13 
Histologically confirmed or radiographic evidence of recurrent/progressive 
glioma  
 
3.14 
History of radiation therapy to the brain for prior diagnosis of glioma 
 
3.15 
Planned radiation treatments at Mayo Clinic Rochester 
 
3.16 
Provide informed written consent 
 
3.17 
Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes 
 
Registry and Biobanking study, IRB number 15-000136 (blood draw optional) 
 
3.18 
Willing to return to enrolling institution for follow-up during Active Monitoring 
 
Phase of the study.  
 
 
 
3.2  
Exclusion Criteria 
 
 
 
3.21 
More than one prior course of radiotherapy or prior prescription doses   
 
 
 
exceeding 60 Gy to re-irradiation target volumes 
 
 
 
 
 
3.22 
Unable to undergo MRI scans with contrast   
 
 
 
3.23 
Unable to undergo an 18F-DOPA-PET scan (e.g., Parkinson’s Disease, taking anti  
 
 
 
dopaminergic, or dopamine agonist medication or less than 6 half-lives from  
 
 
 
discontinuance of dopamine agonists.) 
 
 
 
 
Note: Other potentially interfering drugs: amoxapine, amphetamine,  
 
 
 
 
benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine,  
 
 
 
methylphenidate, norephedrine, phentermine, phenylpropanolamine,selegiline, 
 
 
 
paroxetine, citalopram, and sertraline). If a patient is on any of these drugs, list  
 
 
 
which ones on the On-Study form.  
 
3.24 
Any of the following: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
 
 


 
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4.0 
Test Schedule  
 
 
 
Tests and 
procedures 
Baseline (<21 
days prior to 
registration) 
Radiation 
Treatment 
Planning 
During 
Radiation 
Treatment 
End of 
Radiation 
Treatment 
+/- 3 days  
1 month 
post RT 
+/- 7 
days 
3 
months 
post RT 
+/- 14 
days  
At every 
clinically 
indicated 
follow-up8 
Physical 
examination, 
weight, ECOG 
PS 
X 
 
 
X 
X 
X 
X 
Neurologic 
history and 
examination 
X9 
 
 
X 
X 
X 
X 
Document 
current 
medications 
X 
 
 
X 
X 
X 
X 
Pregnancy 
test 
X1 
 
 
 
 
 
 
QOL 
Assessment: 
MDASI-BT 
and BFI 10 
X11 
 
 
X 
X 
X 
X11 
Standard 
Mayo glioma 
brain MRI 
with and 
without 
contrast 
 
X3 
 
 
X 
X 
X5 
18F-DOPA-PET 
 
X3, R 
 
 
 
 
 
18F-DOPA 
adverse 
event 
assessment 
 
X2 
 
 
 
 
 
CT simulation 
for 
radiotherapy 
planning 
 
X3,4 
 
 
 
 
 
Adverse 
event 
assessment6 
X 
 
X7 
X 
X 
X 
X 


 
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1. For women of childbearing potential only. Must be done ≤48 hours prior to injection of study 
drug. Note: For a positive pregnancy test prior to the pre-RT 18F-DOPA injection the patient will 
not undergo the 18F-DOPA PET scan and will instead be taken off study with no follow-up.  
 
2. 
18F-DOPA post-injection AE assessment: done approximately 40-45 minutes post injection of 18F-
DOPA by the Nuclear Medicine technologist performing the study.  If an AE was observed, a 
second AE assessment is required ≤24 hours post injection. This assessment will be completed 
by the study staff. This information will be used for MCCC DSMB review (Section 16.91) and 
reporting of any AEs under 18F-DOPA IND (Section 10.0).  
 
3. Must be completed ≤ 14 days prior to the start of radiotherapy. 
 
4. CT simulation can be performed prior to or after registration. 
 
5. All follow-up serial imaging after initial treatment will occur until progression or up to 2 years. 
Typical timing of scans is every 2-3 months or until progression. However, the actual timing of 
scans for protocol patients will be per the clinician’s discretion.  
 
6 
To be assessed by Radiation Oncologist at baseline and during radiotherapy and Medical 
Oncologist for follow-up assessments for MCCC DSMB review (Section 16.91). Adverse events 
will be assessed weekly during routinely scheduled management visits (+/- 3 days) 
 
7. Maximum grade of adverse events experienced during radiotherapy can be recorded at the end 
 
of treatment.  
 
8.  Follow up assessments will be completed as per clinician’s discretion 
 
9.  Neurologic history and examination will be completed by treating Radiation Oncologist  
 
10. Quality of Life (QOL) and cognitive function will be evaluated with MD Anderson Symptom 
 
Inventory Brain Tumor Module (MDASI-BT) and the Brief Fatigue Index (BFI).  
 
11. Patient will be asked to complete questionnaires at baseline and at each MRI evaluation for a 
 
maximum of 6 evaluations.   
 
R. Research funded  
 
 
 


 
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5.0 
Grouping/Stratification Factors:  
 
None 
 
 
 


 
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6.0 
Registration Procedures:  
 
 
 
Patient will be registered to the study when they have consented, met eligibility criteria and 
 
have been logged into the Research Participant Tracking system (Ptrax). 
 
 
 
6.1 
Verify following procedures are complete prior to Registration to the study.  
 
 
 
6.11 
Prior to accepting the registration, verify the following: 
 
 
6.12 
IRB approval at the registering institution 
 
 
6.13 
Patient eligibility complete  
 
 
6.14 
Existence of a signed informed consent  
 
 
6.15 
Existence of a signed authorization for use and disclosure of protected  health  
 
 
 
information (optional) 
 
 
 
6.2 
Radiation therapy on this protocol must be performed at Mayo Clinic Rochester under  
 
 
the supervision of a radiation oncologist. 
 
 
 
6.3 
Tests and procedures (Section 4.0) must be completed within the guidelines specified on 
 
 
the test schedule. 
 
 
 


 
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7.0 
Protocol Treatment 
 
 
 
7.1 
CT simulation 
 
 
 
The patient will be immobilized with a BrainLab mask and a CT dataset acquired   
 
of the patient for treatment planning as per standard of care during the CT  
 
 
simulation appointment. 
 
 
 
7.2 
18F-DOPA-PET  
 
 
 
 
 
7.21 
Timing of PET scanning: 
 
 
 
 
 
 
 
The PET scan to be used for radiation treatment planning should be  
 
 
 
 
acquired no more than 14 days prior to beginning radiation treatments. 
 
 
 
 
 
7.22 
Patient preparation for PET scan 
 
 
 
 
 
 
 
7.221 A negative pregnancy test must be done ≤48 hours prior to 18F-DOPA  
 
 
 
 
injection for women of child-bearing potential only.  
 
 
 
 
7.222 Patients will be instructed to follow a low-protein diet after the previous 
 
 
evening meal. Liberal hydration 24 hours before the exam will be  
 
 
encouraged. Carbidopa, used for Parkinson’s patients to inhibit   
 
 
decarboxylation of the 18F-DOPA tracer, is not necessary for brain tumor 
 
 
imaging. 
 
 
 
7.23  
Selection of patients for PET/CT or PET/MRI 
 
7.231   PET/MRI is the planned method for obtaining anatomic correlation with 
18F-DOPA PET.PET/CT information is provided below in the circumstance 
that 18F-DOPA/MRI is not possible/available.  All requests to utilize 18F-
DOPA PET/CT will require approval from nuclear medicine and radiation 
oncology study chairs. 
 
 
 
7.24  
PET/CT 
 
7.241 A total of 5.0 + 10% mCi of 18F-DOPA will be intravenously injected. A 
scout image will be acquired in order to prescribe the scan range for the 
image acquisition. CT images will be obtained and used for attenuation 
correction of the PET data and, at 10 minutes after injection of 18F-
DOPA, a 20 minute 3D PET acquisition will be acquired. The PET data 
will also be acquired concurrently in list mode; this data will be used to 
salvage a scan should the patient move. The PET sinograms will be 
reconstructed with a fully 3D-OSEM algorithm into a 300 mm field of 
view with a pixel size of 1.17mm and slice thickness of 1.96mm. All 
images will be transferred to a Radiation Oncology workstation. 
 
 
 
7.25 
PET/MRI 


 
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7.251   
 The subject will undergo MRI screening for contraindications to 
 
scanning and contrast agent administration as per routine 
 
clinical protocol at Mayo Clinic. MRI will be acquired on a 
 
PET/MR scanner simultaneously during the 20 minute PET 
 
acquisition phase.    
 
7.252   
A total of 5.0 + 10% mCi of 18F-DOPA will be intravenously 
 
injected. A scout image will be acquired in order to prescribe 
 
the scan range for the image acquisition. MR images will be 
 
obtained and used for attenuation correction of the PET data 
 
and, at 10 minutes after injection of 18F-DOPA, a 20 minute 3D 
 
PET acquisition will be acquired. The PET data will also be 
 
acquired concurrently in list mode; this data will be used to 
 
salvage a scan should the patient move. The PET sinograms will 
 
be reconstructed with a time-of-flight algorithm into a 300 mm 
 
field of view with a pixel size of 1.17mm and slice thickness of 
 
2.78mm. All images will be transferred to a Radiation Oncology 
 
workstation. 
 
7.253  
The following MRI sequences will be obtained: Sagittal T1 FLAIR, 
 
Axial DWI, Axial T2 FLAIR, Axial BRAVO ARC, Gad Axial T2, Gad 
 
Sagittal Cube T1. 
 
  
 
7.3 
MRI Scanning 
 
 
 
 
 
7.31 
Patients requiring a separate diagnostic MRI 
 
Patients undergoing PET/CT will require a separate diagnostic MRI. Patients 
undergoing PET/MRI may omit this step, as diagnostic-quality images will be 
obtained with PET/MRI.   
 
7.32 
Screening for MR eligibility 
 
 
 
 
The subject will undergo MRI screening for contraindications to   
 
 
 
 
scanning and contrast agent administration as per routine clinical  
 
 
 
 
protocol at Mayo Clinic. 
 
 
 
 
 
7.33 
Timing of MR scanning 
 
 
 
 
 
 
 
MRI will be acquired at the time of the standard CE-MRI examination on  
 
 
 
a 3.0 Tesla field strength scanner, no more than 14 days prior to  
 
 
 
 
beginning radiation treatments 
 
 
 
 
Note: Standard treatment planning protocols will be used at the  
 
 
 
 
discretion of the radiation oncologist and radiologist, including T1-post   
 
 
 
contrast and T2 FLAIR sequences at a minimum 
 


 
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7.4 
Comparison of volumes 
 
 
 
 
To examine volumes delineated using 18F-DOPA-PET and MRI, the union,  
 
 
 
intersection and discordant regions of PET and MR volumes will be quantified.   
 
 
For patients with PET uptake outside of the MR volume, the percentage of PET   
 
 
uptake encompassed by several different margins beyond the MR defined  
 
 
 
volume will be determined, and the maximal distance (in millimeters) between   
 
 
the margin of the MR volume and the margin encompassing 100% of the PET  
 
 
 
uptake will be quantified. Both PET T/N ratio >2.0 and T/N ratio > 1.5 will be  
 
 
 
used to define the PET volume.  
 
 
 
 
 
7.41 
Exploratory analysis for other T/N thresholds and SUV levels will be investigated 
 
 
7.5 
Radiation therapy 
 
 
 
 
7.51 
Target delineation 
 
 
 
 
 
 
 
Following informed consent and co-registration of PET and MRI datasets  
 
 
 
with the planning CT acquired during standard CT simulation, the  
 
 
 
 
radiation oncologist will define the target volumes to use for radiation   
 
 
 
treatment planning.  
 
 
 
7.52 
Target delineation will be based on MRI and PET imaging, defining a  
 
 
 
 
gross tumor volume (GTV), clinical target volume (CTV), and planning  
 
 
 
 
target volume (PTV) as defined below. In the event that gross disease is   
 
 
 
multifocal on MRI or FDOPA-PET, contours do not need to be  
 
 
 
 
 
contiguous.  
 
 
 
 
 
 
 
 
 
7.5121 GTV_MRI = standard of care MRI contrast enhancement 
 
 
 
 
7.5122 GTV_PET = high signal PET disease  
 
 
 
 
7.5123 GTV_high = boolean of GTV_MRI and GTV_PET 
 
 
 
 
7.5124 CTV_high = GTV_high 
 
 
 
 
7.5125 PTV_high = CTV_high with a 0-2 mm expansion, based on the  
 
 
 
 
 
radiation oncologist’s clinical judgment 
 
 
 
 
 
7.53 
Treatment planning and delivery 
 
 
 
 
 
 
 
The prescription dose will be 35 Gy delivered in 10 fractions of 3.5 Gy  
 
 
 
 
each. Treatments will be delivered daily except weekends and holidays.  
 
 
 
 
7.531 For PTV_high volumes less than 75 cc, a dose of 40 Gy in 10  
 
 
 
 
 
fractions is allowed 
 
 
 
 
 
 
 
7.532 Target coverage and normal tissue constraints are outlined below 
 
 
Constraints Goals 
Highest Priority Constraints 
Structure 
DVH 
Endpoint 
Constraint 
Priority 
DVH 
Endpoint 
Constraint 
Priority 


 
19 
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CTV_high 
D95%[%] 
>=100% 
2 
D95%[%] 
>=95% 
1 
 
- 
- 
- 
CV95%[cc] 
<0.5cc 
1 
 
V110% 
 
Report 
- 
- 
- 
PTV_high 
D95%[%] 
>=99% 
2 
D95%[%] 
>=95% 
1 
 
- 
- 
- 
CV95%[cc] 
<0.5 cc 
1 
 
V110% 
 
Report 
- 
- 
- 
Brain-ptv 
- 
- 
- 
V36Gy 
<0.1 cc 
1 
 
V31Gy[cc] 
<1 cc 
2 
- 
- 
- 
 
V28Gy[cc] 
<5 cc 
2 
- 
- 
- 
 
- 
- 
- 
D0.03cc 
<35 Gy 
1 
Optic_chiasm_PRV 
D0.03cc 
<20 Gy 
2 
D0.03cc 
<25 Gy 
1 
Optic_chiasm 
- 
- 
- 
Dmax 
- 
Report 
Optic_nerve_l_PRV 
D0.03cc 
<20 Gy 
2 
D0.03cc 
<25 Gy 
1 
Optic_nerve_l 
- 
- 
- 
Dmax 
- 
Report 
Optic_nerve_r_PRV 
D0.03cc 
<20 Gy 
2 
D0.03cc 
<25 Gy 
1 
Optic_nerve_r 
- 
- 
- 
Dmax 
- 
Report 
Brainstem 
D0.03cc 
<24 Gy 
2 
D0.03cc 
<30 Gy 
1 
Cord 
- 
- 
- 
Dmax 
- 
Report 
Lens_r 
D0.03cc 
<4 Gy 
2 
- 
- 
- 
Lens_l 
D0.03cc 
<4 Gy 
2 
- 
- 
- 
Eye_r 
Mean 
<20 Gy 
2 
- 
- 
- 
 
D0.03cc 
<35 Gy 
2 
- 
- 
- 
Eye_l 
Mean 
<20 Gy 
2 
- 
- 
- 
 
D0.03cc 
<35 Gy 
2 
- 
- 
- 
Parotid_r 
Mean 
<16 Gy 
2 
- 
- 
- 
Parotid_l 
Mean 
<16 Gy 
2 
- 
- 
- 
Cochlea_r 
D0.03cc 
<35 Gy 
2 
- 
- 
- 
 
Mean 
<20 Gy 
2 
- 
- 
- 
Cochlea_l 
D0.03cc 
<35 Gy 
2 
- 
- 
- 
 
Mean 
<20 Gy 
2 
- 
- 
- 
Hippocampus_l 
Mean 
<20 Gy 
2 
- 
- 
- 
Hippocampus_r 
Mean 
<20 Gy 
2 
- 
- 
- 
 
7.54 
Brain constraints were determined using the cumulative normal tissue 
dose(NTDcumulative) constraint of 100 Gy in 2 Gy fractions (assuming α/β=2 for late 
brain toxicity) reported by Mayer et al. to minimize the risk of radiation 
necrosis.[30] Assuming the brain received a previous dose of 60 Gy in 30 
fractions, keeping the dose less than or equal to 31 Gy will result in an 
NTDcumulative of 99.5 Gy.   
 
7.55 
If the patient previously received less than 60 Gy in 2 Gy equivalent  
 
 
fractions, the brain constraint can be relaxed as to keep the NTDcumulative  below 
100 Gy. 
 
7.56 
Plans created using proton therapy will utilize robust optimization as per the 
departmental standard. No PTV will be needed for these patients. 
 


 
20 
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7.57 
ExacTrac or PAIS will be used for image guidance 
 
 
7.58 
Plan deviations 
 
Deviation 
 
Minor 
Major 
Target volumes 
CTV_high D95% 
between 90% and 
95% 
CTV_high D95% <90% 
Volume 
CTV or PTV margins 
larger than allowed in 
the protocol 
Contoured GTV does 
not include imaging-
visible tumor 
Organs at Risk 
Will be assessed at 
the time of data 
review 
Will be assessed at 
the time of data 
review 
 
7.6 
Concurrent chemotherapy  
 
 
 
Concurrent chemotherapy will not be required by the protocol. However, 
 
retrospective data of Mayo Clinic patients receiving reirradiation revealed a significantly 
 
lower risk of radionecrosis when bevacizumab was administered concurrently. Thus, we 
 
recommend use of concurrent bevacizumab with radiotherapy when possible.  
 
7.7 
Follow-up protocol 
 
7.71 
Follow-up imaging 
 
Once radiation treatment planning is complete, additional 18F-DOPA-PET scans 
will not be required. Standard of care MRI scans will be used for  follow-up 
imaging. 
 
7.8 
Response assessment 
 
 
 
Post-treatment tumor recurrence will be monitored with follow-up MRI  imaging to 
 
assess tumor response based on RANO Working Group criteria until progression or 
 
death (or up to 2 years) 
 
7.9 
Patterns of failure 
 
For patients who recur, follow-up imaging at progression will be co-registered with pre-
treatment imaging in MIM MaestroTM and patterns of failure will be analyzed in the 
Eclipse treatment planning software (Varian Medical Systems, Palo Alto, CA) by 
determining the portion of recurrence volume (RecVol) that falls within the 95% isodose 
line of the PTV from the reirradiation plan.   
 
7.91 
Failures will be documented as ‘central’ relative to the treatment volume if  
 
>95% of the recurrence volume is within the 95% isodose line,‘in field’ (80-95%), 
 
‘marginal’ (20-80%), or ‘distant’ (<20%).  
 


 
21 
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7.92 
Failures will be documented as ‘central’ relative to the T1-CE MRI if  
 
 
>95% of the recurrence volume is within the T1-CE volume, ‘in field’ (80-
 
95%),‘marginal’ (20-80%), or ‘distant’ (<20%). 
 
7.93 
Failures will be documented as ‘central’ relative to the 18F-DOPA-PET  
 
 
avidity if >95% of the recurrence volume is within the PET volume  
 
 
(defined as T/N > 2.0), ‘in field’ (80-95%), ‘marginal’ (20-80%), or ‘distant’ 
 
(<20%). 
 
 
 
7.931 Exploratory analysis for T2 FLAIR volumes, other T/N thresholds and  
 
 
SUV levels and their relationship with sites of failure will be investigated  
 
7.10 
Reoperation rates 
 
Patients undergoing repeat surgical intervention will have the date of the procedure, 
operative intervention performed, and pathologic findings recorded 
 
7.11 
Outcomes 
 
Outcomes for patients treated prospectively with the addition of 18F-DOPA-PET image-
guided radiotherapy will be determined based on comparison with historical controls in 
the published literature.[24-29, 33-36] 
 
7.12 
Acute and late toxicity monitoring 
 
Using the standard doses, target volumes and constraints described above, previous 
studies have reported minimal acute or late toxicity.[24-27, 30]  
 
7.13 
Quality of life  
 
Quality of life (QOL) and cognitive function will be evaluated with the MD Anderson 
Symptom Inventory Brain Tumor Module (MDASI-BT) and the Brief Fatigue Index (BFI). 
Every patient will be asked to complete the whole form packet at baseline and at each 
MRI evaluation for a maximum of 6 evaluations. These time points are selected to 
capture the quality of life profile and correlate findings with radiologic and clinical 
progression as well as time points used on prior studies to allow historical comparisons. 
8.0 
Dosage Modification Based on Adverse Events 
 
 
 
If a patient develops an allergic reaction during injection of 18F-DOPA, the patient is not   
 
to receive any additional tracer and will not undergo PET imaging and will go off study.’ 
 
 
 
 
 


 
22 
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9.0 
Ancillary Treatment/Supportive Care:  
 
 
 
None 
 
 
 


 
23 
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10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Definitions/18F-DOPA 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  Serious 
problems/events can be well defined and include; 
• 
death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor 
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which 
may be physical, psychological, financial, social, economic, or legal) or 
increased risk for the subject or others (including individuals who are not 
research subjects). These include: (1) death; (2) life threatening adverse 
experience; (3) hospitalization - inpatient, new, or prolonged; (4) 
disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information 
(i.e. publications, DSMB reports, interim findings, product labeling change) 
that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the 
research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not 
already described as potential risks in the protocol, consent document, not 
listed in the Investigator’s Brochure, or not part of an underlying disease. A 
problem or event is "unanticipated" when it was unforeseeable at the time of 
its occurrence. A problem or event is "unanticipated" when it occurs at an 
increased frequency or at an increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
• Preexisting Condition- A preexisting condition is one that is present at the start 
of the study.  A preexisting condition should be recorded as an adverse event 
if the frequency, intensity, or the character of the condition worsens during 
the study period. At screening, any clinically significant abnormality should be 
recorded as a preexisting condition.  At the end of the study, any new clinically 


 
24 
MC167B 
 
significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event.  
 
 
10.2 
Recording Adverse Events/18F-DOPA 
 
 
 
 
 
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) 
 
10.21 Adverse event monitoring and reporting is a routine part of every clinical trial.  
 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
 
Next, determine whether the event is expected or unexpected and if the 
 
adverse event is related to the medical treatment or procedure. With this 
 
information, determine whether the event must be reported as an expedited 
 
report (see Section 10.25). 
 
 
 
Expedited and routine reports are to be completed within the timeframes and 
 
via the mechanisms specified in Sections 10.4 and 10.6.  All expected AE reports 
 
must also be sent to the local Institutional Review Board (IRB) according to local 
 
IRB’s policies and procedures. 
 
10.22 Assessment of Attribution/18 F-DOPA 
 
 
Patients will be observed for adverse events for approximately 15-20 minutes 
 
post 18F-DOPA injection by the Nuclear Medicine health professionals 
 
administering the scan. If AE is observed a second AE assessment is required <  
 
24 hours post injection which will be performed by study staff.  
 
 
 
 
 
 
10.221 When assessing whether an adverse event is related to the 18FDOPA  
 
 
 
 
injection, the following attribution categories are utilized: 
 
PET adverse events 
Definite - The adverse event is clearly related to the PET scanning and 18F-DOPA  
 
injection 
Probable - The adverse event is likely related to the PET scanning and 18F-DOPA  
 
injection 
Possible - The adverse event may be related to PET scanning and 18F-DOPA  
 
injection 
Unlikely - The adverse event is doubtfully related to the PET scanning and 18F-
 
DOPA injection 
Unrelated - The adverse event is clearly NOT related to the PET scanning and 
 
18F-DOPA injection 
 
 


 
25 
MC167B 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the agent and the adverse event. 
 
 
10.3 
 Expected vs. Unexpected/ 18F-DOPA 
 
 
• 
The determination of whether an AE is expected is based on agent-specific 
adverse event information provided in Section 15.0 of the protocol.  
 
 
• 
Unexpected AEs are those not listed in the agent-specific adverse event 
information provided in section 15.0 of the protocol.  
 
 
NOTE: “Unexpected adverse experiences” mean any adverse experience that is neither  
 
 
identified in nature, severity, or frequency of risk, in the information neither  
 
 
provided for IRB review nor mentioned in the consent form.  
 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents/ 18F-DOPA 
 
 
 
 


 
26 
MC167B 
 
NOTE: Use paper Adverse Event Expedited Report- Single Agent to report SAEs.  
 
Provide copies of all serious events, regardless of drug relatedness, along with the Event Reporting cover 
sheet to: 
 
Dr. Brian Mullan (18FDOPA IND 61300 sponsor) at bmullan@mayo.edu , and Lori Lutzke (Nuclear 
Medicine Clinical Research Coordinator/IND Coordinator) at Lutzke.Lori@mayo.edu. These email 
notifications will be managed by the SAE, IND, and Safety Reporting Coordinators.  
 
 
 
 
 
10.41 Special Situations for Expedited Reporting/18F-DOPA 
 
 
 
 
 
 
 
Exceptions to Expedited Reporting: 18F-DOPA  
 
 
 
 
An expedited report may not be required for specific Grade 1, 2 and 3   
 
 
 
Serious Adverse Events. Any protocol specific reporting procedures MUST BE SPECIFIED  
 
 
BELOW and will supersede the standard Expedited Adverse Event Reporting  
 
 
 
Requirements: Hospitalizations for reasons deemed to be disease related will not be  
 
 
 
 
reported. 
 
 
System Organ Class (SOC) 
Adverse event/symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported. 
Immune system disorders 
Allergic Reaction 
≤ Grade 3 
Nervous system disorders 
Vasovagal reaction 
≤ Grade 3 
Injury, poisoning and procedural 
complications 
Bruising 
≤ Grade 3 
Skin and subcutaneous tissue 
disorder 
Rash maculo-papular 
≤ Grade 3 
 
 
 
 
 
 
PET scanning, PET tracer injections are the only procedures unique to this study. All other aspects of 
radiation therapy and follow-up are part of standard brain cancer treatment. Consequently, only 
adverse events  possibly, probably, or definitely related to 18F-DOPA PET administration will be graded 
and reported to the IRB. 
 
Report any clinically important increase in the rate of a serious suspected adverse reaction over that 
which is listed in the protocol or investigator brochure as an expedited. 
 
Report an expected event that is greater in severity or specificity than expected as an expedited event. 
 
 
10.5 
Other Required Reporting/ 18F-DOPA 
 
 
 
 
 
10.51 Persistent or Significant Disabilities/Incapacities / 18F-DOPA 
 
 
 
 
 
 
 
Any AE that results in persistent or significant incapacity or substantial   
 
 
 
disruption of the ability to conduct normal life functions (formerly referred to as 
 
 
 
disabilities), congenital abnormities or birth defects, must be reported   
 
 
 
immediately if they occur up to 24 hours post injection following administration  


 
27 
MC167B 
 
of the investigational agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 
312.64(b). 
 
 
 
10.52 Death/18F-DOPA 
 
 
 
 
 
The reporting period for 18F-DOPA for this study is 1 day. 
 
 
 
 
Any death occurring within 1 day after 18F-DOPA agent was last administered or  
 
 
 
within 30 days of the last radiation dose, regardless of attribution requires  
 
 
 
expedited reporting within 24 hours. 
 
 
 
 
Any death occurring greater than 1 day after the last 18F-DOPA agent was  
 
 
 
administered with an attribution of possible, probable, or definite requires  
 
 
 
expedited reporting within 24 hours. 
 
 
 
 
Reportable categories of Death 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term associated with Grade 
5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
 
 
 
10.6 
Reporting of Serious Adverse Events and Unanticipated Problems/ 18F-DOPA 
 
 
When an adverse event has been identified, the study team will take appropriated 
action necessary to protect the study participant and then complete the Study Adverse 
Event Worksheet and log.  The investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
10.61 Serious Adverse Events will be reported as part of regular adverse event 
 
reporting mechanisms via the data capture system and logged for review 
 
reporting. 
 
10.62 Investigator Reporting: Notifying the Mayo IRB/18F-DOPA: 
 
The IRB requirements reflect the guidance documents released by the Office of 
 
Human Research Protections (OHRP), and the Food and Drug Administration 


 
28 
MC167B 
 
 
(FDA) in early 2007 and are respectively entitled “Guidance on Reviewing and 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
 
Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs: 
 
Adverse Event Reporting – Improving Human Subject Protection.” 
 
10.621 
According to Mayo IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible 
but no later than 5 working days after the investigator first 
learns of the problem/event. 
 
10.622 
Non-UPIRTSO – the investigator reports problems or events that 
do NOT meet criteria of an UPIRTSO in summary format at the 
time of the next continuing review. The investigator monitors 
the severity and frequency of subsequent non-UPIRTSOs. 
 
 
Consider the following information to collect when developing  
 
 
any forms for documentation of adverse events. 
 
 
Example 
 
 
Information collected on the adverse event worksheet (and  
 
 
entered in the research database):  
• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, 
procedure, or intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define 
severity scale 1-5) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or 
after discontinuing treatment) 
• 
Date of Resolution:  
 
The investigator will review all adverse event reports to 
determine if specific reports need to be made to the IRB and 
FDA.  The investigator will sign and date the adverse event 
report when it is reviewed (if applicable).  For this protocol, only 
directly related SAEs/UPIRTSOs will be reported to the IRB. 
 
 
 
 
 
 


 
29 
MC167B 
 
10.7 
18F-DOPA adverse events to be graded prior to and post 18F-DOPA scan per the CTCAE 
v4.0 grading unless otherwise stated in the table below: 
 
 
System Organ Class (SOC) 
 
Adverse 
event/Symptoms 
 
Baseline 
Post 
injection 
assessment1 
Immune system 
disorders 
Allergic reaction 
 
X 
Nervous system 
disorders 
Vasovagal reaction 
 
X 
Injury poisoning and 
procedural complications 
Bruising 
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
Renal and urinary 
disorders 
Acute kidney injury 
 
X 
1. This assessment should occur approximately 15-20 minutes post injection (after scan is 
completed) 
 
 
 
10.71 Submit via appropriate reporting mechanisms (i.e., paper or electronic) the 
following AEs experienced by a patient and not specified in Section 10.4: 
 
10.711 
Grade 2 AEs deemed possibly, probably, or definitely related to 
the 18 F-DOPA PET scan. 
 
 
 
 
 
10.712  
Grade 3 and 4 AEs regardless of attribution to the 18 F-DOPA  
 
 
 
PET scan. 
 
10.713  
Grade 5 AEs (Death) 
 
 
10.714 
Any death within 30 days of the patient’s last study treatment 
or procedure regardless of attribution to the study treatment or 
procedure 
 
10.715 
Any death more than 30 days after the patients last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with 
a CTCAE type and attribution assigned. 
 
10.8 
Recording Adverse Events/Radiation Therapy 
 
 
 
 
 
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:  
 
 
 
 
 
 
 
 
 
 


 
30 
MC167B 
 
 
 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
 
10.81 Adverse event monitoring and reporting is a routine part of every clinical trial.  
 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
 
Next, determine whether the event is expected or unexpected and if the 
 
adverse event is related to Radiation Therapy. With this  information, determine 
 
whether the event must be reported as an expedited report (see Section 10.9).  
 
 
 
Expedited and routine reports are to be completed within the timeframes and 
 
via the mechanisms specified in Sections 10.4 and 10.6.  All expected AE reports 
 
must also be sent to the local Institutional Review Board (IRB) according to local 
 
IRB’s policies and procedures. 
 
10.82 Assessment of Attribution 
 
 
10.821 Patients will be regularly evaluated by a radiation oncology health  
 
 
professional per standard clinical practice throughout their course of  
 
 
external beam radiation therapy.  
 
 
 
 
 
 
 
10.822 When assessing whether an adverse event is related to Radiation  
 
 
 
 
Therapy, the following attribution categories are utilized: 
 
 
 
 
RT adverse events 
 
Definite- The adverse event is clearly related to RT 
 
Probable- The adverse event is likely related to RT 
 
Possible- The adverse event may be related to RT 
 
Unlikely- The adverse event is doubtfully related to RT 
 
Unrelated- The adverse event is clearly NOT related to RT 
 
Events determined to be possibly, probably or definitely attributed to a medical treatment 
 
suggest there is evidence to indicate a causal relationship between the treatment and the 
 
adverse event. 
 
10.9 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
 
When an adverse event has been identified, the study team will take appropriate action 
 
necessary to protect the study participant and then complete the Study Adverse Event 
 
Worksheet and log. The investigator will evaluate the event and determine the necessary 
 
follow-up and reporting required.  
 
 
10.91  
Serious Adverse Events will be reported as part of regular adverse event  
 
 
 
reporting mechanisms via the data capture system and logged for review  
 
 
 
reporting.  
 
10.10 Radiation Therapy adverse events to be graded at each evaluation and pretreatment 
 
symptoms/conditions to be evaluated at baseline per CTCAE v4.0 grading unless otherwise 
 
stated in the table below: 
 


 
31 
MC167B 
 
 
 
System Organ Class (SOC) 
 
Adverse 
event/Symptoms 
 
Baseline 
During 
Treatment  
 
Active 
Monitoring 
General disorders and 
administration site 
conditions  
Fatigue 
X 
 
X 
Immune system 
disorders 
Allergic reaction 
 
X 
 
Nervous system 
disorders 
Central nervous 
system necrosis 
 
 
X 
Nervous system 
disorders 
Vasovagal reaction 
 
X 
 
Injury poisoning and 
procedural complications 
Bruising 
X 
X 
 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
 
 
10.101  
Submit via appropriate reporting mechanisms (i.e., paper or electronic) the  
 
following AEs experienced by a patient. 
 
10.1011 
Grade 2 AEs deemed possibly, probably, or definitely related to 
the Radiation Therapy 
 
 
 
 
 
10.1012 
Grade 3 and 4 AEs regardless of attribution to Radiation  
 
 
 
Therapy 
 
10.1013  
Grade 5 AEs (Death) 
 
 
10.1014 
Any death within 30 days of the patient’s last treatment or 
procedure regardless of attribution to the study treatment or 
procedure 
 
10.1015 
Any death more than 30 days after the patients last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with 
a CTCAE type and attribution assigned. 
 
 
10.11  Special Situations for Expedited Reporting/Radiation Therapy 
 
 
Exceptions to Expedited Reporting/Radiation Therapy 
 
 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse Events. 
 
Any protocol specific reporting procedures MUST BE SPECIFIED BELOW and will supersede the 
 
standard Expedited Adverse Event Reporting 
  
 


 
32 
MC167B 
 
 
Requirements: Hospitalizations for reasons deemed to be disease related will not be reported. 
 
 
System Organ Class (SOC) 
Adverse event/symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported. 
General disorders and 
administration site conditions 
Fatigue 
≤ Grade 3 
Immune system disorders 
Allergic Reaction 
≤ Grade 3 
Nervous system disorders 
Central nervous system necrosis  
≤ Grade 3 
Nervous system disorders 
Vasovagal reaction 
≤ Grade 3 
Injury, poisoning and procedural 
complications 
Bruising 
≤ Grade 3 
Skin and subcutaneous tissue 
disorder 
Rash maculo-papular 
≤ Grade 3 
 
All aspects of radiation therapy and follow-up are part of standard brain cancer treatment. All toxicities 
associated with other components of conventional brain cancer treatment (e.g. hematological events 
resulting from chemotherapy) will not be graded or reported as part of this protocol.  
 
Report any clinically important increase in the rate of a serious suspected adverse reaction over that 
which is listed in the protocol or investigator brochure as an expedited. 
 
Report an expected event that is greater in severity or specificity than expected as an expedited event. 
 
10.12 Death/ Radiation Therapy  
 
 
 
The reporting period for radiation therapy for this study is 30 days.  
 
Any death occurring greater than 30 days after the last radiation dose was  
 
 
 
administered with an attribution of possible, probable, or definite requires  
 
 
 
expedited reporting within 24 hours. 
 
Reportable categories of Death 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term associated with Grade 
5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 


 
33 
MC167B 
 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
 
 
 
10.121  
Second Malignancy/ Radiation Therapy  
 
 
 
 
 
 
 
A second malignancy is one unrelated to the treatment of a prior  
 
 
 
 
malignancy (and is NOT a metastasis from the initial malignancy).  
 
 
 
 
Second malignancies require ONLY routine reporting.  
 
 
 
All secondary malignancies that occur following treatment will be reported.  
 
 
 
Three options are available to describe the event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS)  
 
 
 
should also be reported via the routine reporting mechanisms.  
 
 
10.122  
Second Malignancy/ Radiation Therapy  
 
 
 
 
 
 
 
A second malignancy is one unrelated to the treatment of a prior malignancy  
 
 
 
(and is NOT a metastasis from the initial malignancy). Second malignancies  
 
 
 
require ONLY routine reporting.  
 
 
10.13 
Monitoring and Auditing  
 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). Participation as an investigator in 
this study implies acceptance of potential inspection by government regulatory 
authorities and applicable compliance offices 
 
10.131 Medical Monitoring  
 
 
It is the responsibility of the Principal Investigator to oversee the safety of the   
 
study at his/her site.  This safety monitoring will include careful assessment and   
 
appropriate reporting of adverse events as noted above, as well as the   
 
 
construction and implementation of a site data and safety-monitoring plan (see   
 
section 10.7  “Monitoring and Auditing”).  Medical monitoring will include a  
 
 
regular assessment of the number and  type of  serious adverse events.  “Any   
 
serious adverse events will be followed up by the sentinel event reporting  
 
 
procedure” 
 
 
 
 
10.132 Internal Data and Safety Monitoring Board  


 
34 
MC167B 
 
 
 
 
 
 
 
The trial will be reviewed by the Cancer Center Auditing area on a bi-annual or   
 
 
yearly basis dependent on random study selection to assess accrual, adverse  
 
 
 
events, and any endpoint problems.  Any safety issues requiring protocol  
 
 
 
changes will be communicated through protocol amendments.  
 
 
 


 
35 
MC167B 
 
11.0 
Treatment Evaluation 
 
11.1 
Measurement of Effect 
 
 
 
 
 
Tumor response will be assessed, using contrast and non-contrast brain magnetic  
 
 
resonance imaging (MRI) with assessment based on the RANO criteria, until progression  
 
 
of disease (up to 2 years). 
 
 
 
11.2 
Definitions:  
 
 
 
Response and progression will be evaluated in this study using the international criteria  
 
proposed by the Response Assessment in Neuro-Oncology (RANO) Working Group.[14]  
 
 
 
 
 
Note: Lesions are either measurable or non-measurable using the criteria provided  
 
 
below. The term “evaluable” in reference to measurability will not be used because it  
 
 
does not provide additional meaning or accuracy. 
 
 
 
 
 
11.21  Measurable Disease  
 
 
 
 
 
 
 
Defined as bi-dimensionally contrast-enhancing lesions with clearly-defined  
margins by MRI with two perpendicular diameters of at least 10 mm, visible on 
2 or more axial slices which are preferably at most 5 mm apart with 0 mm skip.  
 
 
 
 
In the event the MRI is performed with thicker slices, the size of a measurable  
 
 
 
lesion at baseline should be two times the slice thickness. In the event there are  
 
 
 
inter-slice gaps, this also needs to be considered in determining the size of  
 
 
 
measurable lesions at baseline. Measurement of tumor around a cyst or surgical 
 
 
 
cavity is problematic. In general, such lesions should be considered non-  
 
 
 
measurable unless there is a nodular component measuring at least 10 mm in  
 
 
 
diameter. The cystic or surgical cavity should not be measured in determining  
 
 
 
response. All tumor measurements must be recorded in millimeters (or decimal  
 
 
 
fractions of centimeters). 
 
 
 
 
 
11.22 Non-measurable Disease 
 
This is defined as either uni-dimensionally measurable lesions, masses with 
margins not clearly defined, or lesions with maximal perpendicular diameters 
<10 mm. 
 
11.23 Target Lesions 
 
All measurable lesions up to a maximum of five lesions should be identified as 
target lesions and recorded and measured (sum of the products of the 
perpendicular diameters) at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameters) and their suitability for 
accurate repeated measurements by imaging techniques. Occasionally, the 
largest lesions may not be suitable for reproducible measurements and the next 
largest lesions which can be measured reproducibly should be selected. 


 
36 
MC167B 
 
 
11.24 Non-target Lesions 
 
For patients with recurrent disease who have multiple lesions of which only one 
or two are increasing in size, the enlarging lesions should be considered the 
target lesions for evaluation of response. The other lesions will be considered 
non-target lesions and should also be recorded. Rarely, unequivocal progression 
of a non-target lesion requiring discontinuation of therapy, or development of a 
new contrast-enhancing lesion may occur even in the setting of stable disease 
(SD) or partial response (PR) in the target lesions. These changes would qualify 
as progression. Non-target lesions also include measurable lesions that exceed 
the maximum number of 5. Measurements of these lesions are not required but 
the presence or absence of each should be noted throughout follow-up. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
 
 
All measurements should be taken and recorded in metric notation using a ruler or 
 
calipers. Baseline evaluations should ideally be performed within 21 days before the 
 
beginning of treatment. These techniques should be performed with cuts of 4 mm or 
 
less in slice thickness contiguously. The MRIs will be evaluated both locally and centrally 
 
by a core lab. 
 
11.4 
Response Criteria 
 
11.41  Evaluation of Target Lesions 
 
 
 
11.411 Complete Response (CR): Requires all of the following: 
• 
Complete disappearance of all enhancing measurable and non-
measurable disease sustained for at least 4 weeks 
• 
No new lesions 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions 
• 
Patients must be off corticosteroids 
• 
Stable or improved clinically 
• 
Patients with non-measurable disease cannot have a complete 
response. The best response possible is stable disease. 
 
11.412 Partial Response (PR): Requires all of the following: 
• 
≥50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks 
• 
No progression of non-measurable disease 
• 
No new lesions 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared to baseline scan 
• 
The corticosteroid dose at the time of the scan evaluation should be 
no greater than the dose at time of the baseline scan 
• 
Stable or improved clinically 


 
37 
MC167B 
 
 
11.413 Stable Disease (SD): Requires all of the following:  
• 
Does not qualify for complete response, partial response, or 
progression 
• 
Minimum 4 weeks duration 
• 
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. In the event that the 
corticosteroid dose has been increased, the last scan considered to 
show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose 
• 
Stable clinically 
 
11.414 Progression: Defined by any of the following:  
• 
≥25% increase in the sum of products of perpendicular diameters of 
enhancing lesions compared to the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on 
stable or increasing doses of corticosteroids 
• 
Significant increase in T2/FLAIR non-enhancing lesion on stable or 
increasing doses of corticosteroids compared to baseline scan or 
best response following initiation of therapy, not due to co-morbid 
events (e.g. radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment 
effects) 
• 
Any new lesion 
• 
Clear clinical deterioration not attributable to other causes apart 
from the tumor (e.g. seizures, medication side effects, 
complications of therapy, cerebrovascular events, infection, etc.) or 
changes in corticosteroid dose. The definition of clinical 
deterioration is left to the discretion of the investigator but it is 
recommended that a decrease in 20% of KPS or from any baseline 
to 50% or less be considered, unless attributable to co-morbid 
events. 
• 
Failure to return for evaluation due to death or deteriorating 
condition 
• 
Clear progression of non-measurable disease 
 
11.415 Pseudoprogression (PsP): All of the following must be true: 
• 
Progression of contrast enhancing lesions and or T2/FLAIR is 
restricted to the initial radiation therapy volume. 
• 
There are no new enhancing lesions outside of the initial radiation 
therapy volume. 
• 
Patients are stable or improved clinically. 
• 
PsP may be diagnosed at any time during therapy (beyond the 
typical 12 week window defined by RANO). 
 
 
 




 
39 
MC167B 
 
assessments that should be performed 4  
weeks 
after the criteria for response are first met. 
 
 
 
11.4172 
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).  The duration of overall CR is   
 
 
 
 
measured from the time measurement criteria   
 
 
 
are first met for CR until the first date that  
 
 
 
 
recurrent disease is objectively documented. 
 
 
 
11.4173 
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. 
 
 


 
40 
MC167B 
 
12.0 
Descriptive Factors 
• 
Corticosteroid therapy at study entry: yes (specify dose) vs no 
• 
Histologic grade of primary tumor: 3 vs 4 
• 
Histologic type of primary tumor: oligodendroglioma vs oligoastrocytoma vs astrocytoma vs 
other (specify) 
• 
ECOG PS (see Appendix I): 0 vs 1 vs 2 vs 3 
• 
Neurologic deficit: yes (specify) vs no 
• 
History of seizures:  yes (specify last seizure) vs no 
• 
Prior surgical resection or biopsy: yes vs no 
• 
Age:<=70 vs >70 
• 
MGMT: methylated vs unmethlated vs not available 
• 
IDH status: mutated vs wild type vs not available 
• 
1p/19q status: single deleted vs codeleted vs not available 
• 
Time since last RT course: <6 months vs 6-12 months vs >12 months 
• 
Salvage chemotherapy: yes (specify agents, dates treated) vs no 
 
 
 


 
41 
MC167B 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
 
 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of  
 
 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
 
 
The patient will go off study. 
• 
If the patient received MR and PET for radiotherapy planning, all data up until 
the point of confirmation of ineligibility must be submitted. 
• 
If the patient never received pre-RT PET, on-study material must be submitted. 
No additional follow up is necessary.  
 
 
13.2 
Those patients who will not receive any radiation treatment or who will receive 
radiation treatment elsewhere (not at Mayo Clinic) will be considered non-evaluable for 
the study endpoint and move to Event Monitoring phase per Section 18.0. 
 
 
 
13.3 
Patients who are CR, PR, REGR, or SD will continue to obtain MRI scans at each clinically  
 
 
indicated follow-up for up to 2 years from registration. 
 
 
 
13.4 
Patients who develop PD or withdraw from further follow-up scans will go to the event- 
 
 
monitoring phase per Section 18.0. 
 
 
 


 
42 
MC167B 
 
14.0 
Body Fluid Biospecimens: None 
 


 
43 
MC167B 
 
15.0 
Drug Information 
 
 
18F-DOPA is an investigational PET tracer utilized for the study under a Mayo physician-sponsor 
IND #61300 held by Dr. Brian P. Mullan in the division of Nuclear Medicine.  The 18F-DOPA is 
produced in the Mayo Clinic  PET Radiochemistry Facility using Good Manufacturing Practice as 
defined by 21 CFR Part 212. 
The literature reports no deleterious effect was revealed in toxicity testing of 18F-DOPA-PET, and 
concludes the toxicological safety of the product is guaranteed given the toxicity data of the 
various potential impurities. 18F-DOPA-PET is currently in production at this institution, and is 
used to image malignant gliomas for research studies MC 1373 (IRB 13-005102) and MC 1374 
(IRB 13-005106). 


 
44 
MC167B 
 
16.0 
Statistical Considerations and Methodology 
 
 
 
16.1 
Study Overview 
 
This is a single-arm, single-stage phase II Simon’s Optimum study with an analysis that 
will compare progression-free survival (PFS) at 3 months for recurrent glioma patients 
after radiotherapy targeting volumes designed with both 18F-DOPA-PET and MRI 
information with historical controls.  
 
16.11 
The primary endpoint of this trial is the proportion of patients that experience  
  
progression-free survival at 3 months based on our hypothesis that the   
  
combination of more accurate target delineation of high-grade glioma by 18F- 
  
DOPA-PET will improve overall tumor control.  
 
16.2 
Statistical Design 
 
16.21 Decision Rules 
 
The primary endpoint of this trial is the proportion of patients treated with 18F-
DOPA-PET guided radiotherapy who are alive and have not progressed within 3 
months. A success will be a patient who is alive and without evidence of 
progressive disease within 3 months from registration. Median PFS after 
bevacizumab failure ranges between 1-2 months.[17, 34] Thus, the largest 
success proportion where the proposed treatment would be considered 
ineffective in this population is 20%. The following Simon’s Optimum design 
uses 20 patients to test the null hypothesis that the proportion of successes is at 
most 20% with an overall significance level (alpha) of 0.186, and a power of 
85.9% to detect a true success proportion of 40%.  
 
16.22 After 10 evaluable patients are accrued to this study and followed for at least 3  
 
months, if 2 or more successes are alive and progression-free at 3 months, the 
 
results will wait until conclusion of the study. If 1 or fewer patients are alive 
 
without evidence of progression at 3 months, the study will be stopped  and the 
 
treatment will be deemed ineffective in this population.  
 
16.23 After 20 evaluable patients are accrued to this study and followed for at least 3 
 
months, if 6 or more successes are observed we may recommend further 
 
testing of this regimen in subsequent studies in this patient population.  
 
16.24 We will not suspend accrual between stages to allow the first 20 patients to 
 
become evaluable, unless undue toxicity is observed. 
 
16.3 
Sample Size 
 
 
The design to be utilized is fully described in section 0. A maximum of 20 
 
evaluable patients will be accrued to this pilot study unless undue toxicity is 


 
45 
MC167B 
 
 
encountered. We anticipate accruing an additional 2 patients to account for 
 
ineligibility, cancellation, major treatment violation or other reasons. Maximum 
 
projected accrual is therefore 22 patients. We anticipate screening 30 patients to 
 
register a total of 22 patients necessary for study design. 
 
16.4 
Accrual Time and Study Duration 
 
Based on institutional experience, we deliver RT to an average of 25 recurrent glioma 
patients annually. Our plan to accrue 10 patients per year is based on including less than 
50% of our recurrent glioma RT population, which is readily achievable. We plan to 
accrue patients for years 1-2, leaving years 3-4 for follow-up and analysis. Therefore, the 
overall study duration is expected to be  48 months.  
 
16.5 
Power and Significance Levels 
 
 
Assuming the number of successes is binomially distributed, the significance level is 
0.186 and probability of declaring that this regimen warrants further studies (i.e. 
statistical power) under various success proportions and the probability of stopping 
accrual after the first stage can be tabulated as a function of the true success proportion 
as shown in the following table.  
 
16.6 
Other considerations: 
 
 
 
Adverse events and patterns or failure observed in this study as well as scientific 
 
discoveries or changes in standard care will be taken into account in any decision to 
 
terminate the study. 
 
16.7 
Analysis plan 
 
 
The analysis for this trial will commence at the planned time points (see Section 4.0) and 
at the time patients have become evaluable for the primary endpoint. Such decisions 
will be made by the statistician and the study chair, in accord with the Cancer Center 
Statistics (CCS) Standard Operating Procedures, availability of data for secondary 
endpoints, and level of data maturity. The earliest date anticipated in which results will 
be available for manuscript, abstract or presentation format is when 20 patients have 
either progressed or been followed for at least 3 months. Subgroup analyses will be 
included for this primary endpoint to assess known prognostic factors such as MGMT 
status, age, and time from prior RT to reirradiation. 
 
16.71 Primary Endpoint: 
 
 
16.711 Definition: the primary endpoint of this trial is proportion of patients 
experiencing progression-free survival at 3 months. All patients meeting eligibility 
criteria who have a signed consent form on record and who have begun 18F-DOPA-
guided reirradiation treatment at Mayo Clinic will be evaluable for the endpoint. All 
eligible patients will be followed until death or a maximum of 4 years. Time to disease 
progression is defined as the time from study registration to the earliest date 
documenting disease progression. If a patient dies without evidence of disease 


 
46 
MC167B 
 
progression, the patient will be censored on the last date the tumor was evaluated. If a 
patient is declared to be a major treatment violation, the patient will be censored on 
the date the treatment violation was declared to have occurred. In the case of a patient 
starting treatment and then never returning for any evaluation, the patient will be 
censored for progression on the last day of therapy. 
 
16.712 Estimation: the proportion of successes will be estimated by the  
 
number of successes divided by the total number of evaluable patients.  
 
Confidence intervals for the true success proportion will be calculated 
 
according to the approach of Duffy and Santner.[37] 
 
16.713 Over Accrual: if more than the target number of patients are 
 
accrued, the additional patients will not be used for evaluation  of  
 
stopping rules or in any decision making process. The will be  
 
included in the final point estimates and confidence limits.  
 
16.8 
 
Definitions and Analysis of Secondary and Correlative Endpoints 
 
 
 
Subgroup analyses will be included as appropriate for these secondary 
 
endpoints to assess known prognostic factors.  
 
 
 
16.81  Overall Survival: compare overall survival (OS) at 12 months for   
 
 
 
patients after radiation therapy targeting volumes designed using 18F- 
 
 
 
DOPA in addition to MRI contrast enhancement with historical controls.   
 
 
Survival time will be determined from the time of initial diagnosis to  
 
 
 
death from any cause. Survival from reirradiation will be determined  
 
 
 
from the time of study registration to the time of death from any cause.  
 
 
The distributions of the survival time will be estimated using the Kaplan- 
 
 
Meier method.[38] 
 
 
 
16.82 Volumetric Comparison: to differences in the 18F-DOPA-PET avid region   
 
 
with abnormalities on MRI, the treating radiation oncologists will first   
 
 
define treatment volumes for GTV_MRI using the T1-post contrast MRI   
 
 
scans while blinded to the PET study. A volume named T2_FLAIR_NCET will be  
 
 
defined by outlining T2 hyperintensity on T2 FLAIR MRI sequences. Then  
 
 
the PET study will be fused with the contouring software to allow  
 
 
 
automated contouring of GTV_PET defined by the T/N ratio > 2.0 (and   
 
 
T/N > 1.5). These contours will be reviewed by the treating radiation  
 
 
 
oncologist and then expanded as noted above. The volume of overlap   
 
 
and non-overlap between the GTV_MRI, T2_FLAIR_NCET and GTV_PET will be  
 
 
calculated. Paired t-test statistical analysis will be performed to   
 
 
 
determine if any differences exist and the level of statistical significance  
 
 
between treatment volumes defined by MRI only and the treatment  
 
 
 
volumes defined by both PET and MRI. The analysis of volumes from 20   
 
 
patients will have 80% power to detect differences in volumes with an   
 
 
effect size of 0.63 using a pared t-test with 0.05 two-sided significance level.  
 
 
Alternate metrics for comparison will also be assessed including  spatial overlap,  
 
 
distance, correlations, and 3D shape comparisons. 


 
47 
MC167B 
 
 
 
 
16.83 Patterns of Failure: observe patterns of failure after reirradiation using   
 
 
18F-DOPA-PET to guide treatment volumes. The MRI scan indicating  
 
 
 
progressive disease will be fused with our treatment planning scan and   
 
 
the region of progression will be contoured by an investigator blinded to  
 
 
the GTV_MRI, T2_FLAIR_NCET, GTV_PET, PTV_high, and isodose lines. A  
 
 
volumetric analysis will then be performed to define the doses delivered  
 
 
to the absolute and relative volume of the region where recurrence is   
 
 
defined.  
 
 
16.84 Adverse Events: determine acute and late toxicity after radiotherapy  
 
 
 
treatment using 18F-DOPA-PET to delineate treatment volumes. The rate  
 
 
of acute and late treatment-related toxicities for recurrent high-grade   
 
 
glioma patients treated with 18F-DOPA-PET image-guided radiotherapy   
 
 
will be determined, with acute RT toxicities graded using Common  
 
 
 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (available   
 
 
at http://ctep.cancer.gov), and late toxicities reported using  
 
 
 
 
RTOG/EORTC late toxicity criteria.[39]  
 
 
 
16.85 Reoperation Rates: determine the rate of reoperation for patients  
 
 
 
undergoing reirradiation for recurrent high-grade gliomas treated using   
 
 
18F-DOPA-PET guided volumes. When available, pathologic information   
 
 
detailing the presence of necrosis and/or tumor progression will be  
 
 
 
recorded.  
 
 
 
16.86 Quality of Life: estimate quality of life (QOL) after radiotherapy using  
 
 
 
18F-DOPA-PET to establish treatment volumes. QOL will be evaluated  
 
 
 
using the MD Anderson Symptom Inventory Brain Tumor Module  
 
 
 
(MDASI-BT) and fatigue will be evaluated using the MD Anderson Brief   
 
 
Fatigue Inventory. These questionnaires will be administered at baseline  
 
 
and at each MRI evaluation up to 6 total evaluations to capture quality   
 
 
of life and correlate findings with clinical and radiographic progression.   
 
 
Analysis will include change percent from baseline using t-tests and  
 
 
 
generalized linear models to test for changes at each time point and  
 
 
 
non-zero slope. 
 
16.9 
 
Data Safety Monitoring Plan  
 
 
 
The Study Chairs and the study statistician will review the study at least   
 
twice a year to identify accrual, adverse event, and any endpoint  
 
 
problems that might be developing. The Mayo Clinic Cancer Center  
 
 
(MCCC) Data Safety and Monitoring Board (DSMB) is responsible for  
 
 
reviewing the accrual and safety for this trial at least twice a year, based  
 
on reports provided by the MCCC Statistical Office. 
 
 
16.91 Adverse Event Stopping Rules: As no reactions to 18F-DOPA have been reported 
within the institution, toxicity testing reported in the literature revealed no 
deleterious effects (section 0), and there have been no allergic reactions in all 


 
48 
MC167B 
 
patients accrued to date on multiple studies MC1078, MC1373, and MC1374, no 
reactions are anticipated. As such, if either of the two scenarios below occur, 
enrollment will be suspended so that details of each episode can be examined 
and a trial recommendation will be formulated and presented to the MCCC 
DSMB: 
• 
At any point during the AE evaluation of the first 9 AE-evaluable patients, 
one or more patients is unable to complete PET scanning due to allergic 
reactions to the tracer. 
Or, after 10 or more patients are evaluable for AEs, more than 10% of these patients are 
unable to complete PET scanning due to allergic reactions to the tracer. 
 
 
There have been no reports in the literature of the occurrence of nephrogenic 
systemic fibrosis (NSF) in patients with normal renal function. Additionally, we 
will use the contrast agent gadobenate dimeglumine, which has been shown to 
have a high safety profile (lower incidence of NSF in patients with renal 
failure/insufficiency) compared with many other available Gd-based contrast 
agents. Therefore no reactions are anticipated. As such, if at any time a patient 
develops NSF enrollment will be suspended so that details of the episode can be 
examined and a trial recommendation will be formulated and presented to the 
MCCC DSMB. 
 
 
Using the radiation treatment dosing, fractionation and normal tissue 
constraints outlined in Section 7 have been performed in several studies 
without significant adverse effects. While radiation-induced brain necrosis is 
rare, a cumulative normal brain dose of < 100 Gy in 2 Gy equivalents has been 
suggested as a constraint to minimize the risk of necrosis.[30] Two large studies 
reported no grade 3 or higher toxicity and no radionecrosis using the same 
dosing and fractionation as our protocol.[26, 27] In fact, studies using larger 
fraction sizes (5 Gy/fraction) reported very low rates of radionecrosis when 
keeping reirradiation doses under 40 Gy.[28, 29] However, tumor progression is 
expected in the majority of patients and commonly results in severe neurologic 
symptoms near the end of life. Both acute (available at http://ctep.cancer.gov) 
and late [39] toxicity will be monitored continuously as each patient is accrued 
and follow-up data are accumulated. If at any time, 1) 3 or more of the first 9 
AE-evaluable patients; or, 2) after 10 or more patients are AE-evaluable, more 
than 30% experience any of the following adverse effects considered to be at 
least possibly related to radiation treatment up to and including the three-
month timepoint; enrollment will be suspended so the details of each episode 
may be examined and a trial recommendation will be formulated and presented 
to the MCCC DSMB, adjusting the dose, fraction size or volumes as needed.  
• 
Grade 3 or 4 irreversible CNS toxicity 
• 
Grade 4 non-hematologic, non-CNS toxicity 
• 
Any Grade 5 toxicity 
 
16.10 Results Reporting on ClinicalTrials.gov 
 


 
49 
MC167B 
 
 
Initial estimated Primary Completion Date: At study activation, this  
 
 
study will have been registered within the www.ClinicTrials.gov (CT.gov)  
 
website. The Primary and Secondary endpoints along with other  
 
 
required information for this study will be reported on CT.gov. For  
 
 
purposes of timing of the CT.gov results reporting, the initial estimated   
 
completion date of the primary endpoint of this study is 27 months  
 
 
after the study opens to accrual. 
 
 
16.101 Definition of Primary-Endpoint Completion Date (PCD): The PCD is the   
 
date at which the last progression free patient has been followed for 3   
 
months. 
 
16.11 Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race,  
 
 
 
gender, or ethnic group. 
16.111 There is no information currently available regarding differential effects of this 
regimen in subsets defined by gender, race or ethnicity, and there is no reason 
to expect such differences to exist. Therefore, although the planned analyses 
will, as always, look for differences based on gender and racial groupings, the 
sample size is not increased in order to provide additional power for such subset 
analyses. Based on prior studies involving similar disease, we expect about 7% 
of patients will be classified as minorities by race and about 40% of patients to 
be women. Expected sizes of racial by gender subsets are shown in the following 
table: 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
8 
12 
20 
Ethnic Category: Total of all subjects 
9 
13 
22 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
8 
12 
20 
Racial Category: Total of all subjects 
9 
13 
22 
Ethnic Categories:  
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in addition 
to “Hispanic or Latino.” 
Not Hispanic or Latino 


 
50 
MC167B 
 
Racial Categories:  
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands 
have been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups of Africa. Terms 
such as “Haitian” or “Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of 
Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or North 
Africa. 
 
 


 
51 
MC167B 
 
17.0 
Pathology Considerations/Tissue Bio specimens:  
 
None 
 
 
 


 
52 
MC167B 
 
18.0 
Records and Data Collection Procedures 
 
 
 
18.1 
Submission Timetable  
Initial Material(s)  
CRF 
Active-Monitoring Phase  
(Baseline) 
(Compliance with Test Schedule Section 4.0) 
 
Demographics 
 
 
≤2 weeks after registration 
Institutional Contacts 
Eligibility Checklist 
On-Study Form  
Initial Tumor Form 
Baseline Adverse Event Form FDOPA Pre-
injection 
MD Anderson Symptom Inventory-Brain 
Tumor (MDASI) Questionnaire (Baseline) 
Brief Fatigue Inventory Questionnaire 
(Baseline)   
Concomitant Medications  
Off Treatment1 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Consent Withdrawal (if applicable) 
1. Submit if withdrawal/refusal prior to RT occurs 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
< 1 week 
after 18F-
DOPA-PET 
scan 
< 4 weeks 
after each 
evaluation 
during RT  
< 6 months 
after end of 
RT5 
< 6 months after 
every clinically 
indicated MR 
scan5 
Radiation Therapy 
Reporting Form 
 
 
X3 
 
Adverse Event Form  
X 
X1 
X 
X 
Post 18FDOPA 
Injection 
X6 
 
 
 
Patient Status: 
Clinical Follow-
Up/Observation 
 
X 
X 
X2 
MD Anderson 
Symptom Inventory-
Brain Tumor (MDASI) 
Questionnaire 
X 
X 
X 
X 


 
53 
MC167B 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
< 1 week 
after 18F-
DOPA-PET 
scan 
< 4 weeks 
after each 
evaluation 
during RT  
< 6 months 
after end of 
RT5 
< 6 months after 
every clinically 
indicated MR 
scan5 
Brief Fatigue 
Inventory 
Questionnaire  
X 
X 
X 
X 
Adverse Events : Late 
Toxicities 
 
 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
Notification/ 
Hospitalizations 
At each occurrence 
Off Treatment  
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs after receiving therapy 
Consent Withdrawal 
1. Acute toxicity will be assessed during standard of care monitoring by the radiotherapy team 
during the course of treatment.  
2. Late toxicity will be assessed during standard of care appointments. To be submitted ≤2 weeks 
after each clinically indicated MR scan.  
3. This form should be completed after the radiation is completed.  
4. Timeframes for submission purposefully large as they do not affect patient care i.e. the data 
being collected is for investigational use only and no patient decisions will be made with it, 
which allows us to batch the data for analysis by the study team (e.g. for Radiation Oncologist 
and Radiologists to contour volumes on image data).  
5. See Section 4 for time of assessments.  
6. Done approximately 15-20 minutes post injection of 18F-DOPA after scan is completed and if AE 
observed a second AE assessment is required <24 hours post injection which is performed by 
study staff. 
 
Follow-up Material(s)  
CRF 
 
Event Monitoring Phase1 
Yearly for 2 years 
At PD 
Death 
Adverse Events: Late Toxicities  
X 
X 
 
Patient Status: Survival Status Follow-
up/ Event Monitoring 
X 
X 
X 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
 
 
18.2 
Data Handling and Record Keeping 
 
 
 
 18.21 Confidentiality 
 
 
 


 
54 
MC167B 
 
 
 
Information about study subjects will be kept confidential and managed according to  
 
 
the requirements of the Health Insurance Portability and Accountability Act of 1996  
 
 
(HIPAA).  Those regulations require a signed subject authorization informing the subject  
 
 
of the following:  
 
• What protected health information (PHI) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of 
their PHI.  
 
(This information is contained within the Mayo IRB Informed Consent Template Section 
14) 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (long 
term survival status that the subject is alive) at the end of their scheduled study period. 
 
18.22 Source Documents 
 
 
 
Source data is all information, original records of clinical findings, observations, or other  
 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.   
 
 
Source documents are kept in a secure location.  
 
18.23 Case Report Forms  
 
 
 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.   
 
18.24 Data Management  
 
 
 
All data will be entered into electronic case report forms (eCRF’s) through the Medidata 
Rave system. Case report forms will be automatically rolled out based on a 
predetermined, and visit based schedule to improve study staff workflow and data 
quality. Data will be exported nightly to a secure FTP for analysis and reporting.  
 
18.25 Data Quality Assurance and Clarification Process 
 
 
 
 
 
Each eCRF will contain edit checks and custom functions to ensure the highest   
 
 
possible data quality.  Only necessary eCRFs will be available for data entry to  
 
 
 
reduce the possibility of erroneous entry. The edit checks and custom functions on the  
 
 
eCRFs will trigger queries requesting the attention of appropriate study staff. The fields  
 
 
will be marked in pink to allow study staff to quickly identify the data fields that require  
 
 
attention or actions. Additionally, secure email notifications will be sent for adverse  
 
 
event tracking and monitoring 


 
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18.26 Records Retention 
 
 
 
 
 
The investigator will maintain records and essential documents related to the conduct  
 
 
of the study. These will include subject case histories and regulatory documents. 
 
 
 
The investigator will retain the specified records and reports for; 
 
1. 
 As outlined in the Mayo Clinic Research Policy Manual –“Retention of and 
Access to Research Data Policy”  
   
 
 
 


 
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19.0 
Study Finances 
 
19.1 
Costs charged to patient: routine clinical care 
 
19.2 
Tests to be funded by research. 
 
 
 
19.21 
18F-DOPA-PET scan 
 
19.3 
Conflict of Interest 
 
 
 
Any study team member who has a conflict of interest with this study (patent  
 
 
ownership, royalties, or financial gain greater than the minimum allowable by   
 
their institution, etc.) must have the conflict reviewed by a properly constituted   
 
Conflict of Interest Committee with a Committee-sanctioned conflict  
 
 
 
management plan that has been reviewed and approved by the study sponsor-  
 
investigator prior to participation in this study. 
 
 
 


 
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20.0 
Publication Plan  
 
 
 
The principal investigators hold primary responsibility for publication of the results of  
 
 
this study and approval from the principal investigators must be obtained before any  
 
 
information can be used or passed on to a third party. 
 
 


 
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Appendix I 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 
 


 
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Appendix II 
 
 
 


 
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Appendix II 
 
 


 
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Appendix III