Clinical trial NCT00902577
Conditions: Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma
Sponsor: National Cancer Institute (NCI)
Start date: 2009-08-24; Completion date: 2018-01-31
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial is studying how well positron emission tomography (PET) scan using 18F-fluoromisonidazole works when given together with magnetic resonance imaging (MRI) ) in assessing tumor hypoxia in patients with newly diagnosed glioblastoma multiforme (GBM). Diagnostic procedures, such as MRI and PET scan using 18F-fluoromisonidazole (FMISO), may help predict the response of the tumor to the treatment and allow doctors to plan better treatment.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the association of baseline FMISO PET uptake (hypoxic volume \[HV\]), highest tumor:blood ratio \[T/Bmax\]) and MRI parameters (Ktrans, CBV) with overall survival (OS) in participants with newly diagnosed GBM.

SECONDARY OBJECTIVES:

I. To determine the association of baseline FMISO PET uptake (HV, T/Bmax) and MRI parameters (Ktrans, CBV) with time to progression (TTP) and 6-month progression free survival (PFS-6) in participants with newly diagnosed GBM.

II. To assess the reproducibility of the baseline FMISO PET uptake parameters by implementing baseline "test" and "retest" PET scans (performed within 1 to 7 days of each other).

III. To assess the correlation between highest tissue:cerebellum ratio \[T/Cmax\] and T/Bmax at baseline.

IV. To assess the correlation between other MRI parameters (for example Gadolinium-enhanced T1-weighted (T1Gd), vessel caliber index (VCI), , CBV-S, apparent diffusion coefficient (ADC) , N-acetylaspartate (NAA) to choline (Cho) ratio, blood oxygenation level-dependent (BOLD), T2) and OS, TTP, and PFS-6.

OUTLINE: This is a multicenter study.

Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy. Blood samples are collected at baseline and periodically during study to compare image measures of tissue uptake of FMISO to blood concentrations. Tumor samples are collected from diagnostic biopsy or surgery for analysis of tumor hypoxic markers and methylguanine methyl transferase by immunohistochemical and Polymerase chain reaction (PCR) assays.

After completion of study therapy, patients are followed up every 3 months for up to 5 years.

Arms: arm 1: Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.
Interventions: intervention 1: FMISO intervention 2: MRI intervention 3: PET intervention 4: MRS
Intervention descriptions: intervention 1: FMISO PET scans intervention 2: Undergo MRI intervention 3: Undergo FMISO PET scan intervention 4: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK 
 
ACRIN 6684  
 
MULTICENTER, PHASE II ASSESSMENT OF TUMOR HYPOXIA  
IN GLIOBLASTOMA USING 18F-FLUOROMISONIDAZOLE  
(FMISO) WITH PET AND MRI 
 
Investigational Agent Name: Fluorine-18 Fluoromisonidazole (18F-FMISO) 
Agent NSC Number: NSC 742836 
Cancer Imaging Program, DCTD, NCI-sponsored IND number: IND 76,042 
 
Study Co-Chair 
 
Elizabeth R. Gerstner, MD  
Massachusetts General Hospital 
The Stephen E. and Catherine Pappas Center  
for Neuro-Oncology 
55 Fruit Street 
Yawkey 9E 
Boston, MA 02114 
Phone: 617-724-2887  
Fax: 617-643-2591 
Email: egerstner@partners.org 
Study Co-Chair 
James R. Fink, MD 
University of Washington Medical Center 
Department of Radiology, Box 357115 
1959 N. E. Pacific Street 
Seattle, Washington 98195 
Phone: 206-543-3320 
Fax: 206-598-8475 
Email: jrfink@u.washington.edu 
 
Co-Chair 
David Mankoff, MD, PhD 
Seattle Cancer Care Alliance 
Radiology 
825 Eastlake Avenue East 
G2-600 
Seattle, WA 98109 
Phone: 206-288-2173 
Fax: 206-288-6556 
Email: dam@u.washington.edu 
 
Study Statistician 
Zheng Zhang, PhD 
 
Center for Statistical Sciences 
Brown University 
121 South Main Street, Box G-S121-7 
Providence, RI 02912 
Phone: 401-863-2578 
Fax: 401-863-9182 
Email: zzhang@stat.brown.edu 
 
 
Original Date:    March 24, 2009  
Activation Date: August 24, 2009 
Version Date:     January 24, 2012 
                           Includes Amendments 1–7 
 
CONFIDENTIAL 
This protocol was designed and developed by the American College of Radiology Imaging 
Network (ACRIN). It is intended to be used only in conjunction with institution-specific IRB 
approval for study entry. No other use or reproduction is authorized by ACRIN, nor does 
ACRIN assume any responsibility for unauthorized use of this protocol. 


 
ACRIN 6684 
2 
January 24, 2012 
 
Table of Contents  
 
Schema 
 
1.0 
Abstract ............................................................................................................................ 4 
2.0  
Background and Significance .......................................................................................... 4 
3.0 
Study Objectives/Specific Aims ...................................................................................... 7 
4.0 
Study Drug Information ................................................................................................... 8 
5.0 
Study Overview ............................................................................................................... 11 
6.0 
Participant Selection/Eligibility Criteria .......................................................................... 12 
7.0 
Site Selection ................................................................................................................... 14 
8.0 
Data Management/Online Registration  .......................................................................... 15 
9.0 
Study Procedures ............................................................................................................. 19 
10.0 
Image Guidelines ............................................................................................................. 26 
11.0 
Well-Counter Calibration/Blood Sampling Guidelines ................................................... 32 
12.0 
Adverse Events Reporting ............................................................................................... 33 
13.0 
Ethical Considerations ..................................................................................................... 43 
14.0 
Conflict of Interest ........................................................................................................... 44 
15.0 
Publication Policy ............................................................................................................ 44 
16.0 
Institutional Monitoring and Audits ................................................................................ 44 
17.0 
Statistical Considerations  ................................................................................................ 47 
18.0 
Tissue Specimen Collection for Biomarker Analysis ...................................................... 49 
References .................................................................................................................................... 52 
Appendix I: 
Informed Consent Form Template ....................................................................... 55 
Appendix II: Supplemental Materials Available Online ........................................................... 67 
Appendix III:  Well Counter Cross-Calibration Procedure ......................................................... 68 
Appendix IV:  Blood Sampling Procedure .................................................................................. 70 
Appendix V: Macdonald Radiographic Response Criteria ....................................................... 71 
Attachment A: Report on Radiation Dose Estimates for PET and PET/CT ................................ 72 
 
 


 
ACRIN 6684 
3 
January 24, 2012 
 
AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK 
 
ACRIN 6684  
 
MULTICENTER, PHASE II ASSESSMENT OF TUMOR HYPOXIA  
IN GLIOBLASTOMA USING 18F-FLUOROMISONIDAZOLE  
(FMISO) WITH PET AND MRI 
  
SCHEMA 
 
ELIGIBILITY 
Patients with pathologically-confirmed newly diagnosed glioblastoma (WHO grade IV)  
who have residual disease, are older than 18 years, and scheduled for standard chemoradiotherapy 
alone or with an investigational agent. 
 
VISIT 1 REGISTRATION/SCREENING 
 
VISIT 2 IMAGING: FMISO PET AND MRI SCANS 
(See Study Procedures Section 9.0 for details.) 
 
VISIT 2A IMAGING: REPRODUCIBILITY FMISO PET SCAN 
A sub-set (15 participants) will undergo an additional FMISO PET scan  
prior to initiation of chemoradiation. 
 
FOLLOW UP: UP TO 5 YEARS FOR PROGRESSION AND SURVIVORSHIP 
All standard of care MRIs and CTs will be submitted to ACRIN. 
 
STUDY OBJECTIVES  
To determine the association of baseline FMISO PET uptake (tumor to blood ratio, hypoxic 
volume) and MRI parameters (Ktrans, CBV) with overall survival, time to disease progression, 
and 6-month progression free survival in participants with newly diagnosed glioblastoma 
(GBM).  
 
ELIGIBILITY (see Section 6.0 for details) 
Adult patients newly diagnosed with GBM (World Health Organization [WHO] grade IV) and 
visible residual disease planned for initial treatment with radiation therapy (RT) and 
temozolomide (TMZ), with or without additional agents, will be enrolled. Amount of residual 
tumor will not impact eligibility and visible residual disease can include T2/FLAIR 
hyperintensity. 
 
SAMPLE SIZE  
A minimum of 50 participants will be enrolled. A subset of 15 participants will have test-retest 
FMISO PET scans at baseline performed between 1 and 7 days apart (both scans completed prior 
to initiation of chemoradiation). The timeframe for recruitment will be approximately 1 year, and 
participants will be recruited from 4 to 10 sites. Each institution will not enroll more than 15 
participants to this trial.   


 
ACRIN 6684 
4 
January 24, 2012 
 
1.0 
ABSTRACT  
This protocol for human research study is conducted according to United States and international 
standards of Good Clinical Practice (International Conference on Harmonisation [ICH] 
Guidelines), applicable government regulations (e.g. Title 45, Part 46 Code of Federal 
Regulations) and the American College of Radiology Imaging Network (ACRIN) research 
policies and procedures. 
 
Glioblastoma (GBM) is the most common and, unfortunately, most aggressive type of primary 
malignant brain tumor. Despite treatment with surgery, radiation, and temozolomide (TMZ) 
chemotherapy, median overall survival (OS) is less than 15 months.1 One of the pathologic 
hallmarks of GBM is necrosis, thought to be the result of tumor hypoxia secondary to an 
inefficient blood supply. Hypoxia is a potent stimulator of angiogenesis, a requisite for tumor 
growth.2 In addition, hypoxia limits the efficacy of radiation and chemotherapy and may select 
for a more aggressive tumor phenotype. By better understanding the extent of tumor hypoxia and 
changes in regional tumor hypoxia with treatment, more effective and patient-specific therapies 
could be devised to halt GBM growth. For example, patients with persistent areas of tumor 
hypoxia may benefit from adding therapies that improve oxygenation, are hypoxia-selective, or 
target downstream consequences of hypoxia, especially angiogenesis.  
18F-Fluoromisonidazole (FMISO) PET is a non-invasive method that can estimate tissue 
hypoxia. Several studies have validated FMISO uptake as a robust measure of tissue hypoxia, 
and methodology for FMISO PET imaging has been established in early single-center studies.3-7 
One preliminary study of 22 participants with GBM demonstrated an association with both the 
pre-radiation volume and degree of tumor hypoxia measured by FMISO PET and a shorter time 
to tumor progression and survival (Spence et al 2008).3 Consequently, knowledge of the amount 
and distribution of tumor hypoxia may provide prognostic information as well as useful 
information to guide therapy for patients with GBM.  
New advanced MRI methods, such as dynamic contrast enhanced (DCE) MRI, oxygen breathing 
during BOLD imaging, vessel caliber mapping, or other approaches may also contribute to 
characterization of tumor physiology and/or prognostic information for patients with GBM. 
Combining such vascular-imaging methods with hypoxia data from FMISO uptake is very 
attractive. This also recognizes the mechanistic connection between hypoxia and angiogenesis 
and provides an opportunity to study the association of hypoxia, by FMISO PET, and tumor 
vascularity, by perfusion MRI. We propose using these PET and MRI techniques hand in hand to 
monitor the standard initial treatment of patients with GBM and to perform pilot work to 
determine if FMISO PET may be a useful prognostic marker in patients with GBM. Data gained 
from this study will also serve as the basis for future clinical trials where hypoxia imaging could 
be used for correlative science, patient selection, and response evaluation. Both MRI and PET 
imaging are low-risk tests so the potential knowledge gained about tumor biology in this study 
makes it a worthwhile endeavor. 
 
 
2.0 
BACKGROUND AND SIGNIFICANCE 
Hypoxia is a potent stimulator of angiogenesis, a requisite for tumor growth. In addition, hypoxia 
limits the efficacy of radiation and chemotherapy and may select for a more aggressive tumor 
phenotype. By better understanding the extent of tumor hypoxia and changes in regional tumor 
hypoxia with treatment, more effective and patient-specific therapies could be devised to halt 
GBM growth. For example, patients with persistent areas of tumor hypoxia may benefit from 


 
ACRIN 6684 
5 
January 24, 2012 
 
adding therapies that improve oxygenation, are hypoxia-selective, or target downstream 
consequences of hypoxia, especially angiogenesis. 
2.1 
FMISO PET as a Hypoxia Imaging Biomarker 
Since the 1980s, interest in radiolabeled nitroimidazoles, and particularly FMISO, as 
nuclear imaging agents of hypoxia has been growing. Intracellular nitroreductases 
metabolize nitroimidazoles in the setting of low oxygen levels, thus trapping them in 
hypoxic cells. Importantly, the metabolism of nitroimidazoles relies on an active electron 
transport chain so only live cells can trap FMISO. The binding of FMISO is related to the 
level of hypoxia, and oxygen levels of 3 to 10 mm Hg lead to FMISO binding.8,9 Several 
studies have demonstrated that the uptake of FMISO correlates well with invasive 
polarographic oxygen electrodes, the gold standard to determine tissue oxygenation.10-13  
Preliminary studies of FMISO uptake in glioma have demonstrated the feasibility of this 
technique both in animal models and in humans.6 In a glioma rat model, FMISO uptake 
was significantly greater in tumor tissue than in surrounding normal brain.5 Cher et al 
showed that all high-grade gliomas have increased FMISO uptake while low-grade 
gliomas did not, which is consistent with the underlying biology of gliomas—higher-
grade tumors are more hypoxic than lower-grade tumors.7 In 22 participants with newly-
diagnosed GBM, the greater the volume and degree of hypoxia based on FMISO 
imaging, the shorter time-to-tumor progression and survival.3  In addition, histological 
studies of tumors have correlated tissue pimonidazole staining, a marker of tissue 
hypoxia, and CAIX with FMISO uptake.14,15  In one of these studies, the glioma model 
had the strongest correlation between FMISO uptake and pimonidazole staining.14   
Ex vivo autoradiography has also been used to confirm the correlation of FMISO and 
tumor hypoxia.16 
2.2 
Tissue:Blood or Tissue:Cerebellum 
The most predictive FMISO imaging markers for viewing these hypoxic distinctions have 
derived from tissue:blood FMISO concentration ratios, which compare image measures 
of tissue uptake concentration to blood concentration levels measured by blood sampling. 
The Spence study3 showed that markers established by prior studies,12 namely the 
maximum tumor:blood ratio in the tumor site (T/Bmax) and the hypoxic volume (HV, 
volume of tumor tissue with tissue:blood > 1.2), were predictive of patient survival. 
 
FMISO uptake is currently quantified using tissue:blood (T/B) ratios obtained from 
comparing image measures of tissue uptake to blood concentration from blood samples. 
This approach has been extensively validated against ―gold standard‖ measures of 
hypoxia8,12 and has shown to be predictive of survival in GBM.3  However, this approach 
requires blood sampling and cross-calibration between the PET scanner and the well 
counter used to measure blood concentration. FMISO is highly lipophilic and fairly 
uniformly distributed in normal, non-hypoxic brain tissue; therefore, normal brain uptake 
may provide a reasonable proxy for blood concentration. Preliminary data from Dr. 
Spence‘s group have shown a high degree of correlation between FMISO uptake ratios 
using the normal cerebellum as a reference region and indirect measure of blood 
concentration (T/C ratio) versus T/B. As a secondary objective of this study, we will 
correlate T/C and T/B as measures of FMISO uptake and test the predictive value of T/C. 
If T/C is shown to be equivalent to T/B, this would enable future use of FMISO by 
imaging only, without blood samples, and eliminate the need for cross-calibration of the 


 
ACRIN 6684 
6 
January 24, 2012 
 
PET scanner with a well counter. This would significantly enhance feasibility of FMISO 
PET in future clinical trials. 
Interestingly, a study of 11 participants with various brain tumors that combined hypoxia 
measurement using FMISO and perfusion measurement using 15O-H20 demonstrated that 
low perfusion was not necessarily associated with hypoxia.4 The reason for this 
discrepancy likely reflects the complicated relationship in gliomas between perfusion and 
hypoxia. Recent data suggest that tumor tissue hypoxia may cycle with a periodicity of 
20 to 30 minutes, which may explain some of these findings .2 Other data have suggested 
that, at least in some tumors, FMISO uptake correlates with perfusion measures.17 The 
ability of MRI to assess perfusion and other hemodynamic properties of tumors makes it 
an ideal tool to combine with FMISO PET.  
2.3 
Viewing Vasculature: MRI Complements FMISO PET 
MRI provides functional information as well as anatomical information about tumor 
vasculature. Cerebral blood flow, blood volume, and vessel size can be used to determine 
if a mismatch exists between tumor vascular function and hypoxia because these 
physiologic parameters accurately reflect the heterogeneous nature of gliomas. Changes 
in flow, vascular density, and/or the geometry of microvessels are all thought to regulate 
tumor oxygenation2 and can be measured with dynamic susceptibility MRI. Vascular 
permeability as measured by Ktrans (the vascular transfer constant) or Ve (the volume of 
extravascular extracellular space) would provide further information about vessel 
function and the role that elevated interstitial fluid pressure plays in hypoxia.  
In one animal model of colorectal cancer, reduction in Ktrans and Ve correlated with an 
increase in oxygenation following radiation.18 In addition, breathing oxygen or carbogen 
during BOLD MRI has been shown to reveal dynamic changes in tumor vascular 
physiology.19,20 Therefore, the complementary information provided by physiological 
MRI parameters and metabolic information provided by FMISO PET will help to clarify 
the discrepancy between perfusion and hypoxia, which has significant clinical 
implications. 
Being able to better characterize and target the mechanisms of GBM hypoxia (e.g. 
hypoperfusion) could lead to improvements in therapy for this deadly disease. There are 
approximately 10,000 GBMs diagnosed each year in the United States and the median 
overall survival is less than 15 months. Consequently, better therapies are desperately 
needed. Considering that the standard treatment for GBM—radiation and TMZ 
chemotherapy—relies on adequate oxygenation to be maximally effective, a better 
understanding of tumor hypoxia and perfusion could optimize these therapies and 
improve survival.  
Furthermore, if FMISO becomes a clinically valuable tool, measurement methods such as 
tumor:cerebellum ratios would be more convenient to use than the current practice of 
blood sampling and cross calibration. Hence, in this study we will seek to determine the 
feasibility of the tumor:cerebellum method compared with tumor:blood as we both 
elucidate the presence and mechanisms of hypoxia and assess the robustness of hypoxia 
imaging with FMISO PET. 
2.4 
Justification and Overall Goals of the ACRIN 6684 FMISO PET Trial 
This protocol is a multi-center, phase II trial to assess tumor hypoxia in GMB using 
FMISO with PET and MRI.  In the initial data by Spence et al, FMISO was a useful 


 
ACRIN 6684 
7 
January 24, 2012 
 
prognostic marker.3  However, this was a small single-centered trial so the data will need 
to be confirmed in a multicenter trial.   
For ACRIN 6684, the role of imaging in this trial is primarily prognostic. The overall 
goals of the study are both clinical and biological. The primary aim is to establish 
hypoxia imaging as a tool to select more aggressive and/or hypoxia-targeted therapy in 
particular subsets of patients.   
 
2.5 
Impact of Including Additional Therapeutic Agents 
The primary goal of this study is to determine the prognostic value of FMISO PET prior 
to start of treatment. Therefore, allowing all available therapeutic options for trial 
participants following the FMISO PET does not impact our primary endpoint, which, 
again, looks at the association of baseline hypoxic volume and overall survival. Patients 
with GBM are treated with a variety of therapies, so limiting eligibility to standard 
chemoradiation alone or only with the addition of anti-VEGF treatment or an anti-PARP 
inhibitor is restrictive and unnecessary. Removal of the restrictive therapy-related 
eligibility criteria introduced in earlier amendments to the protocol (revised to be more 
all-inclusive therapeutically as of Amendment 7) will speed study accrual and increase 
the likelihood of trial completion. 
  
 
3.0 
STUDY OBJECTIVES/SPECIFIC AIMS  
3.1 
Primary Aim 
To determine the association of baseline FMISO PET uptake (hypoxic volume [HV], 
highest tumor:blood ratio [T/Bmax]) and MRI parameters (Ktrans, CBV) with overall 
survival (OS) in participants with newly diagnosed GBM.  
3.2 
Secondary Aims 
3.2.1 Aim 1: To determine the association of baseline FMISO PET uptake (HV, 
T/Bmax) and MRI parameters (Ktrans, CBV) with time to progression (TTP) and 
6-month progression free survival (PFS-6) in participants with newly diagnosed 
GBM. 
3.2.2 Aim 2: To assess the reproducibility of the baseline FMISO PET uptake 
parameters by implementing baseline ―test‖ and ―retest‖ PET scans (performed 
within 1 to 7 days of each other). 
3.2.3 Aim 3: To assess the correlation between highest tissue:cerebellum ratio 
[T/Cmax] and T/Bmax at baseline.  
3.2.4 Aim 4: To assess the correlation between other MRI parameters (T1Gd, VCI, 
CBV-S, ADC, NAA-Cho, BOLD, T2) and OS, TTP, and PFS-6.  
 
 


 
ACRIN 6684 
8 
January 24, 2012 
 
4.0 
STUDY DRUG INFORMATION  
4.1 
Description of 18F-fluoromisonidazole (FMISO) (NSC #742836; IND # 76,042) 
The Investigator Brochure for FMISO will be available to ACRIN-approved sites. The 
brochure will provide detailed information regarding the investigational agent. For 
adverse events related to this agent, see Section 13.0. 
 
4.1.1 Chemical Name: 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole 
 
4.1.2 Other Name: [18F]-fluoromisonidazole, [18F]FMISO, FMISO  
 
4.1.3 Molecular Formula:  
N
N
NO2
O
H
N
N
F
NO2
O
H
18
 
 
4.1.4 Description: [18F]-fluoromisonidazole ([18F]FMISO, FMISO) is a radiolabeled 
imaging agent that has been used for investigating tumor hypoxia with PET. 
FMISO is an azomycin-based hypoxic cell sensitizer that binds covalently to 
cellular molecules at rates that are inversely proportional to intracellular oxygen 
concentration, rather than by any downstream biochemical interactions. In 
hypoxic cells, FMISO is trapped, which is the basis for the use of this tracer to 
measure hypoxia. The physical half-life of FMISO is 110 minutes. 
 
4.1.5 Supplier/How Supplied:   
FMISO is available under the National Cancer Institute (NCI), Cancer Imaging 
Program‘s (CIP‘s) Investigational New Drug Application (IND) filed with the 
Food and Drug Administration (FDA). FMISO is supplied by Cardinal Health, 
which has previously provided NCI with a letter of authorization to cross-
reference their Drug Master File filed with the FDA.  
 
 
Local sites may make their own FMISO only if their chemistry, manufacturing, 
and control (CMC) processes and standard operating procedures (SOPs) have 
already been filed within the NCI IND and have met all requirements in 
accordance with FDA regulations and guidance.  
 
 
The radiopharmaceutical product, FMISO, is the only active ingredient and it is 
dissolved in a solution of ≤10 mL of 95% isotonic saline: 5% ethanol (v:v). 
FMISO is provided as a ready to use isotonic, sterile, pyrogen-free, clear, and 
colorless solution. FMISO is typically packaged in a glass vial and does not 
contain any preservatives. 
 
4.1.6 Dosage and Route of Administration: FMISO is administered to subjects by 
intravenous injection by bolus of ≤10 mL. The FMISO dose for this protocol 
should be 3.7 MBq/kg (0.1 mCi/kg) up to a maximum of 260 MBq (7 mCi). 
 
4.1.7 Storage: FMISO should be stored upright in an appropriate lead or tungsten alloy 
shielded container at room temperature.  
 


 
ACRIN 6684 
9 
January 24, 2012 
 
4.1.8 Stability: Refer to the guidelines from the provider, but typically FMISO should 
be used within 8-12 hours of the end of synthesis. 
 
4.1.9 Precaution: The use of FMISO is limited to experimental use for diagnostic 
imaging studies. FMISO should be administered by nuclear medicine personnel 
trained to handle radioactive material. 
 
4.1.10 Synthesis, Apyrogenicity, and Purity: FMISO will be synthesized and tested 
following the procedures filed in IND 76,042 by any site with full CMC data filed 
in the IND or supplied by Cardinal Health from any site that is filed under the 
Cardinal DMF, which is referenced in IND 76,042. All manufacturing and testing 
comply with USP<823>. The apyrogenicity of the product will be established 
with the bacterial endotoxin test. The radiochemical purity of the product will be 
evaluated by high-performance liquid chromatography and/or thin-layer 
chromatography (TLC) and is 95% or greater. 
 
4.2 
Supplier of FMISO 
 
FMISO is supplied by Cardinal Health or is manufactured on site by any site with full 
Chemistry, Manufacturing, and Controls (CMC) data filed in the IND. 
 
4.2.1 Agent Ordering: Sites approved to manufacture their own FMISO may do so for 
this study after providing CMC data to ACRIN regulatory personnel.  
 
Sites who will order the FMISO from Cardinal Health will need to complete a 
study drug request form.  Instructions for request and completion of the request 
form will be made available to those sites. 
 
4.2.2 Agent Returns: Not applicable. Unused drug should be allowed to decay and 
disposed of in accordance with institution guidelines.   
 
4.2.3 Agent Accountability: The investigator or the investigator-designee must maintain 
a detailed record of: 
 
4.2.3.1 Volume/Dose Received – Date, Time, By whom 
4.2.3.2 Volume/Dose Transfer – Date, Time, From/To whom 
4.2.3.3 Volume/Dose Drawn – Date, Time, Method, By whom 
4.2.3.4 Volume/Dose Administered – Date, Time, Subject ID, Administered by 
whom, Volume into subject, Volume remaining in administration device, 
Volume remaining in delivery container, Disposition of all UN-
administered volumes & contaminated containers [may refer to use of 
standard facility protocol document/SOP if that document covers this 
detail, e.g. ―Per (institution) SOP (#)‖]   
 
4.3    FMISO Biodistribution and Radiation Dosimetry 
The radiation exposure from FMISO in this study will be equal to or lower than that of 
other widely used nuclear-medicine experimental research agents. Increased voiding 
frequency will reduce the radiation dose to the bladder wall, which is the organ site that 


 
ACRIN 6684 
10 
January 24, 2012 
 
receives the highest radiation absorbed dose. Potential radiation-specific risks associated 
with this PET study are within generally accepted limits for such studies. 
 
In the dose of FMISO for this study, only a small fraction of the FMISO molecules are 
radioactive. The amount of injected drug is ≤ 15 µg (≤ 80 nmol per dose) of FMISO. 
FMISO is administered to subjects by intravenous injection of ≤ 10 mL. There is no 
evidence that nonradioactive and radioactive FMISO molecules display different 
biochemical behavior. 
 
Table 1. Radiation absorbed dose to organs for standard man 
 
 
Tissue
Mean 
(mGy/MBq) 
Mean 
(mrad/mCi) 
Total / 7 mCi 
(mrad) 
adrenals 
0.0166 
61.4 
430 
brain 
0.0086 
31.8 
223 
breasts 
0.0123 
45.5 
319 
gall bladder wall 
0.0148 
54.8 
383 
lower large intestine 
0.0143 
52.9 
370 
small intestine 
0.0132 
48.8 
342 
stomach 
0.0126 
46.6 
326 
upper large intestine 
0.0140 
51.8 
363 
heart wall 
0.0185 
68.5 
479 
kidneys 
0.0157 
58.1 
407 
liver 
0.0183 
67.7 
474 
lungs 
0.0099 
36.6 
256 
muscle 
0.0142 
52.5 
368 
ovaries 
0.0176 
65.1 
456 
pancreas 
0.0179 
66.2 
464 
red marrow 
0.0109 
40.3 
282 
bone surface 
0.0077 
28.5 
199 
skin 
0.0048 
17.8 
124 
spleen 
0.0163 
60.3 
422 
testes 
0.0146 
54.0 
378 
thymus 
0.0155 
57.4 
401 
thyroid 
0.0151 
55.9 
391 
urinary bladder wall 
0.0210 
77.7 
544 
uterus 
0.0183 
67.7 
474 
eye lens 
0.0154 
57.0 
399 
Total body 
0.0126 
46.6 
325 
 
 (Source: [18F]FMISO Investigators Brochure) 
 
Calculated total body dose for a 70 kg man injected with 3.7 MBq/kg was 0.013 
mGy/MBq; for a 57 Kg woman it was 0.016 mGy/MBq. Effective dose equivalents 
(EDE) were 0.013 mSv/MBq for men and 0.014 mSv/MBq for women. Ninety-seven 
percent of the injected radiation was homogenously distributed in the body, leaving only 
3% for urinary excretion. Doses to smaller organs not directly determined by 
visualization, such as the lens, were calculated assuming average total-body 
concentrations. The absence of tracer visualized in images of those organs indicated that 


 
ACRIN 6684 
11 
January 24, 2012 
 
accumulation there was not increased. Expected EDE for a 56-kg female is 3.0 mSv (300 
mRem) and for a 70-kg male is 3.4 mSv (340 mRem). 
 
More recently, radiation exposure for radiopharmaceuticals has been expressed as the 
effective dose (ED).  The estimated ED for [18F]FMISO  is 0.015 mSv/MBq (see Table 1 
in Attachment A to the protocol). Therefore, for the maximum 7 mCi dose, the maximum 
emission exposure is 3.9 mSv. 
 
4.4  
Monitoring for Physiologic Effects of FMISO 
 
 
 
 
 
4.4.1 Vital signs: 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate, 
will be measured prior to injection and at completion of FMISO PET imaging, 
and subsequently as needed.  
4.4.2  Laboratory studies: 
No routine laboratory studies are required to monitor FMISO use, but this patient 
population will have weekly complete blood counts and frequent serum chemistry 
as part of routine clinical care. These data will not be collected for the study.  
4.5 
Monitoring for Adverse Events 
Adverse events (AEs) will be evaluated at each imaging session; AE monitoring will 
cover at least ten half-lives of the FMISO drug, or 24 hours. AEs for FMISO are defined 
as any signs of illness or symptoms that have appeared or worsened since the infusion of 
the FMISO. Participants will be queried for potential AEs: 
 At the time of injection; 
 Before leaving the PET suite; 
 If they call the site as instructed for any concerns during the 24 hours after FMISO 
administration; 
 By telephone after 24 hours post-FMISO infusion. 
 
The AEs that will be specifically monitored during and after the infusion include: 
localized discomfort at the intravenous (IV) injection site, pain, respiratory difficulties, 
blood pressure instability, flushing, dizziness, pruritis/rash, and any other symptoms that 
could be related to an allergic or anaphylactoid-type reaction. When an AE is reported, 
concomitant medication taken by the participant in the 2 weeks prior to the event and/or 
during the time of the AE will be collected and documented. (See Section 12.0 for AE 
reporting requirements.) 
 
 
5.0 
STUDY OVERVIEW 
A minimum of 50 patients with newly diagnosed GBM will be recruited. The trial will continue 
until accrual meets the target of 50 eligible and evaluable participants. ―Evaluable‖ is defined as: 
images are completed; site deems all images adequate; and images pass initial quality review at 
ACRIN PET and MRI Core Labs. Inevaluable and ineligible cases will be followed per protocol 
(see Section 9.3). Although some visible disease is required for entry, the amount of residual 
tumor after surgery will not impact eligibility and visible residual disease can include T2/FLAIR 
hyperintensity. The timeframe for recruitment will be approximately 1 year, and participants will 
be recruited from 4 to 10 sites. Each institution will not enroll more than 15 participants to this 
trial. The subset of 15 participants in the test-retest substudy will have consented to a second 
baseline FMISO PET scan within 7 days of the first scan; if only one scan is completed for any 


 
ACRIN 6684 
12 
January 24, 2012 
 
reason prior to treatment initiation, then additional participants will need to be recruited until 15 
test-retest sets have been completed. All participants will be asked to complete the test-retest 
substudy until 15 participants have completed the series. After the test-retest substudy has been 
completed, potential participants will be consented only to the baseline scan. Focus will be on 
completing the baseline FMISO PET and MRI scans, and trial accrual will continue to reach 
targeted goals even if the test-retest substudy is incomplete. 
 
In this study, participants with residual GBM will undergo FMISO PET and MRI scans after 
surgery and prior to start of chemoradiation (baseline). The subset of 15 participants will have 
two FMISO PET scans within 1 to 7 days of each other to test reproducibility of FMISO PET; 
this substudy will continue to accrue until 15 participants have completed the two test-retest 
FMISO PET scans. Participants will then resume standard of care imaging for GBM per treating 
physician discretion, which will be submitted to ACRIN. Participants will be followed until 
death or the end of the study. 
 
 
6.0 
PARTICIPANT SELECTION/ELIGIBILITY CRITERIA 
Adult patients who have residual disease after surgical removal of newly-diagnosed GBM, based 
on pathological confirmation, will be eligible for this trial. Additional therapies to temozolomide 
and radiation are allowable; ACRIN requests information about scheduled concomitant therapy 
at registration). Should the concomitant agent be available through another clinical trial, the site 
will need to ensure treatment details (dose, time of administration, and any interruptions in 
therapy) are available to ACRIN. See Appendix VI for a list of example concomitant agents 
allowable for this trial. 
 
6.1 
Inclusion Criteria 
6.1.1 Must be able to provide a written informed consent; 
6.1.2 Must be 18 years or older; 
6.1.3 Newly diagnosed GBM, WHO grade IV based on pathology confirmation; 
6.1.4 Residual tumor after surgery (amount of residual tumor will not impact patient 
eligibility and visible residual disease can include T2/FLAIR hyperintensity); 
NOTE: If patient had a biopsy only, postoperative MRI is not needed to assess 
residual tumor prior to enrollment. 
6.1.5 Scheduled to receive standard fractionated radiation therapy; 
6.1.6 Scheduled to receive TMZ in addition to radiation therapy; 
6.1.7 Karnofsky Performance Score > 60. 
 
6.2 
Exclusion Criteria 
6.2.1 Pregnant or breastfeeding (if a female is of child-bearing potential, and unsure of 
pregnancy status, a standard urine pregnancy test should be done);  
6.2.2 Scheduled to receive chemotherapy, immunotherapy, or investigational agents in 
trials unwilling to share data with ACRIN (i.e., additional therapy added to 
radiation and TMZ is allowed if ACRIN is able to obtain treatment information); 
6.2.3 Not suitable to undergo MRI or use the contrast agent Gd because of: 


 
ACRIN 6684 
13 
January 24, 2012 
 
6.2.3.1 
Claustrophobia; 
6.2.3.2 
Presence of metallic objects or implanted medical devices in body 
(i.e., cardiac pacemaker, aneurysm clips, surgical clips, prostheses, 
artificial hearts, valves with steel parts, metal fragments, shrapnel, 
tattoos near the eye, or steel implants); 
6.2.3.3 
Sickle cell disease; 
6.2.3.4 
Renal failure; 
6.2.3.5 
Reduced renal function, as determined by GFR < 30 mL/min/1.73 m2  
based on a serum creatinine level obtained within 28 days prior to 
registration; 
6.2.4 Presence of any other co-existing condition which, in the judgment of the 
investigator, might increase the risk to the subject; 
6.2.5 Presence of serious systemic illness, including: uncontrolled intercurrent 
infection, uncontrolled malignancy, significant renal disease, or psychiatric/social 
situations which might impact the survival endpoint of the study or limit 
compliance with study requirements; 
6.2.6 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to FMISO. An allergic reaction to nitroimidazoles is highly 
unlikely; 
6.2.7 Not suitable to undergo PET or MRI, including weight greater than  
350 lbs (the weight limit for the MRI and PET table).  
6.2.8 Prior treatment with implanted radiotherapy or chemotherapy sources such as 
wafers of polifeprosan 20 with carmustine. 
 
6.3 
Recruitment and Screening 
Each institution will not enroll more than 15 participants to this trial.  Potential 
participants will be referred by their treating neuro-oncologists or medical oncologists, 
who will be made aware of the study by the site principal investigator (PI). Potential 
participants will be approached and consented by a member of the study team.  
ACRIN will allow patients to join this trial who are enrolled also in trials using additional 
investigational agents even if the trial is blinded. However, ACRIN will eventually need 
to access unblinded treatment and regimen data (specifically, ACRIN will need to know 
details of the timing, dosing, and any interruption of the therapeutic regimen). The site 
and ACRIN may need to coordinate with the other trial‘s sponsorship to determine any 
necessary data sharing prior to patient enrollment to the ACRIN trial. ACRIN requests 
information about the participant‘s scheduled concomitant therapy at time of registration. 
Once eligibility criteria have been assessed and the informed consent is obtained, 
participants will undergo a screening process to further ensure eligibility. Screening prior 
to registration will comprise a review of pathology reports, postoperative MR images, 
operative reports, and medical history; general physical and neurologic exams; routine 
blood work; and urine pregnancy test for women of childbearing age.   
 


 
ACRIN 6684 
14 
January 24, 2012 
 
ACRIN will develop a trial communications plan that will describe the production of 
materials to aid participant recruitment. All materials used for participant recruitment will 
be reviewed and approved by each institution‘s Institutional Review Board (IRB).  
 
6.4 
Inclusion of Women and Minorities  
Both men and women and members of all ethnic groups are eligible for this trial. In 
conformance with the National Institutes of Health (NIH) Revitalization Act of 1993, 
with regard to inclusion of women and minorities in clinical research, the projected 
gender and minority accruals are shown below in Table 2: 
 
Table 2. Gender and Minority Accrual Estimates  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
4 
5 
0 
9 
Not Hispanic or Latino 
17 
24 
0 
41 
Ethnic Category: Total of all subjects 
21 
29 
0 
50 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
3 
4 
0 
7 
Black or African American 
4 
5 
0 
9 
Native Hawaiian  
     or other Pacific Islander 
0 
0 
0 
0 
White 
14 
20 
0 
34 
Racial Category: Total of all subjects 
21 
29 
0 
50 
 
 
7.0 
SITE SELECTION 
7.1 
Institution Requirements 
The potential sites for this study are ACRIN-approved institutions that also meet study-
specific qualifications. If a site previously has not been approved to participate in ACRIN 
clinical trials, a General Qualifying Application (GQA) must be submitted.  In addition, 
each institution must submit a Protocol Specific Application (PSA). The applications and 
form are available at www.acrin.org/6684_protocol.aspx. 
 
Potential site must have access to local or commercial supply of the FMISO agent 
according to the parameters of the NCI-sponsored IND.  This will ensure that the FMISO 
tracer arrives successfully to the site and can be handled appropriately. For any sites 
approved to manufacture their own FMISO, the site must provide CMC data to ACRIN 
regulatory personnel as part of the site qualification process.  
 
In addition, the sites will need to have a well counter appropriate for counting blood 
samples and providing estimates of radioactivity concentrations that are cross-calibrated 
to PET scanner estimates of radioactivity concentrations in the PET images; phantom and 
calibration procedures will need to be run as a pre-qualifier for the well calibration 
procedure 
(see 
Section 
11.0, 
Appendix 
III, 
and 
www.acrin.org/6684_ 
imagingmaterials.aspx for details). 
 


 
ACRIN 6684 
15 
January 24, 2012 
 
Sites must submit and pass a series of qualification steps, including a test FMISO PET 
scan and a test MRI/MRS scan per protocol specifications (see Section 10.0) prior to 
being qualified to participate. Sites must also have PET scanners and MR images 
approved prior to the institution participating in the study. All scanner and image 
qualification materials are available at www.acrin.org/6684_protocol.aspx. Section 10.0 
provides detailed information regarding scanning equipment and imaging-procedure 
protocols. All regulatory documentation must be submitted to ACRIN Headquarters (via 
fax: 215-717-0936, ATTN: ACRIN 6684 Project Manager).  
 
7.2 
Form FDA 1572, IRB Approval Letter, and Informed Consent Form 
All institutions must submit study-specific Institutional Review Board (IRB) approval for 
the protocol and informed consent form (ICF), along with a Form FDA 1572. (The ICF is 
included in this protocol as Appendix I). The investigator and the investigator-designated 
research staff must follow OHRP-approved consent procedures (Title 45, Part 46 Code of 
Federal Regulations), as well as those set by the local IRB at the institution. Prior to 
registering the first participant, the completed Form FDA 1572, a copy of the IRB 
approval letter, and a copy of the IRB-approved, site-specific ICF must be delivered to 
the trial monitor for review and to be kept on file at ACRIN Headquarters (fax: 215-717-
0936, ATTN: Protocol Development and Regulatory Compliance Department). 
 
 
7.3  
Accrual Goals and Monitoring 
The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant 
accrual. Total target accrual for this study is 50 participants within a year. The trial will 
continue until accrual meets the target of 50 eligible and evaluable participants. 
―Evaluable‖ is defined as: images are completed; site deems all images adequate; and 
images pass initial quality review at ACRIN PET and MRI Core Labs. Inevaluable and 
ineligible cases will be followed per protocol (see Section 9.3). Each institution will not 
enroll more than 15 participants to this trial.  During the recruitment period, accrual will 
be reviewed monthly with the intention of discovering and resolving any recruitment 
barriers. In particular, starting approximately one month after a site is approved to begin 
participant enrollment, the site‘s actual accrual will be compared to the average monthly 
accrual potential described in their PSA. If a site‘s actual accrual falls significantly below 
what is reported in their PSA, the Protocol Support Enrollment Committee (PSEC) 
comprised of the trial PI and his or her designees will determine a follow-up action plan 
to identify site accrual barriers and develop strategies to support the site in meeting 
accrual goals. 
 
The ACRIN Steering Committee regularly reviews the overall trial accrual and may 
request information about a trial‘s accrual performance to better understand general 
accrual barriers or issues. Accrual and safety information will be presented to the ACRIN 
Data and Safety Monitoring Committee (DSMC) at regularly scheduled meetings thereof; 
the DSMC may, at its discretion, re-evaluate the study with respect to feasibility or the 
need for additional participating institutions. 
 
 
8.0 
DATA MANAGEMENT/ONLINE REGISTRATION  
8.1 
General 
8.1.1 
The ACRIN web address is www.acrin.org. 
 


 
ACRIN 6684 
16 
January 24, 2012 
 
8.1.2 
Data collection and management will be performed by the Biostatistics and 
Data Management Center (BDMC) of ACRIN under the direction of Dr. 
Constantine Gatsonis. The Biostatistics Center (BC) is located at Center for 
Statistical Sciences at Brown University in Providence, RI, and the Data 
Management Center (DMC) is located at ACRIN in Philadelphia, PA. 
 
8.1.3 
Participant enrollment and data collection occurs through a series of 
programmed 
screens 
accessed 
through 
the 
ACRIN 
web 
site 
to 
register/randomize participants, collect participant data, and maintain calendars 
of data submissions for each participant. By using the World Wide Web, 
ACRIN has made participant registration, data entry, and updated calendar 
information available to clinical sites 24 hours a day, seven days a week. Each 
successful case registration is confirmed through receipt of an e-mail containing 
a registration/randomization confirmation and a case specific calendar 
identifying timelines for data and image submission. If the confirmation e-mail 
is not received, the enrolling person should contact the DMC before attempting 
a re-registration. A DMC contact list is located on the ACRIN web site for each 
protocol. 
 
8.2 
Clinical Data Submission 
8.2.1 
Upon successful participant registration, a confirmation e-mail containing the 
registration and case specific calendar is sent to the research staff enrolling the 
participant via the web. In addition, the investigator-designated research staff 
may download the participant specific data submission calendar, which lists all 
forms and designated reports required by protocol, along with the form due 
dates at the DMC. These calendars will be updated as the study proceeds to 
reflect data that have been received, reply deadlines for queries about unclear 
data, deadlines for follow-up reports of adverse events, or changes in the 
protocol that change the data being collected or the timeframe. Updated 
calendars for each participant can be obtained 24 hours a day from the ACRIN 
web site. The research associate may use the calendar as a case management 
tool for data submission and follow-up scheduling.  
 
8.2.2 
The investigative site is required to submit data according to protocol as 
detailed on each participant‘s calendar, as long as the case status is designated 
as open/alive or until the study is terminated. The case is closed when all data 
have been received, reviewed, and no outstanding data query exists for the case. 
 
8.2.3 
To submit data via the ACRIN web site, the appropriate investigator-designated 
research staff will log onto the ACRIN web site and supply the pre-assigned 
user name and password. Case report forms will be available on the web site 
through a series of links. Each web form is separated into modules; each module 
must be completed sequentially in order for the internal programming to be 
accurate. The user selects the link to the appropriate form and enters data 
directly into the web-based form. As information is entered into the web form 
application, various logic checks will be performed. These logic checks look for 
data that are missing, data that are out of range, and data that are in the wrong 
format (e.g. character data in a field requiring numeric responses). Such errors 
will be detected as soon as the user attempts to either submit the form or move 


 
ACRIN 6684 
17 
January 24, 2012 
 
to the next data element. They must be corrected before the form is transmitted 
to the DMC. The user will not be able to finalize form transmission to the DMC 
until all data entered pass these logic checks. Forms that are not completed in 
one sitting can still be submitted and completed at a later date. The form will 
remain available on the web until the ―Complete Form Submission‖ button is 
depressed.  
 
8.2.4 
Once data entry of a form is complete, and the summary form is reviewed for 
completeness and accuracy, the investigator or the research staff presses the 
―Complete Form Submission‖ button on the form summary screen and the data 
are transferred into the clinical database. No further direct revision of the 
submitted data are allowed after this point. E-mail confirmation of web data 
entry is automatically generated and sent to the site investigator or research 
associate listing all of the data generated and just submitted. Should a problem 
occur during transmission and the e-mail confirmation of data submission is not 
received, the investigator or research associate should contact the DMC for 
resolution of the submission. 
 
8.2.5 
If a temporary problem prevents access to the Internet, all sites are notified of 
the event and estimated down time through an ACRIN broadcast message. The 
investigative site should wait until access is restored to submit data. If the site 
discovers a problem with access to the Internet, the site RA or investigator 
should notify the DMC of the problem and the DMC will give an estimated time 
when access will be restored. If access will be unavailable for an extended 
period, sites must seek another Internet Service Provider (ISP). On a short-term 
basis, the ACR can serve as an ISP. 
 
8.3 
Data Security 
The registration and data collection system has a built-in security feature that encrypts all 
data for transmission in both directions, preventing unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of 
identification codes and passwords. 
 
8.4 
Electronic Data Management 
8.4.1 
Data received from the web-based forms are electronically stamped with the 
date and time of receipt by the ACRIN server. The data are then entered into the 
database. A protocol-specific validation program is used to perform more 
extensive data checks for accuracy and completeness. Complementary 
validation programs are initiated at the Brown BC and the DMC. The logic 
checks performed on the data at this point are more comprehensive than those 
built into the web-based data entry screens. They include checking that answers 
are logical, based on data entered earlier in the current form and the more 
thorough checks. Data elements that fail validation are followed up by the DMC 
research associate. The validation program generated by BC produces a log of 
errors, which is sent to the DMC for resolution. The program is frequently 
updated to incorporate exceptions to rules so that subsequent validity checks 
minimize the time the DMC needs to spend resolving problems. Additional data 
review will take place once the data are transferred to the BC. The BC will run 


 
ACRIN 6684 
18 
January 24, 2012 
 
thorough cross-form validations, frequency distributions to look for unexpected 
patterns in data, and other summaries needed for study monitoring. Any errors 
found at the BC will be reported to the DMC for resolution. All BDMC 
communication with the participating sites is normally done through the DMC.  
 
8.4.2 
If checks at DMC or BC detect missing or problematic data, the DMC personnel 
assigned to the protocol sends a Request for Information (Z1 query letter) to the 
site RA or investigator specifying the problem and requesting clarification. The 
DMC updates the participant‘s data submission calendar with the due date for 
the site RA or investigator‘s response. 
 
8.5 
Missing and Delinquent Data Submission 
In addition to providing the site with a data collection calendar for each case, the DMC 
periodically prompts institutions for timely submission of data through the use of a Forms 
Due Report. Distributed at intervals via the electronic mail system directly to both the RA 
and the investigator at each site, this report lists data items (e.g. forms, reports, and 
images) that are delinquent and those that will be due before the next report date. In 
addition to prompting clinicians to submit overdue data, the Forms Due Report helps to 
reconcile the DMC‘s case file with that of the RA and/or investigator. Future Due Forms 
Report may be sent on an as needed basis in addition to past due reports. The site 
investigator or RA may use the Forms Due and Future Due Reports as a case 
management tool. 
 
8.6 
Data Quality Assurance  
8.6.1 
The BC at Brown University will maintain a study database at its site for 
monitoring data quality and for performing analyses. These data are drawn 
directly from the permanent database of the DMC. The transfer of data 
between the DMC and the BC has been validated through a series of checks 
consisting of roundtrip data verification in which data are sent back and forth to 
verify that the sent data are equivalent to the received data. These checks are 
repeated at random intervals during the course of a given study. Any 
discrepancies and other data quality issues will be referred to DMC for 
resolution, since only the DMC can correct the data file. No changes to the 
data will be made at the BC.  
 
8.6.2 
Ongoing monitoring of data is performed to assess compliance with the protocol 
and to look for unforeseen trends that may be indicative of procedural 
differences among clinical sites. If patterns are discovered in the data that 
appear to arise from causes specific to an institution, the BDMC will apprise the 
ACRIN Headquarters and the site of the problem, and work with the site, along 
with ACRIN Protocol Development and Regulatory Compliance (PDRC) 
department, until the problem has been resolved. If the BDMC, along with the 
PDRC, cannot find a resolution to the problem, it will be brought to the ACRIN 
Quality Assurance (QA) Committee for further discussion and resolution. 
 
8.6.3 
In addition, the ACRIN QA Monitor will review case report forms and source 
documents at several different time points: after first few participants enrolled 
and during the conduct of the trial, including staff changes at the participating 
sites. In addition, the QA Monitor will review the initial and annual regulatory 


 
ACRIN 6684 
19 
January 24, 2012 
 
documents and any revised regulatory documents. This monitoring process 
ensures protocol and regulatory compliance, participant‘s welfare and safety, 
and provides resources to sites for clarification to the protocol and guidance in 
completion of the case report forms. 
 
 
 
9.0 
STUDY PROCEDURES 
The trial will continue until accrual meets the target of 50 eligible and evaluable participants. 
―Evaluable‖ is defined as: images are completed; site deems all images adequate; and images 
pass initial quality review at ACRIN PET and MRI Core Labs. Inevaluable and ineligible cases 
will be followed per protocol (see Section 9.3). Each institution will not enroll more than 15 
participants to this trial. All participants will be asked to complete the test-retest substudy until 
15 participants have completed the series; after the substudy has been completed, potential 
participants will be consented only to the baseline scan. Focus will be on completing the baseline 
FMISO PET and MRI scans, and trial accrual will continue to reach targeted goals even if the 
test-retest substudy is incomplete.  
 
NOTE: All PET scans should be performed on the same ACRIN-qualified scanner; if this is not 
feasible, then the same model scanner should be consistently used for a participant throughout 
the trial if at all possible. All ACRIN-qualified scanners will need to be cross-calibrated to the 
well counter on a quarterly basis or as specified by the manufacturer. 
 
A global time reference will need to be used to record and report timing of dose counting, 
injection times, imaging start time, blood sampling time, and blood counting time. It is important 
that this time source be accessible for all modalities used in the FMISO PET study (dose 
calibration, well counter, etc). A portable stop watch or other time piece accurate to at least a 
minute and preferably seconds is recommended. 
 
NOTE: For this protocol, ―PET‖ may comprise PET, PET/CT, or MR-PET. Any scanner 
considered for use for the trial will need to be ACRIN qualified and approved prior to use. 
 
9.1 
VISIT 1: Eligibility/Registration or Screening Log  
At the registration visit, the potential participant will be screened and confirmed for 
eligibility by the appropriate study-team designee prior to formal electronic registration*: 
 Obtain a signed IRB approved informed consent prior to conducting any study-related 
procedures. 
 Screen and confirm eligibility which includes:  
 Review of the inclusion and exclusion criteria, pathology reports, 
postoperative MR images, operative reports, medical history,  
NOTE: If patient had a biopsy only, postoperative MRI is not needed to 
assess residual tumor prior to enrollment. 
 Conduct mental health assessment (including Karnofsky and Mini Mental 
State Exam [MMSE] scores if these scores have not been completed within 7 
days prior to enrollment),  
 Perform general physical and neurologic exams including vital signs 
assessment, and  


 
ACRIN 6684 
20 
January 24, 2012 
 
 Review routine laboratory studies, including creatinine levels for GFR if not 
assessed 28 days prior to registration.  
 Conduct a standard urine pregnancy test if the participant is unsure of her pregnancy 
status.  
 Report any scheduled therapy at time of registration.† 
 Obtain and send tumor tissue specimen that was obtained for the diagnosis of GBM to 
ACRIN designated pathology laboratory, if feasible; specific collection instructions, 
shipment, and processing facility information will be provided at the initiation of the 
trial and on the ACRIN web site: www.acrin.org/6684_protocol.aspx. See Section 
18.0 for tumor tissue specimen details. 
 
*NOTE: When possible, individuals who are evaluated for participation in this study but 
are not able/willing to participate should have a Screening Log completed 
detailing the reason for non-participation (e.g., participant refused to provide 
consent, patient is ineligible, patient is enrolled on a competing trial, etc.). 
 
†NOTE: ACRIN will allow patients to join this trial who are enrolled also in trials using 
additional investigational agents where the treatment given is randomized and 
initial assessment is blinded. However, ACRIN will eventually need to access 
unblinded treatment and regimen data (specifically, ACRIN will need to know 
details of the timing, dosing, and any interruption of the therapeutic regimen). 
The site and ACRIN may need to coordinate with the other trial‘s sponsorship 
to determine any necessary data sharing prior to patient enrollment to the 
ACRIN trial. 
 
9.2 
VISIT 2: Baseline—Pre-Treatment FMISO PET and Brain MRI With Contrast 
(Within 2 Weeks Prior to Initiation of Chemoradiation) 
Visit 2 will occur between 1 to 14 days prior to initiation of chemoradiation. Participants 
MUST be scanned using the same ACRIN-approved MRI and PET scanners used for trial 
qualification, using the same protocol-specific parameters consistently at each time point. 
NOTE: The contrast agents do not interact, so administration of FMISO followed by 
MRI within the 110 minutes prior to initiation of PET scan is an acceptable approach to 
same-day imaging.  
 Assess participant for Karnofsky and MMSE scores (if not completed within 7 days 
of scan). 
 Conduct a pregnancy test per the institution‘s standard of care if a participant is 
unsure of her pregnancy status. 
 Evaluate creatinine levels for GFR (via participant record review or special testing if 
necessary) if not assessed within 28 days prior to Visit 2 MRI scan. 
 Obtain vital signs before FMISO administration and after completion of imaging. 
 Place two (2) IV catheters into the participant‘s arm veins, one IV catheter in each 
arm; one IV will be used to inject the bolus of FMISO, the other will be used for 
blood extraction. Blood must be drawn from the IV that was not used for the FMISO 
injection. For the FMISO injection, minimize the length of the IV tubing between the 
injection site and the vein to avoid FMISO being left in the tube. 


 
ACRIN 6684 
21 
January 24, 2012 
 
 Perform a saline flush following the FMISO injection.  
 Obtain blood samples at three (3) time points at 5-minute intervals (± 2 minutes) 
during 
the 
FMISO 
PET 
scan; 
see 
Appendix 
IV 
and 
www.acrin.org/ 
6684_imagingmaterials.aspx for details. 
 
NOTE: The first sample will be taken at 5 minutes (± 2 minutes) after the initiation 
of the emission scan. Exact time of collection is key for this protocol. Time will need 
to be recorded from a global resource to be used throughout the study. Minutes and 
seconds will be recorded and reported. 
 QC 
the 
well 
counter 
(see 
Appendix 
III 
and 
www.acrin.org/6684_ 
imagingmaterials.aspx for details). 
 Conduct same-day blood sample analysis; see Appendix IV for details. 
 
NOTE: Must note exact time of analysis (minutes and seconds preferred) using 
study’s global time resource for reporting purposes.   
 Perform the FMISO PET scan per the imaging parameters described in this protocol 
(see Section 10.0 and www.acrin.org/6684_imagingmaterials.aspx for imaging 
specifics).  
 Obtain steroid use/dose information prior to MRI. 
 Perform a brain MRI scan with Gd contrast per the imaging parameters described in 
this protocol (see Section 10.0 and www.acrin.org/6684_imagingmaterials.aspx for 
imaging specifics). OPTIONAL BOLD SEQUENCE: Note that 02 administration 
and collection of 02 saturation levels are necessary with the BOLD MRI. Sites are 
requested to administer oxygen per site preference, at a minimum of 7 L per minute 
via nasal canula. If the participant is unable to undergo the administration of oxygen 
for a period of less than 10 minutes (e.g., because of a history of chronic obstructive 
pulmonary disease), then the BOLD imaging sequence should not be conducted. 
 Query participants for potential AEs. When an AE is reported, collect information 
about concomitant medication taken in the 2 weeks prior to the event and/or during 
the time of any reported AE. AE queries should be conducted by appropriate study-
staff designee at the following time points: 
 At the time of injection; 
 Before leaving the PET suite; 
 If they call the site as instructed for any concerns during the 24 hours after 
FMISO administration; 
 By telephone after 24 hours post-FMISO infusion. 
 
NOTE: Participant disease, preference, or scheduling needs may necessitate two days of 
imaging to complete the FMISO PET and MRI scans; however, each two-day imaging 
cycle will increase the participant‘s risk because an additional IV catheter will be 
necessary. This risk should be discussed with the participant. If two days of imaging are 
necessary, then both scans must be completed during the appropriate divergent period for 
each Visit (in this case, within that 1 to 14 day period prior to initiation of 
chemoradiation). 
 
9.2.1  VISIT 2A: SUBSET OF 15 PARTICIPANTS ONLY – Reproducibility Arm 
for FMISO PET (1 to 7 Days After Visit 2, Prior to Initiation of 
Chemoradiation) 


 
ACRIN 6684 
22 
January 24, 2012 
 
For the subset of 15 participants who enroll in the test-retest substudy, Visit 2A 
will occur within 1 to 7 days after completion of Visit 2 but prior to the start of 
therapy in order to determine the reproducibility of FMISO PET scan results. 
Participants MUST be scanned using the same ACRIN-approved PET scanner 
used for trial qualification, using the same protocol-specific parameters 
consistently at each time point.  
 Conduct a pregnancy test per the institution‘s standard of care if a participant 
is unsure of her pregnancy status. 
 Obtain vital signs before FMISO administration and after completion of 
imaging. 
 Place two (2) IV catheters into the participant‘s arm veins, one IV catheter in 
each arm; one IV will be used to inject the bolus of FMISO, the other will be 
used for blood extraction. Blood must be drawn from the IV that was not used 
for the FMISO injection. For the FMISO injection, minimize the length of the 
IV tubing between the injection site and the vein to avoid FMISO being left in 
the tube. 
 Perform saline flush following the FMISO injection.  
 Obtain blood samples at three (3) time points at 5-minute intervals (± 2 
minutes) 
during 
the 
FMISO 
PET 
scan; 
see 
Appendix 
IV 
and 
www.acrin.org/6684_imagingmaterials.aspx for details. 
NOTE: The first sample will be taken at 5 minutes (± 2 minutes) after the 
initiation of the emission scan. Exact time of collection is key for this 
protocol.  Time will need to be recorded from a global resource to be used 
throughout the study. Minutes and seconds will be recorded and reported. 
 QC the well counter (see Appendix III and www.acrin.org/6684_ 
imagingmaterials.aspx for details). 
 Conduct same-day blood sample analysis;  
NOTE: Must note exact time of analysis (minutes and seconds preferred) 
using study’s global time resource for reporting purposes. See Appendix IV 
for details. 
 Perform the second FMISO PET scan per the imaging parameters described in 
this protocol (see Section 10.0 and www.acrin.org/6684_imagingmaterials 
.aspx for imaging specifics on FMISO preparation, administration, and 
imaging parameters). 
 Query participants for potential AEs. When an AE is reported, collect 
information about concomitant medication taken in the 2 weeks prior to the 
event and/or during the time of any reported AE. AE queries should be 
conducted by appropriate study-staff designee at the following time points: 
 At the time of injection; 
 Before leaving the PET suite; 
 If they call the site as instructed for any concerns during the 24 hours 
after FMISO administration; 
 By telephone after 24 hours post-FMISO infusion. 
 


 
ACRIN 6684 
23 
January 24, 2012 
 
9.3 
FOLLOW UP: Routine Disease Progression/Vital Status Assessment—Site Contacts 
Treating Physician Every 3 Months for Standard Clinical Follow-Up Findings and 
MRI/CT Images   
Disease progression, vital status data, follow-up MRI and CT images, and image findings 
will be collected from all enrolled participants‘ treating physicians until the end of the 
study. 
9.3.1 Participant clinical follow up will be conducted per institutional standard of care 
and per the recommendations of the participant's treating physician.  
 Vital status, disease progression, and other data (e.g., tumor growth, 
neurological status, steroid use, steroid dose at the time of each MRI [or CT], 
treatment details, and interval treatments) will be collected every 3 months 
until the end of the study by the site from the treating physician‘s routine 
clinical follow-up findings.  
NOTE: Disease progression should be defined by Macdonald criteria38 (see 
Appendix V for Macdonald Radiographic Response Criteria). Follow up will 
continue until the end of the study. 
9.3.2 All standard-of-care MRIs and CTs for the participant taken during the trial 
timeframe will be requested every 3-months until the end of the study from the 
treating physician in addition to collecting clinical care follow-up information as 
described above in Section 9.3.1. Images will be submitted to ACRIN per the 
criteria described in Section 10.4 (Image Submission Criteria).  
9.3.3 The end of the study will necessitate a final follow-up form for all surviving 
participants to provide confirmation of vital status and/or disease progression as 
of the last day/end of the study. 
 
9.4 
OFF-IMAGING CRITERIA 
As long as at least the first baseline FMISO PET and MRI scans have been completed, 
participants will continue to be followed for disease progression and survival as outlined 
in Section 9.3.2. No participants will be considered ―off-imaging‖ as long as the FMISO 
PET and MRI scans are completed prior to treatment initiation. 
 
The trial will continue to accrue until evaluable images are available from 50 eligible 
participants. 
 
 


 
ACRIN 6684 
24 
January 24, 2012 
 
9.5  
STUDY PROCEDURES TABLE:  
STUDY PROCEDURE 
 
VISIT 1: 
Eligibility/ 
Registration or 
Screening Log 
VISIT 2*: Baseline— 
Within 2 Weeks Prior 
to the Initiation of 
Chemoradiation 
VISIT 2A†:   
15 PARTICIPANTS 
ONLY—1 to 7 Days After 
Visit 2, Prior to Initiation of 
Chemoradiation 
FOLLOW-UP:  
Every 3 Months 
Until End of 
Study  
Informed Consent Form 
X 
 
 
 
Eligibility/Registration 
X 
 
 
 
Report Concomitant Therapy, If Scheduled  
(See NOTE in Section 9.1) 
X 
 
 
 
Medical History 
X 
 
 
X 
Physical Examination 
X 
 
 
 
Assign Karnofsky and MMSE Mental Performance Scores 
X 
X 
 
 
Neurologic Examination 
X 
 
 
 
Review Pathology Report, Operative Report,  
and Postop MR Image 
X 
 
 
 
Screening Lab Work, Including Creatinine Levels for GFR± 
X 
X 
 
 
Vital Signs (Including Before FMISO Administration  
and After PET Scan) 
X 
X 
X 
 
Urine Pregnancy Test  
X 
X 
X 
 
Obtain & Send Tumor Tissue Specimen  
(If Feasible; See Section 18.0 for Details)  
X 
 
 
 
Place 2 IV Catheters  
(1 in Each Arm) 
 
X 
X 
 
QC Well Counter 
 
X 
X 
 
Blood Sampling (3 Samples at 5-Minute [± 2 Minutes] 
Intervals Starting at Emission Scan Initiation) 
 
X 
X 
 
Note Exact Time of Blood Sample Collections and Sample 
Analyses 
 
X 
X 
 
 
Brain MRI With Contrast 
 
 
X 
 
X‡  
(submit all 
follow up MRI 
and CT Scans) 
FMISO PET (Saline Flush After FMISO Injection) 
 
X 
X† 
 
AEs Assessment With Telephone Follow-Up  
After 24 Hours Post-Infusion 
 
X§ 
X§ 
 


 
ACRIN 6684 
25 
January 24, 2012 
 
*  NOTE: FMISO PET and MRI scans do not have to be completed on the same day; however, participants should be aware that 1 additional 
IV catheter will be needed for each additional day of scanning. Details are described in Section 9.2 above. 
± To be completed if the creatinine levels were not completed within 28 days of registration and within 28 days prior to Visit 2 for the trial-related 
MRI scan with Gd contrast. 
†  Only 15 participants will undergo repeat FMISO PET scans, within 1 to 7 days of each other (independent of timing of baseline MRI scan) to 
evaluate reproducibility of FMISO PET. 
‡ All MRIs (with or without contrast) and CT scans performed as standard of care during participant follow up should be submitted to ACRIN 
per the instructions in Section 10.4 (Image Submission Criteria). 
§  A phone call will be made to participants after 24 hours after the FMISO injection to elicit AEs using open-ended questions. In the event an 
AE is reported, concomitant medication details from the 2 weeks prior to the event and/or during the time of the reported AE will need to be 
collected. 
 
 
 
9.6   TREATMENT AND IMAGING SEQUENCE TABLE: 
 
 
TREATMENT AND IMAGING 
 
Visit 2* 
Chemoradiation Begins 
 
Baseline 
Wk 1 
Temozolomide (mg/m2/day) 
 
75 
Radiation Therapy 
 
• 
FMISO PET Scan 
•† 
 
Brain MRI Scan With Contrast‡ 
• 
 
 
*  NOTE: FMISO PET and MRI scans do not have to be completed on the same day; however, participants should be aware that  
1 additional IV catheter will be needed for each additional day of scanning. Details are described in Section 9.2 above. 
† Only 15 participants will have 2 baseline FMISO PET scans performed 1 to 7 days apart for test-retest analysis  
 (see Section 9.2.1 for details of Visit 2A); both scans must be completed prior to initiation of chemoradiation. 
‡ All MRIs (with or without contrast) and CTs performed as standard of care during participant follow up should be submitted to 
ACRIN per the instructions in Section 10.4 (Image Submission Criteria). 


 
ACRIN 6684 
26 
January 24, 2012 
 
10.0  IMAGING GUIDELINES  
10.1 
MR Imaging With Gadolinium Contrast 
In order to participate in the FMISO trial, sites must be able to perform all of the advanced MRI 
series per vendor-specific parameters. Participating sites also must be able to capture and submit 
processed and raw spectroscopy file data. To ensure that the institution‘s scanners are able to 
perform the advanced imaging MRI/MRS sequences, all institutions must submit pre-
qualification test scans to ACRIN using the scanner that will be used consistently throughout the 
trial. These test scans must be protocol compliant in order to become qualified to participate in 
the trial. 
 
NOTE: All MRI scans must be completed at 1.5 Tesla or 3.0 Tesla; 3.0 Tesla is preferred. 
Participants MUST be scanned using the same ACRIN-approved MR scanner(s) used for trial 
qualification, using the same protocol-specific parameters consistently.  
 
Detailed, vendor-specific technical parameters and site approval instructions are available 
via the ACRIN web site at www.acrin.org/6684_protocol.aspx. 
 
10.1.1 MRI Sequences  
Participating sites are required to complete all of the following MRI sequences for each 
participant for this FMISO trial (exact details available at the web site above): 
 Scout; 
 T1–weighted SE (pre injection); 
 3D T2 Rare; 
 FLAIR; 
 OPTIONAL: BOLD MRI during transient inhalation of oxygen in the magnet per 
institutional standard of care (minimum requirement 7 L/min) using nasal canula; 02 
saturation levels will be collected during this sequence and documented; 
 Dynamic contrast enhanced images with associated T1 mapping; 
 Diffusion-weighted imaging; 
 Dynamic susceptibility contrast imaging; 
 Post  T1 3D–weighted (1 mm isotropic); 
 Post T1–weighted SE; 
 3D volumetric spectroscopy is preferred. 2D CSI spectroscopy is accepted. 
Additional details are available online. 
 
10.1.2 MRI Contrast Agent, Gadolinium 
Gadolinium contrast will be administered according to current clinical standard-of-care 
practice and using only FDA-approved agents. In reflection of recent FDA label changes 
for several gadolinium agents, trial leadership advises caution in using gadolinium 
contrast agents in patients with poor kidney function and encourages education for 
participants in the signs and symptoms of nephrogenic systemic fibrosis (NSF). Sites 
should feel free to contact trial leadership if there are any questions either about NSF in 
general or about the eligibility of a given patient with respect to this issue. 
Each IRB must approve this study, including its gadolinium contrast dosage. Allowed 
contrast agents will be gadopentate dimeglumine (Magnevist), gadoteridol (ProHance), 
gadodiamide (OmniScan), gadoterate meglumine or gadoversetamide (Optimark), 


 
ACRIN 6684 
27 
January 24, 2012 
 
depending on each site‘s clinical practice. We seek to respect individual site‘s decisions 
on the issue of choice of contrast agent, an issue that has garnered substantial discussion 
in the past three years due to the recognition of associated risks of nephrogenic systemic 
fibrosis. The contrast agent will be administered at a dose of 0.1 mmol/kg (for dynamic 
contrast enhanced MRI) followed by 0.1 mmol/kg (for dynamic susceptibility contrast 
MRI) injected at 3 to 5cc/sec as is current clinical practice and only upon approval by the 
IRBs in this trial. We note that one of the agents (ProHance) is explicitly for a dose of up 
to 0.3 mmol/kg (―triple dose‖); use of other agents will be under local IRB approval. 
Gadobenate dimeglumine (MultiHance) and gadofosveset (marketed as Vasovist in 
Europe) are not preferred in this trial because their binding to serum albumin may 
influence DCE MRI measurements in unknown ways.  
 
10.1.3 MRI Quality Assurance Review 
 All institutions must complete qualification procedures to establish an ACRIN-
approved MRI scanner prior to registering participants. 
 Qualification requires sites to submit for review one MRI and one MRS examination, 
performed per protocol specification using the parameters available on the ACRIN 
web site at www.acrin.org/6684_protocol.aspx. All submissions must include raw 
spectroscopy files (e.g. GE: P-files; Siemens: .rda files; Philips: .spar/.sdat files). Raw 
MRS data files can be transmitted to the ACRIN Core Laboratory via secure File 
Transfer Protocol (sFTP) directly to the image archive. All MRS submissions must 
also include an image demonstrating voxel placement. Vendor-specific instructions 
for locating and submitting raw MRS data can be found on the ACRIN web site under 
Imaging Requirements at www.acrin.org/6684_protocol.aspx. 
 
10.2 
FMISO PET SCAN 
Participant must be scanned on PET scanners that have been qualified by the ACRIN PET Core 
Laboratory per the protocol-specific instructions posted on the ACRIN web site at: 
www.acrin.org/CORELABS/PETCORELABORATORY/PETQUALIFICATION/tabid/485/ 
Default.aspx. 
 
A dedicated PET scan unit or hybrid PET/CT scanner is mandatory. The PET scanner must be 
capable of performing both emission and transmission images in order to allow for attenuation-
corrected PET scan images. The ability to calculate standardized uptake values (SUVs) is also 
mandatory. 
 
Serial scans of the same participant must be done on the same scanner for this study. 
The PET scanner must be kept calibrated in accordance with the manufacturer‘s 
recommendations. The scanner should routinely be assessed for quantitative integrity and 
stability by being tested using various imaging protocols on a standard phantom. For SUV 
measurements, this assessment should include a comparison against a dose calibrator to ensure 
accuracy; that is, a comparison of the absolute activity measured versus the measured activity 
injected, should be performed. 
The PET scanner calibrations should be routinely verified according to manufacturer 
recommendations. The scanner should be assessed regularly for quantitative integrity and 


 
ACRIN 6684 
28 
January 24, 2012 
 
stability by scanning a standard quality control phantom with the same acquisition and 
reconstruction protocols used for study participants. The SUV verification measurements must 
include the dose calibrator used to measure the doses of study participants to ensure that the dose 
calibrator and PET scanner are properly cross calibrated, i.e. the dose measured in the dose 
calibrator and injected into the phantom matches the results obtained from analysis of the 
phantom images. 
A quality control (QC) check must be performed at the beginning of the day for the dose 
calibrator and well counter, in accordance with the manufacturer recommendations. If any of the 
QC results are outside of the manufacturer‘s guidelines, the study must be rescheduled and the 
problem rectified before scanning any patients. 
Exact time collection is key to this protocol. A global time piece should be used consistently as 
a standardized measuring tool—such as a portable stop watch—throughout the trial for all time 
collection. The time piece will need to accurately record minutes, at the least, and preferably 
seconds as well. It will be used to collect time at dose counting, injection time, imaging start 
time, blood sampling time, and blood counting time. 
 
10.2.1 Pre-Scan Participant Preparation 
 There will be no deliberate fasting prior to injection for the participant of this study. 
 Participants are encouraged to be well hydrated prior to the scan. 
 Blood glucose measurement is not required. 
 Participant‘s height and weight must be measured using calibrated and medically 
approved devices (not verbally relayed by the participant). 
 Vital signs, including temperature, blood pressure, heart rate, and respiratory rate, 
will be measured prior to injection. 
 
10.2.2 Injection of FMISO 
 Two IV catheter access lines (18 or 20 gauge is preferred) are placed, one in each 
arm—one for the FMISO injection and the other for blood sampling during the scan.   
 The dose of FMISO will be 3.7 MBq/kg (0.1 mCi/kg) (maximum 260 MBq, 7 mCi) 
in < 15 mL. For the FMISO injection, minimize the length of the IV tubing between 
the injection site and the vein to avoid FMISO being left in the tube.  
 A saline flush should follow the FMISO injection.  
 The exact time of calibration of the dose should be recorded using a global time piece 
consistently used throughout the study for time recording; the exact time of injection 
should be noted and recorded to permit correction of the administered dose for 
radioactive decay. In addition, any of the dose remaining in the tubing or syringe, or 
that was spilled during injection, should be recorded. The injection should be 
performed through an IV catheter and 3-way stopcock. 
 AEs will be solicited in open-ended fashion (i.e., ―how are you feeling?‖) at this time. 
 
 
10.2.3 FMISO PET Imaging 
 Single field-of-view emission imaging must begin 110 ± 10 minutes after FMISO 
injection. Imaging start time should be recorded using the global time piece for the 
study. 


 
ACRIN 6684 
29 
January 24, 2012 
 
 The participant will empty his/her bladder immediately before the acquisition of 
images. 
 Participants are imaged in the supine position with head immobilization. Head 
immobilization procedures for PET imaging will be site-specific. 
 An attenuation scan should be performed prior to emission scanning, or just after 
emission scanning if there is a problem before. The transmission scan should be a 
low-dose CT scan without contrast for the PET/CT or a transmission scan for PET-
only devices. The transmission scan type, length, etc, should exactly match that used 
in the calibration and qualification procedure. 
 A 20-minute emission scan is performed. 
 During emission tomography, three (3) venous blood samples are obtained at 
intervals of 5 minutes (± 2 minutes). Blood must be drawn from the IV that was not 
used for the FMISO injection. The exact time of the blood draws should be recorded 
using the standard global time piece for the study. 
 Whole blood samples of 1 mL each are counted (within 60 minutes of collection) in a 
multichannel gamma well counter that is calibrated quarterly, or as specified by the 
manufacturer, in units of cpm/uCi (see Appendix III for well counter cross-calibration 
instructions and Appendix IV for blood sampling procedures).  
 The exact time that each blood sample is counted should be recorded using the global 
time piece.  
 Blood activity is averaged and then expressed as uCi/mL decay corrected to time of 
injection. 
 Vitals signs, including temperature, blood pressure, heart rate, and respiratory rate, 
are measured again at completion of the FMISO PET imaging, and subsequently as 
needed. 
 


 
ACRIN 6684 
30 
January 24, 2012 
 
 
 
 
10.2.4 Image Reconstruction 
 The PET data will be corrected for dead time, scatter, random, and attenuation using 
standard algorithms provided by the scanner manufacturer. 
 Image reconstruction will be performed as specified in the ACRIN certification of the 
PET scanner. 
 
10.3 
Image Analysis 
MRIs are co-registered with the FMISO images to delineate tumor and brain regions of interest 
(ROI). The FMISO image data and blood sample are expressed in common units of uCi/mL. 
Image values are divided by the average blood value to produce tissue/blood (T/B) values. This 
allows a pixel-by-pixel calculation of T/B activity ratios for all image planes. The number of 
pixels in the tumor volume with a T/B ratio > 1.2, indicating hypoxia, is multiplied by the known 
volume/voxel for the scanner to yield milliliter units to measure the HV, based upon prior 
studies. In the tumor region we also locate the pixel with the maximum T/B ratio and record this 
variable, T/Bmax. HV depicts the volume of tumor that has crossed the threshold for hypoxia and 
T/Bmax depicts the magnitude of the hypoxia. 
 
10.4 
Image Submission Protocol 
The protocol-required images must be in DICOM format on CD/DVD-ROM or submitted via the 
internet using sFTP, and transmitted along with an Imaging Transmittal Worksheet (ITW) which 
can be found on the ACRIN web site (www.acrin.org/6684_protocol.aspx). The required images 
Inject FMISO 
bolus followed 
by saline flush 
Baseline 
  Wait 110 ± 10 min 
Figure 1. Timing Sequence for FMISO Injection and PET Imaging 
Position participant  
before imaging begins 
Attenuation scan just 
before emission scan—or 
immediately after if 
necessary—low-dose CT 
without contrast for 
PET/CT or transmission 
scan for PET-only 
NOTE: Global time will need to be recorded for dose counting, injection time, imaging start time, blood 
sampling time, and blood counting time throughout the trial. 
3 blood samples  
at 5-min intervals 
(± 2 min) 
Imaging for 20 min 
 Take Vital Signs 
 Take Vital Signs 


 
ACRIN 6684 
31 
January 24, 2012 
 
must be submitted to the ACRIN core lab. ACRIN can provide electronic image submission and 
anonymity utilities for participating institutions via TRIAD software. For support in sending the 
images via the internet using TRIAD, contact the representatives of the core lab via email at 
Triad-Support@phila.acr.org or via phone: 215-940-8820. 
 
10.4.1 If required and part of the protocol, images maintained at ACRIN Headquarters Image 
Archive may be distributed to other participating sites, using sFTP, or CD-ROM where 
appropriate, for purposes of secondary review. 
10.4.1.1  Removal of Confidential Participant Information: The header record on 
DICOM formatted image data, which often contains information identifying 
the participant by name, MUST be scrubbed before the image are transferred.  
 
This involves replacing the following: 
 Participant Name tag with the ACRIN Institution ID or number, 
 Participant ID tag with the ACRIN case number, and 
 Other Participant ID tag with ACRIN Study Number.  
10.4.1.2 
sFTP Transfer: Digitally generated image files in DICOM v3.0 format can be 
transmitted to the ACRIN core lab via sFTP directly to the image archive. 
This can be performed using a customized software program or by using 
TRIAD software available from ACRIN. An Imaging Transmittal Worksheet 
(ITW) must be faxed at the time images are transmitted. Contact the ACRIN 
core lab for additional details at Triad-Support@phila.acr.org.  
10.4.1.3 
A completed, signed ITW MUST accompany all imaging exams submitted to 
ACRIN for each time point. The ITW must be completed and faxed to 215-
923-1737 at the time the images are being submitted. For exams submitted via 
media, this worksheet may be completed and included with the media 
shipment. Please affix a label to the jacket of the media to include: study 
name, site name, and case number, date of exam, time point, and type of 
imaging. 
 
Please fax the ITW to: 
ACRIN Core Lab at 215-923-1737  
ATTN: ACRIN 6684 Imaging Specialist 
10.4.1.4 
In the event that the transfer of scrubbed image headers is not available, 
images may also be sent on a CD/DVD-ROM to the ACRIN core lab for 
transfer to the image archive. Please contact ACRIN prior to sending the 
media to confirm compatibility. 
 
Images and the ITW may be mailed to: 
American College of Radiology Imaging Network 
Core Laboratory 
Attn: ACRIN 6684 
1818 Market Street 16th floor 
Philadelphia, PA 19103 
 
 


 
ACRIN 6684 
32 
January 24, 2012 
 
10.5 
Spectroscopy Data Submission 
Raw MRS data files can be transmitted to the ACRIN core lab via sFTP directly to the image 
archive. All MRS submissions must include an image demonstrating voxel placement. Vendor-
specific instructions for locating and submitting raw MRS data can be found on the ACRIN web 
site under Imaging Materials at www.acrin.org/6684_imagingmaterials.aspx. 
 
10.6 
Image Quality Control 
All image submissions will be subject to ongoing quality control review by the ACRIN core lab. 
In addition, a central quality review of the first two imaging submissions from each participating 
institution will be formally conducted. Thereafter, a random sampling of 10% of the remaining 
cases will be formally reviewed. 
 
Prompt submissions of all image data are essential to ensure adequate image quality control.  
 
 
11.0  WELL-COUNTER CALIBRATION/BLOOD SAMPLING GUIDELINES  
Exact time of collection is key for this protocol. Time will need to be recorded from a global 
resource to be used throughout the study. Preferably, minutes and seconds will be recorded and 
reported.  
 
11.1 
Well-Counter Calibration 
See www.acrin.org/6684_imagingmaterials.aspx for additional procedural details. 
11.1.1 As a pre-qualification measure, sites will need to demonstrate appropriate well-counter 
cross calibration.  
11.1.2 Well-counter cross calibration should be completed quarterly or as specified by the 
manufacturer. (Routine well-counter QC measures will still be necessary on the day of 
imaging/counting.) 
11.1.3 An Excel document to assist in calculations during cross calibration is provided online at 
www.acrin.org/6684_imagingmaterials.aspx. 
 
11.2 
Blood Sampling 
See Appendix IV for additional procedural details. 
11.2.1 Blood will be drawn from all participants during the 20-minute FMISO PET imaging 
sequence. Figure 1 presents the timeline for the FMISO PET imaging sequence, including 
blood sampling every 5 minutes (± 2 minutes) at 3 time points (e.g., at minutes 5, 10, and 
15 after FMISO emission scan begins).  
11.2.2 Sites are expected to process the blood samples within 60 minutes after completion of the 
PET scan.  
11.2.3 Use of dose calibrators for this procedure is strictly prohibited. 
 
 


 
ACRIN 6684 
33 
January 24, 2012 
 
12.0 
ADVERSE EVENTS REPORTING 
Adverse Event (AE) reporting must follow the guidelines below. The ACRIN Adverse Event Reporting 
Manual [November 2009 version or latest revision—available on the ACRIN web site] provides 
additional details and may be consulted as a reference, but does not supersede AE reporting as specified 
in this protocol. The AdEERS electronic AE reporting system is to be used for AE reporting of AdEERS 
qualified events unless unavailable. AE data are to be entered into the AdEERS electronic system if the 
AE meets AdEERS criteria (see Section 12.8 and 12.9 for AdEERS reporting criteria), even when they 
have been manually captured and/or manually submitted due to system unavailability (see manual 
process below).  
 
12.1 
Definition of Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a participant that does not 
necessarily have a causal relationship with the study intervention. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory or physiological finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite). Abnormal results of diagnostic procedures 
are considered to be AEs if the abnormality: 
 
 Results in study withdrawal; 
 Is associated with a serious adverse event (SAE); 
 Is associated with clinical signs or symptoms; 
 Leads to additional treatment or to further diagnostic tests; 
 Is considered by the investigator to be of clinical significance. 
 
12.2 
Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that meets any 
one of the following criteria: 
 
 Results in death or is life-threatening at the time of the event; or 
 Requires inpatient hospitalization, or prolongs a hospitalization; or 
 Results in a persistent or significant disability/incapacity; or 
 Is a congenital anomaly/birth defect (in a participant‘s offspring); or 
 Requires intervention to prevent any of the above, per the investigator/sponsor. 
 
A life-threatening AE is an AE that places the study participant, in the clinical opinion of the 
investigator, at immediate risk of death. 
 
12.3 
Adverse Event Grading 
Grade denotes the severity of the AE. An AE is graded using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0, or the following categories (if 
the term does NOT appear in the CTCAE v4.0):  
 
 
 
 
1 – Mild  
 
 
 
2 – Moderate 
 
 
 
3 – Severe 


 
ACRIN 6684 
34 
January 24, 2012 
 
 
 
 
4 – Life-threatening or disabling 
 
 
 
5 – Fatal 
 
(For terms listed in the CTCAE, the grade is still recorded as 1, 2, 3, 4, or 5; however, the 
definition of the various grades will be specific to the term being used.) 
 
12.4 
Adverse Event Attribution 
Attribution determines whether an AE is related to a study treatment or procedure. Attribution 
categories are: 
Definite  –  AE is clearly related to the study treatment or procedure. 
Probable  –  AE is likely related to the study treatment or procedure. 
Possible  –  AE may be related to the study treatment or procedure. 
Unlikely –  AE is doubtfully related to the study treatment or procedure. 
Unrelated  –  AE is clearly NOT related to the study treatment or procedure. 
 
12.5 
Expected and Unexpected Adverse Events 
AEs may be expected or unexpected:  
 
 An expected AE is one that is described in the protocol, the ICF, or the investigator‘s clinical 
brochure, even if such an event would be considered extremely rare.  
 An unexpected AE is one that has not been described in the protocol, the ICF, or the 
investigator‘s clinical brochure. 
 
12.6 
Expected Adverse Events From MRI Scans With Contrast and FMISO PET Scans  
12.6.1 Expected Adverse Events Associated With MRI 
 Anxiety/stress; 
 Claustrophobia; 
 Discomfort. 
 
Because of the powerful magnetic force of the MRI scanner, the patient may be ineligible 
to participate in the study if he or she has: 
 
 Metallic or other surgical implants (for example: pacemaker, heart valves, aneurysm 
clips, metal plates or pins and some orthopedic prostheses); 
 Metal pieces in your eye(s) or other body part(s); or 
 Difficulty lying still or inability to lie on your stomach.  
 
12.6.2 Expected Adverse Events From the Gadolinium Contrast Agent (Gd): 
Risks Related to Renal Dysfunction and Hemolytic Anemia 
Precautions should be exercised for participants with severely impaired renal function 
(see below) or hemolytic anemia. The very unlikely possibility of a reaction, including 
anaphylactic or cardiovascular reactions, should be considered especially for participants 
with a known sensitivity to Gd or history of asthma.  
 


 
ACRIN 6684 
35 
January 24, 2012 
 
Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD), 
kidney disorders, may occur in participants with moderate to end-stage kidney disease 
(glomerular filtration rate <30mL/min/1.73m2) and in participants with renal dysfunction 
due to the hepatorenal syndrome or in the perioperative liver transplantation period after 
they have had a MRI scan with Gd-based MR contrast agents (GBMCA).  
 
NSF causes fibrosis of the skin and connective tissues throughout the body. Participants 
develop skin thickening that may prevent bending and extending joints, resulting in 
decreased mobility of joints. NSF usually starts in the lower extremities. Fibrosis can also 
develop in the diaphragm, muscles in the thigh and lower abdomen, and lung vessels. 
Reference: 
FDA/Center 
for 
Drug 
Evaluation 
and 
Research. 
May 
23, 
2007 
(www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm). 
 
Other Gd-Related Risks: 
 Nausea; 
 Headache; 
 Hives; 
 Temporary low blood pressure;  
 Allergic reaction. 
 
12.6.3 Expected Adverse Events From IV Needle Placement: 
 Hemorrhage (hematoma at the injection site); 
 Infection (catheter related infection) at the injection site;  
 Minor discomfort;  
 Bleeding; 
 Bruising.  
 
12.6.4  Expected Adverse Events Associated With Radiation Risks: 
The radiation dosage for PET scanning varies with the part of the body being scanned, 
the source of the attenuation scan, the timing of the scan, the type of PET imaging being 
performed, and institution-specific radiation safety policies. The range of exposure for 
PET scanner can therefore be wide.  
For ACRIN 6684, all PET exposures for the radiopharmaceutical [18F]FMISO and all 
PET imaging will be performed for the head/brain only. Attenuation for PET correction 
can be performed using a calculated attenuation map (no radiation exposure), a 
radioisotope transmission source (PET only devices), or a CT scan (PET/CT devices). 
The following ranges have been estimated by calculating CT transmission doses using the 
ImPACT program from the Medicines Device Agency in the United Kingdom and 
represent the best estimates available to trial leadership at this time for FMISO used at a 
maximum does of 7 mCi. 
For participants who undergo two FMISO PET scans (15 participants who undergo the 
test-retest scans at baseline), the exposure for the FMISO PET examinations in this study 
are likely to range from a minimum of 7.8 mSv (780 mrem) to a maximum of 9.8 mSv 
(980 mrem) (see Table 3 below). For all other participants who have only one FMISO 


 
ACRIN 6684 
36 
January 24, 2012 
 
PET scans, the likely dose is a minimum of 3.9 mSv (390 mrem) to a maximum of 4.9 
mSv (490 mrem).  
The radiation dose from the PET has not been shown to have any adverse effects. Table 3 
below describes the radiation exposure associated with each individual scan for this trial 
based on data collected in a survey of current attenuation correction practices and 
effective radiation doses conducted by the NCI Cancer Imaging Program in conjunction 
with several leading ACRIN research centers, as reported in the report, Estimation of 
Radiation Doses Due to PET Radiopharmaceuticals and to Attenuation Correction of 
PET Images, and applied to the FMISO PET scans planned for the ACRIN 6684 trial.  
For each PET scan included in ACRIN 6684, radiation dose estimates are provided for 
the maximum possible administered FMISO dose (7 mCi) and one of four scenarios:  
(1) Typical CT-based attenuation scan;  
(2) Maximum dose from CT-based attenuation scan from the institutional survey;  
(3) PET-only device transmission scan; and  
(4) Calculated attenuation scan (no transmission scan exposure).  
These approaches are representative of the range of technique used at ACRIN 6684 
participating sites. 


 
ACRIN 6684 
37 
January 24, 2012 
 
Table 3. Radiation Exposure in ACRIN 6684  
 
FMISO PET 
Scan Visit(s) 
Eligible 
Patients 
FMISO PET 
Agent Dose 
FMISO  
ED for 
Maximum 
Dose 
(mSv) 
Equipment 
Type 
FMISO 
PET/CT Image 
Acquisition 
(head) 
Attenuation 
Transmission 
Scan 
ED from 
CT scan 
(mSv) 
(Mean) 
ED from 
CT scan 
(mSv) 
(Max) 
ED from 
- 
mission Scan 
(mSv) (Max) 
Total 
ED 
(mSv) 
(Likely) 
Total 
ED 
(mSv) 
(Max) 
ED with 
Trans- 
mission 
Scan Only 
(mSv) 
ED with No 
Trans- 
mission 
(PET/MRI) 
Prior to Start of 
Chemoradiation 
(Baseline) 
All 
3.7 MBq/kg 
(0.1 mCi/kg) 
maximum 260 
MBq (7 mCi) 
3.9 
PET/CT   
or PET 
Single field-of-
view emission 
imaging at 110 
± 10 minutes 
post injection 
Low-dose CT 
scan or 
transmission 
0.6 
1.0 
0.02 
4.5 
4.9 
3.9 
3.9 
2nd FMISO PET 
Baseline Scan 
(Within 1–7 Days 
Reproducibility 
Test) 
Subset: 
15 
3.7 MBq/kg 
(0.1 mCi/kg) 
maximum 260 
MBq (7 mCi) 
3.9 
PET/CT   
or PET 
Single field-of-
view emission 
imaging at 110 
± 10 minutes 
post injection 
Low-dose CT 
scan or 
transmission 
0.6 
1.0 
0.02 
4.5 
4.9 
3.9 
3.9 
2 Scan 
15 
≤ 14 mCi 
7.8 
 
 
 
1.2 
2.0 
0.04 
9.0 
9.8 
7.8 
7.8 
1 Scan  
All 
≤ 7 mCi  
3.9 
  
  
  
0.6 
1.0 
0.02 
4.5 
4.9 
3.9 
3.9 
ED = Estimated Effective Dose  
Likely dose = radionuclide + mean from CT scan (see report Estimation of Radiation Doses Due To PET Radiopharmaceuticals and to Attenuation Correction of PET Images)


 
ACRIN 6684 
38 
January 24, 2012 
 
 
12.6.5 Expected Adverse Events From PET Scan: 
 Discomfort;  
 Claustrophobia.  
 
12.6.6 Expected Adverse Events Associated With FMISO Injection:  
(NSC #742836; IND #76,042) 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
for 
[18F]Fluoromisonidazole, (FMISO, NSC 742836) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single  
list of reported and/or potential adverse events (AE) associated with an agent using  
a uniform presentation of events by body system. In addition to the comprehensive list, a 
 subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate column  
and is identified with bold and italicized text. This subset of AEs (ASAEL) contains events  
that are considered 'expected' for expedited reporting purposes only. Refer to the  
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers 
for 
further 
clarification. The CAEPR does not provide frequency data; refer to the Investigator's Brochure 
for this information. Below is the CAEPR for [18F]Fluoromisonidazole. 
 
Version 1.0, July 1, 2010 1 
 
Category 
(Body 
System) 
 
 
Adverse Events2  
with Possible Relationship  
to [18F]Fluoromisonidazole  
(CTCAE v4.0 Term) 
 
 
EXPECTED AEs FOR ADEERS 
REPORTING  
Agent Specific Adverse Event List 
(ASAEL) 
 
 
 
 
No AEs reported in human studies. 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol, and the agent should be included in the e-mail. 
 
Note:   No adverse events have been attributed to Positron-Emission Tomography (PET) 
imaging/diagnostic administration of [18F]Fluoromisonidazole at the levels described in the 
Investigators Brochure.  Therefore, no adverse events are expected as a result of the intravenous 
(IV) administration of [18F]Fluoromisonidazole for typical PET imaging applications such as 
tumor hypoxia.   
 
Note:  As with many IV administered agents, [18F]Fluoromisonidazole could cause an allergic 
reaction that could potentially pose a threat to life (anaphylaxis).  This has not been observed in 
limited human exposure to date.  Reasonable precautions should be taken, consistent with normal 
radiologic and clinical facility practice.  The patient should be monitored until the PET 


 
ACRIN 6684 
39 
January 24, 2012 
 
procedure is completed, and trained personnel and emergency equipment should be available per 
facility standards. 
  
For purposes of informed consent regarding reasonably foreseeable risks to subjects in 
trials utilizing [18F]Fluoromisonidazole, the following potential adverse events are 
considered extremely rare: 
 Injection-related risks that may include infection, or accidental extravasation of the 
dose that may lead to discomfort, localized pain, or infection.  
 
Risks related to allergic reaction/anaphylaxis that may be life threatening. 
 
Note: As with all PET imaging agents, [18F]Fluoromisonidazole is a radiopharmaceutical that 
decays with positron emission.  As such, it poses an intrinsic radiation exposure risk.  However, 
when administered in accordance with the Investigator‘s Brochure as a PET imaging agent, this 
risk is felt to be extremely small.  The organ and total body doses associated with 
[18F]Fluoromisonidazole PET imaging are comparable to or lower than those associated with 
other widely used clinical nuclear medicine procedures.   
 
Note: [18F]Fluoromisonidazole in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
12.6.7 Adverse Events Related to Chemotherapy and Radiation Therapy: 
ACRIN will not collect any AEs related to chemotherapy and radiation therapy.  Sites 
will follow institutional policies and procedures for any reported side effects for 
chemoradiation therapy. 
 
ACRIN will collect AEs that occur after 24 hours of FMISO infusion regardless of 
attribution/relatedness. Beyond this period, AEs that are determined to be definitely, 
probably, or possibly related to the participants‘ underlying disease or therapy, that are 
ALSO determined to be unrelated or unlikely related to the FMISO and procedures 
specified in this protocol, will not be reported.  Therefore, most AEs related to 
chemoradiation treatment are not expected to be reported for this trial.  
  
12.7 
Reporting of Adverse Events 
The descriptions and grading scales found in the revised NCI CTCAE v4.0 will be utilized for 
AE reporting. All institutions should have access to a copy of the CTCAE v4.0. A copy of the 
CTCAE v4.0 can be downloaded from the CTEP web site: http://ctep.cancer.gov/ 
reporting/ctc.html. A list of AEs that have occurred or might occur (Reported Adverse Events 
and Potential Risks) can be found in Section 6 (Pharmaceutical Information). 
 
Prompt reporting of AEs is the responsibility of each investigator, clinical research associate 
(RA), and/or nurse engaged in clinical research. Anyone uncertain about whether a particular AE 
should be reported should contact the ACRIN headquarters at 215-574-3150 for assistance. This 
study will be monitored by ACRIN and by the NCI/CIP. 
 
All AEs should be followed by the investigator until the events are resolved, the subject is lost to 
follow-up, the condition is stabilized, or the AEs are otherwise explained. Any death or any AE 


 
ACRIN 6684 
40 
January 24, 2012 
 
(e.g. development of cancer, congenital anomaly in conceived offspring) that is determined to be 
possibly, probably, or definitely related to study agents or procedures as specified in this 
protocol—even if it occurs after a subject has discontinued study participation—must be reported 
to the ACRIN AE Coordinator at DMC and to all appropriate study monitors and applicable 
regulatory authorities as specified herein or as required by regulation or guidance. 
 
Assignment of grades and attribution for each AE/SAE must be completed by the site principal 
investigator or investigator-designee. All AEs/SAEs must be documented in the participant‘s 
study chart, AE form, and events that qualify for AdEERS must be submitted through the 
electronic-AdEERS (e-AdEERS) system in the required timeframes, as specified below. The 
ACRIN RA will capture all AEs as required herein on the AE form and in the e-AdEERS system 
where appropriate. This will ensure that they are provided to the NCI/CIP Monitor and will also 
ensure their receipt by the AE Coordinator at the DMC. Expedited AdEERS reports must be 
entered by the investigator or investigator-designee. The expedited AdEERS report will be 
submitted to the lead group reviewer at ACRIN and then submitted once reviewed to the 
NCI/CIP. A copy of the report must be kept on file at the site. Significant new information on 
any on-going AE/SAE should be promptly reported to NCI/CIP and ACRIN.  
 
At each contact (site visit and/or telephone) with the study participant, the investigator or 
investigator-designee must elicit, through open ended questioning (e.g. ―How are you feeling?‖) 
information on AEs and, if indicated, the subject should be evaluated clinically. When AEs are 
reported, concomitant medication taken by the participant prior to 2 weeks and/or during the 
time of the AE will be collected and documented. Information on all AEs that occur after 24 
hours of FMISO infusion should be recorded immediately into the source document (e.g. ACRIN 
AE Log and/or progress notes of the participant‘s study chart) and retained at the site. These AEs 
will also be recorded in the AE form. SAEs and AEs requiring expedited reporting will be 
entered into the e-AdEERS system as required, pending review by the principal site investigator 
in real time to determine grade and attribution of the event and timeframe for submission to 
ACRIN. 
 
All SAEs that are still ongoing at the end of the study must be followed up to determine, to the 
degree possible, the final outcome. Any SAE that occurs after the study period and is considered 
to be possibly related to the study procedures or study participation should be recorded and 
reported immediately. 
 
 


 
ACRIN 6684 
41 
January 24, 2012 
 
12.8 
E-AdEERS Expedited Reporting Requirements for Adverse Events That Occur After 24 
Hours of a Dose of the Investigational Agent: FMISO  
 
Table 4. Reporting Requirements for Adverse Events That Occur Within 24 Hours  
(± 4 Hours) of a Dose of the Investigational Agent (FMISO)1 
NOTE: All subjects‘ deaths that occur during the study require both routine and expedited 
reporting regardless of causality. Attribution to treatment or other cause should be 
provided. 
 
12.8.1 Expedited AE Reporting Timelines 
 24 Hours; 5 calendar days – The ACRIN investigator or investigator-designee must 
initially report the AE via e-AdEERS within 24 hours of first knowledge of the event 
followed by a complete e-AdEERS report within 5 calendar days of the initial 24-
hour report. 
 10 calendar days – A complete e-AdEERS report on the AE must be submitted 
within 10 calendar days of the ACRIN investigator or investigator-designee‘s first 
knowledge of the event. 
 Any medical event equivalent to CTCAE v4.0 grade 3, 4, or 5 that precipitates 
hospitalization* (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
 
 
Attribution 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 Calendar 
Days 
1 In addition to the above, Grade 4 and 5 unexpected adverse events with attribution of possible, probable, or definite with regard to  
    FMISO, that occur more than 24 hours after administration of FMISO require e-AdEERS 24-hour notification followed by  
   complete report within 5 calendar days. 
 
e-AdEERS 10 calendar day report: 
 
Grade 2 unexpected events with attribution of possible, probable, and definite 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization with attribution of unrelated and unlikely and 
possible, probable, and definite  
 
Grade 3 unexpected events without hospitalization or prolongation of hospitalization with attribution of possible, probable, and 
definite 
 
Grade 3 expected events with hospitalization or prolongation of hospitalization with attribution of unrelated and unlikely and 
possible, probable, and definite 
 
Grade 4 and 5 unexpected events with attribution of unrelated and unlikely 
 
Grade 4 and 5 expected events with attribution of unrelated and unlikely and possible, probable, and definite 
2 Although an e-AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as 
outlined in the table. 
 
For Hospitalization only—Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitated hospitalization (or prolongation of existing 
hospitalization)  must be reported regardless of designation as expected or unexpected and attribution. 
 
 March 2005 


 
ACRIN 6684 
42 
January 24, 2012 
 
 Any event with an IND imaging agent–related attribution of possible, probable, 
or definite that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via e-AdEERS by ACRIN 
if the event occurs following treatment with an agent under a CIP IND. 
 Expedited reporting is defined as immediate notification to ACRIN and NCI/CIP 
through submission of an e-AdEERS report. Some AEs require 24-hour 
notification via e-AdEERS. When Internet connectivity is disrupted, a 24-hour 
notification is to be made to the CIP monitoring service, as specified below, by 
telephone. Routine reporting requirements also apply.† 
 
*  Hospitalizations are defined as lasting 24 hours or longer and these events must be reported 
via e-AdEERS. 
†  Routine reporting is defined as documentation of AEs on source documents and the AE CRF. 
Documentation should be submitted to ACRIN for preparation of a report for DMC review, 
quarterly reports to CDUS, FDA annual reports, and the final study report. 
 
12.9 
How to Report 
NOTE: The e-AdEERS system routes AE reports to the necessary recipients/reviewers. The 
following contact information is provided to indicate the per-protocol recipients, forwarding 
timeframes, and distribution in the event this process must be done manually: 
  
12.9.1 Some AEs require 24-hour notification (refer to Table 4 in Section 12.8) via e-AdEERS. 
When Internet connectivity is disrupted, a 24-hour notification is to be made as follows: 
 
 Fax AE submission form and any additional information1 necessary for thorough 
review of the event(s) to 301-897-7402, attention CIP SAE Team. The phone number 
for the CIP SAE Reporting Desk is 301-897-1704. 
 
 Follow up with an e-mail to CIPSAEReporting@tech-res.com notifying that an AE 
form and additional information (if available) has been faxed. 
 
Once Internet connectivity is restored, a 24-hour notification that was faxed or phoned in 
must be entered electronically into AdEERS by the original submitter at the site.  
  
When the AE requires expedited reporting, submit the report within the number of 
calendar days of first knowledge of the event specified in Table 4 in Section 12.8.  An 
expedited AE report requires submission to NCI by the DMC via the e-AdEERS system. 
CIP will then be notified via e-AdEERS and ACRIN of the expedited reporting. An 
expedited e-AdEERS report will be submitted to the lead group reviewer at ACRIN and 
then submitted once reviewed to the NCI/CIP. 
 
 
 
 
                                                 
1   For events unrelated to the imaging intervention, no additional information is necessary.  For events possibly, probably, or 
definitely related to the imaging intervention, additional information should include, admission and discharge summaries 
(when available), laboratory workup, progress notes, circumstances of the event(s). 


 
ACRIN 6684 
43 
January 24, 2012 
 
12.9.2 Recipients of e-AdEERS Reports:  
e-AdEERS Reports are electronically submitted to the following trial personnel; in the 
event that Internet connectivity is disrupted, AdEERS reports should be submitted as in 
Section 12.9.1 (above) and faxed to the attention of: 
 
To ACRIN: 
Maria Oh: moh@acr.org 
Attention: ACRIN SAE Coordinator 
RE: Adverse Event Report, ACRIN 6684 
ACRIN Protocol 6684 
1818 Market Street 
Suite 1600 
Philadelphia, PA 19103 
 
 
CIP SAE Reporting Desk: 
 
Phone: 301-897-1704 
 
Fax : 301-897-7402 
 
Email: CIPSAEReporting@tech-res.com 
 
 
ATTN: CIP Support S&P Manager, Anna Edouard, MD 
 
12.9.3 All fatal AEs identified in the FMISO PET scan component of the study must be reported 
by telephone within 24-hours of first knowledge of the event. To make a telephone 
report, call ACRIN at 215-717-2763, available 24 hours a day (recorder after hours 
Monday through Friday from 4:30 PM to 8:30 AM Eastern Time and on weekends).  
 
12.9.4 All fatal AEs identified in the FMISO PET scan component of the study must also be 
reported to CIP by telephone at 301-897-1704 within 24-hours of first knowledge of the 
event and via e-AdEERS. 
 
12.9.5 All expedited AE reports should be sent to the local Institutional Review Board (IRB). 
Refer to the IRB policies and procedures for AE reporting.  
 
12.9.6 For automated CDUS reporting for studies using investigational agents, the DMC 
routinely reports AEs electronically to the CTEP Clinical Data Update System (CDUS 
Version 3.0). The DMC submits this data quarterly. The AEs reported through AdEERS 
will also be included with the quarterly CDUS data submissions. 
 
 
13.0 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(International Conference of Harmonisation [ICH] guidelines), applicable government regulations, and 
ACRIN research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB) for formal approval of the study conduct. The 
decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator 
and a copy of this decision will be provided to ACRIN before implementation of the study.  


 
ACRIN 6684 
44 
January 24, 2012 
 
 
The investigator will provide ACRIN with the institution‘s federal wide assurance (FWA) number, 
along with the IRB approval letter and copy of the IRB-approved ICF. The investigator will provide a 
copy(s) of IRB approval letter(s) for any amendment(s), and copy(s) of annual renewal(s). 
 
All study participants in this study will be given an IRB-approved, site-specific ICF describing the study 
and providing sufficient information for participants to make informed decisions about their 
participation in this study (see Appendix I for an ICF template). The ICF will be submitted along with 
the protocol for review and approval by the EC/IRB. The study participant MUST be consented with the 
EC/IRB-approved ICF before the participant is subjected to any study procedures. The approved ICF 
MUST be signed and dated by the study participant or legally acceptable representative and the 
investigator-designated research staff obtaining the consent. Any revisions to the ICF at any time during 
the trial will need to be submitted to the IRB for approval and submission to ACRIN PDRC.  
 
 
14.0 
CONFLICT OF INTEREST 
Any investigator and/or research staff member who has a conflict of interest with this study (such as 
patent ownership, royalties, or financial gain greater than the minimum allowable by their institution) 
must fully disclose the nature of the conflict of interest in accordance with ACRIN Conflict of Interest 
policies and applicable federal, state, and local laws and regulations.  
 
 
15.0 
PUBLICATION POLICY 
Neither complete nor any part of the results of the study obtained under this protocol, nor any 
information provided to the investigator for the purposes of performing the study, will be published or 
passed on to any third party without the consent of ACRIN, the Study Chair, and/or ACRIN Publication 
Committee. Any investigator involved in this study is obligated to provide ACRIN with complete test 
results and all clinical data obtained from the participants in this protocol. Investigators will follow the 
ACRIN Publication Policy (available online at www.acrin.org/PublicationsPolicy.aspx). 
 
 
16.0 
INSTITUTIONAL MONITORING AND AUDITS 
The investigator will permit study-related auditing and inspections of all study-related documents by the 
EC/IRB, government regulatory agencies, and ACRIN. The investigator will ensure the capability for 
inspection of all participating sites‘ study-related facilities (e.g. imaging centers, satellite sites). The 
investigator will allocate adequate time for these activities, allow access to all study-related documents 
and facilities, and provide adequate space to conduct these visits.  
 
16.1 
Monitoring 
Monitoring ensures data quality and the rights, safety, and well-being of the participants are 
protected. Monitoring also makes certain that the trial is in compliance with the currently 
approved protocol/amendments, with GCP and applicable regulatory requirements. It will 
provide the site an opportunity to verify that reported trial data are accurate, complete and 
verifiable from source documents. Institutional monitoring will be implemented at several 
different time points during the conduct of the study.  
 
Monitoring instructions will be sent to the site prior to the implementation of monitoring to aid in 
preparation for the review. The instructions will specify regulatory documents and participant 


 
ACRIN 6684 
45 
January 24, 2012 
 
case records scheduled to be monitored. Case report forms (CRFs) and source documents of 
selected study participants enrolled at each site will be reviewed. In addition, the initial 
regulatory documents and any revised regulatory documents will also be monitored.  
 
16.2 
Audits 
All participating institutions that enroll participants will be audited.  The timing of the initial on-
site audit will depend upon several factors, including the rate of accrual (both study-wide and 
site-specific), the number of evaluable participants enrolled at an individual site, the status of the 
protocol and pending amendments, and monitoring status. Generally, audits will be conducted 
after the number of evaluable participants reaches 30% of targeted accrual, either study-wide 
and/or site-specific. Audits are typically scheduled to occur at least 3 months after an institution 
has been monitored, providing that monitoring did not identify issues that mandate immediate 
auditing.  This schedule may be altered in the event of pending protocol amendments. Closure of 
the study to accrual will trigger auditing of all participating institutions not yet audited.  
Additionally, site-specific circumstances may prompt an audit at any time. 
 
Subsequent audits will be scheduled per the outcome of the initial audit. Audits can be conducted 
more frequently at the discretion of the protocol team. The audits will be conducted per 
procedures established by the Cancer Imaging Program (CIP) of the NCI. Instructions for 
preparation for the audit visit will be sent to the site prior to the scheduled audit visit. These 
instructions will specify which participant case records will be reviewed during the audit. On-site 
records will be verified against the submitted form, and the findings will be recorded on 
specially-prepared audit reports. Major discrepancies will be forwarded to the appropriate 
oversight body within ACRIN. IRB procedures, approvals, and ICFs will also be reviewed at the 
time of the audit visit. The ACRIN Audit Manual is available online at www.acrin.org/pdrc.aspx.  
 
To help sites prepare for monitoring and audits and to assure that the investigator and the 
research staff maintain records appropriately, ACRIN Headquarters will offer training to sites. 
This training will cover all aspects of data collection, including special instructions to obtain and 
file the various source documents needed to verify the accuracy of submitted data for this trial.  
  
16.3 
Source Documents  
Source data are found in all information, original records of findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Source documents represent the first recording of any 
observations made or data generated about a study participant while he or she is enrolled in a 
clinical trial. Source documents for each study participant substantiate the data that are submitted 
to ACRIN. Source documents must verify the eligibility criteria and data submitted on all CRFs.  
 
Research records for each case should contain copies of the source documents for the data 
collected and reported to ACRIN. If data are abstracted from medical charts that are not filed at 
the investigative sites (e.g. hospital charts), copies of these records should be filed in the research 
chart. Every attempt must be made to obtain all records/charts that were used to abstract any 
study data for this protocol. This will prevent any discrepancies and the inability to verify the 
document and the data reported.  
 
 
 


 
ACRIN 6684 
46 
January 24, 2012 
 
16.4  Case Report Forms (CRFs) 
CRFs, both web-based and paper forms, are the primary data collection instruments for the 
study. All data requested on the CRFs must be recorded, and any missing data must be 
explained. If a space is left blank because the procedure was not done or the question was not 
asked, ―N/D‖ must be noted. If the item is not applicable to the individual case, ―N/A‖ must be 
noted. All entries must be printed legibly in black ink on the paper CRFs. In the event of any 
entry errors, corrections must be made by drawing a single straight line through the incorrect 
entry, writing the initials of the person making the correction, recording the date when the 
correction is being made, and entering the correct data above the strike through. Do not use white 
out or an eraser. Please refer to ICH Good Clinical Practice Guidelines. 
 
Data elements that are extracted from the medical record (source documents such as participant 
history or official clinical interpretations of images, pathology, or surgery results) and recorded 
on the CRFs will be reviewed against the appropriate component of the medical record. Data 
elements gathered from signed participant questionnaires must be available for review. Required 
study image interpretation data that are more detailed in information than the image and not 
typically documented in the standard radiology report may be documented on the CRF; the CRF 
is therefore acceptable source documentation if signed by the Investigator.  
 
At the time of audit, the auditor will verify the occurrence of the imaging examination, the 
reader, and the date(s) of the exam(s) from the medical record(s). Any use of approved CRFs as 
source documentation require a signature and date on the CRF with a reference to the 
information source (participant questionnaire, CT, MR, etc.). Any use of CRFs as source 
documentation when the protocol has designated the source data will be medical record 
documentation will be considered a major protocol deficiency. 
 
16.5 
Institutional Review Board 
Sites must obtain initial local IRB approval to participate in ACRIN trials. Prior to participant 
registration, a copy of the IRB approval letter for the protocol and the ICF must be sent to 
ACRIN, along with a copy of the IRB-approved, site-specific ICF. Investigator will provide a 
copy(s) of IRB approval letter(s) for any amendment(s), and copy(s) of annual renewal(s). 
 
 


 
ACRIN 6684 
47 
January 24, 2012 
 
17.0 
STATISTICAL CONSIDERATIONS 
17.1 
Specific Aims and Analysis Plans 
17.1.1 Primary Aim 
To determine the association of baseline FMISO PET uptake (hypoxic volume [HV], 
T/Bmax) and MRI parameters (Ktrans, CBV) with OS in participants with newly diagnosed 
GBM. 
 
Cox-regression model will be used to study the relationship between OS and baseline 
FMISO PET uptake (HV, T/B) and MRI parameters (Ktrans, CBV). Uni-variate analysis 
will be carried out for each parameter individually. Any parameter that has achieved 
statistical significance (P ≤ 0.05) will be included in the multi-variate Cox model.  
 
 
17.1.2 Secondary Aims 
17.1.2.1 
Aim 1 
To determine the association of baseline FMISO PET uptake (HV, T/Bmax) and 
MRI parameters (Ktrans, CBV) with TTP and PFS-6 in participants with newly 
diagnosed GBM. 
 
TTP: Cox-regression model will be used to study the relationship between 
TTP and baseline FMISO PET uptake and MRI parameters. Uni-variate 
analysis will be carried out for each parameter individually and. Any 
parameter that has achieved statistical significance (P ≤ 0.05) will be included 
in the multi-variate Cox model.  
 
PFS-6: Logistic regression model will be used to study the relationship 
between PFS-6 and baseline FMISO PET uptake and MRI parameters. Uni-
variate analysis will be carried out for each parameter individually. Any 
parameter that has achieved statistical significance (P ≤ 0.05) will be included 
in the multi-variate Logistic regression model.  
 
17.1.2.2  Aim 2  
To assess the reproducibility of the baseline FMISO PET uptake parameters 
by implementing baseline “test” and “retest” PET scans (performed between 
1 and 7 days apart). 
 
The reproducibility of the baseline FMISO PET will be quantified through 
intra-class correlation coefficient (ICC) which is defined as the ratio of σb
2 and 
(σb
2+ σc
2) where σb
2 is the variance of measurements between participants and 
σc
2 is the variance of measurements within participants. 
 
17.1.2.3  Aim 3 
To assess the correlation between T/Cmax (tumor:cerebellum) and T/Bmax 
(tumor:blood) at baseline. 
 


 
ACRIN 6684 
48 
January 24, 2012 
 
Pearson correlation coefficient and Spearman‘s rank correlation coefficient 
will be used to quantify the correlation between T/Cmax and T/Bmax. 
 
17.1.2.4  Aim 4 
To assess the correlation between other MRI parameters and OS and PFS. 
These other more-exploratory MRI parameters include the initial size of the 
lesion measured on T1 post Gd images, vessel caliber index, small vessel 
CBV, apparent diffusion coefficient, values measured from MR spectroscopy 
such as NAA-Cho ratio, changes in BOLD signal with transient exposure to 
hyperoxia, and T2 lesion volume.  
 
OS: Cox-regression model will be used to study the relationship between OS 
and other MRI parameters. Univariate analysis will be carried out for each 
parameter individually. 
 
PFS-6: Logistic regression model will be used to study the relationship 
between PFS-6 and other MRI parameters. Uni-variate analysis will be carried 
out for each parameter individually. 
 
17.2 
Sample Size/Accrual Rate 
The sample size is based on a Cox proportional hazards model testing the significance of the 
coefficient of baseline T/Bmax with survival time as the outcome variable and HV as a covariate. 
Using the data from Spence et al,3 the log hazard ratio is estimated to be 1.279, when R2=0.521 
and the standard deviation of T/Bmax is 0.765. Using PASS 2008 with a two-sided hypothesis,  
α =0.05, power of 90%, and an assumed 50% event rate, the adequate sample size is determined 
to be 46 participants. In order to accommodate a loss-to-follow up rate of 8%, we will enroll 50 
patients into the study. Should images be inevaluable, additional patients will be recruited as 
needed to obtain 50 evaluable cases; inevaluable cases will be followed and replaced. The 
participants will be accrued over a one-year period and will be followed up until the end of the 
study. 
 
For testing the reproducibility of the baseline FMISO PET uptake parameters, 15 participants 
will undergo duplicate FMISO PET scans at baseline. With 15 participants—if the observed ICC 
is above 0.85—the half-length of 95% confidence interval (CI) will be less than 0.15.  
 
Table 5. Half-Length of 95% CI of True ICC Coefficient With 2 Baseline Scans 
 
n=15 
n=20 
Observed ICC=0.75 
0.24 
0.21 
Observed ICC=0.80 
0.20 
0.17 
Observed ICC=0.85 
0.15 
0.13 
Observed ICC=0.90 
0.11 
0.09 
 
17.3 Power Calculation 
There will be approximately 80% power to detect the significance of association between 
baseline T/Bmax and TTP with 50 enrolled participants and 46 evaluable participants. The 80% 
power is based on an estimate from modeling TTP with T/Bmax and HV as covariates (log 
hazards ratio=0.781 and R2=0.407), assuming α=0.05 and an 80% event rate.  


 
ACRIN 6684 
49 
January 24, 2012 
 
 
17.4 
Reporting Guidelines 
 
 
17.4.1 Routine reports for this protocol will be included in the ACRIN Biostatistics Center Mid-
Year and Year End Updates and will be provided to oversight bodies, including DSMC 
for review during each of its twice-yearly meeting. 
 
 
Routine reports will include: 
 Accrual and participant characteristics; 
 Timeliness and completeness, eligibility and protocol compliance, and outcome 
data; 
 All reported adverse events. 
 
17.4.2 For automated CDUS reporting for studies using investigational agents, the ACRIN 
Biostatistics Center (BC) will submit quarterly reports of clinical trial data per regulatory 
requirements electronically to Clinical Data Update System (CDUS Version 3.0).  The 
AEs reported through AdEERS will also be included with the quarterly CDUS data 
submissions. 
 
 
18.0 
TISSUE SPECIMEN COLLECTION FOR BIOMARKER ANALYSIS 
Tumor tissue submission is strongly encouraged but not a requirement due to site-specific guidelines on 
tissue distribution. As feasible for each participant, the tumor tissue obtained from the diagnostic biopsy 
or surgery for diagnosis of GBM will be collected, analyzed, and stored until processing at an ACRIN-
designated pathology laboratory for purposes of analysis for tumor hypoxic and vasculature markers and 
MGMT testing. No additional study-specific biopsy will be obtained. Sites will be provided with 
specific detailed collection instructions and shipment information at the initiation of the trial. 
 
18.1 
Tissue Analysis for Tumor Hypoxic Markers and MGMT Testing 
As feasible for each participant, at least 1 block of tumor tissue but preferably no less than 3 
blocks with accompanying representative H&E slides and pathology reports, will be obtained for 
the correlative studies of MGMT status and hypoxia/vascular markers. Blocks are strongly 
preferred. Block tissue areas should ideally be >1cm2. For MGMT testing, the selected block 
should be composed of mostly viable tumor cells (i.e. >70%) but for the hypoxia/vascular 
markers, blocks containing viable tissue and areas of necrosis are preferred. No block will be 
completely depleted of tissue and blocks containing residual tissue will be returned to the sites. 
For a limited-size biopsy specimen and sites not approved to send blocks, a minimum of twenty 
(20) 5-m thick (section areas >1cm2), unstained sections on chemoplus/plus slides will be 
acceptable and are requested.  
A minimum of ten (10) slides for each analysis are needed for the two analyses to be performed:  
 At least 10 slides composed of mostly viable tumor cells (i.e., >70%) for MGMT testing. 
If tissue area is <1cm2, an appropriate number of additional slides are requested in order 
to obtain an amount of tissue similar to that afforded by ten (10) 5-μm thick sections at 
>1cm2. 


 
ACRIN 6684 
50 
January 24, 2012 
 
 Ten (10) additional slides are requested for immunohistochemical analyses; these 
sections should ideally contain viable tumor tissue and areas of necrosis. 
Blocks or slides, representative H&E slides, and pathology reports should be sent to: 
 
Dr. Catherine Nutt 
Molecular Pathology Unit, Massachusetts General Hospital 
Room 6014 
Building 149, Thirteenth Street 
Charlestown, MA  02129 
 
18.1.1 Hypoxia and Vascular Markers 
To investigate the possible relationships between hypoxic markers and FMISO uptake 
with progression-free survival and overall survival, tumor tissue obtained for diagnosis of 
glioblastoma will be analyzed for expression of hypoxic and vascular markers.  No 
additional biopsy will be obtained.  In particular, HIF1-alpha, GLUT1, CAIX, CD31, and 
alpha-SMA, will be assessed using immunohistochemical staining. HIF1-alpha, GLUT1, 
and CAIX will be used to evaluate degree of hypoxia, and CD31 and alpha-SMA will be 
used to look at tumor blood vessels and pericyte coverage. 
Briefly, 5-m sections will be cut from selected blocks. The sections will be 
deparaffinized in xylenes and rehydrated through graded alcohols. Endogenous 
peroxidase activity will be quenched with 0.5% H2O2 in methanol for 10 min during one 
of the rehydration steps. Antigen unmasking will be performed by heating slides 
immersed in sodium citrate or EDTA buffers, according to antigen retrieval protocols 
previously optimized for each antibody. The slides will then be allowed to cool in the 
buffer for 20 min. To block nonspecific immunobinding sites, slides will be incubated in 
10% NHS in PBS/1% BSA for 30 min at room temperature; in addition, 5% milk is 
added to the blocking step for alpha-SMA.  
Immunostaining will be performed by incubation with the appropriate primary antibodies 
(monoclonal or polyclonal) for the optimized time and dilution. Each round of staining 
includes a positive control tissue as well as the positive control tissue incubated without 
primary antibody as a negative control. This also controls for round-to-round variation in 
staining so that samples can be better compared across multiple rounds of staining 
performed over time. The slides will be washed with phosphate-buffered-saline (PBS) 
and then incubated for 30 min with biotin-conjugated secondary antibody in 
PBS/1%BSA; concentrations of secondary antibodies vary for each antibody according to 
previously optimized protocols. Antibody binding sites will be visualized by avidin-
biotin horseradish peroxidase complex solution (Vectastain ABC kit, Vector 
Laboratories) and 3, 3‘-diaminobenzidine (DAB). After rinsing in water, the slides will 
be counterstained with Gills hematoxylin (Sigma Chemicals, St. Louis, MO), dehydrated, 
and coverslipped. 
Immunostains of the biopsy specimens will be scored according to antibody-dependent 
protocols. Briefly, HIF1-alpha will be scored separately for the percentage of tumor cells 
positive for cytoplasmic (non-activated) and nuclear (activated) staining; GLUT1 and 
CAIX will be scored for the percentage of tumor cells demonstrating positive membrane 
staining; CD31 and alpha-SMA staining will be scored by standard microvascular density 


 
ACRIN 6684 
51 
January 24, 2012 
 
techniques in the areas of highest vessel density. Subsequent to detailed scoring of the 
tissues, refined scores of 0-3+ will be assigned based on appropriate antibody-dependent 
scales, as previously determined. The immunostain results will be interpreted by Dr. Nutt, 
who will be blinded to the imaging results and will assign each biopsy with a composite 
score for each marker. 
 
18.1.2 MGMT Testing 
MGMT analysis will be performed by extracting tumor genomic DNA for bisulfite 
conversion (EZ DNA Methylation-Gold Kit, Zymo Research, Orange, CA). MGMT 
methylation-specific PCR (MSP) will then be performed using PCR primer sets specific 
for methylated and unmethylated MGMT promoter sequence.39 Presence of unique PCR 
amplification products generated by the ―methylated MGMT‖ and ―unmethylated 
MGMT‖ primers is assessed along with appropriate bisulfite-treated methylated and 
unmethylated control genomic DNA using agarose electrophoresis. 


 
ACRIN 6684 
52 
January 24, 2012 
 
REFERENCES 
 
1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996. 
2. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and 
radiotherapy response. Nat Rev Cancer. 2008;8:425-437. 
3. Spence AM, Muzi M, Swanson KR, et al. Regional hypoxia in glioblastoma multiforme quantified 
with [18F]fluoromisonidazole positron emission tomography before radiotherapy: Correlation with 
time to progression and survival. Clin Cancer Res. 2008;14:2623-2630. 
4. Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM. Assessment of hypoxia and perfusion in 
human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med. 
2004;45:1851-1859. 
5. Tochon-Danguy HJ, Sachinidis JI, Chan F, et al. Imaging and quantitation of the hypoxic cell 
fraction of viable tumor in an animal model of intracerebral high grade glioma using 
[18F]fluoromisonidazole (FMISO). Nucl Med Biol. 2002;29:191-197. 
6. Valk PE, Mathis CA, Prados MD, et al. Hypoxia in human gliomas: demonstration by PET with 
fluorine-18-fluoromisonidazole. J Nucl Med. 1992;33:2133-2137. 
7.  Cher LM, Murone C, Lawrentschuk N, et al. Correlation of hypoxic cell fraction and angiogenesis 
with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and 
immunohistochemical studies. J Nucl Med. 2006;47:410-418. 
8. Rasey JS, Nelson NJ, Chin L, et al. Characteristics of the binding of labeled fluoromisonidazole in 
cells in vitro. Radiat Res. 1990;122:301-308. 
9. Gross MW, Karbach U, Groebe K, et al. Calibration of misonidazole labeling by simultaneous 
measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer. 
1995;61:567-573. 
10. Koh WJ, Rasey JS, Evans ML, et al. Imaging of hypoxia in human tumors with [F-
18]fluoromisonidazole. Int J Radiat Oncol Biol Phys. 1992;22:199-212. 
11. Bernsen HJ, Rijken PF, Peters H, et al. Hypoxia in a human intracerebral glioma model. J 
Neurosurg. 2000;93:449-454. 
12. Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with positron 
emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat 
Oncol Biol Phys. 1996;36:417-428. 
13. Rasey JS, Grunbaum Z, Magee S, et al. Characterization of radiolabeled fluoromisonidazole as a 
probe for hypoxic cells. Radiat Res. 1987;111:292-304. 
14. Troost EG, Laverman P, Kaanders JH, et al. Imaging hypoxia after oxygenation-modification: 
comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human 
xenograft tumors. Radiother Oncol. 2006 Aug;80(2):157-64. 
15. Dubois L, Landuyt W, Haustermans K, et al. Evaluation of hypoxia in an experimental rat tumour 
model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer. 2004 Nov 
29;91(11):1947-54. 


 
ACRIN 6684 
53 
January 24, 2012 
 
16. Sorensen, M., Horsman, M. R.,Cumming, P., Munk, O. L.,Keiding, S. Effect of intratumoral 
heterogeneity in oxygenation status on FMISO PET, autoradiography, and electrode Po2 
measurements in murine tumors. Int J Radiat Oncol Biol Phys. 2005;62(3):854-61. 
17. Gagel B, Piroth M, Pinkawa M, et al. pO polarography, contrast enhanced color duplex sonography 
(CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: 
validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the 
puzzle of tumor hypoxia? BMC Cancer. 2007;7:113. 
18. Ceelen W, Smeets P, Backes W, et al. Noninvasive monitoring of radiotherapy-induced 
microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) 
in a colorectal tumor model. Int J Radiat Oncol Biol Phys. 2006;64(4):1188-1196. (ePub 2006Feb2.) 
19. Rauscher A, Sedlacik J, Barth M, Haacke EM, Reichenbach JR. Noninvasive assessment of vascular 
architecture and function during modulated blood oxygenation using susceptibility weighted 
magnetic resonance imaging. Magn Reson Med. 2005 Jul;54(1):87-95. 
20. Taylor NJ, Baddeley H, Goodchild KA, et al. BOLD MRI of human tumor oxygenation during 
carbogen breathing. J Magn Reson Imaging. 2001;14(2):156-163. 
21. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour 
angiogenesis factor in human gliomas in vivo. Nature. 1992;359(6398):845-848. 
22. Jensen RL, Ragel BT, Whang K, Gillespie D. Inhibition of hypoxia inducible factor-1alpha (HIF-
1alpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in 
malignant gliomas. J Neurooncol. 2006;78(3):233-247. 
23. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene 
transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9): 4604-4613. 
24. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 
2007;6(4): 273-286. 
25. Vredenburgh JJ, Desjardins A, Jerndon JE 2nd, et al. Phase II trial of bevacizumab and irinotecan in 
recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253-1259. 
26. Friedman HS, Prado MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in 
recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733-4740. 
27. Batchelor TT, Sorensen AG, diTomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase 
inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 
2007;11(1):83-95. 
28. Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous 
recombination and as a target for cancer therapy. Cancer Res. 2005; 4:1176-1178. 
29. Masutani M, Nakagama H, Sugimura T. Poly(ADP-ribosyl)ation in relation to cancer and 
autoimmune disease. Cell. Mol. Life Sci. 62; 769-783, 2005. 
30. Wielckens K, Garbrecht M, Kittler M, Hilz H. ADP-ribosylation of nuclear proteins in normal 
lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem. 
1980;104(1):279-287. 
31. Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in 
human colon adenomatous polyps and cancers. Cancer Res. 1983;43(7):3441-3446. 


 
ACRIN 6684 
54 
January 24, 2012 
 
32. Tomoda T, Kurashige T, Moriki T, et al. Enhanced expression of poly(ADP-ribose) synthetase genre 
in malignant lymphoma. Am J Hematol. 1991;37(4):223-227. 
33. Shiobara M, Miyazaki M, Ito H, et al. Enhanced polyadenosine diphosphate-ribosylation in cirrhotic 
liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 
2001;16(3):338-344. 
34. Tentori L, Leonetti C, Scarsella M, et al. Brain distribution and efficacy as chemosensitizer of an 
oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. Int J 
Oncol. 2005;26(2) :415-422.   
35. Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase 
inhibitor that ptentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 
2007;13(9):2728-2737. 
36. Tentori L, Portarena I, Torino F, et al. Poly(ADP-ribose) polymerase inhibitor increases growth 
inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma 
cells. Glia. 2002;40:44-54. 
37. Curtin NJ, Wang LZ, Yiakouvaki A, et al. Novel poly(ADP-ribose) polymerase-1 inhibitor, 
AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res. 
2004;10:881-889. 
38. Macdonald DR, Cascino TL, Schold C, Cairncross JG. Response criteria for phase II studies of 
supratentorial malignant glioma. J Clin Oncol. 1990;8:1277-1280. 
39. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene 
O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in 
primary human neoplasia. Cancer Res. 1999;59: 793-797. 


 
ACRIN 6684 
55 
January 24, 2012 
 
APPENDIX I 
 
ACRIN 6684 
 
MULTICENTER, PHASE II ASSESSMENT OF TUMOR HYPOXIA (LOW OXYGEN)  
IN GLIOBLASTOMA BRAIN TUMORS USING THE INVESTIGATIONAL  
18F-FLUOROMISONIDAZOLE (FMISO) AGENT WITH PET AND MRI SCANS 
 
INFORMED CONSENT FORM TEMPLATE 
 
[Note: The American College of Radiology Imaging Network (ACRIN) does not monitor compliance 
with the Health Insurance Portability and Accountability Act (HIPAA); that is the responsibility  
of local Institutional Review Boards (IRBs). Local IRBs may choose to combine the authorization 
elements in the informed consent. Information on ACRIN’s HIPAA policy, as well as a template 
 for HIPAA authorization, can be found at www.acrin.org.] 
 
This is a clinical trial, a type of research study. Your study doctor will explain this clinical trial to you. 
Clinical trials include only participants who choose to take part. Please take your time with your 
decision to take part. You are encouraged to discuss all parts of this study with your family and friends 
and to ask your healthcare team as many questions as needed.  
 
If you want more information about participating in clinical trials, ask your study doctor for the National 
Cancer Institute (NCI) booklet Taking Part in Cancer Treatment Research Studies. Also, you can learn 
more about clinical trials at http://cancertrials.nci.nih.gov or by calling the NCI‘s help line at 1-800-4-
CANCER (1-800-422-6237 or TTY: 1-800-332-8615). 
 
You are being asked to be in this study because you have been diagnosed with a form of brain cancer 
called glioblastoma. This clinical trial involves taking pictures of the brain with imaging technology. 
Two types of images will be taken at different times during your brain cancer treatment. Contrast-
enhanced magnetic resonance imaging (MRI) is used routinely to create pictures of the brain. This study 
will also be using positron emission tomography (PET) scans with a new investigational imaging agent 
that the Food and Drug Administration (FDA) is studying. If you decide to volunteer for this study, you 
will be asked to sign and date this form. 
 
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to see if the investigational radioligand 18F-fluoromisonidazole (commonly 
known as FMISO) used during PET scans can help doctors see if a tumor is getting enough oxygen. 
Radiation and chemotherapy do not appear to work as well on tumors with low oxygen levels. 
 
This clinical trial will study brain images from PET scans using the investigational radioligand FMISO. 
A radioligand is a molecule that carries a small amount of radioactive substance in to the body, where 
the PET scanner can pick up the radiation being released to create a picture from within the body. When 
the study doctors take pictures of the brain using a PET scanner after the FMISO agent has been injected 
into the body, they hope to see how well the tumor is getting oxygen.  
 


 
ACRIN 6684 
56 
January 24, 2012 
 
If a brain tumor is not getting enough oxygen (called hypoxia), then the treatments that can destroy it 
might not work as well. The more doctors know about how the amount of oxygen a tumor gets effects 
treatment, the more likely they are to give a patient the right treatment from the beginning. This study 
will add to doctors‘ knowledge of how tumors, hypoxia, and treatments are related.  
 
FMISO is not approved yet by the FDA for routine use in people diagnosed with brain cancer. This 
trial‘s results will add to the evidence available on this agent as the FDA decides whether it should be 
used regularly to help people with brain cancer. 
 
About MRI Scans With Gadolinium Contrast 
An MRI uses powerful magnets and radio waves linked to a computer to create cross-sectional images 
of the body, in this case of the brain, that are remarkably clear and detailed. The MRI scans taken in this 
study will help the study doctors view your brain tumor. A contrast agent called gadolinium will be used 
during your MRI scans. A contrast agent is a liquid-like dye that goes into the body to help imaging 
machines create pictures of the body‘s organs and bones.  
 
About PET Scans 
PET scan is a nuclear medicine imaging technique that produces a 3-D image of how the body functions. 
In other words, PET scans take pictures of the cells and how they work in the body—in this case, in the 
brain and, with the FMISO, how much oxygen is getting into the brain tumor. 
 
About the Radioligand FMISO  
The FMISO agent is an investigational radioligand, a molecule containing radioactive substance. The 
low dose of radiation that it gives off from inside the body is picked up on PET scan images. The images 
show color where the FMISO emits radiation so study doctors can see whether oxygen is available to 
different areas of the tumor. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?  
About 50 people newly diagnosed with advanced brain cancer (glioblastoma) from 4 to 10 institutions 
will take part in this study.   
 
 
HOW LONG WILL I BE IN THE STUDY? 
You will be directly involved with this clinical trial‘s imaging procedures for the two (2) weeks after 
you are enrolled to participate, during the time before you start treatment. You may sign this consent 
form and then be unable to participate because of new information about your health; in these instances, 
you will be informed and the reason you were unable to participate will be collected. However, 
information about your cancer—including whether it gets worse—will be collected from your treating 
doctor(s) until the study ends, which may be up to 5 years. The FMISO PET and MRI scans in this study 
will be taken as you undergo different stages of treatment for your brain tumor. 
 
This study is expected to end after all study participants have completed the imaging visits and all the 
information has been collected. This study may be stopped at any time by your study doctor, ACRIN, 
FDA, or NCI without your consent should: 


 
ACRIN 6684 
57 
January 24, 2012 
 
 
 Your health or safety be at risk; 
 You not follow study instructions; 
 The study drug no longer be available; 
 New information becomes available that might change your mind about 
participating in the trial; 
 An administrative decision made by the study doctor, ACRIN, FDA, or NCI. 
 
These actions do not require your consent, but you will be informed of any of these decisions if such a 
decision is made. 
 
You can stop participating in this study at any time. However, if you want to stop participating in the 
study, we encourage you to talk to the study doctor and your treating doctor before making your final 
decision. Withdrawal will not interfere with your future care. There will be no penalty for deciding not 
to participate.  
   
 
WHAT AM I BEING ASKED TO DO IN THE STUDY? 
If you agree to take part in this study and are determined to be eligible by your study doctor, you will be 
asked to read and sign this consent form before you are enrolled to participate in this trial and before any 
study procedures are performed.  When you are enrolled into the study, you will have the following tests 
and procedures. As part of this study, a sample of your tumor tissue obtained from a biopsy or surgery 
that resulted in the diagnosis of a brain tumor will be sent and stored until processed at ACRIN 
designated pathology laboratory for analysis as part of this study. You will not need to have any 
additional biopsies to participate in the study.   
 
See the Study Chart at the end of this section for a visit-by-visit outline of what will be expected of you 
if you decide to participate in this trial. 
 
Standard medical procedures that are part of regular cancer care and would probably be done 
even if you do not join the study: 
 Chemotherapy (cancer fighting drug) called temozolomide and possibly an additional 
medication ; 
 Radiation therapy; 
 Standard-of-care imaging during your treatment and follow up; 
 Short mental health examinations; 
 Physical examination; 
 Neurologic examination; 
 Routine blood laboratory studies; 
 Pregnancy test (if applicable). 
 
*  If you are taking an additional agent as part of another clinical trial, you will be agreeing to allow 
ACRIN and its affiliates involved in the ACRIN trial collect data from the other clinical trial on 
the type of treatment and its administration. 


 
ACRIN 6684 
58 
January 24, 2012 
 
Standard medical procedures that are being done specifically because you are in this study (these 
may or may not be done if you were not in this study): 
 Blood samples will be taken each scanning visit during the trial; 
 One (1) or two (2) PET scans with FMISO—if you are one of the 15 participants to be asked 
to have the extra imaging, you will have a total of 2 PET scans with FMISO; 
 Additional imaging related to the pre-treatment MRI scan (this will mean more time than 
usual in the MRI machine); 
 Your kidney function will need to be tested within 28 days prior to each study MRI scan. 
 
Before treatment. You will be asked to have one (1) FMISO PET scan and one (1) MRI scan with 
contrast within the two (2) weeks prior to starting treatment for your brain cancer.  
 
A group of 15 participants will also be asked to have one (1) FMISO PET scan within one (1) week 
prior to starting treatment. Those 15 people will get two (2) FMISO PET scans prior to starting 
treatment.  
 
Please circle your answer. 
If I qualify, I choose to take part in the test-retest substudy that is being done for research and that will 
require a second FMISO PET scan prior to beginning treatment. 
 
             Yes                No 
 
 
 
   
                                                               Your Initials 
 
Intravenous (IV) catheters. Each visit when you have the FMISO PET scan, you will need to have two 
(2) IV catheters placed, one in a vein in your left arm, the other in a vein in your right arm. During the 
FMISO PET scan, blood samples will be taken from one of the IV catheters. The other IV catheter will 
be used to inject the radioligand FMISO for the PET scan or the gadolinium contrast for the MRI scan. 
Two (2) IV catheters will be important to ensure that the blood samples taken during the study do not 
contain any of the FMISO contrast agent.  
 
Note that if you have the MRI scan on a separate day from the FMISO PET scan, then you will need 
only one (1) IV catheter that day. You and your study and/or treating doctors should discuss the risks 
and benefits associated with two-days of scanning, as you would be exposed to additional risk from one 
more IV catheter placement for each additional imaging day throughout the study. 
 
Preparation for a PET scan. Before each FMISO PET scan, do not deliberately fast and drink lots of 
liquids. You will be given details of what to do to prepare for your PET scan prior to each imaging visit. 
 
During the PET exam. Each day of your FMISO PET scan, you first will be given an injection of a 
small amount of the radioactive drug/tracer into a vein in your arm or hand. The amount of radiation is 
small, about the same as x-ray studies like CT. The radioactive tracer only stays in your body for a few 
hours. The FMISO will travel to your brain to aid in the images created by the PET scanner.  
 
During the PET scan, small amounts of blood will be collected from the IV catheter in the arm that did 
not receive the FMISO agent.  
 


 
ACRIN 6684 
59 
January 24, 2012 
 
The PET scanner is a large machine with a hole in the middle. It looks like a donut with a table in the 
middle. Almost two hours (110 minutes) after the injection of FMISO, you will be asked to go to the 
bathroom (urinate) and then lie on a partially enclosed scanning table, face up. The table will slide into 
the machine. You will be asked to remain still during the scan. You will hear buzzing or clicking sounds 
during the scan. You will need to lie still for about 20 minutes before coming off of the scanning table.  
 
The size of the opening is 27 to 30 inches. How much space you feel you have around you will depend 
on your body size and the scanner type. If you feel any anxiety over being in enclosed spaces, let your 
study doctor know. A mild sedative may be used to help you feel more comfortable during the exam. 
 
Time required. The entire FMISO PET scan procedure is expected to take no more than 3 hours from 
the time of the FMISO injection. MRI scans can take approximately 90 minutes. Once you have had 
your FMISO PET scan(s), you will receive radiation and chemotherapy (also known as chemoradiation) 
about a week after completing your first scan(s). The chemoradiation you will be getting is not a part of 
this study. It will be the usual treatment for your kind of brain cancer. You and your treating doctor will 
decide how much chemoradiation you will get.  
 
Follow up. You will continue to see your treating doctor once the chemoradiation treatments have 
ended. You will see your treating doctor at regular intervals according to her/his recommendations and 
usual practice. Information gathered by your treating doctor as part of your normal follow-up visits will 
be given to your study doctor or research staff so they can find out more about your health. Any MRI or 
CT scans that are performed as routine care during the study period will be submitted along with your 
health status to ACRIN Headquarters in Philadelphia, PA. Your personal information will not be 
included on the images, though, to protect your privacy.  
 
Your treating doctor will be asked to inform the study doctor or research staff about your health and 
your disease status until the end of the study (up to five [5] years after you completed your treatment and 
had your last FMISO PET scan). The study doctors will want to collect follow-up images (standard of 
care MRI and CT scans) during this time. Your follow-up care will be decided between you and your 
treating doctor.  


 
ACRIN 6684 
60 
January 24, 2012 
 
STUDY CHART 
 
VISIT 1: Registration/Screening 
 
 
 
 
 
Sign the informed consent form; 
 
Have a physical examination; 
 
Provide medical history and take short mental health examinations; 
 
Routine lab studies, including checking your kidney health, if necessary; 
 
Have a pregnancy test, if necessary. 
 
VISIT 2: Baseline—Pre-Treatment 
FMISO PET and Brain MRI With 
Contrast  
 
(Within 2 Weeks Prior to the 
Beginning of Treatment) 
 
 
 
 
 
 
 
Follow instructions in preparation for the PET and MRI scans; 
 
Have a pregnancy test, if necessary; 
 
Check your kidney health, if necessary; 
 
Have vital signs taken before the FMISO injection; 
 
Have 2 IV catheters placed, one in a vein in each arm; 
 
Have the FMISO radioligand injected; 
 
Have a PET scan; 
 
Small amounts of blood (about 18–30 mL total—about 1 ounce) will be 
taken during the PET scan; 
 
Have vital signs taken after the PET scan is over; 
 
Describe your steroid use/dose prior to MRI; 
 
Undergo MRI scan with gadolinium contrast agent, injected while in the 
scanner; 
 
The day after the PET scan, a researcher will call you to see how you are 
feeling. 
 
NOTE: You and your doctor have the option of scheduling 2 days to complete 
the FMISO PET and MRI scans. These scans would need to be completed 
within the same 14-day period prior to start of treatment.  
 
VISIT 2A: FOR 15 
PARTICIPANTS ONLY – 
Reproducibility Arm for PET  
 
(1 to 7 Days After Completion of 
Visit 2 Scans, and Within 1 Week 
Prior to the Beginning of Treatment) 
 
 
 
 
 
Follow instructions for preparation for the PET scan; 
 
Have a pregnancy test, if necessary;  
 
Have vital signs taken before the FMISO injection; 
 
Have 2 IV catheters placed, one in a vein in each arm; 
 
Have the FMISO radioligand injected; 
 
Have a PET scan; 
 
Small amounts of blood (about 18–30 mL total) will be taken during the 
PET scan; 
 
Have vital signs taken after the PET scan is over; 
 
The day after the PET scan, a researcher will call you to see how you are 
feeling. 
 
NOTE: Visit 2A must be completed 1 to 7 days after the completion of both 
Visit 2 scans (FMISO PET and MRI) and before the start of treatment. 
FOLLOW UP: Every Three 
Months Until the End of Study  
(5 Years at Most)  
 
 
Every three months after the imaging for this study is completed, a 
researcher will contact your treating physician to collect copies of any 
MRIs or CT scans taken during routine follow up.  
The researcher will also ask about your condition, including whether you have 
received any new treatments, are taking steroids for your disease, and whether 
your tumor has grown or shrunk. 
 


 
ACRIN 6684 
61 
January 24, 2012 
 
 
WHAT ARE THE POSSIBLE RISKS OR DISCOMFORTS OF THE STUDY? 
While on the study, you may be at risk for side effects. You should discuss the possible side effects 
listed below with the study doctor, research staff, and/or your treating doctor. There also may be other 
side effects that we cannot predict. Other drugs may be given to make side effects less serious and 
uncomfortable. Many side effects go away shortly after the imaging scan is stopped and IV catheters are 
removed, but in some cases side effects can be serious, long lasting, or permanent.  
 
If you receive Ativan or another sedative, there is a small risk of a reaction to the sedative medication. 
We will not administer this drug if you have had a bad reaction to similar medications in the past or if 
your medical history suggests that you are at risk for a reaction. If you receive a sedative, you will not be 
allowed to drive yourself home. 
 
Risks Associated With an IV Injection:  
 Bruising, pain, or infection at the injection site; 
 Leaking of IV fluid into tissues near the injection; 
 Allergic reaction, which could be serious or life threatening. 
 
Risks Associated With MRI: 
 Anxiety/stress; 
 Claustrophobia; 
 Discomfort. 
 
Because of the powerful magnetic force of the MRI scanner, you may not be able to participate in the 
study if you have: 
 
 Metallic or other surgical implants (for example: pacemaker, heart valves, aneurysm clips, metal 
plates or pins and some orthopedic prostheses); 
 Metal pieces in your eye(s) or other body part(s); or 
 Difficulty lying still or inability to lie on your stomach.  
 
Notify your doctor if any of the above relate to you. Also, carefully read the information you should 
receive at the MRI facility about other risks.  
 
While there are no significant risks from MRI, you may be uncomfortable due to the loud noise and/or 
feelings of claustrophobia during the MRI. If you experience a sensation of claustrophobia while in the 
magnet, the MRI will be immediately stopped. You will be excluded from the study if you are pregnant 
or have a pacemaker or other electromagnetic device, or have a vascular clip in your head. No serious 
biologic effects have been reported from the magnetic fields used in clinical MRI. 
 
Risks Associated With Gadolinium: 
Approximately two percent (2%) of participants experience some side effects with the use of 
gadolinium; however, they are mostly mild (nausea, headache, hives, temporary low blood pressure). 
Serious side effects are very rare and are discussed below. Recent information has suggested that the use 
of gadolinium may contribute to kidney disease in patients with poor kidney function. Therefore, we 


 
ACRIN 6684 
62 
January 24, 2012 
 
will monitor your kidney function closely while you participate in this study. If there is any change in 
your kidney function, we may have to remove you from the study. 
 
Less likely 
 Headaches; 
 Nausea. 
 
Less likely, but serious 
 Allergic reaction. 
 
Very rare, but serious 
 Nephrogenic systemic fibrosis (NSF)/Nephrogenic Fibrosing Dermopathy (NFD). NSF is a 
condition associated with the gadolinium contrast agent when there is severe kidney disease. 
Symptoms include tightening or scarring of the skin and organ failure. In some cases, it can be 
deadly. NSF has not been seen in patients with normal working kidneys or mild problems in kidney 
function. Prior to study entry, we will determine if your kidneys are working properly in order to 
help make sure the gadolinium contrast agent is safe for you. 
 
Risks Associated With PET Scans:  
 Discomfort from lying still on your back for a total of about 20 minutes for each scan;  
 Claustrophobia (feeling anxious and ‗closed in‘). 
 
Risks Associated With [18F]FMISO PET/CT: 
There are a few possible risks of [18F]FMISO  PET and PET/CT scans. The most common ones are not 
considered serious. Any serious risks of [18F]FMISO PET or PET/CT scans are considered very 
unlikely. All of the known risks are described below. 
 
Radiation Risk 
<<Each site may need to modify this section to quote the correct PET and CT dosimetry for its own 
PET/CT and PET-only scanners in accordance with its own institutional policies and procedures. The 
following language and dosing range is an example only.>> 
FOR EXAMPLE: 
There are some risks from the PET scans used to monitor your tumor status and your response to 
treatment. These scans will expose you to radiation. If you live in the US, you receive about 300 
millirem of radiation each year. It comes from space and the earth around you. This is called 
―background radiation.‖ A ―millirem‖ (mrem) is a unit used to measure doses of radiation. The radiation 
dose to your whole body from each of your PET scans will range from 780 to 980 mrem for participants 
who have two total study-related FMISO PET scans (15 participants who have two FMISO baseline 
scans). For participants who undergo one total study-related FMISO PET scans, the likely doses will 
range from 390 to 490 mrem. This dose can vary from person to person. Each dose of FMISO will 
expose you to about one-half to three-quarters of the amount of radiation in a routine CT scan of a large 
body area such as your abdomen. 
 
At a dose of 1500 mrem, your risk of harm might be as high as 1 in 1000. Most likely, the effects of this 
radiation exposure will be years away. If you have more procedures that expose you to radiation, your 
risk will go up. Risks of harm may include getting a new cancer or changes in your genes. You may 


 
ACRIN 6684 
63 
January 24, 2012 
 
need to have other x-rays or scans for your care. Your doctors will explain the risks of the other x-rays 
or scans. 
 
As with any experimental procedure, there may be unanticipated side effects. But if you notice anything 
differently, please feel free to contact the investigators (contact number given below). 
 
Reproductive Risk  
If you are pregnant or nursing or plan to become pregnant leading up to the imaging component of the 
study, you cannot take part in this research study. We do not know the effects of the FMISO agent on 
the fetus, breastfeeding baby, or mother-to-be, and this study may cause harm. Because the PET and 
MRI scans and the investigational radioligand FMISO in this study can affect an unborn or nursing 
baby, you should not become pregnant or breastfeed, or father a baby, while undergoing imaging with 
FMISO for this study.  
 
You and your study doctor should discuss taking precautions. If you or your partner does become 
pregnant, you will need to tell your study doctor immediately. If you are unsure of your pregnancy status 
on the day of your imaging scans for the trial, you will need to tell your study doctor and have a 
pregnancy test before any of the day‘s study procedures. 
 
Ask about counseling and more information about preventing pregnancy.  
 
 
WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART IN THE STUDY? 
You will not receive any direct benefit from participation in this research study. We hope the 
information learned from this study will benefit other patients with brain cancer in the future. Doctors 
may be able to use the information from this study to help them determine the best treatment approaches 
for people with certain types of brain cancer or help treatments work better in brain cancers that are 
difficult to treat. 
 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT WANT TO PARTICIPATE? 
You may choose to not participate in this study. You could have PET and MRI scans done without 
participating in this study. If you decide not to participate, there will be no penalty or loss of benefits to 
which you are otherwise entitled. Please talk with your treating doctor about this and other options.  
 
 
WHAT ABOUT PRIVACY? 
Every attempt will be made by the investigators to keep all the information collected in this study 
strictly private, including your personal information. We cannot guarantee absolute privacy. Records of 
your participation in this study, your progress, and images taken while on the study (such as the FMISO 
PET and MRI scans) will be kept secure at this institution and in a computer file at ACRIN headquarters 
in Philadelphia, PA. All data sent to ACRIN over the Internet will be coded so that other people cannot 
read it. Your personal information may be disclosed if required by law.  
 


 
ACRIN 6684 
64 
January 24, 2012 
 
You further understand that authorized representatives of ACRIN, the Center for Statistical Sciences at 
Brown University, the FDA, the NCI, Cardinal Health (supplier of FMISO), the IRB of 
<<Institution>>, and other groups or organizations that have a role in this study will have access to and 
may copy both your medical and research records due to your participation in this study. This access is 
necessary to ensure the accuracy of the findings and your safety and welfare. If any publication or 
presentations result from this study, you will not be identified by name. Results will be reported in a 
summarized manner that you cannot be identified. 
 
Your research records and images will be kept permanently on file at ACRIN and may be used for future 
research. All personal identifiers are removed and replaced with a unique identifying number. The 
information that may be done with the information will not specifically help you. But, it might help 
people in the future who have cancer and other diseases. 
 
 
WILL I HAVE TO PAY FOR ANYTHING? 
Taking part in this study will not lead to added costs to you or your insurance company.   
You or your insurance company will not be charged for the following parts of this research study:  
 Blood samples collected at each scanning visits; 
 One (1) or two (2) PET scans with FMISO. 
You or your insurance company will be charged for any other portion of your care that is considered 
standard of care for your condition.  You may be responsible for any co-payments and deductibles that 
are standard for your insurance coverage.   
 
 
WILL I BE PAID FOR BEING IN THE STUDY? 
The National Cancer Institute (NCI) allows reasonable reimbursement for travel expenses and time 
away from work associated with trial participation. If you are eligible to enroll in the study, you will 
receive a total of $<<institution to provide appropriate amount—sites can determine a per-visit rate 
based upon appropriateness for their institution >> upon completion of the study as compensation for 
time and travel associated with your participation in this research study. You will have one (1) or two 
(2) FMISO PET scans for this trial; the number of unique visits depends on your standard-of-care 
treatment. If, for whatever reason, you do not complete all the research-related imaging scans, you will 
be given $<<institution to provide appropriate amount—sites can determine a per visit rate based upon 
appropriateness for their institution>> per each research-related scan completed. 
 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE STUDY? 
It is important that you tell your study doctor, <<insert name>>, if you feel you have been injured 
because of taking part in this study. You can tell the study doctor in person or call him/her at <<insert 
telephone number>>. 
 
In the case of medical emergency, injury, or illness during this study, emergency medical treatment is 
available but will be provided at the usual charge. You and/or your insurance will be responsible for the 
cost of the medical care of that illness or injury. The study will not pay for medical treatment. 
 


 
ACRIN 6684 
65 
January 24, 2012 
 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
Taking part in this study is voluntary. You may choose not to take part in the study. If you decide to take 
part in the study, you are free to leave the study at any time. No matter what decision you make, there 
will be no penalty and you will not lose any of your regular benefits. Leaving the study will not affect 
your medical care. You can still be treated at our institution, and your decision will not interfere with 
your future care.  
 
During the study, we may find out more information that could be important to you. A Data Safety and 
Monitoring Board, an independent group of experts, may be reviewing the data from this research 
throughout the study. This includes information that might cause you to change your mind about being 
in the study. If information becomes available from this or other studies that may affect your health, 
welfare, or willingness to stay in this study, we will tell you about it as soon as possible. 
 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
(This section must be completed) 
You can talk with your study doctor(s) about any questions or concerns you have about this study. 
Contact your study doctor <<insert name>> at <<insert telephone number>>. 
 
This document explains your rights as a study participant. It you have any questions at any time 
regarding your participation in this research study or you have any questions regarding your rights as a 
research participant, do not hesitate to speak with your study doctor or anyone listed below.  
 
For additional information about your health or medical emergency, you may contact: Usually the name 
of the local hospital information is provided and with instructions to study participants to inform the ER 
doctor of their participation in a clinical trial. 
 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
For information about your rights as a research subject, you may contact <<Institution Name>> 
Institutional Review Board (a group of people who review the research to protect your rights): 
(Provide the name of local IRB contact person) 
 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
 
WHERE CAN I GET MORE INFORMATION? 
You may call the NCI‘s Cancer Information Service at 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 


 
ACRIN 6684 
66 
January 24, 2012 
 
You may also visit the NCI‘s Web sites for comprehensive clinical trials information, 
http://cancertrials.nci.nih.gov. For cancer information from the NCI, visit http://cancernet.nci.nih.gov. 
ACRIN‘s web site is www.acrin.org. 
 
 
ACKNOWLEDGEMENT 
When you sign this document, you are agreeing to take part in this study. This means you have read all 
the above information, asked questions regarding your participation, and received answers that you 
understand to all your questions. You have also had the opportunity to take this consent form home for 
review or discussion if you want to.  
 
You willingly give your consent to participate in this study. A copy of this signed informed consent 
form will be given to you. You may also request a copy of the protocol (full study plan). 
 
 
 
 
 
 
 
 
 
Printed Name of Study Participant/ 
Signature 
Date 
Legal Representative 
 
<Insert other signature and date lines as appropriate per local IRB policies and procedures> 


 
ACRIN 6684 
67 
January 24, 2012 
 
APPENDIX II 
 
ACRIN 6684 
 
SUPPLEMENTAL MATERIALS AVAILABLE ONLINE 
 
 
Supplemental materials that support the conduct of the trial are available on the ACRIN Web site at the 
ACRIN 6684 Protocol Web page (www.acrin.org/6684_protocol.aspx). Types of materials posted 
include: 
 Application and protocol activation documents (General Qualifying and Protocol Specific 
Applications, Form FDA 1572, ACRIN Statement of Investigators, protocol activation checklist, 
etc.);  
 Data forms; 
 Imaging materials (Image Transmittal Worksheet, imaging parameter charts, and scanning and 
image qualification instructions), see www.acrin.org/6684_imagingmaterials.aspx;  
 Recruitment and education materials; 
 Regulatory resources; 
 Participating site list.  
 
For more information related to the trial, contact the ACRIN 6684 Contact Personnel link on the above-
mentioned Web page for a list of protocol team members at ACRIN Headquarters and their roles. 


 
ACRIN 6684 
68 
January 24, 2012 
 
APPENDIX III 
 
ACRIN 6684 
 
WELL COUNTER CROSS-CALIBRATION PROCEDURE 
 
NOTE:  As a pre-qualification measure, sites will need to demonstrate appropriate well counter 
cross calibration.   
1. The time of all measurements should be documented in reference to a single clock.  If possible, 
the clocks on the PET scanner, well counter, and dose calibrator (if it has a clock) should be 
synchronized to this reference clock. 
2. Fill a uniform cylindrical phantom (18-22 cm diameter) with water and eliminate as many air 
bubbles as possible. 
3. Fill a syringe with a sufficient activity of 18F to achieve a concentration in the phantom of 
approximately 0.2 uCi/mL.  Make sure the syringe is properly placed inside the dose calibrator.  
Assay the syringe activity in the dose calibrator and record the assay result in mCi and the assay 
time.  
4. Withdraw approximately 60 cc of water from the phantom using a large syringe and an 18-gauge 
needle. 
5. Add the 18F into the phantom and thoroughly rinse the syringe contents into the phantom.. Assay 
the residual activity in the syringe in the dose calibrator and record the assay result and assay 
time, seal the phantom and repeatedly invert to mix the solutions. Enter the measured full syringe 
activity (mCi), measured full syringe activity assay time, residual syringe activity (mCi), residual 
syringe activity assay time, and volume of the completely filled phantom (mL) in the EXCEL 
spreadsheet. 
6. Add water to the phantom to fill it completely.  Re-seal and thoroughly mix the contents of the 
phantom, to make sure that the 18F is uniformly distributed. 
7. Using a calibrated balance (with at least 1 mg precision), weigh each of the three (labeled 1,2,3) 
gamma tubes with their respective caps, and enter the weight of each gamma tube (including 
cap) separately in the EXCEL spreadsheet. 
8. Withdraw three 1.0 mL samples from the phantom with a syringe or pipette and place into the 
weighed gamma counting tubes from Step 7.  Replace the cap on each gamma counting tube... 
9. Re-seal the phantom and position in the center of the gantry using the phantom holder supplied 
with the scanner. 
10. Perform a 20 minute static scan using identical acquisition and reconstruction parameters used 
for FMISO patient acquisitions.  
11. Using the same calibrated balance as in step 7, weigh each of the gamma counting tubes 
containing the samples and enter the results in the EXCEL spreadsheet. 
12. With a pipette or syringe, place 1.0 mL of tap water into a gamma counting tube labeled ―BKG‖ 
for measuring background radiation. 


 
ACRIN 6684 
69 
January 24, 2012 
 
13. Count each of the samples and the BKG tube in the well counter for 60 seconds using a counting 
window set for 511 keV photons, or close equivalent.  Enter the counting results and start times 
of the counting of each sample into the EXCEL spreadsheet 
14. The formulas in the spreadsheet will combine the weight of the samples and the number of 
counts per minute and display the well counter rate concentration, R(wc) (cpm/mL), decay 
corrected back to the start time of the PET scan.  The cpm/mL is calculated by dividing by the 
net volume of the sample in the gamma counting tube, assuming a density of 1 g/mL. 
15. Upon completion of the image reconstruction measure the mean SUV (based on weight) by 
centering a large circular ROI with a diameter that is at least 3 cm smaller than the diameter of 
the uniform cylindrical phantom, on one plane and then copying that ROI, to all planes 
(EXCEPT THE FIRST AND LAST PLANE). Average the mean SUV‘s for all the ROI‘s 
throughout the phantom as measured by the PET scanner. 
16. Using the EXCEL spreadsheet provided, enter the data from the procedure above to compute the 
cross-calibration factor. 
17. The calibration factor (CF) between the well counter (wc) and the Dose Calibrator (dc), and the 
calibration factor between the PET scanner and the DOSE Calibrator is calculated as follows: 
 
CFwc = R(wc)/R(wc) 
CFPET = R(dc)/PET 
 
Note: The units of CF are uCi/CPM, which is used by multiplying the blood sample CPM by CFwc 
to convert the units to uCi/mL.  The units of CFPET are (uCi/mL)/SUV.  The ACRIN Core PET Lab 
will complete the calculations when processing FMISO image and blood data. 


 
ACRIN 6684 
70 
January 24, 2012 
 
 
Appendix IV 
 
ACRIN 6684 
 
BLOOD SAMPLING PROCEDURES 
 
 
NOTE:  As a pre-qualification measure, sites will need to demonstrate appropriate well counter 
cross calibration. Use of dose calibrators for this procedure is strictly prohibited as the dose 
calibrator is not sensitive enough for the following measurements. 
 
1. Find a single global clock that can be used to record each count time.  Synchronize all clocks to 
the PET scanner time prior to performing the procedures, especially the well-counter clock and 
the clock used to measure blood draw times. 
2. The well counter being used should have a CF calibration within one week prior to the study.  
The value and the date of calibration must be entered on the appropriate data submittal form. 
3. Three venous blood samples are obtained at intervals of five minutes (± two minutes) at 5, 10, 
and 15 minutes after the start of emission scanning. The exact time of the blood draws must be 
recorded. 
4. The blood samples must be drawn from the IV placed in the opposite arm, which was not used 
for the FMISO injection. 
5. To avoid dilution, 3 – 5 mL must be drawn for ―waste‖ prior to each of the blood samples drawn. 
6. To ensure adequate volume to pipette into the counting tubes, 3 – 5 mL must be drawn for each 
blood sample. 
7. Prior to adding the blood sample to the gamma tube, the tube must be weighed. The weight must 
be recorded on the appropriate form. 
8. After weighing the empty tube, approximately 0.5 mL will be pipetted into the gamma tube. 
9. The weight of the filled tube will then be measured. Results must be recorded on the appropriate 
form. 
10. Background counts must be measured in the well counter prior to counting each of the blood 
samples. The background count must be performed with nothing in the well counter for an 
interval of 2 minutes. Results must be recorded on the appropriate data submittal form. 
11. Following the background measurement, the gamma tube containing the blood sample will be 
counted for 2 minutes. Results must be recorded on the appropriate form. 
12. Steps 4 through 10 will be repeated for each of the three blood draw time points. 


 
ACRIN 6684 
71 
January 24, 2012 
 
Appendix V 
 
ACRIN 6684 
 
MACDONALD RADIOGRAPHIC RESPONSE CRITERIA 
 
 
Response 
Enhancing Tumor 
Area 
Neurological Status 
Steroids 
Complete Response 
≥ 95% decrease 
Improved or Stable 
Off 
Partial Response 
50% – 94% decrease 
Improved or Stable 
Stable or Decreased Dose 
Progressive Disease 
≥ 25% increase 
Worsened 
Stable or Increased Dose 
Stable Disease 
All other situations 
All other situations 
All other situations 
 
Source: Macdonald et al.  Response criteria for phase II studies of supratentorial malignant glioma.   
J Clin Oncol. 1990; 8:1277-1280. 
 


Attachment A to Protocol ACRIN 6684 
Report: Radiation Dose Estimates for PET and PET/CT 
 
ACRIN 6684 
72 
January 24, 2012 
 
Estimation of Radiation Doses Due To PET Radiopharmaceuticals  
and to Attenuation Correction of Pet Images 
 
There are multiple reasons that contribute to the various radiation doses reported with PET and PET/CT 
scanning. They can be attributed to: 
 
1. Source of Attenuation Correction: The radiation dose due to attenuation correction varies widely based on 
the attenuation correction method used. This can be a low dose cesium or germanium source, a low dose 
or higher dose non-diagnostic CT scanner, a diagnostic CT scanner.  The method of attenuation correction 
can be a major source of radiation dose variation. The CT scanner characteristics and recommended 
settings vary considerably between manufacturers and different centers use different scanning settings to 
meet the needs for their studies. 
 
2. The PET tracer being evaluated: Different PET tracers have varying biodistribution as well as varying 
levels of uptake in areas of interest – such as a tumor. The tracer uptake can vary not only across 
histologies (different tumor types) but also in different grades of the same histology. Most of the studies 
that the NCI is performing are to define these attributes for PET tracers of interest in the relevant 
histologies, so different studies may require different doses of the same radiopharmaceutical in order to 
provide evaluable quantitative or qualitative output. 
 
3. The timing of the scan: Given that these PET tracers have fairly short half lives, the dose of the PET 
tracer may vary depending on when the scan is performed relative to the injection to deliver information 
of biological relevance. The longer the time between injection and scanning, the larger the dose that needs 
to be administered. 
 
4. The area of the body being evaluated: Depending on the biodistribution, metabolic and the excretory 
pathways for a PET tracer, different amounts of the PET tracer may need to be injected in order to obtain 
an image with sufficient signal for accurate image interpretation in different body areas. In addition, the 
amount of attenuation changes based on the body part being imaged – and the dose is varied accordingly 
– for example, a brain PET can be performed with a smaller dose than a body PET T due to less 
attenuation and a more limited imaging field. 
 
5. The type of PET imaging being performed:  Some studies require dynamic scans to determine tracer 
kinetics, while other measures only static tracer uptake across a larger area of the body.  Different 
radiopharmaceutical doses may be needed for these different types of studies depending upon tracer 
kinetics, area of the body imaged, and quantitative imaging requirements 
 
6. Institution radiation safety policies:  Different radiation-safety committees and IRBs have different 
approaches to estimating and communicating total radiation dose.  A given institution may have 
standardized values that they use for all PET scans or may demand protocol and instrument specific dose 
evaluation.  They may then communicate the maximum dose possible or the likely dose or the range.  In 
all cases each institution‘s radiation safety committee and IRB have the ultimate responsibility to 
communicate the exposure in the informed consent to their patients. 
 


Attachment A to Protocol ACRIN 6684 
Report: Radiation Dose Estimates for PET and PET/CT 
 
ACRIN 6684 
73 
January 24, 2012 
 
Further details are provided below. 
 
The radiation dose from a PET scan has two components.  The first is the dose from the radioactive 
material used in the study.  The second is the dose from attenuation correction, which is almost always 
performed, both in routine clinical practice and in research studies. Table 1  shows the reported effective 
dose (ED) from the radioactive isotope for the various radiopharmaceuticals that are being studied under 
IND by the Cancer Imaging Program of the Division of Cancer Treatment and Diagnosis at the National 
Cancer Institute, along with FDG for comparison.  Since these are empirically determined values 
involving model fitting and calculations, other estimates may not be identical to these, but will be 
similar.  The exposure from a typical 10 mCi dose is also given, but note that the dose for these 
radiopharmaceuticals can vary.  FDG for example, is labeled for 8-12 mCi, but some clinicians give 
substantially higher doses.   
 
Table 1.  Radiation dose for F-18 PET radiopharmaceuticals (Effective Dose) 
Emission Doses 
ED* (mSv/MBq) 
ED (mrem/mCi) 
Dose (mSv)  for 
370 MBq (10 
mCi) 
F-18 FDG2 
0.016 
60.8 
5.9 
F-18 Fluoride3 
0.024 
88.8 
8.9 
F-18 FMISO4 
0.015 
55.5 
5.6 
F-18 FLT5 
0.026 
96.2 
9.6 
F-18 FES6 
0.023 
83.4 
8.5 
*The ED was calculated from the individual organ doses (from published data), multiplying each by their weighting 
factor (as per ICRP60 and ICRP80) and summing the results to get the ED. 
 
Attenuation correction is usually performed for research scans and can be performed three ways: 
 
Rotating rods of Ge-68 or point sources of Cs-137 
 
Low dose, non-diagnostic CT 
 
Diagnostic CT 
 
The CT methods can have a range of radiation doses depending on scanner type and setting. 
Furthermore, the overall scan can be performed for three different imaging regions, which affects the 
effective dose from the transmission scan, depending upon the extent of the body that is imaged: 
 
Torso Survey (oropharynx to mid-thigh) 
 
Single Axial Field of View  
 
 Head Only 
 
The non-diagnostic CT provides both attenuation correction and anatomic correlation, so that the lesions 
identified in the PET scan can be localized anatomically with greater resolution than provided by a PET 
scan with gamma-ray source attenuation.  In practice, the non-diagnostic CT has mostly replaced the use 
                                                 
2 Hays MT, J Nucl Med, 43:210, 2002 
3 ICRP publication 53; calculated by ICRP and published in ICRP publication 80 on page 114) 
4 Graham MM et al, J Nucl Med 38:1361, 1997 
5 Vesselle H et al, J Nucl Med 44:1482, 2003 
6 Mankoff DA et al, J Nucl Med 42:679, 2001; for 56 kg female 


Attachment A to Protocol ACRIN 6684 
Report: Radiation Dose Estimates for PET and PET/CT 
 
ACRIN 6684 
74 
January 24, 2012 
 
of the gamma ray source attenuation because of the decreased scanning time and the improved anatomic 
correlation. 
 
The radiation dose from attenuation by rotating rod with Ge-68 is low compared to that from the 
radiopharmaceutical or the low dose CT and has been reported7 as 0.02, 0.08 and 0.20 mSv per exam for 
brain, single slice, and whole body.  The dose from Cs-137 is much less, with an ED of 0.011 mSv 
reported8 for a whole body scan. 
 
Additionally, the CT scans, regardless of classification as diagnostic or non-diagnostic, are not 
necessarily identical at different institution or with different scanners even at the same institution.  These 
four factors – the specific radiopharmaceutical, type of attenuation correction, institution 
instrumentation/practices and anatomic coverage – lead to a large range of effective doses being 
reported for a given PET radiopharmaceutical scan.   
 
With the assistance of David Mankoff, MD, PhD, University of Washington, Seattle, a survey was done 
of the current attenuation correction practices and effective radiation doses for five major cancer centers 
experienced in PET/CT.  The sites provided the CT settings they typically use for low dose scans and in 
two cases for diagnostic clinical scans.  Radiation dose was calculated using ImPACT9.  This program is 
a tool for calculating patient organ and effective doses from CT scanner examinations.  It makes use of 
the National Radiological Protection Board (NRPB) Monte Carlo dose data sets produced in report 
SR250 from the UK Health Protection Agency.  SR250 provides normalized organ dose data for 
irradiation of a mathematical phantom by a variety of CT scanners.  A summary of the survey results is 
shown in Table 2 and the parameters used in the calculations are given in the appendix.  The radiation 
dose for the transmission scans with Ge-68 and Cs-137 are included for comparison. 
 
These survey results will only really apply to the more advanced research-orientated centers, but those 
are also the ones most likely to be participating in these early phase trials, so we expect these data to be 
representative of good practices at centers likely to perform phase 2 trials with investigational imaging 
agents. 
                                                 
7 Wu T et al, Eur J Nucl Med Mol Imaging 31:38-43 (2004) 
8 Schaefer A et al, Nuklearmedizen 39: 204-208 (2000) [German] 
9 Medical Devices Agency. ImPACT CT patient dosimetry calculator, version (0.99X). London, England: ImPACT, 2006. 
 


Attachment A to Protocol ACRIN 6684 
Report: Radiation Dose Estimates for PET and PET/CT 
 
ACRIN 6684 
75 
January 24, 2012 
 
Table 2. Radiation doses calculated with ImPACT for multiple sites and procedures 
 
 
Torso survey 
(mSv) 
Single Chest Field 
(mSv) 
Head Only 
(mSv) 
Research Scans (non-diagnostic) 
 
Site 1 
 
6.1 
1.0 
0.1 
Site 2 
GE Lightspeed 
4.9 
1.6 
0.4 
Site 3 
Siemens Sensation 16 
8.0 
2.4 
1.0 
 
GE Lightspeed 
8.7 
2.2 
1.0 
Site 4 
Phillips Mx8000 IDT 
5.2 
1.6 
 
 
Phillips Big Bore 
3.6 
1.0 
 
Site 5 
 
8.6 
 
 
Median 
6.1 
1.6 
0.7 
Mean 
6.4 
1.6 
0.6 
Range 
3.6-8.6 
1.0 - 2.4 
0.1 - 1.0 
Transmission Scans 
 
  Ge-68 
0.2 
0.08 
0.02 
  Cs-137 
0.01 
NA 
NA 
Clinical Scans (diagnostic) 
Site 1 
 
13 
3.7 
0.2 
Site 2 
 
13 
4.1 
1.1 
 
From these data, the following observations can be made: 
1. The largest radiation dose is from the diagnostic scans, approximated twice that for non-diagnostic torso 
scans, and 3-4 times that for single axial scan at the same institution. These values are similar to those 
reported in a European study10 of 14 to 18 mSv ED for high quality diagnostic scans. 
2. Torso scanning, whether for diagnosis or for attenuation, exposes the patient to much more radiation than 
either single slice or head scans. 
3. The ED for a torso scan using the low-dose non-diagnostic CT is approximately equivalent to the ED for 
the radiopharmaceutical at 10 mCi dose. 
4. Head scans expose the patient to the smallest dose. 
5. For a given machine, increasing the kVp or the mAs increases the dose. 
 
When the dose for the attenuation scans is combined with the dose for the radiopharmaceuticals, the 
range of exposure for a specific radiopharmaceutical can be wide.  As a result, there can be protocol to 
protocol differences as well as site to site differences for the same protocol.  
 
Another important factor is that different radiation-safety committees and IRBs may well have different 
approaches to estimating and communicating total radiation dose.  While the ImPACT program from the 
                                                 
10 Brix G, et al, J Nucl Med, 46:608-613 (2005) 


Attachment A to Protocol ACRIN 6684 
Report: Radiation Dose Estimates for PET and PET/CT 
 
ACRIN 6684 
76 
January 24, 2012 
 
Medicines Device Agency in the UK is one of the more commonly used methods of estimating CT dose, 
it is not the only one.   A given institution may have standardized values that they use for all PET scans 
or may utilize protocol and instrument specific dose evaluation.  They may then communicate the 
maximum dose possible or the likely dose.  In all cases each institution‘s radiation safety committee and 
IRB have the ultimate responsibility to communicate the exposure in the informed consent to their 
patients. 
 
As a result, in a specific protocol, we can include our best estimates in the trial protocol and also include 
them in a draft informed consent form, but institutions can, and should, modify these in accordance with 
their local policies and practices.