A Study to Evaluate Vascular Normalization in Patients With Recurrent Glioblastoma Treated With Bevacizumab Using [11C]Temozolomide PET and Vascular MRI
Phase: NA
Conditions: Recurrent Glioblastoma
Sponsor: Massachusetts General Hospital



Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................................................... 5 
1.1 
Study Design ............................................................................................................................................... 5 
1.2 
Primary Objectives ..................................................................................................................................... 5 
1.3 
Secondary Objectives ................................................................................................................................. 5 
2. 
BACKGROUND ................................................................................................................................................ 5 
2.1 
Study Agent(s) ............................................................................................................................................. 5 
2.2 
Study Disease.............................................................................................................................................. 7 
2.3 
Rationale .................................................................................................................................................... 7 
3. 
PARTICIPANT SELECTION .......................................................................................................................... 8 
3.1 
Eligibility Criteria ...................................................................................................................................... 9 
3.2 
Exclusion Criteria .................................................................................................................................. 10 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ............................................ 11 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 11 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ..................................................................... 11 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................. 11 
4.3 
General Guidelines for Other Participating Institutions ................................................................... 12 
4.4 
Registration Process for Other Participating Institutions ...................................................................... 12 
5. 
STUDY PLAN .................................................................................................................................................. 12 
5.1 
Pre-MR-PET Scan Criteria .................................................................................................................... 13 
5.2 
MR-PET Scan Procedure ........................................................................................................................ 13 
5.3 
Definition of Dose-Limiting Toxicity ..................................................................................................... 14 
5.4 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 14 
5.5 
Duration of Therapy .................................................................................................................................. 14 
5.6 
Duration of Follow Up ............................................................................................................................. 15 
5.7 
Criteria for Removal from Study .............................................................................................................. 15 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 15 
6.1 
Anticipated Toxicities ............................................................................................................................... 16 
6.2 
Toxicity Management ............................................................................................................................... 17 
6.3 
Dose Modifications/Delays ....................................................................................................................... 17 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 18 
7.1 
[11C]Temozolomide ................................................................................................................................... 18 
7.2 
Temozolomide ........................................................................................................................................... 20 
Please refer to the FDA-approved package insert for more information. ............................................................ 20 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7.3 
Bevacizumab ............................................................................................................................................. 21 
Please refer to the FDA-approved package insert for more information. ............................................................ 21 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 22 
8.1 
Pharmacokinetic Studies .......................................................................................................................... 22 
8.2 
Pharmacodynamic Studies ....................................................................................................................... 22 
9. 
STUDY CALENDAR ...................................................................................................................................... 22 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS .......................................................................... 23 
10.1 
Definitions ................................................................................................................................................ 23 
10.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 25 
10.3 
Reporting Requirements ........................................................................................................................... 25 
10.4 
Reporting to the Study Sponsor ................................................................................................................ 26 
10.5 
Reporting to the Institutional Review Board (IRB)................................................................................... 27 
10.6 
Reporting to the Food and Drug Administration (FDA) .......................................................................... 27 
10.7 
Reporting to the NIH Office of Biotechnology Activities (OBA) .............................................................. 27 
10.8 
Reporting to the Institutional Biosafety Committee (IBC) ........................................................................ 27 
10.9 
Reporting to Hospital Risk Management .................................................................................................. 27 
10.10 
Monitoring of Adverse Events and Period of Observation ....................................................................... 27 
11. 
DATA AND SAFETY MONITORING ..................................................................................................... 28 
11.1 
Data Reporting ......................................................................................................................................... 28 
11.2 
Safety Meetings ......................................................................................................................................... 28 
11.3 
Monitoring ................................................................................................................................................ 29 
12. 
REGULATORY CONSIDERATIONS ..................................................................................................... 29 
12.1 
Protocol Review and Amendments ........................................................................................................... 29 
12.2 
Informed Consent ..................................................................................................................................... 30 
12.3 
Ethics and Good Clinical Practice (GCP) ............................................................................................... 30 
12.4 
Study Documentation ................................................................................................................................ 31 
12.5 
Records Retention ..................................................................................................................................... 31 
12.6 
Multi-center Guidelines ............................................................................................................................ 31 
13. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 31 
13.1 
Study Design/Endpoints ............................................................................................................................ 31 
13.2 
Sample Size/Accrual Rate ......................................................................................................................... 32 
13.3 
Stratification Factors ................................................................................................................................ 32 
13.4 
Reporting and Exclusions ......................................................................................................................... 32 
14. 
PUBLICATION PLAN ............................................................................................................................... 32 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
15. 
REFERENCES ............................................................................................................................................ 33 
16. 
APPENDICES ............................................................................................................................................. 37 
Appendix A: Performance Status Criteria ............................................................................................................ 37 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
5
1. OBJECTIVES 
 
1.1 Study Design 
 
Our goal is to explore changes in tumor vasculature resulting from treatment with 
bevacizumab and the impact these changes have on drug delivery. Results from this study 
will shed light on the vascular normalization hypothesis. Patients with recurrent glioblastoma 
will undergo simultaneous PET with radiolabeled temozolomide and MRI to assess changes 
in tumor blood flow, blood volume, vessel caliber, and vascular permeability while 
simultaneously measuring the pharmacokinetics and brain penetration of temozolomide 
(TMZ).  
 
We plan to study patients with recurrent glioblastoma whose clinical care plan includes 
treatment with bevacizumab and temozolomide.  Patients taking daily temozolomide 50 
mg/m2/day will undergo a PET scan using radiolabeled temozolomide (TMZ-PET) at 3 time 
points: 7-13 days after initiation of temozolomide but before beginning bevacizumab 
(“baseline”- temozolomide steady-state scan), 1 day after initiation of bevacizumab (day 15), 
and before the third bevacizumab infusion. Arterialized venous blood samples will be 
collected during the imaging in order to measure radioactivity, blood metabolites, and the 
relationship between radiotracer uptake and tumor features such as blood-brain barrier (BBB) 
breakdown and tumor blood flow.   
 
In addition, we will explore the link between flow, permeability, and tumor temozolomide 
retention. These studies will be performed using our human simultaneous MR-PET imaging 
camera. No diagnostic decisions or therapy decisions will be based on any results obtained 
from these PET scans, and we expect no change in the care of these patients. The success of 
these studies should enable methods that could be used in larger studies to more completely 
understand the role of anti-angiogenic agents in the treatment of cancer. 
 
1.2 Primary Objectives 
1. To assess temozolomide delivery before and after bevacizumab in glioblastoma. 
 
1.3 Secondary Objectives 
1. To explore the link between flow, permeability, and tumor temozolomide retention. 
a. Measure tumor blood flow with MRI perfusion and compare with 
temozolomide retention. 
b. Estimate permeability from Ktrans MRI measurements and compare with 
temozolomide retention. 
2. BACKGROUND 
 
2.1 Study Agent(s) 
 
[11C]Temozolomide 
 
The study agent is a radiopharmaceutical that is chemically identical to the 
prescription drug temozolomide except that it has a substitution of the positron 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
7
used PET and a dual labeling strategy, where [11C]temozolomide was radiolabeled 
in two different positions: at the 4-carbonyl and 3-N-methyl positions of the 
molecule.  Besides determining the mechanism of action, the study also determined 
that there was no difference the amount of observed ring opening between tumor 
and normal tissues (p>0.05), suggesting that the ring opening of temozolomide was 
tissue specific but not tumor specific.   
Rosso et al. (2009) used a new PET system analysis method to characterize 
temozolomide distribution in tissues and predicted normal brain and brain tumor 
temozolomide concentration profiles for different temozolomide dosing regimens.  
They concluded higher temozolomide exposures in brain tumor relative to normal 
brain was attributable to breakdown of the blood brain barrier and possibly to 
increased intratumoral angiogenesis. 
 
 
2.2 Study Disease 
 
An estimated 51,410 primary brain tumors were diagnosed in 2007, and 19% of these 
tumors were glioblastomas 1.  GBM is the most common malignant primary brain tumor 
and is a uniformly fatal disease with 5-year survival rates less than 4% despite aggressive 
treatment with surgery, radiation and chemotherapy.  There is no curative therapy for 
patients with GBM.  Current standard of care for patients with newly diagnosed GBM is 
concomitant involved field radiation and oral temozolomide chemotherapy followed by 
monthly temozolomide for 6-12 months (Stupp et al., 2005).  If patients relapse, there is no 
standard of care treatment and some patients will be treated with temozolomide again, albeit 
on a different dosing schedule.  Instead of 5 consecutive days every month, patients may be 
treated with a lower daily dose of temozolomide but for more days every month (Perry et 
al., 2010).  The goal of this dose dense regimen is to saturate the enzyme, MGMT, which is 
believed to counteract the DNA-damaging effects of temozolomide. Bevacizumab was 
approved by the FDA for recurrent GBM and is ultimately used in most recurrent GBM 
patients.  
 
2.3 
Rationale 
 
The dependence of tumor growth and metastasis on angiogenesis — which has been 
extensively demonstrated in animal models — has provided a powerful rationale for 
anti-angiogenic approaches to cancer therapy (van de Beek, 2007; Carmeliet & Jain, 
2000; Kleihues, Burger, & Scheithauer, 1993).  Targeting blood vessels in brain tumors 
has been a particularly attractive strategy, given the characteristic high degree of 
endothelial proliferation, vascular permeability, and pro-angiogenic growth-factor 
expression (for example, VEGF) (Dvorak, 2002; Sundberg, 2001).  The approval of 
bevacizumab, which neutralizes VEGF, in May 2009 for recurrent glioblastoma 
(rGBM) represented the first new therapy for this disease in many years. A strong anti-
edema effect is clearly seen with anti-VEGF therapy in many patients. Whether this 
conveys a survival benefit is still not clear; cediranib did not improve survival over 
lomustine in rGBM in a recent phase III trial, and while definitive phase III studies of 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
8
bevacizumab are underway, recent data suggests that bevacizumab does not improve 
overall survival when given to newly diagnosed glioblastoma patients (Lai et al., 2010). 
 
Bevacizumab is not an effective monotherapy outside the brain, but it is effective when 
combined with other drugs. The mechanism of this clinical efficacy is still incompletely 
understood. 
Anti-VEGF 
therapies 
have 
been 
shown 
to 
promote 
vascular 
“normalization” (Batchelor et al., 2007; Jain, 2005; Willett et al., 2004) in many 
patients, which could improve local tumor blood flow and therefore cytotoxic 
chemotherapy delivery to the tumor. We have shown that the ‘normalization window’ 
of the anti-VEGF agent cediranib can be detected using serial, non-invasive MRI 
techniques in rGBM (Batchelor et al., 2007), and we have seen increases in blood flow2. 
However, since anti-VEGF therapies were originally designed to block blood vessel 
formation, in theory these agents could potentially also inhibit drug delivery to the 
tumor (Jain, 2005; Jain, 2001).  An additional complication in the brain arises due to the 
presence of efflux pumps (Sharom, 2008).  These pumps actively remove 
chemotherapeutic drugs from the brain tissue and are a key component of the blood-
brain barrier. Our data from autopsy specimens obtained after cediranib suggests not 
only that vascular normalization has occurred but that the efflux protein P-glycoprotein 
is upregulated (di Tomaso et al, 2011)3, which suggests that vascular normalization 
could lead to increased perfusion but decreased retention of temozolomide. If this is the 
case, drugs or other therapies that are not affected by efflux pumps, such as radiation, 
might be a better strategy. A tool that could assess the true delivery of the specific 
therapy under consideration could integrate all these potentially conflicting and/or 
synergistic effects and provide a summary result. 
 
Beyond the scientific question of the mechanisms of anti-angiogenic therapy, such a 
tool could potentially have clinical value. Because both bevacizumab and cytotoxic 
chemotherapy are routinely administered to glioblastoma patients, there could be very 
high value to tools that could identify whether bevacizumab is changing the delivery of 
chemotherapy in a given patient. This in turn could provide opportunities to personalize 
and optimize these specific treatments and dose regimens for each patient.  
 
In previous studies, an increased uptake of [11C]temozolomide in tumor tissue as 
compared to white and gray matter was observed (Saleem et al, 2003). However, to date 
it has been not possible to determine if the higher uptake was due to actual higher 
(specific) retention of temozolomide in tumor tissue, or simply due to a more 
compromised blood-brain barrier in the tumor location resulting simply in a higher 
delivery of the drug.  Our novel hybrid MR-PET technology should allow us to assess if 
temozolomide delivery is indeed related to the level of blood-brain barrier disruption, as 
we will be able to quantify this disruption by the simultaneous acquisition of dynamic 
contrast enhanced MR data of the tumor area. 
 
 
3. PARTICIPANT SELECTION 
 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
9
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Participants must have histologically confirmed glioblastoma and evidence of 
recurrence > 2 months since last cycle of temozolomide or other alkylating agent. 
Patients with low-grade tumors who have progressed to glioblastoma are eligible. 
 
3.1.2 Patients must have received prior temozolomide or an alkylating agent (ex. 
CCNU/BCNU). 
   
3.1.3 Participants must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded) as > 10 mm. See section 10 for the evaluation of measureable disease. 
 
3.1.4 Only patients for whom their neuro-oncologist has planned to give bevacizumab 
and temozolomide 50mg/m2/day as part of their treatment are eligible for this 
study 
  
3.1.5  Age > 18 years. Because no dosing or adverse event data are currently available 
on the use of radiolabeled temozolomide in participants <18 years of age, 
children are excluded from this study but will be eligible for future pediatric 
trials. 
 
3.1.6 Life expectancy of greater than 3 months. 
 
3.1.7 Karnofsky performance status > 60 (see Appendix A). 
  
3.1.8 Participants must have normal organ and marrow function as defined below: 
• Leukocytes > 3,000/mcL 
• Absolute neutrophil count > 1,000/mcL 
• Platelets > 100,000/mcL 
• total bilirubin within normal institutional limits 
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• creatinine within normal institutional limits or creatinine clearance > 60 
mL/min/1.73 m2 for subjects with creatinine levels about institutional 
normal                  . 
3.1.9 Patient must be able to undergo MRI and PET scans. 
 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
10
3.1.10 Patients must be maintained on a stable corticosteroid regimen for 5 days prior 
each MR-PET scan.  
 
3.1.11 The effects of radiolabed temozolomide on the developing human fetus are 
unknown. For this reason and because radiopharmaceuticals agents are known 
to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.1 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to temozolomide. 
 
3.2.2 Participants who have already received anti-VEGF or experimental anti-
angiogenic therapy for glioblastoma. 
 
3.2.3 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.4 Pregnant women are excluded from this study because radiolabeled 
temozolomide is a radiopharmaceutical agent with the potential for teratogenic 
or abortifacient effects. Because there is an unknown but potential risk of adverse 
events in nursing infants secondary to treatment of the mother with 
radiopharmaceutical agents, breastfeeding should be discontinued if the mother 
is treated with radiopharmaceutical agents. These potential risks may also apply 
to other agents used in this study. 
  
3.2.5 HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with radiolabeled 
temozolomide. In addition, these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy. Appropriate 
studies will be undertaken in participants receiving combination 
antiretroviral therapy when indicated. 
 
3.2.6 Patients who are no suitable to undergo MRI or use gadolinium contrast due to: 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
11
• Claustrophobia 
• Presence of metallic objects or implanted medical devices in body (i.e. 
cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial 
hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the 
eye, or steel implants) 
• Sickle cell disease 
• Renal failure 
• Reduced renal function, as determined by creatinine clearance 
< 30 mL/min based on a serum creatinine level obtained within 28 days 
prior to registration 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
 
4. REGISTRATION PROCEDURES 
   
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If 
a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 
 
and follow the instructions for registering participants after hours. 
   
The registration procedures are as follows: 
 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
12
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
  
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
  
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 
. 
  
Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT. 
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
  
5. 
The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
  
4.3 General Guidelines for Other Participating Institutions 
 
N/A 
 
4.4 
Registration Process for Other Participating Institutions 
 
N/A 
 
5. STUDY PLAN 
 
This study does not add any additional treatment to patients with malignant glioma who are 
already scheduled to receive bevacizumab and daily temozolomide as part of their treatment. 
There will be no change in the diagnosis or management of the patient based on any 
procedures or tests carried out as a part of this study. 
 
In brief, patients will be administered temozolomide at a dose of 50 mg/m2 PO on a daily 
basis starting on Day 1.  Bevacizumab will be administered as an infusion at a dose of 10 
mg/kg i.v. every two weeks starting no later than Day 14. Standard computerized order entry 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
13
(COE) orders will be utilized for administering this drug. A cycle is defined as 28 days.  The 
treatment goal is 12 months of treatment.  Treatment beyond 12 months or at the time of 
disease progression is per discretion of the responsible physician.  The administration of both 
of these FDA-approved drugs will be per standard practice at our hospital. 
 
[11C]temozolomide (and the MR-PET scans) will ONLY be administered (and conducted), 
respectively, on Cycle 1.   
 
There are no expected toxicities and potential risks for [11C]temozolomide. All scans will be 
performed at the Martinos Center for Biomedical Imaging in Charlestown on the combined 
MR-PET scanner.    
 
5.1 
Pre-MR-PET Scan Criteria 
5.1.1 Stable dose of corticosteroids for 5 days prior to MR-PET scan. 
5.1.2 Creatinine clearance >30 mL/min based on a serum creatinine level obtained 
within 30 days. 
5.1.3 β-HCG in woman of childbearing age (prior to each MR-PET scans). 
Please see 
http://healthcare.partners.org/phsirb/Guidance/Pregnancy Testing in Research Involving
Radiation.1.09.pdf for Pregnancy Testing guidelines) 
5.1.4 Adequate laboratory values as outlined in eligibility criteria. 
 
5.2 MR-PET Scan Procedure  
Patients will have their scans performed in Charlestown, MA at the Martinos Center. 
Two lines will be placed for each scan: one venous line to inject [11C]temozolomide) 
and gadolinium for the MRI scan, and a second to draw blood to assay for radioactivity 
and metabolites.  If a patient has a port, the port can replace one of the IVs. 
5.2.1  [11C]temozolomide PET scans 
 
The PET scan will be approximately 90 minutes.  There will be one injection of 
radiolabeled temozolomide in the PET protocol.  Following the injection of the 
radiotracer, serial blood samples will be taken from a second IV. The blood will 
be drawn by a nuclear medicine technologist or a nurse trained in radiation safety. 
 
[11C]temozolomide will be injected at a dose of 7mCi by an infusion pump or 
hand over approximately 30 seconds followed by a saline flush. The IV will 
remain in place for injection of the gadolinium for the MRI scan. 
 
PET data will be acquired in list mode format for an additional 70-90minutes after 
the [11C]temozolomide injection. Serial blood will be drawn from a venous line 
not used to inject the [11C]temozolomide at times t = 2.5,5,10,20,40,60,75, and 90 
minutes after the [11C]temozolomide injection to allow for kinetic modeling. The 
whole blood will be counted and then centrifuged to separate plasma from cells. 
Aliquots of plasma and blood will be separately counted for radioactivity.  The 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
14
plasma will be further analyzed using high performance liquid chromatography 
for radiolabeled metabolites.  Blood will be transported to the well counter and 
HPLC systems in a properly shielded container.  
 
PET volumes will be reconstructed using the ordinary Poisson ordered subsets 
expectation maximization (OP-OSEM) 3D algorithm. Corrections will be applied 
for variable detector dead time and efficiency, random coincidences, photon 
attenuation and scatter, and 11C decay. 
 
5.2.2 MRI Scan 
MR scans will be performed with the same sequences and in the same order during 
each visit, including T1- and T2-weighted volumetric images, fluid attenuated 
inversion recovery (FLAIR), contrast agent enhanced T1-weighted permeability, 
diffusion tensor imaging (DTI), T2/T2*-weighted perfusion scans, and MR 
Spectroscopy. The “Autoalign” package available from the manufacturer will be 
used to achieve the same slice prescription in the same patient at each visit. Each 
MRI will last 60-75 minutes versus 45 minutes for standard brain MRIs. 
Gadolinium-diethylenetriaminepentaacetic acid (or gadopentetate dimeglumine, 
Gd-DTPA) will be used as a contrast agent and injected intravenously twice in each 
scan session. The first bolus will be for the dynamic susceptibility contrast 
sequence. The second bolus will be injected for the dynamic contrast enhanced 
sequence. The maximum contrast dose that could be given is 0.3 mmol/kg per visit, 
in line with the FDA-approved dosing for this class of contrast agents. 
 
5.3 
Definition of Dose-Limiting Toxicity 
N/A 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
Corticosteroids: Should be used at the lowest possible dose to control cerebral edema and 
mass effect and discontinued if possible. 
Anti-coagulation: Therapeutic anticoagulation with low molecular weight heparin or 
warfarin is permitted. Patients in warfarin must have INR <3. 
Anti-seizure medications: Should be used as indicated. 
 
5.5 
Duration of Therapy 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
15
Patients will be treated with temozolomide and bevacizumab for up to 1 year. 
Treatment beyond 1 year is per discretion of responsible physician. 
 
Patients may remain on study  unless one of the following criteria applies: 
 
• Intercurrent illness that prevents administration of [11C]temozolomide, 
temozolomide, or bevacizumab, 
• Unacceptable adverse event(s), 
• Unacceptable adverse reaction  
• Participant decides to withdraw from the study,  
• General or specific changes in the participant's condition render the participant 
unacceptable for MRI or PET in the opinion of the treating investigator. 
Importantly, the following do NOT remove the patient from the study if they have 
already undergone the first MR-PET scan: 
 
• Disease progression 
 
5.6 
Duration of Follow Up  
 
Participants will be followed for 3 years after removal from study or until death, 
whichever occurs first. Participants removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. Patients 
will be followed for survival, subsequent treatments received, and response to treatment 
by chart review or phone call if patient does not return to clinic. Follow-up will be 
assessed every 3 months. 
  
5.7 
Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 5.5 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will 
be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator at 
. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
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All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible.  
 
6.1 
Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with the agents administered 
in this study appear below and will determine whether dose delays and modifications 
will be made or whether the event requires expedited reporting in addition to routine 
reporting. 
  
6.1.1 Adverse Event Lists(s) for [11C]temozolomide 
There are no known adverse effects of [11C]temozolomide, although there are 
adverse effects of temozolomide. [11C]TMZ will be administered at >0.1 
mCi/nmol.  Assuming a maximum injection of 15 mCi at the lowest specific 
activity, 150 nmols (29 micrograms) will be the maximum amount of the active 
component [11C]TMZ administered. 
  
 
6.1.2 Adverse Event Lists(s) for temozolomide 
Myelosuppression (including neutropenia, lymphopenia, leukopenia, anemia, an 
thrombocytopenia), has been reported inpatients receiving temozolomide and is a 
dose-limiting side effect. Thrombocytopenia and leukopenia reach grade 2 or higher 
in up to 40% of patients on temozolomide therapy. Leukocyte/platelet nadirs 
usually occur in 3 weeks (about day 22) with a 5-day schedule, although leukocyte 
nadirs may be seen slightly later (day 29). Dose-limiting thrombocytopenia has 
persisted for 7 to 42 days, whereas recovery from leukopenia may be quicker. 
Bleeding has been infrequent with temozolomide therapy. In one large trial 
involving adult patients with malignant glioma, the predominant effect was 
lymphopenia, which reached grade 3 and grade 4 in 41% and 15%, respectively, 
receiving a 5-dayschedule of temozolomide. Corresponding incidences of 
neutropenia were 2% and 4%. The incidence of grade 3 or 4 thrombocytopenia was 
11%. The incidence of myelosuppression may be higher with the use of a dose 
intense regimen. Opportunistic infections (e.g., pneumocystis jeroveci pneumonia 
(PCP)) have been reported with the use of temozolomide. Rarely, aplastic anemia 
and secondary leukemia have been described with temozolomide. 
Hepatic toxicity: Mild transaminase elevations (up to 40% of patients) and 
hyperbilirubinemia (up to 19%) have been reported; increases in alkaline 
phosphatase have also occurred in some patients. Grade 4 increases in bilirubin 
have been seen rarely. There are no reported cases of overt hepatotoxicity.   

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
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Fatigue is among the most commonly reported adverse effect with the use of 
temozolomide in clinical trials, and is clearly drug-related. Fatigue with 
temozolomide therapy may be moderate to severe. The estimated incidence is 34%. 
 
Nausea and vomiting occur in up to 75% of patients with temozolomide therapy, 
but is not usually severe (mostly grade 1 or 2).These symptoms have often been 
limited to day 1 of the first cycle of temozolomide. Standard antiemetics have been 
effective in most patients. The estimated incidence is 42% to 53%. Bedtime 
administration of temozolomide may help to minimize nausea and vomiting. 
 
 
6.1.3 Adverse Event Lists(s) for bevacizumab 
 
Hypertension: An increased incidence of hypertension has been reported. Grade 4 
and 5 hypertension events are rare as are hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leucoencephalopathy syndrome (RPLS). 
 
Proteinuria: An increased incidence of proteinuria up to 38% has been observed. 
Patients with HTN may be at increased risk of developing proteinuria.  
 
Thromboembolic events: Both venous and arterial thromboembolic events (TE) 
have been reported with a range of 2.8-17.3% in bevacizumab treated patients 
compared to 3.2%-15.6% in chemotherapy alone treated patients.  
 
The following have been additional reported complications of bevacizumab: 
gastrointestinal perforation, fistula development, wound healing delay, hemorrhage 
(Grade 3 and 5 events reported in 4.0% of patients), tumor associated hemorrhage, 
and congestive heart failure. 
 
6.2 
Toxicity Management 
 
 
Patients will be managed symptomatically as clinically indicated. Hypertension in 
particular should be treated at the first sign of elevated blood pressure.  
 
6.3 
Dose Modifications/Delays 
6.3.1 [11C]temozolomide 
  
No dose reduction of [11C]temozolomide is permitted. 
6.3.2 Temozolomide 
 
Prior to initiation of each temozolomide cycle, the following hematologic 
parameters are required: platelet ≥100,000 and ANC ≥ 1500.  
 
In the event of a NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 grade 3 or 4 toxicity the temozolomide will be suspended 

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until recovery to grade ≤ 1 and re-started at a dose reduction of 37.5 mg/m2. 
 
 
Temozolomide may be held for up to 28 days. 
6.3.3 Bevacizumab 
  
Prior to each bevacizumab infusion, the following parameters should be met: 
platelet count >75,000, proteinuria < grade 3, creatinine <1.5, hypertension < 
grade 4.  
 
 
If other toxicities (as determined CTCAE version 4.0) of grade >2 are observed 
(except alopecia, nausea and vomiting) and related to bevazicumab, then the dose 
of bevazicumab should held until recovery to grade ≤ 1. All grade 3 or 4 non-
hematological toxicities (except alopecia, nausea and vomiting) should have 
resolved to grade ≤ 1 for bevazicumab to be re-initiated at a dose of 5mg/kg. 
 
Bevacizumab may be held for up to 28 days.  
 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
[11C]Temozolomide 
7.1.1 Description 
 
The chemical name is: [3-N-¹¹C-methyl]temozolomide.  This agent is a 
radiolabeled version of temozolomide that can be used to explore the 
pharmacokinetics of temozolomide therapy. 
 
7.1.2 Form 
 
[11C]Temozolomide is prepared as an intravenous injection in sodium acetate 
buffer with 5% ethanol (Brown et al., 2002) at a tracer level mass dose that should 
exhibit no pharmacological effect. 
 
7.1.3 Storage and Stability 
 
[11C]Temozolomide will be produced onsite on the day of the scheduled PET 
scan.  Proper transportation will take place according to Martinos Center 
policies.  Following synthesis and quality control, the radiopharmaceutical will 
be used immediately (injection time not to exceed expiration of 1 hr post 
synthesis).  
  
7.1.4 Compatibility 
 
N/A 

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7.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
7.1.6 Availability 
 
[11C]Temozolomide is an investigational agent and will be produced onsite. 
 
7.1.7 Preparation 
 
[11C]Temozolomide will be produced onsite as a fully prepared agent ready for 
intravenous administration.  Radioactivity dose can be adjusted by modifying the 
injection volume.  No other changes in constitution should be made.  
  
7.1.8 Administration 
 
[11C]Temozolomide will be injected intravenously as a bolus at a dose of 7 (±1) 
mCi using an infusion pump or by hand over approximately 30 seconds.  The 
bolus will be followed by a 10 mL saline flush. 
 
7.1.9 Ordering 
 
[11C]Temozolomide will not be ordered.  [11C]Temozolomide will be prepared on a 
single injection basis as dictated by MR-PET scheduling of studies at the Martinos 
Center.  
 
7.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the agent 
(investigational or free of charge) using the NCI Drug Accountability Record or 
another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for  
Accountability and Storage of Investigational Agents” or to obtain a copy of the 
drug accountability form.) 
 
7.1.11 Destruction and Return 
 
At the end of the study, unused supplies of [11C]temozolomide should be 
decayed in storage according to institutional policies. This will be documented 
in the [11C]temozolomide individual batch record and scan log. 
 

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7.2 
Temozolomide 
 
7.2.1 Description 
 
Please refer to the FDA-approved package insert for more information. 
. 
 
7.2.2 Form 
 
Temozolomide is available in commercially available in 5 mg, 20 mg, 100 mg, 140 mg, 180 
mg, and 250 mg capsules. 
 
7.2.3 Storage and Stability 
 
Temozolomide capsules should be stored at controlled room temperature. 
  
7.2.4 Compatibility 
 
N/A 
7.2.5 Handling 
 
N/A 
 
7.2.6 Availability 
 
Temozolomide is commercially available in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 
and 250 mg capsules. 
 
7.2.7 Preparation 
 
N/A 
  
7.2.8 Administration 
 
The capsules are administered orally and should not be chewed. They should be 
swallowed whole with a glass of water. Procedures for handling and disposal of 
anticancer drugs should be considered. 
 
7.2.9 Ordering 
 
Temozolomide will be ordered commercially. 

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7.2.10 Accountability 
 
N/A 
 
7.2.11 Destruction and Return 
 
N/A 
7.3 
Bevacizumab 
 
7.3.1 Description 
 
Please refer to the FDA-approved package insert for more information. 
 
 
7.3.2 Form 
 
Bevacizumab is an intravenous medication. 
 
7.3.3 Storage and Stability 
 
Bevacizumab will be stored per standard clinical guidelines. 
  
7.3.4 Compatibility 
 
N/A 
7.3.5 Handling 
 
Bevacizumab will be handled per standard clinical guidelines 
 
7.3.6 Availability 
 
Bevacizumab is commercially available. 
 
7.3.7 Preparation 
 
Bevacizumab will be prepared per standard guidelines 
  
7.3.8 Administration 
 
Administration will be IV per standard clinical guidelines. 

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7.3.9 Ordering 
 
Bevacizumab will be ordered commercially. 
 
7.3.10 Accountability 
 
Per standard clinical guidelines 
 
7.3.11 Destruction and Return 
 
Per standard clinical guidelines. 
 
 
 
8. CORRELATIVE/SPECIAL STUDIES  
8.1 
Pharmacokinetic Studies 
 
During PET data acquisition, blood samples will be drawn for analysis of total 
radioactivity and to determine the proportion of labeled radioactive metabolites.  
8.2 
Pharmacodynamic Studies 
 
N/A 
 
9. STUDY CALENDAR 
 
 
Screening 
 Prior to 
bevacizumab  
1 day after initial 
bevacizumab dose 
Prior to third dose 
of bevacizumab 
[11C]TMZ PET/ 
MRI scan 
 
Xa 
X 
Xf 
Informed 
consent 
X 
 
 
 
History 
X 
 
 
 
Physical exam 
(Ht, Wt, VS) 
X 
 
 
 
Steroid dose 
X 
 
X 
X 
KPS 
X 
 
 
 

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CBC with diff 
X 
 
 
 
CMPb 
X 
 
 
 
B-HCGc 
X 
X 
X 
X 
Adverse event 
evaluationd 
 
24±6 hours post 
PET scan 
 
24±6 hours post PET scan 
24±6 hours post PET 
scan 
Follow-upe 
 
 
 
 
a – 0-7 days prior to start of bevacizumab. Patient had to have received at least 7 doses of temozolomide 
prior to the MR-PET (i.e. steady state of temozolomide). 
b – Sodium, potassium, chloride, glucose, BUN, creatinine, calcium, total protein, albumin, total 
bilirubin, SGOT [AST], SGPT [ALT], alkaline phosphatase. 
c – Serum pregnancy test (for women of childbearing potential) 
d – Can be phone call or clinic visit 
e – Patients will be scanned approximately every 2 months per standard of care guidelines. Follow-up 
every 3 months will assess subsequent treatments, tumor response to treatment, and 
survival 
f – within 3 days prior to the 3rd bevacizumab dose- i.e. can be same day as bevacizumab but must be 
prior to the infusion or up to 3 days before the 3rd infusion 
10. ADVERSE EVENT REPORTING REQUIREMENTS 
10.1 Definitions 
10.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
10.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 

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• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
 
10.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
10.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s). 
10.1.3.2 Unexpected adverse event 

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For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
10.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
10.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
10.3 Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report serious adverse events to the study sponsor and/or others as described below.  

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Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.   
10.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS). 
10.6 Reporting to the Food and Drug Administration (FDA) 
 
N/A 
10.7 Reporting to the NIH Office of Biotechnology Activities (OBA) 
 
N/A 
 
10.8 Reporting to the Institutional Biosafety Committee (IBC) 
 
N/A 
10.9 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
10.10 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 

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unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
Investigators must immediately report directly to the Radioactive Drug Research 
Committees (RDRC) all adverse effects associated with the use of the radioactive drug. 
 
11. DATA AND SAFETY MONITORING 
11.1 Data Reporting 
11.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
11.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 
 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
11.2 Safety Meetings 
 

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The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
11.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
12. REGULATORY CONSIDERATIONS 
12.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 

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12.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
12.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr11 02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  

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12.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
12.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
12.6 Multi-center Guidelines 
N/A 
 
13. STATISTICAL CONSIDERATIONS  
13.1 Study Design/Endpoints 
 
This is a pilot study. The target population of recurrent GBM patients who are 2 
months or more from their last temozolomide treatment is a small group of patients, 
which will limit the number of patients eligible for accrual.  
 
The primary comparison will be for the change in the within-tumor concentration of 
radiolabelled temozolomide. The change will be expressed as day 15 concentration 
relative to baseline measurement. Additional analysis will look at the ~day 42 
concentration relative to baseline measurement of radiolabeled temozolomide as it is 
unclear when changes in drug delivery may occur.   We will use an exact two-sided, 
one-sample Wilcoxon signed rank test on log- relative total within-tumor 
temozolomide concentration to test the primary hypothesis. Due to pilot nature of this 
study enrollment will be limited to only n=17 patients. Our goal is for 15 evaluable 
patients so the maximal enrollment will be 17 to allow for 2 nonevaluable patients (i.e. 
PET data not evaluable) With 15 patients, we would anticipate having a sufficient 
sample size to identify the subset of patients who respond to bevacizumab with 
increased perfusion and thus drug delivery. We will have 80% power to detect a 
difference of 0.81 standard deviation units between baseline and day 15 using a two-
sided, 0.05 level Wilcoxon signed rank test with 15 subjects.   

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13.2 Sample Size/Accrual Rate 
 
A maximum of 17 patients will be enrolled with an accrual rate of 0-1 per month.   
13.3 Stratification Factors 
 
N/A 
13.4 Reporting and Exclusions 
13.4.1 Evaluation of toxicity. All participants will be evaluable for toxicity for 24hours 
+/- 6hours after each MR-PET  scan. 
13.4.2 Evaluation of response.  All participants included in the study must be assessed 
for response to treatment, even if there are major protocol treatment deviations or 
if they are ineligible. Each participant should be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
 
14. PUBLICATION PLAN 
The Principal Investigator holds primary responsibility for publication of the study results. 
The results are to be made public via abstract meeting the requirements of the International 
Committee of Medical Journal Editors or via publication in a peer-reviewed journal within 
24 months of the end of data collection and analysis. A full report of the outcomes will be 
made public no later than three years after the end of data collection and analysis. 
 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
33
 
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Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
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08/23/13 
 
37
16. APPENDICES  
Appendix A: Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 
1. CBTRUS. Statistical report: primary brain tumors in the United Status, 2000-2004.  Central 
Brain Tumor Registry of the United States2008. 
2. Sorensen AG, Emblem KE, Polaskova P, et al. Increased Survival of Glioblastoma Patients 
Who Respond to Antiangiogenic Therapy with Elevated Blood Perfusion. Cancer Res 
2012;72:402-7. 

Protocl Short Title: Vascular normalization in patients with recurrent glioblastoma treated with bevacizumab 
using [11C]temozolomide PET and Vascular MRI 
08/23/13 
 
38
3. di Tomaso E, Snuderl M, Kamoun WS, et al. Glioblastoma recurrence after cediranib therapy 
in patients: lack of "rebound" revascularization as mode of escape. Cancer Res 2011;71:19-28.