Clinical trial NCT01478321
Conditions: Adult Anaplastic Astrocytoma Adult Anaplastic Ependymoma Adult Anaplastic Oligodendroglioma Adult Giant Cell Glioblastoma Adult Glioblastoma
Keywords: Information Not Provided
Sponsor: Northwestern University
Start date: 2011-12-14; Completion date: 2018-09-12
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well giving hypofractionated radiation therapy together with temozolomide and bevacizumab works in treating patients with high-grade glioblastoma multiforme or anaplastic glioma. Specialized radiation therapy, such as hypofractionated radiation therapy, that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving hypofractionated radiation therapy together with temozolomide and bevacizumab may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the overall survival (OS) for patients with recurrent high grade malignant gliomas treated with concurrent radiation, temozolomide, and bevacizumab followed by adjuvant temozolomide and bevacizumab.

SECONDARY OBJECTIVES:

I. Determine the impact of this regimen on neurologic symptoms via Functional Assessment of Cancer Therapy-Brain (FACT-Br) and FACT-Fatigue scales and Eastern Cooperative Oncology Group (ECOG) performance status.

II. Determine the safety profile of this regimen. III. Determine the progression free survival (PFS) at 6 and 12 months (all patients) as well as at 3 months (bevacizumab-exposed patients only).

OUTLINE:

CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on day 0. Patients also receive temozolomide orally (PO) once daily (QD) and bevacizumab intravenously (IV) over 30-90 minutes once every 2 weeks beginning on days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months.

Arms: arm 1: CONCURRENT THERAPY: Patients undergo hypofractionated radiation therapy 5 days a week beginning on day 0. Patients also receive temozolomide PO QD and bevacizumab IV over 30-90 minutes once every 2 weeks beginning on days -3 to 0. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

ADJUVANT THERAPY: Beginning 2 weeks after completion of radiation therapy, patients receive temozolomide PO QD for 6 weeks and bevacizumab IV over 30-90 minutes once every 2 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Temozolomide intervention 2: hypofractionated radiation therapy intervention 3: bevacizumab intervention 4: questionnaire administration
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo hypofractionated radiation therapy intervention 3: Given IV intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Study of the Efficacy of Hypofractionated Radiation Therapy with 
Bevacizumab and Temozolomide Followed by Maintenance Temozolomide and 
Bevacizumab for Recurrent High-Grade Gliomas
PRINCIPAL INVESTIGATOR: 
Karan Dixit, MD
Northwestern University, Dept of Neurology
710 N Lake Shore Drive
Abbott Hall Room 1123
Chicago, IL  60611
Phone: 312-503-4724
Fax: 312-908-5073
karan.dixit@northwestern.edu   
SUB-INVESTIGATORS:
Maryanne Marymont, MD
Hannah Yoon, MD
Department of Radiation Oncology
Jeffrey Raizer, MD
Priya Kumthekar, MD
Department of Neuro-Oncology
James Chandler, MD
Kristin Swanson, PhD
Department of Neurological Surgery
PARTICIPATING SITES:
Edward Cancer Center
William Broderick, MD
120 Spaliding Drive, Suite 111
Naperville, IL  60540
Phone: 630-527-3788
wbroderick@edward.org 
University of Chicago
Steven Chmura, MD
Suite 1D, MC 9006
5758 S. Maryland Ave
Chicago, IL  60637
Phone:  773-702-6860
schmura@radonc.uchicago.edu  
Northwestern Lake Forest Hospital
Joseph Imperato, MD
660 North Westmoreland Road
Lake Forest, IL  60045
Phone: 847-535-6135
jimperato@lfh.org 
Central Dupage Hospital
Vinai Gondi, MD
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4455 Weaver Parkway
Warrenville IL 60555
Phone: 630-821-6459
Vgondi@chicagocancer.org
CDH-Delnor Health System d/b/a Cadence Health
Vinai Gondi, MD
4455 Weaver Parkway
Warrenville IL 60555
Phone: 630-821-6459
Vgondi@chicagocancer.org
BIOSTATISTICIAN: 
Alfred Rademaker, PhD
Email: rademaker@northwestern.edu
VERSION DATE:
February 5, 2019
Northwestern University
Robert H. Lurie Comprehensive Cancer Center
Clinical Research Office
676 N. St. Clair Street, Suite 1200
Chicago, IL 60611
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SYNOPSIS
Title
A Phase II Study of the Efficacy of Hypofractionated Radiation Therapy 
with Bevacizumab and Temozolomide Followed by Maintenance 
Temozolomide and Bevacizumab for Recurrent High-Grade Gliomas
Short Title
Radiation Therapy with Bevacizumab and Temozolomide for Recurrent 
Gliomas
Protocol Date
February 5, 2019, Amendment 11
Study Duration
3 years
Study Center(s)
Northwestern Memorial Hospital, Northwestern Medical Faculty 
Foundation, Edward Cancer Center, Northwestern Lake Forest Hospital, 
University of Chicago, Central Dupage Hospital, CDH-Delnor Health 
System d/b/a Cadence Health 
Objectives
To determine the efficacy of concurrent radiation therapy, 
temozolomide, and bevacizumab followed by adjuvant temozolomide 
and bevacizumab in the setting of recurrent high grade gliomas, as 
measured by overall survival.  Secondary endpoints will include 
progression free survival, toxicities, and the impact of this regimen on 
neurological symptoms. 
Number of Subjects
77 total (40 GBM bevacizumab-naïve, 25 GBM bevacizumab-exposed, 
6 anaplastic glioma bevacizumab-naïve, 6 anaplastic glioma 
bevacizumab-exposed).  
Diagnosis and Main 
Inclusion Criteria
All patients will be diagnosed with recurrent high grade gliomas 
(glioblastoma or anaplastic glioma), and will be placed into groups 1-4 
based on their histologic diagnosis and prior exposure to bevacizumab.
Treatment Summary
Patients will be given radiation therapy in 25 fractions over five weeks 
using a simultaneous integrated boost (SIB) technique.  Concurrent 
temozolomide and bevacizumab will be given during radiation therapy, 
and adjuvant temozolomide and bevacizumab will be continued until the 
time of progression or toxicity.
Analysis Summary
Data will be analyzed using Kaplan-Meier curves for survival 
endpoints. Toxicity data will be summarized descriptively.
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TABLE OF CONTENTS
Synopsis...........................................................................................................................................3
Schema.............................................................................................................................................6
1
Introduction - Background and Rationale ................................................................................7
1.1
High Grade Gliomas .........................................................................................................7
1.2
Recurrent Disease – Systemic Agents ..............................................................................7
1.3
Recurrent Disease – Re-irradiation...................................................................................9
1.4
Bevacizumab and Treatment of Radiation Necrosis.........................................................9
1.5
Rationale for the Current Trial........................................................................................10
2
Objectives...............................................................................................................................10
2.1
Primary Objective: ..........................................................................................................10
2.2
Secondary Objectives:.....................................................................................................11
3
Selection of Patients ...............................................................................................................11
3.1
Inclusion Criteria.............................................................................................................11
3.2
Exclusion Criteria ...........................................................................................................13
4
Patient Registration ................................................................................................................13
4.1
Access to the Registration Program................................................................................14
4.2
Registering a Patient .......................................................................................................14
4.3
Beginning Study Treatment ............................................................................................14
5
Treatment Plan .......................................................................................................................14
5.1
Overview.........................................................................................................................14
5.2
Administration ................................................................................................................15
5.3
Dose Modifications.........................................................................................................17
5.4
Supportive Care Guidelines & Use of Concomitant Medications ..................................22
5.5
Duration of Therapy........................................................................................................23
5.6
Follow-Up .......................................................................................................................23
6
Endpoint Assessment .............................................................................................................24
6.1
Definitions.......................................................................................................................24
6.2
Primary Endpoint ............................................................................................................24
6.3
Secondary Endpoints.......................................................................................................24
6.4
Evaluation of Response...................................................................................................25
7
Study Parameters....................................................................................................................27
8
Drug Formulation and Procurement.......................................................................................29
8.1
Temozolomide ................................................................................................................29
8.2
Bevacizumab...................................................................................................................33
9
Statistical Considerations .......................................................................................................36
9.1
Endpoints ........................................................................................................................36
9.2
Sample Size Justification & Assumptions ......................................................................36
9.3
Analysis...........................................................................................................................37
9.4
Reporting and Exclusions ...............................................................................................37
10
Adverse Event Monitoring & Reporting ............................................................................38
10.1
Adverse Event Monitoring..............................................................................................38
10.2
Definitions & Descriptions .............................................................................................39
10.3
Adverse Event Reporting................................................................................................41
11
Records to be Kept..............................................................................................................42
11.1
Patient Registration.........................................................................................................42
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11.2
Data Submission .............................................................................................................43
12
Pathology Requirements.....................................................................................................43
13
Administrative, Ethical & Regulatory Considerations .......................................................43
13.1
Conduct ...........................................................................................................................43
13.2
Amendments ...................................................................................................................43
13.3
Informed Consent............................................................................................................43
13.4
Protected Health Information..........................................................................................44
13.5
Participating Sites ...........................................................................................................44
13.6
Data Management and Monitoring/Auditing..................................................................44
13.7
Publication Policy ...........................................................................................................44
14
References...........................................................................................................................46
15
Appendices .........................................................................................................................47
15.1
Appendix I –  Data and Safety Monitoring Plan.............................................................47
15.2
Appendix II – CTCAE v 4.0 ...........................................................................................48
15.3
Appendix III – ECOG Performance Status.....................................................................49
15.4
Appendix IV – FACT-Br & FACT-Fatigue Scales ........................................................50
15.5
Appendix V – Protocol History of Changes ...................................................................51
15.6
Appendix VI – Data Collection & Submission Guidelines ............................................58
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SCHEMA
Patient identified to have 
recurrent glioblastoma or 
anaplastic glioma by imaging 
criteria or histologic analysis, 
meets eligibility criteria.
Baseline Evaluation: MRI scan, blood work (CBC, differential, comprehensive metabolic panel, 
B-HCG if applicable), urine protein: creatinine ratio, history and physical examination, neurologic 
examination and FACT-BR and FACT-fatigue scales.
Group 2: Bevacizumab-
exposed and refractory 
recurrent GBM
Group 1: Bevcizumab-
naïve recurrent GBM
Group 3: Bevacizumab 
naïve recurrent anaplastic 
glioma
Based on prior treatment and histology, 
patient placed into group 1-4
Group 4: Bevacizumab-
exposed recurrent 
anaplastic glioma
Concurrent therapy
Radiation Therapy: 25 fractions, 1st dose = day 0
Bevacizumab 10 mg/kg every 2 weeks, first dose day -3 to 0.
Temozolomide: 75 mg/m2 daily during radiation therapy, first dose day 0
Adjuvant Therapy (begins 2 weeks (+/- 7 days) after radiation therapy completion)
ONE CYCLE = 8 WEEKS
Temozolomide: 50 mg/m2 daily, 6 weeks on, 2 weeks off
Bevacizumab: 10 mg/kg every 2 weeks
Systemic treatment to be continued until progression of disease or severe toxicity
Follow up
Patients will be followed every 2-3 months (or as clinically indicated) via clinic 
visit or phone calls to assess for survival endpoints.
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1
INTRODUCTION - BACKGROUND AND RATIONALE 
1.1
High Grade Gliomas
High grade gliomas arise from astrocytes and oligodendrocytes.  The most common 
type of malignant glioma is glioblastoma (GBM), which comprises 60% of gliomas.  
Other high grade gliomas include anaplastic astrocytoma, anaplastic 
oligodendroglioma, and anaplastic oligoastrocytoma, all of which are categorized as 
anaplastic gliomas.
The prognosis of patients with these diagnoses is poor.  The overall survival (OS) rate 
for GBM is  27.2% at 2 years, 16.0% at 4 years, and 9.8% at 5 years with the standard 
treatment of surgical resection and adjuvant radiation therapy with concurrent and 
adjuvant temozolomide[1].  Patients generally undergo resection, followed by 
conformal radiation therapy (60 Gy) over 6 weeks with concurrent temozolomide 
followed by adjuvant temozolomide for a minimum of 6 months for responding 
patients.  This regimen has also been used as “standard treatment” for patients with 
other forms of high grade gliomas, despite more limited data in this setting.
Addition of bevacizumab to standard first-line therapy has been shown to improve 
progression free survival (PFS) in the phase II setting compared to historical controls, 
but level 1 evidence for its use in the up-front setting does not exist, and such use is 
currently uncommon in most centers [2, 3].  In a single-arm study, 70 patients were 
treated with daily temozolomide (75 mg/m2) and biweekly bevacizumab (10 mg/kg) 
with concurrent standard radiation therapy, followed by adjuvant temozolomide and 
bevacizumab.  Median PFS was 13.6 months in the tri-modality therapy group and 
7.6 months in a group of historical control patients [2].  Synergy of bevacizumab and 
temozolomide has been shown in several preclinical models [4-6].  Phase III studies 
of this combination in the first-line setting are currently in development.
1.2
 Recurrent Disease – Systemic Agents
1.2.1
Clinical experience
Recurrent disease is almost universal in high grade gliomas [7, 8].  The 
current standard of care for recurrent GBM employs the use of the 
antiangiogenic agent bevacizumab.  In the BRAIN study, a phase II, non-
comparative, multicenter trial of 167 patients with recurrent GBM treated 
with bevacizumab alone (n=85) or in combination with irinotecan (n=82), 
those patients who received bevacizumab alone had a response rate of 25.9% 
with median duration of response of 4.2 months and 6 month PFS of 36%[9].  
In an NCI-sponsored phase II study, 48 patients with recurrent GBM were 
treated with bevacizumab followed by bevacizumab with irinotecan at tumor 
progression.  In these patients, the response rate was 19.6 % with a median 
duration of response of 3.9 months [10].  In the recurrent setting, cytotoxic 
chemotherapy such as CPT-11 or temozolomide is frequently combined with 
bevacizumab, resulting in somewhat higher response rates, and slightly 
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longer 6 month PFS (51% with CPT-11 plus bevacizumab in the BRAIN 
trial) [9, 11].  In several trials, the median survival ranges between 6.5 and 
9.8 months  In the randomized BRAIN trial, median survival was 
approximately 9 months for both cohorts; according to the literature, the 
composite median survival for recurrent GBM is approximately 8 months.   
Attempts have also been made to salvage recurrent GBM with temozolomide 
alone [12] or in combination with bevacizumab[11], and the overall data 
suggest modest clinical activity with 6 month PFS of 23.9% with 
temozolomide alone, and 40% with the 2 agents combined.  One year OS for 
those patients treated with temozolomide alone was 14.8-28.6%, depending 
on risk stratification group.
1.2.2
Dosing & safety
Several dosing schedules for bevacizumab and temozolomide have been 
employed.  Bevacizumab has been given at 10 mg/kg every 2 weeks 
concurrent with and adjuvant to radiation therapy ([2, 9, 11]). Temozolomide 
has been dosed at 75 mg/m2 [2] concurrent with radiation therapy.  Adjuvant 
temozolomide dosing schedules have been more varied, and have included 
150-200 mg/m2/day for the first 5 days of a 28 day cycle [2, 13], as well as 
100 mg/m2/day for the first 21 days of a 28 day cycle[13].  Alteration of 
treatment schedule to continuous treatment with 50 mg/m2/day in patients 
who have recurrent disease to has been shown to be a valuable therapeutic 
option [12]. 
Toxicity with combination therapy with bevacizumab and temozolomide has 
been moderate.  The most common toxicities in the primary setting include 
cerebrovascular ischemia (9%), fatigue (20%), hypertension (11%), 
hyperglycemia (10%), hyponatremia (11%), proteinuria (11%), and venous 
thrombosis/pulmonary embolism (19%), GI bleed (3%), and GI perforation 
(3%) [2].  In the recurrent disease setting, re-challenge with temozolomide 
alone was associated with a 15.8% incidence of grade 3 lymphopenia and 
other grade 3-4 hematologic toxicities were uncommon.  The most common 
non-hematologic toxicities included grade 3-4 nausea/vomiting (6.7%) and 
fatigue (5.8%) [12]. Treatment with bevacizumab alone in the recurrent 
disease setting was associated with a 46.4% incidence of grade 3 or higher 
adverse events, most commonly hypertension (8.3%) and convulsion (6.0%), 
along with arterial thromboembolism (2.4%), venous thromboembolism 
(3.6%), and grade 3 GI perforation (2.5%) [9].  Treatment with irinotecan in 
combination with bevacizumab in the recurrent glioblastoma setting was 
associated with increased side effects as compared to bevacizumab alone, 
with 65.8% of patients experiencing grade 3 or greater adverse events, the 
most common being convulsion (13.9%), neutropenia (8.9%), and fatigue 
(8.9%).  Adverse events resulted in termination of bevacizumab treatment in 
4.8% of the bevacizumab alone treatment group and 17.7% of the 
combination therapy group [9]. 
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1.3
 
Recurrent Disease – Re-irradiation
Re-irradiation has also been investigated for patients with recurrent disease. There 
are several studies showing that radiation therapy may be delivered safely in this 
setting [14-16].  Some series suggest that those patients who receive bevacizumab 
and radiotherapy have improved response rates compared to those who receive 
either modality alone [17].  In 1 small single institution report of 25 patients (20 
recurrent GBM and 5 recurrent anapalastic gliomas) treated with bevacizumab 
and hypofractionated radiotherapy (30 Gy in 5 fractions), the response rate for 
rGBM was 50% with  6 month PFS of 65% and  median survival of 12.5 months; 
this was in a cohort of well selected patients with small volume recurrence (< 3.5 
cm maximum diameter) [17].  Table 1 summarizes the above data.
Table 1. Efficacy of treatment options for patients with recurrent GBM
Response Rate (%)
6 month PFS (%)
MS (months) 
Bevacizumab Alone
28.2[9]
42.6[9]
9.2[9]
Bevacizumab + CPT-11
37.8[9]
50.3[9]
8.7[9]
Bevacizumab + 
Chemotherapy
34.1[18]
42[18]
7.2[13]
Temozolomide Alone
23.9[12]
7.2[13]
Radiation Therapy 
Alone
34.8[15]
11[14]
Bevacizumab + 
Radiation Therapy
50[17]
65[17]
12.5[17]
Most importantly, the above trial demonstrated the safety of re-irradiation. 
Three of 25 patients discontinued treatment with bevacizumab due to grade 3 
toxicity related to bevacizumab, but no patients experienced radiation necrosis.  In 
another study of re-irradiation alone in 108 patients with pulsed reduced dose rate 
radiotherapy(to a median of 50 Gy in 1.8-2 Gy fractions), 4 of 15 patients at the 
time of autopsy had notable radiation necrosis.  No patients manifested obvious 
blindness from treatment[15].  In another group of 147 patients with recurrent 
GBM treated with hypofractionated radiation therapy (median dose 35 Gy in 3.5 
Gy fractions), no patients experienced significant acute morbidity or required 
treatment breaks.  One patient did experienc grade 3 late central nervous system 
(CNS) toxicity (headaches), but no patients required hospitalization or surgical 
intervention for toxicity [14]. 
1.4
 
Bevacizumab and Treatment of Radiation Necrosis
It is important to recognize the role of bevacizumab in treating and effectively 
reversing radiation-induced cerebral necrosis[19].  A randomized double-blind 
placebo-controlled trial with cross-over design of radiation therapy for radiation 
necrosis of the CNS involved 14 patients with radiation necrosis in the CNS with 
associated neurologic signs and symptoms.  Five of 5 patients who were 
randomized to initial treatment with bevacizumab had improvement in their 
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neurologic signs and symptoms, and 7 of 7 who were initially randomized to the 
control group had no improvement.  After crossover, all patients had symptomatic 
improvement.  Bevacizumab is thought to be effective in treatment of central 
nervous system radiation necrosis by restoring the blood brain barrier which is 
made dysfunctional by radiation therapy, causing edema and neurologic 
symptoms.
1.5
 
Rationale for the Current Trial
Based upon the modest activity of all 3 treatment modalities (bevacizumab, 
temozolomide, and radiotherapy), possible synergy as demonstrated in several 
pre-clinical models, and data supporting that the use of bevacizumab is also likely 
protective against brain necrosis, we propose to combine these in a triple modality 
approach for patients with recurrent malignant glioma.  Furthermore, the 
extensive use of this triple modality combination as first-line treatment in over 
1000 newly diagnosed GBM patients supports the exploration of this same 
combination in the recurrent setting.  
We propose to conduct a phase II trial of concurrent radiation, 
temozolomide, and bevacizumab followed by adjuvant temozolomide and 
bevacizumab in patients with recurrent high grade gliomas including GBM and 
anaplastic glioma.  Patients will be stratified into 4 groups on the basis of 
histology and prior therapy:  bevacizumab-naïve with recurrent GBM (Group 1), 
bevacizumab-exposed with refractory recurrent GBM (Group 2), bevacizumab-
naïve with recurrent anaplastic glioma (Group 3), and bevacizumab-exposed with 
recurrent anaplastic glioma (Group 4).  We will assess survival and toxicity 
endpoints for this regimen in the recurrent setting.  
Since there is no standard re-irradiation dose, and attempts to 
hypofractionate the radiation dose seems to be safe and effective, we have chosen 
a modest but safe re-irradiation dose of 45 Gy using a simultaneous integrated 
boost (SIB) technique to increase the dose per fraction to the area of recurrent 
disease[14, 15, 17].  Bevacizumab dosing and schedule in both the primary and 
recurrent disease settings have been somewhat standard; thus we will utilize this 
standard dose of 10 mg/kg biweekly throughout both treatment periods [2, 9, 11]. 
We have chosen a temozolomide dose of 75 mg/m2/day during the re-irradiation 
phase, followed by 50 mg/m2/day in the adjuvant setting, as supported by the 
above trials [2, 12].
2
Objectives 
2.1
 
Primary Objective:
The primary objective of this phase II study will be to determine the overall 
survival (OS) for patients with recurrent high grade malignant gliomas treated 
with concurrent radiation, temozolomide, and bevacizumab followed by adjuvant 
temozolomide and bevacizumab.  OS is the most appropriate endpoint for this 
trial given that response rates are very low and do not serve as a useful surrogate. 
Additionally, PFS is confounded on the MRI due to changes consistent with 
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pseudoprogression, a well-described phenomenon in this disease.
2.2
 
Secondary Objectives:
Secondary objectives will include the following:
2.2.1
Determine the impact of this regimen on neurologic symptoms via FACT-Br 
and FACT-Fatigue scales and ECOG performance status. 
2.2.2
Determine the safety profile of this regimen.
2.2.3
Determine the progression free survival (PFS) at 6 and 12 months (all 
patients) as well as at 3 months (bevacizumab-exposed patients only).
3
SELECTION OF PATIENTS
Potentially eligible patients will be identified by their treating physicians at each 
participating site; at the lead site, patients will be identified by the Neuro-Oncology 
outpatient clinic of Northwestern Medical Faculty Foundation or by the in-patient Neuro-
Oncology service of Northwestern Memorial Hospital.  Patients may also be referred to the 
Principal Investigator, Dr. Karan Dixit, at 312-695-0990, or to the local PI at each 
participating site.  
Approximately 60 patients fitting the criteria listed above are seen per year at these 
locations.  We estimate that we will accrue approximately 2-3 patients per month to this 
trial.
3.1
 
Inclusion Criteria
3.1.1
Patients must have histologically confirmed diagnosis of GBM or anaplastic 
glioma, WHO grade 3 or 4
3.1.2
Patients must have measurable or non-measurable (evaluable) disease 
recurrence.  
3.1.2.1
Recurrence must be documented based on a combination of clinical 
and imaging parameters, consistent with routine clinical practice, 
with or without histologic confirmation.
3.1.2.2
Patients may have had any number of relapses and be eligible for the 
study.
3.1.3
Patients must have been previously treated with radiation therapy and 
temozolomide (bevacizumab-naïve – Groups 1 and 3) or radiation therapy, 
temozolomide and bevacizumab (bevacizumab-exposed – Groups 2 and 4). 
Therapy with these agents may be given together or sequentially in the past.
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3.1.4
All patients may have had prior surgery, chemotherapy, and radiation 
therapy.  Prior biologic therapy is permitted only for bevacizumab-exposed 
patients (Groups 2 and 4).  Prior treatment with Gliadel is permitted for all 
groups.
3.1.5
For bevacizumab-naïve patients (Groups 1 and 3) a minimum of 6 months 
must have elapsed since completion of radiation therapy for study entry, and 
there is no minimum time since completion of last chemotherapy. For 
bevacizumab-exposed patients (Groups 2 and 4) no minimum time since 
completion of last radiation therapy, biologic agents, or chemotherapy will be 
required for study entry.
3.1.6
Patients must be 18 years or older.
3.1.7
Patients must have an ECOG performance status of ≤ 2.
3.1.8
Patients must have adequate bone marrow function (within 14 days prior to 
registration) defined as:
3.1.8.1
Hemoglobin ≥ 10
3.1.8.2
Platelets ≥ 100,000/mm3
3.1.8.3
Absolute neutrophil count ≥ 1500/mm3
3.1.9
Patients must have adequate liver function (within 14 days prior to 
registration) defined as:
3.1.9.1
Bilirubin ≤ 1.5 x upper limit of normal range
3.1.9.2
AST and ALT ≤ 3 x upper limit of normal range
3.1.10 Patients must have adequate renal function (within 14 days prior to 
registration) defined as: 
3.1.10.1 BUN and Creatinine ≤ 1.5 x upper limit of normal range
3.1.10.2 Urine protein/creatinine ratio should be ≤ 1. 
3.1.11 Patients’ baseline blood pressure must be adequately controlled with or 
without antihypertensive medications prior to enrollment (systolic < 145 
mmHg, diastolic < 90 mmHg).
3.1.12 Patients must have a baseline evaluation including history and physical 
examination with neurological evaluation and MRI of the brain (with and 
without gadolinium-based contrast), all completed within 30 days prior to 
initiation of treatment.
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3.1.13 Female patients of child-bearing potential must have a negative pregnancy 
test within 14 days prior to enrollment on study.  Child-bearing potential is 
defined as any female (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets one of the 
following criteria:
3.1.13.1 Has not undergone a hysterectomy or bilateral oophorectomy; OR
3.1.13.2 Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e. has had menses at any time in the preceding consecutive 
12 months).
3.1.14 Females of child-bearing potential and sexually-active males must consent to 
follow acceptable birth control methods to avoid contraception while on 
treatment.
3.1.15 All subjects must have given signed, informed consent prior to registration 
on study.
3.1.16 Patients previously treated outside of Northwestern must have their 
pathology slides sent to Northwestern for review and confirmation.  
NOTE:  A copy of the pathology report is sufficient for 
registration.
3.2
 
Exclusion Criteria
3.2.1
Patients who are pregnant or breast-feeding will NOT be eligible for 
participation.
3.2.2
Patients with a prior malignancy will NOT be eligible for participation aside 
from the following exception:
3.2.2.1
Patients who have had any curatively treated malignancy and have 
been disease free without treatment for 1 year prior to study entry 
ARE eligible for participation.
3.2.3
Patients with an active second malignancy (other than non-melanoma skin 
cancer or cervical cancer in situ) are NOT eligible for participation.
3.2.4
Patients with uncontrolled hypertension (≥ 145/90 mmHg) are NOT eligible 
for participation.
3.2.5
Patients who exhibit any other serious concurrent infection or other medical 
illness which would jeopardize their ability to receive the therapy outlined in 
this protocol with reasonable safety will NOT be eligible for participation.
 The eligibility criteria listed above are interpreted literally and cannot be waived.
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4
 PATIENT REGISTRATION 
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office (CRO) at Northwestern 
University before enrollment to study. Please contact the assigned Quality Assurance 
Monitor (QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration.  
4.1
 
Access to the Registration Program
Prior to registration, the eligibility checklist must be reviewed by the assigned 
QAM. The study coordinator will screen all subjects for potential registration via 
the Northwestern Oncology Trial Information System (NOTIS) using the web-
based application, which can be found at:  https://notis.nubic.northwestern.edu.  
Please note that a password is required to use this program and will be provided 
during site activation prior to training on the NOTIS system..
4.2
 
Registering a Patient
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification number:

Patient’s signed and dated informed consent form (upload to NOTIS).

Eligibility checklist (signed and dated by the treating physician – upload 
to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload in NOTIS).
Training on eCRF completion will be provided at the time of site activation. 
Please refer to the eCRF demonstration videos on the CRO website 
(https://www.cancertrials.northwestern.edu/collaborations/nu-iit-sites) for 
additional instructions on registering a patient.
4.3
 
Beginning Study Treatment
The QAM will review the registration, register the patient, assign a subject ID 
number, and send a confirmation of registration to study personnel..  Registration 
will then be complete and the patient may begin study procedures.
5
TREATMENT PLAN
5.1
Overview
This will be a phase II trial to assess the survival and toxicity associated with 
concurrent re-irradiation plus temozolomide and bevacizumab, followed by adjuvant 
temozolomide and bevacizumab in patients with recurrent high grade gliomas.  A 
total of 77 patients will be enrolled on this trial.  Patients will be stratified into 4 
groups on the basis of histological diagnosis (GBM or anaplastic glioma) and prior 
therapies received (bevacizumab-naïve or bevacizumab-exposed).  Treatment will be 
divided into 2 phases. The first phase (initial phase) will include all treatments 
(temozolomide and bevacizumab) given during (concurrently with) re-irradiation 
therapy, whereas the second phase (adjuvant phase) will consist of treatments 
(temozolomide and bevacizumab) given after re-irradiation therapy is completed.  Re-
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irradiation therapy will last for 5 weeks.  One cycle of systemic therapy in the 
adjuvant phase will be defined as 8 weeks in duration.  Cycles in the adjuvant phase 
may be spaced +/- 1 week apart. Patients will continue on adjuvant therapy until 
disease progression or removal due to toxicity.  Overall survival will be the primary 
endpoint of this phase II trial.  
5.2
Administration
5.2.1
Re-irradiation Therapy
The first day of re-irradiation therapy will be considered Day 0.  Re-
irradiation therapy will be given using a simultaneous integrated boost (SIB) 
technique, with a dose of 1.8 Gy per fraction for 25 fractions to a total dose 
of 45 Gy to the MR FLAIR abnormality (the T2 may substitute for FLAIR, if 
the FLAIR sequence is not available) as the clinical target volume (CTV), 
and simultaneously 2.2 Gy per fraction to a total dose of 55 Gy to a CTV of 
the enhancing disease on the MR MPRAGE sequence (or equivalent).  There 
will be a minimal expansion from each CTV to planning target volume 
(PTV) of at most 2mm.  At least 90% of each CTV should receive 90% of 
the prescribed dose. If standard SIB technique is not felt to be in the patient’s 
best interest due to potential toxicity, then standard fractioned EBRT at 180-
200 cGY will be used.  
It is reasonable to assume that during the initial course of radiation therapy, 
the optic nerves and chiasm would have received approximately 50 Gy.  
Therefore, no more than an additional 20 Gy to the optic nerves or chiasm 
will be permitted during re-irradiation with the caveat that the total 
cumulative dose to these structures will not exceed 70 Gy.
Please note that proton therapy is an acceptable mode of radiotherapy for this 
study.
5.2.2
Temozolomide
Temozolomide will be administered orally, at the same time each day; the 
time of day may be selected according to the patient’s and treating 
physician’s discretion.  The dose and frequency of administration will 
depend on the treatment phase (see below). Doses will be rounded to the 
nearest 5 mg.  Patients will be instructed to take temozolomide on an empty 
stomach (no food 1 hour before or 1 hour after).  Temozolomide tablets will 
be swallowed whole and may be taken with water.  Patients will take 
compazine 5-10 mg, Zofran 4-8 mg, or Kytril 1-2 mg 30-40 minutes before 
temozolomide, as necessary.  If vomiting occurs after taking temozolomide, 
the patient should not take a replacement dose on that same day.  The patient 
should resume taking temozolomide at the next scheduled dose on the 
following day.
If a dose is missed, the patient should take the dose as soon as possible, but 
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only if there are 12 or more hours remaining before the next dose is due.  If 
the next dose is due in less than 12 hours, the patient should skip the missed 
dose and take the next dose as scheduled.  Patients will be given a study diary 
to record each dose of temozolomide, as well as any missed and/or vomited 
doses.  
5.2.2.1
Initial Phase:  During Re-irradiation Therapy
Temozolomide will be administered at a dose of 75 mg/m2 per day. 
Treatment will begin on Day 0 and continue daily during re-
irradiation therapy (7 days per week for a total of 5 weeks). The last 
day of temozolomide during the initial phase of treatment will be the 
last day of re-irradiation therapy.
5.2.2.2
Adjuvant Phase:  After Re-irradiation Therapy
Temozolomide will be discontinued for 2 weeks (+/- 7 days) after re-
irradiation therapy.  Temozolomide will then be restarted at a dose of 
50 mg/m2 per day on a schedule of 6 weeks on, 2 weeks off for a 
total of 8 weeks per cycle. Subsequent cycles during this phase may 
occur +/- 1 week apart. Treatment will continue as long as there is no 
clinical or radiographic progression and no severe toxicity occurs.  
Please refer to Section 5.3 for dose delays and/or modifications to 
temozolomide.
5.2.3
Bevacizumab
Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 
2 weeks; the timing of the infusions will vary depending on the treatment 
phase (see below).  Bevacizumab will be diluted in a total volume of 100 mL 
of 0.9% sodium chloride Injection, USP.  Anaphylaxis precautions should be 
observed during drug administration.  The dose will be based on current 
weight at each dosing time point.  It is not necessary to correct dosing based 
on ideal weight.
For patients who are bevacizumab-naïve (Groups 1 and 3), the first dose will 
be delivered over a period of 30-90±15 minutes (per institutional practice).  If 
the patient has been exposed to bevacizumab prior to study entry (Groups 2 
and 4) without any infusion-associated adverse events, the first infusion may 
be delivered over a period of 30-60±10 minutes.  If a patient experiences an 
infusion-associated adverse event, he/she may be premedicated for the next 
bevacizumab administration per institutional practice.  
5.2.3.1
Initial Phase:  During Re-irradiation Therapy
The first dose of bevacizumab will be given between Days -3 and 0, 
and will continue every 2 weeks (+/- 3 days) during re-irradiation 
therapy as long as no severe toxicity occurs.
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5.2.3.2
Adjuvant Phase:  After Re-irradiation Therapy
Bevacizumab will be continued every 2 weeks, with the first 
adjuvant dose occurring approximately 2 weeks (+/- 7 days) after re-
irradiation therapy is complete.  Patients will receive 4 infusions of 
bevacizumab per cycle (1 cycle = 8 weeks).  Subsequent cycles 
during this phase may occur +/- 1 week apart. Treatment will 
continue as long as there is no clinical or radiographic progression 
and no severe toxicity occurs.
5.3
Dose Modifications
All toxicities will be assessed according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version 4.0.
5.3.1
Temozolomide
5.3.1.1
Initial Phase Delays/Modifications
There will be no reductions to the temozolomide dose during the 
initial treatment phase.  However, during re-irradiation therapy, dose 
delays may occur for specified toxicities (as noted below) for up to 7 
days.  Toxicity will be assessed weekly during the initial phase of 
treatment; assessment may occur more frequently as needed.
Temozolomide may be held for up to 7 days if any of the following 
is experienced during the initial phase:
5.3.1.1.1 Febrile neutropenia (any grade)
5.3.1.1.2 Grade 3 hematologic toxicity that, in the opinion of the 
investigator, is trending downward and has potential for 
further myelosuppression  
5.3.1.1.3 Grade 4 hematologic toxicity (including a platelet count 
of < 25,000/mm3)
5.3.1.1.4 Any grade 3 or higher non-hematologic toxicity 
considered by the investigator to be related to 
temozolomide. 
Please refer to Section 5.3.1.3 for conditions for re-starting 
temozolomide.  NOTE:  Dose interruption or study discontinuation
is not required for lymphopenia of any grade.
5.3.1.2
Adjuvant Phase Delays/Modifications
During the adjuvant treatment phase, temozolomide will be given in 
8-week cycles (daily administration for the first 6 weeks followed by 
2 weeks off).  Assessment of toxicity will occur prior to initiation of 
each cycle during the adjuvant phase; assessment may occur more 
frequently if toxicity occurs as noted below.
New cycles may be delayed up to 4 weeks if any of the following 
occurs:
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5.3.1.2.1 Febrile neutropenia
5.3.1.2.2 Grade 3 hematologic toxicity that, in the opinion of the 
investigator, is trending downward and has potential for 
further myelosuppression  
5.3.1.2.3 Grade 4 hematologic toxicity excluding lymphopenia 
(including a platelet count of < 25,000/mm3)
5.3.1.2.4 Any grade 3 or higher non-hematologic toxicity 
considered by the investigator to be related to 
temozolomide.  
Please refer to Section 5.3.1.3 for conditions for re-starting 
temozolomide.  NOTE:  Dose interruption or study discontinuation 
is not required for lymphopenia of any grade.  
During the period that the treatment is delayed due to hematologic 
toxicity, the CBC will be repeated 1-2 times per week until the 
conditions for re-starting temozolomide are met.  The temozolomide 
dose will then be reduced by 20% when it is re-started.  Patients will 
be allowed up to 2 dose reductions by 20%; after 2 reductions, 
patients will be removed from the study due to toxicity.
Patients who require a toxicity-related treatment delay of > 4 weeks 
will also be removed from the trial.  Patients who experience 
persistent grade 3 or higher hematologic or non-hematologic 
toxicity with a temozolomide dose of 50 mg/m2 will be discontinued 
from the study.
5.3.1.3
Conditions for Re-starting Temozolomide
A new cycle of temozolomide therapy may begin when:
5.3.1.3.1 All drug-related non-hematologic toxicity (≥ grade 3) has 
resolved to ≤ grade 1
5.3.1.3.2 Patients with abnormal liver (AST/ALT/bilirubin) and 
renal function at baseline may receive treatment if the 
values have not risen by more than 1.5 x the upper limit 
for protocol eligibility
5.3.1.3.3 Hematologic toxicity has recovered to ANC ≥ 1500/mm3, 
platelet count ≥ 100,000/mm3, and Hgb >10 (may be 
given a transfusion to get > 10)
5.3.2
Bevacizumab
There will be no reductions to the dose of bevacizumab.  There will be no 
difference in dosing between the initial and adjuvant phases of treatment for 
bevacizumab.  If adverse events occur that require holding bevacizumab, the 
dose will remain the same once treatment resumes.  Treatment may resume 
when all toxicities have resolved to ≤ grade 1. Up to 2 scheduled doses of 
bevacizumab may be missed, but treatment may not be held for > 6 weeks 
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due to toxicity.  Please refer to Table 2 for adverse events requiring delays or 
permanent discontinuation of bevacizumab treatment.  Regardless of the 
reason for holding bevacizumab treatment, the maximum allowable length of 
bevacizumab treatment interruption is 6 weeks.
Any toxicities related or possibly related to bevacizumab treatment should be 
managed according to standard medical practice.  Discontinuation of 
bevacizumab will have no immediate therapeutic effect.  Bevacizumab has a 
terminal half-life of 21 days; therefore, its continuation results in slow 
elimination over several months.  There is no available antidote for 
bevacizumab.
Patients will be assessed clinically for toxicity prior to, during, and after each 
infusion.  If unmanageable toxicity occurs because of bevacizumab at any 
time during the study, treatment with bevacizumab should be discontinued.  
Please refer to Table 2 below for guidelines regarding management of 
bevacizumab with regards to adverse events.
 
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Table 2:  Bevacizumab dose management due to adverse events
Event
Grade
Action to be Taken
1 or 2
No dose modification required.
3
If not controlled to 150/100 mm/Hg with medication, 
discontinue bevacizumab. 
Hypertension
4 (including hypertensive 
encephalopathy)
Discontinue bevacizumab.
1 or 2
No dose modification required.
Hemorrhage: non-pulmonary & non-CNS events
3
Patients who are also receiving full-dose anticoagulation: 
discontinue bevacizumab.
All other patients:  hold bevacizumab until all of the 
following criteria are met:

Bleeding is resolved and Hgb is stable.

There is no bleeding diathesis that would increase 
the risk of therapy.

There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence.
Patients who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from bevacizumab.
(cont)  Hemorrhage: non-pulmonary & non-CNS events
4
Discontinue bevacizumab.
1
Patients who are also receiving full-dose anticoagulation: 
discontinue bevacizumab.
All other patients:  hold bevacizumab until all of the 
following criteria are met:

Bleeding is resolved and Hgb is stable.

There is no bleeding diathesis that would increase 
the risk of therapy.

There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence.
Hemorrhage: pulmonary or CNS
2, 3, or 4
Discontinue bevacizumab.
1 or 2
 No dose modification required.
Venous thrombosis
3 or 4
Hold bevacizumab.
If the planned duration of full-dose anticoagulation is < 2 
weeks, hold bevacizumab until the full-dose period is over. 


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If the planned duration of full-dose anticoagulation is > 2 
weeks, resume bevacizumab during the full-dose period if 
all of the following criteria are met:

The patient has an in-range INR if on warfarin; 
anticoagulant dosing must be stable prior to 
restarting bevacizumab treatment.

The patient must not have had a Grade 3 or 4 
hemorrhagic event while on anticoagulation.
Arterial thromboembolic event (new onset, worsening, or unstable 
angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, or any other arterial thromboembolic event)
Any grade
Discontinue bevacizumab.
1 or 2
No dose modifications required.
Congestive heart failure (left ventricular systolic dysfunction)
3 or 4
Discontinue bevacizumab.
1 or 2
No dose modifications required.
3 (UPC > 3.5, urine 
collection > 3.5 g/24 hr)
Hold bevacizumab treatment until ≤ Grade 2, as determined 
by either UPC ration ≤3.5 or 24 hr collection ≤ 3.5 g.
Proteinuria
4 (nephrotic syndrome)
Discontinue bevacizumab.
GI perforation
Any grade
Discontinue bevacizumab.
Any grade (TE fistula)
Discontinue bevacizumab.
Fistula
Other Grade 4 fistula
Discontinue bevacizumab.
1
Continue bevacizumab for partial obstruction NOT 
requiring medical intervention.
2
Hold bevacizumab for partial obstruction requiring medical 
intervention – resume upon complete resolution.
Bowel obstruction
3 or 4
Hold bevacizumab for complete obstruction.
If surgery is necessary, patient may restart bevacizumab 
after full recovery from surgery if within allowed time 
frame and at the investigator’s discretion.
Wound dehiscence
Any grade (requiring 
medical or surgical therapy)
Discontinue bevacizumab.
Reversible posterior leukoencephalopathy
Any grade (confirmed by 
MRI)
Discontinue bevacizumab.
Grade 3
Hold bevacizumab until recovery to ≤ Grade 1.
Other unspecified bevacizumab-related adverse events
Grade 4
Discontinue bevacizumab.


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5.3.2.1
Infusion reactions
Infusion of bevacizumab should be interrupted for subjects who 
develop dyspnea or clinically significant hypotension.  Patients who 
experience Grade 3 or 4 allergic reaction/hypersensitivity, adult 
respiratory distress syndrome, or bronchospasm (regardless of grade) 
will be discontinued from bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for 
patients who experience any infusion-associated symptoms not 
specified above.  When symptoms have completely resolved, the 
infusion may be continued at no more than 50% of the rate prior to 
the reaction and increased in 50% increments every 30 minutes if 
well-tolerated.  Infusions may be restarted at the full rate during the 
next infusion.
5.3.3
Radiation Therapy
There will be no dose modifications to the radiation therapy treatment 
regimen.
5.4
 
Supportive Care Guidelines & Use of Concomitant Medications
All medications taken during study participation, including reasons for use, will 
be recorded in the appropriate eCRF.  For all subsequent visits, all concomitant 
therapy that is continuing or has been added, discontinued, or had a dosage 
change since the previous visit must also be recorded.
5.4.1
Antiemetic therapy may be used as needed will be recorded.  Compazine 5-
10 mg may be taken 30-40 minutes prior to temozolomide administration.  
Alternately, Zofran 4-8mg or Kytril 1-2 mg may be used if nausea persists.
5.4.2
Hematopoietic growth factors (G-CSF) may be used per ASCO guidelines 
and at the investigator’s discretion.
5.4.3
Prophylactic antibiotics for Pneumocystis carinii pneumonia (PCP) may be 
used for patients who are on corticosteroids.  Options include Bactrim DS, 1 
tablet 2x/week, Dapsone 50 mg/day, or inhaled Pentamidine 300 mg in 6 mL 
of sterile water by aerosol every 4 weeks. 
5.4.4
Corticosteroids should be used in the smallest dose to control symptoms of 
cerebral edema and mass effect, and should be discontinued if possible.
5.4.5
Anti-seizure medications should be used as indicated.
5.4.6
Febrile neutropenia may be managed according to the institution’s 
infections disease/ASCO guidelines.  Measures may include appropriate 
laboratory testing (including blood and urine cultures) and the institution of 
broad-spectrum antibiotics.  If a source for the fevers is not identified or the 
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fever resolves when the neutrophil count recovers, antibiotics may be 
discontinued and the patient observed.  In this case, growth factors may be 
used.
5.4.7
If neurosurgical intervention is required for indications not related to tumor 
progression, these procedures must be documented, including indications for 
surgery, surgical operative note, and pathology report. 
5.4.8
Other therapies considered necessary for the well-being of the patient may 
be given at the discretion of the investigator.  
5.4.9
Any use of complementary or alternative medications should be cleared 
by the Principal Investigator.
5.5
Duration of Therapy
Patients will undergo approximately 5 weeks of concurrent re-irradiation therapy, 
temozolomide, and bevacizumab.  Following this initial treatment phase, patients will 
receive adjuvant temozolomide and bevacizumab until clinical or radiologic disease 
progression or severe or intolerable toxicity as previously described.  Patients will be 
evaluated weekly during the initial phase, and monthly during the adjuvant phase 
until disease progression or discontinuation due to toxicity.  
5.5.1
Criteria for Discontinuation of Treatment
5.5.1.1
Clinical or radiographic disease progression. Patients will be treated 
clinically as indicated thereafter and will be tracked for survival.
5.5.1.2
Severe toxicity in which continuing treatment poses a safety risk.  
Please refer to Sections 5.3.1 and 5.3.2 for additional guidelines 
concerning treatment discontinuation due to toxicity.  
5.5.2
Criteria for Withdrawal from Study
Patients who discontinue treatment for any reason, but have demonstrated 
stable disease or response from treatment, will be followed on study until 
disease progression unless one of the following occurs:
5.5.2.1
The patient or his/her legally authorized representative requests to 
discontinue protocol therapy or withdraws consent.
5.5.2.2
The decision is made by the treating physician to remove the patient 
from study due to patient non-compliance or lack of follow-up.
5.6
Follow-Up
Long-term follow-up after treatment discontinuation will occur every 2-3 months (or 
as clinically indicated) via clinic visit or phone calls; follow-up will continue until 
death to assess for survival endpoints.
Note: As of December 31, 2018, patients will no longer be followed and follow up 
information will not be collected.
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6
ENDPOINT ASSESSMENT
Response to therapy will require completion of the initial phase of therapy (consisting of 
concurrent re-irradiation, temozolomide, and bevacizumab) with a follow up MRI scan that 
can be compared to the pre-treatment scan.  Tumor measurements and assessments will be 
based on Updated Response Assessment Criteria of High Grade Gliomas- Neuro-Oncology 
Working Group (RANO criteria).  Tumor assessments may include either a CT or MRI scan 
of the brain, however the same method should be used throughout the treatment period for 
each patient.
6.1
Definitions
6.1.1
Measurable Disease
Measurable disease is defined as bi-dimensionally measurable lesions with 
clearly defined margins by CT or MRI scan and 2 perpendicular diameters of 
at least 10 mm.
6.1.2
Nonmeasurable Disease (Evaluable disease)
Nonmeasurable disease is defined as either uni-dimensionally measurable 
lesions, masses with margins not clearly defined, or lesions with maximal 
perpendicular diameters less than 10 mm.
6.1.3
Overall Survival  
Overall survival (OS) will be defined as the time from first re-irradation 
treatment until death from any cause.  
Note: As of December 31, 2018, patients will no longer be followed and 
follow up information will not be collected.
6.1.4
Progression Free Survival
Progression free survival (PFS) will be defined as the time from the first 
study treatment to the first occurrence of disease progression or death.
Note: As of December 31, 2018, patients will no longer be followed and 
follow up information will not be collected.
6.2
Primary Endpoint
The primary objective is to determine the OS of patients on this study.  Please refer to 
Section 6.1 for definition.  
6.3
Secondary Endpoints
6.3.1
Change in neurological status
One secondary objective of this study is to determine the change in 
neurological status associated with this treatment regimen in this population.  
This will be assessed in several ways:
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6.3.1.1
Examination
Changes in neurological and physical exam, as compared to baseline 
assessment.
6.3.1.2
Patient-reported outcomes 
FACT-BR and FACT-fatigue scales will be obtained at baseline 
(pre-therapy) and at the time of each subsequent MRI or CT scan.
6.3.1.3
Performance Status
Patients will be graded according to ECOG Performance Status, at 
baseline, weekly during the initial phase of treatment, and then 
monthly during adjuvant treatment.
6.3.2
Safety profile
Another secondary objective is to determine the safety profile of this tri-
modality approach.  Toxicity will be assessed using the NCI CTCAE version 
4.0 criteria (see appendices).  Toxicity assessments will occur weekly during 
the initial phase of treatment, and then prior to the start of each cycle during 
the adjuvant phase of treatment.  Assessments may occur more frequently if 
needed.
6.3.3
Determine the PFS
PFS will be calculated at the 6 and 12 month time points for all patients.  For 
the bevacizumab-exposed patients (Groups 2 and 4), PFS will also be 
calculated at the 3 month timepoint.  Please refer to 6.4 below for evaluation 
of response.
6.4
Evaluation of Response
Response will be evaluated using RANO criteria. If there are multiple contrast-
enhancing lesions, a minimum of the 2 largest lesions should be measured, and the 
sum of the products of the perpendicular diameters of these lesions should be 
determined. A maximum of 5 of the largest lesions may be measured; the largest 
enlarging lesion(s) should be selected, with emphasis placed on lesions that allow 
reproducible repeated measurements.
For patients with recurrent disease who have multiple lesions of which only 1 or 2 are 
increasing in size, the enlarging lesions should be considered the target lesions for 
evaluation of response. The other lesions will be considered nontarget lesions and 
should also be recorded. Rarely, unequivocal progression of a nontarget lesion 
requiring discontinuation of therapy or development of a new contrast enhancing 
lesion may occur, even in the setting of stable disease or partial response in the target 
lesions. These changes would qualify as progression.  Please refer to Table 3 below 
for response criteria and categories.
Table 3:  Evaluation of Response by RANO Criteria
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Response Category
Criterion
CR
PR
SD
PD
T1 gadolinium 
enhancing disease
None
≥ 50% ↓
< 50% ↓ but < 25% ↑
≥ 25% ↑
T2/FLAIR
Stable or ↓
Stable or ↓
Stable or ↓
↑
New lesion
None
None
None
Present1
Corticosteroids
None
Stable or ↓
Stable or ↓
n/a
Clinical status
Stable or ↑
Stable or ↑
Stable or ↑
↓
Requirement for 
response
All
All
All
Any1
1 Progression occurs when this criterion is present
↓ = decreased, ↑ = increased, CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease—If PD is unclear based on white matter changes, patients may be kept on trial
6.4.1
Pseudo-progression & Continuation of Treatment
Due to possible radiation effects using large dose per fraction, the initial scan 
1 week following RT should NOT be used to declare progression. In the 
absence of neurologic worsening OR a new distant area of tumor, the initial 
post-radiation scan should not be used to declare progression. Progressive 
worsening on subsequent imaging studies usually distinguishes true 
progression from pseudo-progression. If true progression is determined by 
subsequent imaging, then the date of progression returns to the earlier date 
with increasing mass. 
In the event that the radiographic changes are equivocal and it is unclear 
whether the patient is stable or has developed progressive disease, it is 
permissible to continue treatment and observe the patient closely, for 
example at 4 weekly intervals. If subsequent imaging studies demonstrate 
that progression has occurred, the date of progression should be the scan at 
which this issue was first raised.
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7
STUDY PARAMETERS
Screening1
Initial Phase4
Treatment
Break7
Adjuvant Phase Cycles (1 
cycle =8 weeks)
End of 
Treatment 
Visit17
Follow-
Up19
Baseline
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
D1 of each 
cycle
W3, W5, W7
Re-irradiation5
X
Temozolomide
X6
X8
Bevacizumab
X9
X9
X9
X10
X10
Informed consent
X
Neurologic & physical 
examination & ECOG 
PS
X2, 3
X3
X
X
Monthly during each 8 week 
cycle
X
Vital Signs15
X
X
X
X
X
X
X
X
MRI with contrast or 
CT
X11
X11
X11
X
Hematology12
X 2, 3
X3
X
X
X
X
Chemistries13
X
Urine 
protein/creatinine ratio
X
X18
X18
X
Urine Dip
X18
X18
X18
X18
Pregnancy test 14
X
FACT-BR and FACT-
fatigue scales16
X
X
X
X
Symptom and toxicity 
assessment
X
X
X
X
Survival Follow-up
X
1 Unless otherwise noted, screening assessments must be done within 14 days prior to registration.
2 Baseline examination must be done within 30 days of registration and will also include medical history and documentation of concomitant medications.
3 If screening labs and history/physical were performed within 14 days prior to the first dose of bevacizumab, they do not need to be repeated.
4 The initial phase of treatment will last approximately 5 weeks, and will begin with Day 0.  
5 Re-irradiation will begin on Day 0 and will consist of a dose of 45 Gy using a simultaneous integrated boost (SIB) technique; re-irradiation will consist of 25 
fractions given over 5 weeks. 
6 Temozolomide will be administered orally at a dose of 75 mg/m2 during the initial phase; temozolomide will begin on Day 0 and will continue daily 
throughout the initial phase (7 days/week for 5 weeks).  Patients will take compazine 5-10 mg, Zofran 4-8 mg, or Kytril 1-2 mg 30-40 minutes before 
temozolomide, as necessary.
7 There will be a 2 week (+/- 7 days) treatment break between the initial and adjuvant phases.


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8 Temozolomide will be administered orally at a dose of 50 mg/m2 per day on a schedule of 6 weeks on, 2 weeks off for a total of 8 weeks per cycle during the 
adjuvant phase; treatment will continue until disease progression or discontinuation due to toxicity. Cycles during the adjuvant phase may be spaced 
+/- 1 week apart.
9 Bevacizumab will be administered at a dose of 10 mg/kg IV; the 1st dose will occur between Days -3 and 0, and will continue every 2 weeks (+/- 3 days) 
during the initial phase.  
10 Bevacizumab will continue at a dose of 10 mg/kg IV every 2 weeks for a total of 4 infusions per cycle (1 cycle = 8 weeks) during the adjuvant phase; 
treatment will continue until disease progression or discontinuation due to toxicity. Cycles during the adjuvant phase may be spaced +/- 1 week apart.
11 MRI/CT will be performed at baseline (within 30 days of registration), after the initial phase of treatment (approximately 1 week after the last dose of re-
irradiation therapy), and then on Day 1 or within 7 days prior to each cycle of therapy during the adjuvant phase (1 cycle = 8 weeks).  The same 
method of assessment should be used throughout for each patient.
12 CBC with platelets and differential
13 Comprehensive metabolic panel
14 Females of child-bearing potential must have a negative serum or urine pregnancy test within 14 days of registration.
15 Baseline vitals will include height, weight, BSA, B/P, pulse and temperature.  All vitals during treatment will include weight, BSA, B/P, pulse and 
temperature.  
16 FACT BR and FACT-fatigue scales will be completed at baseline (within 14 days prior to registration) and then on D1 of each adjuvant cycle
17 At time of treatment discontinuation (for any reason), patients will have final round of assessments; This is referred to as the end of treatment visit.  
18 Reflex UPC is required on Day 1 of Initial Phase. Urine dip may be performed thereafter during the Initial Phase on weeks when the patient is scheduled to 
receive bevacizumab (Weeks 3 and 5). If urine dip is < 2, treatment may proceed; if dip is ≥ 2, reflex UPC should be performed and results should be 
< 3.5 to proceed with treatment. Reflex UPC will be performed during the treatment break and during Week 1 of each cycle during the Adjuvant 
Phase. Urine dip may be performed prior to subsequent bevacizumab treatments during each cycle in the Adjuvant Phase. If urine dip is < 2, 
treatment may proceed; if dip is ≥ 2, reflex UPC should be performed and results should be < 3.5 to proceed with treatment.
19Patients will be followed at least once every 3 months (or as clinically indicated) via clinic visit or phone calls to assess for survival endpoints until death or 
patient is considered lost-to follow-up.  Note: As of December 31, 2018, patients will no longer be followed and follow up information will not 
be collected.  


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8
DRUG FORMULATION AND PROCUREMENT
8.1
Temozolomide
8.1.1
Other Names
Temodar®, TMZ, Temodal®, methazolastone
8.1.2
Classification – type of agent
Temozolomide is an oral cytotoxic alkalyting agent.
8.1.3
Mode of Action
Temozolomide is not directly active but undergoes rapid non-enzymatic 
conversion at physiologic pH to the reactive compound MTIC.  The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA.  
Alkylation (methylation) occurs mainly at the O6 and N7 positions at 
guanine.  It has demonstrated activity against breast, ovarian, non-small 
cell lung, renal cell, colon, prostate and pancreatic cancer as well as 
melanoma and malignant glioma.
8.1.4
Storage and Stability
Temozolomide capusles are packaged in amber glass bottles and should 
be stored at 25°C (temperature excursions between 15-30°C are 
permitted).  Refer to the product label for storage and stability 
information.  
8.1.5
Protocol Dose
The dose for the initial (re-irradiation) phase of treatment will be 75 
mg/m2 taken orally starting on Day 0 (1st day of re-irradiation treatment).  
Administration will continue throughout the initial phase (7 days/week for 
5 weeks) followed by a 2 week (+/- 7 days) treatment break.  
Administration will resume during the adjuvant phase of treatment at a 
dose of 50 mg/m2 per day on a schedule of 6 weeks on and 2 weeks off 
for a total of 8 weeks per cycle.  Please refer to Section 5.3 for any 
applicable dose modifications.
8.1.6
Preparation
Temozolomide is supplied in white opaque, preservative-free capsules in 
a variety of dosage strengths.  Doses should be rounded to the nearest 5 
mg.
8.1.7
Protocol Administration
Temozolomide will be administered orally at the same time each day.  
Capsules should be swallowed whole with a glass of water.  Absorption is 
affected by food, so patients will be instructed to fast before and after.  
Temozolomide may be administered on an empty stomach or at bedtime 
to reduce nausea and vomiting.  A dose should not be repeated if vomiting 
occurs after administration.  Capsules should not be opened or chewed.  
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Contact with skin should be avoided if capsules are accidentally opened 
or damaged.
8.1.8
Incompatibilities
Administration of valproic acid decreases oral clearance of temozolomide 
by about 5%.  The clinical implication of this effect is not known.
8.1.9
Availability
Temozolomide is FDA-approved for the treatment of anaplastic 
astrocytoma and GBM.  Locally-obtained, commercial supplies of 
temozolomide will be prescribed for this study (study will not provide this 
drug).   
8.1.10 Side Effects
Side effects, according to the product information, may include:
8.1.10.1 Cardiovascular
Peripheral edema was reported in 11% of patients receiving 
temozolomide in clinical trials. 
8.1.10.2 Dermatologic
Alopecia, rash and pruritus are described with the administration 
of temozolomide.  Alopecia (grade 1 or 2) occurred in 9% of 
malignant melanoma patients receiving the 5-day regimen of 
temozolomide in 1 trial.  Skin rashes may infrequently occur 
following therapeutic administration of temozolomide.  Skin rash 
with pruritus has been described occasionally during oral therapy 
with temozolomide. 
8.1.10.3 Endocrine/Metabolic
One case report describes ovarian suppression in a patient who 
received temozolomide.  Hypercalcemia has been reported in 
approximately 1% of patients with the 5-day regimen of 
temozolomide. 
8.1.10.4Gastrointestinal Effects:  
Constipation (incidence up to 33%) is described with the 
administration of temozolomide.  Gastrointestinal bleeding, 
presumably related to thrombocytopenia, has been reported rarely 
with temozolomide therapy.  Diarrhea and dysphagia have been 
reported in up to 16% of patients with temozolomide therapy.  
Nausea and vomiting occur in up to 75% of patients with 
temozolomide therapy, but is not usually severe (mostly grade 1 
or 2); standard antiemetics have been effective in most patients.  
Less frequent adverse effects have included mucositis (up to 
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20%), stomatitis, anorexia (up to 40%) are described with the 
administration of temozolomide.  
8.1.10.5
Hematologic
Anemia has been reported following therapeutic administration of 
temozolomide, and may be secondary to gastrointestinal 
bleeding.  Anemia frequently coexists with neutropenia and 
thrombocytopenia, although it is generally less frequent and 
severe. Very rare cases of myelodysplastic syndrome and 
secondary malignancies, including myeloid leukemia have been 
observed.
8.1.10.6 Hepatic
Mild transaminitis (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 cases 
of overt hepatotoxicity. Elevated hepatic enzymes are described 
with the administration of temozolomide. 
8.1.10.7Neurologic
During a phase I clinical trial of temozolomide in pediatric 
patients with advanced cancer, 14% of patients (n=16) reported 
mild to moderate ataxia.  Headache is among the most commonly 
reported adverse effects with the use of temozolomide in clinical 
trials; headache has been reported in 41% of patients, with 6% of 
those patients experiencing a grade 3/4 headache, following 
temozolomide administration during a clinical efficacy trial.  
CNS effects occurring in greater than 5% of patients in clinical 
trials include anxiety, depression, insomnia, convulsions, 
paresis/hemiparesis, dizziness, coordination or gait disturbance, 
amnesia, paresthesia, somnolence, and ataxia. Causality is 
uncertain in many patients due to the underlying disease or other 
factors (eg, glioma, other drug therapy).  Transient neurologic 
deterioration was estimated to have occurred in approximately 
2% of temozolomide-treated patients (Rosenthal et al, 2002).  
Seizures were reported in 23% of patients, with anaplastic 
astrocytoma, who received temozolomide during a clinical trials 
(n=153), however it is unclear whether the seizures were drug-
related or as a consequence of the patients' underlying disease.
8.1.10.8  Psychiatric
Anxiety, depression, and insomnia are described with the 
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administration of temozolomide. 
8.1.10.9 Renal
Urinary tract infection and increased urinary frequency were 
reported in 8% and 6%, respectively, of patients receiving 
temozolomide in clinical trials.
8.1.10.10 Reproductive
Testicular function may be affected with the administration of 
temozolomide. 
8.1.10.11 Respiratory
Upper respiratory tract infections, including pharyngitis, 
sinusitis, and rare cases of Pneumocystis carinii pneumonia 
(PCP) have been reported with the use of temozolomide.
8.1.10.12 Fatigue
Fatigue is among the most commonly reported adverse effect 
(34%) with the use of temozolomide in clinical trials, and is 
clearly drug-related.  Fatigue with temozolomide therapy may 
be moderate to severe.
8.1.10.13
Infections disease
Opportunistic infections (eg, Pneumocystis carinii pneumonia 
(PCP)) have been reported rarely with the use of temozolomide
8.1.10.14 Teratogenicity/Effects in Pregnancy/Breastfeeding: 
There is positive evidence of human fetal risk, but the benefits 
from use in pregnant women may be acceptable despite the risk 
(e.g., if the drug is needed in a life-threatening situation or for a 
serious disease for which safer drugs cannot be used or are 
ineffective).  It is unknown if temozolomide crosses the 
placenta.  Adequate, well-controlled studies have not been 
conducted in humans.  Due to potential for adverse effects in 
the fetus, women of childbearing potential should be advised 
against becoming pregnant while taking temozolomide and in 
the 6 months following the end of treatment.  For breastfeeding 
women, the Thomson Lactation Rating indicates that infant risk 
cannot be ruled out.  The available evidence and/or expert 
consensus is inconclusive or is inadequate for determining 
infant risk when used during breastfeeding. 
8.1.11 Nursing implications
Monitor CBC carefully and report any significant changes to the treating 
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physician.  Instruct patients to report signs/symptoms of infection, 
unusual bruising and bleeding to health care team.
Instruct patients to report any fever, cough, chest pain, or other signs of 
infection to the health care team.
Advise patients that a mild-moderate rash may be experienced.
Work with patients in energy conserving lifestyle methods to combat 
fatigue.
Encourage patients to increase fluid intake.  Administer stool softeners or 
laxatives as ordered and monitor for their effectiveness.
8.2
Bevacizumab
8.2.1
Other Names
Avastin
8.2.2
Classification – type of agent  
Bevacizumab is a vascular endothelial growth factor- specific 
angiogenesis inhibitor.
8.2.3
Mode of Action
Bevacizumab binds VEGF and prevents the interaction of VEGF to its 
receptors (Flt-1 and KDR) on the surface of endothelial cells.  The 
interaction of VEGF with its receptors leads to endothelial cell 
proliferation and new blood vessel formation in in vitro models of 
angiogenesis.  Administration of bevacizumab to xenotransplant models 
of colon cancer in nude (athymic) mice caused reduction of 
microvascular growth and inhibition of metastatic disease progression.
8.2.4
Storage and Stability
Upon receipt of the study drug, vials are to be refrigerated at 
2°C–8°C (36°F–46°F) and should remain refrigerated until just 
prior to use.  DO NOT FREEZE.  DO NOT SHAKE.   Vials 
should be protected from light.  Opened vials must be used 
within 8 hours.   VIALS ARE FOR SINGLE USE ONLY. 
Vials used for 1 subject may not be used for any other subject.  
Once study drug has been added to a bag of sterile saline, the 
solution must be administered within 8 hours.
8.2.5
Protocol Dose
Bevacizumab will be administered at a dose of 10 mg/kg every 2 
weeks (+/- 3 days).  The first dose will occur between Days -3 
and 0 during the initial phase of study treatment.  During the 
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adjuvant phase of treatment, there will be 4 infusions per cycle.
8.2.6
Preparation
Bevacizumab will be diluted in a total volume of 100 mL of 
0.9% Sodium Chloride Injection, USP.
8.2.7
Protocol Administration:  
Administration will be as an intravenous infusion.
8.2.8
Incompatibilities
Bevacizumab should not be diluted in dextrose.
8.2.9
Availability
Bevacizumab is commercially available and will not be provided 
by the study.
8.2.10 Side Effects
8.2.10.1 Allergy/Immunology
Allergic reaction/hypersensitivity. infusion-related 
reactions.
8.2.10.2 Blood/Bone marrow
Leukopenia, neutropenia, thrombocytopenia
8.2.10.3 Cardiac
Hypertension/hypertensive crisis, cardiac
ischemia/infarction, supraventricular arrhythmia, left 
ventricular dysfunction (congestive heart failure), 
hypotension, syncope
8.2.10.4 Constitutional symptoms
Asthenia, fever, rigors/chills, weight loss
8.2.10.5 Dermatology/skin
Exfoliative dermatitis, complications with wound 
healing, rash, skin ulceration, urticarial
8.2.10.6 Gastrointestinal
GI perforation and wound dehiscence, sometimes 
complicated by intra-abdominal abscesses, large bowel 
leakage, GI fistula, intestinal obstruction, intestinal 
necrosis, mesenteric venous occlusion, colitis, 
mucositis/stomatitis, nausea, vomiting, anorexia, 
constipation, diarrhea, heartburn/dyspepsia, dry mouth, 
taste disturbance.
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8.2.10.7 Hemorrhage/Bleeding
Life-threatening or fatal pulmonary hemorrhage 
(primarily in lung cancer patients), CNS bleeding, GI 
hemorrhage, subarachnoid hemorrhage, hemorrhagic 
stroke, epistaxis (nose bleeds), vaginal bleeding, gum 
bleeding.
8.2.10.8 Infection
Infection with normal ANC.
8.2.10.9 Metabolic
Increased:  alkaline phosphatase, ALT(SGPT), AST 
(SGOT), bilirubin, serum creatinine.  Hyponatremia and 
hypokalemia.
8.2.10.10 Neurology
Cerebrovascular ischemia, dizziness, abnormal 
gait, confusion.
8.2.10.11 Ocular
Excessive lacrimation.
8.2.10.12 Pain
Abdominal pain, chest/thoracic pain, headache, 
arthralgias, myalgias, generalized.
8.2.10.13 Pulmonary/Upper respiratory
Dyspnea, cough, bronchospasm/wheezing, voice 
changes (hoarseness).
8.2.10.14 Renal/Genitourinary
Proteinuria, nephrotic syndrome
8.2.10.15 Vascular
Life-threatening and potentially fatal arterial 
thromboembolic events: cerebral infarction,transient 
ischemic attacks, myocardial infarction, angina. 
Venous thromboembolic events: deep vein 
thrombosis, intra-abdominal thrombosis
8.2.10.16 Reversible Posterior Leukoencephalopathy Syndrome  
There have been rare reports of bevacizumab-treated 
patients developing signs and symptoms that are 
consistent with RPLS, a rare neurologic disorder that 
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can present with the following signs and symptoms 
(among others):  seizures, headache, altered mental 
status, visual disturbance, or cortical blindness, with 
or without associated hypertension.  Brain imaging is 
mandatory to confirm the diagnosis of RPLS.  In 
patients who develop RPLS, treatment of specific 
symptoms, including control of hypertension, is 
recommended along with discontinuation of 
bevacizumab.  The safety of reinitiating bevacizumab 
therapy in patients previously experiencing RPLS is 
not known. [34,35].
8.2.11 Nursing Implications
Monitor CBC and platelets. 
Monitor patient closely during infusion, for infusion related 
events and for bleeding.
Monitor blood pressure prior to each dose to assess for 
development of hypertension.
Instruct patient to monitor and report signs/symptoms of 
bleeding (nose bleeds, blood in sputum), wound healing 
problems, abdominal pain, thromboembolic problems (chest or 
leg pain, dyspnea, vision changes, severe headache, cough, 
swelling).
9
STATISTICAL CONSIDERATIONS 
9.1
Endpoints
The primary endpoint in this phase II study will be overall survival (OS). 
Secondary endpoints will be hematologic and neurologic toxicities, progression 
free survival (PFS), and survival after re-irradiation.
9.2
Sample Size Justification & Assumptions
9.2.1
Glioblastoma (Groups 1 and 2)
Using the limited data available in similar groups of patients, as noted 
above in Table 1, those who have received systemic therapy alone have 
median survival ranging from 7.2-9.2 months [9, 13], and those who have 
received radiation seems to be in the range of 11-12.5 months [14, 17]. 
Those patients with GBM who are bevacizumab-naïve (Group 1) will 
presumably have improved overall outcomes compared to those who have 
been previously treated with bevacizumab (Group 2). 
In Group 1, the primary hypothesis will be a 60% prolongation of survival 
(although we will measure survival as a hazard function, this is expected 
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to shift median from an anticipated 10 to 16 weeks.  Using a one sample 
exponential survival model, to have at least 80% power to observe this 
delta, with a one-sided significance level of 0.1, a minimum of 22 patients 
will be required.  This assumes 36 months of follow-up.  Allowing for 
approximately 15% non-evaluability/drop-off, we anticipate a cohort size 
of 25.  
In Group 2, the primary hypothesis will be a 50% prolongation of survival 
(although we will measure survival as a hazard function, this is expected 
to shift median from an anticipated 8 to 12 months).  Using a one sample 
exponential survival model, to have at least 80% power to observe this 
delta, with a one-sided significance level of 0.1, a minimum of 34 patients 
will be required.  This assumes 24 months of follow-up.  Allowing for 
approximately 15% non-evaluability/drop-off, we anticipate a cohort size 
of 40. 
9.2.2
Anaplastic Glioma (Groups 3 and 4)
There are no relevant clinical data to truly estimate the PFS in these 
patients.  The purpose of enrolling these patients is to generate 
preliminary descriptive data and statistics for future clinical trial design.  
Therefore, in Groups 3 and 4, up to 6 patients will be enrolled in each 
group to determine response, PFS, and OS endpoints. 
9.3
Analysis
Data will be analyzed using Kaplan-Meier curves for overall survival and the 
median survival will be determined from these curves.
9.4
Reporting and Exclusions
9.4.1
Evaluation of toxicity
All patients will be evaluable for toxicity from the time of their first 
treatment with bevacizumab, temozolomide, or radiation therapy.
9.4.2
Evaluation of Response
All patients 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 patient will 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 8) unknown (not 
assessable, insufficient data).  [Note:  By arbitrary convention, category 8 
usually designates the “unknown” status of any type of data in a clinical 
database.]
All of the patients who met the eligibility criteria should be included in 
the main analysis of the survival and response endpoints.  Patients in 
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response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the 
response rate.  Precise definitions for categories 4-8 will be protocol 
specific.
All conclusions should be based on all eligible patients.  Subanalyses may 
then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death 
due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these subanalyses may not serve as the basis 
for drawing conclusions concerning treatment efficacy, and the reasons 
for excluding patients from the analysis should be clearly reported.  The 
95% confidence intervals for response rate should also be provided.
10 ADVERSE EVENT MONITORING & REPORTING 
This trial will be conducted in accordance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (see 
Appendices for link).  The level of risk attributed to this study requires High Intensity 
Monitoring, as outlined in the DSMP.  The assigned QAM, with oversight from the Data 
and Safety Monitoring Committee, will monitor this study in accordance with the study 
phase and risk level. Please refer to the Appendices for additional data submission 
instructions.
10.1 Adverse Event Monitoring
Collection and reporting of adverse event (AE) data is required as part of every 
clinical trial, and is done to ensure the safety of patients enrolled in this study as 
well as those who will enroll in future studies using similar agents.  Toxicity will 
be assessed weekly during the initial phase of treatment and then prior to each 
cycle during the adjuvant phase (may be more frequently if needed), as described 
in Section 7.0.  All adverse events will be reported on the appropriate eCRF (as 
outlined in Section 11.3) to the assigned QAM.  Additionally, certain serious 
adverse events (SAEs) will be reported in an expedited manner to allow for 
optimal monitoring of patient safety and care.  
All patients experiencing an AE, regardless of its relationship to study drug, will 
be monitored until one of the following occurs: 

The AE resolves or the symptoms or signs that constitute the AE return to 
baseline.

Any abnormal laboratory values have returned to baseline.

There is a satisfactory explanation other than the study drug for the 
changes observed.

Death.
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10.2 Definitions & Descriptions
10.2.1 Adverse Event
An AE is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of an experimental intervention, 
whether or not related to the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or 
measurements, but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement. Preexisting conditions that 
worsen in severity or frequency during the study should also be recorded 
(a preexisting condition that does not worsen is not an AE). Further, a 
procedure or surgery is not an AE; rather, the event leading to the 
procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the 
diagnosis should be provided. For example, if clinically significant 
elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If 
the cause is not known, the abnormal test or finding should be recorded as 
an AE, using appropriate medical terminology (e/g/ thrombocytopenia, 
peripheral edema, QT prolongation).
10.2.2 Severity of AEs
All adverse events will be graded according to the NCI’s CTCAE version 
4.0 (please see Appendices for link).
10.2.3 Serious Adverse Event
All SAEs, regardless of attribution, occurring from time of signed 
informed consent, through 30 days after the last administration of study 
drug, must be reported upon discovery or occurrence.
An SAE is any untoward medical occurrence that at any dose results in 
one of the following outcomes: 

Results in death.
If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself.

Is life-threatening.
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The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it 
were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“. 
10.2.4 Exceptions to AE & SAE Definitions
Generally speaking, any adverse event that results in hospitalization or 
prolonged hospitalization should be documented and reported as an SAE, 
as described above.  Likewise, any condition responsible for surgery 
should be documented as an AE if the condition meets the criteria for an 
AE.  However, for the purposes of this study, neither the condition, 
hospitalization, prolonged hospitalization, nor surgery are reported as AEs 
or SAEs under the following circumstances:
10.2.4.1 Hospitalization or prolonged hospitalization is for a diagnostic or 
elective surgical procedure for a preexisting condition.  Surgery 
should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the 
outcome was uneventful.
10.2.4.2 Hospitalization or prolonged hospitalization is required to allow 
efficacy measurement for the study.
10.2.4.3 Hospitalization or prolonged hospitalization is required for study-
directed therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as 
judged by the principal investigator.
10.2.4.4 Hospitalization or prolonged hospitalization is due to social 
reasons (i.e. awaiting transport home).
10.2.5 Unanticipated Problem Involving Risk to Subject or Others (UPIRSO)
In order for an adverse event to be reported to the Northwestern 
University IRB, it must qualify as a UPIRSO.  In order to qualify as a 
UPIRSO, the event must meet all three of the following criteria:  
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10.2.5.1 The event must be unanticipated in terms of nature, severity, or 
frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators 
brochure, etc.).  
10.2.5.2 The event must place the research subject or others at a different 
or greater risk of harm (including physical, psychological, 
economic, or social harm).
10.2.5.3 The event must be related or possibly related to participation in 
the study.
10.3 Adverse Event Reporting 
10.3.1 Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely 
or definitely not related to study participation, are to be reported on the 
appropriate eCRF. Routine AEs will be reviewed by the Data and Safety 
Monitoring Committee (DSMC) according to the study’s phase and risk 
level, as outlined in the DSMP.
10.3.2 Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last 
dose of treatment and is attributed (possibly, probably, or definitely) to 
the agent(s) must also be reported accordingly.
1. Identify the type of adverse event using the NCI CTCAE v 4.0.
2. Grade the adverse event using the NCI CTCAE v 4.0.
3. Determine whether the adverse event is related to the protocol 
therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4. Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not 
listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
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10.3.3 Expedited Reporting of SAEs/Other Events
10.3.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours 
of becoming aware of the event. Completion of the NU CRO 
SAE Form, provided as a separate document, is required. 
The completed form should assess whether or not the event 
qualifies as a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and 
outcome (if known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DSMC at 
their next meeting.
10.3.3.2 Reporting to the Northwestern University IRB
•
Any death of an NU subject that is unanticipated in nature and 
at least possibly related to study participation will be promptly 
reported to the NU IRB within 24 hours of notification. 
•
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to 
study treatment)
•
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the 
NU IRB within 10 working days of notification.
•
All other deaths of NU subjects not previously reported, other 
non-NU subject deaths that were unanticipated and unrelated, 
and any other SAEs that were not previously reported as 
UPIRSOs will be reported to the NU IRB at the time of annual 
continuing review.
11 RECORDS TO BE KEPT
Please refer to Appendix VI for detailed instructions regarding the entry and submission 
of data using eCRFs through NOTIS. Instructional videos are also available on the CRO 
website at: https://www.cancertrials.northwestern.edu/collaborations/nu-iit-sites. 
In addition to the regular hospital chart, a separate patient folder will be kept which 
includes the patient's signed, dated informed consent document.
11.1 Patient Registration
Please refer to section 4.0 for detailed instructions.
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11.2 Data Submission
Once subject is confirmed and enrolled to the study, the following eCRFs should 
be submitted to the assigned Quality Assurance Monitor through NOTIS 
according to the data submission schedule found in the appendices:
12  PATHOLOGY REQUIREMENTS
All patients who had surgery outside of Northwestern Memorial Hospital will be asked to 
submit their pathology for review at NMH for confirmation of diagnosis.  A copy of the 
pathology report from the primary surgery is sufficient for registration.  Biopsy proof of 
recurrent disease is not required.  Dr. Qinwen Mao is the designated Neuro-Oncology 
Neuropathologist.
13 ADMINISTRATIVE, ETHICAL & REGULATORY CONSIDERATIONS
13.1 Conduct
This study will be conducted in accordance with the Declaration of Helsinki, 
Good Clinical Practices (GCP) guidelines and all applicable government 
regulations and Institutional research policies and procedures.  The Principal 
Investigator or qualified designees are responsible for reporting all amendments, 
safety updates, and protocol violations.  This study will be monitored in 
accordance with the Data Safety Monitoring Plan of the Lurie Cancer Center of 
Northwestern University and will abide by its policies and practices.  
13.2 Amendments
The Principal Investigator will formally initiate all amendments to the protocol 
and/or informed consent.  All amendment s will be subject to the review and 
approval of the appropriate local, institutional, and governmental regulatory 
bodies.   Amendments will be distributed by the lead institution (Northwestern) to 
all affiliate sites upon approval by the Northwestern University IRB.
13.3 Informed Consent
The investigator is responsible for ensuring that no patient participates in any 
study-related examination or activity before that patient has given informed 
consent.  The informed consent will be provided both through the written 
informed consent document and through verbal review of all information 
contained therein.  Information provided in this way is to include potential 
benefits, aims of the study, potential harms or side effects and methods of the 
study.  The patient will be given opportunity to ask questions about any aspect of 
the information and will be given time to review the information on their own.  
The patient may, after having been provided with this detailed written and verbal 
information, provide written consent.  The patient will then be provided a copy of 
the executed informed consent for their reference.  The patient is free to withdraw 
consent at any time and for any reason.  The only consequence of consent 
withdrawal is that the patient is no longer able to participate in the study.
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13.4 Protected Health Information
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), patients who have provided written informed consent must also sign a 
subject authorization to release medical information to the study Sponsor and 
allow a regulatory authority, or Institutional Review Board access to subject’s 
medical information relevant to the study.  This authorization may be combined 
with the informed consent form in accordance with local institutional practice.  
13.5 Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:
•
Signed and completed Letter of Invitation to participate in the study.
•
Signed copy of Northwestern University’s Data and Safety Monitoring 
Committee policy pertaining to data submission.
•
A copy of the official IRB approval letter for the protocol and informed 
consent. 
NOTE: Informed consent form should be submitted to the Clinical 
Research Office for review/approval prior to submission to the local 
IRB.
•
CVs and medical licensure for the local PI and any sub-investigators who 
will be involved in the study at the site.
•
Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
13.6 Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to Appendix I). The level of risk attributed to this study 
requires High Intensity Monitoring, as outlined in the DSMP. The assigned QAM, 
with oversight from the Data and Safety Monitoring Committee, will monitor this 
study in accordance with the study phase and risk level. Please refer to the 
Appendix VI for additional data submission instructions.
13.7 Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with 
the policies and processes set forth in the Lurie Cancer Center DSMP. The 
assigned QAM will prepare a preliminary data summary (to be approved by the 
DSMC) no later than 3 months after the study reaches its primary completion date 
(the date that the final subject is examined or receives an intervention for the 
purposes of final data collection for the primary endpoint). If the investigator’s 
wish to obtain DSMC-approved data prior to this point (or prior to the point 
dictated by study design), the PI must send a written request for data to the QAM 
which includes justification. If the request is approved, data will be provided no 
later than 4 weeks after this request approval. The data will be presented to the 
DSMC at their next available meeting, and a final, DSMC-approved dataset will 
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be released along with any DSMC decisions regarding publication. The 
investigators are expected to use only DSMC-approved data in future publications. 
The investigators should submit a copies of the manuscript to the biostatistician to 
confirm that the DSMC-approved data are used appropriately. Once the 
biostatistician gives final approval, the manuscript may be submitted to external 
publishers.
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14 REFERENCES 
1.
Stupp, R., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the 
EORTC-NCIC trial. Lancet Oncol, 2009. 10(5): p. 459-66.
2.
Lai, A., et al., Phase II study of bevacizumab plus temozolomide during and after radiation therapy for 
patients with newly diagnosed glioblastoma multiforme. J Clin Oncol, 2011. 29(2): p. 142-8.
3.
Vredenburgh, J.J., et al., The Addition of Bevacizumab to Standard Radiation Therapy and 
Temozolomide Followed by Bevacizumab, Temozolomide and Irinotecan for Newly Diagnosed 
Glioblastoma. Clin Cancer Res, 2011.
4.
Mathieu, V., et al., Combining bevacizumab with temozolomide increases the antitumor efficacy of 
temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia, 2008. 10(12): p. 1383-
92.
5.
Narayana, A., et al., Feasibility of using bevacizumab with radiation therapy and temozolomide in 
newly diagnosed high-grade glioma. Int J Radiat Oncol Biol Phys, 2008. 72(2): p. 383-9.
6.
Combs, S.E., et al., In vitro responsiveness of glioma cell lines to multimodality treatment with 
radiotherapy, temozolomide, and epidermal growth factor receptor inhibition with cetuximab. Int J 
Radiat Oncol Biol Phys, 2007. 68(3): p. 873-82.
7.
Durmaz, R., et al., Management of glioblastoma multiforme: with special reference to recurrence. Clin 
Neurol Neurosurg, 1997. 99(2): p. 117-23.
8.
Salcman, M., et al., Long-term survival in patients with malignant astrocytoma. Neurosurgery, 1994. 
34(2): p. 213-9; discussion 219-20.
9.
Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in recurrent 
glioblastoma. J Clin Oncol, 2009. 27(28): p. 4733-40.
10.
Kreisl, T.N., et al., Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan 
at tumor progression in recurrent glioblastoma. J Clin Oncol, 2009. 27(5): p. 740-5.
11.
Mark R. Gilbert, Meihua Wang, Ken Aldape, A. Gregory Sorensen, Tom Mikkelsen, Felix Bokstein, 
Shaio Y. Woo, Steven J.Chmura, Ali K. Choucair, and Minesh Mehta, RTOG 0625: A Randomized 
Phase II Trial Of Bevacizumab With Either Irinotecan (CPT) Or Dose-Dense Temozolomide (TMZ) In 
Recurrent Glioblastoma (GBM). Neuro-Oncology. Vol. 12. 2010. iv39.
12.
Perry, J.R., et al., Phase II trial of continuous dose-intense temozolomide in recurrent malignant 
glioma: RESCUE study. J Clin Oncol, 2010. 28(12): p. 2051-7.
13.
Brada, M., et al., Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-
grade glioma. J Clin Oncol, 2010. 28(30): p. 4601-8.
14.
Fogh, S.E., et al., Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent 
high-grade gliomas. J Clin Oncol, 2010. 28(18): p. 3048-53.
15.
Adkison, J.B., et al., Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate 
radiotherapy. Int J Radiat Oncol Biol Phys, 2011. 79(3): p. 835-41.
16.
Shepherd, S.F., et al., Hypofractionated stereotactic radiotherapy in the management of recurrent 
glioma. Int J Radiat Oncol Biol Phys, 1997. 37(2): p. 393-8.
17.
Gutin, P.H., et al., Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation 
for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys, 2009. 75(1): p. 156-63.
18.
Norden, A.D., et al., Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of 
recurrence. Neurology, 2008. 70(10): p. 779-87.
19.
Levin, V.A., et al., Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for 
Radiation Necrosis of the Central Nervous System. Int J Radiat Oncol Biol Phys, 2010.
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15 APPENDICES
15.1 Appendix I – 
Data and Safety Monitoring Plan
This trial will be conducted and monitored in accordance with the Data and Safety 
Monitoring Plan (DSMP) of the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University; a copy of the current DSMP can be obtained from the following 
link:
https://cancertrials.northwestern.edu/cpsrms/cpsrms-p-ps
Data is expected to be submitted according to requirements described in appendix VI. The 
QAM will review and assess each submitted eCRF for completeness, protocol 
adherence/compliance, toxicities or potential subject safety issues, and disease outcome and 
response. The QAM will routinely query study teams regarding any issues or for outstanding 
data. The QAM will present SAEs, protocol deviations, data summaries, and any other issues 
that may impact patient safety or data integrity to the DSMC on a semi-monthly basis.  
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15.2 Appendix II – CTCAE v 4.0
A copy of the NCI’s Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 and 
guidelines for use can be found at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
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15.3 Appendix III – ECOG Performance Status
ECOG PERFORMANCE STATUS*
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* As published in Am. J. Clin. Oncol:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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15.4 Appendix IV – FACT-Br & FACT-Fatigue Scales
FACT-Br and FACT-Fatigue scales that will be used are attached as separate PDF 
documents.
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15.5 Appendix V – Protocol History of Changes
Original IRB-Approved Version – November 2, 2011 
Amendment 1 – February 3, 2012
Scientific Review Committee Approval – February 23, 2012
Section(s) Affected
Prior Version
Amendment 1 
Changes
Rationale
Cover-page, Synopsis
No additional sites 
participating.
Adds Dr. William 
Broderick (Edward 
Cancer Center) and 
Dr. Joseph Imperato 
(Northwestern Lake 
Forest Hospital) as 
participating sites.  
Removes Dr. 
Virginia Diavolitsis 
from the list of 
Northwestern sub-
investigators.
Administrative
7.0 (Study Parameters)
Chemistry panel 
tests required at 
baseline/screening 
but not marked on 
table.
Adds an “X” for 
chemistry panel 
tests at 
baseline/screening.
Corrects an error.
Amendment 2 – July 18, 2012
Scientific Review Committee Approval – July 18, 2012
Section(s) Affected
Prior Version
Amendment 2 
Changes
Rationale
Cover-page, Synopsis
Dr. Minesh Mehta 
listed as the PI
1. Drs. Raizer and 
Sean Grimm 
listed as sub-
investigators.
2. n/a
1. Replaces Dr. 
Mehta with Dr. 
Jeffrey Raizer
2. Removes Dr. 
Raizer (now the 
PI) and Dr. 
Grimm and lists 
Dr. Priya 
Kumthekar.
3. Adds University 
of Chicago (Dr. 
M. Kelly 
Nicholas) as a 
1. Dr. Mehta is 
leaving the 
institution.
2. Dr. Grimm is 
leaving the 
institution and 
Dr. Kumthekar 
has recently 
come on 
board.
3. Administrative
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participating 
site.
Section 3.1 (Inclusion 
Criteria)
Lab parameters for 
baseline eligibility 
to have been within 
14 days prior to 
initiation of study 
treatment.
Revises lab 
parameters to have 
been within 14 days 
prior to study 
registration.
This was done to 
correct an error 
and to align this 
section with 
Section 7.0 (Study 
Parameters)
Amendment 3 – August 30, 2012
Scientific Review Committee Approval – September 19, 2012
Section(s) Affected
Prior Version
Amendment 3 
Changes
Rationale
Cover-page, Synopsis
n/a
Adds Dr. Vinai 
Gondi (Central 
Dupage Hospital) as 
a participating site.
Administrative
Section 5.2.1 (Re-
Irradiation Therapy)
n/a
Adds statement 
clarifying that 
proton therapy is an 
acceptable mode of 
radiotherapy for this 
study.
Clarification
Synopsis, Sections 5.1 
(Treatment Overview) & 
9.2 (Sample Size 
Justification & 
Assumptions)
Overall sample size 
listed as 80 
subjects.
Corrects errors in 
the power analysis 
and adjusts sample 
size accordingly to 
120 subjects.
Change 
necessitated to 
correct an error, as 
pointed out during 
review at an 
affiliate site.
Section 5.3.1.2 
(Adjuvant Phase 
Delays/Modifications)
Stated that new 
cycles may be 
delayed up to 4 
weeks in the event 
of Grade 4 
hematologic 
toxicity (including 
a platelet
count of < 
25,000/mm3)
Adds that this 
excludes 
lymphopenia.
Clarification
Amendment 4 – October 30, 2012
Scientific Review Committee Approval – November 7, 2012
Section(s) Affected
Prior Version
Amendment 4 
Changes
Rationale
5.1 (Treatment Plan – 
Adjuvant cycles 
Adds statements 
Revised to allow 
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Overview), 5.2.2 
(Temozolomide 
Administration), 5.2.3 
(Bevacizumab 
Administration), 7.0 
(Study Parameters)
occur every 8 
weeks with no 
spacing between.
allowing cycles 
during the adjuvant 
phase of treatment 
to be spaced +/- 1 
week apart.
flexibility in 
scheduling.
7.0 (Study Parameters)
MRI/CT to be 
performed at 
baseline (within 30 
days of 
registration), after 
the initial phase of 
treatment 
(approximately 1 
week after the last 
dose of  
re-irradiation 
therapy), and then 
prior to each new 
cycle of therapy 
during the adjuvant 
phase (1 cycle = 8 
weeks).
Specifies that scans 
during the adjuvant 
phase will be done 
on Day 1 or within 
7 days prior to each 
new cycle of 
therapy.
Added for clarity.
Amendment 5 – May 29, 2013
Scientific Review Committee Approval – June 5, 2013
Section(s) Affected
Prior Version
Amendment 5 
Changes
Rationale
Cover Page
CDH/ProCure were 
not listed as 
separate sites.
CDH and ProCure 
are now listed as 
two sites.
Administrative
Synopsis, 5.1 
(Overview), 9.2 (Sample 
Size Justification & 
Assumptions)
Total accrual goal 
was 120 subjects.
Revises accrual goal 
to 77 subjects 40 
GBM bevacizumab-
naïve, 25 GBM 
bevacizumab-
exposed, 6 
anaplastic glioma 
bevacizumab-naïve, 
6 anaplastic glioma 
bevacizumab-
exposed).
This was revised 
at the request of 
the Data 
Monitoring 
Committee as a 
result of concerns 
over the slow 
accrual thus far.
3.0 (Selection of 
Patients)
Dr. Minesh Mehta 
still mentioned as 
the PI. 
Replaces this with 
Dr. Jeffrey Raizer.
Administrative
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3.1 (Inclusion Criteria), 
3.2 (Exclusion Criteria)
Systolic blood 
pressure required to 
be <140 mmHg to 
be eligible.
Changed to require 
< 145 mmHg.
The PI determined 
that the previous 
requirement was 
too strict.
6.4 (Evaluation of 
Response)
n/a
Adds information 
regarding 
pseudoprogression, 
including how to 
distinguish between 
that vs. true 
progression and 
whether or not to 
continue treatment.
Added for clarity.
7.0 (Study Parameters)
1. Physical 
exam/ECOG 
score & 
hematology 
tests required 
weekly during 
the Initial (re-
irradiation) 
phase.
2. n/a
1. Changes this to 
be required only 
during weeks 
when the patient 
is scheduled to 
receive 
bevacizumab 
(Weeks 3 and 
5).
2. Adds a footnote 
clarifying when 
reflex UPC is 
required vs. 
when urine dip 
is acceptable 
throughout the 
initial phase, 
treatment break, 
and adjuvant 
phase of 
treatment.
3. Clarifies that if 
screening labs & 
physical were 
performed 
within 14 days 
prior to the first 
dose of 
bevacizumab, 
they do not need 
Changes made to 
simplify the study 
schedule and 
avoid unnecessary 
tests/assessments.
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 55 -
to be repeated.
Amendment 6 – March 14, 2014
Scientific Review Committee Approval – May 2, 2014
Section(s) Affected
Prior Version
Amendment 6 
Changes
Rationale
Cover-page
Listed Drs. Levy, 
Batjer, and Getch 
as NU sub-
investigators.
Removes Drs. Levy, 
Batjer, and Getch as 
NU sub-I’s.
No longer at NU.
Cover-page, Synopsis
Referred to “CDH 
Proton Center, A 
Procure Center” as 
a participating site.
Changes this to 
“CDH-Delnor 
Health System d/b/a 
Cadence Health”
Administrative – 
needed to match 
contract language.
4.0 (Patient 
Registration)
Contained outdated 
language and 
instructions.
Updates language 
and instructions to 
reflect current 
practices and 
procedures. Adds 
use of the eligibility 
checklist.
Administrative
7.0 (Study Parameters)
n/a
Revises study 
parameters table to 
more clearly reflect 
the requirements.
Administrative
10.0 (Adverse Event 
Monitoring)
Contained outdated 
language and 
instructions.
Updates language 
and instructions to 
reflect current 
practices and 
procedures. Adds 
use of the NU CRO 
SAE form.
Administrative
11.0 (Records to be 
Kept)
Contained outdated 
language and 
instructions.
Updates language 
and instructions to 
reflect current 
practices and 
procedures.
Administrative
Appendices
n/a
Updates the DSMP 
link and 
information. Adds a 
whole new appendix 
VI to provide study-
specific instructions 
for data submission.
Administrative
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
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Amendment 7 – August 21, 2014
Scientific Review Committee Approval – N/A
Section(s) Affected
Prior Version
Amendment 6 
Changes
Rationale
7.0 (Study Parameters)
Deleted 
demarcation of 
required procedures 
in EOT column of 
parameters table.
Added demarcation 
of required 
procedures in EOT 
column in 
accordance with 
5/29/2013 version 
of the protocol.
Administrative
Amendment 8 – April 1, 2015
Scientific Review Committee Approval – April 15, 2015
5.2.1 (Re-irradiation 
Therapy)
n/a
Revised to add “If 
standard SIB 
technique is not felt 
to be in the patient’s 
best interest due to 
potential toxicity, 
then standard 
fractioned EBRT at 
180-200 cGY will 
be used.”
Added radiation 
option for patients 
due to potential 
toxicity with 
standard SIB 
technique
9.2.1 (Statistical 
Considerations)
n/a
Revised to clarify 
that group 1 is bev-
naïve GBM, and 
group 2 is bev-
exposed GBM to be 
in line with the rest 
of the protocol.
Administrative
Amendment 9 – May 21, 2018
Scientific Review Committee Approval – 5-23-2018
Section(s) Affected
Prior Version
Amendment 9 
Changes
Rationale
Throughout Protocol
n/a
Formatting was 
updated 
To align with the 
NU IIT template
Dr. Jeffrey Raizer 
listed as the PI
Replaces Dr. Raizer 
with Dr. Dixit
Dr. Raizer is listed 
as Sub-I
Dr. Raizer will no 
longer serve as the 
PI.
Cover-page, Synopsis
“Statistician”
“Biostatistician”
To align with NU 
IIT Template
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 57 -
n/a
Version date was 
included
To align with NU 
IIT Template
Section 3.0 (Selection of 
Patients)
Dr. Raizer is 
mentioned as the 
PI. 
Replaces this with 
Dr. Dixit.
Administrative
Section 10 (Adverse 
Event Monitoring & 
Reporting); Section 
10.3.3.1 (Reporting to 
the Northwestern 
University 
QAM/DSMC); Section 
13.5 (Participating Sites)
Data Monitoring 
Committee (DMC)
Data and Safety 
Monitoring 
Committee (DSMC)
Committee name 
has been changed.
Section 10.2 
(Definitions & 
Descriptions); Section 
10.3 (Adverse Event 
Reporting); 13.6 (Data 
Management and 
Monitoring/Auditing); 
Section 13.7 
(Publication Policy)
n/a
Updated section 
with language from 
the NU IIT template
To align with NU 
IIT Template
Amendment 10 – September 11, 2018
Scientific Review Committee Approval – 9/12/18
Section(s) Affected
Prior Version
Amendment 10 
Changes
Rationale
Dr. Nicholas listed 
as PI at University 
of Chicago
Dr. Chmura listed as 
PI at University of 
Chicago
Administrative
Cover Page
n/a
Addition of Dr. 
Rademaker’s email 
address.
Administrative.
Amendment 11 – February 5, 2019
Scientific Review Committee Approval –
Section(s) Affected
Prior Version
Amendment 11 
Changes
Rationale
Section 5.6 (Follow-
Up); Section 6.1.3 
(Overall Survival); 
Section 6.1.4 
(Progression Free 
Survival); Section 7 
(Study Parameters); 
Appendix VI (Data 
Patients followed 
until death
Included note “As 
of December 31, 
2018, patients will 
no longer be 
followed and follow 
up information will 
not be collected.”
Study PIs are 
already working 
on publication and 
not going to 
collect any more 
data.
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 58 -
Collection and 
Submission Guidelines)
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 59 -
15.6 Appendix VI – Data Collection & Submission Guidelines
Study-specific instructions regarding the entry and submission of data using eCRFs through 
NOTIS will be provided at the time of training prior to study activation. In addition, 
instructional videos on data entry using NOTIS and eCRFs are available on the CRO’s 
website at: https://www.cancertrials.northwestern.edu/working-with-the-cro. The Internal and 
Affiliate Data Compliance Policies of the Lurie Cancer Center’s DSMC regarding will be 
strictly enforced.
Study Chart & eCRFs
In addition to the regular hospital chart, a separate patient folder will be kept which includes 
the patient's signed, dated informed consent document. Once a subject is confirmed and 
enrolled to the study, the following eCRFs should be submitted to the QAM through NOTIS.
Forms to be submitted prior to registration:
Please see Section 4.0 for all forms/documentation to be submitted prior to registration.  
Forms to be submitted within 5 days of registration:

Concomitant Medications Form: updated to reflect the patients’ information at the time of 
registration. 

Adverse Event Forms: update to reflect the adverse events that were present at baseline

On-Study Form: dates and results of all baseline exams/tests/labs required to be 
performed prior to registration including:

Medical history

Physical exam (vitals, weight)

ECOG PS

CBC with platelets and differential, comprehensive metabolic panel

Pregnancy test (if applicable)

MRI or CT 

Urine Protein/Creatinine Ratio

Study-specific document uploads:
o
RANO Spreadsheet Upload: should reflect the measurements assessed at 
baseline
o
FACT-BR and FACT-fatigue Uploads: Upload the assessments from baseline
Forms to be submitted after the Initial Phase of treatment: 

Labs Order Form: There should be separate entries for weeks 3 and 5.  

Adverse Events Form:  Should include all adverse events that occurred/were reported on 
a weekly basis through the initial phase.

Patient Vitals Form: There should be separate entries for each weekly assessment 
conducted during this period.  

Concomitant Medications Form: Should be updated as necessary.
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 60 -

Treatment Log: All doses of bevacizumab and temozolomide should be recorded for all 
treatment administered in the initial phase.  A completed medication diary should be 
collected and uploaded under the treatment log.  

RT Reports: The radiation treatment summary should be uploaded to NOTIS at the end of 
RT.  
Forms to be submitted after the “treatment break”:

Labs Order Form: Enter just Urine Protein/creatinine ratio.

RANO Spreadsheet Upload: Upload the RANO spreadsheet for measurements assessed 
during treatment break.

FACT-BR and FACT-fatigue Uploads: Upload the assessments performed during the 
treatment break.  
Forms to be submitted after every cycle (every 8 weeks) during the Adjuvant Phase:  

Labs Order Form

Adverse Events Form:  Should include all adverse events that occurred/were reported 
during each cycle.  

Patient Vitals Form: These are to be performed monthly (there should be 2 entries 
submitted for each cycle).  

Concomitant Medications Form: Should be updated as necessary.

Treatment Log: All doses of bevacizumab and temozolomide should be recorded for all 
treatment administered after each cycle.  Completed medication diaries (2 monthly 
calendars for each cycle) should be collected and uploaded under the treatment log.  

RANO Spreadsheet Upload: Upload the RANO spreadsheet for measurements assessed 
after each cycle.  

FACT-BR and FACT-fatigue Uploads: Upload the assessments performed after each 
cycle.  
Forms to be submitted after the end-of treatment visit is conducted:  

Labs Order Form

Adverse Events Form:  Should include all adverse events through the end of treatment 
visit

Patient Vitals Form

Concomitant Medications Form: Should be updated as necessary.

RANO Spreadsheet Upload: Upload the RANO spreadsheet for measurements assessed at 
the end of treatment visit.

FACT-BR and FACT-fatigue Uploads: Upload the RANO spreadsheet for measurements 
assessed at the end of treatment visit.

Off-treatment Form: Complete part of this form within 1 week the subject’s end of 
treatment visit.  
Forms to be completed during follow-up period: 

Survival Status Form: Complete every 3 months until death or patient is lost to follow-up
Note: As of December 31, 2018, patients will no longer be followed and follow up 
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 61 -
information will not be collected.
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.


NU 11C02
Version Date: Amendment-11 dated February 5, 2019
- 62 -
Prior to 
registration
Within 5 
days of 
registration
After 
Initial 
Phase is 
Complete
After 
Treatment 
Break
After 
each 
Cycle of 
Adjuvant 
Phase
End of 
Treatment 
Visit
Follow-up
Eligibility Form
X
Informed Consent 
Form
X
Pathology Report
X
Eligibility Checklist
X
On-Study Form 
X
Concomitant 
Medications Form
X1
X5
X5
X5
X5
Patient Vitals Form
X3
X8
X
Labs Order Form
X3
X9
X
AE  Form
X2
X
X
X
X
Treatment form
X4
X4
Medication Diary 
Upload
X4
X4
RT Summary 
Upload
X6
RANO Spreadsheet 
Upload
X7
X10
X11
X
Off-Treatment 
Form
X12
Survival Status 
Form
X13
1 Should reflect medications taken at baseline
2 Should reflect all AEs present at baseline
3May be entered at end of initial treatment phase, but should reflect vitals required after weeks 3 and 5 
4 Bevacizumab and temozolomide doses to be entered and diary to be uploaded after pt returns completed medication diary for 
initial phase of treatment and each diary completed during adjuvant phase 
5 Update as required 
6 RT Treatment summary to be uploaded under “RT reports” after radiation is complete.  
7 Should reflect assessment done at baseline.  
8 To be completed after each cycle.  There should be two entries submitted for monthly vitals required during the cycle.  
9 To be completed after each cycle.  
10 Should reflect assessment done during treatment break 
11 Completed RANO spreadsheet should be uploaded for every cycle it’s assessed in adjuvant phase.  
12 Complete part of this form within 1 week the subject’s end of treatment visit.  
13 Complete every 3 months until death or patient is lost to follow-up.   Note: As of December 31, 2018, patients will no 
longer be followed and follow up information will not be collected.
IRB #: STU00053636-CR0005 Approved by NU IRB for use on or after 5/28/2019 through 5/21/2020.