A Phase II Study of Pulse Reduced Dose Rate Radiation Therapy With Bevacizumab
Phase: PHASE2
Conditions: Glioma
Sponsor: University of Wisconsin, Madison

 
 
 
 
 
 
 
 
 
A Phase II Study of Pulsed Reduced Dose-Rate Radiation Therapy with 
Bevacizumab for Recurrent High-Grade Gliomas 
 
9/13/2023 
 
NCT01743950 

 
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CO11374:  A Phase II Study of Pulsed Reduced Dose-Rate Radiation Therapy with 
Bevacizumab for Recurrent High-Grade Gliomas 
 
 
CO-PRINCIPAL INVESTIGATOR:                             Steven Howard, MD, PhD 
                                                                                        Department of Human Oncology 
                                                                                        Wisconsin School of Medicine and                        
                                                                                        Public Health 
                                                                                        Madison. WI 53792 
                                                                                        howard@humonc.wisc.edu 
 
CO-PRINCIPAL INVESTIGATOR:                              
Patrick Grogan, MD, PhD 
Department of Medicine 
Division of Hematology and Oncology 
University of Wisconsin School of Medicine 
and Public Health 
Madison, WI 53792 
pgrogan@uwhealth.org 
 
  
  
CO-INVESTIGATORS:                                               Shahriar Salamat, M.D. 
 
              Department of Pathology       
 
                                                                          University Wisconsin School of Medicine  
                                                                                      and Public Health 
                                                                                      Madison. WI 53792 
                                                                                      Shahriar Salamat ssalamat@wisc.edu 
 
 
 
 Jeffrey Helgager, M.D. 
 
 
 Department of Pathology       
 
                                                                         University Wisconsin School of Medicine  
                                                                                     and Public Health 
                                                                                     Madison. WI 53792 
 
 
 
 
 
 
 
jhelgager@wisc.edu  
 
 
 
 
  
 
 
 
 
 Christopher Platta, M.D. 
 
 
 
 
 
 
 
 Aspirus Regional Cancer Center 
 
 
 
 
 
 
 
 215 N. 28th Avenue 
 
 
Wausau, WI 54401 
 
 

 
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STATISTICIAN:                                                        Rick Chappell PhD 
Depts. of Statistics, Biostatistics and   
Medical Informatics 
                                                                                    University of Wisconsin School of       
                                                                                    Medicine and Public Health 
                                                                                    Madison. WI 53792 
                                                                                    chappell@biostat.wisc.edu 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH PROGRAM MANAGER                           Diana Trask BS 
                                                                                          Department of Human Oncology 
                                                                                          Wisconsin School of Medicine and                        
                                                                                          Public Health 
                                                                                          Madison. WI 53792 
                                                                                          trask@humonc.wisc.edu 
 
 
 
 
 
 
 
      (608)263-9528 
 
 
 
 
 
 
                                                                                         
   
 
 CONSULTANT                                                            Minesh Mehta, MD 
 
               University of Maryland 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SYNOPSIS 
 
Title 
A Phase II Study of the Efficacy of  Pulsed Reduced Dose-Rate  (PRDR) 
Radiation  Therapy with Bevacizumab for Recurrent High-Grade Gliomas 
Short Title 
Radiation Therapy with Bevacizumab for Recurrent Gliomas 
Protocol Date 
10/14/2020 
Study Duration 
Group2 (1 year); Group 1 (2.0 years); group 3&4 (4 years)  
Study Center(s) 
UW 
Objectives 
To determine the efficacy of PRDR retreatment radiation therapy (RT), and 
bevacizumab followed by adjuvant 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 
80 
Diagnosis and Main 
Inclusion Criteria 
All patients will be diagnosed with recurrent high grade gliomas (glioblastoma 
[group 1&2] or anaplastic glioma [group 3&4]) 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 27 fractions over 5.5 weeks using a 
PRDR technique.  Concurrent bevacizumab will be given during radiation 
therapy. Post radiation, bevacizumab may be continued “off study” per SOC 
schedules and guidelines 
Analysis Summary 
Data will be analyzed using Kaplan-Meier curves for survival endpoints. 
Toxicity data will be summarized descriptively. 
 
Note: prior bevacizumab = group 2 &4, no prior bevacizumab = group 1 & 3 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
Synopsis 
 
 
 
 
 
 
 
3 
Schema 
 
 
 
 
 
 
 
5 
1.0 
Introduction – Background & Rationale  
 
6 
2.0 
Objectives 
 
 
 
 
 
 
13 
3.0 
Selection of Patients  
 
 
 
 
14 
4.0 
Patient Registration  
 
 
 
 
16 
5.0  
Treatment Plan 
 
 
 
 
 
16 
6.0 
Endpoint Assessment 
 
 
 
 
25 
7.0 
Study parameters 
 
 
 
 
 
28 
8.0 
Drug Formulation and Procurement  
 
 
30 
9.0 
Statistical considerations 
 
 
 
 
32 
10.0 
Adverse Event Monitoring & Reporting   
 
34 
11.0 
Records to be Kept  
 
 
 
 
35 
12.0 
Pathology requirements 
 
 
 
 
36 
References 
 
 
 
 
 
 
 
37 
 
Appendices 
1 
Data Safety Monitoring Plan 
2 
FACT BR and FACT fatigue scales 

 
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SCHEMA  
 
 
 
 
Patients identified to have recurrent glioblastoma or anaplastic glioma by imaging criteria or histologic analysis, meets eligibility 
criteria.   
Patients are placed into groups 1 -4 based on prior treatment and histology 
Baseline Evaluation: MRI scan, blood work (CBC, differential, B-HCG if applicable), urine protein, history and physical 
examination, neurologic examination and FACT-BR and FACT-fatigue scales 
Follow up 
Bevacizumab Naïve and Bevacizumab exposed patients will be followed every 2-3 months and may be treated 
with Bevacizumab after completion of Concurrent therapy, per MD discretion. 
Concurrent therapy 
Radiation Therapy: 27 fractions, 1st dose = Day 0 
Bevacizumab Naïve: Bevacizumab 10mg/kg every two weeks, first dose day  -3 to 0 (5 doses) 
Bevacizumab exposed: 10 mg/kg every 2-4 weeks, first dose day -3 to 0 (2-3 doses) 
Group 1: 
Bevacizumab-naïve 
recurrent IDH 
wildtype high grade 
glioma 
Group 2: 
Bevacizumab-exposed and 
refractory  recurrent  
IDH wildtype high grade 
glioma 
Group 3: 
Bevacizumab-naïve 
recurrent IDH mutant 
glioma 
Group 4: 
Bevacizumab-exposed 
recurrent IDH mutant 
glioma 

 
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1.0 
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]. 
   
 
           1.2 Recurrent Disease – Systemic Agents 
 
1.2.1 Clinical experience 
Recurrent disease is almost universal in high grade gliomas [4, 5].  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%[6].  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 [7].  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 increased 6 month PFS (51% 
with CPT-11 plus bevacizumab in the BRAIN trial) [6, 8].  In several 

 
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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 [9] or in combination with bevacizumab[8], and the 
overall data suggest modest clinical activity with 6 month PFS of 23.9% 
with temozolomide alone. 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 of Bevacizumab 
Several dosing schedules for bevacizumab have been employed.  
Bevacizumab has been given at 10 mg/kg every 2 weeks concurrent with 
and adjuvant to radiation therapy ([2, 6, 8]). 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 perforations (2.5%) [6].  Adverse events resulted in termination of 
bevacizumab treatment in 4.8% of the bevacizumab alone patients [6].  
 
1.2   
Recurrent Disease – Re-irradiation 
 
                        1.2.1 Background: 
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 [10-12]. .  In the largest of these studies,  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 experience grade 3 late central 
nervous system (CNS) toxicity (headaches), but no patients required 
hospitalization or surgical intervention for toxicity [10].  
  Some series suggest that those patients who receive bevacizumab and 
radiotherapy have improved response rates compared to those who receive either 
modality alone [13].  In 1 small single institution report of 25 patients (20 
recurrent GBM and 5 recurrent anaplastic gliomas) treated with bevacizumab and 
hypofractionated radiotherapy (30 Gy in 5 fractions), the response rate for GBM 
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) [13].  Table 1 summarizes the above data. 
 
 
 
 
 

 
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Table 1. Efficacy of treatment options for patients with recurrent GBM 
 
 
Response Rate 
(%) 
6 month PFS 
(%) 
MS 
(months)  
Bevacizumab Alone 
28.2[6] 
42.6[6] 
9.2[6] 
Bevacizumab + 
CPT-11 
37.8[6] 
50.3[6] 
8.7[6] 
Bevacizumab + 
Chemotherapy 
34.1[14] 
42[14] 
7.2[15] 
Temozolomide 
Alone 
 
23.9[9] 
7.2[15] 
Radiation Therapy 
Alone 
 
34.8[11] 
11[10] 
Bevacizumab + 
Radiation Therapy 
50[13] 
65[13] 
12.5[13] 
 
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.   
 
1.2.1 Pulsed Reduced Dose Rate Radiation (PRDR) as an Alternate Technique for Re-
irradiation 
 
One unique approach to such recurrent glioma patients is the use of dose rate 
modulated re-treatment irradiation. Radiotherapy (RT) delivered below standard 
dose-rates reduces normal tissue toxicity and can induce significant tumor 
regression in some tumor types including glioma. By reducing the effective dose-
rate and increasing the treatment time, it becomes possible for repair processes to 
be active during irradiation. This reduction in dose-rate can result in a therapeutic 
advantage, as repair of sub-lethal damage in normal neural tissues is greater for 
late complications than for neoplastic cells; furthermore tumor cells (that have 
received prior RT) can accumulate in a sensitive phase of the cell cycle, e.g., G2, 
thus leaving them at risk for radiation induced killing.  
 
1.2.2.1 Biological Basis for PRDR 
      
 
The general concept for RT dose rate modulation relates to exploiting the  
biological differences between normal neural tissue and glial neoplasms in terms  
of repair of radiation damage and the induction of radiation-induced lethal lesions.  
In this regard, it is of interest to note that low dose rate interstitial brachytherapy 
has been used for the treatment of recurrent glioma with reported improved 
median survivals [9]. The radio-biological properties of low dose-rate radiation 
have long been established relative to tumor/tissue sparing.  Currently, a superior 
dose distribution is felt to be the reason for the efficacy and tolerance observed 
with brachytherapy as a treatment for malignant glioma. Beyond this, however, 

 
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there is theoretical and experimental evidence relating to lower dose-rates 
potentially providing more efficient radiation damage. Indeed, there is increasing 
experimental evidence as well as clinical observations suggesting that reduced 
dose-rate irradiation may be a biologically different and distinct process in 
contrast to acute high dose rate fractionated irradiation. 
Shultz and Geard [16] evaluated 2 human glioblastoma cell lines relative 
to the effects of dose rate on radiosensitivity. Dose rates ranged from 0.2 Gy/h to 
5.4 Gy/h.  An inverse dose rate effect, (i.e., a paradoxical increase in cell killing 
within a narrow range of decreasing dose-rate) was demonstrated at 
approximately 0.4 Gy/h [16]. This phenomenon is thought to be a consequence of 
the accumulation of cycling cells at the G2M checkpoint. During continuous low 
dose-rate irradiation, the G2M blocked cells are preferentially killed as they are 
relatively more radiosensitive than cells in G1 and S phase. In support of this 
concept, Shultz and Davies, performed cell cycle analysis which revealed 
maximal accumulation of cells at G2M checkpoint at a dose rate of 0.4 Gy/h 
 
 
[17, 18]. Based on these experimental observations, one can extrapolate to the  
 
 
hypothesis that actively proliferating glial tumors may be selectively more  
 
 
radiosensitive to continuously delivered low dose-rate irradiation than the   
 
            quiescent surrounding normal brain tissue. 
Beyond the aforementioned considerations, breaking each fraction of 
radiation into a number of subfractions takes advantage of a second intriguing 
radiation phenomenon known as low-dose hyper-radiosensitivity (LDHRS), (i.e., 
increased radiosensitivity to doses <0.3–0.5 Gy). This translates to a cell survival 
that is considerably lower than that which would be predicted from extrapolation 
of the survival curves derived from higher doses. Such data are available (i.e., 
low-dose responses) for many human cell lines [19], most of which have 
demonstrated LDHRS [20, 21]. As alluded to above, low dose hypersensitivity 
might be a product of radiation-damaged G2 cells entering mitosis prematurely 
[20]. That is to say there was inefficient cell cycle arrest of irradiated cells as a 
result of the inverse dose effect [20].  Short et al. [22] have hypothesized that 
low-dose hypersensitivity can be thought of as the constitutive response of cells 
without the enabling of repair mechanisms triggered by higher doses. Modeling of 
these phenomena has been accomplished by Short and colleagues [23].  
Building on the above concepts, Tomé and Howard used modeling to 
develop a treatment strategy for gliomas that employs both a reduced dose-rate 
and pulsed treatment dose delivery [24]. Using five established glioma cell lines 
they demonstrated that a pulsed delivery scheme can yield a substantial increase 
in tumor control probability. They proposed a pulsed delivery scheme for the 
treatment of gliomas in which the daily treatment fraction is delivered using 0.20 
Gy pulses, separated by three minutes for a time-averaged dose-rate of 0.0667 
Gy/min. The dose per pulse of 0.2 Gy was near or below the transition dose 
observed in vitro for four of the five glioma cell lines studied [24].  
Although most evidence for low-dose hypersensitivity has been 
demonstrated in vitro, analysis of LDHRS in metastatic tumors (i.e.,  breast, 
melanoma, and sarcoma involving skin and subcutaneous tissue) has revealed a 

 
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potential advantage to low-dose ultrafractionated therapy compared with more 
standard fraction sizes [21]. 
     
 
 
 In the next section the technical aspects of applying these radio-biological  
concepts to clinical practice are described, as well as the clinical experience 
regarding their application to recurrent glioma patients.  
 
1.2.2.2  The University of Wisconsin (Madison) Clinical Experience with PRDR- RT 
We have recently reported on a series of 103 recurrent glioma patients using a dose 
modulation technique we designated this technique as PRDR-RT as described in 
section II above [11]. Histologies included: low-grade glioma (n=25); grade 3 
oligodendroglioma (n=3); grade 3 oligoastrocytoma (n= 3); grade 3 astrocytoma 
(n=25), grade 4 oligoastrocytoma (n= 1), grade 4 astrocytoma (n= 44); brainstem 
glioma (n=1); (pineal tumor (n=1).  Strikingly, the mean treatment volume was 
403.5 ± 189.4 cm3 according to T2-weighted magnetic resonance imaging and a 2-
cm margin. The PRDR-RT regimen was well tolerated, and no patient discontinued 
treatment because of associated toxicity. 
Autopsy of the brain was performed in 15 patients, of which 4 had notable 
necrosis. In 2 of these 4 patients the PRDR dose was 50 Gy in 2 patients originally 
treated to a dose of 54 Gy and 59.4 Gy, with an interval of 12 and 40 months to 
PRDR-RT. In the other 2 of 4 patients, the PRDR dose was 54 Gy in 2 patients 
originally treated to 60 Gy, with an interval of 11 and 28 months to PRDR-RT.  In 
addition, one of these patients received stereotactic radiosurgery to 12 Gy prescribed 
to the 50% isodose line 25 months after initial RT to 60 Gy. Other pathological 
findings only included punctuate necrosis in the presence of recurrent tumor, usually 
associated with mitoses or vascular endothelial proliferation. Follow-up MRI scans 
in this series revealed changes consistent with disease progression, pseudo-
progression, or necrosis. Clinical deterioration was treated with increases in steroid 
dosage and supportive care. Three patients underwent post-PRDR-RT subtotal 
resection with the pathologic findings revealing progressive disease without 
treatment related necrosis. Although no formal endocrine, neuro-cognitive, or visual 
testing was performed, no patient manifested obvious blindness from treatment. 
Multivariate analysis revealed age at the initial diagnosis, initial low-grade 
disease, and KPS of ≥80 to be significant predictors of survival after initiation of 
PRDR. No significant survival difference (from the initiation of PRDR) was 
observed for patients who had previously been treated with no systemic therapy 
(including temozolomide), one previous regimen, two previous regimens, three 
previous regimens, or four or more previous regimens (as described below) . 
  Regarding GB patients, we found that time from initial RT (≥14 months) was 
prognostic, and the OS of these patients compared favorably relative to palliative 
chemotherapy [25]. Such PLDR-RT patients had a median survival of 28 weeks; 
patients reirradiated within 14 months of previous therapy had a median survival of 
only 21 weeks (p = 0.004). It is noteworthy that 77% of the patients treated in the 
Phase II drug studies [25] had received previous chemotherapy, 25% of whom had 
received at least two regimens. In the UW series, 92% of patients had received 

 
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previous chemotherapy, and 45% had received at least two regimens. Of 
parenthetical interest, de novo GB patients were compared with those who were 
initially diagnosed with a lower grade glioma and transformed to grade 4 (confirmed 
by the biopsy); there was no significant difference in survival from the initiation of 
PRDR-RT (median survival 5.2 vs. 5.9 months, p = .12) 
In considering histologic findings at the initial diagnosis, median survival for 
those with low-grade glioma from the initiation of PRDR-RT was 11.4 months 
(range, 1–33.8); for those with Grade 3 glioma: 5.6 months (range, 1.2–23.7); for 
those with GB: 5.1 months (range, 1–48.4). The 6-month and 1-year actuarial 
survival rate after retreatment with PRDR was 73.9% and 47.8% for those with low-
grade glioma, 38.2% and 9.7% for those with Grade 3 glioma, and 34.8% and 4.4% 
for those with GB, respectively. For the entire cohort, the median survival from the 
initiation of PRDR-RT was 5.8 months (range, 1–48.4), and the 6-month and 1-year 
actuarial survival rate was 44.7% and 15.9%, respectively. 
For the reader’s interest, a series of MRI’s demonstrating a typical PRDR-RT 
response was published in 2007 as part of a case report [26].  
In summary, PRDR as a reirradiation strategy was well tolerated, allowing 
for safe retreatment of larger target volumes to high doses (>100 Gy) with palliative 
benefit.  
 
 
1.3   Bevacizumab and Treatment of Radiation Necrosis 
 
It is important to recognize the role of bevacizumab in treating and effectively 
reversing radiation-induced cerebral necrosis[27].  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 
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. 
 
1.4   Rationale for the Current Trial 
 
Based upon the modest activity of both treatment modalities (bevacizumab, 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 bi- modality approach for 
patients with recurrent malignant glioma. We propose to conduct a phase II trial 
of concurrent radiation and bevacizumab followed by adjuvant 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:  

 
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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.   
 
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, 6, 8].  
 In summary recent approval of bevacizumab for the treatment of recurrent 
GB has yielded a new clinical cohort of patients with a uniquely poor prognosis, 
i.e., patients who have progressed after bevacizumab therapy [28, 29]. The 6-
month progression free survival (PFS) for these patients is negligible.  Relative to 
this, anecdotal experience at the UW (Howard and Robins, unpublished 2011) 
suggests that PRDR-RT does provide some palliation and even responses in this 
patient population.  Beyond this, our experience with continuing bevacizumab 
with PRDR RT after progression on bevacizumab may have utility. Additionally, 
adding bevacizumab to PRDR-RT in bevacizumab naïve patients may provide 
durable responses in excess of the typical PFS (i.e., ~ 4 months) seen with 
bevacizumab [6, 7]. These observations may in part relate to the potential for 
bevacizumab to prevent, and or treat, radiation induced necrosis[27]. 
 
1.4.1              Updated Experience with Bevacizumab and PRDR-RT June 2014 
 (see reference 31) 
 
 Our recent published retrospective review in the Journal of Neuro-
oncology demonstrated that in patient who have progressed on bevacizumab 2 to 
3 cycles of bevacizumab at 10mg/kg/ every 4 weeks is adequate to salvage 
patients and improve survival. The abstract of that paper appears below: 
 
“Outcomes after bevacizumab failure for recurrent glioblastoma (GBM) are poor. Our analysis of 16 phase 
II trials (n = 995) revealed a median overall survival (OS) of 3.8 months (±1.0 month SD) after bevacizumab 
failure with no discernible activity of salvage chemotherapy. Thus, the optimal treatment for disease progression 
after bevacizumab has yet to be elucidated. This study evaluated the efficacy of reirradiation for patients with 
GBM after progression on bevacizumab. An IRB approved retrospective (2/2008–5/ 2013) analysis was 
performed of 23 patients with recurrent GBM (after standard radiotherapy/temozolomide) treated with 
bevacizumab (10 mg/kg) every 2 weeks until progression 
(median age 53 years; median KPS 80; median progression free survival on bevacizumab 3.7 months). 
Within 7–14 days of progression on bevacizumab, patients initiated reirradiation to a dose of 54 Gy in 27 
fractions using pulsed-reduced dose rate (PRDR) radiotherapy. The median planning target volume was 424 cm3. 
At the start of reirradiation, bevacizumab (10 mg/kg) was given every 4 weeks for two additional cycles. The 
median OS and 6 month OS after bevacizumab failure was 6.9 months and 65 %, respectively. Reirradiation was 
well tolerated with no symptomatic grade 3–4 toxicities. Favorable outcomes of reirradiation after bevacizumab 
failure in patients with recurrent GBM suggest its role as a treatment option for large volume recurrences not 
amenable to stereotactic radiosurgery. 
 As PRDR is easily accomplished from a technological standpoint, we are in the process of expanding 
this approach to a multi-institutional cooperative group trial.” 
 
1.4.2 
2017 Updated rationale for “A Phase II Study of Pulsed Reduced Dose-Rate 
Radiation Therapy with Bevacizumab for Recurrent High-Grade Gliomas” 
 
 

 
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CO11374; “A Phase II Study of Pulsed Reduced Dose-Rate Radiation Therapy 
with Bevacizumab for Recurrent High-Grade Gliomas” has been open and 
actively accruing 4 to 5 patients per year for the past five years. This accrual rate 
reflects the limited numbers of this small patient population. Since we opened 
CO11374 at the University of Wisconsin, numerous small retrospective, mostly 
single institution studies have suggested that re-irradiation is a feasible treatment 
option achieving both a palliative benefit and prolongation of survival (1) 
However, the recent 2017 ASCO radiotherapy guidelines by expert consensus 
panel (2) regards re-irradiation of recurrent high-grade glioma as “experimental” 
and acknowledges that there is minimal high-quality evidence regarding re-
irradiation which creates a need for guidance in the form of prospective clinical 
trials. Furthermore, this 2017 report also stresses that the majority of the 
published re-irradiation experience is in patients with small volume recurrences. 
The current trial, CO11374 is evaluating PRDR as a reirradiation strategy for safe 
retreatment of larger treatment volumes to high doses (>100 Gy). The rationale 
for the continued accrual of patients to CO11374 continues to be significant in 
2017.  
 
 
 
(1) The evolving role for re-irradiation in the management of recurrent grade 4 glioma. Howard SP, Krauze A, 
Chan MD, Tsien C, Tomé WA. J Neurooncol. 2017 Apr 6. doi: 10.1007/s11060-017-2392-1. PMID: 
28386661 
 
(2) Sulman EP, Ismaila N, Armstrong TS, Tsien C, Batchelor TT, Cloughesy T, Galanis E, Gilbert M, Gondi 
V, Lovely M, Mehta M, Mumber MP, Sloan A, Chang SM. Radiation Therapy for Glioblastoma: American 
Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for 
Radiation Oncology Guideline. J Clin Oncol. 2017 Jan 20;35(3):361-369. doi: 10.1200/JCO.2016.70.7562. 
 
(3) Tipping M, EichoFF JC, Robins HI, Clinical Outcomes in Recurrent Glioblastoma with BEV therapy: An 
Analysis of the Literature. J   Clin Neuro-Science 2017, in press  
 
 
 
2.0 
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, and bevacizumab followed by adjuvant 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 pseudo-progression, a well-described 
phenomenon in this disease. 
 
 
2.2   
Secondary Objectives: 
Secondary objectives will include the following: 
 

 
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2.2.1 Determine the safety profile of this regimen. 
2.2.2 Determine the progression free survival (PFS) at 6 and 12 months (all 
patients) as well as at 3 months (bevacizumab-exposed patients only). 
2.2.3 Qualitatively compare the results of brain autopsy in patients who have 
received PRDR-RT /Bevacizumab to prior results (n=15) obtained with 
 
PRDR-RT 
2.2.4 Determine the impact of this regimen on neurologic symptoms via FACT-
Br and FACT-Fatigue scales and Karnofsky performance status (KPS).  
 
3.0   
SELECTION OF PATIENTS 
Potentially eligible patients will be identified by their treating physicians in the Neuro-
Oncology outpatient clinic of the University of Wisconsin or at Aspirus Regional Cancer 
Center. Approximately 60 to 80 patients fitting the criteria listed above are seen per year.  
We estimate that we will accrue approximately 1-2 patients per month to this trial. 
 
3.1   
Inclusion Criteria 
3.1.1 Patients must have histologically or molecularly confirmed Grade 3 or 
Grade 4 glioma, IDH mutant or wildtype, as defined by the 2021 WHO 
guidelines. 
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. 
3.1.4 All patients may have had prior surgery, chemotherapy, and radiation 
therapy.  Patients with prior VEGF inhibitor exposure will be placed in the 
Bevacizumab exposed group (Groups 2 and 4).  Prior treatment with 
Gliadel is permitted for all groups. 
3.1.5 Prior radiation requirements 
• For bevacizumab-naïve patients (Groups 1 and 3) a minimum of 5 
months must have elapsed since completion of initial radiation 
therapy for study entry, and there is no minimum time since 
completion of last chemotherapy.  
• For bevacizumab-exposed patients (Groups 2 and 4) minimum of 3 
months must have elapsed since completion of initial radiation 
therapy and there is no minimum time since completion of last 
chemotherapy 
3.1.6 Patients must be 18 years or older. 
3.1.7 Patients must have a KPS performance status of ≥ 60. 

 
Version Date: 9/13/23 
 
 
 
 
15
 
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 Urine protein via dipstick ≤ 2+or < 100mg/d 
3.1.10 Patients’ baseline blood pressure must be adequately controlled with or 
without antihypertensive medications prior to registration (systolic < 160 
mmHg, diastolic < 90 mmHg). 
3.1.11 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 
registration. 
3.1.12 Females of child-bearing potential, based on institutional guidelines, must 
have a negative pregnancy test within 14 days prior to registration.    
3.1.13 Females of child-bearing potential and sexually active males must consent  
to follow acceptable birth control methods to avoid conception while on 
treatment. 
3.1.14 All subjects must have given signed, informed consent prior to registration 
on study. 
3.1.15 Patients previously treated outside of the UW must have their pathology 
slides sent to the UW for review and confirmation. (see section 12)  
3.1.15.1 
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 invasive 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 (> 160/90 mmHg) are NOT 
eligible for participation. 
3.2.5 Patients who exhibit any other serious concurrent active 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. 
 
 
 
 

 
Version Date: 9/13/23 
 
 
 
 
16
 
4.0   
PATIENT REGISTRATION  
  
Patients may not begin protocol treatment prior to registration.  
 
• All patients must meet eligibility criteria listed in Section 3 and provide written informed 
consent. Eligibility will be verified by UW Radiation Oncology Coordinators prior to study 
registration.  Email completed protocol checklist to: dho-datamgrs@lists.humonc.wisc.edu  
UW Radiation Coordinators will verify that the checklist is completed, will assign a case 
number and arm for ONCORE Registration 
• Each center is responsible for registration directly into UWCCC ONCORE database prior to 
study treatment.  The following information will be recorded: 
o Protocol number 
o Patient’s name and initials 
o Patient’s medical record number 
o Patient demographic data, including gender, birth date, and race.  
 
 
 
5.0 
TREATMENT PLAN 
 
 
5.1 
Overview 
This will be a phase II trial to assess the survival and toxicity associated with 
concurrent re-irradiation plus bevacizumab, followed by adjuvant bevacizumab in 
patients with recurrent high grade gliomas.  A total of 80 patients will be enrolled 
on this trial.  Patients will be stratified into 4 groups on the basis of histological 
diagnosis (IDH wild type high grade or IDH mutant high grade 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 
(bevacizumab) given during (concurrently with) re-irradiation therapy, whereas 
the second phase (adjuvant phase) will consist of treatments (bevacizumab) given 
after re-irradiation therapy is completed.  Re-irradiation therapy will last for 5.5 
weeks.  One cycle of systemic therapy in the adjuvant phase will be defined as 4 
weeks in duration.  Patients may continue on adjuvant therapy(MD discretion) 
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 PRDR Re-irradiation Therapy 
The first day of re-irradiation therapy will be considered Day 0.  Re-
irradiation therapy will be given using the UW PRDR-RT technique, with 
a total daily dose of 2.0 Gy delivered in .2 Gy pulses for 27 fractions to a 
total dose of 54 Gy delivered to the MR FLAIR abnormality (the T2 may 
substitute for FLAIR, if the FLAIR sequence is not available) as the 
clinical target volume (CTV).  There will be a minimal expansion from 

 
Version Date: 9/13/23 
 
 
 
 
17
each CTV to planning target volume (PTV) of at most 2mm. At least 90% 
of each CTV should receive 90% of the prescribed dose. In the rare 
instance of the presence of extensive disease requiring essentially whole 
brain radiation, a total daily dose of 1.8 Gy delivered in .2 Gy pulses for 
23 fractions to a total dose of 41.4 Gy will be utilized. 
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 30 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. 
 
 
                            
5.2.1.1 Technique for pulsed reduced-dose-rate (PRDR)- RT  
The technique at the University of Wisconsin (UW) for pulsed 
reduced-dose-rate (PRDR) RT [11, 30] is to generate 0.2-Gy 
pulses separated by 3-min intervals, thus creating an apparent 
average dose rate of 0.0667 Gy/min [24]. The dose rate of the 
linear accelerator is reduced to 1 Gy/min during each 0.2-Gy pulse. 
In a large series (n=103) of glioma patients [11] described  in the 
next section,  the median dose was 50 Gy (range, 20–60) delivered 
in 1.8–2.0-Gy fractions; with a mean treatment volume of 403.5 ± 
189.4 cc3 according to T2-weighted magnetic resonance imaging 
and a 2-cm margin. 
 
 
 
 
 
 
5.2.2 Bevacizumab or FDA approved Biosimilar  
 
 
Bevacizumab is commercially available and FDA approved for use in 
recurrent gliomas. The Bevacizumab biosimilars - MVASI™  and 
Zirabev™is also approved for us as a substitute for Avastin and can 
be administered for use in recurrent gliomas. 
 
Commercial drug will be used and drug preparation will be per 
package insert and infused per institutional guidelines. 
 
 
Bevacizumab will be administered intravenously at a dose of 10 mg/kg 
every 2-4 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. 

 
Version Date: 9/13/23 
 
 
 
 
18
Bevacizumab will be administered per institutional practice. If a 
patient experiences an infusion-associated adverse event, he/she may be 
premedicated for the next bevacizumab administration per institutional 
practice.   
 
 
5.2.2.1 Protocol Therapy: 
The first dose of bevacizumab will be given between Days -3 & 0.  
 
Bevacizumab Naïve patients: Patients will receive 10mg/kg which 
will continue every 2 weeks (+/- 3 days) during re-irradiation 
therapy as long as no severe toxicity occurs.  Protocol therapy will 
be considered complete after a total of 5 doses of Bevacizumab are 
given. 
 
Bevacizumab Exposed Patients: Patients will receive 10mg/kg of 
bevacizumab every 2-4 weeks (+/- 3 days) for 2-3 cycles, per MD 
discretion, during re-irradiation therapy as long as no severe 
toxicity occurs. Protocol therapy will be considered complete after 
the last fraction of PRDR is given (+/-3 days to account for the last 
dose of concurrent therapy Bevacizumab administration).  Any dose 
given after the end of PRDR, will be considered SOC during the follow-
up phase. 
 
After completion of protocol therapy, patient will be moved to 
study follow-up and Bevacizumab may be continued, per MD 
discretion, and administered per institutional guidelines.  
 
5.3 
Dose Modifications 
All toxicities will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0. 
 
  
5.3.1 Bevacizumab 
The bevacizumab dose may be reduced if any of the criteria outlined in 
Table 2 below are met.  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, treatment may resume 
when all toxicities have resolved to ≤ grade 1 or baseline. Up to 2 
scheduled doses of bevacizumab may be missed, but treatment may not be 
held for > 6 weeks 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.  

 
Version Date: 9/13/23 
 
 
 
 
19
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. 
  
 
 
 
Table 2:  Bevacizumab dose management due to adverse events 
Event 
Grade 
Action to be Taken 
Hypertension 
1 or 2 
No dose modification 
required. 
3 
If not controlled to < 
160/90 mm/Hg with 
medication, hold 
bevacizumab until BP 
improved to 
institutional goal. 
4 (including 
hypertensive 
encephalopathy) 
Discontinue 
bevacizumab. 
Hemorrhage: non-
pulmonary & non-CNS 
events 
1 or 2 
No dose modification 
required. 
3 
All 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 

 
Version Date: 9/13/23 
 
 
 
 
20
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. 
Hemorrhage: pulmonary 
or CNS 
1 
All 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. 
2, 3, or 4 
Hold bevacizumab 
until recovery to ≤ 
Grade 1.. 
Venous thrombosis 
1 or 2 
 No dose modification 
required. 
3 or 4 
Hold bevacizumab 
until recovery to ≤ 
Grade 1.. 
Arterial thromboembolic 
event (new onset, 
worsening, or unstable 
angina, myocardial 
infarction, transient 
Any grade 
Discontinue 
bevacizumab. 

 
Version Date: 9/13/23 
 
 
 
 
21
ischemic attack, 
cerebrovascular accident, 
or any other arterial 
thromboembolic event) 
Congestive heart failure 
(left ventricular systolic 
dysfunction) 
1 or 2 
No dose modifications 
required. 
3 or 4 
Hold bevacizumab 
until recovery to ≤ 
Grade 1.. 
Proteinuria 
 
 
 
 
 
 
 
 
 
 
Proteinuria Dipstick 
≥100mg/dl 
 
Patients on bevacizumab 
having a spot urinary 
protein of ≥100mg/dl may 
be delayed up to 2 weeks at 
the investigator’s discretion.  
4 (nephrotic 
syndrome) 
Discontinue 
bevacizumab. 
GI perforation 
Any grade 
Discontinue 
bevacizumab. 
Fistula 
Any grade (TE 
fistula) 
Discontinue 
bevacizumab. 
Other Grade 4 
fistula 
Discontinue 
bevacizumab. 
Bowel obstruction 
1 
Continue bevacizumab 
for partial obstruction 
NOT requiring medical 
intervention. 
2 
Hold bevacizumab for 
partial obstruction 
requiring medical 
intervention – resume 
upon complete 
resolution. 
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 
Discontinue 

 
Version Date: 9/13/23 
 
 
 
 
22
(requiring 
medical or 
surgical therapy) 
bevacizumab. 
Reversible posterior 
leukoencephalopathy 
Any grade 
(confirmed by 
MRI) 
Discontinue 
bevacizumab. 
Other unspecified 
bevacizumab-related 
adverse events 
Grade 3 
Hold bevacizumab 
until recovery to ≤ 
Grade 1. 
Grade 4 
Discontinue 
bevacizumab. 
 
  
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. 
 
 
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 Corticosteroids should be used in the smallest dose to control symptoms 
of cerebral edema and mass effect and should be discontinued if possible. 
5.4.2 Anti-seizure medications should be used as indicated. 
5.4.3 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. In 
such situations, bevacizumab will be held and may be restarted at the 
discretion of the investigator 
5.4.4 Other therapies considered necessary for the well-being of the patient 
may be given at the discretion of the investigator.   
5.4.5 Any use of complementary or alternative medications should be cleared 

 
Version Date: 9/13/23 
 
 
 
 
23
by the Principal Investigator. 
 
5.5 Criteria for Discontinuation of Treatment and Withdrawal from Study 
 
 
 
 
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 concurrent therapy 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. 
 
6.0  
ENDPOINT ASSESSMENT 
 
 
Response to therapy will require completion of the initial phase of therapy (consisting of 
concurrent re-irradiation, 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 

 
Version Date: 9/13/23 
 
 
 
 
24
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-irradiation 
treatment until death from any cause. 
 
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. 
 
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: 
 
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), end of PRDR, and at the time of each subsequent 
MRI or CT scan. 
 
6.3.1.3 Performance Status 
Patients will be graded according to Karnofsky Performance 
Status, at baseline and at each bevavizumab infusion timepoint 
(while receiving PRDR).  
 
 
 
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 5.0 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 

 
Version Date: 9/13/23 
 
 
 
 
25
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 
Criterion 
Response Category 
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

 
Version Date: 9/13/23 
 
 
 
 
26
7.0 
STUDY PARAMETERS 
 
 
Screening/Baseline1 
Concurrent (PRDR & BEV)3 
Follow-up13 
Re-irradiation 
 
X4 
 
Bevacizumab 
 
X5 
X14 
Informed consent 
X 
 
 
Neurologic/ physical examination, vitals, and KPS  
X2 
X10 
X 
QOL evaluations (MMSE, FACT-Br & FACT-Fatigue)12 
X 
End of PRDR 
X 
MRI with contrast or CT6 
X 
 
X 
Hematology7 
X 
as clinically indicated 
 
Urinalysis, no microscopy (for urine protein)8 
X 
X 
 
Pregnancy test 9 
X 
 
 
Symptom and toxicity assessment11 
X 
X 
X 
 
1 Unless otherwise noted, screening assessments must be done within 30 days prior to registration. 
2 Baseline exam will include medical history and documentation of concomitant medications. 
3 For Bev naïve: treatment will last approximately 10 weeks and will consist of 27 fractions of radiation and 5 doses of bevacizumab.  
 For Bev exposed: treatment will consist of 27 fractions of radiation and 2-3 doses of bevacizumab. 
4 Re-irradiation will begin on Day 0 and will consist of a dose of 27 fractions (total of 54Gy) over 5.5 weeks using PRDR-RT. 
5 For Bev naïve: Bevacizumab will be administered at a dose of 10 mg/kg IV for  2-week cycles. The 1st dose will occur between Days -3 
and 0 and will continue every 2 weeks (+/- 3 days) during the concurrent phase for a total of 5 doses.   
For Bev exposed:  Bevacizumab will be administered at a dose of 10 mg/kg every 2-4 weeks (+/- 3 days) for a total of 2-3 cycles. The 1st 
dose will occur between Days -3 and 0. Any dose given after end of PRDR, will be considered SOC during the follow-up phase.  
6 MRI/CT will be performed at baseline (within 30 days of registration) and per MD discretion in the follow-up phase. 
7 CBC with differential drawn at baseline then as clinically indicated. 
8 UA no micro within 28 days of registration and prior to each dose of bevacizumab starting with subsequent cycle/day after C1D1. 
9 Females of childbearing potential must have a negative serum or urine pregnancy test within 14 days of registration. 
10 Neurologic, physical examination (with KPS) and vitals will be performed prior to each bevacizumab dose.  
11 Patients will be assessed prior to each protocol infusion of bevacizumab, at completion of PRDR, and each follow-up MRI appointment.  
12 QOL’s and MMSE will be performed at baseline, end of PRDR-RT, and each follow-up MRI appointment if patient has not progressed.  
13 Long-term follow-ups after completion of PRDR therapy or early 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. 
14After completion of Concurrent therapy (see footnote 3), the patient will be moved to study follow-up and Bevacizumab may be 
continued, per MD discretion, and administered per institutional guidelines.

 
Version Date: 9/13/23 
 
 
 
 
27
 
8.0 
DRUG FORMULATION AND PROCUREMENT 
 
 
 
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 
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. 

 
Version Date: 9/13/23 
 
 
 
 
28
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, and 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, urticaria 
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. 
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 

 
Version Date: 9/13/23 
 
 
 
 
29
 
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 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.  
 
8.2.11 Nursing Implications 
 
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). 
 
9.0 
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 

 
Version Date: 9/13/23 
 
 
 
 
30
median survival ranging from 7.2-9.2 months [6, 15], and those who have 
received radiation seems to be in the range of 11-12.5 months [10, 13]. 
Those patients with GBM who are bevacizumab-naïve (Group 2) will 
presumably have improved overall outcomes compared to those who have 
been previously treated with bevacizumab (Group 1).  
In Group 1, the primary hypothesis will be a 40% prolongation of 
survival (although we will measure survival as a hazard function, this is 
expected to shift median from an anticipated 8 to 11.2 months).  To have 
at least 80% power to observe this delta, with a one-sided significance 
level of 0.1, a minimum of 24 patients will be required, and allowing for 
approximately 15% non-evaluability/drop-off, we anticipate a cohort size 
of 28.  
 
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 10 to 15 weeks.  To have at 
least 80% power to observe this delta, with a one-sided significance level 
of 0.1, a minimum of 19 patients will be required, and allowing for 
approximately 15% non-evaluability/drop-off, we anticipate a cohort size 
of 22.   
 
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 15 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, 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 

 
Version Date: 9/13/23 
 
 
 
 
31
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 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.  Sub-
analyses 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 sub-analyses 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. 
All patients enrolled on this study will be provided a separate 
consent that will allow for a brain autopsy at the time of death which is 
standard clinical consent at the University of Wisconsin.  Patients will be 
encouraged to take the brain autopsy consent home and review it with 
family and friends.  Their decision to consent or not consent will have no 
impact on this clinical trial. It is anticipated that approximately 50% of 
subjects will consent to a brain autopsy.  This will allow us qualitatively 
compare the results of brain autopsy in patients who have received PRDR-
RT /Bevacizumab to prior results (n=15) obtained with  
PRDR-RT 
 
 
10.0 
ADVERSE EVENT MONITORING & REPORTING  
 
The ongoing review of safety data will include review of clinical adverse events (AEs) 
and serious adverse events (SAEs) including skin-related toxicity assessment and 
laboratory studies.  The CTCAE version 5.0 will be used to grade all AEs. 
10.1 
Definition 
 
An AE is an undesirable medical occurrence (sign, symptom, or diagnosis) or 
worsening of a pre-existing medical condition (diabetes, congestive heart failure, 
rheumatoid arthritis) that occurs after initiation of the investigational product whether 
or not it is considered to be investigational product related.  A worsening of an 
existing medical condition is one that was present at baseline (e.g., cancer, diabetes, 
migraine headaches, gout) and became more severe, more frequent, or increased in 
duration during investigational product treatment. 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or 
side effect, regardless of the investigator or sponsor’s opinion on the relationship to 

 
Version Date: 9/13/23 
 
 
 
 
32
investigational product.  This includes, but may not be limited to, any event that (at 
any dose): 
1. Is fatal 
2. Is life threatening (places the subject at immediate risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Is a persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. A hospitalization meeting the regulatory requirement for the “serious” criteria 
is any inpatient hospital admission that includes a minimum of an overnight 
stay in a health care facility 
7. Any event that does not exactly meet this definition yet, in the investigator’s 
opinion represents a significant hazard can be assigned the “other significant 
hazard” regulatory reporting serious criteria 
8. Additionally, important medical events that may not be immediately life 
threatening or result in death or hospitalization but that may jeopardize the 
subject or require intervention to prevent one of the outcomes listed above, or 
result in urgent investigation, may be considered serious.  Examples include 
allergic bronchospasm, convulsions, and blood dyscrasias. 
 
Serious adverse events 
Serious adverse events will be collected and recorded at least throughout the study 
period beginning with the signing of the informed consent through 30 days after 
the end of the treatment phase or through the safety follow-up visit, whichever is 
longer.   
 
 All serious adverse events that occur after the subject has signed the informed 
consent form must be reported to UWCCC Data Safety and Monitoring Board and 
other regulatory agencies as per appendix 1.  
 
Serious adverse events occurring after conclusion of the study AND thought to be 
possibly related to the investigational study will be collected and reported within 
10 working days of discovery or notification of the event via the same 
mechanism. 
 
 
 
11.0  RECORDS TO BE KEPT 
This protocol will be conducted according to Good Clinical Practice Guidelines.  
Participating investigators/institutions agree to permit trial related monitoring, audits, 
IRB review, and regulatory inspections, providing direct access to source 

 
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33
documents/data.  
 
All data identified in patient evaluation table, Section 7.0 will be collected. The planning 
data, simulation films, isodose distributions (axial, coronal, and sagittal planes through 
the PTV) will be archived per radiation therapy standard clinical practice 
  
Eligibility Checklist  
 
Submitted prior to registration 
 
On Study Forms: 
 
 
Within 2 weeks of Registration 
-Baseline Form 
-Pre-Study Labs 
-Imaging form  
-QOL’s (MMSE, FACT-BR and FACTIT-Fatigue) 
 
End of Radiation: 
 
 
Within 2 weeks of Completion 
-XRT summary form 
-Appropriate Bevacizumab treatment form 
- QOL’s (MMSE, FACT-BR and FACTIT-Fatigue) 
-AE form 
 
For patients in follow-up: 
 
Every 2-3 months 
-AE form 
-MRI form (if patient hasn’t progressed) 
- QOL’s (if patient hasn’t progressed) ( MMSE, FACT-BR and FACTIT-Fatigue) 
 
Time of Death  
 
 
Within 2 weeks 
-Follow-up form 
 
 Follow-up data and signed informed consents will be kept for a minimum of five years.  
Forms will be labeled with study number, subject initials sequence numbers assigned 
sequentially when subjects are registered. 
 
12.0   PATHOLOGY REQUIREMENTS 
 
All patients who had surgery outside of UW Hospital will be asked to submit 1 H&E 
slide for review at UW 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. Shahriar Salamat and Dr. Jeffrey Helgager are the designated Neuro-Oncology 
Neuropathologists.  Send slide to Marissa Weiss. See protocol cover page for mailing address.

 
Version Date: 9/13/23 
 
 
 
 
34
 
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Lai, A., et al., Phase II study of bevacizumab plus temozolomide during and after radiation therapy for 
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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 
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Durmaz, R., et al., Management of glioblastoma multiforme: with special reference to recurrence. Clin 
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Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J 
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Kreisl, T.N., et al., Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at 
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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. 
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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. 
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Fogh, S.E., et al., Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-
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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. 
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Shepherd, S.F., et al., Hypofractionated stereotactic radiotherapy in the management of recurrent glioma. 
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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. 
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Norden, A.D., et al., Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of 
recurrence. Neurology, 2008. 70(10): p. 779-87. 
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Brada, M., et al., Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade 
glioma. J Clin Oncol, 2010. 28(30): p. 4601-8. 
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Schultz, C.J. and C.R. Geard, Radioresponse of human astrocytic tumors across grade as a function of 
acute and chronic irradiation. Int J Radiat Oncol Biol Phys, 1990. 19(6): p. 1397-403. 
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Schultz, C.J. and B.M. Davies, Confirmation of an inverse dose rate effect associated with a G2M block in 
two human glioblastoma cell lines. Proceedings of the 41st Annual Meeting of the Radiation Research 
Society, 1993: p. 156. 
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Schultz, C.J. and B.M. Davies, G2M block characteristics as a function of dose rate in two human 
glioblastoma cell lines. . Proceedings of the Radiation Research Society 42nd Annual Meeting, 1994: p. 
177. 
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Joiner, M.C., et al., Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol 
Biol Phys, 2001. 49(2): p. 379-89. 
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Marples, B., Is low-dose hyper-radiosensitivity a measure of G2-phase cell radiosensitivity? Cancer 
Metastasis Rev, 2004. 23(3-4): p. 197-207. 
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Harney, J., et al., Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys, 
2004. 59(4): p. 1190-5. 
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Short, S.C., et al., The response of human glioma cell lines to low-dose radiation exposure. Int J Radiat 
Biol, 1999. 75(11): p. 1341-8. 
23. 
Short, S.C., et al., Low-dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat 
Biol, 2001. 77(6): p. 655-64. 

 
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24. 
Tome, W.A. and S.P. Howard, On the possible increase in local tumour control probability for gliomas 
exhibiting low dose hyper-radiosensitivity using a pulsed schedule. Br J Radiol, 2007. 80(949): p. 32-7. 
25. 
Wong, E.T., et al., Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II 
clinical trials. J Clin Oncol, 1999. 17(8): p. 2572-8. 
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Cannon, G.M., et al., Pulsed reduced dose-rate radiotherapy: case report : a novel re-treatment strategy in 
the management of recurrent glioblastoma multiforme. J Neurooncol, 2007. 83(3): p. 307-11. 
27. 
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. 
28. 
Lassman, A.B., et al., Patterns of relapse and prognosis *after* bevacizumab (BEV) failure in recurrent 
glioblastoma (GBM). J Clin Oncol, 2008. 26: p. 96S abstr 2028. 
29. 
Khasraw, M., et al., Phase two trial of continuous low-dose Temozolomide (TMZ) for patients with 
recurrent glioma (MG) with and with out prior exposure to t bevacizumab (BEV). Neuro-oncology, 
2010(Piv 72 Abstract OT-14.). 
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Richards, G.M., et al., Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy 
for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region. 
Breast Cancer Res Treat, 2009. 114(2): p. 307-13. 
31.        Magnuson W, Robins HI, Mohindra P, Howard S, Large Volume Reirradiation as Salvage   
          
Therapy for  Glioblastoma after Progression onBevacizumab, J Neuro-oncology 2014     
          
(currently available on line pre publication) 
 
 
 

 
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Appendix I –  Data and Safety Monitoring Plan 
 
Oversight And Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular 
review and monitoring of ongoing clinical research in the UWCCC.  A summary of DSMC 
activities are as follows: 
• Review clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• Review Serious Adverse Events (SAE) requiring expedited reporting, as defined in 
the protocol, for clinical trials conducted at the UWCCC, and studies conducted at 
external sites for which the UWCCC acts as an oversight body. 
• Review reports generated through the UWCCC DSMS elements (Internal Audits, 
Quality Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol 
Summary Reports). 
• Notify the protocol Principal Investigator of DSMC decisions and, if applicable, any 
requirements for corrective action related to data or safety issues. 
• Work in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and unanticipated 
problems reported by the UWCCC research staff, when appropriate.  
• 
Ensure notification of SAEs which require expedited reporting are provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
 
• 
. 
 
Monitoring And Reporting Guidelines 
 
UWCCC quality assurance and monitoring activities are determined by study sponsorship and 
risk level of the protocol as determined by the PRMC. Protocols (including Intervention Trials, 
Non-Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a 
Training Grant) are evaluated by the PRMC at the time of committee review. UWCC monitoring 
requirements for trials without an acceptable external DSMB are as follows 
 
Intermediate Monitoring 
Protocols subject to intermediate monitoring generally include UW Institutional Phase I/II and Phase II Trials. These 
protocols undergo review of subject safety at regularly scheduled DOT meetings where the results of each subject’s 
treatment are discussed and the discussion is documented in the DOT meeting minutes. The discussion includes the 
number of subjects enrolled, significant toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted on a semi-annual basis by the study team for review by the DSMC. 
 
I. REVIEW AND OVERSIGHT REQUIREMENTS  
 
II.   
a)   
Serious Adverse Event – Reported Within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) must also be 

 
Version Date: 9/13/23 
 
 
 
 
37
reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day.  A 24 hr. initial “SAE Details” Report, generated 
in the UWCCC database, must be attached to the email along with any pertinent information available at 
the time of initial reporting. The DSMC Chair will review the information and determine if immediate 
action is required. Within 10 working days, all subsequent SAE documentation must be submitted 
electronically along with a 24 hour follow-up “SAE Details” Report and a completed UWCCC SAE 
Routing Form to saenotify@uwcarbone.wisc.edu. All information is entered and tracked in the UWCCC 
database. 
If the SAE occurs on a multiple-institutional clinical trial coordinated by UW Radiation Oncology, the UW 
Radiation Oncology coordinators should be notified by phone (see cover page) and email at: dho-
datamgrs@lists.humonc.wisc.edu who will ensure that all participating sites are notified of the event and 
resulting action within one working day of the determination. 
 
b)  
Serious Adverse Event – Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 working days (as described in the protocol) will also 
be sent to the UWCCC DSMC Chair via email to saenotify@uwcarbone.wisc.edu. A 10 day “SAE Details” 
report, generated in the UWCCC database must be attached to the email along with pertinent information 
regarding the SAE and the UWCCC SAE Routing Form. The Committee Chair will review the information 
and determine if further action is required.  This information is entered and tracked in the UWCCC 
database. 
If the SAE occurs on a multiple-institutional clinical trial coordinated by UW Radiation Oncology, the UW 
Radiation Oncology coordinators should be notified by phone (see cover page) and email at: dho-
datamgrs@lists.humonc.wisc.edu who will ensure that all participating sites are notified of the event and 
resulting action within one working day of the determination. 
 
c)  
Study Progress Review 
Study Progress Review- Protocol Summary Reports 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC commensurate with the Phase of 
the study. The PSR provides a cumulative report of serious adverse events, as well as any protocol violations, 
deviations or unanticipated problems, toxicities and responses that have occurred on the protocol in the 
timeframe specified. PSRs are reviewed at each DSMC meeting. 
Protocol Summary Reports enable DSMC committee members to assess whether significant benefits or risks are 
occurring that would warrant study closure. This information is also provided by Disease Oriented Working 
Group meeting minutes, internal audit and/or response review reports.  In addition, the DSMC requires the 
DOWG or protocol Study Chair to submit external DSMB reports or any other significant study-related 
information.  
In the event that there is significant risk warranting study suspension or closure, the DSMC will notify the PI of 
the DSMC findings.  The DSMC ensures that the PI reports any temporary or permanent suspension of a 
clinical trial to the sponsor (e.g., NCI Program Director, Industry Sponsor Medical Monitor, Cooperative Group 
Study Chair, etc.) and other appropriate agencies. 
 
II     EXPEDITED REPORTING OF SERIOUS ADVERSE 
EVENTS 
 
Depending on the nature, severity, and attribution of the serious adverse event an SAE 
report will be phoned in, submitted in writing, or both according to Table C below. All 

 
Version Date: 9/13/23 
 
 
 
 
38
serious adverse events must also be reported to the UWCCC Data and Safety Monitoring 
Committee Chair.  All serious adverse events must also be reported to the UW IRB (if 
applicable), and any sponsor/funding agency not already included in the list. 
 
Determine the reporting time line for the SAE in question by using the following table.  
Then refer to sections A and B below if the SAE occurred at the UWCCC or sections C 
and D if the SAE occurred at 1 South Park, Johnson Creek, or a WON Site. 

 
Version Date: 9/13/23 
 
 
 
 
39
 
Expedited Reporting Requirements for Adverse Events that Occur in Non-IND/IDE Studies Within 
28 Days Post Commercial Drug Therapy 
Reporting Requirements for Serious Adverse Events  
 
NOTE: Investigators MUST immediately report to the UWCCC DSMC, and the IRB (if applicable) ANY 
Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention. See below. 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition (FDA, ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to 
the UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization ≥ 24 
hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
* Hospitalization for medical management of grade 1-2 seizure disorders does not require reporting as 
an SAE  and consideration of a seizure as an Important Medical Event is at the discretion of the 
treating physician.* 
 
 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 28 days after study intervention and have an 
attribution of possibly, probably, or definitely related study will be reported as follows:  
      Expedited 24-hour notification followed by complete report within 10 calendar days for: 
• All Grade 4, and 5 SAEs 
 
 

 
Version Date: 9/13/23 
 
 
 
 
40
 
 
A. 
SAE Requiring 24 Hour Reporting Occurs at UWCCC: 
a.  To the IRB: 
       
 
Consult the UW-IRB website for reporting guidelines.   
      
    b.   To the UWCCC: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting 
Workflow for DOWGs on the UWCCC website (http://www.uwccc.wisc.edu) 
for specific instructions on how and what to report to the UWCCC for [24] hour 
initial and follow-up reports.  A follow-up report is required to be submitted 
within 10 days of the initial [24] hour report.   
 
For this protocol, the following entities are required to be notified: 
 
 
1. 
saenotify@uwcarbone.wisc.edu 
2.  
Steve Howard, MD: PI 
3. 
Diana Trask Research Program Manager 
 
 
SAE Requiring [10] Day Reporting Occurs at UWCCC: 
a. 
To the FDA: 
Report the SAE using the online FDA Med Watch form available at  
https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm.  Also 
print the report or save it as a pdf for reporting to the IRB (see section b)  
UWCCC (see section c).  
  
 
b.  To the IRB: 
       
 
Consult the UW-IRB website for reporting guidelines.   
      
 
c.   To the UWCCC: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting 
Workflow for DOWGs on the UWCCC website (http://www.uwccc.wisc.edu) 
for specific instructions on how and what to report to the UWCCC for [24] hour 
initial and follow-up reports.  A follow-up report is required to be submitted 
within 10 days of the initial [24] hour report.   
 
For this protocol, the following entities are required to be notified: 
 
 
1. 
saenotify@uwcarbone.wisc.edu 
2.  
Steve Howard, MD: PI 
3. 
Diana Trask Research Program Manager 

 
Version Date: 9/13/23 
 
 
 
 
41
 
Appendix IV – FACT-Br & FACT-Fatigue Scales 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 

 
Version Date: 9/13/23 
 
 
 
 
42
 
 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous .......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying .............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
GS7 
I am satisfied with my sex life .............................................
0 
1 
2 
3 
4 

 
Version Date: 9/13/23 
 
 
 
 
43
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
Br1 
I am able to concentrate ......................................................
0 
1 
2 
3 
4 
Br2 
I have had seizures (convulsions) .......................................
0 
1 
2 
3 
4 
Br3 
I can remember new things .................................................
0 
1 
2 
3 
4 
Br4 
I get frustrated that I cannot do things I used to ..................
0 
1 
2 
3 
4 
Br5 
I am afraid of having a seizure (convulsion) .......................
0 
1 
2 
3 
4 
Br6 
I have trouble with my eyesight ..........................................
0 
1 
2 
3 
4 
Br7 
I feel independent ................................................................
0 
1 
2 
3 
4 
NTX6 
I have trouble hearing .........................................................
0 
1 
2 
3 
4 
Br8 
I am able to find the right word(s) to say what I mean .......
0 
1 
2 
3 
4 
Br9 
I have difficulty expressing my thoughts ........................... 
0 
1 
2 
3 
4 
Br10 
I am bothered by the change in my personality ..................
0 
1 
2 
3 
4 
Br11 
I am able to make decisions and take responsibility .......... 
0 
1 
2 
3 
4 
Br12 
I am bothered by the drop in my contribution to the 
family ................................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
Br13 
I am able to put my thoughts together .................................
0 
1 
2 
3 
4 
Br14 
I need help in caring for myself (bathing, dressing, 
eating, etc.) ......................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Br15 
I am able to put my thoughts into action .............................
0 
1 
2 
3 
4 
Br16 
I am able to read like I used to ............................................
0 
1 
2 
3 
4 
Br17 
I am able to write like I used to ...........................................
0 
1 
2 
3 
4 
Br18 
I am able to drive a vehicle (my car, truck, etc.) .................
0 
1 
2 
3 
4 
Br19 
I have trouble feeling sensations in my arms, hands, or 
legs ......................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Br20 
I have weakness in my arms or legs ....................................
0 
1 
2 
3 
4 
Br21 
I have trouble with coordination .........................................
0 
1 
2 
3 
4 
An10 
I get headaches ................................................................... 
0 
1 
2 
3 
4 
 
 
 

 
Version Date: 9/13/23 
 
 
 
 
44