Conditions: Glioblastoma Multiforme Glioblastoma - Category
Keywords: Border Zone Stereotactic Radiosurgery Bevacizumab Recurrent Glioblastoma Multiforme Progressive Glioblastoma Multiforme Magnetic Resonance Spectroscopy Glioblastoma Brain Cancer Brain Tumor Radiosurgery
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This is a phase II study on the usage of stereotactic Gamma Knife radiosurgery as a boost to the tumor bed border zone in conjunction with the usage of bevacizumab.

Detailed description:
Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults. Unfortunately, despite aggressive surgery, radiation therapy (RT) and chemotherapy, the prognosis for this disease is poor. It is our hypothesis that GBM is a "local" disease wherein treatment failure is due to failure to eradicate tumor cells in the pathways along which the tumor eventually spreads (the "border zone").

The investigators hypothesize that treatment volume escalation will be successful at improving overall survival in patients with GBM when appropriate targeting and precision dose delivery is performed in a single treatment session. The 'border zone' of the tumor will be targeted for SRS (defined as a combination of the MRI volume of gadolinium enhancement plus up to 2 cm of the surrounding T2 volume). This represents the volume of tumor infiltrated white matter and is the route of GBM spread. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), has been used with safety and clinical success with concomitant chemotherapy in solid tumors, including GBM.

The investigators further hypothesize that a combined approach of SRS with this VEGF inhibitor will be an effective strategy for GBM because bevacizumab will maximize the effects of radiation in the treated volume and potentially reduce radiation toxicity in the adjacent brain.

Arms:
arm 1: All patients will receive Border Zone Stereotactic Radiosurgery (BZ-SRS) and additionally receive bevacizumab (10 mg/kg) one day before and then at day 14 followed by 10 mg/kg/day every 14 days until progression.

One to 14 days before BZ- SRS procedure, patients at centers with MRS experience will undergo standard brain MRI /MRS

Interventions: intervention 1: Bevacizumab intervention 2: Magnetic Resonance Spectroscopy (MRS) intervention 3: Border Zone Stereotactic Radiosurgery (BZ-SRS)
Intervention descriptions: intervention 1: Patients will receive bevacizumab (10 mg/kg) one day before and then at day 14 followed by10 mg/kg/day every 14 days until progression. intervention 2: Subjects will have MRS prior to BZ-SRS. intervention 3: The 'border zone' of the tumor will be targeted by SRS in a single session.

Protocol document:
Prot_SAP_000.pdf: 
 
UPCI 13-063 Page 1 of 45 
Phase II Study of Border Zone Stereotactic Radiosurgery With Bevacizumab in Patients with 
Recurrent or Progressive Glioblastoma Multiforme 
 
Protocol Number: 
UPCI 13-063 
(Genentech ML28725) 
 
Principal Investigator: 
Ajay Niranjan, M.D, MBA 
Department of Neurosurgery 
UPMC Presbyterian  
200 Lothrop Street, F158 
Pittsburgh, PA  15213  
Phone:  412-647-6779;  
Email:  niraax@upmc.edu 
 
 
 
Clinical Research 
Coordinators 
Melinda Vargas-Jaffe, RN, BSN 
Clinical Research Services 
UPMC Cancer Pavilion 
5150 Centre Ave, 
Pittsburgh, PA 15232 
Phone: 412-235-1320 
Email: vargasjaffema@upmc.edu 
 
Lisa Baxendell, RN 
Sarah J. Anderson,  RN , BSN 
Clinical Research Coordinator 
UPMC Cancer Pavilion 
5150 Centre Avenue 
Pittsburgh, PA 15232 
Phone:  412-647-8569 
Email: andersonsj3@upmc.edu 
 
 
Department of Neurosurgery 
UPMC Presbyterian  
200 Lothrop Street, F158 
Pittsburgh, PA  15213  
Phone: 412-647-4994 
Email: decesx@upmc.edu 
 
 
Statistician: 
Daniel Normolle, PhD 
UPCI Biostatistics Shared Resource Facility 
Phone:  412-383-1591; E-mail:  dpn7@pitt.edu  
 
Version 
November 23, 2016 
IND# 
Exempt 
 
 


 
UPCI 13-063 Page 2 of 45 
Table of Contents 
1. PROTOCOL SUMMARY .................................................................................................................... 4 
2. BACKGROUND/RATIONALE .......................................................................................................... 5 
3. OBJECTIVES ....................................................................................................................................... 8 
4. STUDY DESIGN AND ELIGIBILITY CRITERIA ............................................................................ 8 
4.1  
Study Design .............................................................................................................................. 9 
4.2 
Inclusion Criteria ........................................................................................................................ 9 
4.3 
Exclusion Criteria ..................................................................................................................... 10 
4.4 
Proposed SRS Target and Dose ............................................................................................... 11 
4.5 
Protocol Schema ....................................................................................................................... 12 
4.6 
Sample Size .............................................................................................................................. 18 
5. PATIENT REGISTRATION .............................................................................................................. 18 
6. STEREOTACTIC RADIOSURGERY TREATMENT PROTOCOL ............................................... 18 
6.1 
General Plan: ............................................................................................................................ 18 
6.2 
Treatment Plan Requirements .................................................................................................. 18 
6.3 
Treatment Volume Definition .................................................................................................. 18 
7. CONCOMITANT MEDICATIONS .................................................................................................. 19 
8. TOXICITY MANAGEMENT ............................................................................................................ 19 
8.1 
Radiation Toxicity: ................................................................................................................... 19 
8.2 
Hematologic Toxicity:.............................................................................................................. 19 
8.3 
Other Toxicities: ....................................................................................................................... 19 
9. SCHEDULE OF ASSESSMENTS ..................................................................................................... 19 
9.1 
Screening Procedures ............................................................................................................... 19 
9.2  
 Post SRS Study Procedures ..................................................................................................... 20 
9.3  
Follow-up post 12 months SRS: .............................................................................................. 20 
10.0. CRITERIA FOR EVALUATION ................................................................................................. 21 
10.1  
Clinical Neurological Examination ...................................................................................... 21 
10.2 
Brain Imaging ....................................................................................................................... 21 
10.3 
MR Spectroscopy: ................................................................................................................ 22 
10.4 
Definition of Tumor Progression .......................................................................................... 22 
10.5 
Overall Response .................................................................................................................. 23 
11. CRITERIA FOR TERMINATION................................................................................................... 23 
12. STATISTICAL CONSIDERATIONS ............................................................................................. 24 
12.1 
Study Design and Sample Size ............................................................................................. 24 


 
UPCI 13-063 Page 3 of 45 
12.3 
Safety Stopping Rule ............................................................................................................ 24 
12.4 
Endpoint Definitions and Statistical Analysis ...................................................................... 25 
12.5 
Futility Stopping Rule ........................................................... Error! Bookmark not defined. 
12.6 
Replacement of Patients ....................................................................................................... 26 
13.  ETHICAL ASPECTS ...................................................................................................................... 26 
13.1 
Regulatory Considerations ................................................................................................... 26 
13.2 
Independent Ethics Committees/Institutional Review Board ............................................... 26 
14 SAFETY REPORTING OF ADVERSE EVENTS ........................................................................ 27 
14.1 
Assessment of Safety ............................................................................................................ 27 
Specification of Safety Variables........................................................................................................ 27 
    14.2         Methods and Timing for Assessing and  Recording Safety Variables ................................. 28 
14.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events .................................. 29 
14.4 
Publishing and FDA Reporting ............................................................................................ 32 
15. 
DATA SAFETY MONITORING PLAN .................................................................................... 32 
16. REFERENCES ................................................................................................................................. 33 
17. APPENDICES .................................................................................................................................. 36 
Appendix 1:  Karnofsky Performance Status ...................................................................................... 36 
Appendix 2 Current Response Criteria for Malignant Gliomas ......................................................... 37 
Appendix 3 Radiosurgery Dose-Volume Curve ................................................................................. 39 
Appendix 4 Study Flowchart .............................................................................................................. 40 
Appendix 5 Study Schedule ................................................................................................................ 41 
l upon completion copies of  the forms will be forwarded to the PI. .................................................. 42 
Appendix 6 RTOG/EORTC Acute Radiation Morbidity Scoring ...................................................... 42 
Appendix 7 Bevacizumab Related Events of Special Interest ............................................................ 44 
Appendix 8  Safety Reporting Fax Cover Sheet ................................................................................. 45 
 
 
 


 
UPCI 13-063 Page 4 of 45 
1. PROTOCOL SUMMARY 
 
Title:  Phase II Study of Border Zone Stereotactic Radiosurgery with Bevacizumab in Patients with 
Recurrent or Progressive Glioblastoma Multiforme 
 
Indication: Recurrent or Progressive Glioblastoma Multiforme  
 
Objectives:    
Primary Objective:  
To assess the efficacy of Border Zone SRS with bevacizumab by overall survival in patients 
with recurrent or progressive glioblastoma following conventional management with surgery, 
fractionated radiation therapy, and chemotherapy. 
 
Secondary Objectives:  
1. To estimate progression-free and overall survival at 6 months 
2. To evaluate the CNS toxicity of combined treatment, as measured by 
RTOG/EORTC Acute Radiation Morbidity Scoring and the NCI CTCAE v4.0 for 
late toxicity. Unacceptable toxicity will be considered to be irreversible grade 3 
(severe), any grade 4 (life threatening) or grade 5 (fatal) RTOG CNS toxicity 
occurring within 3 months of GK. 
3. To evaluate whether border zone SRS with bevacizumab improves tumor response 
or reduces radiosurgical toxicity compared to historical outcomes. 
4. To evaluate the quality of life of border zone SRS with bevacizumab administration 
5. To evaluate the potential value of magnetic resonance spectroscopy (MRS) in 
improvement of border zone target selection and detection of therapeutic response 
 
 
Study Type:  Interventional 
 
Study Design:  Single-arm, one-stage phase II trial for patients with recurrent glioblastoma. 
Allocation: Non-Randomized 
Endpoint Classification: Safety/Efficacy Study 
Masking: Open Label 
Primary Purpose: Treatment 
 
Patient Numbers:  A total of 40 patients with recurrent glioblastoma will be enrolled.    
 
 
 
 
Summary of Patient Eligibility Criteria 


 
UPCI 13-063 Page 5 of 45 
Histological confirmation of glioblastoma; prior first-line treatment with surgery, fractionated radiation 
therapy, and chemotherapy for glioblastoma; age > 18 years; life expectancy >12 weeks; Karnofsky 
Performance Status ≥ 60; adequate organ function; signed patient informed consent; willingness to 
forego additional therapy until evidence of disease progression. 
 
End Points   
 
Primary:   
Overall survival (OS)  
Secondary:   Progression-free survival at 6 months (PFS-6) and overall survival at 6 months (OS),  
progression-free survival (PFS),  
location of recurrence,  
symptomatic adverse radiation effect (ARE) rate,  
rate and type of adverse effects by bevacizumab, 
reoperation rate, reoperation findings (estimated percentage of viable tumor vs. ARE),  
QOL analysis  
 
 
Project Summary in Lay Terms 
 
Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults. Unfortunately, 
despite aggressive surgery, radiation therapy (RT) and chemotherapy, the prognosis for this disease is 
poor. It is our hypothesis that GBM is a “local” disease wherein treatment failure is due to failure to 
eradicate tumor cells in the pathways along which the tumor eventually spreads (the “border zone”). 
We hypothesize that treatment volume escalation will be successful at improving overall survival in 
patients with GBM when appropriate targeting and precision dose delivery is performed in a single 
treatment session. The ‘border zone’ of the tumor will be targeted for SRS (defined as a combination of 
the MRI volume of gadolinium enhancement plus up to 2 cm of the surrounding T 2 volume). This 
represents the volume of tumor infiltrated white matter and is the route of GBM spread. Bevacizumab, 
a monoclonal antibody to vascular endothelial growth factor (VEGF), has been used with safety and 
clinical success with concomitant chemotherapy in solid tumors, including GBM. We hypothesize that 
a combined approach of SRS with this VEGF inhibitor will be an effective strategy for GBM because 
bevacizumab will maximize the effects of radiation in the treated volume and potentially reduce 
radiation toxicity in the adjacent brain.  
 
2. BACKGROUND/RATIONALE 
 
Glioblastoma Multiforme (GBM) is the most common primary brain tumor in adults, with 
nearly 10,000 cases diagnosed annually in the United States. Unfortunately, despite aggressive surgery, 
radiation therapy (RT) and chemotherapy, the prognosis for this disease is poor. The expected five-year 
survival rate is less than 5%.1 GBM is never a surgically curable lesion. The local control of the disease 
however has been improved markedly using image guided neurosurgical cytoreductive techniques 
followed by aggressive local therapy. Indeed, the resectability of the initial lesion correlates with 
survival.2-3 In addition, the volume of locally recurrent disease correlates inversely with survival.4 
Recurrence and disease progression generally is adjacent to the surgical treatment volume. 
 


 
UPCI 13-063 Page 6 of 45 
Research has shown that glial cells mutate over time, become polarized, develop increasing 
local invasiveness, express genes that create proteins which cause breakdown of the extracellular 
matrix along white matter pathways, and develop actin contractility, in order to become motile. This 
motile behavior suggests a reappearance of the motile phenotype seen in glial cells migrating from the 
germinal matrix during embryonic development.5 Indeed, there is a suggestion that if these mutated 
cells cannot migrate, they die. It is our hypothesis that GBM is a “local” disease whose treatment 
failure is due to neglect of the pathways along which the tumor eventually spreads (the “border zone”). 
It would be expected that treatment directed at local control would improve overall outcomes, as 90% 
of recurrences in malignant gliomas are located within 2 cm of the enhancing edge of the original 
tumor on CT scans6-7 Indeed, many efforts at intensifying local radiation therapy suggest an 
improvement in outcome with higher doses. In an analysis of data from the Brain Tumor Study Group 
protocols, an improvement in median survival time was demonstrated with increasing RT dose 
(delivered conventionally): from 18 weeks without radiation, to 28 weeks with 50 Gy, 36 weeks with 
55 Gy and 42 weeks with 60 Gy.8 Unfortunately, efforts to increase radiation dose beyond 60 Gy did 
not improve outcomes but did increase toxicity. Fractionated stereotactic reirradiation for recurrent 
GBMs (performed with a median dose of 36 Gy in with fractions of 5 X 2 Gy/week) was associated 
with an additional median survival time of 8 months without severe radiation effects.9 
 
Stereotactic radiosurgery (SRS) is a less-invasive treatment technique, and is usually performed on an 
outpatient basis.  Numerous review articles discuss this delivery method.10-12 The safety of SRS has 
been investigated by the RTOG in a phase I dose escalation study (RTOG 90-05) for the treatment of 
recurrent primary brain tumors and CNS metastases in patients who have previously received 
irradiation to the brain. The maximal tolerable dose based on overall toxicity was determined to be 24 
Gy for <= 20mm tumors, 18 Gy for 21-30 mm tumors, and 15 Gy for 31-40 mm tumors.13 Appropriate 
targeting is essential to improve the success of additional radiation techniques in treating GBM. It has 
become clear that treating the contrast enhancing portion of the tumor is insufficient in most cases. For 
example, image guided stereotactic biopsies have shown infiltrating tumor cells in the adjacent high T2 
signal  region around the contrast-enhancing tumor on MRI 14 In addition, work with glioma cell lines 
has shown that diffuse astrocytoma, and especially GBM, invade the brain preferentially along white 
matter fiber tracts.15-17 Because this property is shared with human fetal brain cells that have been 
transplanted into the adult brain, it has been hypothesized that the migratory mechanisms of glioma 
cells may be related to embryonic development.5 Spread along white matter pathways generally leads 
to contralateral spread via the corpus callosum, and diffuse, incurable disease.17 Thus, based on the 
known invasive and migratory properties of glioma cells, it is not surprising that dose escalation 
focused on the contrast-enhancing portion of glioblastoma tumor has not been successful. In addition to 
the RTOG efforts at dose escalation with conventional techniques, a recently reported RTOG trial 
(RTOG 93-05) of upfront SRS to the contrast-enhancing portion of GBM failed to show a significant 
benefit for SRS over RT alone.18  
 
Re-irradiation with SRS has been used in patients with focally recurrent glioblastoma because of its 
beneficial effect on survival.  McDermott et al. 19 reported a series of 79 patients with recurrent 
glioblastoma treated with SRS at UCSF.  The authors achieved a median survival of 40.6 weeks 
patients with glioblastoma and 61.6 weeks for those with recurrent anaplastic astrocytoma; similar 
results have been reported from other series 20-21.  Most single or multiple agent chemotherapy 
regimens used in this setting, in contrast, can only control disease progression an average of 8-24 
weeks, with median survival expectation of only 20-42 weeks 22-25.  It is unusual to have an effective 


 
UPCI 13-063 Page 7 of 45 
response to additional chemotherapy, and treatment with these agents can be complicated by the 
systemic effects of treatment, such as myelosuppression, nausea, and anorexia.    
 
Patterns of recurrence following SRS are similar to those reported for conventional radiation, with 
focal recurrence in 83.5% of patients 19.  Patients tend to fail within 1 to 2 cm from the contrast-
enhancing edge of the lesion being treated, in keeping with the biology of this tumor, which is a highly 
infiltrative, invasive tumor.  One potential reason for the high rate of subsequent local recurrence after 
radiosurgery at recurrence is inadequate targeting of viable tumor when radiosurgery is performed.  It 
is standard practice to use the region of gadolinium enhancement on T1-weighted magnetic resonance 
imaging (MRI) as the basis for the treatment plan for SRS.  
 
However, it is known that gadolinium enhancement does not correspond fully to active tumor; there are 
often regions of non-enhancing tumor that extend beyond the areas of contrast enhancement.  These 
areas may be better defined using MRS; elevation of choline (Cho) levels and an increased ratio 
between choline and n-acetyl-acetate (NAA) correlate with tumor presence (26).   In addition, selected 
reports suggest that  the outcome of patients with recurrent gloiblastoma treated with SRS is correlated 
with the degree of overlap between treatment target (based on gadolinium-enhanced MRI) and 
presence of tumor as assessed by MRS (27-29). Areas of tumor detected by MRS that are not included 
in the SRS target volume are likely to recur, and that there is a trend toward poorer survival in these 
patients. We hypothesize that the use of a combination of gadolinium enhancement and elevated 
Cho:NAA ratio via MRS to determine the treatment target volume (the “border zone”) for SRS may 
improve target selection during SRS for  focally-recurrent glioblastoma.  
 
Glioblastomas are innately hypoxic tumors with strong endogenous expression of vascular endotherial 
growth factor (VEGF) and VEGF receptors and consequently demonstrate vigorous angiogenesis. 
Bevacizumab, a humanized monoclonal antibody to VEGF, has been used with safety and clinical 
success with concomitant chemotherapy in solid tumors 26-28, including GBM 29-31. Several reasons 
exist to combine bevacizumab and RT. These include the ability of antiangiogenic agents to sensitize 
tumor endothelium to RT by depletion of VEGF and the reduction of its pro-survival signaling.32-33 
Recently,  a Phase II trial of single-agent bevacizmab at tumor progression in recurrent GBM patients 
who underwent conventional RT and temozolomide chemotherapy reported that six (12.5%) of 48 
patients had drug-associated toxicity (five thromboembolic events, one bowel perforation). The median 
progression free survival (PFS) and overall survival (OS) was 16 weeks and 31 weeks, respectively. 
The 6 months PFS and OS was 29% and 57%, respectively.34 We hypothesized that a combined 
approach of SRS with VEGF inhibitor would be an effective 
strategy for GBM because bevacizumab could maximize the effects 
of radiation and avoid radiation toxicity. 
 
Figure. SRS followed by Bevacizumab  
GBM patient who underwent surgical resection followed by 
fractionated RT and Temozolomide chemotherapy developed tumor 
progression. This patient underwent Gamma Knife radiosurgery (14 
Gy/50% isodose) followed by Bevacizumab. The target was only 
Gd enhanced area with progression. The tumor was significantly 
smaller in size 10 months after SRS with Bevacizumab without 
adverse radiation effects. 
 


 
UPCI 13-063 Page 8 of 45 
Recently the University of Pittsburgh published a case-control study of salvage Gamma Knife 
stereotactic radiosurgery followed by bevacizumab for recurrent GBMs comparing to recurrent GBM 
without bevacizumab 35.  Compared with patients who did not receive bevacizumab, the patients who 
received bevacizumab had significantly prolonged PFS (6-months PFS: 73% vs. 58%, median PFS: 15 
months vs 7 months, p=0.035) and OS (6-months OS: 100% vs. 89%, median OS: 18 months vs 12 
months, p=0.005), and were less likely to develop an adverse radiation effect (9% vs 46%, p=0.037). 
 
The significance of this research is that Border Zone SRS itself is a novel technique. We hypothesize 
that the addition of bevacizumab will reduce the risk of ARE in the volume treated by SRS, while 
having a direct therapeutic effect to the solid tumor itself.  It is critical to study the safety, toxicity, and 
effectiveness of Border Zone SRS with bevacizumab. Volumetric maps of Border Zone radiosurgical 
volumes will be defined using T2 MRI. The greatest potential impact of this treatment paradigm is 
soon after conventional management of GBM (after initial surgery or biopsy, radiation therapy, and 
concomitant temozolomide chemotherapy) has been confirmed to fail.  
 
Because of the high mortality of GBM, statistically significant data should become available within 3 
years of the onset of the trial.  
 
3. OBJECTIVES 
 
Primary Objective:  
To assess the efficacy of Border Zone SRS with bevacizumab as measured by overall survival 
in patients with recurrent or progressive glioblastoma following conventional management with 
surgery, fractionated radiation therapy, and chemotherapy. 
 
Secondary Objectives:  
 To evaluate progression free and overall survival at 6 months 
 To evaluate the CNS toxicity of combined treatment, as measured by RTOG/EORTC 
Acute Radiation Morbidity Scoring and the NCI CTCAE v4.0 for late toxicity. 
Unacceptable toxicity will be considered to be irreversible grade 3 (severe), any grade 4 
(life threatening) or grade 5 (fatal) RTOG CNS toxicity occurring within 3 months of 
GK. 
 To evaluate whether border zone SRS with bevacizumab improves tumor response or 
reduces radiosurgical toxicity compared to historical outcomes. 
 To evaluate the quality of life of border zone SRS with bevacizumab administration 
 To evaluate the potential value of magnetic resonance spectroscopy (MRS) in 
improvement of border zone target selection and detection of therapeutic response. 
 
 
 
 
4. STUDY DESIGN AND ELIGIBILITY CRITERIA 
 


 
UPCI 13-063 Page 9 of 45 
4.1  
Study Design 
This is a Non-Randomized Phase II trial.  A total of 40 recurrent GBM patients will be enrolled into the 
trial and all will undergo Border Zone Stereotactic Radiosurgery (BZ-SRS) with bevacizumab. They 
will receive BZ-SRS and additionally receive bevacizumab (10 mg/kg) one day before and then at day 
14 followed by 10 mg/kg/day every 14 days until progression. All patients enrolled in the study will be 
evaluated for progression-free survival, overall survival, symptomatic ARE, reoperation rate, 
reoperation findings (estimated percentage of viable tumor vs. ARE), quality of life evaluation, and 
toxicity. 
 
4.2 
Inclusion Criteria 
 
1) Histologically confirmed glioblastoma multiforme, WHO grade IV astrocytoma. 
2) Prior first-line treatment with surgery or biopsy followed by fractionated radiotherapy with 
concurrent temozolomide-containing chemotherapy is required for glioblastoma patients.  
Additional prior chemotherapy is allowed, without limitation on number of recurrences.   
3) An interval of  2 months since completion of fractionated radiotherapy. 
 
4) Age > 18 years  
5) Life expectancy of at least 12 weeks. 
 
6) Karnofsky Performance Status score (KPS) of ≥ 60 (Appendix 1). 
7) Documented recurrent disease: Recurrent disease is defined either as radiological 
confirmation of the tumor, as an increase in tumor size of at least 25% based upon serial MR 
images, or as development of a new site of disease.   
 Tumor volume will be calculated using the sum of the largest cross-sectional 
perpendicular diameters of contrast-enhancing tumor, the sum of the largest cross-
sectional perpendicular diameters of FLAIR abnormality, or as worsened spectroscopic 
characteristics for any tumor type (development of ≥ 2 new voxels with CNI ≥ 3, or ≥ 
25% increase in the sum of the CNI ratios within a group of previously abnormal voxels 
[where abnormal is defined as CNI ≥ 3]).   
 Disease must be evaluable, but does not need to be measurable.  
 The target site for SRS does not need to be located in a previously-irradiated area. 
 
8) Eligibility for stereotactic radiosurgery using MRI targeting: The decision to treat with 
stereotactic radiosurgery will be made by a consensus of the radiation oncology, neurosurgery 
and neuro-oncology providers or their alternates at the weekly Brain Tumor or Stereotactic 
Radiosurgery Tumor Conferences. All patients must have no restrictions to obtaining MRI with 
and without paramagnetic contrast.  
9) BUN < 25 and Cr < 1.7 
10) Adequate bone marrow, hepatic and renal function (ANC ≥1,500/μL, hemoglobin of ≥10.0 
g/dL, platelet count of ≥100,000/L, aspartate aminotransferase/ alanine aminotransferase of 
≤2.5 × upper limit of normal, serum bilirubin of ≤1.5 × upper limit of normal, urine protein and 
urine blood negative to trace on POCT urine dip to Proteinuria at screening as demonstrated by 
either:  Urine Protein:Creatinine (UPC) ratio ≥ 1.0 at screening OR Urine dipstick for 
proteinuria ≥ 2+ (patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline 
should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to 
be eligible) 


 
UPCI 13-063 Page 10 of 45 
11) Negative pregnancy test at the time of SRS in any patient who could be pregnant. 
12) Willingness to forego additional therapy until evidence of disease progression.  
 
13) Signed and witnessed informed consent and signed authorization for the release of their 
protected health information. 
 
4.3 
Exclusion Criteria 
 
1. General Medical Exclusions:  
1) Current, recent (within 4 weeks of the first infusion of this study), or planned participation in 
an experimental drug study.  
2) Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or 
carcinoma in situ of the cervix within last 3 years. 
3) Prior radiosurgery 
4) Prior intracavitary irradiation or Gliadel wafers. 
 
2. Disease-Specific Exclusions:  
1) Inability to comply with protocol or study procedures  
2) Prior treatment with bevacizumab.  
3) Inability to undergo MRI with and without contrast administration. 
 
3. Bevacizumab-Specific Exclusions:  
1) Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg and/or 
diastolic blood pressure > 90 mmHg).  
2) Prior history of hypertensive crisis or hypertensive encephalopathy. 
3) New York Heart Association (NYHA) Grade II or greater congestive heart failure.  
4) History of myocardial infarction or unstable angina within 6 months prior to Day 1.  
5) History of stroke or transient ischemic attack within 6 months prior to Day 1.  
6) Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1.  
7) History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1 month 
prior to Day 1.  
8) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation).  
9) Major surgical procedure, open biopsy, or significant traumatic injury within 14 days prior to 
Day 1 or anticipation of need for major non -cranial surgical procedure during the course of the 
study.  
10) Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to Day 1.  
11) History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.  
12) Serious, non-healing wound, active ulcer, or untreated bone fracture. 
13) Proteinuria as demonstrated by: (a) Urine protein: creatinine (UPC) ratio >/= 1.0 at 
screening OR (b) Urine dipstick for proteinuria >/= 2+ (patients discovered to have >/= 2+ 
proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and 
must demonstrate </= 1g of protein in 24 hours to be eligible).  
14) Known hypersensitivity to any component of bevacizumab  


 
UPCI 13-063 Page 11 of 45 
15) Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception 
(men and women) in subjects of child-bearing potential. 
 
4.4 
Proposed SRS Target and Dose 
 
 
Standard MRI Targeting 
 
On the day of the SRS procedure, after application of an MRI compatible Stereotactic head 
frame, each patient will undergo stereotactic brain MRI. The target volume will be determined using 
commercially available radiosurgery software.  The target volume will include up to 2 cm of the high 
T2 signal brain surrounding the contrast enhancing tumor. This volume may include signal change 
noted within the corpus callosum. The total SRS dose will depend on the target volume and the 
proximity of dose limiting adjacent critical structures, such as the optic nerve and brain stem.   
 
Whenever feasible, the centers will have the option of using MRS during radiosurgery planning. One 
to 14 days before SRS procedure, patients at centers with MRS experience will undergo standard brain 
MRI and MRS). A choline to N-acetyl aspartate index (CNI) on MRS ≥ 3 is considered tumor 
metabolism (see 10.3). Depending on total T2 treatment volume, we will attempt to include the area of 
CNI ≥ 3 within the 50% isodose volume at the time of SRS procedure. The target volume will include 
up to 2 cm of the high T2 signal brain surrounding the contrast enhancing tumor. Using the 
preoperative MRS coregistered to the intraoperative MRI, we will adjust the SRS target volume. This 
volume may include signal change noted within the corpus callosum. The total SRS dose will depend 
on the target volume and the proximity of dose limiting adjacent critical structures, such as the optic 
nerve and brain stem.   
 
Target definition:  
Standard MRI targeting 
1) Gadolinium enhanced area + all T2 hyper intensity area if it is < 2 cm (maximum diameter): 
 
 
 
 
Or  
2) Gadolinium enhanced area + maximum 2 cm margin of T2 hyper intensity area  if T2 hyper 
intensity areais  > 2 cm.  
 
Optional: Whenever feasible, at selected centers MRS will be used during radiosurgery 
planning. The area of CNI on MRS (1-14 days before SRS) ≥ 3 will be targeted provided that it 
falls within the volume limitation of up to 2 cm of T2 signal surrounding the contrast enhancing 
tumor volume. 
 
 
 
 
 
 
Figure. Border zone SRS 
GBM patient who underwent surgical resection followed by fractionated RT 
and Temozolomide chemotherapy developed tumor progression. 
(Upper) Gamma Knife planning for only Gd enhanced area. The target volume 
= 21.4 cc. 
(Lower) Border zone Gamma Knife planning for Gd enhanced area + T2 hyper intensity area. The target volume = 42.6 cc. 
 
 


 
UPCI 13-063 Page 12 of 45 
 
 
Figure. MRS targeting 
The various steps in delineating the 
metabolic lesion. First, a 3D array of 
spectra is acquired (a) and the CNI for 
each voxel in the array of spectra is 
calculated (b) to produce a low- 
resolution CNI map (c). This map is 
resampled 
to produce a high-resolution CNI map 
(d) that is contoured using a CNI 
value of 2. This contour is overlaid 
onto the reference image (e). 
CNI = Cho/NAA index 
 
J Neurosurg 101:467–475, 2004 
 
 
 
 
 
 
Margin dose: 
The dose will be prescribed to the isodose surface (50%) which encompasses the border zone of the 
tumor. The maximum dose will be normalized to the 100% and dose prescribed to the 50% isodose 
surface. 
 
The 100% (maximum) dose will be recorded for each patient. The prescription dose shall be delivered 
to the 50% (maximum = 100%) isodose surface, and is defined as the minimum dose to the target 
volume. . This minimum dose shall be established by an examination of the target dose-volume 
histogram and the dose distribution on surrounding normal brain. Following doses are suggested 
however, these doses may need to be adjusted depending upon the interval period between the RT and 
radiosurgery. In case RT was completed less than 3 months ago these doses may need to be lowered. 
. 
 
Less than or equal to 8 cc: 
18 Gy 
 
8-15 cc: 
 
 
16 Gy 
 
16-30 cc: 
 
 
14 Gy 
 
31-35 cc:  
 
 
12 Gy 
 
36 cc or more:  
 
10 Gy 
 
4.5 
Protocol Schema  
a) Day -14 to -1: Patients will undergo MRS, at 
participating centers with MRS experience.  
 
b) Day -1: Patients will be treated with bevacizumab 10 
mg/kg 1 day before SRS.  
 
c) Day 1: Patients will undergo Border Zone SRS. 
Total dose of Border Zone SRS will depend on the 
size of the target volume and the proximity of adjacent 
GBM patients who underwent 
surgical resection or biopsy followed by
fractionated RT and Temozolomide chemotherapy
Residual tumor after partial tumor resection or biopsy
Recurrent or progressive tumor: > 25% growth 
on gadlinium-enhanced, T2, FLAIR or MRS imaging
(Day 0) Border Zone Stereotactic Radiosurgery
Combined tumor volume
on combined gad-enhanced and T2 abnormal area
MRS of CNI > 3 must be included in the target
(Day -1 to -14) MRS (CNI > 3 as tumor recurrence)
(Day -1) Bevacizumab
Evaluation of toxicity
(Day 14, 14-day cycle)
Bevacizumab
Evaluation of tumor control, type of failure, survival


 
UPCI 13-063 Page 13 of 45 
critical structures. When possible the target volume will include the edematous area surrounding 
the contrast enhancing tumor and the area of elevation of choline (Cho) levels and an increased 
ratio between choline and n-acetyl-acetate (NAA) in the MRS along the white matter pathways of 
spread (“border zone”).  
 
d) Fourteen days after SRS, patients will be treated with 14-day cycle of bevacizumab (10 mg/kg) until 
progression. Dose delays were allowed for reversible and preventable toxicity (See 4.5.2).  
  
e) All patients will have an evaluation of SRS toxicity 6 months after SRS.  
 
f) All patients will undergo a MRI in order to ascertain study eligibility, at the time of SRS, and then 
after every four cycles of bevacizumab. MRI scans will be assessed using both the historical 
subjective Levin criteria and the more recent objective Macdonald criteria (30, 31). The Levin 
criteria consider extent of gadolinium enhancement, edema, and mass effect in a global assessment 
of the scan compared with baseline. Response is scored as a complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) using RECIST criteria. In contrast, 
the Macdonald criteria use linear measurements of target lesion cross-sectional diameters to define 
response (Appendix 2-1). The RANO (Response Assessment in Neuro-Oncology) Response 
Criteria will be also used as updated response assessment criteria (Appendix 2-2) (40). 
 
 
4.5.1 Bevacizumab administration 
 
 
4.5.1.1 Rate of Infusion 
 
The initial bevacizumab dose should be delivered over 90 minutes as a continuous IV infusion 
prior to all chemotherapy infusions. If the first infusion is tolerated without infusion-associated 
adverse events (fever and/or chills), the second infusion may be delivered over 60 minutes. If the 
60-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 minutes. 
 
 
If a patient experiences bevacizumab infusion-associated adverse events, patient may receive pre-
medication (acetaminophen, diphenhydramine, steroids or other medications given for symptom 
control) at the investigators’ discretion, prior to the next bevacizumab infusion. If pre-medication 
is required, the infusion time may not be decreased for the subsequent infusion. However, if the 
next infusion is well tolerated with pre-medication, the subsequent infusion time may then be 
decreased by 30 minutes per infusion to a minimum infusion time of 30 minutes, as long as the 
patient continues to receive the same pre-medication. 
 
 
If a pre-medicated patient experiences infusion-associated adverse events with the 60-minute 
infusion, all subsequent doses should be given over 90 minutes. Similarly, if a pre-medicated 
patient experiences infusion-associated adverse events with the 30-minute infusion, all subsequent 
doses should be given over 60 minutes. 
 
 
A rate-regulating device should be used for all bevacizumab infusions. When the bevacizumab IV 
bag is empty, 50 mL of 0.9% sodium chloride injection, USP, should be added to the IV bag or an 
additional bag should be hung. An alternative method of flushing the infusion line would be to 
replace the empty bevacizumab infusion bag with a 50 mL bag of 0.9% sodium chloride injection 


 
UPCI 13-063 Page 14 of 45 
and infuse a volume equal to that of the tubing to ensure complete delivery of the bevacizumab. 
The infusion should be continued for a volume equal to that of the tubing to ensure complete 
delivery of the bevacizumab. 
 
 
  
4.5.1.2 Anaphylaxis Precautions 
 
Anaphylaxis precautions should be observed during bevacizumab administration. 
 
 
The patient’s blood pressure and heart rate should be monitored every 15 minutes during the first 
infusion. 
 
 
Emergency agents including oxygen, oral and endotracheal airways, intubation equipment, 
epinephrine, antihistamines and corticosteroids should be available. 
 
 
In the event of a suspected anaphylactic reaction during bevacizumab infusion, stop the 
bevacizumab infusion and apply a tourniquet proximal to the injection site, if possible, to slow 
systemic absorption of bevacizumab. Administer antihistamines, epinephrine, or other medications 
at the investigator’s discretion. 
 
4.5.1.3 Bevacizumab Infiltration 
 
Should infiltration of the bevacizumab infusion occur, the following steps are to be taken: 
 
 Discontinue the IV. 
 If a significant volume of the bevacizumab infusion remains, restart the IV and complete the 
infusion. 
 Treat the infiltration according to institutional guidelines for infiltration of a non-caustic agent. 
 
4.5.1.4 Hypertension 
 
Hypertension is a known and potentially serious adverse event associated with bevacizumab 
treatment. Patients should have their BP monitored closely during the first cycle of therapy and 
prior to each infusion of bevacizumab. Hypertensive mediation should be initiated or increased per 
routine practice.  
 
4.5.1.5 Wound complications and surgery 
 
The appropriate interval between the last dose of bevacizumab and elective surgery is unknown; 
however, the half-life of bevacizumab is estimated to be 20 days. The study will suspend 
bevacizumab for at least 28 days prior to elective surgery if needed because of continued tumor 
progression. In addition, bevacizumab should not be restarted until at least 4 weeks after major 
surgery provided that the wound has adequately healed. 
 
 
 
NOTE: If, for any reason, patient is off bevacizumab for > 4 weeks, Study Principal Investigator 
must be contacted, and the case discussed, before patient may resume protocol treatment. 
 
 
 
 
 


 
UPCI 13-063 Page 15 of 45 
Dose Modifications/Delays 
 
There are no reductions in the bevacizumab dose. If adverse events occur that require holding 
bevacizumab, the dose will remain the same once treatment resumes. 
 
Any toxicities associated or possibly associated with bevacizumab treatment should be managed 
according to standard medical practice. Bevacizumab has a terminal half-life of 2 to 3 weeks; 
therefore, its discontinuation results in slow elimination over several months. There is no available 
antidote for bevacizumab.  
 
Subjects should 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.  
 
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects who develop 
dyspnea or clinically significant hypotension. Subjects who experience a NCI CTCAE v. 4.0 
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 subjects who experience any 
infusion-associated symptoms not specified above. When the subject’s 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 cycle.  
 


 
UPCI 13-063 Page 16 of 45 
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed in 
Table 1. Regardless of the reason for holding study drug treatment, the maximum 
allowable length of treatment interruption is 2 months.Table 1: Bevacizumab Dose 
Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension 
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled to 150/100 mmHg with medication, discontinue 
bevacizumab. 
Grade 4 (including RPLS 
(confirmed by MRI) or 
hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1/2 nonpulmonary and non-CNS events 
Grade ≥ 2 pulmonary or 
CNS hemorrhage or tumor 
Related bleeding 
 
Discontinue bevacizumab. 
Grade 3  nonpulmonary 
and non-CNS hemorrhage 
All subjects will have study treatment held until all of the following criteria  
are met: 
 
The bleeding has resolved and hemoglobin 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. 
Subjects who experience a repeat Grade 3 hemorrhagic event will be 
discontinued from receiving bevacizumab. 
Grade 4 
Discontinue bevacizumab. 
Venous Thrombosis  
If patient develops DVT during study and requires full dose anticoagulation, bevacizumab will be 
discontinued.  
 
 
Table 1 
Bevacizumab Dose Management due to Adverse Events (continued) 
 
Arterial Thromboembolic event 
(Angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, and any other arterial 
thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 


 
UPCI 13-063 Page 17 of 45 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1/2 events 
Grade 3 
(UPC> 3.5, urine 
collection > 3.5 g/24 hr, 
or dipstick 4+)   
 
Hold bevacizumab treatment until  Grade 2, as determined by either UPC 
ratio ≤ 3.5 or 24 hr collection ≤ 3.5 g 
 
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring medical 
intervention. 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  
Patient may restart upon complete resolution. 
Grade 3/4 
Hold bevacizumab for complete obstruction.  If surgery is necessary, patient 
may restart bevacizumab after full recovery from surgery, and at investigator’s 
discretion. 
Wound dehiscence 
requiring medical or 
surgical therapy 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
 
Discontinue bevacizumab. 
 


 
UPCI 13-063 Page 18 of 45 
4.6 
Sample Size 
The sample size is justified in terms of the primary analysis, 
comparing the overall survival of the protocol participants to a 
historical control set of patients treated at this institution.  The 
estimated survival function of the control set (246 events in 269 
patients) is presented in Figure 4.6.1.  A Monte Carlo 
simulation is used to estimate the power for increases in median 
OS of treated patients, compared to controls, from 0% to 100%.  
For each percent increase, 1000 bootstrap samples are drawn 
from the control set of size 269 (the simulated control sets) in 
addition to 1000 bootstrap samples of size 40 (the simulated 
treatment sets).  Each survival time in the simulated treatment 
sets is increased by the given percentage.   The, for each of the 
1000 simulated trial results, the proportion of control-treatment 
pairs of sets for which the null hypothesis of no treatment effect 
is rejected (at α=0.10) by a proportional hazards (Cox) 
regression is determined.  The result is the power curve in 
Figure 4.6.2, where it is seen that the expected power is in 
excess of 80% when the median overall survival in the 
treatment group exceeds 14.3 months, a 59% increase.  
 
 
5. PATIENT REGISTRATION 
 
All patients who are consented will be entered into University 
of Pittsburgh Clinical Trial Management Application (CTMA) 
database.   
 
 
6. STEREOTACTIC RADIOSURGERY TREATMENT 
PROTOCOL 
 
6.1 
General Plan:   
All SRS procedures will be done at the participating NAGKC institutions.  All patients considered for 
the protocol must have a lesion deemed suitable for stereotactic radiosurgery after presentation to a 
multidisciplinary Brain Tumor Conference and/or Stereotactic Radiosurgery Conference.  SRS 
procedures must be done within 21 days of study registration. 
 
6.2 
Treatment Plan Requirements   
Patient treatments will be planned using available radiosurgery dose planning software. The dose will 
be prescribed to the margin of target volume.  The radiosurgery dose will be prescribed based on 
volume within the prescribed isodose surface according to the curve shown in Appendix 3. 
 
6.3 
Treatment Volume Definition 
0
50
100
150
0.0
0.2
0.4
0.6
0.8
1.0
Months Since SRS
Overall Survival
Median OS = 9.03
P(Survival at 6 Months)= 0.726
Figure 4.6.1  Estimated survival function of the 
control set. 
10
12
14
16
18
0.0
0.2
0.4
0.6
0.8
1.0
Median OS from SRS of Treated Patients (Months)
Power, n=40 Treated
Median Control OS from SRS = 9.03 Months
Figure 4.6.2  Power of primary analysis as a 
function of median survival in the treatment arm 


 
UPCI 13-063 Page 19 of 45 
The target volume will include enhancing tumor plus up to 2 cm of the high T2 signal brain 
surrounding the contrast enhancing tumor.  
 
7. CONCOMITANT MEDICATIONS 
Patients may receive all concomitant therapy deemed necessary to provide adequate support, such as 
steroids or anticonvulsants; treatment with other anti-cancer agents or therapies is not permitted.   
 
8. TOXICITY MANAGEMENT 
 
8.1 
Radiation Toxicity:  Expected side effects of radiosurgery include adverse radiation effects 
(ARE) in the treatment region, or adjacent to it.  Radiation toxicity will be divided into acute (within 
the first 90 days after treatment) and late (occurring more than 90 days after treatment) manifestations.  
Assessment of radiation toxicity will be done using the RTOG/EORTC Radiation Morbidity Scoring 
Scheme (see Appendix 6) for acute toxicity and the NCI CTCAE v4.0 (see 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf ) for late 
toxicity.  Patients who develop ARE may require treatment with steroids or surgical resection of the 
affected volume. 
 
8.2 
Hematologic Toxicity: All toxicities including hematologic due to bevacizumab therapy will 
be rated according to the NIH Common Toxicity Criteria (version 4.0). 
 
8.3 
Other Toxicities:  All other toxicities and adverse events will also be recorded using the 
CTCAE v4.0.   
 
9. SCHEDULE OF ASSESSMENTS 
 
A flow chart of the study assessments is given in Appendix 4. 
 
9.1 
Screening Procedures 
The following procedures will be conducted within 14-21 days prior to SRS. Registration is defined as 
the point after the patient signs the informed consent and prior to meeting all eligibility requirements.. 
9.1.1 Signed and witnessed informed consent within 30 days prior to registration 
9.1.2 Medical history. 
9.1.3 Physical and neurological examination including KPS, review of systems, vital signs, 
height, and weight. 
9.1.4 Quality of life questionnaires 
9.1.5 EKG (12-lead) 
9.1.6 CBC, Serum Chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, 
chloride, creatinine, glucose, potassium, total protein, SGOT[AST], SGPT[ALT], 
sodium.), PT/INR and Urine Protein Creatinine Ratio (or point of care (POCT)  urine 
dipstick for blood and protein) 
9.1.7 Pregnancy test for women of child-bearing potential. 


 
UPCI 13-063 Page 20 of 45 
9.1.8 Contrast-enhanced Gd-DPTA MRI (may be MRI showing progression, even if 
performed more than 21 days prior to SRS) 
9.19 
MRS (at selected sites) – within 14 days of SRS 
9.1.10 Stable or decreasing dose of steroids for at least 5 days. 
 
9.2  
 Post SRS Study Procedures 
 
9.2.1. Physical and neurological examination, including Karnofsky Performance Status score, 
review of systems, vital signs, height, and weight every 2 weeks. 
 
9.2.2. All patients will undergo a gadolinium-enhanced MRI at baseline, and at 8-week 
intervals or after every 4 cycles.  
 
9.2.3 Laboratory tests (complete blood counts, basic metabolic panel and urinary protein to 
creatinine ratio) will be obtained every 2 weeks or every cycle. 
 
9.2.4 Imaging studies after every 4 cycles of post SRS bevacizumab at the 6-month toxicity 
evaluation. (The toxicity evaluation MRI may be part of the post Cycle 12 imaging.) If 
there is a question of worsening of the MRI at the time of other evaluations, the patient 
should undergo reevaluation with repeat MRI) 
 
9.2.5 Quality of life questionnaires after the first 4 cycles of bevacizumab 
 
 
9.3  
Follow-up post 12 months SRS:   
 
 The following evaluations will be done one year after SRS, followed by every 3 months year two  post 
SRS, then every 4 months for year 3 post SRS, then every 6 months thereafter: 
9.3.1. Physical and neurological examination, including Karnofsky Performance Status score, 
review of systems, vital signs, height, and weight, as well as Quality of Life 
Questionnaires. 
 
9.3.2. Gadolinium-enhanced MRI.  
 
9.3.3 Laboratory tests (complete blood counts, basic metabolic panel and urinary protein to 
creatinine ratio)  
 
 
If not being seen in-person otherwise, all patients who received treatment will be contacted via mail or 
telephone every two to three months to determine survival. A review of medical records or other 
official documentation are also acceptable to confirm patient status. 
 
 
 
 


 
UPCI 13-063 Page 21 of 45 
10.0. CRITERIA FOR EVALUATION 
 
10.1  Clinical Neurological Examination 
Neurological performance will be monitored by grading both symptoms and signs.  Evaluation will be 
based on any changes in the neurological clinical exam in the interval since the last examination.  
Changes should be unrelated to post-ictal state or other unrelated events such as infection, and steroid 
requirement will be considered in the evaluation as well. 
The following scale will be used to designate relative changes: 
 
+2 = definitely better 
 
+1 = possibly better 
 
  0 = unchanged 
-1 = possibly worse 
-2 = definitely worse 
 
10.2 
Brain Imaging 
The following MRI protocol will be performed on each patient before treatment and with each 
subsequent imaging follow-up.:  pre-contrast sagittal T1-weighted, axial and coronal T2 weighted 
imaging, diffusion-weighted, post-contrast axial and coronal T1-weighted imaging.  From the MRI 
scan, the following parameters will be assessed:  volumes of contrast enhancing lesion, T2 
abnormality, as well as areas of restricted diffusion from ADC maps, .  In addition, tumor and 
treatment related complications such as edema, hemorrhage, hydrocephalus, and degree of mass 
effect/midline shift will be assessed.  Any new areas of contrast enhancing or T2 lesions will also be 
recorded. 
 
Tumor response will be evaluated using RANO Criteria.   
 
RANO Response Criteria 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing 
disease 
None 
≥ 50% ↓ 
< 50% -< 25% ↑ 
≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present*  
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement for response 
All 
All 
All 
Any* 


 
UPCI 13-063 Page 22 of 45 
 
10.3 
MR Spectroscopy:  
 
Whenever there is a question as to whether the appearance of the MRI represents true tumor 
progression versus treatment effect, the use of proton MR spectroscopy is encouraged at centers with 
MRS capability.  Proton MR Spectroscopy will be performed using a three-dimensional (3D), multi-
voxel technique.  A region of interest to target the spectroscopic examination will be placed on the 
anatomic MRI abnormality defined on FLAIR and contrast-enhanced T1-weighted images.  The 
maximal dimension of the 3D spectroscopic box will be 10x10x10mm.  Spectroscopic data will be 
processed on an offline UNIX workstation using a program developed in-house that allows 
quantification of relative metabolite ratio index within a given spectroscopic voxel size of 1cc.  The 
following metabolite ratio indices will be measured on a voxel-by-voxel basis:  choline to N-acetyl 
aspartate index (CNI) and lactate and lipid index (LLI).  A CNI ≥ 3 will be considered suspicious for 
tumor metabolism and LLI ≥ 3 in a region of CNI ≤ 2 will be considered suspicious for treatment 
effect. 
 
10.4 
Definition of Tumor Progression 
 
If surgery is not done for histological confirmation, tumor progression will be defined by evaluating 
both traditional MRI sequences (gadolinium-enhanced T1 and T2) and spectroscopic data, as follows: 
 
 Outside the area targeted by SRS: 
 
o Development of an area of new or increased (by ≥ 25% in the product of two 
perpendicular diameters despite stable or increased steroid dose) gadolinium-enhanced 
T1 or FLAIR abnormality will be considered to be tumor progression. 
o If there is discordance between the traditional MRI (gadolinium-enhanced T1 or T2) and 
the spectroscopy (e.g. one modality is concerning for progression but the other is not), 
the MRI and MRS will be repeated in 1-2 months at the treating physician’s discretion.  
If there remains concern for progression in either or both modalities (traditional MRI or 
MRS) on the second scan, the tumor will be considered to have progressed and the date 
of progression will be retrospectively determined to be the date of the initial scan 
demonstrating concerning changes. 
 
 Within the area targeted by SRS: 
 
o The sum of the CNI ratios within the voxels considered abnormal (e.g. CNI ≥ 3) will be 
taken at the time of treatment planning and at the time of each follow-up MRI.  If there 
is a ≥ 25% increase in the sum relative to the smallest sum at baseline or subsequently, 
in an area of new or increased (by ≥ 25% in the product of two perpendicular diameters 
despite stable or increased steroid dose) gadolinium-enhanced T1 MRI or T2 
abnormality, this will be considered to be tumor progression.   
o If there is discordance between the traditional MRI (gadolinium-enhanced T1 or T2 ) 
and the spectroscopy (e.g. one modality is concerning for progression but the other is 
not), the MRI and MRS will be repeated in 1-2 months at the treating physician’s 


 
UPCI 13-063 Page 23 of 45 
discretion.  If there remains concern for progression in either or both modalities 
(traditional MRI or MRS) on the second scan, the tumor will be considered to have 
progressed and the date of progression will be retrospectively determined to be the date 
of the initial scan demonstrating concerning changes. 
 
Regardless of imaging, failure to return for evaluation due to death or deteriorating condition will be 
considered progression, unless clearly unrelated to this tumor. 
 
10.5 
Overall Response 
 
The overall response will be a combination of neurological and imaging status.  Imaging findings will 
be emphasized, but will be interpreted with attention to steroid dosing and findings on neurological 
examination.   
 
10.6 
Progression-Free Survival 
Because of the complexity of interpreting imaging changes in these patients, PFS will need to be 
retrospectively determined in many patients, based on clinical course and analysis of serial MRIs at 
later time points.  For example, if a patient’s 6-month MRI shows increased enhancement, it may not 
be obvious at that moment whether this represents adverse radiation effect, pseudo-progression or 
tumor progression.  In that case, if clinically appropriate the patient will be followed, and an interval 
MRI will be done 8 weeks later.  If the next MRI has stabilized or improved, the patient will be 
considered to have had radiation necrosis.  If the MRI continues to worsen, additional imaging 
evaluation will be undertaken if possible, surgical evaluation will be considered, if appropriate, and the 
case will be discussed either at a multidisciplinary tumor board meeting or amongst the investigators to 
determine an appropriate course of action.   
 
 
11. CRITERIA FOR TERMINATION 
 
11.1 
Conditions for Terminating the Study 
The Principal Investigator may terminate the study for any of the following reasons: 
 
a)  Significant toxicities (see Safety Stopping Rule, 12.3) 
b)  If it becomes clear that the study treatment is ineffective (see Futility Stopping Rule, 12.5) 
c)  Once all data has been completed. 
 
11.2 
Conditions for Individual Patient Termination 
The Principal Investigator may terminate the participation of an individual patient for any of the 
following reasons: 
  
a)  Disease progression 
 
b) Need for exclusionary concurrent treatment 
 
c)  Withdrawal of informed consent 
 
d)  Protocol non-compliance 
 
e)  Loss to follow-up 
 
f)  Death 


 
UPCI 13-063 Page 24 of 45 
Patients are free to withdraw from the study at any time without giving a reason.  Full documentation 
will be made of any withdrawals that may occur during the study.  The Investigator will document the 
date of the withdrawal, the reason for withdrawal, if known, and the result of any assessments made at 
that time.  Whenever possible, patients whose participation is terminated due to progression of disease 
will be followed for safety measurements as detailed in this protocol. 
 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design 
 
This is a single-arm phase II trial to evaluate the safety, toxicity, and potential efficacy of bevacizumab 
combined with border zone stereotactic radiosurgery) and can be compared to the published results of  
bevacizumab alone). Forty patients with recurrent glioblastomas will be enrolled.  Overall survival, 
progression-free survival and measures of toxicity and clinical response will be compared to a 
historical series of 297 patients (269 evaluable for overall survival and 219 evaluable for progression-
free survival)) treated at this institution with gamma knife radiosurgery alone.  A propensity-matched 
subset of that series will also be used as a comparison series. 
 
12.2 
Safety and Futility Stopping Rules 
We intend to monitor adverse events on a monthly basis to determine if there are unacceptable 
toxicities. A formal stopping rule for safety will allow the possibility of terminating the trial early in 
the event that an excessive number of acute or late toxicities thought to be related to the treatment is 
observed. Specifically, we will look at acute toxicity when 10 and 20 patients have been enrolled and 
followed for acute toxicities for 90 days after SRS treatment.  A 10% rate of acute toxicity is 
considered to be acceptable.  If the number of patients experiencing acute toxicity thought to be related 
to treatment exceeds 2 out of 10 patients, or 4 out of 20 patients, the investigators will meet to discuss 
early termination of the trial.   
 
Late toxicity will be assessed at least every 6 months, but will also be specifically assessed a year after 
the registration of the 10th and 20th patients.  40% is considered to be an acceptable maximal late 
toxicity rate.  If the number of patients experiencing late toxicity exceeds 6 out of 10 or 11 out of 20, 
the investigators will meet to discuss early termination of the trial.   
 
The specific rule for safety stopping is based on the 1-sided lower 90% confidence interval for the 
probability of toxicity exceeding the respective acceptable rates. The probability of stopping under 
various true toxicity rates are given in Tables 1 and 2 below. 
 
Table 1. Acute toxicity stopping rule 
 
 
 
Probability of stopping under various true acute toxicity rates 
# pts 
Stop if >= 
toxicities 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
10 
3 
.07 
.32 
.62 
.83 
.95 
.99 
.99 
.99 
.99 


 
UPCI 13-063 Page 25 of 45 
20 
5 
.04 
.37 
.76 
.95 
.99 
.99 
.99 
1 
1 
 
Table 2. Late toxicity stopping rule  
 
 
 
Probability of stopping under various true late toxicity rates 
# pts 
Stop if >= 
toxicities 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
10 
7 
<.001 
.001 
.01 
.05 
.17 
.38 
.65 
.88 
.99 
20 
12 
<.001 
<.001 
.005 
.06 
.25 
.60 
.89 
.99 
.99 
A futility analysis will be conducted when 20 recurrent glioblastoma patients have been enrolled to 
allow for the possibility of stopping the trial if progression-free survival is unacceptably low. 
Specifically, if more than 17 patients have progressed at the 6-month time point, the trial will be 
stopped for futility. If the true rate of PFS-6 is only 10% (under the null), there would be a 68% chance 
of stopping that arm of the trial early. On the other hand, if the true probability of being progression-
free at 6 months is 25% (under the alternative), the chance of stopping that arm of the trial early would 
be 9%.  
 
 
12.3 
Endpoint Definitions and Statistical Analysis 
Primary Endpoint: 
 
To assess the efficacy of Border Zone SRS with bevacizumab by overall survival (OS) in patients with 
recurrent or progressive glioblastoma following conventional management with surgery, fractionated 
radiation therapy, and chemotherapy.  OS is defined as number of days from the day of diagnosis until 
the date of death due to any cause. Patients who are lost to follow-up will be censored at the date of last 
contact. OS of protocol patients will be compared to the OS of 269 evaluable University of Pittsburgh 
historical controls (patients who were managed using standard treatment with gamma knife 
radiosurgery without Avastin) by means of a log-rank test applied to Kaplan-Meier estimates of the 
respective survival functions. The median OS of the historical control set is 18.1 months (95% CI:  
(17.0,19.6)).  The same test will be applied to compare protocol patients and selected controls 
propensity-score matched on age and gender. If the proportionality assumption is not met, a time 
covariate will be created and the data will be analyzed via conditional multiple logistic regression 
models with time as a covariate.   
 
Secondary Endpoints: 
 
1. Evaluate progression-free and overall survival at 6 months (PFS-6 and OS-6).  OS-6 is 
defined as the percentage of patients who remain alive as of 6 months from the date of 
radiosurgery; PFS-6 is defined in a similar fashion (see Section 10.4). Any patient who receives 
bevacizumab treatment will be included in the statistical analysis, except for patients who are 
followed for less than 6 months for reasons other than death. Cases will be compared with our 
internal historical controls (patients who were managed using standard treatment with gamma 
knife radiosurgery without Avastin).  Fisher’s exact test will be used to compare the proportion 
of protocol patients alive, and alive and disease-free at six months to the historical control set.  
The test will be repeated to compare protocol patients and the propensity-matched control set. 


 
UPCI 13-063 Page 26 of 45 
 
2.  To evaluate the CNS toxicity of combined treatment, as measured by RTOG/EORTC Acute 
Radiation Morbidity Scoring and the NCI CTCAE v4.0 for late toxicity.  
Unacceptable toxicity, considered to be irreversible grade 3 (severe), any grade 4 (life 
threatening) or grade 5 (fatal) RTOG CNS toxicity occurring within 3 months of GK, will be 
tabulated by grade.  A cumulative logit modelwill be used to compare the distribution of Grad 
3-5 toxicities to the full control set and the propensity score-matched controls.  A similar model 
will be used to compare the RTOG/EORTC Acute Radiation Morbidity Scoring, a patient-level 
0-4 scale, between both the full and propensity-matched protocol and control samples.  The 
presence or absence of unacceptable toxicity will be compared by means of Fisher’s exact test.  
Adverse events will be tabulated in the protocol patients by location and CTCAE grade.  
 
3.  To evaluate whether border zone SRS with bevacizumab improves tumor response or 
reduces radiosurgical toxicity compared to historical outcomes. 
Tumor response is defined in Appendix 2.  A cumulative logit model will be used to compare 
tumor response (complete response, partial response, stable disease or progression) between the 
protocol and historical control samples. 
 
4.  To evaluate the quality of life of border zone SRS with bevacizumab administration.  The 
following assessments and instruments will be available at baseline and, after the first 4 cycles 
of bevacizumab and each follow up visit:  Karnofsky score; Barthel’s Index of Activities of 
Daily living; Center for Epidemiological Studies Depression Scale (CES-D); Functional 
Assessment of Cancer Therapy-Brain Specific (FACT-Br).  These QoL assessments are not 
available from the control set, so the analyses will be descriptive, focusing on trends over time.    
 
5.  To evaluate the potential value of magnetic resonance spectroscopy (MRS) in improvement 
of border zone target selection and detection of therapeutic response.  This is an exploratory 
aim comparing the derived treatment volumes between MRI and MRI+MRS in the current trial.  
The analyses will be descriptive, and there will be no comparison to the control sample. 
 
 
 
12.4 
Replacement of Patients 
 
Patients who enroll but are unable to begin treatment will be replaced.  Given that SRS is completed 
within a single session, any patient who initiates SRS will by definition complete treatment, so there 
will be no other indication for replacement of patients. 
 
13.  ETHICAL ASPECTS 
 
13.1 
Regulatory Considerations 
 
This study will be reviewed University of Pittsburgh Institutional Review Board (IRB; see below). 
 
13.2 
Independent Ethics Committees/Institutional Review Board 


 
UPCI 13-063 Page 27 of 45 
 
This protocol and the informed consent will be approved by the University of Pittsburgh Institutional 
Research Board (IRB).  The Principal Investigator is responsible for keeping the IRB advised of the 
progress of the study and of any changes made in the protocol prior to implementation.  The Principal 
Investigator will also keep the IRB informed of any significant adverse reactions, and any protocol 
exceptions or deviations.  Records of all study review and approval documents must be kept on file by 
the Principal Investigator and are subject to FDA inspection during or after completion of the study.  
The IRB will receive notification of the termination of the study. 
 
 
14  SAFETY REPORTING OF ADVERSE EVENTS 
  
14.1 Assessment of Safety 
14.1.1 Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse 
events (SAEs) that are considered related to {study drug}, all events of death, and any study specific 
issue of concern. 
14.1.2 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of 
attribution. 
 
This includes the following: 
 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with Glioblastoma 
Multiforme that were not present prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the investigator to 
have worsened in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
14.1.3 Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 


 
UPCI 13-063 Page 28 of 45 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 
 
14.2 Methods and Timing for Assessing and  Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in 
accordance with CFR 312.32 (IND Safety Reports).  
14.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of initiation of any study procedures” and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After this 
period, investigators should only report SAEs that are attributed to prior study treatment. 
14.2.2 Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be reported 
appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the {study drug} (see following 
guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the {study drug}, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the {study drug}; and/or the AE abates or 
resolves upon discontinuation of the {study drug} or dose reduction and, if applicable, 
reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to {study drug} 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert 
or current Investigator Brochure.  


 
UPCI 13-063 Page 29 of 45 
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator 
Brochure (I.B.) or not identified. This includes adverse events for which the specificity or severity is 
not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
14.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
14.3.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be adopted. 
Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
14.3.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. 
14.3.2.1 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be reported 
as follow-up information. 
14.3.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period regardless of attribution, will 
be reported to the appropriate parties. When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical concept. If the cause of death 
is unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
14.3.2.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions should 
be reported as medical and surgical history. A preexisting medical condition should be re-assessed 
throughout the trial and reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study. When reporting such events, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
14.3.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported 
as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, 
the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For 
example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 


 
UPCI 13-063 Page 30 of 45 
 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study. 
14.3.2.5 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 30 days) after 
the last dose of study drug, a report should be completed and expeditiously submitted to the Genentech, 
Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should always be classified as serious, and expeditiously reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to the 
{study drug} should be reported as an SAE. 
14.3.2.6 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior {study drug} exposure. If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject who participated in the study, this should be reported as an SAE.  
14.3.2.7 
Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will agree to 
the reconciliation periodicity and format, but agree at minimum to exchange monthly line listings of 
cases received by the other party. If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution. 
 
14.3.2.8 
AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product. See Appendix 7 for  bevacizumab events of special interest for this study. 
 
 
14.3.2.9 
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at: 
 
(650) 225-4682 


 
UPCI 13-063 Page 31 of 45 
OR 
(650) 225-5288 
 
 
 
Fax Cover Sheet is located in Appendix 8 
 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon 
as it becomes available. 
 
Serious AE reports that are related to the bevacizumab and AEs of Special Interest 
(regardless of causality) will be transmitted to Genentech within fifteen (15) calendar 
days of the Awareness Date. 
 
Serious AE reports that are unrelated to the bevacizumab will be transmitted to 
Genentech within thirty (30) calendar days of the Awareness Date. 
 
Additional Reporting Requirements to Genentech include the following: 
 
Any reports of pregnancy following the start of administration with the bevacizumab 
will be transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
 
All Non-serious Adverse Events originating from the Study will be forwarded in a 
bevacizumab report  Genentech. 
 
Note: Investigators should also report events to the University of Pittsburgh IRB as per institutional 
guidelines. 
14.3.3 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
14.3.3.1 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the new 
information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and adverse event was reported. For questions regarding 


 
UPCI 13-063 Page 32 of 45 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
14.4 Publishing and FDA Reporting 
14.4.1 Publishing 
Any literature articles that are a result of the study should be sent to Genentech. Copies of such reports 
should be mailed to the assigned Clinical Operations contact for the study. 
 
Clinical Operations Contact: 
Amber Lapp 
Country Study Manager On Assignment with Genentech 
P: 484-533-2019 Ext. 3051 Email: lappa@gene.com  
 
14.4.2 FDA Reporting 
Genentech is responsible for all FDA reporting. The PI will not submit reports directly to the FDA.   
 
 
15. 
DATA SAFETY MONITORING PLAN 
 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet monthly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the 
following: 
 
 serious adverse events 
 subject safety issues 
 recruitment issues 
 accrual 
 protocol deviations 
 unanticipated problems 
 breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are serious, 
at least possibly related and unexpected will be reported to the IRB.  Any modifications necessary to 
ensure subject safety and decisions to continue, or close the trial to accrual are also discussed during 
these meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated 
Problem submission and the study may be terminated.  
 


 
UPCI 13-063 Page 33 of 45 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPCI DSMC which also meets monthly 
following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend 
accrual or further investigate treatment on any trial based on information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records.  
 
 
 
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UPCI 13-063 Page 36 of 45 
17. APPENDICES 
Appendix 1:  Karnofsky Performance Status 
 
Normal: no complaints, no evidence of disease 
 
 
 
 
100 
Able to carry on normal activity; minor signs or symptoms of disease 
 
90 
Normal activity with effort; some signs or symptoms of disease 
 
 
80 
Cares for self; unable to carry on normal activity or to do active work 
 
70 
Requires occasional assistance but is able to care for most of his needs 
 
60 
Requires considerable assistance and frequent medical care  
 
 
50 
Disabled; requires special care and assistance 
 
 
 
 
40 
Severely disabled; hospitalization is indicated although death is not imminent 
30 
Very sick; hospitalization necessary  
 
 
 
 
 
20 
Moribund; fatal processes progressing rapidly 
 
 
 
 
10 
Dead  
 
 
 
 
 
 
 
 
 
0 
 
 
 


 
UPCI 13-063 Page 37 of 45 
Appendix 2 Current Response Criteria for Malignant Gliomas 
Appendix 2-1:  
Current Response Criteria for Malignant Gliomas (Macdonald Criteria) 26-27 
Response 
Criteria 
Complete response 
Requires all of the following: complete disappearance of all 
enhancing measurable and nonmeasurable disease sustained for at 
least 4 weeks; no new lesions; no corticosteroids; and stable or 
improved clinically 
Partial response 
Requires all of the following: > 50% decrease compared with 
baseline in the sum of products of perpendicular diameters of all 
measurable enhancing lesions sustained for at least 4 weeks; no new 
lesions; stable or reduced corticosteroid dose; and stable or improved 
clinically 
Stable disease 
Requires all of the following: does not qualify for complete response, 
partial response, or progression; and stable clinically 
Progression 
Defined by any of the following: > 25% increase in sum of the 
products of perpendicular diameters of enhancing lesions; any new 
lesion; or clinical deterioration 
 


 
UPCI 13-063 Page 38 of 45 
Appendix 2-2: 
RANO (Response Assessment in Neuro-Oncology)  Response Criteria45 
Criterion 
complete response 
partial response 
stable disease 
progressive disease 
T1 gadolinium 
enhancing disease 
None 
> 50% decrease 
< 50% decrease but 
< 25% increase 
> 25% increase* 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increase* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA† 
Clinical status 
Stable or increase 
Stable or increase 
Stable or increase 
Decrease* 
Requirement for 
response 
All 
All 
All 
Any* 
*Progression occurs when this criterion is present.  
†Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 
 
Several reports have documented good outcome of Criteria for Response Assessment Incorporating MRI 
and Clinical Factors42 
Response 
Criteria 
complete response 
Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on physiologic 
replacement doses only); and stable or improved clinically. 
Note: Patients with nonmeasurable disease only cannot have a complete response; the best 
response possible is stable disease. 
partial response 
Requires all of the following: >50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with 
baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater 
than the dose at time of baseline scan; and stable or improved clinically. 
Note: Patients with nonmeasurable disease only cannot have a partial response; the best 
response possible is stable disease. 
stable disease 
Requires all of the following: does not qualify for complete response, partial response, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in corticosteroids 
was required because of disease progression, the last scan considered to show stable disease 
will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
progressive disease 
Defined by any of the following: > 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids*; significant increase in T2/FLAIR nonenhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy* not caused by comorbid events (eg, radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any 
new lesion; clear clinical deterioration not attributable to other causes apart from the tumor 
(eg, seizures, medication adverse effects, complications of therapy, cerebrovascular events, 
infection, and so on) or changes in corticosteroid dose; failure to return for evaluation as a 
result of death or deteriorating condition; or clear progression of nonmeasurable disease. 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
*Stable doses of corticosteroids include patients not on corticosteroids. 
 
 


 
UPCI 13-063 Page 39 of 45 
Appendix 3 Radiosurgery Dose-Volume Curve 
  
 
 
 


 
UPCI 13-063 Page 40 of 45 
Appendix 4 Study Flowchart 
 
 
GBM patients who underwent 
surgical resection or biopsy followed by
fractionated RT and Temozolomide chemotherapy
Residual tumor after partial tumor resection or biopsy
Recurrent or progressive tumor: > 25% growth 
on gadlinium-enhanced, T2, FLAIR or MRS imaging
(Day 0) Border Zone Stereotactic Radiosurgery
Combined tumor volume
on combined gad-enhanced and T2 abnormal area
MRS of CNI > 3 must be included in the target
(Day -1 to -14) MRS (CNI > 3 as tumor recurrence)
(Day -1) Bevacizumab
Evaluation of toxicity
(Day 14, 14-day cycle)
Bevacizumab
Evaluation of tumor control, type of failure, survival


 
UPCI 13-063 Page 41 of 45 
Appendix 5 Study Schedule 
  
 
Evaluations 
Screening: 
Within 21 
days of 
SRS 
Within 
14 
days 
of 
SRS 
1 
day 
prior 
to 
SRS 
SRS 
Every 
Cycle 
(2 
weeks) g 
Every 4 
Cycles 
(8 weeks) 
g 
> 6 months 
post-SRSh 
follow up 
> 12 
months 
post-
SRSe 
follow up 
History and 
Physical 
X 
 
 
 
X 
 
 
X 
Neuro Exam + 
KPS 
X 
 
 
 
X 
 
 
X 
Vital signs 
X 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
X 
Quality of Life 
Questionnairesl 
X 
 
 
 
 
Xj 
 
X 
EKG 
X 
 
 
 
 
 
 
 
CBC 
X 
 
 
 
X 
 
 
X 
Serum chemistrya 
X 
 
 
 
X 
 
 
X 
Beta-HCGb 
X 
 
 
 
 
 
 
 
PT-INR 
X 
 
 
 
Xc 
 
 
Xc 
Urine Protein 
Creatinine Ratiod 
X 
 
 
 
X 
 
 
X 
Adverse event 
evaluation 
 
 
 
 
X 
 
X 
X 
Bevacizumab f 
 
 
X 
 
X 
 
 
 
MRI with Gd-
DPTA  
X 
 
 
X 
 
X 
 
X 
MRS  
 
Xk i 
 
 
 
 
 
 
aAlbumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, creatinine, glucose 
potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
bSerum or urine pregnancy test (women of childbearing potential). 
cFor patients on systemic anticoagulation with warfarin 
dUrine analysis for calculation of Urine Protein: Creatinine Ratio (UPC ratio) should be performed.  
prior to each cycle. If UPC ration is > 1, collection of 24 hour 
urine for measurement of urine protein level is recommended but not required. 
UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a UPC ratio of 1 is roughly 
equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using on of the following 
formula: 
- [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
Alternately,  POCT urine dipstick for blood and protein can be  be performed. If POCT urine dipstick, blood and 
protein need to be <+2 for treatment. 
 
eEvaluations to be done every 3 months for one year, then every 4 months for one year, then every 6 months 
thereafter. 
f bevacizumab (10 mg/kg) will be administered one day before SRS and then at day 14 after SRS followed by 10 
mg/kg/day every 14 days until progression 
g +/- 2 days 
h +/-3 days 
i at MRS capable facilities; to be done 14 days prior to SRS  


 
UPCI 13-063 Page 42 of 45 
j at the end of the first 4 cycle visit only (i.e. at about week 8) 
k research scans 
l upon completion copies of  the forms will be forwarded to the PI. 
Appendix 6 RTOG/EORTC Acute Radiation Morbidity Scoring 
RTOG/EORTC Acute Radiation Morbidity Scoring Scheme (Partial) 
 
[ 0 ] 
[ 1 ]  
[ 2 ]  
[ 3 ]  
[ 4 ]  
SKIN  
No change over 
baseline  
Follicular, faint or dull 
erythema/ epilation/dry 
desquamation/ decreased 
sweating 
Tender or bright 
erythema, patchy moist 
desquamation/ moderate 
edema  
Confluent, moist 
desquamatiom other 
than skin folds, pitting 
edema  
Ulceration, hemorrhage, 
necrosis  
MUCOUS 
MEMBRANE  
No change over 
baseline  
Injection/ may experience 
mild pain not requiring 
analgesic  
Patchy mucositis which 
may produce an 
inflammatory 
serosanguinitis 
discharge/ may 
experience moderate 
pain requiring analgesia  
Confluent fibrinous 
mucositis/ may include 
severe pain requiring 
narcotic  
Ulceration, hemorrhage 
or necrosis  
EYE  
No change  
Mild conjunctivitis with 
or without scleral 
injection/ increased 
tearing  
Moderate conjunctivitis 
with or without keratitis 
requiring steroids &/or 
antibiotics/ dry eye 
requiring artificial tears/ 
iritis with photophobia  
Severe keratitis with 
corneal ulceration/ 
objective decrease in 
visual acuity or in visual 
fields/ acute glaucoma/ 
panopthalmitis  
Loss of vision (unilateral 
or bilateral)  
EAR  
No change over 
baseline  
Mild external otitis with 
erythema, pruritis, 
secondary to dry 
desquamation not 
requiring medication. 
Audiogram unchanged 
from baseline  
Moderate external otitis 
requiring topical 
medication/ serious 
otitis medius/ 
hypoacusis on testing 
only  
Severe external otitis 
with dischange or moist 
desquamation/ 
symptomatic 
hypoacusis/tinnitus, not 
drug related  
Deafness  
SALIVARY 
GLAND  
No change over 
baseline  
Mild mouth dryness/ 
slightly thickened saliva/ 
may have slightly altered 
taste such as metallic 
taste/ these changes not 
reflected in alteration in 
baseline feeding behavior, 
such as increased use of 
liquids with meals  
Moderate to complete 
dryness/ thick, sticky 
saliva/ markedly altered 
taste  
-------  
Acute salivary gland 
necrosis  
PHARYNX & 
ESOPHAGUS  
No change over 
baseline  
Mild dysphagia or 
odynophagia/ may require 
topical anesthetic or non-
narcotic analgesics/ may 
require soft diet 
Moderate dysphagia or 
odynophagia/ may 
require narcotic 
analgesics/ may require 
puree or liquid diet  
Severe dysphagia or 
odynophagia with 
dehydration or weight 
loss(>15% from pre-
treatment baseline) 
requiring N-G feeding 
tube, I.V. fluids or 
hyperalimentation  
Complete obstruction, 
ulceration, perforation, 
fistula 
LARYNX  
No change over 
baseline  
Mild or intermittent 
hoarseness/cough not 
requiring antitussive/ 
erythema of mucosa 
Persistent hoarseness but 
able to vocalize/ referred 
ear pain, sore throat, 
patchy fibrinous exudate 
or mild arytenoid edema 
not requiring narcotic/ 
cough requiring 
antitussive  
Whispered speech, 
throat pain or referred 
ear pain requiring 
narcotic/ confluent 
fibrinous exudate, 
marked arytenoid edema 
Marked dyspnea, stridor 
or hemoptysis with 
tracheostomy or 
intubation necessary  
CNS  
No change  
Fully functional status 
(i.e., able to work) with 
minor neurologic 
findings, no medication 
needed  
Neurologic findings 
present sufficient to 
require home case/ 
nursing assistance may 
be required/ medications 
including steroids/anti-
seizure agents may be 
required  
Neurologic findings 
requiring hospitalization 
for initial management  
Serious neurologic 
impairment which 
includes paralysis, coma 
or seizures>3 per week 
despite 
medication/hospitalizati
on required  
(Patients with  
seizure disorders at 
baseline who have 
breakthrough seizures 
would not be considered 
to have a grade IV) 
GUIDELINES: The acute morbidity criteria are used to score/grade toxicity from radiation therapy. The critera are relevant from day 1, the 
commencement of therapy, through day 90.  
 


 
UPCI 13-063 Page 43 of 45 
 
 


 
UPCI 13-063 Page 44 of 45 
Appendix 7 Bevacizumab Related Events of Special Interest 
·     Hypertension ≥ grade 3 
·     Proteinuria ≥ grade 3 
·     GI perforation, abscesses and fistulae (any grade) 
·     Wound healing complications ≥ grade 3 
·     Haemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ grade 2 haemoptysis) 
·     Arterial thromboembolic events  (any grade) 
·     Venous thromboembolic events ≥ grade 3 
·     PRES (any grade) 
·     CHF ≥ grade 3 
·     Non-GI fistula or abscess ≥ grade 2 
 
 
 
 


 
UPCI 13-063 Page 45 of 45 
Appendix 8  Safety Reporting Fax Cover Sheet 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 
Version 1 31-May-2012