Clinical trial NCT01740258
Conditions: Malignant Glioma Grade 4 Malignant Glioma Glioblastoma Gliosarcoma
Keywords: malignant glioma Grade 4 malignant glioma glioblastoma gliosarcoma adult brain tumor
Sponsor: Duke University
Start date: 2013-01-01; Completion date: 2019-11-14
Enrollment: 68 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Studies which have separately studied bevacizumab for recurrent gliomas and bevacizumab for newly-diagnosed glioma have shown good results and the regimens have been well-tolerated by patients. This study seeks to investigate the use of bevacizumab with the standard therapy (radiation therapy and temozolomide) in newly diagnosed patients, followed by bevacizumab and temozolomide with the continuation of bevacizumab following progression. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis.

Detailed description:
Given the possible synergism with irinotecan and bevacizumab for colorectal carcinomas, the combination has been studied in gliomas. In a study of 21 patients, the combination of irinotecan and bevacizumab produced a 43% response rate, with acceptable toxicity. The response rate is significantly higher than irinotecan alone and any other therapy for recurrent glioma. There were two serious adverse events, one intracranial hemorrhage and one bowel perforation. At the Duke Brain Tumor Center, the investigators have treated over 1000 glioblastoma patients with a bevacizumab-containing regimen, and there is marked clinical benefit and acceptable toxicity. Our initial study looking at the combination of bevacizumab and irinotecan for patients with recurrent glioblastoma published in 2007 found impressive response rates and survival and corroborated the earlier experience of Starks-Vance.

The investigators completed a study for newly diagnosed glioblastoma that utilized bevacizumab, radiation therapy and temozolomide followed by 6 months of bevacizumab, irinotecan and temozolomide. In addition, the group at University of California at Los Angeles published a study with bevacizumab, radiation therapy and temozolomide followed by 12 months of bevacizumab and temozolomide for newly diagnosed glioblastoma. These two phase II studies reported acceptable toxicity and a suggestion of improved survival compared to historical controls, and led to two large phase III randomized, placebo controlled studies of the addition of bevacizumab for newly diagnosed glioblastoma patients. The current proposal builds on the encouraging results of the addition of bevacizumab to the standard therapy for newly diagnosed glioblastoma patients. Two critical questions remain- the role of bevacizumab maintenance and bevacizumab at the time of progression in a patient previously treated with bevacizumab at the time of initial diagnosis. In addition, a retrospective analysis of data collected at our center from patients with recurrent disease suggests that continuation of bevacizumab at the time of progression may improve overall survival in comparison with cessation of bevacizumab.

Arms: arm 1: In Part A, newly-diagnosed patients with Grade 4 malignant gliomas will receive standard radiation therapy, daily Temodar 75mg/M for 6-8 weeks. Bevacizumab will be given concurrently with radiation therapy and Temodar, 10 mg/kg every two weeks.

If they are stable at the end of Part A, they will continue to Part B. In Part B patients will receive up to 12 cycles of bevacizumab and Temodar. Bevacizumab will be given on Days 1 and 15 of a 28-day cycle. Temodar will be 200 mg/meter squared daily for 5 days (days 1-5) of each cycle.

If they have not progressed, patients will start Part C. In Part C, patients will receive bevacizumab 10mg/kg approximately every 2 weeks or 15 mg/kg approximately every 3 weeks.

If patients progress during Part B or C, they will start Part D. In Part D, patients will receive bevacizumab-based therapy containing bevacizumab in combination with a chemotherapy and/or biologic agent, as determined by the Duke treating physician.
Interventions: intervention 1: Radiation Therapy intervention 2: Temozolomide intervention 3: Bevacizumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol Version 4.0 09Mar2016 
 
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The Preston Robert Tisch Brain Tumor Center  
Duke University Medical Center 
 
Title 
Phase II Trial of Bevacizumab, Radiation Therapy and Temodar followed by Bevacizumab and 
Temodar with Continuation of Bevacizumab Beyond Progression  
(BBP-Bevacizumab Beyond Progression) 
 
Study Drugs 
Bevacizumab (Avastin) 
Temozolomide (Temodar) 
 
Support Provided By 
Genentech, Inc. 
 
Principal Investigator 
Annick Desjardins, MD, FRCPC 
 
Sub-Investigators 
Daniel Barboriak, MD 
Henry Friedman, MD 
John Kirkpatrick, MD 
Katherine B. Peters, MD, PhD 
 
Gordana Vlahovic, MD 
Dina Randazzo, DO 
 
Statistician 
James E. Herndon II, PhD 
 
Research Coordinator 
Stevie Threatt, BA 
Version 4.0 09Mar2016  
 


 
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1 Table of Contents 
2 
Background ......................................................................................................................................... 5 
2.1 
Disease Background ..................................................................................................................... 5 
2.2 
Bevacizumab Clinical Experience ............................................................................................... 5 
2.2.1 
Safety Profile ........................................................................................................................ 6 
2.3 
Bevacizumab for Malignant Gliomas ........................................................................................ 11 
2.4 
Bevacizumab and Radiation Therapy ........................................................................................ 11 
2.5 
Rationale for Study Design ........................................................................................................ 12 
3 
Objectives ......................................................................................................................................... 12 
3.1 
Primary Objective ...................................................................................................................... 12 
3.2 
Secondary Objective .................................................................................................................. 12 
3.3 
Exploratory Objective ................................................................................................................ 13 
4 
Study Design ..................................................................................................................................... 13 
4.1 
Overview .................................................................................................................................... 13 
4.2 
Outcome Measures ..................................................................................................................... 13 
4.2.1 
Primary efficacy outcome measure ..................................................................................... 13 
4.2.2 
Secondary efficacy outcome measure ................................................................................. 13 
4.2.3 
Safety outcome measures .................................................................................................... 13 
4.2.4 
Quality of life outcome measure ......................................................................................... 13 
5 
Safety Plan ........................................................................................................................................ 14 
5.1 
Bevacizumab-specific ................................................................................................................ 14 
5.2 
Temodar ..................................................................................................................................... 14 
5.2.1 
Temodar administration during XRT.................................................................................. 14 
6 
Study Population ............................................................................................................................... 15 
6.1 
Inclusion Criteria ........................................................................................................................ 15 
6.2 
Exclusion Criteria ....................................................................................................................... 16 
7 
Study Conduct ................................................................................................................................... 17 
7.1 
Treatment Plan ........................................................................................................................... 17 
7.2 
Drug Administration/Dosing Schedule ...................................................................................... 18 
7.2.1 
Radiation Therapy: Dose Definition and Schedule ............................................................ 18 
7.2.2 
Bevacizumab Only (Part C) ................................................................................................ 18 


 
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7.2.3 
Treatment at Progression (Part D) ...................................................................................... 19 
7.3 
Re-Treatment Criteria ................................................................................................................ 19 
7.3.1 
Part B- Initiation of each cycle will require: ....................................................................... 19 
7.3.2 
Re-treatment criteria for Part C........................................................................................... 19 
7.3.3 
Re-treatment criteria for Part D .......................................................................................... 19 
7.4 
Quality of Life Assessments ...................................................................................................... 19 
7.5 
Miscellaneous ............................................................................................................................. 20 
7.6 
Suggested Image Acquisition ..................................................................................................... 20 
7.6.1 
MR image acquisition ......................................................................................................... 20 
7.6.2 
CT image acquisition ....................................................................................................... 20 
7.7 
Response Criteria ....................................................................................................................... 21 
8 
Study Medication .............................................................................................................................. 21 
8.1 
Bevacizumab .............................................................................................................................. 21 
8.1.1 
Description .......................................................................................................................... 21 
8.1.2 
Administration .................................................................................................................... 22 
8.1.3 
Storage ................................................................................................................................ 22 
8.1.4 
Dose modification and toxicity management ..................................................................... 22 
8.2 
Temozolomide (Temodar).......................................................................................................... 26 
8.2.1 
Description .......................................................................................................................... 26 
8.2.2 
Formulation ......................................................................................................................... 26 
8.2.3 
Storage ................................................................................................................................ 26 
8.2.4 
Administration .................................................................................................................... 26 
8.2.5 
Toxicities............................................................................................................................. 26 
8.2.6 
Packaging and labeling ....................................................................................................... 27 
8.3 
Radiation Therapy and Chemotherapy ....................................................................................... 27 
8.3.1 
External Beam Radiation Therapy – Standard of Care ............................................... 27 
8.3.2 
Temodar administration ...................................................................................................... 28 
9 
Clinical and Laboratory Evaluations ................................................................................................ 29 
9.1 
Pre-treatment evaluations within 2 weeks of starting treatment ................................................ 29 
9.2 
Evaluations During Radiation Treatment (Part A) ..................................................................... 29 
9.3 
Evaluations During Part B ......................................................................................................... 29 


 
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9.4 
Evaluations During Bevacizumab Only (Part C) ....................................................................... 30 
9.5 
Evaluations During Bevacizumab-based Therapy After Progression (Part D) .......................... 30 
10 Treatment Discontinuation................................................................................................................ 30 
11 Study Discontinuation ....................................................................................................................... 31 
12 Safety Reporting of Adverse Events ................................................................................................. 31 
12.1 
Assessment of Safety .............................................................................................................. 31 
12.1.1 Specification of Safety Variables........................................................................................ 31 
12.2 
Definition of Adverse Event ................................................................................................... 31 
12.2.1 Adverse Event (AE) ............................................................................................................ 31 
12.2.2 Serious Adverse Events ...................................................................................................... 32 
12.3 
Methods and Timing for Assessing and Recording Safety Variables .................................... 32 
12.3.1 Adverse Event Recording Period ........................................................................................ 32 
12.3.2 Assessment of Adverse Events ........................................................................................... 32 
12.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events .................................... 33 
12.4.1 Eliciting Adverse Events..................................................................................................... 33 
12.4.2 Specific Instructions for Recording Adverse Events .......................................................... 33 
12.4.3 MedWatch 3500A Reporting Guidelines............................................................................ 36 
13 Statistical Considerations .................................................................................................................. 37 
13.1 
Study Design and Sample Size Justification .......................................................................... 37 
13.2 
Analytic Methods ................................................................................................................... 37 
13.3 
Toxicity Monitoring ............................................................................................................... 38 
14 Study Management: Data Safety and Monitoring Plan .................................................................... 39 
14.1 
Audits and Inspections............................................................................................................ 39 
14.2 
Data Safety and Monitoring ................................................................................................... 40 
14.3 
Data Collection ....................................................................................................................... 41 
14.3.1 Study Close-out ................................................................................................................... 41 
14.4 
Retention of Records .............................................................................................................. 41 
15 References ......................................................................................................................................... 41 
 
Appendix A:  Schedule of Events in Part A of the Study  
Appendix B:  Schedule of Events in Part B of the Study  
Appendix C:  Schedule of Events in Part C of the Study (Bevacizumab Only) 
Appendix D:  Schedule of Events in Part D of the Study (Bevacizumab-based Therapy) 


 
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2 Background 
2.1 Disease Background 
There is an unmet clinical need for the therapy of malignant gliomas with a median survival of 
<20 months despite available therapies.  The current standard of care is radiation therapy with 
daily temozolomide followed by 6 cycles of temozolomide.[1] Vascular endothelial growth factor 
(VEGF) is present on the cell surface and around malignant gliomas.[2, 3]  It appears that the 
presence of vascular endothelial growth factor is a prognostic growth factor with more VEGF 
expression correlating with a poor prognosis.[4, 5]  Monoclonal antibodies to VEGF have 
inhibited growth of malignant gliomas in a mouse xenograft.[6] Bevacizumab is a humanized 
monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular 
endothelial growth factor.  Bevacizumab has been shown to have acceptable toxicity and efficacy 
in colorectal, non-small cell lung, renal carcinomas and glioblastoma in a multitude of studies.[7-
11] 
2.2 Bevacizumab Clinical Experience 
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more than 5000 
patients and in multiple tumor types. In addition, data are available from 3,863 patients enrolled in 
two post-marketing studies in metastatic colorectal cancer (CRC).  Approximately 130,000 
patients have been exposed to bevacizumab as a marketed product or in clinical trials.  The 
following discussion summarizes bevacizumab’s safety profile and presents some of the efficacy 
results pertinent to this particular trial. Please refer to the bevacizumab Investigator Brochure for 
descriptions of all completed Phase I, II, and III trials reported to date. 
 
Arnold and al. were the first to show in a randomized study that bevacizumab plus chemotherapy 
continued beyond progression significantly prolongs the overall survival and progression-free 
survival of metatastic colorectal cancer patients.[12] In a large phase III study (AVF2107g) in 
patients with metastatic colorectal cancer, the addition of bevacizumab, a monoclonal antibody 
directed against vascular endothelial growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin 
(IFL) chemotherapy resulted in a clinically and statistically significant increase in duration of 
survival, with a hazard ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  
Similar increases were seen in progression-free survival (6.2 vs. 10.6 months; p < 0.001), overall 
response rate (35% vs. 45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; p < 0.01) for 
the combination arm versus the chemotherapy only arm (bevacizumab Investigator Brochure, 
October 2005). 
 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was designated 
for priority review and was approved on 26 February 2004 in the United States for first-line 
treatment in combination with IV 5-FU−based chemotherapy for subjects with metastatic 
colorectal cancer.  
 
Additional data from Phase III trials in metastatic CRC (E3200), non-small cell lung cancer 
(NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated clinical benefit 
from bevacizumab when added to chemotherapy.  In Study E3200, the addition of bevacizumab to 
FOLFOX chemotherapy resulted in improved overall survival compared with FOLFOX alone 


 
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(13.0 vs. 10.8 months, respectively, HR = 0.75; p < 0.01) in a population of previously treated 
CRC patients.   
 
There was also improved overall survival in first-line NSCLC patients (E4599) treated with 
carboplatin/paclitaxel +  bevacizumab compared with chemotherapy alone (12.3 vs. 10.3 months, 
respectively; HR = 0.80; p = 0.003).  The results from this trial were the basis for FDA approval of 
bevacizumab for use in combination with carboplatin + paclitaxel as first-line treatment of patients 
with unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC in October 
2006.  Finally, patients with untreated metastatic breast cancer (E2100) who received bevacizumab 
in combination with weekly paclitaxel had a marked improvement in PFS compared with 
chemotherapy alone (13.3 vs. 6.7 months, respectively; HR = 0.48; p < 0.0001) (see the 
Bevacizumab Investigator Brochure for additional details). 
2.2.1 Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety signals 
were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage.  Additional 
completed Phase II and Phase III studies of bevacizumab as well as spontaneous reports have 
further defined the safety profile of this agent. Bevacizumab-associated adverse events identified 
in phase III trials include congestive heart failure (CHF) primarily in metastatic breast cancer, 
gastrointestinal perforations, wound healing complications, and arterial thromboembolic events 
(ATE). These and other safety signals are described in further detail as follows and in the 
bevacizumab Investigator Brochure. 
 
Hypertension: An increased incidence of hypertension has been observed in patients treated 
with bevacizumab.  Grade 4 and 5 hypertensive events are rare. Clinical sequelae of hypertension 
are rare but have included hypertensive crisis, hypertensive encephalopathy, and reversible 
posterior leukoencephalopathy syndrome (RPLS).[13, 14] 
 
There is no information on the effect of bevacizumab in patients with uncontrolled hypertension 
at the time of initiating bevacizumab therapy.  Therefore, caution should be exercised before 
initiating bevacizumab therapy in these patients.  Monitoring of blood pressure is recommended 
during bevacizumab therapy.  Optimal control of blood pressure according to standard public 
health guidelines is recommended for patients on treatment with or without bevacizumab.   
 
Temporary interruption of bevacizumab therapy is recommended in patients with hypertension 
requiring medical therapy until adequate control is achieved.  If hypertension cannot be 
controlled with medical therapy, bevacizumab therapy should be permanently discontinued.  
Bevacizumab should be permanently discontinued in patients who develop hypertensive crisis or 
hypertensive encephalopathy. 
 
Proteinuria:  An increased incidence of proteinuria has been observed in patients treated with 
bevacizumab compared with control arm patients.  In the bevacizumab-containing treatment 
arms of clinical trials (across all indications), the incidence of proteinuria (reported as an adverse 
event) was up to 38% (metastatic CRC Study AVF2192g). The severity of proteinuria has ranged 
from asymptomatic and transient events detected on routine dipstick urinalysis to nephrotic 


 
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syndrome; the majority of proteinuria events have been grade 1. NCI-CTC Grade 3 proteinuria 
was reported in up to 3% of bevacizumab-treated patients, and Grade 4 in up to 1.4% of 
bevacizumab-treated patients.  The proteinuria seen in bevacizumab clinical trials was not 
associated with renal impairment and rarely required permanent discontinuation of bevacizumab 
therapy.  Bevacizumab should be discontinued in patients who develop Grade 4 proteinuria 
(nephrotic syndrome). 
 
Patients with a history of hypertension may be at increased risk for the development of 
proteinuria when treated with bevacizumab.  There is evidence from the dose-finding, Phase II 
trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 proteinuria may be 
related to bevacizumab dose. 
 
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio at least every 6 weeks.  If 
the UPC ratio is not available, a dipstick urinalysis may be used to allow treatment to proceed. 
 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter-associated phlebitis to fatal, have been reported in patients treated with 
bevacizumab in the colorectal cancer trials and, to a lesser extent, in patients treated with 
bevacizumab in NSCLC and breast cancer trials.  
 
Venous thromboembolism (including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis:  In the phase III pivotal trial in metastatic CRC, there was a slightly higher 
rate of venous TE events in patients treated with bevacizumab plus chemotherapy compared with 
chemotherapy alone (19% vs. 16%).  
 
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, including deep 
venous thrombosis, pulmonary embolism, and thrombophlebitis, occurred in 15.2% of patients 
receiving chemotherapy alone and 16.6% of patients receiving chemotherapy + bevacizumab.  
 
The incidence of NCI-CTC Grade ≥ 3 venous VTE events in one NSCLC trial (E4599) was 
higher in the bevacizumab-containing arm compared to the chemotherapy control arm (5.6% vs. 
3.2%).  One event (0.2%) was fatal in the bevacizumab-containing arm; not fatal events were 
reported in the carboplatin/paclitaxel arm (see Bevacizumab Investigator Brochure).  
In metastatic CRC clinical trials, the incidence of VTE events was similar in patients receiving 
chemotherapy + bevacizumab and those receiving the control chemotherapy alone.  
 
In clinical trials across all indications the overall incidence of VTE events was 2.8%−17.3% in 
the bevacizumab-containing arms compared with 3.2%−15.6% in the chemotherapy control 
arms.  The use of bevacizumab with chemotherapy does not substantially increase the risk of 
VTE event compared with chemotherapy alone.  However, patients with metastatic CRC who 
receive bevacizumab and experienced a VTE event may be at higher risk for recurrence of VTE 
event. 
 
Arterial Thromboembotic Events:  An increased incidence of ATE events was observed in 
patients treated with bevacizumab compared with those receiving control treatment.  ATE events 


 
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include cerebrovascular accidents, myocardial infarction, transient ischemic attacks (TIAs), and 
other ATE events.  In a pooled analysis of data from five randomized Phase II and III trials 
(mCRC [AVF2107g, AVF2192g, AVF0780g]; locally advanced or metastatic NSCLC 
[AVF0757g]; metastatic breast cancer [AVF2119g]), the incidence rate of ATE events was 3.8% 
(37 of 963) in patients who received chemotherapy + bevacizumab compared with 1.7% (13 of 
782) in patients treated with chemotherapy alone.  ATE events led to a fatal outcome in 0.8% (8 
of 963) of patients treated with chemotherapy +  bevacizumab and 0.5% (4 of 782) of patients 
treated with chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 2.3% 
of patients treated with chemotherapy +  bevacizumab and 0.5% of patients treated with 
chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients treated with 
chemotherapy + bevacizumab compared with 0.7% of patients treated with chemotherapy alone 
(see the Bevacizumab Investigator Brochure for additional details). 
 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial thromboembolic 
events in patients at high risk of such events, and the use of aspirin ≤ 325 mg daily was allowed 
in the five randomized studies discussed above. Use of aspirin was assessed routinely as a 
baseline or concomitant medication in these trials, though safety analyses specifically regarding 
aspirin use were not preplanned. Due to the relatively small numbers of aspirin users and arterial 
thromboembolic events, retrospective analyses of the ability of aspirin to affect the risk of such 
events were inconclusive. However, similarly retrospective analyses suggested that the use of up 
to 325 mg of aspirin daily does not increase the risk of grade 1-2 or grade 3-4 bleeding events, 
and similar data with respect to metastatic colorectal cancer patients were presented at ASCO 
2005.[15] Further analyses of the effects of concomitant use of bevacizumab and aspirin in 
colorectal and other tumor types are ongoing. 
 
Gastrointestinal perforation Patients with metastatic carcinoma may be at increased risk for the 
development of gastrointestinal perforation and fistula when treated with bevacizumab and 
chemotherapy. Bevacizumab should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-abdominal inflammatory processes and 
gastrointestinal perforation to bevacizumab treatment has not been established. Nevertheless, 
caution should be exercised when treating patients with intra-abdominal inflammatory processes 
with bevacizumab. Gastrointestinal perforation has been reported in other trials in non-colorectal 
cancer populations (e.g., ovarian, renal cell, pancreas, breast, and NSCLC) and may be higher in 
incidence in some tumor types. 
 
Fistula:  Bevacizumab use has been associated with serious cases of fistulae including events 
resulting in death.  Fistulae in the GI tract are common (1%–10% incidence) in patients with 
metastatic CRC, but uncommon (0.1%−1%) or rare (0.01%–0.1%) in other indications.  In 
addition, fistulae that involve areas of the body other than the GI tract (e.g., tracheoesophageal, 
bronchopleural, urogenital, biliary) have been reported uncommonly (0.1%–1%) in patients 
receiving bevacizumab in clinical studies and postmarketing reports.  Events were reported at 
various timepoints during treatment, ranging from 1 week to > 1 year following initiation of 
bevacizumab, with most events occurring within the first 6 months of therapy. 
 


 
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Permanently discontinue bevacizumab in patients with tracheoesophageal fistulae or any Grade 4 
fistula.  Limited information is available on the continued use of bevacizumab in patients with 
other fistulae.  In cases of internal fistula not arising in the GI tract, discontinuation of 
bevacizumab should be considered. 
 
Wound healing complications: Wound healing complications such as wound dehiscence have 
been reported in patients receiving bevacizumab. In an analysis of pooled data from two trials in 
metastatic colorectal cancer, patients undergoing surgery 28-60 days before study treatment with 
5-FU/LV plus bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone.[16] Surgery in patients 
currently receiving bevacizumab is not recommended. No definitive data are available to define a 
safe interval after bevacizumab exposure with respect to wound healing risk in patients receiving 
elective surgery; however, the estimated half-life of bevacizumab is 21 days. Bevacizumab 
should be discontinued in patients with severe wound healing complications. 
 
If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure.  Patients 
undergoing a major surgical procedure should not begin or restart bevacizumab until 4 weeks 
after that procedure (in the case of high-risk procedures such as liver resection, thoracotomy, or 
neurosurgery, it is recommended that chemotherapy be restarted no earlier than 6 weeks and 
bevacizumab no earlier than 8 weeks after surgery). 
 
In the study of patients with relapsed glioblastoma (study AVF3708g), the incidence of post-
operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal 
fluid leak) was 3.6% in patients treated with single-agent Avastin and 1.3% in patients treated 
with Avastin plus irinotecan. 
 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1132 patients 
treated with bevacizumab in a pooled database from eight phase I, II, and III clinical trials in 
multiple tumor types (bevacizumab Investigator Brochure, October 2005). The hemorrhagic 
events that have been observed in bevacizumab clinical studies were predominantly tumor-
associated hemorrhage (see below) and minor mucocutaneous hemorrhage.  
 
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or hemoptysis has 
been observed primarily in patients with NSCLC.  Life-threatening and fatal hemoptysis was 
identified as a bevacizumab-related adverse event in NSCLC trials.  These events occurred 
suddenly and presented as major or massive hemoptysis.  Among the possible risk factors 
evaluated (including squamous cell histology, treatment with anti-rheumatic/anti-inflammatory 
drugs, treatment with anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical 
history of atherosclerosis, central tumor location, and cavitation of tumors during therapy), the 
only variables that showed statistically significant correlations with bleeding were bevacizumab 
therapy and squamous cell histology. 
 
GI hemorrhages, including rectal bleeding and melena have been reported in patients with CRC, 
and have been assessed as tumor-associated hemorrhages. 


 
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Tumor-associated hemorrhages were also seen rarely in other tumor types and locations, 
including a case of CNS bleeding in a patient with hepatoma with occult CNS metastases and a 
patient who developed continuous oozing of blood from a thigh sarcoma with necrosis. 
 
Mucocutaneus Hemorrhage:  Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated with bevacizumab. These were most 
commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical 
intervention and did not require any changes in bevacizumab treatment regimen.  
 
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding.  
 
Reversible Posterior Leukoencephalopathy Syndrome:  There have been rare reports of 
bevacizumab-treated patients developing signs and symptoms that are consistent with RPLS, a 
rare neurologic disorder that can present with the following signs and symptoms (among others):  
seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or 
without associated hypertension.  Brain imaging is mandatory to confirm the diagnosis of RPLS.  
In patients who develop RPLS, treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of bevacizumab.  The safety of 
reinitiating bevacizumab therapy in patients previously experiencing RPLS is not known.[13, 14] 
 
Congestive heart failure:  In clinical trials CHF was observed in all cancer indications studied 
to date, but predominantly in patients with metastatic breast cancer.  In the Phase III clinical trial 
of metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab-treated patients experienced CHF, 
compared with two (1%) control arm patients.  These events varied in severity from 
asymptomatic declines in left ventricular ejection fraction (LVEF) to symptomatic CHF 
requiring hospitalization and treatment.  All the patients treated with bevacizumab were 
previously treated with anthracyclines (doxorubicin cumulative dose of 240−360 mg/m2).  Many 
of these patients also had prior radiotherapy to the left chest wall.  Most of these patients showed 
improved symptoms and/or left ventricular function following appropriate medical therapy.[17] 
 
In a randomized, Phase III trial of patients with previously untreated metastatic breast cancer 
(E2100), the incidence of LVEF decrease (defined as NCI-CTC Grade 3 or 4) in the 
paclitaxel + bevacizumab arm was 0.3% versus 0% for the paclitaxel alone arm. 
  
No information is available on patients with preexisting CHF of New York Heart Association 
(NYHA) Class II−IV at the time of initiating bevacizumab therapy, as these patients were 
excluded from clinical trials. 
 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may be possible risk 
factors for the development of CHF.  Caution should be exercised before initiating bevacizumab 
therapy in patients with these risk factors. 
 


 
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A Phase II trial in patients with refractory acute myelogenous leukemia reported 5 cases of 
cardiac dysfunction (CHF or LVEF decrease to < 40%) among 48 patients treated with 
sequential cytarabine, mitoxantrone, and bevacizumab.  All but 1 of these patients had significant 
prior exposure to anthracyclines as well.[18] 
 
Other studies in patients with various tumor types and either a history of anthracycline exposure 
or concomitant use with bevacizumab are ongoing.  
 
Patients receiving concomitant anthracyclines or with prior exposure to anthracyclines should 
have a baseline MUGA scans or echocardiograms (ECHOs) with a normal LVEF. 
 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or infection with 
severe neutropenia (including some fatalities) have been observed in patients treated with some 
myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone.[19] 
 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional details 
regarding the safety experience with bevacizumab. 
2.3 Bevacizumab for Malignant Gliomas 
Given the synergism with irinotecan and bevacizumab for colorectal carcinomas, the combination 
has been studied in gliomas.  In a study of 21 patients, the combination of irinotecan and 
bevacizumab produced a 43% response rate, with acceptable toxicity.[20] The response rate is 
significantly higher than irinotecan alone and any other therapy for recurrent glioma.  There were 
two serious adverse events, one intracranial hemorrhage and one bowel perforation.  At the Duke 
Brain Tumor Center, we have treated 68 patients on an IRB approved Phase 2 Study under a FDA 
IND with irinotecan and bevacizumab, and there were two CNS hemorrhages, one asymptomatic 
hemorrhage after ten cycles and the other after eight cycles and the patient was started on 
enoxaparin two weeks prior to the hemorrhage for a DVT.  There was acceptable toxicity in the 
phase II trial.  The response rate was 59%, and the 6-month progression-free survival was 43% in 
GBMs, which are some of the best results seen to date.[21] A follow-up randomized phase II trial 
of bevacizumab alone vs. bevacizumab and irinotecan confirmed the activity of bevacizumab, 
which led to accelerated approval of single agent bevacizumab for recurrent GBM by the FDA in 
May 2009.[7]  We completed a phase II trial of bevacizumab, radiation therapy and temozolomide, 
followed by bevacizumab, irinotecan and temozolomide for newly diagnosed GBMs, and the 
median PFS was 14 mos, which is more the doubled the median PFS in the Stupp trial.[1] The 
regimen was well tolerated with one treatment-related death during radiation therapy and 
encouraging early overall survival results.  We have enrolled 125 patients, and two died of toxicity 
during the post-radiation phase, one from a pulmonary embolus and the other from sepsis.  At a 
median follow-up of 16 mos for the original 75 patients enrolled, 80% remain alive compared with 
a median OS of 15 mos in the Stupp trial with radiation and temozolomide followed by 
temozolomide. 
2.4 Bevacizumab and Radiation Therapy 
Bevacizumab may reverse some of the tissue hypoxia around tumor cells, making radiation 
therapy more effective.  A radioresistant tumor can become radiosensitive with the addition of 


 
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agents that block VEGF activity or prevent VEGF intracellular signaling.[22-24] VEGF blockade 
by bevacizumab reduces tumor hypoxia, interstitial pressure, increases chemotherapy drug 
delivery and optimizes radiation therapy.[25-27] Bevacizumab has been combined with radiation 
therapy and chemotherapy in rectal and pancreatic carcinomas, with acceptable toxicity and a 
suggestion of improved tumor control.[28, 29] 
2.5 Rationale for Study Design 
Given the possible synergism with irinotecan and bevacizumab for colorectal carcinomas, the 
combination has been studied in gliomas.  In a study of 21 patients, the combination of irinotecan 
and bevacizumab produced a 43% response rate, with acceptable toxicity.[20] The response rate is 
significantly higher than irinotecan alone and any other therapy for recurrent glioma.  There were 
two serious adverse events, one intracranial hemorrhage and one bowel perforation.  At the Duke 
Brain Tumor Center, we have treated over 1000 glioblastoma patients with a bevacizumab-
containing regimen, and there is marked clinical benefit and acceptable toxicity.  Our initial study 
looking at the combination of bevacizumab and irinotecan for patients with recurrent glioblastoma 
published in 2007 found impressive response rates and survival and corroborated the earlier 
experience of Starks-Vance.[20, 21] 
 
We completed a study for newly diagnosed glioblastoma that utilized bevacizumab, radiation 
therapy and temozolomide followed by 6 months of bevacizumab, irinotecan and 
temozolomide.[30] In addition, the group at UCLA published a study with bevacizumab, radiation 
therapy and temozolomide followed by 12 months of bevacizumab and temozolomide for newly 
diagnosed glioblastoma.[31] These two phase II studies reported acceptable toxicity and a 
suggestion of improved survival compared to historical controls, and led to two large phase III 
randomized, placebo controlled studies of the addition of bevacizumab for newly diagnosed 
glioblastoma patients.  The current proposal builds on the encouraging results of the addition of 
bevacizumab to the standard therapy for newly diagnosed glioblastoma patients. Two critical 
questions remain- the role of bevacizumab maintenance and bevacizumab at the time of 
progression in a patient previously treated with bevacizumab at the time of initial diagnosis.  In 
addition, a retrospective analysis of data collected at our center from patients with recurrent 
disease suggests that continuation of bevacizumab at the time of progression may improve overall 
survival in comparison with cessation of bevacizumab.[32] 
3 Objectives 
3.1 Primary Objective 
To assess the effect on overall survival of continuing bevacizumab treatment after disease 
progression in patients treated with bevacizumab from the time of first diagnosis of grade IV 
malignant glioma. 
3.2 Secondary Objective 
To describe the toxicity of bevacizumab, 10 mg QOW, in combination with radiation therapy and 
daily Temodar, followed by bevacizumab and 5-day Temodar with continuation of bevacizumab  
beyond progression. 
 


 
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To assess the effect on progression-free survival of continuing bevacizumab treatment after 
disease progression in patients treated with bevacizumab from the time of initiation of treatment to 
the first occurrence of progression, or death  
3.3 Exploratory Objective 
To describe patient-reported quality of life outcomes of patients who continue to receive 
bevacizumab beyond progression 
4 Study Design 
4.1 Overview 
This is a Phase II trial of bevacizumab, radiation therapy (XRT) and Temodar (temozolomide), 
followed by bevacizumab and Temodar, then bevacizumab maintenance and continuation of 
bevacizumab beyond progression for newly diagnosed patients with malignant gliomas. 
4.2 Outcome Measures 
The patients will undergo a baseline MRI, as well as a MRI at the beginning of every other cycle 
during post chemoradiotherapy treatment to determine response and progression. 
4.2.1 Primary efficacy outcome measure 
Overall survival 
4.2.2 Secondary efficacy outcome measure 
Progression-free survival 
4.2.3 Safety outcome measures 
Incidence and severity of CNS hemorrhage and systemic hemorrhage 
 
Incidence of grade ≥ 4 hematologic and ≥ 3 non-hematologic toxicities 
4.2.4 Quality of life outcome measure 
Patient-Reported Outcomes (PROs) as assessed by standardized and validated questionnaires 
including: Quality of Life (Functional Assessment of Cancer Therapy-Brain); Fatigue 
(Functional Assessment of Cancer Therapy-Fatigue); Cognition (Functional Assessment of 
Cancer Therapy-Cognition), Depression (Beck Depression Inventory); Epworth Sleepiness 
Scale, Pittsburgh Sleep Quality Index, Godin Leisure-Time Exercise Questionnaire short scale 
 
Functional Capacity (Six-minute walk test) 
 
Neurocognitive Function (a computerized neurocognitive test battery called CNS Vital Signs®) 


 
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5 Safety Plan 
5.1 Bevacizumab-specific Monitoring during Parts A and B 
A number of measures will be taken to ensure the safety of patients participating in this trial.  
These measures will be addressed through exclusion criteria (see Section 6.2) and routine 
monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study.  Safety evaluations will 
consist of medical interviews, recording of adverse events, physical examinations, blood 
pressure, and laboratory measurements. Patients will be evaluated for adverse events, serious 
adverse events, and adverse events requiring study drug interruption or discontinuation at each 
study visit for the duration of their participation in the study.  
 
Specific monitoring procedures are as follows: 
• Hypertension will be monitored through routine evaluation of blood pressure prior to each 
bevacizumab treatment.  Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without bevacizumab. 
• Proteinuria will be monitored by urine dipstick or 24 hour urine at least every cycle.  
• If patients on treatment with bevacizumab require elective major surgery, it is recommended that 
bevacizumab be held for 6 weeks prior to the surgical procedure. Patients undergoing a major 
surgical procedure should not begin/restart bevacizumab until 4 weeks after that procedure (in 
the case of high risk procedures such as liver resection, thoracotomy, or neurosurgery, it is 
recommended that chemotherapy be restarted no earlier than 2 weeks and bevacizumab no 
earlier than 6 weeks after surgery). 
 
Bevacizumab may be given by the local oncologists under the direction of the Duke 
investigators.  The Duke investigators will review all the laboratory data and order the treatment.  
The local oncologist will be an agent of the Duke investigators, and just administer the therapy; 
the Duke investigators will be responsible for all the research data. 
5.2 Temodar 
The patients will receive standard anti-emetic therapy to prevent temozolomide-induced nausea 
and vomiting.  Patients will have a CBC weekly and serum chemistries every four weeks. 
5.2.1 Temodar administration during XRT 
Temodar should be initiated within 5 days of the start of external beam radiotherapy but must not 
be started until the following initiation criteria are met: 
 
a.    ANC > 1,500/µl  
b.    Platelet count > 125,000/µl 
c.    Adequate hepatic function - SGOT and total bilirubin ≤2 x upper limit of normal 
d.   Adequate renal function – serum creatinine < 1.5 mg/dl  
 
Complete blood count (CBC) with differential should be measured weekly and complete 
metabolic panel (CMP) should be monitored every other week during XRT with concurrent daily 


 
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Temodar.  Temodar will be held if thrombocytopenia (grade 3), neutropenia (grade 4) or grade 4 
non-hematologic toxicity attributable to Temodar develop.  CBC/diff and/or CMP levels will be 
followed more frequently as clinically indicated in patients who develop abnormalities that 
surpass the above guidelines. Temodar may resume when the following re-treatment criteria are 
met: ANC ≥ 1,000 cells/µl, platelets ≥ 100,000 cells/µl.  However, the Temodar dose will be 
modified according to the following table: 
 
 
 
 
Temodar Dose at Toxicity 
 
Modified Dose 
 
 
 
75 mg/m2 
 
 
      50 mg/m2 
 
       
       
If a patient experiences dose toxicity as defined above at 50 mg/m2 during XRT, Temodar will 
be held for the duration of the remaining external beam radiotherapy but may be resumed upon 
completion of XRT on the 28-day dosing schedule once the above-defined initiation criteria are 
met.  
 
See sections 7.2 and 7.3 for the Temodar and bevacizumab safety plan post-radiation therapy. 
6 Study Population 
The patients will have a newly diagnosed brain tumor with a histologic diagnosis of grade 4 
malignant glioma (glioblastoma or gliosarcoma). If the patient had a prior surgical procedure, the 
patient must be within 8 weeks of the last major surgical procedure, craniotomy, open biopsy, or 
stereotactic biopsy. 
6.1 Inclusion Criteria 
• Patients with histologically confirmed WHO Grade IV primary malignant glioma 
(glioblastoma or gliosarcoma); 
• Patients ≥ 18 years of age; 
• An interval of at least 2 weeks, but not ≥ 8 weeks between prior surgical procedure and 
initiation of treatment; 
• Karnofsky Performance Status (KPS) ≥ 60% 
• Laboratory Values: 
o Platelet Count ≥ 125,000 cells/µL 
o Absolute neutrophil count (ANC) ≥ 1,500 cells/µL 
o Adequate renal function indicated by all of the following:  
 Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance ≥ 50 
ml/min 
 Urine dipstick for proteinuria < 2+ unless a 24-hour urine protein < 1 g of 
protein is demonstrated 
o PT and aPTT ≤ 1.5 x ULN within 14 days prior to starting any protocol specific  
treatment.  The use of full-dose oral or parenteral anticoagulants is permitted as 
long as the PT or aPTT is within these limits.  In order to begin treatment with 
bevacizumab,   the patient has to be on a stable dose of anticoagulants for at least 
two weeks prior to the first bevacizumab treatment. 


 
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• Patients will sign an IRB-approved informed consent form. 
• Female patients must not be pregnant or breast-feeding.  Female patients of childbearing 
potential (defined as < 2 years after last menstruation or not surgically sterile) must use a 
highly effective contraceptive method (allowed methods of birth control, [i.e. with a 
failure rate of < 1% per year] are implants, injectables, combined oral contraceptives, 
intra-uterine device [IUD; only hormonal], sexual abstinence or vasectomized partner) 
during the trial and for a period of > 6 months following the last administration of trial 
drug(s).  Female patients with an intact uterus (unless amenorrhea for the last 24 months) 
must have a negative serum pregnancy test within 7 days prior to first study treatment. 
• Fertile male patients must agree to use a highly effective contraceptive method (allowed 
methods of birth control [i.e. with a failure rate of < 1% per year] include a female 
partner using implants, injectables, combined oral contraceptives, IUDs [only hormonal], 
sexual abstinence or prior vasectomy) during the trial and for a period of > 6 months 
following the last administration of trial drugs. 
 
6.2 Exclusion Criteria 
• Any prior treatment for any grade glioma, including, but not limited to gliadel wafers, 
immunotherapy (including vaccine therapy), radiation therapy or chemotherapy, 
irrespective of grade of the tumor (NOTE: 5-aminolevulinic acid (ALA)-mediated 
photodynamic therapy administered prior to surgery to aid in optimal surgical resection is 
not considered a chemotherapy agent.); 
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents 
other than corticosteroids; 
• Active infection requiring intravenous antibiotics; 
• Prior or current treatment with bevacizumab or other anti-angiogenic treatment (i.e. anti-
VEGF or VEGFR therapies or tyrosine kinase inhibitors) for any condition; 
• Treatment with any other investigational agent within 28 days or 2 investigational agent 
half-lives (whichever is longer) prior to first study treatment; 
• Prior, unrelated malignancy requiring current active treatment with the exception of 
cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma 
of the skin; 
• Evidence of > Grade 1 CNS hemorrhage on post-operative MRI scan, unless repeat MRI 
or CT performed prior to initiating bevacizumab shows stable grade 1 or resolving (< 
grade 1) CNS hemorrhage. 
 
Bevacizumab-Specific Exclusion Criteria: 
• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg 
and/or diastolic blood pressure > 100 mmHg) within 28 days of first study treatment; 
• Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior 
leukoencephalopathy syndrome (RPLS); 
• Prior history of gastrointestinal perforation or abscess; 
• Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular 
accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to 
study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or 


 
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greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by 
medication or potentially interfering with protocol treatment;  
• History or evidence upon physical/neurological examination of central nervous system 
disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or 
potentially interfering with protocol treatment; 
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
arterial thrombosis) within 6 months prior to start of study treatment.  Any previous 
venous thromboembolism > NCI CTCAE Grade 3; 
• History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red 
blood per episode) within 1 month of first study treatment; 
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of 
bleeding (i.e. in the absence of therapeutic anticoagulation); 
• Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day), 
clopidogrel (>75 mg/day) or equivalent.  Prophylactic use of anticoagulants is allowed; 
• Surgical procedure (including open biopsy, surgical resection, wound revision, or any 
other major surgery involving entry into a body cavity) or significant traumatic injury 
within 28 days prior to  first study treatment, or anticipation of need for major surgical 
procedure during the course of the study; 
• Minor surgical procedure, e.g. stereotactic biopsy,  within 7 days of first study treatment; 
placement of a vascular access device, within 2 days of first study treatment; 
• History of intracranial abscess within 6 months prior to first study treatment; 
• History of  active gastrointestinal bleeding within 6 months prior to first study treatment; 
• Serious, non-healing wound, active ulcer, or untreated bone fracture; 
• Known hypersensitivity to any component of bevacizumab or any of the study drugs; 
7 Study Conduct 
7.1 Treatment Plan 
This is a Phase II trial of bevacizumab, radiation therapy (XRT) and Temodar (temozolomide), 
followed by bevacizumab and Temodar then bevacizumab maintenance with continuation of 
bevacizumab beyond progression for newly diagnosed patients with Grade 4 malignant gliomas.  
Patients will receive bevacizumab and Temodar and XRT treatment (Part A), then bevacizumab 
and Temodar for 12 cycles (Part B).  If the patient remains stable throughout Part B of the study, 
they will continue on bevacizumab alone, i.e. 10 mg/kg q o week (Part C). If the patient’s disease 
progresses during either Part B or Part C of the study, the patient will always receive their Duke 
treating physician’s best bevacizumab-based treatment regimen (Part D), unless contraindicated by 
toxicity. 
 
Bevacizumab doses may be given by the local oncologists under the direction of the Duke 
investigators.  The Duke investigators will review all the laboratory data and order the treatment 
by faxing the orders to the oncologist.  The orders that are sent to the local oncologist will contain 
a bevacizumab dose that is rounded to the nearest 100mg to mimic the Duke standard of practice in 
bevacizumab dosing.  Due to the multiple local oncology offices that are being used and due to the 
fact that each office will differ in their standard practice, it will not be considered a reportable 


 
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deviation if the local oncologist does not round the dose of the bevacizumab.  The local oncologist 
will be an agent of the Duke investigators, and just administer the therapy; the Duke investigators 
will be responsible for all the research data.  The study coordinator will send the local oncologist a 
letter giving specific details of the study, including what regular laboratory tests need be 
performed, and requesting all laboratory results be faxed to the coordinator, along with all 
information related to toxicities or adverse events.  If labs are not provided in a timely fashion, the 
study coordinator will contact the local oncologist’s office to obtain them.  See section 8.1.2 for 
bevacizumab administration. 
 
The patient population will include up to 68 patients.     
7.2 Drug Administration/Dosing Schedule 
During Part A of the study, patients will receive standard radiation therapy and daily Temodar, 75 
mg/M2, for six-seven weeks, beginning a minimum of 2 weeks and not > 8 weeks post-operatively.  
Bevacizumab (10 mg/kg every 2 weeks) will be given concurrently with radiation therapy and 
daily Temodar, beginning a minimum of 4 weeks following the last surgical procedure.   
 
If there is no evidence of progression 2-4 weeks after radiation therapy, but not greater than 8 
weeks, the patients start Part B of the study and will receive up to 12 cycles of bevacizumab and 
Temodar.  The bevacizumab will be administered 10 mg/kg q o week on approximately days 1 and 
15.  The Temodar will be 200 mg/m2 daily for 5 days, days 1-5 of each cycle.  Each cycle will be 4 
weeks. The dose of Temodar will be reduced to 150 mg/m2 if the patient has a grade 3 
thrombocytopenia, grade 4 neutropenia or grade 4 non-hematologic toxicity that the investigators 
attribute to Temodar. After 12 cycles of bevacizumab and Temodar, if the patient’s disease is 
stable, he/she will begin Part C of the study, bevacizumab-only therapy (see Section 7.2.2).  
 
Whenever a patient has evidence of progression (during either Part B or Part C of the study), 
treatment will be terminated and the patient will begin Part D of the study involving the Duke 
treating physician’s best bevacizumab-based treatment (see Section 7.2.3). 
7.2.1 Radiation Therapy: Dose Definition and Schedule 
External beam radiation therapy (XRT) should begin 2-8 weeks after surgery.  One treatment of 
1.8 -2Gy will be given daily, 5 days per week, (30-33 fractions over less than seven weeks) for a 
total of 59-60Gy. All portals shall be treated during each treatment session. Doses are prescribed 
at the maximum isodose line encompassing the target volume. 
7.2.2 Bevacizumab Only (Part C) 
Bevacizumab will be continued at 10 mg/kg approximately every 2 weeks or 15 mg/kg 
approximately every 3 weeks.  Ideally, infusions will not be given more than 2-3 days early.  
Infusions can be given late, if needed, based on re-treatment criteria, scheduling issues, holidays, 
etc.  These adjustments in the infusion dates will not be considered reportable deviations.  Cycles 
will ideally be approximately 8 weeks long for patients on 10mg/kg dosing and approximately 9 
weeks long for patients on 15mg/kg dosing, however, the cycle lengths may be adjusted per the 
Duke treating physician based on the patient’s response to the treatment. 


 
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7.2.3 Treatment at Progression (Part D) 
At the time of progression, the patient will receive bevacizumab-based therapy containing 
bevacizumab in combination with a chemotherapy and/or biologic agent, as determined by the 
Duke treating physician and patient, as long as there are no contraindications to bevacizumab 
(see Table 1 and Section 10).  The bevacizumab-based therapy may not, however, be within the 
context of another clinical trial. 
7.3 Re-Treatment Criteria  
7.3.1 Part B- Initiation of each cycle will require: 
o ANC  > 1,000 cells/µl 
o Platelets  > 100,000 cells/µl 
o AST, bilirubin, creatinine ≤ 2.0 x upper limit of normal 
o Resolution of any grade 3 or greater toxicity felt to be possibly, probably or definitely 
attributable to the study regimen to grade 1 or pre-treatment baseline. 
o Proteinuria < 4+ on urinalysis or ≤ 3.5g protein in a 24-hour urine collection 
7.3.2 Re-treatment criteria for Part C 
o Platelets > 50,000 cells/µl 
o Proteinuria < 4+ on urinalysis or  ≤ 3.5g protein in a 24-hour urine collection 
7.3.3 Re-treatment criteria for Part D 
This will be determined by the patient’s treating physician at Duke, as appropriate for the 
bevacizumab-based treatment regimen. 
7.4 Quality of Life Assessments 
Quality of Life will be assessed using standardized and validated questionnaires.  These 
questionnaires include Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale[33], 
Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) subscale, version 4,[34] 
Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) subscale,[35] Epworth 
Sleepiness Scale (ESS)[36], Pittsburgh Sleep Quality Index (PSQI)[37], Godin Leisure-Time 
Exercise Questionnaire short scale[38],  and  Beck depression inventory (BDI).[39] 
 
Functional capacity will be assessed using 6-minute walk test.[40] The patient will be instructed to 
walk at their fastest pace and to cover the longest possible distance over 6 minutes under 
supervision of trained personnel.  Distance walked will be determined in a measured corridor and 
performed according to ATS guidelines.    
 
 
Neurocognitive testing will include the performance on the following testing using a computerized 
battery CNS Vital Signs®.[41] Normative data is available for this testing through CNS Vital 
Signs® and patients’ performance will be compared to this normative data. 
 
All quality of life, functional capacity, neurocognitive assessments will be completed at baseline, 
after radiation therapy (Part A), and then approximately every 6 months (in correlation with the 
Duke visit) during Part B, Part C, and Part D of the study.    


 
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7.5 Miscellaneous 
Steroids and anti-emetics will be administered as clinically warranted.  Attempts will be made to 
keep the steroid dose stable or lower prior to the next MRI. 
7.6 Suggested Image Acquisition 
Imaging evaluation of patients in this study will be performed as part of the treatment assessment 
and to determine progression free survival as described in section 7.7.  Generally, brain MRI with 
and without gadolinium-based contrast agents will be performed unless contraindicated, in which 
case brain CT with and without iodinated contrast-agent will be performed. 
7.6.1 MR image acquisition 
The MR evaluation of these patients will be performed with and without gadolinium-based 
contrast agents and using the routine clinical protocol, with the exception listed below.  The 
routine clinical protocol must at minimum include T1-weighted images obtained in the axial 
plane both before and after the administration of contrast agent; T1-weighted imaging after the 
administration of contrast agent in either the sagittal or coronal plane; and T2-weighted or 
FLAIR imaging in the axial plane.  For all of these sequences, a slice thickness of 5mm or less 
and an interslice gap of 3mm or less will be used.  Full recommended dose of gadolinium-based 
contrast agent will be generally be used, although half-dose of contrast agent may be used for 
patients with mild renal impairment as directed by local imaging guidelines. 
 
For those patients that undergo MR imaging at Duke University Medical Center and Duke 
University Health system affiliated centers, an additional MR imaging procedure designed to 
better evaluate the margins of mildly enhancing tumor margins may be used.  The imaging 
procedure will include a sagittal T1-weighted 3D acquisition (isotropic voxel size of 1.5mm or 
less) obtained before the administration of contrast agent.  An identical sequence will be 
performed after the administration of contrast agent.  The latter images will be reformatted into 
isotropic coronal images.  The additional imaging will be acquired on studies performed on MR 
imaging units which have been pre- approved by the study team for use for the research imaging 
protocol.   
 
MR contraindications:  MRI is the imaging modality of choice for patients evaluated in this 
study; however, patients may be excluded from MR imaging due to criteria in place at the sites 
where imaging is performed.  As a general rule, patients with cardiac pacemakers, intraorbital 
metallic foreign bodies, neurostimulators, aneurysms, and/or significant claustrophobia may be 
excluded from MR imaging.  If the patient is excluded from brain MR imaging or is unable to 
receive gadolinium-based contrast agents due to allergy, brain CT with and without 
administration of iodinated contrast agent can be performed as an alternative.  
7.6.2 CT image acquisition 
For patients who cannot receive a brain MRI with gadolinium-based contrast agents, a brain CT 
with and without iodinated contrast agent will be performed using the standard site clinical 
protocol.  The routine clinical protocol must include axial images with a slice thickness of no 
more than 5mm. 


 
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7.7 Response Criteria 
The imaging response criteria described below will be used by the treating physician to assess the 
patient while in clinic and will take into consideration their clinical status, corticosteroid use and 
imaging assessment. The criteria described below serve as a guideline for the treating physician 
while in clinic, and does not represent the need to describe response rate by the study team. 
Therefore, no formal measurements will be made for study purposes and the CTRAF form will not 
be completed. 
Stable Disease:  Neurological exam is at least stable and maintenance corticosteroid dose not 
increased, and MRI/CT imaging does not meet the criteria for Progressive Disease.  In order to 
classify this category of response as a clinical benefit, Stable Disease status must be maintained for 
at least 8 weeks for patients on this study. 
Progressive Disease:  Progressive neurological abnormalities or worsening neurological status 
not explained by causes unrelated to tumor progression (e.g. anticonvulsant or corticosteroid 
toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.) OR ≥25% increase in the bi-
dimensional measurement of enhancing or non-enhancing tumor on MR/CT when compared to 
nadir OR a new area of enhancement or FLAIR consistent with tumor progression.   The RANO 
criteria will be used to determine progression and pseudo-progression, as defined by Wen et al., 
2010, below.[42] 
 
Criterion 
Stable Disease (SD) 
Progressive Disease (PD) 
T1 gadolinium enhancing disease 
< 50% ↓ but < 25% ↑ 
≥ 25% ↑ * 
T2/FLAIR 
Stable or ↓ 
↑ * 
New lesion 
None 
Present * 
Corticosteroids 
Stable or ↓ 
Not applicable ** 
Clinical status 
Stable or ↑ 
↓ * 
Requirement for response 
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. 
8 Study Medication 
8.1 Bevacizumab 
8.1.1 Description 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate 
for solution for intravenous (IV) infusion.  Bevacizumab may be supplied in 5-cc (100-mg) and 
20-cc (400-mg) glass vials containing 4 mL or 16 mL bevacizumab, respectively (all at 25 
mg/mL).  Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile 
Water for Injection (SWFI), USP.  Vials contain no preservative and are suitable for single use 
only. 
For further details and molecule characterization, see the bevacizumab Investigator Brochure. 


 
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Bevacizumab will be provided by Genentech for use in this study. 
8.1.2 Administration 
Bevacizumab will be diluted in 0.9% Sodium Chloride Injection, USP, to a total volume of 
100 mL.  Administration will be given as a continuous IV infusion.  Anaphylaxis precautions 
should be observed during study drug administration.  It is not necessary to correct dosing based 
on ideal weight. 
The initial dose will be delivered over 90±10 minutes. The 2nd dose may be delivered over 60+10 
minutes. All subsequent infusions may be delivered over 30±10 minutes.  It will not be 
considered a reportable deviation if the local oncologist chooses to infuse the bevacizumab over 
a longer period of time than the recommended infusion times listed above.  
If a subject experiences an infusion–associated adverse event, he or she may be premedicated for 
the next study drug infusion; however, the infusion time may be increased to 60 minutes for the 
subsequent infusion at the discretion of the investigator.  If the next infusion is well tolerated 
with premedication, the subsequent infusion time may then be decreased by 30±10 minutes as 
long as the subject continues to be premedicated.  If a subject experiences an infusion-associated 
adverse event with the 60-minute infusion, all subsequent doses should be given over 
90±15 minutes.  Similarly, if a subject experiences an infusion-associated adverse event with the 
30-minute infusion, all subsequent doses should be given over 60±10 minutes. 
8.1.3 Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2°C–8°C (36°F–46°F) and should 
remain refrigerated until just prior to use.  DO NOT FREEZE.  DO NOT SHAKE.   Vials should 
be protected from light.  
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE ONLY.  Vials used 
for 1 subject may not be used for any other subject.  Once study drug has been added to a bag of 
sterile saline, the solution must be administered within 8 hours. 
8.1.4 Dose modification and toxicity management 
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.  Discontinuation of bevacizumab will have no immediate 
therapeutic effect.  Bevacizumab has a terminal half-life of 21 days; therefore, its discontinuation 
results in slow elimination over several months. There is no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity for 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 


 
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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 will 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.  
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed in Table 
1.  
 
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 hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1/2 non-pulmonary and non-CNS events 
Grade 3  non-pulmonary and non-CNS 
hemorrhage 
Subjects who are also receiving full-dose 
anticoagulation will be discontinued from receiving 
bevacizumab.   
All other subjects will have study bevacizumab 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 non-pulmonary or non-CNS 
hemorrhage 
Discontinue bevacizumab. 


 
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Grade 1 pulmonary or CNS 
hemorrhage 
Subjects who are also receiving full-dose 
anticoagulation will be discontinued from receiving 
bevacizumab.   
All other subjects will have bevacizumab 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. 
Grade 2, 3, or 4 pulmonary or CNS 
hemorrhage 
Discontinue bevacizumab. 
Venous Thrombosis 
No dose modifications for grade 1/2 events 
Hold study drug treatment.  If the planned duration 
of full-dose anticoagulation is <2 weeks, 
bevacizumab should be held until the full-dose 
anticoagulation period is over.  If the planned 
duration of full-dose anticoagulation is >2 weeks, 
bevacizumab may be resumed during the period of 
full-dose anticoagulation if all of the following 
criteria  are met: 
• The subject must have an in-range INR 
(usually between 2 and 3) if on warfarin; 
LMWH, warfarin, or other anticoagulant 
dosing must be stable prior to restarting 
bevacizumab treatment. 
• The subject must not have had a Grade 3 
or 4 hemorrhagic event while on 
anticoagulation. 
Arterial Thromboembolic event 
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, 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 
Discontinue bevacizumab. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1/2 events 


 
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Grade 3 
(Urine protein dipstick 4+, or urine 
collection > 3.5 g/24 hr)   
Hold bevacizumab treatment until ≤ Grade 2, as 
determined by either urine dipstick < 3+, or 24 hr 
collection ≤ 3.5 g 
 
Grade 4 (nephrotic syndrome) 
Discontinue bevacizumab 
GI Perforation 
Discontinue bevacizumab. 
Fistula 
 
Any grade (TE fistula) 
Discontinue bevacizumab. 
Grade 4 fistula 
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 or 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 Any grade 
(requiring medical or surgical therapy) 
Discontinue bevacizumab. 
Reversible Posterior Leukoencephalopathy   
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 


 
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8.2 Temozolomide (Temodar) 
8.2.1 Description 
(SCH 52365, temozolomide, NSC-362856, 8-Carbamoyl-3-methylimidazol[5,1-d]-1,2,3,5-
tetrazine-4-(3H)-one, CCRG 81045, M&B 39831).  Temodar is commercially available and not 
provided in this study.   
8.2.2 Formulation 
Temodar is supplied as a machine-filled, white opaque, preservative-free, two-piece, hard gelatin 
capsule available in 250 mg, 180 mg, 140 mg, 100 mg, 20 mg, and 5 mg strengths.  Refer to 
Investigator Brochure for contents of the formulation.  Temodar capsules are packaged in 30 cc, 
28 mm 480 Type 1 amber glass bottles containing 30 capsules of 5 mg, 20 mg, 100 mg, 140 mg, 
180 mg, or 250 mg strengths. 
8.2.3 Storage 
Temodar capsules should be stored between 2oC to 30oC.  Commercial supply and packaging 
will be used. 
8.2.4 Administration 
Temodar is administered orally on an empty stomach.  The drug is approximately 100% 
bioavailable.  The dose should be rounded to the nearest 5 mg.  Effects of food on product 
absorption are not yet known.  DO NOT OPEN CAPSULES.  DO NOT MIX WITH FOOD.   
DO NOT CHEW CAPSULES. 
 
Temodar at a dose of 75mg/m2 po daily will be started within the first 5 days of external beam 
radiation.  Temodar will be held for grade 3 thrombocytopenia, grade 4 neutropenia, or grade 4 non-
hematologic toxicity secondary to Temodar.  Temodar will be re-started at 50 mg/m2 after resolution 
of the toxicity, or < grade 1. If the grade 3 thrombocytopenia, grade 4 neutropenia, or grade 4 non-
hematologic toxicity secondary to Temodar recurs at 50 mg/m2, Temodar will be held during 
radiation therapy, but may resume after radiation therapy if the patient meets the treatment criteria.  
 
Beginning approximately 2-3 weeks after the last radiation treatment, Temodar will be given at 
200 mg/m2 daily the first 5 days of each 28-day cycle.  The dose of Temodar will be reduced to 
150 mg/m2 if the patient had grade 3 thrombocytopenia, grade 4 neutropenia, or grade 4 non-
hematologic toxicity secondary to Temodar. If the patient has grade 3 thrombocytopenia, grade 4 
neutropenia, or grade 4 non-hematologic toxicity secondary to Temodar at 150 mg/m2 daily, the 
Temodar will be reduced to 100 mg/ m2 daily, which will be the last dose reduction.  If the 
toxicity recurs at 100 mg/m2 daily, Temodar will be discontinued. 
8.2.5 Toxicities 
Temodar has been well tolerated by both adults and children with the most common toxicity 
being mild myelosuppression.  Other, less likely, potential toxicities include nausea and 
vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, 
diarrhea, lethargy, and hepatotoxicity.  Hypersensitivity reactions have not yet been noted with 
Temodar.  As is the case with many anti-cancer drugs, Temodar may be carcinogenic.  Rats 


 
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given Temodar have developed breast cancer.  The significance of this finding for humans is not 
presently known. 
8.2.6 Packaging and labeling 
Temodar is manufactured by Schering-Plough and commercial drug will be used:  
• Product Identity: Temozolomide (SCH 52365) 
• Bottles of dose strength of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg 
8.3 Radiation Therapy and Chemotherapy 
8.3.1 External Beam Radiation Therapy – Standard of Care 
Guidelines and final radiation therapy plan to be completed by treating radiation oncologist.  
Below are guidelines that will be given to the local radiation oncologist, however, if the local 
radiation oncologist feels that a variation of this plan is better for the patient, then the radiation 
oncologist may use his/her plan.  
8.3.1.1 Dose definition and schedule 
External beam radiation therapy (XRT) should begin 2-6 weeks after surgery.  One treatment of 
1.8-2Gy will be given daily, 5 days per week, (30-33 fractions over less than seven weeks) for a 
total of 59-60Gy. All portals shall be treated during each treatment session. Doses are prescribed 
at the maximum isodose line encompassing the target volume.  IMRT is allowed. 
8.3.1.2 Physical factors 
Treatment shall be delivered on megavoltage machines of energy ranging from 4 to 18 MV 
photons. Selection of the appropriate photon energy(ies) should be based on optimizing the RT 
dose distribution within the target volume and minimizing dose to non-target normal tissue. 
Photon energies > 10 MV should be utilized only in dual energy beam arrangements using at 
least one beam with energy < 10 MV. Source skin distance for SSD techniques or source axis 
distance for SAD techniques must be at least 80 cm. 
8.3.1.3 Localization, simulation, and immobilization 
The patient shall be treated in the supine or another appropriate position for the location of the 
lesion. A head-holding device that is transparent to x-rays and provides adequate immobilization 
must be utilized at all times during planning and therapy to ensure reproducibility. 
 
The initial target volume shall include the contrast-enhancing lesion and surrounding edema (if it 
exists) demonstrated on the pre-operative T2-weighted MRI plus a 2.0-cm margin. If no 
surrounding edema is present, the initial target volume should include the contrast-enhancing 
lesion plus a 2.5-cm margin.  This primary target volume will be treated to 45 Gy in 25 daily 
fractions, at 1.8 Gy per fraction.   
 
The boost volume will be based on the post-operative contrast-enhanced T1-weighted MRI 
performed during treatment planning.  After 45 Gy, the boost volume will include the contrast-
enhancing lesion plus a 1.5-cm margin or, if minimal contrast-enhancing lesion is present at a 
portion of the resection cavity on MRI, the surgical defect plus a 2.0-cm margin, whichever is 
greater at that segment of the MRI image.  The boost volume will be treated to an additional 14.4 


 
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Gy in 8 daily fractions, 1.8 Gy per fraction. This will bring the total target dose to 59.4 Gy in 33 
fractions. 
 
All parts of the target volumes are to receive at least 95% but no more than 112% of the dose at 
the prescription isodose line, with at least 95% of the target volumes receiving at least 100% of 
the prescribed dose. However, coverage as low as 90% of the boost target volume receiving at 
least 90% of the prescribed dose is acceptable if needed to meet the dose limitations to critical 
structures, described below(8.3.1.5). 
8.3.1.4 Treatment planning and safety 
Treatment plans may include opposed lateral fields, a wedge pair of fields, rotation, or multiple-
field techniques, including intensity-modulated radiotherapy (IMRT). MRI-guided 3D treatment 
planning is necessary to assure accuracy in the selection of field arrangements.  Isodose 
distributions for the primary and boost target volume are required on all patients, including those 
treated with parallel-opposed fields. A composite plan is required showing the respective target 
volumes. The inhomogeneity across the target volume shall be kept to a minimum. The 
maximum dose should be no higher than 112% of the dose at the prescription isodose line.  
 
Possible side effects include swelling of the brain, hair loss, localized skin irritation, low blood 
counts, fatigue, memory loss, hearing loss, nausea and/or vomiting, loss of appetite, headaches, 
radiation necrosis (death of tissue or skin), and secondary cancer.   
8.3.1.5 Dose limitations to critical structures 
The lens and cervical spine must be shielded from the direct beam at all times. The maximum 
dose to the optic apparatus (optic chiasm, optic nerves, eyes) must be limited to 54 Gy, and the 
brain stem limited to 60 Gy. During radiation therapy, patients will recive Temozolomide 75 
mg/m2/day as described below (8.3.2) 
8.3.2 Temodar administration  
Patients will receive 75 mg/m2 of Temodar on a continuous daily schedule throughout the course 
of external beam radiotherapy.  Temodar should be initiated within 5 days of the start of external 
beam radiotherapy but must not be started until the following initiation criteria are met: 
 
a.    ANC > 1,500/µl; 
b.    Platelet count > 125,000/µl 
 
c.    Adequate hepatic function - SGOT and total bilirubin < 2 x upper limit of normal 
                        d.    Adequate renal function – serum creatinine < 1.5 mg/dl 
 
Complete blood count (CBC) with differential should be measured weekly and complete 
metabolic panel (CMP) should be monitored every other week during XRT with concurrent daily 
Temodar.  Temodar will be held if thrombocytopenia (grade 3), neutropenia (grade 4) or grade 4 
non-hematologic toxicity attributable to Temodar develop.  CBC/diff and/or CMP levels will be 
followed more frequently as clinically indicated in patients who develop abnormalities that 
surpass the above guidelines. Temodar may resume when the above initiation criteria are met, 
but the temozolomide dose will be modified according to the following table: 
 


 
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Temodar Dose at Toxicity 
 
Modified Dose 
 
 
 
       
75 mg/m2 
 
 
        50 mg/m2 
 
       
       
If a patient experiences dose toxicity as defined above at 50 mg/m2 during XRT, Temodar will 
be held for the duration of the remaining external beam radiotherapy but may be resumed upon 
completion of XRT on the 28-day dosing schedule once the above-defined initiation criteria are 
met. 
 
9 Clinical and Laboratory Evaluations 
9.1 Pre-treatment evaluations  
• Vital signs, including blood pressure (within 2 weeks of starting treatment) 
• History and physical exam including a full neurologic exam at baseline Duke visit.  
• CBC with diff, CMP, PT, PTT (within 2 weeks of starting treatment), Beta-HCG if 
appropriate (Beta-HCG must be performed within 48 hours of starting study drug)  
• Urinalysis (within 2 weeks of starting treatment) 
• Baseline MRI of the brain (or CT if unable to have MRI) within eight weeks of 
starting treatment 
• Baseline assessments of Quality of Life, Functional Capacity, and Neurocognitive 
Testing (at baseline Duke visit). 
 
9.2 Evaluations During Radiation Treatment (Part A) 
Blood pressure 
CBC with differential  
CMP 
Urine dipstick for protein on a spot urinalysis 
Quality of Life Assessments 
Functional Capacity Assessments 
Neurocognitive Testing 
Before each dose of bevacizumab 
Weekly 
Before each dose of bevacizumab 
Once per month 
At the end of XRT 
At the end of XRT 
At the end of XRT 
9.3 Evaluations During Part B 
Blood pressure 
CBC with differential  
CMP 
Urine dipstick for protein on a spot urinalysis 
Physical Exam, including a full neurologic exam 
MRI of the brain (or CT if unable to have MRI) 
Toxicity assessment 
Quality of Life Assessments 
Before each dose of bevacizumab 
Every 2 weeks 
Prior to every cycle 
Prior to every cycle 
Prior to every other cycle 
Prior to every other cycle 
Continuous 
Every 6 months  


 
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Functional Capacity Assessments 
Neurocognitive Testing 
Every 6 months  
Every 6 months  
9.4 Evaluations During Bevacizumab Only (Part C) 
Blood pressure 
CBC with differential  
CMP 
Urine dipstick for protein on a spot urinalysis 
Physical Exam, including a full neurologic exam 
MRI of the brain (or CT if unable to have MRI) 
Toxicity assessment 
Quality of Life Assessments 
Functional Capacity Assessments 
Neurocognitive Testing 
Before each dose of bevacizumab 
Prior to every cycle 
Prior to every cycle 
Prior to every cycle 
Prior to every other cycle 
Prior to every other cycle 
Continuous 
Every 6 months 
Every 6 months 
Every 6 months 
9.5 Evaluations During Bevacizumab-based Therapy After Progression (Part D) 
Blood pressure 
CBC with differential  
CMP 
Urine dipstick for protein on a spot urinalysis 
Physical Exam, including a full neurologic exam 
MRI of the brain (or CT if unable to have MRI) 
Toxicity assessment 
Quality of Life Assessments 
Functional Capacity Assessments 
Neurocognitive Testing 
Before each dose of bevacizumab 
Prior to every cycle 
Prior to every cycle 
Prior to every cycle 
Prior to every other cycle 
Prior to every other cycle 
Continuous 
Every 6 months 
Every 6 months 
Every 6 months 
10 Treatment Discontinuation 
In addition to the guidelines presented in Table 1, patients may be discontinued from treatment at 
any time at the discretion of the investigator.  Specific reasons for discontinuation from treatment 
are: 
• Subject decides to withdraw 
• Protocol non-compliance 
• Patients will be discontinued from treatment for specific adverse events as described in 
Table 1. 
• The treating physician feels that another treatment option is better for the patient. 


 
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Patients that are discontinued from the treatment portion of the study may remain on study (if they 
are not receiving additional treatment) and will be followed for adverse events and survival.  The 
patients will continue to follow the return schedule, if possible, unless the treating physician 
recommends a different schedule. 
11 Study Discontinuation 
Patients will be discontinued from the study if they enroll into another study or if other treatment 
outside of this study is needed.  Those patients will continue to be followed for survival until death 
or withdrawal of consent.  Patients may also be discontinued from the study for protocol non-
compliance.  Those patients will continue to be monitored for survival. 
12 Safety Reporting of Adverse Events 
12.1 Assessment of Safety 
12.1.1 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 bevacizumab, all events of death, and any 
study specific issue of concern.   
 
Adverse events (AE) will use the descriptions and grading scales found in the revised NCI 
Common Toxicity Criteria (CTC).  This study will utilize the CTC version 4.0 for adverse event 
reporting.  All appropriate treatment areas should have access to a copy of the CTC version 4.0. 
12.2 Definition of Adverse Event 
12.2.1 Adverse Event (AE) 
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 malignant glioma 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. 


 
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12.2.2 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. 
• 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). 
              
* Since participants may remain on study treatment with bevacizumab well past initial disease 
progression, (i.e. part D of the study) it is expected that patients may die while still being treated or 
within 30 days of being treated with bevacizumab. Deaths that are attributed to disease progression 
while participants are in Part D of the study, will be recorded as an AE, but will not be reported as 
an SAE. 
12.3 Methods and Timing for Assessing and Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed during the 
study are collected and reported, if applicable, to the Duke IRB and Genentech, Inc. in accordance 
with CFR 312.32 (IND Safety Reports). 
12.3.1 Adverse Event Recording Period 
The study period during which all AEs and SAEs must be recorded, begins after informed 
consent is obtained and initiation of study treatment and ends after the last administration of 
study treatment or study discontinuation/termination, whichever is earlier. In addition, SAEs that 
occur within the 30 days after the last administration of study treatment or study 
discontinuation/termination will be reported to both the Duke IRB and Genentech. Deaths that 
occur during the 30 days after the last administration of study treatment or study 
discontinuation/termination will only be reported if the death is attributed to the study treatment. 
Deaths due to disease progression, or other non-study treatment related reasons, will not be 
reported as an SAE.  
12.3.2 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 
recorded appropriately. Each recorded 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. 
 


 
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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 
bevacizumab, 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 
bevacizumab; and/or the AE abates or resolves upon discontinuation of the bevacizumab or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the bevacizumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to bevacizumab 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.  
 
Unexpected adverse events are those not listed in the Package Insert 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 insert or I.B. For example, under this 
definition, hepatic necrosis would be unexpected if the insert or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
12.4  Procedures for Eliciting, Recording, and Reporting Adverse Events 
12.4.1 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?” 
12.4.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
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 
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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.” Deaths due to disease progression after a patient has entered part D of the 
study treatment will not be reported as an SAE.  
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”). 
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. 
 
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. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 6 months 
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 bevacizumab should be reported as an SAE. 
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 bevacizumab 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 
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Reconciliation 
The Investigator agrees to conduct reconciliation for the product. Genentech and the Investigator 
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 
Investigator 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. 
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.  
  
Bevacizumab Events of Special Interest are:   
• 
Hypertension greater than or equal to Grade 3 
• 
Proteinuria greater than or equal to  Grade 3 
• 
Gl perforation, abscesses and fistulae (any grade) 
• 
Wound healing complications greater than or equal to Grade 3 
• 
Haemorrhage greater than or equal to Grade 3 (any grade CNS bleeding; greater than or 
equal to Grade 2 haemoptysis) 
• 
Arterial Thromboembolic events (any grade) 
• 
Venous thromboembolic events greater than or equal to Grade 3 
• 
PRES (any grade) 
• 
CHF greater than or equal to Grade 3 
• 
Non-Gl fistula or abscess greater than or equal to Grade 2 
 
SAE Reporting to Genentech 
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 
OR 
(650) 225-5288 
 
• 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: 


 
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• Any reports of pregnancy following the start of administration with 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 quarterly 
report to Genentech. 
 
SAE Reporting to Duke IRB 
In the event of an adverse event the first concern will be for the safety of the subject.   
 
Only adverse events that the Duke Sponsor-Investigator determines to be serious, unanticipated, 
and related or possibly/probably (i.e. more likely than not) related to the research must be 
reported to the Duke IRB.  Those adverse events will be submitted in the electronic IRB (eIRB) 
system, according the following guidelines: 
• Report within 24 hours of learning about any subject’s death that was unanticipated and more 
likely related to the research than unrelated; 
• Report within 5 business days of learning about any serious, unanticipated, and related or 
possibly/probably related adverse event; 
• Report within 10 business day of learning about any other unanticipated problem or event 
that was more likely related to the research than unrelated. 
  
12.4.3 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 
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 


 
Protocol Version 4.0 09Mar2016 
 
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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/AboutFDA/ReportsManualsForms/Forms/default.htm 
13 Statistical Considerations 
13.1 Study Design and Sample Size Justification 
A single-arm phase II trial is proposed in which 68 patients newly diagnosed with glioblastoma or 
gliosarcoma will receive the following treatment regimen:  bevacizumab-Temodar and XRT 
treatment then bevacizumab and Temodar for 12 months followed by bevacizumab alone; at the 
time of failure, the patient will always receive bevacizumab-based treatment regimens, unless 
contraindicated by toxicity.  The goal of this study is to determine whether continued 
administration of bevacizumab after initial disease progression is worthy of further investigation.  
The primary basis for this assessment will be overall survival, with data from Duke’s newly 
diagnosed bevacizumab-Temodar-CPT11 study used as the historical benchmark for this 
assessment.  In that study, the median survival was 21 months. 
 
The following power calculation is generated under the following assumptions: 
 
• Type I error rate = α = 0.1 (one-tailed) 
• Accrual Rate ≈ 11 patients per month 
• Accrual period = 6 months 
• Total patient accrual = 68 patients 
• Follow-up period = 28 months 
• Exponential survival 
• No loss to follow-up 
 
Under these assumptions, there is 80% power to detect a hazard ratio of 0.71 assuming a one-tailed 
test conducted at the 0.10 level of significance.  Such an improvement in overall survival is 
characterized by an increase from a median survival of 21 months within the historical cohort to 
29.5 months.[43] The calculator for one-arm survival sample size and power as found on 
www.crab.org was used in this determination. 
13.2 Analytic Methods 
The product limit estimator developed by Kaplan and Meier will be used to describe overall 
survival and progression-free survival.  Overall survival is defined as the time between initiation 
of treatment and death, or censored at last follow-up if the patient has not died.  Progression-free 
survival (PFS) is defined as the time between initiation of treatment and the first occurrence of 
progression or death.  PFS will be censored at last known follow-up if the patient remains alive 
without disease progression. 
 


 
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For each type of toxicity observed, the maximum grade experienced by each patient will be 
tabulated overall and for each 6-month period of follow-up. 
 
The mean change between baseline and each follow-up assessment for QOL and functional 
capacity will be computed. 
13.3 Toxicity Monitoring 
 Given that both long- and short-term toxicities are of interest in this study, it is not feasible to 
suspend accrual while toxicity is assessed as is often done in phase I trials.  If the following 
criteria are satisfied or there are other reasons for concern about the safety of patient treatment 
(e.g. treatment-related toxic death), accrual will be suspended and data will be carefully reviewed 
to determine if accrual should be permanently terminated or the protocol modified.  These 
guidelines have not been adjusted for differential length of follow-up of accrued patients. 
 
For the purpose of toxicity monitoring, the occurrence of ≥ grade 2 CNS hemorrhage or grade 4 
or 5 non-hematologic toxicity is defined as being unacceptable.  One of the more common 
“unacceptable” adverse events observed with brain tumor patients treated with and without 
bevacizumab are venous thromboembolisms (VTEs).  Simanek (2007, Neuro-Oncology) reports 
a cumulative probability of VTEs of 21% after 3 months and 26% after 12 months among 
patients with high-grade glioma.  VTE incidence is generally in the range of 20-30% over the 
course of the disease (Jenkins, 2010).  Clinical studies of bevacizumab usage typically until 
initial disease progression have reported VTE rates of 10-20% (Friedman, 2009; Fine, 2009; 
Vredenburgh, 2007).  With many VTEs being considered unacceptable, one would expect that an 
unacceptable toxicity rate of approximately 25% if long-term treatment with bevacizumab did 
not increase the changes for unacceptable toxicity.  Therefore, “unacceptable” toxicity rates of 
25% or less are considered desirable, while rates of 45% or greater are considered as undesirable.  
The statistical hypothesis that will be considered in defining monitoring rules differentiates 
between a 5% (null hypothesis) and 20% (null hypothesis) rate of unacceptable toxicity. 
 
Tabulated below are the conditions under which accrual will be temporarily suspended and data 
carefully reviewed to determine the appropriate action, including permanent study termination, 
continuation with patient accrual after appropriate amendment, or continuation with patient 
accrual with no modification of the protocol.  Accrual will also be suspended whenever a death 
occurs that is possibly, probably, or definitely related to protocol treatment. 
 
 
Number of 
patients 
accrued 
Number of patients 
with unacceptable 
toxicity requiring 
accrual suspension 
8-12 
>4 
13-15 
>5 
16-18 
>6 
19-21 
>7 
22-24 
>8 


 
Protocol Version 4.0 09Mar2016 
 
39 
 
 
 
25-28 
>9 
29-32 
>10 
33-37 
>11 
38-42 
>12 
43-49 
>13 
50-60 
>14 
>60 
>15 
 
These guidelines have not been adjusted for differential length of follow-up of accrued patients.  
The probability of accrual suspension as a function of the true unacceptable toxicity rate is 
tabulated below based upon simulation studies.  These statistics were generated assuming 
toxicity outcome was known at the time of accrual, and ignored issues such as time to toxicity, 
accrual rate, and length of follow-up. 
 
Underlying 
unacceptable 
toxicity Rate 
Probability 
of accrual 
suspension 
0.1 
0.004 
0.15 
0.03 
0.2 
0.10 
0.25 
0.22 
0.3 
0.39 
0.35 
0.56 
0.4 
0.72 
0.45 
0.85 
0.5 
0.92 
 
Every 6 months the toxicity experienced by patients accrued to this study will be summarized 
and reviewed regardless of the number of patients accrued to determine whether the overall 
toxicity profile of treatment is unacceptable or not. 
14 Study Management: Data Safety and Monitoring Plan 
14.1 Audits and Inspections 
Authorized representatives of the Institutional Review Board (IRB) or Duke Cancer Institute 
(DCI) may visit the center to perform audits or inspections, including source data verification. The 
purpose of such an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements. 


 
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14.2 Data Safety and Monitoring 
This clinical research study will be monitored both internally by the PI and externally by the Duke 
University Medical Center Cancer Center’s Protocol Review and Monitoring System in accord 
with their NCI-approved “Institutional Protocol Monitoring Procedures and Guidelines for NIH-
sponsored Research Involving Human Subjects.” In terms of internal review, the PI will 
continuously monitor and tabulate adverse events (see Section 13.3). Appropriate reporting to the 
Duke University Medical Center IRB will be made. If an unexpected frequency of grade III or IV 
events occur, depending on their nature, action appropriate to the nature and frequency of these 
adverse events will be taken.  This may require a protocol amendment or potentially closure of the 
study.  The PI of this study will also continuously monitor the conduct, data, and safety of this 
study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of adverse events and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
 
External review of this protocol begins with an initial review by the Cancer Protocol Committee 
(CPC), which performs a risk assessment of the trial. The PI will abide by their assessment of the 
level of risk, which will determine the intensity of subsequent external monitoring. Documentation 
of this assessment will be maintained. Formal, independent monitoring will be conducted by the 
DCI Monitoring Team. 
 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure 
that the protocol is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures, good clinical practice, and applicable regulatory requirements.  As specified 
in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine 
monitoring after the third subject is enrolled, followed by annual monitoring of 1 – 3 subjects until 
the study is closed to enrollment and subjects are no longer receiving study interventions that are 
more than minimal risk.   
 
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the 
DCI Monitoring Team visit and additional safety and toxicity data submitted by the Principal 
Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency 
of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of 
DUHS and DCI leadership, the CPC, the Safety Oversight Committee (SOC), the sponsor, the 
Principal Investigator, or the IRB.  All study documents must be made available upon request to 
the DCI Monitoring Team and other authorized regulatory authorities, which may include but is 
not limited to the National Institute of Health, National Cancer Institute, and the FDA.  Every 
reasonable effort will be made to maintain confidentiality during study monitoring. 


 
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41 
 
 
 
This phase II study is limited to Duke University Medical Center. Routine monitoring will be 
carried out via a monthly team conference among investigators during which toxicity data, 
including all SAEs, will be reviewed and other issues relevant to the study such as interim 
assessment of accrual, outcome and compliance with study guidelines will be discussed.  
Monitoring will be carried out on an ongoing basis.  .  The severity, relatedness and whether or not 
the event is expected will be reviewed via email. 
14.3 Data Collection 
The study coordinator and investigators are responsible for ensuring that the eligibility checklist 
is completed in a legible and timely manner for every patient enrolled on study. This form will be 
maintained in the patient’s clinical chart at the Preston Robert Tisch Brain Tumor Center at Duke 
(PRTBTC). Any errors on source data should be lined through, but not obliterated, with the 
correction inserted, initialed and dated by the study coordinator or PI. All source documents will 
be available for inspection by the FDA, DUHS IRB, and the Duke Cancer Institute Safety 
Oversight Committee.  
Patient data will be entered into an Oracle Clinical database created and maintained by DUMC 
CCIS. The data are backed up daily and stored on a secure medical center server. The PI, study 
investigators, study statisticians, clinical research coordinator and data coordinator for the study 
are the only individuals who will have access to the web-based Oracle application. All study 
personnel with data editing rights will have documented training. 
 
14.3.1 Study Close-out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, 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: 
 
Avastin Protocols 
Email: avastin-gsur@gene.com 
Fax : 650-745-0978 
14.4 Retention of Records 
All documentation of adverse events, records of study drug receipt and dispensation, patient 
records, regulatory documents and all correspondence will be kept for at least 2 years after the 
study is closed, as required by the FDA. 
15 References 
1. 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 
N Engl J Med, 2005. 352(10): p. 987-96. 
2. 
Salmaggi, A., et al., Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent 
malignant glioma. J Neurooncol, 2003. 62(3): p. 297-303. 


 
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Lamszus, K., et al., Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in 
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4. 
Godard, S., et al., Classification of human astrocytic gliomas on the basis of gene expression: a 
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Birner, P., et al., Vascular patterns in glioblastoma influence clinical outcome and associate 
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Stefanik, D.F., et al., Monoclonal antibodies to vascular endothelial growth factor (VEGF) and 
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7. 
Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in recurrent 
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8. 
Cobleigh, M.A., et al., A phase I/II dose-escalation trial of bevacizumab in previously treated 
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Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic 
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Yang, J.C., et al., A randomized trial of bevacizumab, an anti-vascular endothelial growth factor 
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Botrel, T.E., et al., Efficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone 
in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): 
systematic review and meta-analysis. Lung Cancer, 2011. 74(1): p. 89-97. 
12. 
Arnold, D., et al., Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first 
progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV 
plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol, 2012. 
30((suppl; abstr CRA3503)). 
13. 
Ozcan, C., S.J. Wong, and P. Hari, Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med, 2006. 354(9): p. 980-2; discussion 980-2. 
14. 
Glusker, P., L. Recht, and B. Lane, Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med, 2006. 354(9): p. 980-2; discussion 980-2. 
15. 
Hambleton, J., et al. Safety of low-dose aspirin (ASA) in a pooled analysis of 3 randomized, 
controlled trials (RCTs) of bevacizumab (BV) chemotherapy (CT) in patients (pts) with 
metastatic colorectal cancer (mCRC). in Proceedings of the American Society of Clinical 
Oncology. 2005. Orlando, FLA. 
16. 
Scappaticci, F.A., et al., Surgical wound healing complications in metastatic colorectal cancer 
patients treated with bevacizumab. J Surg Oncol, 2005. 91(3): p. 173-80. 
17. 
Miller, K.D., et al., Randomized phase III trial of capecitabine compared with bevacizumab plus 
capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol, 2005. 
23(4): p. 792-9. 


 
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18. 
Karp, J.E., et al., Targeting vascular endothelial growth factor for relapsed and refractory adult 
acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, 
mitoxantrone, and bevacizumab. Clin Cancer Res, 2004. 10(11): p. 3577-85. 
19. 
Sandler, A., et al., Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung 
cancer. N Engl J Med, 2006. 355(24): p. 2542-50. 
20. 
Stark-Vance, V. Bevacizumab and CPT-11 in the Treatment of Relapsed Malignant Glioma. in 
World Federation of Neuro-Oncology Second Quadrennial Meeting and the Sixth Meeting of the 
European Association for Neuro-Oncology. 2005. Edinburgh, Scotland: Duke University 
Press. 
21. 
Vredenburgh, J.J., et al., Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J 
Clin Oncol, 2007. 25(30): p. 4722-9. 
22. 
Fuks, Z. and R. Kolesnick, Engaging the vascular component of the tumor response. Cancer 
Cell, 2005. 8(2): p. 89-91. 
23. 
Semenza, G.L., Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell, 2004. 
5(5): p. 405-6. 
24. 
Wachsberger, P.R., et al., VEGF trap in combination with radiotherapy improves tumor 
control in u87 glioblastoma. Int J Radiat Oncol Biol Phys, 2007. 67(5): p. 1526-37. 
25. 
Jain, R.K., Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. 
Science, 2005. 307(5706): p. 58-62. 
26. 
Moeller, B.J., et al., Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer 
Cell, 2005. 8(2): p. 99-110. 
27. 
Semenza, G.L., Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 2003. 3(10): p. 721-32. 
28. 
Crane, C.H., et al., Phase I trial evaluating the safety of bevacizumab with concurrent 
radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol, 2006. 24(7): 
p. 1145-51. 
29. 
Willett, C.G., et al., Combined vascular endothelial growth factor-targeted therapy and 
radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol, 2006. 33(5 Suppl 10): 
p. S35-40. 
30. 
Vredenburgh, J.J., et al., The addition of bevacizumab to standard radiation therapy and 
temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed 
glioblastoma. Clin Cancer Res, 2011. 17(12): p. 4119-24. 
31. 
Lai, A., et al., Phase II study of bevacizumab plus temozolomide during and after radiation 
therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol, 2011. 29(2): 
p. 142-8. 
32. 
Reardon, D.A., et al., Bevacizumab (BV) continuation following BV progression: meta-
analysis of five consecutive recurrent glioblastoma (GBM) trials. J Clin Oncol, 2011. 
29((suppl; abstr 2030)). 
33. 
Weitzner, M.A., et al., The Functional Assessment of Cancer Therapy (FACT) scale. 
Development of a brain subscale and revalidation of the general version (FACT-G) in patients 
with primary brain tumors. Cancer, 1995. 75(5): p. 1151-61. 


 
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34. 
Van Belle, S., et al., Comparison of proposed diagnostic criteria with FACT-F and VAS for 
cancer-related fatigue: proposal for use as a screening tool. Support Care Cancer, 2005. 13(4): 
p. 246-54. 
35. 
Jacobs, S.R., et al., Evaluation of the functional assessment of cancer therapy cognitive scale 
with hematopoietic stem cell transplant patients. J Pain Symptom Manage, 2007. 33(1): p. 13-
23. 
36. 
Johns, M.W., A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep, 1991. 14(6): p. 540-5. 
37. 
Buysse, D.J., et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric 
practice and research. Psychiatry Res, 1989. 28(2): p. 193-213. 
38. 
Godin, G. and R.J. Shephard, A simple method to assess exercise behavior in the community. 
Can J Appl Sport Sci, 1985. 10(3): p. 141-6. 
39. 
Beck, A.T., et al., Comparison of Beck Depression Inventories -IA and -II in psychiatric 
outpatients. J Pers Assess, 1996. 67(3): p. 588-97. 
40. 
ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med, 2002. 
166(1): p. 111-7. 
41. 
Gualtieri, C.T. and L.G. Johnson, Reliability and validity of a computerized neurocognitive 
test battery, CNS Vital Signs. Arch Clin Neuropsychol, 2006. 21(7): p. 623-43. 
42. 
Wen, P.Y., et al., Updated response assessment criteria for high-grade gliomas: response 
assessment in neuro-oncology working group. J Clin Oncol. 28(11): p. 1963-72. 
43. 
Lawless, J.F., Statistical models and methods for lifetime data. Wiley series in probability 
and mathematical statistics Applied probability and statistics,1982, New York: Wiley. xi, 
580 p. 
 
 
 


 
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Appendix A:  Schedule of Events in Part A of the Study 
 
 
 
Weeks During Radiation Therapy 
 
Pre-treatment evaluations  
1 
2 
3 
4 
5 
6 
Blood pressurea 
X 
Xa 
 
Xa 
 
Xa 
 
H&P with 
neurological 
assessment 
X 
 
 
 
 
 
 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
CMPa 
X 
X 
 
X 
 
X 
 
PT, PTT 
X 
 
 
 
 
 
 
Beta-HCG, if 
appropriate 
(within 48 hours) 
X 
 
 
 
 
 
 
Urinalysisb 
X 
 
 
 
X 
 
 
MRIc 
X 
 
 
 
 
 
 
Quality of Life 
Assessmentsd 
X 
 
 
 
 
 
 
Bevacizumabe 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Radiation 
Therapy (XRT)f 
 
X 
X 
X 
X 
X 
X 
Temodarg 
 
X 
X 
X 
X 
X 
X 
 
a Blood pressure and CMP should be obtained prior to each dose of bevacizumab. 
b Urinalysis will be obtained once per month. 
c MRI with and without contrast (or CT if unable to have MRI) within 8 weeks of starting treatment. 
d Includes quality of life and functional capacity assessments, as well as neurocognitive testing.  These 
assessments will also be obtained at the end of radiation therapy. 
e Bevacizumab will be administered approximately every other week (but is listed on the table under 
each week since the treatment may start on an even or odd numbered week).  
f Radiation therapy will be administered 5 days/week for approximately 6.5 weeks. 
g Temodar will be taken daily. 
 
 
 


 
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Appendix B:  Schedule of Events in Part B of the Study 
 
 
 
Cycles 1, 2, 3, 4, …12a 
 
Post- XRTb 
1 
2 
3 
4 
Blood pressurec 
 
X 
X 
X 
X 
H&P with 
neurological 
assessmentd 
 
X 
 
X 
 
CBC with 
differentiale 
 
X 
X 
X 
X 
CMPf 
 
X 
X 
X 
X 
Urinalysisf 
 
X 
X 
X 
X 
MRId 
 
X 
 
X 
 
Toxicity 
Assessment 
Continuous 
Quality of Life 
Assessmentsg 
 
X 
 
 
 
Bevacizumabh 
 
X 
X 
X 
X 
Temodari 
 
X 
X 
X 
X 
 
a Each cycle is 4 weeks long.  Subjects can receive up to 12 cycles. 
b If there is no evidence of progression 2-4 weeks after XRT, but not greater than 8 weeks, subjects will 
start Part B of the study. 
c Blood pressure should be obtained prior to each dose of bevacizumab. 
d H&P with neurological assessment and MRI should be obtained prior to the beginning of every other 
cycle. 
e CBC with differential should be obtained every 2 weeks. 
f CMP and urinalysis should be obtained prior to the beginning of every cycle. 
g Includes quality of life and functional capacity assessments, as well as neurocognitive testing.  
Assessments will occur after XRT and then every 6 months.   
h Bevacizuamb will be administered approximately every other week during a cycle on approximately 
Days 1 and 15. 
i Temodar will be taken on Days 1-5 of each cycle. 
 
 
 


 
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Appendix C:  Schedule of Events in Part C of the Study (Bevacizumab Only) 
 
 
Cycles 1, 2, 3, 4, …12a 
 
1 
2 
3 
4 
Blood pressureb  
X 
X 
X 
X 
H&P with 
neurological 
assessmentc 
X 
 
X 
 
CBC with 
differentiald 
X 
X 
X 
X 
CMPd 
X 
X 
X 
X 
Urinalysisd 
X 
X 
X 
X 
MRIc 
X 
 
X 
 
Toxicity 
Assessment 
Continuous 
Quality of Life 
Assessmentse 
X 
 
 
 
Bevacizumabf 
X 
X 
X 
X 
 
a Cycle lengths may vary based on the dosing schedule and per the treating physician.  The cycle lengths 
can be increased or decreased per the treating physician based on the patient’s response to treatment.   
b Blood pressure should be obtained prior to each dose of bevacizumab. 
c H&P with neurological assessment and MRI should be obtained at the beginning of every other cycle. 
d CBC with differential, CMP, and urinalysis should be obtained prior to the beginning of every cycle. 
e Includes quality of life and functional capacity assessments, as well as neurocognitive testing.  
Assessments will occur every 6 months.   
f Bevacizuamb will be administered approximately every other week during a cycle on approximately 
Days 1 and 15 (unless the treatment regimen calls for different timing of bevacizumab per the treatment 
physician).  At the time of progression, the patient will begin Part D of the study and receive 
bevacizumab-containing therapy (alone or with chemotherapy and/or biologic agents), as long as there 
are no contraindications to bevacizumab. 
 
 


 
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Appendix D:  Schedule of Events in Part D of the Study (Bevacizumab-based Therapy) 
 
 
Cycles 1, 2, 3, 4, …12a 
 
1 
2 
3 
4 
Blood pressureb  
X 
X 
X 
X 
H&P with 
neurological 
assessmentc 
X 
 
X 
 
CBC with 
differentiald 
X 
X 
X 
X 
CMPd 
X 
X 
X 
X 
Urinalysisd 
X 
X 
X 
X 
MRIc 
X 
 
X 
 
Toxicity 
Assessmenta 
Continuous 
Quality of Life 
Assessmentse 
X 
 
 
 
Bevacizumabf 
X 
 
X 
 
 
a Cycle lengths may vary based on the dosing schedule and per the treating physician.  The cycle lengths 
can be increased or decreased per the treating physician based on the patient’s response to treatment.   
 
b Blood pressure should be obtained prior to each dose of bevacizumab. 
c H&P with neurological assessment and MRI should be obtained at the beginning of every other cycle. 
d CBC with differential, CMP, and urinalysis should be obtained prior to the beginning of every cycle. 
e Includes quality of life and functional capacity assessments, as well as neurocognitive testing.  
Assessments will occur every 6 months.   
f At the time of progression, the patient will receive bevacizumab-containing therapy (alone or with 
chemotherapy and/or biologic agents), as long as there are no contraindications to bevacizumab.