Clinical trial NCT02490878
Conditions: Radionecrosis Brain Metastases
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2016-04-01; Completion date: 2022-12-15
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II study aims to investigate whether the addition of bevacizumab to standard corticosteroid therapy results in greater improvement in symptoms and less treatment-induced symptoms compared with standard corticosteroid therapy for patients with symptomatic brain radionecrosis following radiosurgery. It is hypothesized that the addition of bevacizumab to standard care corticosteroids will reduce treatment-induced toxicities and improve neurologic impairments in patients with brain radionecrosis following radiosurgery for brain metastases.

Detailed description:
This is a randomized double-blinded phase II study of corticosteroids with bevacizumab vs. corticosteroids with placebo for brain radionecrosis following radiosurgery for brain metastases. This is a two-arm clinical trial with parallel group design for longitudinal quality of life endpoint. Patients will be stratified according to age (≤ 65 years vs. \> 65 years), pathological confirmation of necrosis (yes vs. no), MDASI-BT mean global score (symptom + interference scores) ( \< 4.0 vs. \> 4.0) and prior whole brain radiotherapy (yes vs. no). The primary and secondary objectives are detailed below.

Primary Objective:

To investigate whether the addition of bevacizumab to standard corticosteroid therapy results in greater improvement in symptoms (clinical and patient-reported symptom improvement associated with radionecrosis and less radionecrosis treatment-induced symptoms) compared with standard corticosteroid therapy.

Secondary Objectives:

1. To evaluate the toxicity profile associated with bevacizumab and corticosteroid therapy.
2. To compare self-reported health related quality of life (HRQOL) using LASA, Dexamethasone Symptoms Questionnaire-Chronic (DSQ-C), and MDASI-BT symptom and interference score between treatment arms.
3. To compare intracranial progression-free survival and time to maximum radiographic response between treatment arms.
4. To compare the dose and duration of corticosteroids required between treatment arms and correlate steroid requirement with DSQ-C and MDASI-BT scores.

Patient event monitoring will occur every 2 months after treatment up to 6 months. Then event monitoring will occur up to one year.

Arms: arm 1: The patient will receive bevacizumab 10 mg/kg IV given on days 1 and 15 of a 28 day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms.

Patients who meet the criteria for clinical progression will be treated as per treating MD. arm 2: The patient will receive placebo 0.9% NaCl volume equal to bevacizumab volume added to 100 mL bag of 0.9% NaCl delivered IV given on days 1 and 15 of a 28-day cycle for 4 cycles. Once the patient has started the study treatment, the dose of corticosteroids will be tapered every 5 days (e.g., dexamethasone 2 mg or prednisone 15 mg per taper), as tolerated, under the management of the treating MD. If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 16 mg per day, as per treating MD, to manage symptoms.

Patients who meet the criteria for clinical progression will be allowed to receive bevacizumab according to the protocol.
Interventions: intervention 1: bevacizumab intervention 2: corticosteroids intervention 3: placebo
Intervention descriptions: intervention 1: IV intervention 2: IV intervention 3: IV

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
Participating NCTN Groups:  
Alliance/Alliance for Clinical Trials in Oncology (lead); ECOG-ACRIN/ECOG-ACRIN Cancer Research Group; 
NRG/NRG Oncology; SWOG/SWOG; CCTG/Canadian Cancer Trials Group 
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ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A221208 
 
RANDOMIZED PHASE II STUDY: CORTICOSTEROIDS + BEVACIZUMAB VS. CORTICOSTEROIDS + 
PLACEBO (BEST) FOR RADIONECROSIS AFTER RADIOSURGERY FOR BRAIN METASTASES 
 
Industry-supplied agent: bevacizumab (IND EXEMPT), Commercial agent: corticosteroids. 
ClinicalTrials.gov Identifier: NCT02490878 
 
Study Chair 
Caroline Chung, MD 
MD Anderson Cancer Center 
 
 
 
 
Symptom Intervention 
Committee Chair 
 
 
Study Co-Chair 
 
 
  
Radiation Oncology Co-chair 
 
 
Radiation Oncology Co-
chair 
 
Community Oncology Chair 
 
 
Medical Oncology Co-chair 
 
 
 
Neurosurgery Co-chair 
 
 
Neuroradiology Imaging Co-chair 
 
  
Health Outcomes Co-chair 
 
  
Biomarker Correlative Co-
chair 
  
 
Biomarker Correlative Co-
chair 
 
   
 
NRG Study  
Champion 
 
 
Primary Statistician 
 
 
Secondary Statistician 
 
   
 
Data Manager 
 
  
 
Protocol Coordinator 
 
 
 
 
 
 


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Protocol Resources 
Adverse Event Reporting 
 
Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
Biospecimen Management System 
 
 
Protocol Contacts: 
A221208 Nursing Contacts 
 
A221208 Pharmacy Contact 
 
 
 
 
 
Alliance Biorepository at Mayo Clinic BAP Freezer 
 
 
 
 
 
 
 
IROC 
 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, and 
dose modification: 
Study Chair, Nursing Contact, Protocol Coordinator, 
and (where applicable) Data Manager 
Questions related to data submission, RAVE or patient 
follow-up: 
Data Manager  
Questions regarding the protocol document and model 
informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen submissions: 
Roxann Neumann 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For study data submission:  
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: (Sign in 
at www.ctsu.org, and select the 
Regulatory Submission sub-tab under 
the Regulatory tab.)  
 
Institutions with patients waiting that 
are unable to use the Portal should alert 
the CTSU Regulatory Office 
immediately at 
 to 
receive further instruction and support. 
 
Contact the CTSU Regulatory Help 
Desk at 
 for regulatory 
assistance 
Please refer to the patient 
enrollment section for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN), which can 
be accessed at 
. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
. 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Please see the data 
submission section of the 
protocol for further 
instructions. 
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For clinical questions (i.e., patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
, or 
. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at 
 


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RANDOMIZED PHASE II STUDY: CORTICOSTEROIDS + BEVACIZUMAB VS. CORTICOSTEROIDS + 
PLACEBO (BEST) FOR RADIONECROSIS AFTER RADIOSURGERY FOR BRAIN METASTASES 
Pre-registration Eligibility Criteria  
Required Initial Laboratory Values 
Symptomatic brain radionecrosis after receiving radiosurgery for  
≤ 14 days of registration 
brain metastases (see §3.2.1) 
Absolute neutrophil 
 
Registration/Randomization Eligibility Criteria 
count (ANC) 
≥ 1500/mm3 
Diagnosis of radionecrosis based on clinical onset of symptoms and  
Platelet Count 
≥ 100,000/mm3 
radiological findings of radionecrosis at 3-24 months following 
Hemoglobin 
≥ 10 g/d * 
radiosurgery, with or without pathological confirmation (see §3.3.1) 
BUN 
< 30 mg/dL 
On a stable dose of corticosteroids ≥ 1 week before baseline MRI. 
Creatinine 
< 1.7 mg/dL 
No systemic therapy within 2 weeks prior to, or within 8 weeks  
Bilirubin 
≤ 2.0 mg/dL 
following registration  (see §3.3.2) 
AST and ALT 
≤ 3.0 x upper limits  
No bevacizumab within 3 months prior to registration 
 
of normal (ULN) 
Central imaging review to confirm eligibility, for institutions 
INR 
<1.5 x ULN * 
that opt to use real-time central imaging review to confirm eligibility 
UPC Ratio 
<0.5 * 
Not pregnant and not nursing (see §3.3.3) 
* 
See Section 3.3.6 
Age ≥ 18 years 
 
Karnofsky Performance Status ≥ 60% 
Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA) questionnaires (see § 3.3.7) 
No evidence of recent hemorrhage on baseline MRI of the brain (see § 3.3.8) 
No excess risk of bleeding (see § 3.3.9) 
No clinically significant cardiovascular disease (see § 3.3.10) 
No bowel obstruction, abdominal fistula, GI perforation, or intra-abdominal abscess within past 12 months.  
No central lung metastases with excessive active bleeding.  
No uncontrolled intercurrent illness including, but not limited to any of the following: ongoing or active infection 
requiring IV antibiotics, cardiac arrhythmia, or psychiatric illness and/or social situations that would limit 
compliance with study requirements.  
No history of serious non-healing wound, ulcer, or bone fractures  
SCHEMA 
P 
 
 
 
 
 
Bevacizumab 10 mg/kg IV 
days 1 and 15 x 4 cycles** 
plus  
Corticosteroids 
 
 
R 
 
 
 
R 
 
 
 
E 
 
Optional* 
Central 
imaging 
review 
submission 
 
A 
 
 
 
R 
 
 
N 
 
 
 
E 
 
 
D 
 
 
 
G 
 
 
O 
 
 
 
 
I 
 
 
M 
 
Placebo IV days 1 and 15 x 
4 cycles**  
plus  
Corticosteroids 
 
Bevacizumab 10 mg/kg IV 
days 1 and 15 x 4 cycles** 
plus  
Corticosteroids 
S 
 
 
I 
 
Crossover*** 
T 
 
 
 
Z 
 
 
E 
 
 
 
E* 
 
 
R* 
 
 
 
 
 
 
* 
Central imaging review is not required for this study 
** 
1 cycle = 28 days 
*** 
Patients who experience progression of radionecrosis while on blinded treatment may elect to cross over to open label 
bevacizumab.  
Treatment is to continue for a total of 4 cycles or until progression or unacceptable adverse event (see 
Section 12.0).  Patients will be followed every 2 months for 6 months with clinical visits and patient 
reported outcomes (MDASI-BT, DSQ-C, LASA); then will be followed for progression and survival 
follow-up only up to one year after end of treatment or until death, whichever comes first. 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
 


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Table of Contents 
 
Section 
Page 
1.0 
BACKGROUND ............................................................................................................................. 7 
1.1 
Introduction ................................................................................................................................................ 7 
1.2 
Corticosteroids ........................................................................................................................................... 7 
1.3 
Bevacizumab .............................................................................................................................................. 7 
1.4 
Diagnosis of radionecrosis ......................................................................................................................... 8 
1.5 
Study design ............................................................................................................................................... 8 
2.0 
OBJECTIVES ................................................................................................................................. 9 
2.1 
Primary objective ....................................................................................................................................... 9 
2.2 
Secondary objectives ................................................................................................................................. 9 
2.3 
Correlative objectives .............................................................................................................................. 10 
3.0 
PATIENT SELECTION............................................................................................................... 10 
3.1 
On-Study Guidelines ................................................................................................................................ 10 
3.2 
Pre-Registration Eligibility Criteria ......................................................................................................... 11 
3.3 
Registration/Randomization Eligibility Criteria ...................................................................................... 11 
4.0 
PATIENT REGISTRATION/RANDOMIZATION .................................................................. 14 
4.1 
CTEP / DCP Investigator Registration Procedures .................................................................................. 14 
4.2 
CTSU Site Registration Procedures ......................................................................................................... 15 
4.3 
Patient Pre-Registration/Registration Requirements ................................................................................ 17 
4.4 
Patient pre-registration (Step 0) procedures ............................................................................................. 17 
4.5 
Review of baseline MR imaging .............................................................................................................. 18 
4.6 
Patient Registration/Randomization (Step 1) procedures ........................................................................ 18 
4.7 
Registration to Correlative and Companion Studies ................................................................................ 19 
4.8 
Stratification Factors and Treatment Assignments .................................................................................. 19 
4.9 
Crossover Re-registration (step 2) Procedures ......................................................................................... 20 
5.0 
STUDY CALENDAR ................................................................................................................... 22 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................... 23 
6.1 
Data collection and submission ................................................................................................................ 23 
6.2 
Specimen collection and submission ....................................................................................................... 24 
6.3 
Imaging submission ................................................................................................................................. 27 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 29 
7.1 
Bevacizumab and Placebo ....................................................................................................................... 29 
7.2 
Clinical progression allowing cross-over to bevacizumab ....................................................................... 30 
7.3 
Clinical Assessments ............................................................................................................................... 30 
7.4 
Neuro-imaging ......................................................................................................................................... 30 
7.5 
Patient-Reported Symptoms .................................................................................................................... 32 
7.6 
Quality of Life ......................................................................................................................................... 32 
7.7 
Definitions of Deviations in Protocol Performance ................................................................................. 32 
8.0 
TREATMENT MODIFICATIONS, UNBLINDING ................................................................ 33 
8.1 
Ancillary therapy, concomitant medications, and supportive care ........................................................... 33 
8.2 
Discontinuation of bevacizumab .............................................................................................................. 33 
8.3 
Unblinding Procedures ............................................................................................................................. 36 
9.0 
ADVERSE EVENTS .................................................................................................................... 37 
9.1 
Routine adverse event reporting .............................................................................................................. 37 
9.2 
CTCAE Routine Study Reporting Requirements ..................................................................................... 38 
9.3 
Expedited Adverse Event Reporting System (CTEP-AERS) .................................................................. 38 
10.0 
DRUG INFORMATION .............................................................................................................. 41 
10.1 
General Considerations: ........................................................................................................................... 41 


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10.2 
Bevacizumab (Avastin) ......................................................................................................................... 41 
10.3 
Placebo ..................................................................................................................................................... 48 
10.4 
Nursing Guidelines .................................................................................................................................. 49 
11.0 
MEASUREMENT OF EFFECT ................................................................................................. 50 
11.1 
Schedule of Evaluations: .......................................................................................................................... 50 
11.2 
Guidelines for Evaluation of Measurable Disease ................................................................................... 50 
11.3 
Definitions of analysis variables .............................................................................................................. 51 
12.0 
END OF TREATMENT/INTERVENTION .............................................................................. 51 
12.1 
Duration of Treatment .............................................................................................................................. 51 
12.2 
Managing ineligible patients and major protocol violations .................................................................... 51 
12.3 
Extraordinary Medical Circumstances ..................................................................................................... 52 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 53 
13.1 
Study Overview ....................................................................................................................................... 53 
13.2 
Sample Size, Accrual Time and Study Duration ...................................................................................... 53 
13.3 
Statistical Design and Analysis for the Primary Endpoint ....................................................................... 53 
13.4 
Supplementary Analysis Plans ................................................................................................................. 55 
13.5 
Study Monitoring ..................................................................................................................................... 56 
13.6 
Study Reporting ....................................................................................................................................... 57 
13.7 
Descriptive Factors .................................................................................................................................. 57 
13.8 
Missing Data ............................................................................................................................................ 57 
13.9 
Inclusion of Women and Minorities ........................................................................................................ 58 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 59 
14.1 
Alliance A221208-ST1 ............................................................................................................................ 59 
14.2 
Alliance A221208-IM1 ............................................................................................................................ 61 
15.0 
REFERENCES .............................................................................................................................. 62 
APPENDIX I: 
INFORMED CONSENT ......................................................................................... 66 
APPENDIX II: 
SYSTEMIC THERAPIES ALLOWED CONCURRENTLY WITH 
BEVACIZUMAB ..................................................................................................... 81 
APPENDIX III: 
MR IMAGING REMOTE CENTRAL REVIEW ................................................. 82 
APPENDIX IV: 
A221208 TUMOR IMAGING PROTOCOLS ....................................................... 83 
APPENDIX V: 
PATIENT INFORMATION SHEET ..................................................................... 88 
APPENDIX VI: 
MD ANDERSON SYMPTOM INVENTORY-BT ................................................ 89 
APPENDIX VII: DEXAMETHASONE SYMPTOMS QUESTIONNAIRE-CHRONIC ............... 91 
APPENDIX VIII: LINEAR ANALOGUE SELF ASSESSMENT (LASA) ........................................ 93 
APPENDIX IX: 
CORTICOSTEROID MEDICATION LOG ......................................................... 94 
APPENDIX X: 
INTELLECTUAL PROPERTY OPTION TO COLLABORATORS ................ 96 
 


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1.0 
BACKGROUND 
1.1 
Introduction 
While brain tumor control is improving, the incidence of brain radionecrosis is rising as the 
cumulative doses of radiation used and the utilization of stereotactic radiosurgery for the 
treatment of both primary and secondary brain tumors is increasing. Approximately 10% of 
patients receiving radiosurgery for their brain tumor develop radionecrosis.[1] Gamma Knife 
usage statistics indicate that 50,000 patients per year receive Gamma Knife radiosurgery 
worldwide, therefore the number of patients treated with radiosurgery using all devices (Gamma 
Knife, Linac, Cyberknife) is much higher.   
1.2 
Corticosteroids 
In current clinical practice, an initial trial of corticosteroids is started based on clinical 
presentation (neurological deterioration within the typical 3-18 month time-frame following 
radiosurgery) accompanied by radiological findings consistent with radionecrosis. Following 
the initiation of high-dose corticosteroids, if symptoms do not resolve, surgical resection may 
assist some patients. However, in rapidly progressive cases or for lesions that are not surgically 
amenable, there are no alternative effective therapies and patients can suffer significant 
morbidity and may ultimately die from progressive radionecrosis.[2-5]  For patients who 
respond and notice neurological improvement with high-dose steroids, the toxicities of treatment 
can be quite troublesome – insomnia, acne, weight-gain, peripheral edema, severe mood 
instability, acid reflux, fatigue. [6]  Although less common, high-dose and/or prolonged 
corticosteroid use can also result in significant morbidity and increased hospital admissions due 
to toxicities such as severe steroid-induced myopathy, avascular necrosis of the femoral head, 
bone fractures, high blood pressure, hyperglycemia complicated by metabolic disturbances and 
renal impairment, and increased infections.[7, 8] Therefore, it is imperative that novel and 
effective treatments for radionecrosis be developed. 
1.3 
Bevacizumab 
The pathophysiology of radionecrosis in the brain is not well understood, but the development 
of brain edema, reflecting a disruption of the blood-brain barrier, is a consistent finding after 
high-dose radiation.[9-11] Once this barrier is disrupted, vasogenic edema and vascular 
compromise can result in tissue hypoxia, which induces the release of vasoactive proteins 
including vascular endothelial growth factor (VEGF).[10, 11] Studies have shown that hypoxia 
can increase microvessel permeability and that there is co-expression of EF5 (a marker of 
hypoxia), HIF1α (a marker of cellular response to hypoxia) and VEGF in areas of disruption of 
this barrier.[12, 13]  VEGF has been shown to induce fenestrations in capillary endothelial cells 
and interfere with tight junction assembly thereby impairing the blood-brain barrier.[14, 15]  
This appears to be independent of VEGF binding to VEGF receptor.[16] Models of radiation 
necrosis have proposed that elevated levels of VEGF may perpetuate an avalanche effect of 
increased vascular permeability leading to further edema, hypoxia and eventually white matter 
necrosis.[17] Therefore, interruption of this cycle of damage by VEGF blockade is a rational 
target in the treatment of radionecrosis. 
Bevacizumab (Avastin®) is a humanized murine monoclonal antibody that selectively binds and 
neutralizes the biological activity of human VEGF-A.[18] It has demonstrated therapeutic effect 
in the treatment of several solid tumors and more recently has shown some promise in the 
treatment of gliomas.  Recent case reports and case series of patients with radionecrosis have 
demonstrated radiological and symptomatic improvement after bevacizumab treatment.[19, 20]  
Subsequently, a small prospective study of radionecrosis following high-dose radiotherapy for 
primary brain and head and neck cancers has suggested that bevacizumab results in radiological 


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and symptomatic improvement in patients with symptomatic radionecrosis.[21] In this study, 6 
of 11 patients receiving bevacizumab for radionecrosis experienced adverse events including 
thrombotic, ischemic and infectious events. Therefore, the toxicities associated with 
bevacizumab administration in patients with radionecrosis following radiosurgery for brain 
metastases requires further evaluation in order to consider the true therapeutic benefit of this 
agent in this context. 
1.4 
Diagnosis of radionecrosis 
It is recognized that a radiological diagnosis of brain radionecrosis can be challenging using 
conventional methods for acquisition and evaluation of CT and MR images, as the appearance 
of brain tumors and brain radionecrosis can be very similar. However, stereotactic biopsy has 
been faced with its own limitations and challenges such that it also fails to have 100% sensitivity 
or specificity. This is often due to spatial heterogeneity within these lesions, which can often 
contain both tumor cells (which may or may not be viable) and necrosis. As stereotactic biopsy 
is an invasive procedure with imperfect diagnostic capabilities that can be associated with 
additional risks to the patient, many practices do not utilize biopsy especially in the setting of 
possible radionecrosis after radiosurgery for brain metastases; therefore efforts have been made 
to improve the imaging techniques used to assist in the diagnosis of radionecrosis.  
Further analysis of conventional MR imaging data have suggested that specific quantitative 
measures in the patterns of enhancement such as the lesion quotient (the proportional value of 
maximal cross-sectional area of the post-gadolinium T1-weighted contrast enhancement to the 
T2-weighted hyperintensity) may help identify cases suspicious for radionecrosis.[22] A lesion 
quotient of less than 0.3 was found in 80% of cases of pure radionecrosis whereas a lesion 
quotient of greater than 0.6 was found in tumor.[22] The incorporation of new physiological and 
metabolic imaging techniques including proton MR spectroscopy, perfusion MRI and diffusion-
weighted MRI have been investigated as tools to further improve the radiological diagnosis of 
radionecrosis following radiotherapy. [7, 19-23] Following radiosurgery for brain metastases, 
relative cerebral blood volume (rCBV) measured on dynamic susceptibility-weighted contrast-
enhanced (DSC) MRI has shown the greatest promise in differentiating radionecrosis from 
progressive or recurrent tumor.[23-25] Although both radionecrosis and progressive tumor show 
increased contrast enhancement, areas of radionecrosis have not shown the same increase in 
intravascular blood volume as seen in progressive tumor.[26-28] Specifically, several studies 
have suggested that a cut-off of rCBV value of 1.5-2.0 relative to white matter may be used to 
diagnose tumor progression rather than radionecrosis.[23, 25] Changes in rCBV have also been 
used to measure response to treatment with radiotherapy as well as anti-VEGF therapy.[29] 
Using a combination of these imaging parameters can improve the overall sensitivity and 
specificity of MRI in the radiological diagnosis of brain radionecrosis.  
1.5 
Study design  
This randomized phase II study aims to investigate whether the addition of bevacizumab to 
standard corticosteroid therapy results in greater improvement in symptoms and less treatment-
induced symptoms compared with standard corticosteroid therapy for patients with symptomatic 
brain radionecrosis following radiosurgery. We hypothesize that the addition of bevacizumab to 
standard care corticosteroids will reduce treatment-induced toxicities and improve neurologic 
impairments in patients with brain radionecrosis following radiosurgery for brain metastases. In 
part, we hypothesize that the use of bevacizumab will allow for rapid de-escalation of 
corticosteroid requirements and thereby decrease the corticosteroid-related toxicities.  
Recognizing that stereotactic biopsy is an invasive procedure with additional risks to the patient 
with imperfect diagnostic capabilities and acknowledging that many practices do not utilize 
biopsy-confirmation in the setting of suspected radionecrosis after radiosurgery for brain 


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metastases, we will be using a combination of imaging parameters to maximize the specificity 
for radionecrosis in conjunction with the clinical presentation.  
As traditional endpoints, such as time to tumor progression and overall survival, are less 
clinically meaningful in patients requiring treatment for brain radionecrosis following 
radiosurgery for brain metastases, we have aimed to evaluate the impact of both the disease and 
therapy by using patient-reported symptoms as the primary endpoint.[30] Symptom assessment 
measures such as the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) have been 
specifically developed in patients with brain tumors to capture patient self-reports of symptom 
severity and interference with daily activities.[31-34] The MDASI-BT has demonstrated 
reliability and validity in the metastatic brain tumor patient population.[32] This tool represents 
a modification of the widely used and validated MDASI, with particular attention to symptoms 
common in patients with brain tumors. In RTOG 0525, a randomized study of standard vs. dose-
intense adjuvant temozolomide in patients with glioblastoma, MDASI-BT demonstrated 
adequate sensitivity to detect differences in treatment-related toxicity between the two arms and 
early changes in MDASI-BT global scores were associated with progression free and overall 
survival [35].  In the small prospective study of bevacizumab versus placebo in patients with 
brain radionecrosis, the MDASI-BT was able to detect self-reported symptomatic 
improvement.[21]  In RTOG 0825, the MDASI-BT was used to assess symptomatic differences 
in brain tumor patients treated with bevacizumab versus placebo and the results of these findings, 
which were presented at the American Society of Clinical Oncology (ASCO) annual meeting in 
June 2013, provided additional information about MDASI-BT changes over time with 
bevacizumab. As this study aims to evaluate the toxicities of bevacizumab and corticosteroids, 
we identified a Dexamethasone Symptom Questionnaire (DSQ) to gather more detailed 
information about symptoms associated with dexamethasone use.  The DSQ was developed and 
the content validity evaluated in patients receiving prophylactic dexamethasone with their 
systemic therapy.[36] Subsequently, modifications have been added to create a DSQ-Chronic 
for patients with brain tumors, which is currently being evaluated in a validation study in patients 
with brain metastases at MD Anderson.  
Finally, this study aims to additionally evaluate serial imaging and biofluid biomarker measures 
that may predict for treatment response and may ultimately assist in patient selection or adapted 
bevacizumab treatment regimens in patients with radionecrosis.  This preliminary data would 
guide the utility of these biomarkers in a subsequent larger study.  Although this study 
specifically evaluates radionecrosis following radiosurgery for brain metastases, the 
pathophysiology for brain radionecrosis is the same for fractionated radiotherapy and therefore 
results of this trial may be applicable to a broader patient population experiencing brain 
radionecrosis following radiation treatment. 
2.0 
OBJECTIVES  
2.1 
Primary objective 
To investigate whether the addition of bevacizumab to standard corticosteroid therapy results in 
greater improvement in symptoms (clinical and patient-reported symptom improvement 
associated with radionecrosis and less radionecrosis treatment-induced symptoms) compared 
with standard corticosteroid therapy. 
2.2 
Secondary objectives 
2.2.1 To evaluate the toxicity profile associated with bevacizumab and corticosteroid therapy. 


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2.2.2 To compare self-reported health related quality of life (HRQOL) using LASA, 
Dexamethasone Symptoms Questionnaire-Chronic (DSQ-C), and MDASI-BT symptom 
and interference score between treatment arms. 
2.2.3 To compare intracranial progression-free survival and time to maximum radiographic 
response between treatment arms.  
2.2.4 To compare the dose and duration of corticosteroids required between treatment arms and 
correlate steroid requirement with DSQ-C and MDASI-BT scores. 
2.3 
Correlative objectives 
2.3.1 To explore serum/urine biomarkers that predict for treatment response. 
2.3.2 To explore early imaging biomarkers that predict for treatment response. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Contact Information page. Please note that the 
Study Chair cannot grant waivers to eligibility requirements. 
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study due to the teratogenic potential of 
the therapy utilized in this trial. Appropriate methods of birth control include abstinence, 
oral contraceptives, implantable hormonal contraceptives or double barrier method 
(diaphragm plus condom). 
 
 


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3.2 
Pre-Registration Eligibility Criteria 
Following Update 2 to this protocol, central imaging review to confirm eligibility is not required. 
However, this central review will continue to be made available for institutions who wish to take 
advantage of this service. 
___ 
3.2.1 Documentation of Disease: Patients who present with symptomatic brain radionecrosis 
after they have received radiosurgery for brain metastases from primary solid tumor 
including but not limited to lung, breast, colorectal cancer but excluding melanoma, 
choriocarcinoma, renal cell carcinoma or gliomas (due to high risk of intratumoral 
hemorrhage). 
• 
Patients at institutions that elect to utilize central imaging review to confirm eligibility 
must be pre-registered prior to submission of these images. Images should be submitted as 
soon as possible after the pre-registration MRI is obtained. Turnaround time for this review 
will be ≤ 72 business hours after receipt of images by the IROC (see Section 6.3 and 
Appendix III). 
• 
Patients at institutions that elect to confirm eligibility locally may be pre-registered at 
the same time as they are randomized (see Section 4.6). 
3.3 
Registration/Randomization Eligibility Criteria 
 
3.3.1 A diagnosis of radionecrosis will be based on a clinical onset of symptoms and radiological 
findings of radionecrosis at 3-24 months following radiosurgery, with or without 
pathological confirmation. 
___ 
• 
‘Symptomatic’ brain radionecrosis to at least one lesion following radiosurgery 
treatment for brain metastases where ‘symptomatic’ is defined as: 
o New or increasing headache associated with mass effect, sensory or motor 
abnormality, cognitive changes, speech difficulty, balance or coordination 
difficulty, cranial nerve deficits 
o Symptoms are persistent or worsening despite administration of at least 
dexamethasone 4 mg (or equivalent corticosteroid) daily for 1 week  
___ 
• 
Clinical eligibility supported by central imaging real-time review. 
The presence of at least the following conventional MR image characteristic: 
o Conventional MR 
Lesion quotient of < 0.3, where lesion quotient is defined as the proportional value 
of the maximum axial cross-sectional area of the T2-weighted defined lesion over 
the maximum axial cross-sectional area of the contrast-enhancing lesion on the T1-
weighted post-gadolinium sequence on a comparable axial slice. 
If the conventional MR findings are not seen, the following dynamic susceptibility-
contrast (DSC) MR characteristics may be used to meet eligibility for this study: 
o DSC MR 
The cut-offs below will be based on GRE EPI DSC perfusion images, acquired 
without using a gadolinium pre-load: 
1. Relative cerebral blood volume (rCBV) <1.5 in the enhancing-lesion relative to 
normal-appearing white matter (NAWM) [25] 


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2. Percentage of signal recovery (PSR) > 76%, where PSR is determined by 
comparing the lower signal intensity during passage of the contrast bolus with 
the post-contrast signal intensity on the signal intensity-time curve.[25] 
o Centers that standardly use PET or MRS to determine a diagnosis of radionecrosis 
are permitted to use these modalities to assist in their patient selection; however the 
criteria described for conventional MR and/or DSC should also be met for study 
eligibility. Both PET and MRS are not mandatory for study eligibility. 
 
3.3.2 Prior to start of treatment 
___ 
• 
Must have been taking a stable dose of corticosteroids for symptom management for at 
least 1 week before baseline MRI. 
___ 
• 
No systemic therapy within 2 weeks prior to registration or plan for systemic therapy 
within the first 8 weeks after study registration. Exceptions: Appendix II provides a list 
of ‘approved systemic’ therapies that are allowed for concurrent use with bevacizumab. 
___ 
• 
No bevacizumab ≤ 3 months of study registration. 
___ 
• 
Central imaging real-time review (72 hour turn around) to confirm eligibility (for 
institutions that opt to utilize central imaging review to confirm eligibility). 
___ 
3.3.3 Not pregnant and not nursing, because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are 
unknown. Therefore, for women of childbearing potential only, a negative urine or 
serum pregnancy test done ≤ 14 days prior to registration and confirmation they are 
not nursing is required. 
___ 
3.3.4 Age ≥ 18 years 
 
___ 
3.3.5 Karnofsky Performance Status ≥ 60% 
 
___ 
3.3.6 Required Initial Laboratory Values ≤14 days of registration:  
Absolute Neutrophil 
Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Hemoglobin 
≥ 10 g/dL (allowing transfusion or other intervention to achieve 
this minimum hemoglobin) 
BUN 
< 30 mg/dL 
Creatinine 
< 1.7 mg/dL 
Bilirubin 
≤ 2.0 mg/dL 
ALT 
≤ 3.0 x upper limits of normal (ULN) 
AST 
≤ 3.0 x ULN 
INR 
<1.5 x ULN unless patients are receiving anti-coagulation therapy.  
Patients receiving anti-coagulation therapy with an agent such 
as warfarin or heparin are allowed to participate if INR ≤3.0. 
UPC Ratio 
<0.5 or if ≥ 0.5, 24-hour urine protein must be <1000 mg 
 
___ 
3.3.7 Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA) 
questionnaires. Assistance by research personnel is acceptable if participant has disabilities 
that make reading or writing difficult. 
 
___ 
3.3.8 No evidence of recent hemorrhage at pre-registration MRI of the brain, however the 
following are permitted: presence of hemosiderin, resolving hemorrhagic changes related 


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to surgery, and presence of punctate hemorrhage in the tumor. If there are questions, the 
treating physician should contact the overall Study Chair, Dr. Caroline Chung. 
 
___ 
3.3.9 No excess risk of bleeding (any of the following):  
• 
Bleeding diathesis or coagulopathy 
• 
Thrombocytopenia 
• 
Major surgical procedure, open biopsy, or significant traumatic injury within the past 
28 days or anticipation of need for major surgical procedure during the course of the 
study. 
• 
Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy 
within the past 7 days. 
 
___ 
3.3.10 No clinically significant cardiovascular disease. 
• 
No uncontrolled hypertension (systolic blood pressure ≤ 160 mm Hg or diastolic ≤ 100 
mm Hg). Patients with hypertension must be adequately controlled with appropriate 
anti-hypertensive therapy or diet. 
• 
No history of arterial thrombotic events within the past 6 months, including:  
- 
transient ischemic attack (TIA) 
- 
cerebrovascular accident (CVA) 
- 
peripheral arterial thrombus 
- 
unstable angina or angina requiring surgical or medial intervention 
- 
myocardial infarction (MI) 
- 
significant peripheral artery disease (i.e., claudication on less than one block) 
- 
significant vascular disease (i.e., aortic aneurysm, history of aortic dissection) 
• 
Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 
months are eligible if they are on stable therapeutic anticoagulation. 
• 
No current New York Heart Association classification II, III, or IV congestive heart 
failure. 
 
___ 
3.3.11 No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within past 12 months. 
 
___ 
3.3.12 No central lung metastases with excessive active bleeding. 
 
___ 
3.3.13 No uncontrolled intercurrent illness including, but not limited to any of the following: 
ongoing or active infection requiring IV antibiotics, cardiac arrhythmia, or psychiatric 
illness and/or social situations that would limit compliance with study requirements. 
 
___ 
3.3.14 No history of serious non-healing wound, ulcer, or bone fractures. 
 
 


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4.0 
PATIENT REGISTRATION/RANDOMIZATION 
4.1 
CTEP / DCP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) 
 Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email at 
 
Registration requires the submission of: 
• 
Human Subject Protection (HSP) training certificate 


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4.2 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses 
extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to:  
• 
an active Federal Wide Assurance (FWA) number, 
• 
 an active roster affiliation with the Lead Network or a participating organization,  
• 
a valid IRB approval, and  
• 
compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are 
not required to submit separate IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied to 
the RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet 
for Local Context (SSW) to the CIRB via IRBManager to indicate their intention to open the 
study locally.  The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office. In order for the SSW approval to be processed, the Signatory Institution must inform the 
CTSU which CIRB-approved institutions aligned with the Signatory Institution are participating 
in a given study. 
 
 


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4.2.1 Downloading Site Registration Documents  
Site registration forms may be downloaded from the A221208 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
• 
Go to 
 and log in to the members’ area using your CTEP-IAM 
username and password. 
• 
Click on the Protocols tab in the upper left of your screen. 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or, 
• 
Click on the By Lead Organization folder to expand. 
• 
Click on the Alliance link to expand, then select trial protocol # A221208. 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
4.2.2 Requirements for A221208 Site Registration 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted)  
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members’ area)   Regulatory 
Tab   Regulatory Submission Portal 
When applicable, original documents should be mailed to: 
 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 
 in order to receive further instruction 
and support. 
 
 


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4.2.4 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website.  
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to 
 and log in to the members’ area using your CTEP-IAM 
username and password. 
• 
Click on the Regulatory tab  
• 
Click on the Site Registration tab. 
• 
Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
4.3 
Patient Pre-Registration/Registration Requirements 
• 
Informed consent: the patient must be aware of the nature of his/her disease and willingly 
consent after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Human 
protection committee approval of this protocol and a consent form is required. 
• 
Patient completed booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient completed booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents 
section of the A221208 website) and faxing the form to the CTSU data operations center at 
 Samples of the booklet questionnaires are found in Appendices V-VII. 
4.4 
Patient pre-registration (Step 0) procedures  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
 and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at 
 or from the OPEN tab on the 
CTSU members’ side of the website at 
. A user manual is available for 
OPEN users on the CTSU site. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All pre-registration eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of pre-registration. 
Please print this confirmation for your records. 


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Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at 
 or at 
 For any additional 
questions contact the CTSU Help Desk at 
 
4.5 
Review of baseline MR imaging 
Baseline MR images must be analyzed for eligibility based on imaging criteria. Images and the 
quantitative results for all patients must be submitted to IROC at the Ohio State University per 
Section 6.3  Images may be analyzed locally or may be submitted to IROC for real-time central 
review.  
4.5.1 Local imaging review for determination of eligibility 
Participating sites may use institutional resources to perform imaging review for the 
determination of eligibility. After the patient is determined to be eligible for this study, s/he 
may be pre-registered and registered/randomized at the same time. 
4.5.2 Real time central review of baseline MR images 
For institutions that are unable (or opt not) to complete the required imaging analysis, 
images may be submitted to IROC per Section 6.3 for determination of eligibility. These 
images must be submitted after pre-registration and prior to registration/randomization,. 
Within 72 hours after receipt of the images, baseline MR imaging data sets will be reviewed 
by the A221208 central review panel per Appendix III to determine patient eligibility. 
The Alliance registration office will be notified by IROC of the central review result within 
24 hours after receiving it from the central review panel. The enrolling institution will then 
be notified by email of the central review result.  
Patients should be randomized within 3 days after receiving confirmation of patient 
eligibility following central imaging review. 
4.6 
Patient Registration/Randomization (Step 1) procedures  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at 
) and a 
'Registrar' role on either the LPO or participating organization roster.  Registrars must hold a 
minimum of an AP registration type.   
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at 
 or from the OPEN tab on the 
CTSU members’ side of the website at 
 To assign an IVR or NPIVR as 
the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer 
in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used 
on the site’s IRB approval.   
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
Confirmation of patient eligibility must be received from IROC. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 


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To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at 
 or at 
.  For any additional 
questions contact the CTSU Help Desk at 
 
4.7 
Registration to Correlative and Companion Studies 
4.7.1 Registration to Sub-studies described in Section 14.0  
There are two correlative sub-studies within Alliance A221208. Registration to these 
correlative sub-studies will be done at the same time as registration to the main cancer 
control study, A221208. These sub-studies do not require separate IRB approval. 
Registration to the main study and the sub-studies will not be completed if eligibility 
requirements are not met. 
The following correlative science study must be offered to all patients enrolled on Alliance 
A221208 (although patients may opt to not participate): 
• 
Alliance A221208-ST1: Evaluation of Biofluid Biomarkers of Radiation Necrosis 
Alliance A221208 (Section 14.1) 
If a patient answers “yes” to the model consent question “My coded samples and related 
coded information may be used in the research described above to learn about, prevent, find 
or treat cancer”, they have consented to participate in the sub-study described in Section 
14.1. The patient should be registered to Alliance A221208-ST1 at the same time they are 
registered to the main cancer control trial (A221208). Blood and urine samples should be 
submitted per Section 6.2. 
While all sites are encouraged to participate, institutional participation in the following 
correlative science study is optional. If an institution opts to participate in the following 
correlative study, the study must be offered to all patients enrolled on Alliance A221208 
at that institution (although patients may opt to not participate): 
• 
Alliance A221208-IM1: Evaluation of Imaging Biomarkers of Radionecrosis Response 
to Corticosteroid and Bevacizumab Therapy in Alliance A221208 (Section 14.2) 
If a patient answers “yes” to the model consent question “I choose to take part in the imaging 
study and will have the extra MRIs”, they have consented to participate in the sub-study 
described in Section 14.2. The patient should be registered to Alliance A221208-IM1 at the 
same time they are registered to the main cancer control trial (A221208). Images should be 
submitted per Section 6.3.  
4.8 
Stratification Factors and Treatment Assignments  
4.8.1 Stratification Factors 
4.8.1.1 
Age:  ≤ 65 years vs. > 65 years 
4.8.1.2 
Pathological Confirmation of Necrosis:  yes vs. no 
4.8.1.3 
MDASI-BT mean global score (symptom + interference scores) [37, 38]:  
< 4.0 vs. > 4.0 
(Site staff must calculate the average score on the MDASI questionnaire 
completed prior to randomization.) 


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4.8.1.4 
Prior whole brain radiotherapy: yes vs. no 
4.8.2 Treatment Assignments  
The factors defined in 4.9.1 will be used as stratification factors for dynamic randomization. 
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure which balances the marginal 
distributions of the stratification factors between the treatment groups [39]. 
• 
Placebo + corticosteroids 
• 
Bevacizumab + corticosteroids 
To ensure both the patient and the medical professionals who care for the patient are blinded 
to the identity of the treatment assignment, the Registration Specialist will follow the 
double-blinding procedures outlined in Section 4.9.3 and unblinding procedures in Section 
8.3. 
4.8.3 Procedures for Double-Blinding the Treatment Assignment 
After the treatment assignment has been ascertained by randomization, the Registration 
Specialist will notify the designated data manager/nurse/pharmacist at the patient’s 
institution. The name of this contact person is to be indicated on the eligibility checklist at 
the time of registration. This contact person may not be involved in assessing adverse events 
or any other outcome measure and should not be the same person listed on page one of the 
Eligibility Checklist Form as the person completing the form. The Eligibility Checklist Form 
should provide the source of communication, either fax or e-mail, and the appropriate 
contact information. The Registration Specialist will then communicate the treatment 
assignment “active or placebo” to designated contact at the patient’s institution. 
If the patient has been assigned to "active" treatment, the designated contact should order 
patient-specific bevacizumab per the instructions included in Section 10.2. If the patient 
assignment is "placebo," the designated contact should prepare placebo for delivery to the 
patient 1-3 days after registration/randomization. In order to maintain the blind, it is 
recommended that placebo not be delivered to the patient immediately after 
registration/randomization. 
The dose will be prepared and labeled as “bevacizumab 10 mg/kg or placebo” so that the 
contents are not discernible to the person administering the treatment. 
The pharmacist or designated contact person will maintain records that indicate the identity 
of the patient and their corresponding treatment assignment. 
4.9 
Crossover Re-registration (step 2) Procedures 
Patients who meet the criteria for clinical progression will complete the MDASI-BT, DSQ-C, 
and LASA prior to unblinding. If the patient is on placebo, he/she will be allowed to receive 
bevacizumab 10 mg/kg IV or stop placebo. If on bevacizumab, the patient will be treated as per 
treating MD. 
Patients receiving placebo who choose to crossover and receive bevacizumab must be registered 
to the bevacizumab arm of the study, as follows:  
1. Site logs into OPEN registration system and selects the appropriate patient. 
2. Select the next registration step. 
3. Complete OPEN Enrollment Form for the patient to change arms. 


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4. Enter Cycle # of the last treatment received on the placebo arm, as well as 
Stratification/Grouping factors, on the OPEN Enrollment Form. 
5. OPEN will determine eligibility for the patient to crossover to the new arm.  If patient is not 
eligible, OPEN will indicate this. 
6. Once the new arm assignment has been successfully completed a confirmation email will 
be sent to the CRA. 
7. If assistance is needed with this process, contact the Alliance Registration Office at 
 
 
 


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5.0 
STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
on this trial. 
Tests & Observations 
Pre-
registration 
≤ 14 days 
prior to 
randomiz
ation 
Day 1 
Cycles 1-4 
prior to 
treatment 
Day 15 
Cycles 1-4 
prior to 
treatment 
At the 
end of 
Cycle 4 
For patients 
who crossover 
to open label 
bevacizumab 
Clinical 
Follow-up: 
Every 2 months 
for 6 months* 
MRI (standard of care) 
X(1) 
 
A(1,2) 
 
X(1,2) 
Repeat tests 
and 
observations as 
listed in the 
previous three 
columns.** 
X(1,2) 
History and physical, weight, 
Karnofsky PS, blood pressure 
 
X (8) 
X (8) 
X 
X (8) 
X (8) 
Height 
 
X 
 
 
 
 
Concomitant Medications 
 
X 
X(3) 
 
 
 
Recording corticosteroid dose 
 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
Patient Assessments 
MDASI-BT (see Appendix VI) 
 
X 
X(3,7) 
X(4) 
X(7) 
Repeat 
Assessments 
X(7) 
DSQ-C (see Appendix VII) 
 
X 
X(3,7) 
X(4) 
X(7) 
X(7) 
HRQOL/LASA (see Appdx VIII) 
 
X 
X(3,7) 
X(4) 
X(7) 
X(7) 
Laboratory Studies 
Hematology: 
CBC with diff. (ANC, PLTs, 
HgB, WBC and lymphocytes) 
 
X 
X(3,5) 
 
X 
Repeat Lab 
studies 
 
Chemistry: creatinine, glucose, 
BUN, bilirubin, ALT, AST 
 
X 
X(3,5) 
 
X 
 
Coagulation PT/INR 
 
X 
 
 
 
 
Urinalysis for urine protein 
creatinine (UPC) Ratio 
 
X 
X(3,5) 
 
X 
 
Urine or serum pregnancy test 
 
X(6) 
 
 
 
 
Correlative studies: For patients who consent to participate 
Biomarker MRI  
See Sections 6.3 and 7.4 for image collection requirements, time points, and submission instructions. 
Blood and urine samples 
See Section 6.2 for sample collection time points and processing and submission instructions. 
* 
After 6 months of clinical follow up, follow patients for progression and survival until 1 year following the end of treatment. 
** The scan used to determine progression prior to crossover will be considered the Prior to Day 1 scan for crossover patients. 
A 
Prior to Cycle 1 and Cycle 3 only. If the pre-registration scan includes all the imaging requirements of the study and is 
performed within 4 weeks prior to registration, MRI need not be repeated prior to Cycle 1. 
1. See Sections 6.3 and 7.4. 
2. For institutions and patients who are participating in the optional biomarker MRI substudy, the DCE + DSC protocol is to be 
used for all scans (including those done after crossover), starting with the scan performed prior to Cycle 2. 
3. Tests/assessments/labs to be collected only on Day 1 of cycles 2-4 prior to treatment. These tests/assessments/labs do NOT 
need to be collected for Day 1 of cycle 1. 
4. Patient assessments to be collected only on Day 15 of cycles 1 and 2 prior to treatment. These assessments do NOT need to be 
collected for Day 15 of cycles 3 and 4. 
5. Lab tests obtained ≤ 2 days prior to day 1 start of the treatment cycle are acceptable. 
6. For women of childbearing potential (see Section 3.3.3).  
7. These assessments should be done before MRI results are given to the patient. 
8. Neurological exam will be included in the history and physical at this visit. 


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6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data collection and submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the enrolling 
site. To hold the Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an 
AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave.  
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login
 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. 
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at 
 or by contacting the CTSU Help Desk at 
 or by e-mail at 
   
A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms 
section. The Schedule of Forms is also available on the CTSU site within the study-specific 
Education and Promotion folder, and is named Time & Events. 
Patient-completed questionnaire booklets for this study are to be ordered prior to the 
registration of any patients (see Section 4.4). Samples of questionnaires are available in 
Appendices IV-VII for reference and IRB submission only. They are not to be used for patient 
completion. Booklets must be given to patients to complete and patients should be instructed to 
return the booklets to site staff either in person or by mail and site staff will enter patient 
responses into Rave.  
CCTG institutions are to provide patient completed booklets translated into French to French 
speakers. The site is responsible for transcribing the patient responses from the French version 
into the English version, within Medidata Rave to submit to the Alliance Statistics and Data 
Center. The institution should retain the completed French version as source documentation. 
 
 


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6.2 
Specimen collection and submission  
All participating institutions must ask patients for their consent to participate in the correlative 
sub-studies planned for Alliance A221208-ST1 and A221208-IM1, although patient 
participation is optional. Biomarker and imaging studies will be performed. Rationale and 
methods for the scientific components of these studies are described in Section 14.0. For patients 
who consent to participate, blood, urine and MRI imaging will be collected at the following time 
points for these studies: 
For patients registered to A221208-ST1, submit the following: 
 
After 
randomization 
prior to treatment 
Day 1 cycles 2 
and 3 prior to 
treatment 
After 4 
cycles of 
treatment 
Storage/ 
Shipping 
conditions 
Submit to: 
Serum1 
No additive (red top) 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic  
Plasma/buffy coat1 
EDTA (purple top) 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic  
Urine1 
vacutainer cup 
~1 x 50 mL 
~1 x 50 mL 
~1 x 50 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic 
 
 
 
 
 
 
For patients registered to A221208-ST1 and who cross over to bevacizumab treatment, 
submit the following: 
 
After crossover  
re-registration and 
prior to treatment 
Day 1 cycles 2 
and 3 prior to 
treatment 
After 4 
cycles of 
treatment 
Storage/ 
Shipping 
conditions 
Submit to: 
Serum1 
No additive (red top) 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic  
Plasma/buffy coat1 
EDTA (purple top) 
1 x 10 mL 
1 x 10 mL 
1 x 10 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic  
Urine1 
vacutainer cup 
~1 x 50 mL 
~1 x 50 mL 
~1 x 50 mL 
Dry ice, ship 
over night 
Alliance BAP 
Mayo Clinic 
1 
Research blood products and urine to be used for biomarker analyses described in Section 14.1. 
 
 
 


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6.2.1 Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials.  Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer).  For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, 
and training videos. To report technical problems, such as login issues or application errors, 
please contact: 
  For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A221208), Alliance 
patient number, patient’s initials and date and type of specimen collected (e.g., serum, whole 
blood, urine). 
Note for CRA – The following PHI must be removed or blacked out for all specimens or 
reports: signature, name, date of birth, other identifying information, except initials and 
study identification number. 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
The institution is expected to pay the cost of mailing specimens and will be reimbursed 
through capitation fees set for each individual study. 
6.2.2 Blood and urine sample processing 
For patients who consent to participate in A221208-ST1, serum, EDTA whole blood, and 
urine samples will be collected after randomization prior to cycle 1 treatment, after 1 cycle, 
after 2 cycles, and after 4 cycles of treatment and used for the biomarker analyses described 
in Section 14.1.  
Draw blood sequentially into 2 x 10 mL red top (no additive) tubes and 1 x 10 mL EDTA 
purple top tube.  Gently invert each tube 8-10 times. 
Serum: Collect 20 mL peripheral venous blood into (2) 10 mL plain red top no additive 
vacutainer tubes. Gently invert approximately 8-10 times to mix clot activator with blood. 
Let blood clot for 15-30 minutes at room temperature. Observe a dense clot. Centrifuge at 
approximately 3000 rpm (or in accordance with centrifuge manufacturer’s instructions) for 
10 minutes at room temperature.   
After centrifugation, aspirate the top clear serum layer from both red top vacutainer tubes 
(being careful to avoid the transfer of red cells or clot from the bottom layer) and transfer 
sera to clean 50 mL conical tube.  Gently mix serum in conical tube. Aliquot approximately 
1 mL aliquots into (6) 2.0 mL cryogenic vials*. Label and freeze cryovials at −70°C or 


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colder. If −70°C is not available, temporary storage o n  d r y  i c e  o r  at –20°C prior 
to shipment is acceptable for up to approximately 48 hours. Ship on dry ice to the BAP at 
Mayo Clinic per Section 6.2.1. 
Plasma/Buffy Coat: Collect 10 mL peripheral venous blood into (1) 10 mL EDTA (purple-
top) vacutainer tubes. Gently invert approximately 8-10 times to mix anti-coagulant with 
blood. Centrifuge at approximately 3000 rpm (or in accordance with centrifuge 
manufacturer’s instructions) for 10 minutes at room temperature.  
After centrifugation, three different fractions are distinguishable: the upper clear plasma 
layer, the intermediate buffy coat layer containing concentrated leukocytes, and the bottom 
layer of red cells.  Aspirate the top plasma layer from the purple-top vacutainer tube, 
minimizing removal of the intermediate buffy coat layer and transfer to a clean 15 mL or 50 
mL conical tube.  Gently mix plasma in conical tube. Aliquot approximately 1 mL aliquots 
into (3) 2.0 mL cryogenic vials*.  Also transfer off the intermediate buffer coat layer into a 
2.0 mL cryogenic vial. Label and freeze cryovials at −70°C or colder. (If −70°C is not 
available, temporary storage o n  d r y  i c e  o r  at –20°C prior to shipment is 
acceptable for up to approximately 48 hours.) Ship on dry ice to the BAP at Mayo Clinic 
per Section 6.2.1). 
*2 mL Cryovial Choices: Some examples of acceptable 2.0 mL cryovials are: Nalgene (Cat 
#5012-0020), Fisher (Cat #05-669-57), Corning (Cat #430488), VWR (Cat#16001-102). 
Urine: Antiseptically collect urine (mid-stream collection), voided directly into a sterile 
container. Pour urine into a 50 mL conical tube and centrifuge at approximately 3000 rpm 
(or in accordance with centrifuge manufacturer’s instructions) for 10 minutes at room 
temperature until sediment and debris settles to the bottom of the conical tube. Remove the 
clear urine from the 50 mL conical tube, minimizing removal of the sediment and debris at 
the bottom of the tube, and transfer to another clean 50 mL conical tube. Gently mix urine 
in conical tube. Aliquot approximately 4 mL aliquots into (6) 5 mL cryogenic vials.**  
Specimens must be stored at ≤ –20° as soon as possible after collection. Ship on dry ice to 
the BAP at Mayo Clinic per Section 6.2.1. 
**5 mL Cryovial Choices: Some examples of acceptable 5.0 mL cryovials are: Nalgene (Cat 
#5000-5050), Fisher (Cat #03-391-168), Corning (Cat #8084-5). 
6.2.3 Blood and urine sample labeling 
Label all samples using a moisture-proof cryomarker (e.g., BioHit brand) with the following 
identification: 
1. Alliance study number (A221208-ST1) 
2. Alliance patient ID number 
3. Patient’s initials (L, F M) 
4. Date and time of specimen procurement  
5. Sample type (i.e. serum, plasma, buffy coat, urine, etc.) 
 
 


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6.2.4 Sample submission 
Shipment on Monday through Friday by overnight service to assure receipt is encouraged. 
If shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For 
Saturday delivery” and an email should be sent with the tracking number to Mayo Clinic 
BAP contact (see ‘Protocol Resources’ page). The bank cannot receive specimens on 
Sundays or holidays. Do not send specimens the day before a holiday.  
All blood and urine specimens should be sent to the following address: 
  
 
 
 
 
6.3 
Imaging submission 
Imaging submission requirements for this study are provided in the table below. Submit all MR 
imaging data to IROC per instructions below. Additional details are provided in Sections 7.4 
and 14.2. 
 
 
1 
2 
3 
4 
Crossover 
After Protocol 
Treatment 
 
Pre-
registration 
Prior to 
Cycle 1 
(Baseline) 
Prior to 
Cycle 2 
(4 weeks)† 
Prior to 
Cycle 3 
(8 weeks)† 
At the end of 
Cycle 4 
(16 weeks)† 
Repeat 
Columns 
2-4*** 
Every 2 
months for 6 
months 
MRI* 
X 
X (1) 
 
X (2) 
X (2) 
X (2) 
X (2) 
Biomarker 
MRI** 
 
 
X (2) 
 
 
X (2)‡ 
 
* 
Standard of care MRI, to be collected and submitted for all patients enrolled to A221208. 
** 
Research MRI, to be collected and submitted for all patients participating in companion study A221208-IM1. 
Images will be used for the imaging biomarker analyses described in Section 14.2. 
*** 
The scan used to determine progression prior to crossover will be considered the Prior to Day 1 scan for 
crossover patients. 
† 
+/- 4 days 
‡ 
Biomarker MRI is required only prior to Cycle 2 of crossover treatment. 
1 
If the pre-registration scan includes all the imaging requirements of the study and is performed within 4 weeks 
prior to registration, it need not be repeated prior to cycle 1.   
2 
For institutions and patients who are participating in the optional biomarker MRI substudy, the DCE + DSC 
protocol is to be used for all scans (including those done after crossover), starting with the scan performed prior 
to Cycle 2. 
 
 


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MRI Data Archiving, Storage, and Submission for Alliance A221208 (all images) 
The complete MR imaging data sets must be submitted to IROC in digital DICOM format, 
within no more than 3 business days following pre-registration and all other subsequent post 
MR image acquisition. BMP files, JPEG files, or hard copies (films) are not acceptable. 
The Supplemental Information Form must be submitted to IROC by fax or email together 
with the entire MRI DICOM data sets. 
De-identify the patient data using institutional procedures to remove patient name and medical 
record number while preserving the patient ID number and protocol number of the Alliance 
A221208 trial. The de-identified digital images may be burned to a CD or transferred to a PC 
based system for further electronic data transfer purposes. 
Data should be electronically transferred to IROC by 1) Web Transfer or 2) FTP transfer: 
1) Web Transfer: Any PCs with internet access and web browser (e.g., Internet Explorer, 
Mozilla Firefox) can be used to transfer DICOM images and other required files to IROC 
through the website: upload.imagingcorelab.com. The standard Web Transfer information 
will 
be 
provided 
separately 
through 
the 
specific 
trial 
e-mail 
 per the request by participating sites before their first data 
submission. 
2) FTP Transfer: Any FTP software can be used to initiate access to the secure FTP Server 
of the IROC. The standard FTP access information will be provided separately through the 
specific trial e-mail 
, per the request by participating sites 
before their first data submission. 
Send an e-mail notification to inform IROC at the specific trial email of the data submission 
once the data transfer is completed. 
3) Shipment/Mail (not recommended): If the above electronic data transfers cannot be 
achieved, the de-identified images in DICOM format can be burned to a CD, labeled with 
info of patient ID, study ID, MRI date, MRI timepoint (e.g., baseline, after 1 cycle of 
treatment, after 2 cycles of treatment, etc.) listed on the CD cover, and mailed to the IROC 
via over-night shipment at: 
 
 
 
For questions about the data transfer, please contact IROC via either the trial email at 
  
 
 


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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 7 days of randomization.  
Bevacizumab/placebo may be administered within 1 business day before or after the protocol defined 
date.  For example, if the treatment due date is a Friday, the window for treatment includes the 
preceding Thursday through the following Monday. In addition, patients are permitted to have a new 
cycle of chemotherapy delayed up to 7 days for major life events (e.g., serious illness in a family 
member, major holiday, vacation that cannot be rescheduled) without this being considered a protocol 
violation. Documentation to justify this delay should be provided. 
Protocol therapy will consist of 4 cycles administered every 28 days or until clinical progression or 
unacceptable adverse event.  
7.1 
Bevacizumab and Placebo 
Both arms: continue corticosteroid dose prior to study enrollment, taper as tolerated. 
7.1.1 Bevacizumab 
The patient will receive bevacizumab 10 mg/kg IV (prepared as described in Section 10.3) 
over 90 minutes* given on days 1 and 15 of a 28 day cycle for 4 cycles. 
* 
Subsequent bevacizumab infusions may be administered over 60 minutes if tolerated.  
If tolerated over 60 minutes, may administer over 30 minutes.  
7.1.2  Placebo 
The patient will receive placebo 0.9% NaCl volume equal to bevacizumab volume added to 
100 mL bag of 0.9% NaCl delivered IV over 90 minutes* given on days 1 and 15 of a 28 
day cycle for 4 cycles.  
* 
Subsequent placebo infusions may be administered over 60 minutes if tolerated.  If 
tolerated over 60 minutes, may administer over 30 minutes. 
7.1.3 Corticosteroid taper 
Once the patient has started the study treatment (bevacizumab or placebo), the dose of 
corticosteroids will be tapered every 5 days (e.g., dexamethasone 2mg or prednisone 15 mg 
per taper), as tolerated, under the management of the treating MD 
If patients deteriorate while tapering, dexamethasone will be increased up to a maximum of 
16 mg per day, as per treating MD, to manage symptoms. 
Example of a common dexamethasone tapering schedule is as follows:  
• 
Dexamethasone 4 mg po BID x 2 weeks 
• 
Then dexamethasone 4 mg po in AM and 2mg po in PM x 5 days 
• 
Then dexamethasone 4 mg po in AM x 5 days 
• 
Then dexamethasone 2 mg po in AM x 5 days  
• 
Then dexamethasone 1 mg po in AM x 5 days then stop. 
 
 


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7.2 
Clinical progression allowing cross-over to bevacizumab 
Clinical progression is defined as neurological progression despite increases in dexamethasone 
(or equivalent corticosteroid) up to 16 mg a day or highest dose the patient tolerates for greater 
than 48 hours.  
Patients who meet the criteria for clinical progression will complete the MDASI-BT, DSQ-C, 
and LASA prior to unblinding. If the patient is on placebo, he/she will be allowed to receive 
bevacizumab per the table below. If on bevacizumab, the patient will be treated as per treating 
MD.  
Unblinded (Cross-Over) Therapy 
Agent* 
Dose 
Route 
Day 
ReRx 
Bevacizumab 
10 mg/kg 
IV over 90 minutes* 
Days 1 and 15 
Every 28 days x 
4 cycles 
Continue corticosteroid, taper as tolerated. 
* 
Subsequent bevacizumab infusions may be administered over 60 minutes if tolerated.  If 
tolerated over 60 minutes, may administer over 30 minutes. 
7.3 
Clinical Assessments 
Patients will be assessed every 2 weeks for the first 16 weeks of the study. The clinic visit will 
take place prior to each dose of placebo or bevacizumab. History and physical exam, including 
neurological examination will be completed within 14 days prior to randomization, day 1 of 
each cycle of treatment, and at each scheduled follow-up assessment. Further details are 
summarized in the Study Calendar, Section 5.0. 
7.4 
Neuro-imaging 
7.4.1 Overview 
Detailed study MR imaging will be acquired at the time points listed in Section 6.3. 
Standard MRI imaging: For institutions and patients who are not participating in the 
optional biomarker MRI substudy, standard anatomic T2 weighted imaging, T2-weighted 
FLAIR imaging, diffusion-weighted imaging and pre- and post-contrast T1 weighted 
imaging will be performed. 
DCE + DSC imaging protocol:  For institutions and patients who are participating in the 
optional biomarker MRI substudy, the DCE + DSC protocol is to be used for all imaging 
excepting those collected after 6 months following the end of treatment (see Section 6.3). 
Images will include the following image sequences: (1) Anatomic T1, T2 weighted imaging 
(2) Variable flip angle (VFA) T1 weighted imaging (T1 mapping) – required for dynamic 
contrast enhanced (DCE) MR analysis (3) Diffusion weighted imaging (4) Dynamic 
susceptibility weighted (DSC) perfusion imaging (5) Dynamic contrast enhanced (DCE) 
perfusion imaging (6) Anatomic, post-contrast T1 weighted imaging. 
 
 


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7.4.2 MR Imaging Guidelines and Recommendations 
General: The following general MR imaging equipment and procedures are recommended:  
1) Accredited MR scanners are strongly preferred, e.g. by the American College of 
Radiology.  
2) 3.0 Tesla field strength is preferred, but 1.5 Tesla is acceptable. 
3) It is preferred for individual subjects to be scanned on the same scanner for their baseline 
and all follow-up MR exams, but at the least, the same field strength and scanner vendor 
are strongly suggested. 
Brain Imaging should be performed per Appendix IV. 
Gadolinium Contrast Injection 
High T2 relaxivity gadolinium agents are also preferred over lower T2 relaxivity agents. 
Single dose  
Gadolinium Pre-load: IV gadolinium 0.05 mmol/kg at 5-10 minutes prior to the DSC series 
(DCE can be acquired with this preload injection OR series including the FSE/TSE T2-
weighted images could be interposed between the 2 gad administrations)  
Gadolinium bolus: IV gadolinium 0.05 mmol/kg administered with a power injector through 
an 18-20 gauge right antecubital IV at 3-5 mL/s (5 mL/s preferred), followed by a saline 
bolus at the same injection rate.  
Double dose 
Gadolinium Pre-load: IV gadolinium 0.1 mmol/kg at 5-10 minutes prior to the DSC series 
(DCE can be acquired with this preload injection OR series including the FSE/TSE T2-
weighted images could be interposed between the 2 gad administrations)  
Gadolinium bolus: IV gadolinium 0.1 mmol/kg administered with a power injector through 
an 18-20 gauge right antecubital IV at 3-5 mL/s (5 mL/s preferred), followed by a saline 
bolus at the same injection rate.  
The Supplemental Information Form will be submitted with the images at each time point 
to capture the following details:  Gadolinium agent, dose, and injection rate. 
Dynamic Contrast Enhanced MRI (for optional A221208-IM1 sub-study):  
If sites are capable of performing dynamic contrast enhanced (DCE) perfusion imaging in 
addition to DSC perfusion, the gadolinium administered for a DCE series will serve as the 
preload for a later DSC series.   
Recommended parameters:  
- 
fast T1-weighted spoiled gradient-recalled echo acquisition  
- 
matrix 128 x 128 mm 
- 
5 mm slice thickness 
- 
3-6 second temporal resolution 
- 
3-6 minutes acquisition time 
- 
IV gadolinium injection of 0.05 mmol/kg, at 2-4 mL/s, should occur 20 seconds or more 
after the start of the imaging series and should be followed by a saline bolus at the same 
injection rate.   
 
 


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7.5 
Patient-Reported Symptoms 
MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and Dexamethasone Symptom 
Questionnaire-Chronic (DSQ-C) will be administered prior to randomization, and prior to 
treatment on day 1 of cycles 2-4, and on day 15 of cycles 1 and 2, and every 2 months after 4 
cycles of treatment for up to 6 months. These assessments should be completed before MRI 
results are given to the patient. 
MDASI-BT [Appendix VI] 
The MDASI-BT was developed and validated for use in the brain tumor patient population, 
including those with brain metastases and typically requires less than 4 minutes to complete.  It 
consists of 23 symptoms rated on a 0 to 10 numerical rating scale (NRS) to indicate the presence 
and severity of the symptom, with 0 being “not present” and 10 being “as bad as you can 
imagine.” MDASI-BT Symptom Scoring: A global symptom score for the MDASI symptom 
severity scale is obtained by taking the average of the 23 items together. [33] MDASI-BT 
Interference Scoring: The MDASI-BT also includes ratings (from 0-10) of how symptoms have 
interfered with different aspects of the patient’s life. These interference items include: general 
activity, mood, work (outside the home and housework), and relations with other people, 
walking, and enjoyment of life. The mean of the 6 interference items can be used as a measure 
of the overall symptom distress.  
Dexamethasone Symptom Questionnaire-Chronic (DSQ-C) [Appendix VII] 
The DSQ-C was developed for use in the brain tumor patient population. It consists of 18 
questions rated on a 4-point scale (1 to 4) to indicate the presence and severity of symptoms. 
This is followed by 3 questions that address the patient’s risk of diabetes and hyperglycemia and 
finally an open ‘comment’ section and rank of most bothersome symptoms.  
7.6 
Quality of Life  
HRQOL will be measured using the single-item linear-analogue scale (LASA) [40] [Appendix 
VIII]. This instrument has demonstrated reliability and validity for measuring overall QOL in 
the brain tumor patient population while allowing for reduced patient burden.  Quality of life 
measures will be acquired within 14 days prior to randomization, day 1 of cycles (cycles 2-4) 
prior to treatment, day 15 cycle 1 and cycle 2 prior to treatment, and every 2 months after 4 
cycles of treatment for up to 6 months. These assessments should be completed before MRI 
results are given to the patient. 
7.7 
Definitions of Deviations in Protocol Performance  
7.7.1 Major Deviations 
The following will be considered major protocol deviations: 
• 
MDASI-BT assessment completed beyond +/- 7 days during active treatment phase and 
beyond +/- 10 days during post-treatment follow-up, from the scheduled date. 
7.7.2 Minor Deviations 
The following will be considered minor protocol deviations: 
• 
MDASI-BT assessments completed between 4-7 days beyond the scheduled date during 
the active treatment phase, and +/- 8 days beyond the scheduled treatment date during 
post-treatment follow-up. 


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8.0 
TREATMENT MODIFICATIONS, UNBLINDING  
8.1 
Ancillary therapy, concomitant medications, and supportive care 
8.1.1 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint, except agents listed on the 
“approved systemic therapies” list in Appendix II. 
8.1.2 Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
8.1.3 Treatment with hormones for non-disease-related conditions (e.g., insulin for diabetes) is 
permitted while on this study. 
8.1.4 Antiemetics may be used at the discretion of the attending physician. 
8.1.5 Hypertension:  Blood pressure should be assessed before each administration of 
bevacizumab. High blood pressure may require initiation or increase in antihypertensive 
medication according to routine clinical practice. 
8.1.6 Patients should not receive any live vaccines while receiving corticosteroids.  
8.1.7 Patients who require radiation therapy during protocol treatment will be removed 
from protocol therapy and study treatment will be stopped prior to radiotherapy. 
These patients will continue to be followed on study for the brain specific endpoints. 
8.2 
Discontinuation of bevacizumab 
There are no dose reductions for bevacizumab. Bevacizumab may be delayed or discontinued 
for toxicity as described below. 
Bevacizumab will be temporarily suspended for at least 4 weeks prior to elective surgery 
8.2.1 Hypersensitivity and/or Infusion Reactions 
Allergic or Infusion-Related Reactions 
• 
The initial bevacizumab dose should be administered over a minimum of 90 minutes. If 
no hypersensitivity or infusion reactions occur, the second dose should be administered 
over a minimum of 60 minutes. If no hypersensitivity or infusion reactions occur with 
the second dose, the third and subsequent doses should be administered over a minimum 
of 30 minutes. 
• 
For grade 1 or 2 hypersensitivity reactions during bevacizumab infusion, interrupt 
bevacizumab until symptoms resolve to < grade 1, then resume bevacizumab at the 
shortest infusion rate tolerated. Manage symptoms according to institutional procedures. 
Subsequent infusion rates should be titrated as stated above. Consider premedication 
with antihistamines for subsequent doses. 
• 
Subjects who experience clinically evident bronchospasm (regardless of grade) should 
discontinue bevacizumab. Manage symptoms according to institutional procedures. 
For grade 3 or 4 allergic reactions considered related to bevacizumab, discontinue 
bevacizumab. Manage symptoms according to institutional procedures.  
For grade 1 or 2 infusion-related reaction or cytokine release syndrome as characterized by 
back pain, headache, rigors, erythema, vasodilation, considered related to bevacizumab, 


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decrease infusion rate to 50% of the previous rate. Manage symptoms according to 
institutional procedures. When symptoms improve to < grade 1, the infusion rate may be 
increased in 50% increments every 30 minutes. Subsequent infusions can be started at the 
planned rate. 
For grade 3 or 4 infusion-related reaction or cytokine release syndrome considered related 
to bevacizumab, discontinue bevacizumab. Manage symptoms according to institutional 
procedures.  
For anaphylaxis considered related to bevacizumab, discontinue bevacizumab. Manage 
anaphylaxis according to institutional procedures.   
8.2.2 Injection Site Reactions 
For grade 1 or 2 injection site reactions, continue on study; make sure to rotate injection 
sites as instructed in Administration section. Manage symptoms according to institutional 
procedures. 
8.2.3 Hypertension 
For grade 1 to 3 hypertension controlled with medication to <150/90 mmHg, continue 
bevacizumab.  
For persistent or symptomatic hypertension despite antihypertensive therapy, delay 
bevacizumab for up to 6 weeks until BP <150/90 mmHg. If bevacizumab is held 6 weeks, 
patient is to discontinue bevacizumab. 
For grade 4 hypertension, discontinue bevacizumab.  
8.2.4 Hemorrhage 
For grade 1 or 2 bleeding, restart bevacizumab once resolved to < grade 1. If bevacizumab 
is held 6 weeks, patient is to discontinue bevacizumab. 
For grade 3 or 4 bleeding: Discontinue bevacizumab.  
8.2.5 Venous thromboembolic events  
Grade 1, 2, 3 or asymptomatic grade 4: Delay bevacizumab. If the planned duration of 
full-dose anticoagulation is <2 weeks, protocol treatment should be held until the full-dose 
anticoagulation period is over. If the planned duration of full-dose anticoagulation is >2 
weeks, protocol treatment may be resumed during the period of full-dose anticoagulation if 
all the following criteria are met:  
• 
The patient must have an in-range INR (usually between 2 and 3) on a stable dose of 
warfarin (or other anticoagulant) prior to restarting therapy; 
• 
The patient must not have had a grade 3 or 4 hemorrhagic event while on study; and 
For recurrent/worsening venous thromboembolic events after resumption of 
treatment: Discontinue bevacizumab.  
For symptomatic grade 4: Discontinue bevacizumab. 
If bevacizumab is held 6 weeks, patient is to discontinue bevacizumab. 
8.2.6 Arterial thromboembolic events 
Arterial thrombosis may include angina, myocardial infarction, stroke (CNS 
cerebrovascular ischemia), or other arterial thrombotic event. In the event of new or 
worsening grade 2 or any grade 3, or 4 arterial thrombotic event, treatment with 
bevacizumab should be discontinued.  


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8.2.7 Renal and urinary disorders: Proteinuria 
For proteinuria of ≥ 2+: Confirm total urine protein with a 24-hour urine collection or 
urine protein to creatinine (UPC) ratio. For 2+ proteinuria, give scheduled bevacizumab 
while awaiting the results of the 24-hour collection or UPC ratio. For > 2+ proteinuria, delay 
bevacizumab while awaiting results of the 24-hour urine collection or UPC ratio.  
If monitoring urine protein with UPC, no confirmation is necessary.  
For urine protein 2-3.4 g/24 hours or UPC ratio 2-3.4: Delay bevacizumab until urine 
protein improves to < 2g/24 hours or UPC < 2. If bevacizumab is held 6 weeks, patient is to 
discontinue bevacizumab. 
For urine protein ≥ 3.5 g/24 hours or UPC ratio ≥ 3.5: Discontinue bevacizumab.  
8.2.8 Fistula, perforation involving any organ, bowel obstruction, and wound dehiscence  
• 
For any grade perforation of any organ, GI leak, or any fistula: Discontinue 
bevacizumab.  
• 
For any grade bowel obstruction requiring medical intervention: Hold 
bevacizumab therapy until complete resolution. Continue HSPCC-96. If surgery is 
required, the patient may restart bevacizumab after full recovery from surgery and 
after consultation with the study chair. 
• 
For wound dehiscence requiring medical or surgical intervention: Discontinue 
bevacizumab.  
If bevacizumab is held 6 weeks, patient is to discontinue bevacizumab. 
8.2.9 Posterior leukoencephalopathy syndrome 
For signs and symptoms suggestive of reversible posterior leukoencephalopathy syndrome 
(RPLS) such as confusion, headache, seizures, and cortical blindness, hold bevacizumab for 
up to 6 weeks. Suspected RPLS should be investigated with MRI as described in Section 
11.5. If diagnosis of RPLS is confirmed, bevacizumab should be permanently discontinued. 
If RPLS is ruled out via MRI, and signs and symptoms attributed to another cause, may 
resume bevacizumab.  
 
 


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8.3 
Unblinding Procedures 
Unblinding can be done only in cases of an emergency or at the time protocol-specified 
unblinding is allowed. Follow the directions below to unblind patient treatment. Please note 
that if a treatment assignment is unblinded, the patient must discontinue protocol therapy. 
1. Emergency Unblinding Procedures: 
Emergency unblinding requests for A221208 should be made directly to the Alliance 
Executive Officer on call. This memorandum describes changes to the emergency 
unblinding procedure. Institution staff should contact the Alliance Executive Officer on call 
by calling 
pressing 1 to speak with an operator and then asking for pager ID 
 to return their call. 
The institution must provide the following information to the Alliance Executive Officer: 
- 
Alliance study ID (A221208) 
- 
Alliance patient ID number 
- 
Patient initials (e.g., “L,FM”) 
- 
Name and telephone number of treating physician 
- 
Name and contact information of person requesting unblinding procedure 
- 
Name and contact information of person to inform of treatment assignment 
- 
Reason for unblinding request 
Please remember that emergency unblinding requests may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. 
2. Protocol-specified Unblinding: 
Trial participants may be unblinded upon failure of the assigned treatment arm, defined as 
clinical deterioration despite increasing doses beyond their baseline dexamethasone (or 
equivalent corticosteroid) dose for greater than 48 hours. Patients who meet the criteria for 
clinical progression will complete the MDASI-BT, DSQ-C, and LASA prior to 
unblinding.  
Contact the Alliance Registration Office at 
during regular business hours. 
Upon confirmation by the Primary Statistician (or designee) that the criteria for treatment 
failure have been met, the treatment assignment may be unblinded. If the patient is on 
placebo, he/she will be allowed to receive bevacizumab. Refer to Section 4.9 for details 
about crossover procedures. If on bevacizumab, the patient will be treated as per treating 
MD.  
No Alliance Executive Officer (or designee) approval is required. 
 
 


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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0.  However, CTCAE v5.0 must be used for serious AE reporting 
through 
CTEP-AERS 
as 
of 
April 
1, 
2018. 
The 
CTCAE 
is 
available 
at 
  Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms, using the codes provided. 
9.1 
Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Event Form is 
used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Allergic reaction 
Immune system disorders; not at baseline 
Infusion related reaction 
General disorders and administration site conditions; not 
at baseline 
Injection site reaction 
General disorders and administration site conditions; not 
at baseline 
Hypertension 
Vascular disorders 
Thromboembolic event, venous 
or arterial 
Vascular disorders 
Proteinuria 
Renal and urinary disorders 
Wound dehiscence 
Injury, poisoning and procedural complications 
 
 


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9.2 
CTCAE Routine Study Reporting Requirements 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
a 
a 
a, b 
a, b 
a, b 
Probable 
a 
a 
a, b 
a, b 
a, b 
Definite 
a 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the patient’s 
last treatment date. 
9.3 
Expedited Adverse Event Reporting System (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below. Alliance investigators are required to notify the Alliance Central Office, the Study Chair, 
and their Institutional Review Board if a patient has a reportable serious adverse event. The 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5 will be utilized for AE reporting.  The CTCAE is identified and 
located on the CTEP website at:  
 All appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause should be provided. 
 
 


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9.3.1 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND ≤ 30 Days of the Last Administration of the 
Investigational Agent/Placebo. 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 


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Additional Instructions or Exclusions to CTEP-AERS Reporting Requirements for Phase 2 and 
3 Trials: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
• 
All new malignancies must be reported through CTEP-AERS whether or not they are thought to 
be related to either previous or current treatment. All new malignancies should be reported, i.e., 
solid tumors (including non-melanoma skin malignancies), hematologic malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
unless otherwise specified. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. New primary malignancies should also be reported via 
routine reporting in Medidata Rave. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours.  
• 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, 
or definitely related to the investigational agent/intervention. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the CAEPR for 
bevacizumab. NOTE: the SPEER (specific protocol exceptions to expedited reporting) list in the 
bevacizumab CAEPR includes “expected” severity grades in addition to event terms. 
• 
Pregnancy loss 


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• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC. 
• 
A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this event as 
a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
• 
Pregnancies and suspected pregnancies occurring in female patients during or within 120 days 
after completion of treatment on A221208 must be reported via CTEP-AERS.. 
CTEP-AERS reports and pregnancy information forms should be amended upon completion of 
the pregnancy to report pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic 
abortion, fetal death, congenital abnormalities). 
10.0 DRUG INFORMATION 
10.1 
General Considerations: 
• 
The total administered dose of bevacizumab may be rounded up or down within a range of 
5% of the actual calculated dose.  
• 
It is not necessary to change the doses of bevacizumab or placebo due to changes in weight 
unless the calculated dose changes by ≥10%. 
10.2 
Bevacizumab (Avastin)  
Genentech will supply bevacizumab. The Mayo Clinic Cancer Treatment Center Pharmacy in 
Rochester, MN will store and ship bevacizumab to the non-Canadian Alliance institutions. 
Roche Canada will distribute bevacizumab to participating Canadian sites. Because 
bevacizumab must be stored at 2°C-8°C, it will be shipped via FedEx Overnight in a cooler with 
an ice pack. Bevacizumab will only be shipped out Monday-Thursday with delivery to occur on 
Tuesday-Friday. No shipments will be made the day before a Holiday. 
Participating institutions will order patient-specific supplies of bevacizumab from the Alliance 
Research Base Pharmacy each time a patient is enrolled to the study and randomized to the 
bevacizumab arm.  Complete the Clinical Drug/Order/Return Form, which is available on the 
A221208 page of the Alliance 
web site and fax 
the completed form to: 
 
 
 
 
 
Patient-specific supplies of bevacizumab for participants who cross over from placebo to 
bevacizumab treatment must also be ordered as above at the time of registration to bevacizumab 
per Section 4.9.  
Drug accountability 
Agent disposition (receipt, dispensing, transfer, return or authorized local destruction of un-
dispensed agent) shall be documented on the NCI Investigational Agent (Drug) Accountability 


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Record (DARF) or the NCI Investigational Agent Accountability Record (DARF) as 
appropriate. Electronic accountability systems may be used. Paper printouts of electronic 
DARFs must be identical to the NCI DARF. 
IND Status 
Bevacizumab is IND exempt as used in this trial. This exemption has been determined by 
attestation that neither the investigator nor sponsor intends to seek a new indication for use or to 
support any other significant change in the labeling or product advertising for bevacizumab.  
This investigation will use an approved route of administration and dosage of bevacizumab and 
has no factors that increase the risk of the product.  This investigation will be in compliance with 
21CFR parts 56, 50, and 312.7 and neither the investigator nor sponsor will promote or represent 
that bevacizumab is safe or effective for the context that is under investigation in this study. This 
investigation will not commercially distribute or test market the study agent, and will not 
unnecessarily prolong an investigation. 
Formulation 
Bevacizumab is manufactured by recombinant DNA technology, using a genetically engineered 
Chinese hamster ovary (CHO) cell line. The protein is purified from the cell culture medium by 
routine methods of column chromatography and filtration. The final product is tested for quality, 
identity, safety, purity, potency, strength, and excipient/chemical composition according to 
International Conference on Harmonisation (ICH) guidelines. The purity of bevacizumab is > 
95%. 
Bevacizumab is supplied as 400 mg (25 mg/mL x 16 mL) glass vials. These will come as a box 
with 2 x 16mL vials. 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. 
Storage and Stability: 
Bevacizumab vials should be stored in a refrigerator at 2°C-8°C. Keep vial in the outer carton 
due to light sensitivity.  DO NOT FREEZE. DO NOT SHAKE. 
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-30°C in 0.9% 
sodium chloride solution. Do not administer or mix with dextrose solution.  From a 
microbiological point of view, the product should be used immediately. If not used immediately, 
in-use storage times and conditions are the responsibility of the user and would normally not be 
longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated 
aseptic conditions. 
Preparation 
Withdraw the necessary amount of bevacizumab and dilute to the required administration 
volume with 0.9% sodium chloride solution. The concentration of the final bevacizumab 
solution should be kept within the range of 1.4 - 16.5 mg/mL. Discard any unused portion left 
in a vial, as the product contains no preservatives. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration. The dose will be 
prepared and labeled as “bevacizumab 10 mg/kg or placebo” so that the contents are not 
discernible to the person administering the treatment.   
Administration 


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Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) 
infusion. Do not initiate bevacizumab for 28 days following major surgery and until surgical 
wound is fully healed. Refer to Section 7 for protocol-specific administration instructions.  
First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer second 
infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 
30 minutes if infusion over 60 minutes is tolerated. 
Drug Interactions 
Increased Effect/Toxicity: Bevacizumab may increase the levels/effects of anthracyclines, 
inotecan, sorafenib, and sunitinib. Serum concentrations of irinotecan’s active metabolite may 
be increased by bevacizumab; an approximate 33% increase has been observed. 
Pharmacokinetics 
Distribution: Vd: 46 mL/kg (limited extravascular distribution) 
Half-life elimination: ~20 days (range: 11-50 days) 
Clearance: 2.75-5 mL/kg/day. A low serum albumin and high tumor burden increase clearance 
by 30% and 7% respectively.  Clearance increases with increasing body weight, and is 15% 
slower in women than men. 
Time to steady state: 100 days 
Adverse Events 
Consult the investigator’s brochure and package insert for the most current and complete 
information. U.S. Boxed Warnings include severe or fatal hemorrhage, including hemoptysis, 
gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding. 
Avoid use in patients with serious hemorrhage or recent hemoptysis.  
 
Revised Bevacizumab CAEPR – Version 2.5, May 2, 2018 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
  
for further clarification. Frequency is provided based on 3540 patients. Below is the CAEPR for 
Bevacizumab (rhuMAb VEGF). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.5, May 2, 20181 


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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
 
 
Hemolytic uremic syndrome 
  
CARDIAC DISORDERS 
  
 
Cardiac disorders - Other 
(supraventricular arrhythmias)2  
 
 Cardiac disorders - Other (supraventricular 
arrhythmias)2 (Gr 3) 
 
 
Chest pain - cardiac3 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction3 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)  
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal hemorrhage5 
 
 Gastrointestinal hemorrhage5 (Gr 2) 
 
Gastrointestinal obstruction6 
 
  
 
 
Gastrointestinal perforation7 
  
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Gallbladder perforation 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - 
Other (necrotizing fascitis) 
  
 
Infections and infestations - Other 
(peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 


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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
 
 
Injury, poisoning and procedural 
complications - Other 
(anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased (Gr 3) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 3) 
 
Aspartate aminotransferase increased  
 Aspartate aminotransferase increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased  
(Gr 2) 
 
Creatinine increased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperglycemia 
 
  
 
Hypokalemia 
 
  
 
Hyponatremia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
 
Avascular necrosis11 
  
 
Generalized muscle weakness 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other (bone 
metaphyseal dysplasia)12 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw13 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular 
  
 
Peripheral sensory neuropathy14 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
Reproductive system and breast 
disorders - Other (ovarian 
failure)15 
 
 
  
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 2) 
 
 
Bronchopleural fistula 
  
 
 
Bronchopulmonary hemorrhage   
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Pulmonary hypertension 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism3,16 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial flutter. 
 
3The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in patients 
with a history of diabetes. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric 
fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC. 


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6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal 
anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic 
leak. 
 
11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 
treated with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
13Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone.  
 
15Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to 
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level 
<30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack, and 
stroke. 
 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that bevacizumab (rhuMAb VEGF) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; 
Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation); 
Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye 
disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - Other (transient 
increased IOP > or =30 mm Hg); Eye pain; Floaters; Keratitis; Optic nerve disorder; Photophobia; Retinal 
detachment; Retinal tear; Retinopathy; Vitreous hemorrhage; Watering eyes 


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GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral 
pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema 
limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized 
edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; 
Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis 
radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; 
CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram 
QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase 
increased; Lymphocyte count decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest 
wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; Muscle weakness lower limb; 
Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); 
Neck pain; Osteonecrosis; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid 
leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; 
Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory 
impairment; Myasthenia gravis; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; 
Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Dysuria; 
Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - Other (pulmonary 
infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain of skin; 
Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin 
and subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin 
induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
10.3 
Placebo 
The placebo will be 0.9% Sodium Chloride Injection (0.9% NaCl).  Sites will provide their own 
0.9% NaCl. 
Each institution will use 100 ml bags or bottles of 0.9% NaCl as the placebo agent. A volume 
of 0.9% NaCl equal to the volume of bevacizumab will be added to the 100 mL bag of 0.9% 


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NaCl.  The placebo will be given intravenously over 90 minutes at specified infusion time points 
(see Section 7.1). Each institution will use 0.9% NaCl from their commercial inventory. The 
Alliance will not provide placebo (0.9% NaCl) to study sites. 
The dose will be prepared and labeled as “bevacizumab 10 mg/kg or placebo” so that the 
contents are not discernible to the person administering the treatment.  
Refer to Section 7.0 for protocol-specific administration instructions.  
First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer second 
infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 
30 minutes if infusion over 60 minutes is tolerated. 
10.4 
Nursing Guidelines 
10.4.1 
Monitor patients closely for infusion type reactions, including fever, chills, myalgias, 
rigors, or other allergic reactions.  While this is less likely given that bevacizumab is a 
humanized antibody, there still exists the potential for severe allergic reactions.  If these 
signs or symptoms occur stop the infusion immediately and contact treating physician.  
Have emergency equipment nearby and be prepared to administer emergency treatment 
as ordered by treating physician. 
10.4.2 
Monitor urine dipstick or UPC as required by the test schedule. 
10.4.3 
Evaluate IV site regularly for signs of infiltration. 
10.4.4 
Bleeding in the absence of thrombocytopenia is a serious toxicity that necessitates patient 
monitoring.  Monitor patient closely for hemorrhagic events, including CNS hemorrhage, 
epistaxis, hematemesis and hemoptysis.  Most cases of bleeding have occurred at the 
tumor site.  Advise patient about the potential for bleeding or thrombosis. 
10.4.5 
In patients receiving treatment for lung cancer, hemoptysis and pulmonary hemorrhage 
occurred in up to 10% of patients in one study.  Monitor these patients especially closely.  
10.4.6 
Patient may experience Grade 1-2 nausea, however, vomiting is uncommon.  Medicate as 
ordered and monitor for effectiveness.  
10.4.7 
Monitor for skin rash, instruct patient to report to treating physician. 
10.4.8  Monitor blood pressure.  Administer antihypertensives as ordered by treating physician. 
10.4.9 
Monitor for signs and symptoms of deep vein thrombosis (DVT) or pulmonary embolism 
(PE), or myocardial infarction (MI) including new or worsening angina.  These have been 
reported with therapy.  Instruct patient to report any calf pain, chest pain or shortness of 
breath to treating physician immediately.  
10.4.10 Asthenia and headache were reported commonly during therapy (in up to 70% and 50% 
of patients respectively).  Administer acetaminophen as needed.  Monitor for its 
effectiveness.  Avoid the use of aspirin, or ibuprofen as this may interfere with the 
coagulation cascade and further add to the risk of bleeding. 
10.4.11 Monitor CBC, including platelets.  Instruct patient to report signs and symptoms of 
infection, unusual bruising or bleeding to the treating physician. 
10.4.12 Patients receiving warfarin therapy for thrombosis should have their PT or INR monitored 
weekly until two stable therapeutic levels are attained.  For patients on warfarin for venous 


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access prophylaxis, routine monthly monitoring is satisfactory; however, more frequent 
monitoring can be done according to local standard practices. 
10.4.13 A rare but serious complication of bevacizumab is wound dehiscence.  Patients who have 
had recent surgery or have other open wounds should be monitored carefully. 
10.4.14 Gastrointestinal perforation with or without abdominal abscess is rare but possible.  This 
may present itself as vague abdominal pain associated with constipation and vomiting.  
Instruct patient to report abdominal pain to the treating physician.  
10.4.15 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a rare (<1%) but serious 
condition.  Presenting symptoms may include changes in mental status, visual disturbance, 
seizure, or other CNS changes.  Patients with this syndrome generally had HTN as well, 
therefore BP monitoring is important.  Instruct patient to report any mental status changes, 
visual changes, seizures, or other CNS changes to the treating physician immediately.  
These may be a sign of RPLS or more serious condition, such as hemorrhagic event in the 
CNS.  
10.4.16 Warn female patients of the possibility of ovarian failure and subsequent infertility. 
Vaginal hemorrhage is also possible. Instruct patients to report any heavy or unusual 
vaginal bleeding to health care team. 
11.0 MEASUREMENT OF EFFECT 
11.1 
Schedule of Evaluations: 
For the purposes of this study, patients should be reevaluated on Days 1 and 15 of each cycle of 
bevacizumab or placebo.  
11.2 
Guidelines for Evaluation of Measurable Disease 
11.2.1 Response and Progression Criteria 
11.2.1.1 Clinical Response is defined as neurological and MDASI-BT global score stability 
or improvement. Progression is defined as neurological progression despite increases 
in dexamethasone (or equivalent corticosteroid) back to or beyond the patient’s 
baseline corticosteroid dose for greater than 48 hours.  
11.2.1.2 Radiographic response: Measurable disease will be defined as a contrast-enhancing 
lesion with clearly defined margins on MRI and perpendicular diameters of at least 
10 mm (i.e. with two transaxial perpendicular diameters of at least 10 mm and also 
visualized on two or more contiguous axial slices summing up to at least 10 mm).  
Thin enhancement around a cyst or surgical cavity should be considered non-
measurable unless there is a nodular component measuring at least 10 mm in diameter.  
11.2.1.3 Radiographic response and progression will follow RANO criteria for the target 
lesion(s). 
11.2.2 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to study 
treatment or other medical conditions, should be reported as PD due to “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even 
after discontinuation of treatment due to symptomatic deterioration. 


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11.3 
Definitions of analysis variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 
12.0 END OF TREATMENT/INTERVENTION  
12.1 
Duration of Treatment  
12.1.1 Responding: Patients who are symptomatically stable or improving on treatment will 
continue on the assigned therapy for a total of 4 cycles.  After treatment is discontinued, 
patients will be followed per the study calendar in section 5.0. 
12.1.2 Progression of radionecrosis 
Patients who experience progression of radionecrosis while on blinded treatment may be 
unblinded. See Section 8.3 for unblinding instructions. 
• 
Patients who were receiving placebo may elect to crossover to open label bevacizumab 
treatment. See Section 4.9 for cross-over instructions. 
• 
Patients who experience progression of radionecrosis while receiving bevacizumab 
treatment (either blinded or open-label) will discontinue bevacizumab and will be 
followed for survival. 
12.1.3 Progression of metastatic disease  
Patients on blinded drug who experience metastatic progression requiring systemic therapy 
that is not listed in the Appendix II as safe to give with bevacizumab will discontinue 
protocol treatment and be treated per the treating physician.  These patients will be followed 
for survival.   
Patients on blinded drug who experience metastatic progression requiring systemic therapy 
that is listed in the Appendix II as safe to give with bevacizumab will continue protocol 
treatment and may start systemic therapy per the treating physician. 
Patients who have progression of metastatic disease after completion of bevacizumab should 
continue to be followed for progression of radionecrosis and survival per the study calendar 
in Section 5.0. Document details, including measurements of the target lesion(s), on data 
forms. 
12.1.4 Discontinuation of study agent: Patients who discontinue treatment for reasons other than 
progression should be followed per the study calendar (Section 5.0). 
12.2 
Managing ineligible patients and major protocol violations 
Data must be submitted per Section 5.0 for patients deemed ineligible. See also the Forms Packet 
for full details of data submission requirements. 
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient continues protocol treatment. All scans, 
tests, and data submission are to continue as if the patient were eligible. Notification of the local 
IRB may be necessary per local IRB policies. 
Study participants who are registered to the trial but never receive study intervention (for a 
reason other than because they were deemed ineligible) must still complete baseline, on-study 
and off-treatment notice data submission. 


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12.3 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
 
 


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13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Overview 
This is a randomized double-blinded phase II study of corticosteroids with bevacizumab vs. 
corticosteroids with placebo for brain radionecrosis following radiosurgery for brain metastases.  
13.2 
Sample Size, Accrual Time and Study Duration 
13.2.1 Sample Size 
Applying guidelines used in the evaluation of the minimal clinically important difference 
(MCID) [57] in health-related quality of life instruments to estimate the sample size for this 
study, that is, the MCID is expressed in standard deviation (σ). 
Assuming a compound symmetry structure, we have calculated the number of patients 
required to achieve 80% power to detect the specified effect sizes in slope at the 5% or 10% 
significance level in the following table. This is a direct application of equation (2.4.1) on 
page 20 of Diggle et al. [41]  
Effect size in 
slope (t=8) 
Compound 
symmetry ρ 
Type I error 
α 
Power (%) 
Sample size 
per arm 
0.25σ/t 
0.8 
0.10 
80 
64 
0.30σ/t 
0.8 
0.10 
80 
44 
0.30σ/t 
0.8 
0.05 
80 
56 
0.50σ/t 
0.8 
0.05 
80 
21 
Although 0.50σ is generally considered for a moderate effect size, we believe a smaller 
effect size (0.30σ) is still clinically meaningful and thus warranted for a comparison of 
bevacizumab plus corticosteroid vs. placebo plus corticosteroid for this patient population. 
Therefore, we will need a sample size of 112 patients, which will be further inflated by 
approximately 15% to 130 patients (65 patients per arm) to account for patient ineligibility 
and major violation. 
13.2.2 Accrual Rate and Accrual Duration 
The accrual rate for Alliance is estimated as 30 patients per year, which lead to 
approximately 4.5 years for patient accrual. 
13.2.3 Primary Endpoint Completion Date for ClinicalTrials.gov Reporting 
For purpose of ClinicalTrial.gov reporting, the Primary Endpoint Completion Date (PECD) 
for this study is the time the last patient registered has been followed for at least four months. 
13.3 
Statistical Design and Analysis for the Primary Endpoint 
13.3.1 Primary Endpoint 
Patient-reported outcome (symptoms) of radionecrosis as repeatedly measured by MDASI-
BT symptom score during the first two cycles of treatment (prior to first treatment, 2, 4, 6 
and 8 weeks). 
13.3.2 Statistical Design 
This is a two-arm randomized phase II clinical trial with parallel group design for 
longitudinal quality of life endpoint. There is no formal interim analysis specified due to the 
sample size. 


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13.3.3 Analysis Plan 
13.3.3.1  A modified intent-to-treat principle will be applied for statistical analysis of efficacy 
in all evaluable patients, where ‘evaluable patients’ are defined as all patients meeting 
the eligibility criteria who received their assigned study treatment with no major 
violations and completed MDASI-BT at baseline and at least once in follow-up.  
13.3.3.2  For patients who cross-over from placebo to bevacizumab or discontinue 
bevacizumab, primary analysis will only be applied to their assessments prior to cross-
over. Further sensitivity analyses will explore additional per-treatment approaches for 
analyzing the primary endpoint data, such as incorporating a time-dependent 
treatment covariate. 
13.3.3.3 Generalized linear models with repeated measures will be used to compare the rates 
of change in MDASI-BT symptom score (𝒚𝒚𝒊𝒊𝒊𝒊) between treatment arms (𝒙𝒙𝒊𝒊) during the 
first two cycles of treatment. 
    
 
Where time index 𝑗𝑗= 0, 2, 4, 6, 8 week, subject index 
 patient and 
possibly other covariate such as stratification factors (𝑧𝑧𝑖𝑖).  In this notation, 
 
represents the difference in rates of change in MDASI-BT symptom score when 𝑥𝑥𝑖𝑖=
1 for bevacizumab plus corticosteroid arm and 𝑥𝑥𝑖𝑖= 0 for placebo plus corticosteroid 
arm. Generalized estimating equation (GEE) approach with an independence working 
correlation matrix will be utilized and parameter estimation will account for the 
covariance between repeated measures [41]. Since the identity link function is used 
for the MDASI-BT symptom score, we will also explore the random effects model 
approach with a random intercept. Supplementary graphical procedures associated 
with repeated measures of MDASI-BT will include a stream plot of individual scores 
over time and a line plot of average symptom scores over time for each arm. 
13.3.3.4  For the primary analysis described above, all patients deemed to be eligible at 
enrollment will be included; however, after central review of imaging data, some of 
these patients may be reclassified as ineligible.  Thus, we will re-run the above 
primary analyses using only patients who are determined to be eligible based on 
central review of imaging data.  These can be considered additional sensitivity 
analyses. 
13.3.3.5  As study sites are not required to have imaging credentials at the time of activation, 
there may be some between-patient variability in the quality of the imaging data.  If a 
noticeable  proportion of patients are determined to have poor quality imaging data, 
we may also re-run the above primary analyses using only those patients whose 
images meet (or have minor deviations from) the recommended imaging protocol 
(Appendix IV). 
 
 


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13.4 
Supplementary Analysis Plans 
13.4.1 Secondary Endpoints 
13.4.1.1 Toxicities associated with bevacizumab and corticosteroids in patients with 
radionecrosis using CTCAE Version 4.0 and DSQ-C. 
13.4.1.2 Quality of life measured using the Single Item Linear Analogue Scale (LASA), 
Dexamethasone Symptoms Questionnaire – Chronic (DSQ-C), MDASI-BT symptom 
score (12 and 16 weeks) and the MDASI-BT interference score. 
13.4.1.3 Progression free survival and time from start of treatment to maximum radiographic 
response. 
13.4.1.4 Corticosteroid dose over time and time to stopping corticosteroids. 
13.4.2 Correlative Endpoints 
13.4.2.1 Biofluid Biomarkers: angiogenic factors (VEGF-A, B, C, D, angiopoietin-1 and 2, 
PDGF), inflammatory cytokines (TNF-α, TGF-β, IL1, and IL6) and genetic markers 
(Apo E). 
13.4.2.2 Imaging Biomarker Measures: Diffusion weighted imaging (apparent diffusion 
coefficient = ADC), Dynamic susceptibility weighted contrast enhanced (DSC), 
Dynamic contrast enhanced (DCE measures - Ktrans, iAUGC). 
13.4.3 Secondary Analyses 
Statistically significant findings from secondary analyses are exploratory in nature and 
therefore shall be interpreted as such because multiplicity from multiple secondary analyses 
will not be adjusted.  Descriptive statistics and graphical approaches will form the basis for 
most secondary analyses, though statistical comparisons may be conducted in some 
appropriate circumstances.  
13.4.3.1 Toxicities associated with bevacizumab and corticosteroids in patients with 
radionecrosis using CTCAE Version 4.0 and DSQ-C will be summarized in 
descriptive statistics. Chi-square tests may be conducted to investigate differences in 
incidence rates of toxicities between arms. 
13.4.3.2  Quality of life measured using the Linear Analog Self-Assessment (LASA), 
Dexamethasone Symptoms Questionnaire – Chronic (DSQ-C), MDASI-BT symptom 
score (baseline, 2, 4, 8 and 12 and 16 weeks and during follow-up) and the MDASI-
BT interference score will be analyzed with the same approach as the primary 
analysis, i.e., generalized linear models. 
13.4.3.3  Progression free survival and time (from start of treatment) to maximum radiographic 
response will be summarized by Kaplan-Meier curve. Date of progression for 
progression free survival will be the date the patient stops placebo or bevacizumab 
for either alternative therapy or crossover to bevacizumab, if initially on placebo. Log-
rank statistics may be conducted to investigate differences in time to event 
(progression and maximum radiographic response) between treatment arms. 
 
 


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13.4.3.4  Corticosteroid dose over time will be summarized by descriptive statistics and may 
be incorporated as a time-dependent covariate in the following joint models: 
• 
Time to stopping corticosteroid will be summarized by Kaplan-Meier curve with 
log-rank tests conducted to investigate differences between treatment arms.  
• 
In order to study the correlation and trend between corticosteroid dose and 
MDASI-BT symptom score, we will extend the generalized linear model to 
allow the covariate to be time-dependent (𝑧𝑧𝑖𝑖𝑖𝑖).  
• 
In order to study the correlation and trend between corticosteroid dose and PFS 
and time to maximum radiographic response, we will use the joint models [42] 
for survival and longitudinal data. 
13.4.4 Correlative Studies Analyses 
The serial changes in biofluid and imaging biomarkers for radionecrosis will be summarized 
using descriptive statistics. The correlation between these biomarkers will be explored by 
generalized linear models allowing for time-dependent covariate (for longitudinal primary 
endpoint) and/or joint models (for time to event secondary endpoints). 
13.5 
Study Monitoring 
13.5.1 Adverse Event Stopping Rule 
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial 
and in consideration of newly acquired information regarding the adverse event profile of 
the treatment(s) under investigation. The study team may choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the specified rule below. Accrual 
will be temporarily suspended to this study if at any time we observe events considered at 
least possibly related to study treatment (i.e., an adverse event with attribute specified as 
possible, probable, or definite) that satisfy the following criteria: 
• 
If 7 or more of the first 20 treated patients (or 35% of all patients after 20 patients have 
been accrued) experience a grade 3 or higher non-hematologic adverse event and the 
adverse event rate is higher in the active treatment arm. 
• 
If 3 or more of the first 20 treated patients (or 15% of all patients after 20 patients have 
been accrued) experience a grade 4 or higher non-hematologic adverse event and the 
adverse event rate is higher in the active treatment arm. 
13.5.2 Accrual Monitoring Stopping Rule 
Patient accrual will be closely monitored by the investigators and secondary statistician on 
a monthly basis. If the accrual rate falls below 50% of expected accrual rate, investigators 
will carefully review feedback from sites and consider taking measures to encourage patient 
enrollment. 
 
 


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13.6 
Study Reporting 
13.6.1 This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and 
administrative information will be provided to the DSMB every six months as per NCI 
guidelines. 
13.6.2 Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrials.gov” web site. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. 
13.7 
Descriptive Factors 
None  
13.8 
Missing Data 
We will examine the mechanisms of missing data if the proportion of missing assessments is 
not small (≥ 5%). Graphical presentation, correlation analysis (Kendall's) and logistic regression 
will be performed to examine whether the missing data mechanism depends on the covariates 
(patient characteristics and other baseline risk factors), observed patient-reported outcome 
(PRO) scores, and missing PRO scores. 
13.8.1 If the missing data mechanism solely depends on the covariates (missing completely at 
random, MCAR) or depends on the covariates and observed PRO scores only (missing at 
random, MAR) [43], we will enhance the primary analysis to incorporate these covariates 
in the repeated measures model. The generalized linear model with repeated measures model 
is a quasi-likelihood based approach that uses all observed data and the covariates that 
explain the missing data mechanism, therefore results in unbiased estimates under MCAR 
and MAR [44]. 
13.8.2 If the missing data mechanism depends not only on the covariates and observed PRO scores, 
but also on the missing PRO score (missing not at random, MNAR), we will explore 
advanced models that consider both longitudinal PRO assessments and missing data 
mechanism, such as pattern mixture model and selection model [44]. 
 
 


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13.9 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist. Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial and gender groupings, the sample size is not increased in order 
to provide additional power for subset analyses. 
The geographical region served by the Alliance, has a population which includes approximately 
13.5% minorities. Based on prior Alliance studies involving similar disease sites, we expect 
about 11.6% of patients will be classified as minorities by race and about 60% of patients will 
be women. Expected sizes of racial by gender subsets for patients randomized to this study are 
shown in the following table. 
 
Racial Categories 
Ethnic Categories 
Not Hispanic or Latino Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
1 
0 
0 
0 
1 
Asian 
2 
1 
0 
0 
3 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
8 
7 
0 
0 
15 
White 
62 
45 
3 
1 
111 
More Than One Race 
0 
0 
0 
0 
0 
Total 
73 
53 
3 
1 
130 
 
 
 


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14.0 CORRELATIVE AND COMPANION STUDIES  
There will be two sub-studies and all patients are encouraged to participate.  
14.1 
Alliance A221208-ST1 
Evaluation of Biofluid Biomarkers of Radiation Necrosis in Alliance A221208  
14.1.1 Background 
Radiation necrosis in the brain and clinical response to treatments of radiation 
necrosis in the brain is associated with alterations in inflammatory cytokines, including 
TNFα, TGFβ, IL1, and IL6: Biomarkers of tissue damage associated with radiation late 
toxicities are poorly studied in the brain.  However, in other tumor systems, alterations in 
the serum level of a number of inflammatory cytokines have been associated with radiation 
effects.  In breast cancer patients, baseline levels of transforming growth factor β1 (TGFβ1) 
have been associated with subsequent radiation fibrosis [45].  Similarly, in non-small cell 
lung cancer, normalization of TGFβ1 levels has been associated with decreased occurrence 
of radiation pneumonitis [46].  In addition, both interleukin-1α and 6 (IL1α and IL6, 
respectively) have been associated with radiation pneumonitis e. We will therefore 
investigate an association between these cytokines and alternations in radiation necrosis. 
Alternations in serum markers of angiogenesis, specifically VEGF subtypes, Ang-1, 
Ang-2, PDGF, Tie-2, and Hif1α, correlate with improvement of radiation response 
using the anti-angiogenic agent bevacizumab: .Bevacizumab targets VEGF-A, a member 
of the platelet-derived growth factor (PDGF) family, which modulates microvascular 
permeability. Other family members include VEGF-B, C, D as well as PDGF. Other 
angiogenesis factors, including angiopoieten-1 (Ang-1) and angiopoieten-2 (Ang-2) are 
known to be differentially expressed, along with VEGF-A, following cranial irradiation in 
animal models and may play important roles in microvascular alterations in response to 
radiotherapy. We will profile changes in such factors, as well as known inflammatory 
cytokines (TNF-α, TGF-β, etc. which may play unknown roles) as a function of time 
following bevacizumab or dexamethasone therapy. 
Therapy-induced changes in serum inflammatory markers (those indicated in 1.2.3) 
predict for cognitive alterations (as measured by MDASI-BT): Markers of inflammation 
are elevated with aging and their increase has been associated with cognitive decline ([47, 
48]. Epidemiological and retrospective data reveals an improvement in neurocognitive 
function with the use of NSAIDs in patients with Alzheimer’s dementia, hence, supporting 
an inflammatory process involved in neurocognitive decline [49]. Chronic inflammation as 
a result of mass effect from tumor or treatment related inflammation may be associated with 
neurocognitive deficits and can be measured in plasma. Interleukin 1 (IL-1), Interleukin 6 
(IL-6), and Tumor Necrosis Factor alpha are pro-inflammatory cytokines that are a measure 
of inflammation and have been shown to be elevated in patients with Alzheimer’s dementia 
[50-54]. In this study, inflammatory biomarkers will be measured at baseline (after 
registration, but prior to treatment) and at each follow-up visit when MDASI-BT 
questionnaires are completed. 
Germline alterations in Apo E (Apo E2, Apo E3, and Apo E4) are associated with 
cognitive alterations (as measured by MDASI-BT): Apolipoprotein E (ApoE) is an 
important factor in remodelling and repairing neurons in response to injury or stress through 
its lipid transport function. In fact, recent data suggests that patients having the Apo E4 
isoform realize Alzheimer’s dementia far earlier than those without it [55].  This allele is 
present in 16% of the general population and 50% of patients with late onset Alzheimer’s 
dementia [49]. Given the similar mechanisms of dementia between Alzheimer’s dementia 


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and radiation induced dementia (e.g. vascular or metabolic), Apo E4 genotyping may prove 
to be a predictor of radiation induced neuronal damage. The Apo E4 protein binds rapidly 
and tightly to beta amyloid. Normally beta amyloid exists in a soluble form. However, when 
bound by Apo E4 protein, beta amyloid becomes insoluble and is more likely to be deposited 
in plaques, which may lead to changes in microvasculature, ultimately leading to 
neurocognitive decline. Further, patients with just one copy of the Apo E4 allele have 
demonstrated accelerated hippocampal volume loss which can also compromise 
neurocognitive function [56]. Recent preclinical mouse data from Crawford and Villasana 
have shown neurogenesis in the hippocampus and hippocampal dysfunction depending on 
Apo E status [57, 58]. Patients with Apo E2 and Apo E3 alleles, on the contrary, tend to 
have ¼ the risk of developing Alzheimer’s disease. It is felt that the E2 and E3 alleles are 
able to facilitate repair and protection from neuronal damage. Apo E genotyping will be 
performed to assess whether a subgroup of patients exists that is genetically predisposed to 
developing cognitive decline.   
14.1.2 Objectives 
See Section 2.3 for correlative objectives. 
14.1.3 Methods 
Research blood products and urine will be collected at baseline (after randomization and 
prior to treatment), prior to cycles 2 and 3, and after cycle 4. For patients who crossover, 
collection will be performed at the same time points following cross-over.  At each interval, 
(2) 10 mL red top no additive tubes and (1) 10 mL EDTA purple top of blood and (1) (50 
mL) random urine will be collected. In addition, urine will be collected in a urine collection 
container and transferred to aliquot tubes for transport.  Analysis of all cytokine alterations, 
pre and post therapy, will be performed in urine and serum specimens using the xMAP 
microsphere system (Luminex Corp.), which allows for the simultaneous quantification 
numerous sera factors within a single 50μl sample. Ambiguous results will be validated 
using commercially available ELISAs (R&D Systems).  To minimize variability, pre and 
post therapy serum samples from each patient will be analyzed on individual plates in 
triplicate.   DNA will be extracted from whole blood samples by Mayo BAP, and Apo E 
genotype determination will be performed by evaluation of single nucleotide 
polymorphisms (SNPs) using real-time PCR methods.   Serum profile changes and SNPs 
will in turn be correlated with alterations in neurocognitive function and objective imaging 
response.  All assays will be performed in the laboratories study translational co-
investigators (EPS and DRG) at the University of Texas M.D. Anderson Cancer Center.  
Results of cytokine analysis and genetic testing will not be released to the patient or their 
treating physician.  Correlative studies will be performed blinded to the overall trial outcome 
with analysis performed under central statistical review.  According to patient consent 
information, the remaining body fluid biospecimens will be stored in the Alliance tissue 
bank. 
 
 


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14.2 
Alliance A221208-IM1 
Evaluation of Imaging Biomarkers of Radionecrosis Response to Corticosteroid and 
Bevacizumab Therapy in Alliance A221208 
14.2.1 Background 
Early reduction in DCE-MRI measures (ktrans, iAUGC) at 1 month will predict for 
clinical and radiological response: Radiological response to bevacizumab in the setting of 
radionecrosis has predominantly been reported in terms of change in volume of T2-FLAIR 
hyperintensity and change in volume of the post-gadolinium T1-weighted contrast-
enhancement.  In the study by Levin et al., DCE-MRI was acquired serially and a dramatic 
reduction in Ktrans was reported at their earliest time point, 6 weeks following initiation of 
bevacizumab. [21] All patients in this small study demonstrated a Ktrans (a constant that 
reflects the rate at which contrast extrudes from the intravascular to extravascular space) 
and clinical response to bevacizumab. Given the dramatic and rapid decrease in Ktrans in 
these patients, we will be evaluating changes in DCE-MRI measures (Ktrans and iAUGC) 
at an earlier time point of 4 weeks following the start of study treatment to determine 
whether these early measures can be used to predict for ultimate clinical response and 
thereby facilitate treatment optimization. 
14.2.2 Objectives 
See Section 2.3 for correlative objectives. 
14.2.3 Methods 
Patients enrolled to A221208-IM1 will have serial multiparametric MRI including DCE-
MRI, DWI to acquire ADC and gadolinium enhanced T1-weighted at the time points listed 
in Section 6.3.  
Detailed imaging analysis will be centrally and retrospectively performed to 
evaluate the correlation of the following measures with clinical outcome: 
• 
Change in volume of the enhancement on post-contrast T1-weighted images over time 
• 
Change in volume of T2 or FLAIR hyperintensity over time 
• 
Change in apparent diffusion coefficient (ADC) on diffusion weighted imaging over 
time 
• 
Change in rCBV on DSC over time 
• 
Change in ktrans on DCE over time 
For ADC and rCBV measurement, image datasets for post-gadolinium T1-weighted images, 
T2/FLAIR images, ADC and DSC will be spatially co-registered. Regions of interest (ROIs) 
will be delineated as (1) contrast-enhancing abnormalities on the post-gadolinium T1-
weighted images and (2) T2 signal abnormality. ADC and rCBV measures will be sampled 
in all ROIs at each time point. Delineation of ROIs on both the post-gadolinium T1-weighted 
images and T2/FLAIR images will enable consistent comparison of changes in ADC and 
DSC over time, particularly in cases where the enhancing lesions significantly decrease at 
early time points following bevacizumab. 


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19. 
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necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-
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height and percentage of signal intensity recovery derived from dynamic susceptibility-
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1078-84. 
27. 
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Ludemann, L., et al., Quantitative measurement of leakage volume and permeability in 
gliomas, meningiomas and brain metastases with dynamic contrast-enhanced MRI. Magn 
Reson Imaging, 2005. 23(8): p. 833-41. 
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30. 
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from the development of the Brain Tumor Module of the M.D. Anderson Symptom Inventory. 
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32. 
Armstrong, T.S., et al., Clinical utility of the MDASI-BT in patients with brain metastases. J 
Pain Symptom Manage, 2009. 37(3): p. 331-40. 
33. 
Armstrong, T.S., et al., Validation of the M.D. Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT). J Neurooncol, 2006. 80(1): p. 27-35. 
34. 
Mauer, M.E., A. Bottomley, and M.J. Taphoorn, Evaluating health-related quality of life and 
symptom burden in brain tumour patients: instruments for use in experimental trials and clinical 
practice. Curr Opin Neurol, 2008. 21(6): p. 745-53. 
35. 
Armstrong T, W.J., Wang M, Won M, Bottomley A, Mendoza TR, Coens C, Werner-Wasik 
M, Brachman DG, Choucair AK, Mehta M, Gilbert MR   Clinical utility of quality of life 


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(QOL) and symptom assessment as prognostic factors for survival and measures of treatment 
effects on RTOG 0525. Neuro-Oncology, 2011. 13(supplement 3): p. 121. 
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delayed emesis after moderately emetogenic chemotherapy. Br J Cancer, 2006. 94(7): p. 1011-
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Brief Fatigue Inventory. Cancer, 1999. 85(5): p. 1186-96. 
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interference with function. Pain, 1995. 61(2): p. 277-84. 
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factors in the controlled clinical trial. Biometrics, 1975. 31(1): p. 103-15. 
40. 
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in neuro-oncology patients. J Pain Symptom Manage, 2007. 34(6): p. 628-38. 
41. 
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Chapman & Hall/CRC biostatistics series 62012, CRC Press,: Boca Raton. p. xiv, 261 p. 
43. 
Little, R.J.A. and D.B. Rubin, Statistical analysis with missing data. 2nd ed. Wiley series in 
probability and statistics2002, New York: Wiley. xv, 381 p. 
44. 
Fairclough, D.L., Design and analysis of quality of life studies in clinical trials : 
interdisciplinary statistics. Interdisciplinary statistics series2002, Boca Raton: Chapman & 
Hall/CRC. xvii, 307 p. 
45. 
Li, C., et al., TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of 
developing post-radiotherapy fibrosis. Int J Cancer, 1999. 84(2): p. 155-9. 
46. 
Anscher, M.S., et al., Changes in plasma TGF beta levels during pulmonary radiotherapy as a 
predictor of the risk of developing radiation pneumonitis. Int J Radiat Oncol Biol Phys, 1994. 
30(3): p. 671-6. 
47. 
Krabbe, K.S., M. Pedersen, and H. Bruunsgaard, Inflammatory mediators in the elderly. Exp 
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48. 
Yaffe, K., et al., Inflammatory markers and cognition in well-functioning African-American 
and white elders. Neurology, 2003. 61(1): p. 76-80. 
49. 
Teunissen, C.E., et al., Biochemical markers related to Alzheimer's dementia in serum and 
cerebrospinal fluid. Neurobiol Aging, 2002. 23(4): p. 485-508. 
50. 
Blum-Degen, D., et al., Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal 
fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett, 1995. 202(1-2): 
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51. 
Cacabelos, R., et al., Brain interleukin-1 beta in Alzheimer's disease and vascular dementia. 
Methods Find Exp Clin Pharmacol, 1994. 16(2): p. 141-51. 
52. 
Cacabelos, R., et al., Serum tumor necrosis factor (TNF) in Alzheimer's disease and multi-
infarct dementia. Methods Find Exp Clin Pharmacol, 1994. 16(1): p. 29-35. 
53. 
Martinez, M., et al., Increased cerebrospinal fluid fas (Apo-1) levels in Alzheimer's disease. 
Relationship with IL-6 concentrations. Brain Res, 2000. 869(1-2): p. 216-9. 
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Tarkowski, E., et al., Intracerebral production of tumor necrosis factor-alpha, a local 
neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol, 1999. 
19(4): p. 223-30. 


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55. 
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Behav Brain Funct, 2009. 5: p. 32. 
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irradiated human apoE transgenic mice. Radiats Biol Radioecol, 2008. 48(2): p. 167-70. 
 
 
 


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APPENDIX I: 
INFORMED CONSENT  
 
Consent Form 
 
Study Title for Study Participants: 
Testing the addition of the antibody, bevacizumab, to the usual treatment for 
radionecrosis that results from brain radiation. 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
A221208 Randomized Phase II Study: Corticosteroids + Bevacizumab vs. 
Corticosteroids + Placebo (BeSt) for Radionecrosis after Radiosurgery for 
Brain Metastases 
 
This study is conducted by the Alliance for Clinical Trials in Oncology, a national clinical 
research group supported by the National Cancer Institute. The Alliance is made up of cancer 
doctors, health professionals, and laboratory researchers, whose goal is to develop better 
treatments for cancer, to prevent cancer, to reduce side effects from cancer, and to improve the 
quality of life of cancer patients. 
 
 
What is the usual approach to my diagnosis?  
You are being asked to take part in this study because you have symptoms and test results 
showing you have brain radionecrosis.  Brain radionecrosis is a non-cancerous condition that 
makes up an area of dead tissue in the brain that is surrounded by inflamed (swollen) tissue. 
Brain radionecrosis can cause headaches, nausea, vomiting, weakness and other neurological 
symptoms. This condition can happen after you receive intense radiation therapy for brain 
cancer, such as if you have radiosurgery. Radiosurgery is an intense radiation therapy that targets 
brain cancers and is usually given as a one-day treatment.  
 
The most common initial treatment for brain radionecrosis is corticosteroid therapy (drugs given 
to reduce inflammation, or swelling).  However, not all patients respond to corticosteroid therapy 
alone. If the symptoms of brain radionecrosis become worse while receiving corticosteroid 
therapy, you may need to have surgery to remove the tissue where the radionecrosis in the brain 
has occurred. This is only done if your doctors think it is safe and appropriate procedure for you.   
 
 
Why is this study being done? 
Usually the first treatment for brain radionecrosis only works for some patients and can cause 
significant side effects in many patients. The purpose of this study is test whether adding a drug 
called bevacizumab to your standard corticosteroid therapy will improve your symptoms over 
corticosteroid therapy alone by improving the radionecrosis and minimizing treatment-related 


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side effects. The effects of bevacizumab with standard corticosteroid therapy will be compared to 
a placebo with standard corticosteroid therapy 
 
Bevacizumab has been approved for the treatment of many types of cancer, including brain 
cancers.  In cancers, bevacizumab is thought to prevent the growth of new blood vessels (that 
feed tumor growth) and stop the leakage of other blood vessels to improve oxygen and 
chemotherapy delivery. In the case of radionecrosis, it is thought that bevacizumab can reduce 
inflammation (by reducing leaking of the blood vessels) and lessen the symptoms of the 
radionecrosis.  
 
In this study, we will compare the effects of receiving bevacizumab with standard corticosteroid 
therapy to the effects of receiving a placebo with standard corticosteroid therapy. A placebo is a 
liquid that looks like the study drug but contains no medication.  
 
 
How many people will take part in the study? 
About 130 people will take part in this study.  
 
 
What will happen if I take part in this research study?   
 
 
A computer will by chance assign you to treatment groups in the study.  This is called 
randomization.  This is done by chance because no one knows if one study group is better or 
worse than the other.  
 
 
This study has two study groups: 
 
Group 1 will receive the study drug bevacizumab with corticosteroids  
Group 2 will receive a placebo, a liquid that looks like the study drug but contains no 
medication, with corticosteroids.  
 
Whether you are in Group 1 or 2, the corticosteroid dose will be adjusted by your doctor in order 
to manage your symptoms. 
 
Each treatment group will receive treatment over 4 weeks. This 4-week period is called “a 
cycle.” Regardless of which treatment group you are in, you will receive treatment on the 
following schedule:  
 
 


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Study Schedule 
Each cycle is made up of 4 weeks 
 
Week 1 
Week 2 
Week 3 
Week 4 
Bevacizumab/placebo 
X 
Rest 
X 
Rest 
Corticosteroids 
Daily  
Daily 
Daily 
Daily 
 
At any time after you begin study treatment, if you have worsening symptoms despite 
increasing corticosteroids, you will be informed about whether you have been receiving 
bevacizumab or placebo.  If you have been receiving placebo, you may decide to “cross-over” 
and receive bevacizumab. If you decide to receive bevacizumab, you will receive treatment for 
an additional 4 cycles as shown above. 
 
This will require ongoing on-study assessments including clinical assessments, laboratory 
testing, MRI and patient-reported outcome questionnaires.  
 
 
How long will I be in this study? 
You will receive either bevacizumab or a placebo, as well as corticosteroids, as recommended by 
your treating doctor to manage your symptoms, for up to four 4-week cycles, as tolerated. As 
mentioned above, if you have worsening symptoms and you have been receiving placebo, you 
may crossover and receive bevacizumab for four additional 4-week cycles.  
 
After you finish the study treatment of about 16 weeks (or 32 weeks if you have “crossed over”), 
your doctor will continue to watch you for side effects and follow your condition for up to 1 year 
after you stopped study treatment. 
 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra tests and assessments that you will need to have if you 
take part in this study. 
 
Before you begin the study: 
You will need to have the following extra tests to find out if you can be in the study: 
• 
MRI images of your brain will be sent to a central radiology lab for review (“central 
review”). Any identifying information will be removed from the images sent to the 
radiology lab. Even though images are sent to the lab, your doctor may decide to 
review your MRI images at your hospital to see if you can be in the study.   
• 
Blood tests and urine tests to determine blood counts and urine proteins 
• 
Pregnancy test (if you are able to have children) 
 
If the exams, tests, and procedures show that you can take part in the study, and you choose to 
take part, then you will need the following extra tests during the study. They are not part of the 


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usual approach for your condition but they are part of usual monitoring while taking 
bevacizumab. 
 
During the study: 
• 
Blood tests every 4 weeks while on study treatment   
• 
Urine tests every 4 weeks while on study treatment,  
 
You will also be asked to complete questionnaires before you start treatment and 2, 4, 6, 8 and 
12 weeks after you start treatment. If you “cross-over” to bevacizumab treatment, you will need 
to repeat these questionnaires at the same time points. After treatment, you will be asked to 
complete the questionnaires every 2 months for 6 months. 
 
 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• 
You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• 
You may be asked sensitive or private questions which you normally do not discuss 
• 
The study drug(s)/study approach may not be better, and could possibly be worse, than 
the usual approach for your condition. 
  
The drugs used in this study may affect how different parts of your body work such as your 
kidneys, heart, and blood. The study doctor will be testing your blood and urine will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug. 
 
Here are important points about side effects: 
• 
The study doctors do not know who will or will not have side effects. 
• 
Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• 
Some side effects may interfere with your ability to have children. 
• 
Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• 
Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• 
The study doctor may be able to treat some side effects. 
• 
The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
 
 


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Possible Side Effects of Bevacizumab: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab (rhuMAb VEGF), more than 20 and up to 100 may 
have: 
• High blood pressure which may cause headaches, dizziness, blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab (rhuMAb VEGF), from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Low white cell count that may increase the risk of infection  
• Infection, including collection of pus in the belly or rectum  
• Abnormal heartbeat which may cause palpitations or fainting 
• Pain in the belly, rectum, chest, joints, muscles, or tumor 
• Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration  
• Bleeding from multiple sites including the vagina or nose  
• Internal bleeding which may cause black tarry stool, blood in vomit, coughing up 
blood, or blood in urine 
• Blockage of internal organs which may cause vomiting or inability to pass stool 
• Sores in the mouth  
• Allergic reaction during or after infusion of bevacizumab which may cause fever, 
chills, rash, itching, hives, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Delay in healing of wounds or spontaneous opening of wounds  
• Weight loss, tiredness, or dizziness 
• Muscle weakness 
• Damage to the jawbone which may cause loss of teeth 
• Headache 
• Numbness, tingling or pain in the fingers or toes 
• Hoarseness, stuffy nose, or cough  
• Dry skin 
• Swelling and redness of the skin 
• Blood clot in limbs or lungs which may cause swelling, pain, shortness of breath 
• Leakage of protein in the urine, which can rarely lead to damage to the kidney 
 
 


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RARE, AND SERIOUS 
In 100 people receiving bevacizumab (rhuMAb VEGF), 3 or fewer may have: 
• Clots in the arteries, causing stroke (which may cause paralysis or weakness) or 
heart attack (which may cause chest pain or shortness of breath). This risk is 
significantly increased in patients who are elderly or with history of diabetes  
• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require 
surgery to repair 
• A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, 
rectum, or vagina. These conditions may cause serious infections or bleeding and 
require surgery to repair  
• Sores in the throat 
• Flesh-eating bacteria syndrome, an infection in the deep layers of skin  
• Damage to organs (bone, lungs, others) which may cause loss of motion  
• Bleeding in the tumor, brain, belly or lungs which may cause confusion, blood in 
stool or coughing up blood   
• Brain damage which may cause headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
• Kidney damage which may require dialysis  
• Redness, pain or peeling of palms and soles 
 
 
Additional Notes on Possible Side Effects for Bevacizumab: 
• 
Risk in children or adolescents: abnormal bone changes which may interfere with growth. 
• 
Risk in pre-menopausal women: more likely to develop menopause when taking 
bevacizumab. 
 
Possible Side Effects of Corticosteroids: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving corticosteroids, more than 20 and up to 100 may have: 
• Trouble sleeping 
• Weight gain around the stomach 
• Puffiness (especially in the face) 
• Buildup of fluids and a rise in blood pressure 
• Possible rise in your blood sugar 
• Muscle weakness 
• Mood swings 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving corticosteroids, from 4 to 20 may have: 
• Changes in the blood levels of potassium.   
• Infection 
• Menstrual changes 
• Changes in personality 
• Dizziness 
• Stomach and throat ulcers or worsening of any ulcers you had before treatment 
 
 
RARE, AND SERIOUS 
In 100 people receiving corticosteroids, 3 or fewer may have: 
• Depression 
• Seizures 
• Patients who are more likely to get heart disease may have heart failure 
• Brittle bones  
• Swelling and pain of the pancreas 
• Itching, and other allergic reactions, some severe. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study and for at least 90 days after you stop taking the study drugs.  Check with your study 
doctor about what kind of birth control methods to use and how long to use them.  Some 
methods might not be approved for use in this study. If you suspect you may be pregnant, 
immediately inform your study doctor or health care team. It is not known whether bevacizumab 
will affect your ability to have children in the future.  You should talk to your doctor about your 
choices.    
 
For more information about risks and side effects, ask your study doctor. 
 
 
Are there benefits to taking part in the study? 
It is not possible to know at this time if the study drug/study approach is better than the usual 
approach so this study may or may not help you. This study will help researchers learn things 
that will help people in the future. 
 
 


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What other choices do I have if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. Your other choices may 
include: 
• 
Getting treatment or care for your radionecrosis without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• 
If your health changes and the study is no longer in your best interest 
• 
If new information becomes available 
• 
If you do not follow the study rules 
• 
If the study is stopped by the sponsor, IRB or FDA 
 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
 
 
What are the costs of taking part in this study? 
The bevacizumab or placebo will be supplied at no charge while you take part in this study. The 
cost of getting the bevacizumab/placebo ready and giving it to you is not paid by the study so 
you or insurance company may have to pay for this. It is possible that the bevacizumab may not 
continue to be supplied while you are on the study. Although not likely, if this occurs, your study 
doctor will talk to you about your options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your condition while in this study, including the cost of tests, procedures, or medicines 
to manage any side effects, unless you are told that certain tests are supplied at no charge. Before 


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you decide to be in the study, you should check with your health plan or insurance company to 
find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury.  Your insurance company may or may not be willing to pay for study-related injury.  If 
you have no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
 
Will my medical information be kept private?  
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• 
The Alliance for Clinical Trials in Oncology (Alliance)  
• 
The Alliance Data and Safety Monitoring Board, a group of experts who regularly review 
the progress of the study. 
• 
The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• 
The Food and Drug Administration (FDA), the Office for Human Research Protection 
(OHRP), and the National Cancer Institute (NCI) in the U.S., and similar ones if other 
countries are involved in the study. 
• 
The Cancer Trials Support Unit (CTSU), a research group sponsored by the NCI to 
provide greater access to cancer trials. 
• 
Genentech Inc. and the Roche Group, makers of bevacizumab 
 
 


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Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
 
 
ADDITIONAL STUDIES SECTION: 
 
Please note:  This section of the informed consent form is about additional research studies 
that are being done with people who are taking part in the main study.  You may take part 
in these additional studies if you want to.  You can still be a part of the main study even if 
you say ‘no’ to taking part in any of these additional studies. 
 
You will not get health benefits from any of these additional studies. The researchers leading 
these optional studies hope the results will help other people with cancer in the future. 
 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to these studies. If you sign up for but cannot complete any of the studies for any 
reason, you can still take part in the main study. 
 
You can say “yes” or “no” to each of the following studies.  Please mark your choice for each 
study. 
 
 
Optional imaging study – extra research MRIs 
NOTE TO INSTITUTIONS: The Optional Imaging study section is not to be removed from the 
consent. Please select one of the following based on whether or not your institution elected to 
participate in the advanced imaging sub-study.* 
*This note for investigators is instructional and should not be included in the consent form sent 
to IRBs. 


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☐ Your health care facility has extra MRI testing available, known as “DCE” MRI. DCE MRI is 
a specialized kind of MRI that allows analysis of blood vessels related to a brain tumor or brain 
lesions like radionecrosis. If your facility has this available, researchers would like to use these 
scans for a related research study to see whether they can predict how well a patient will do 
following treatment. If you choose to take part in this study, you will have extra research MRIs. 
These scans are already used in medical care but extra scans would be taken at a time point in 
your treatment that is not usual. Your scans will be submitted to a central image library. 
Researchers would use these scans to see if there are early imaging markers that may predict how 
you will respond to treatment, so that in future studies, these markers may be used to guide 
treatment in patients with the same condition. These scans will be saved so that researchers can 
look back at these scans after the study is over.  
 
If you agree to have extra scans, it would involve extra time to have an extra MRI done after 1 
cycle of bevacizumab/placebo treatment, and again after 1 cycle of bevacizumab if you “cross-
over.” The most common risks related to the MRI are anxiety/stress, claustrophobia, and 
discomfort.  The most common risks related to the drug used for MRI (called gadolinium) are 
headache, nausea, vomiting, hives, temporary low blood pressure, and allergic-like reaction. The 
scan would only be used for research and not to guide your medical care. There are educational 
materials available about this type of scan. Ask your study doctor about them, if you would like 
more information.  
 
The costs of these optional extra scans will not be paid by the study or your insurance company, 
but your hospital will cover these costs.  
 
☐ Your health care facility does NOT have extra DCE MRI testing  which will be necessary for 
the optional imaging study.  DCE MRI is a specialized kind of MRI that allows analysis of blood 
vessels related to a brain tumor or brain lesions like radionecrosis. You should circle the answer 
“no” below.  
 
Please circle your answer to show whether or not you would like to take part:  
1. 
I choose to take part in the imaging study and will have the extra MRIs. 
 
  YES NO 
 
   Initial: _______ Date: _________ 
 
 
Optional Sample Collections for Laboratory Studies  
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from your tissue, blood, urine, or other fluids. Through these 
studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
 


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Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes 
affect how your body responds to treatment. 
 
If you choose to take part in this study, the study doctor for the main study would like to collect 
blood and urine for research to study possible markers that may predict how you will respond to 
treatment so that in future studies, these markers may be used to guide treatment in patients with 
the same condition. 
 
 
What is involved? 
If you agree to take part, here is what will happen next: 
1) About 2 tablespoons of blood will be collected from a vein in your arm and you will be 
asked to provide a random urine sample. These samples will be collected before you start 
treatment and after 1, 2, and 4 months of treatment. 
2) Your sample and some related health information will be sent to a researcher for use in 
the study described above. Remaining samples may be stored in the Biobank, along with 
samples from other people who take part. The samples will be kept until they are used up. 
3) Qualified researchers can submit a request to use the materials stored in the Biobanks. A 
science committee at the clinical trials organization, and/or the National Cancer Institute, 
will review each request. There will also be an ethics review to ensure that the request is 
necessary and proper. Researchers will not be given your name or any other information 
that could directly identify you. 
4) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
5) Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. Information that could 
directly identify you will not be included. 
 
 
What are the possible risks? 
1) The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise. 
2) There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored about you. 
3) There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique to you. 
The researchers believe the chance that someone will identify you is very small, but the 
risk may change in the future as people come up with new ways of tracing information. 
4) In some cases, this information could be used to make it harder for you to get or keep a 
job or insurance. There are laws against the misuse of genetic information, but they may 
not give full protection. There can also be a risk in knowing genetic information. New 
health information about inherited traits that might affect you or your blood relatives 
could be found during a study. The researchers believe the chance these things will 
happen is very small, but cannot promise that they will not occur. 


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Biobanking for Possible Future Studies 
The researchers will also ask your permission to store and use your samples and related health 
information (for example, your response to cancer treatment, results of study tests and medicines 
you are given) for medical research. The research that may be done is unknown at this time. 
Storing samples for future studies is called “biobanking”. The Biobank is being run by the 
Alliance and supported by the National Cancer Institute. 
 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only. 
2) The list that links the unique code to your name will be kept separate from your sample 
and health information. Any Biobank and Alliance staff with access to the list must sign 
an agreement to keep your identity confidential. 
3) Researchers to whom the Alliance sends your sample and information will not know who 
you are. They must also sign an agreement that they will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be 
used. 
 
 
What are the possible benefits? 
You will not benefit from taking part of this additional study. The researchers, using the samples 
from you and others, might make discoveries that could help people in the future. 
 
 
How will information related to my samples be protected? 
We have many ways to protect the information related to your samples: 
Your samples and information receive a unique code. Researchers only receive coded samples 
and information, and will not be able to link the code to you. Only approved people in the 
Alliance can match you to the code on your samples and related information.  
 
Strict security safeguards are in place to reduce the chance of misuse or unplanned release of 
information. Steps we take include, but are not limited to, restricted access to buildings, rooms 
and freezers housing patient samples, numeric coding of both patient data and samples, and 
password protected access to databases housing patient data. 
 
Before samples are given to researchers, studies are reviewed for the quality of the science and 
for patient protection. Records from research studies can be reviewed by the Cooperative Group, 


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by the sponsor, and by government agencies. This is to make sure the research follows the rules 
of the Cooperative Group and state or federal laws. 
 
In most cases, research results will not be returned to you or your doctor. If research results are 
required to make a decision regarding your treatment on this study then research results may be 
shared with you or your doctor. If research results are published, your name and other personal 
information will not be given. 
 
The Alliance also has a Certificate of Confidentiality from the U.S. Department of Health and 
Human Services. The Certificate protects against the forced release of personal information from 
the Cooperative Group bank or database. 
 
What this means is that Alliance cannot be forced to disclose your identity to any third party. It is 
possible that for some legal proceedings, the Certificate of Confidentiality could be over-ridden 
by a court of law. 
 
 
Making your choice 
The choice to take part is up to you. You may choose not to let us use and store your samples. If 
you decide not to let us store and use your samples, you will still receive the same medical care. 
You may also take part in other research studies. 
To learn more, ask the study staff for the booklet called “Giving Samples for Research" or visit 
http://www.cancer.gov. You may want to read the section “What types of research use samples?”  
If you decide that your samples can be kept, you may change your mind at any time. Contact the 
study staff at your hospital and let them know that you do not want your samples used for 
research. Then, any sample that remains in the bank will no longer be used. Samples or related 
information that have already been given to or used by researchers cannot be returned or 
destroyed. 
Thank you for considering whether to allow your samples to be used for the research described 
above and/or banked for future research. 
Please circle your answer to show whether or not you would like to take part in each 
option:  
 
2.  My coded samples and related coded information may be used in the research described 
above to learn about, prevent, find or treat cancer. This may also include research on 
inherited traits (genes passed on in families).  
Yes____   No____ 
3. 
My coded samples and related coded information may be kept for use in future research 
to learn about, prevent, find or treat cancer. This may also include research on inherited 
traits (genes passed on in families). 
Yes____   No____ 
4. 
My coded samples and related coded information may be kept for use in future research 
to learn about, prevent, find or treat other health problems (for example: diabetes, 


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Alzheimer's disease, or heart disease). This may also include research on inherited traits 
(genes passed on in families).  
Yes____   No____ 
5. 
Someone from my hospital or Alliance may contact me in the future to ask me to take 
part in more research. 
Yes____   No____ 
Are there any costs or payments? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
 
What if I change my mind? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main trial) who will 
let the researchers know. Then, any sample that remains in the bank will no longer be used and 
related health information will no longer be collected. Samples or related information that have 
already been given to or used by researchers will not be returned. 
 
 
What if I have more questions? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
This is the end of the section about optional studies. 
 
 
My Signature Agreeing to Take Part in the Main Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
 


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APPENDIX II: 
SYSTEMIC THERAPIES ALLOWED CONCURRENTLY WITH BEVACIZUMAB 
 
- 
Irinotecan 
- 
Fluorouracil / leucovorin 
- 
Doxorubicin (with close cardiac assessment) 
- 
Carboplatin 
- 
Paclitaxel 
- 
Cyclophosphamide 
- 
Vincristine 
- 
Endocrine therapy for breast or prostate cancer 
- 
Trastuzumab 
- 
Xeloda 
- 
Abraxane 
- 
Pemetrexed  
- 
Erlotinib  
- 
Gemcitabine 
- 
Lapatinib  
- 
Hormonal therapy for breast or prostate cancer 
 
 


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APPENDIX III: 
MR Imaging Remote Central Review  
The following procedures will be followed in cases where institutions opt to utilize real time 
central review of baseline imaging for the determination of patient eligibility (see Section 4.6): 
 
MR imaging data sets of baseline will be reviewed by the A221208 central review panel within 
no more than 72 hours after data receipt to determine patient eligibility.  
IROC will contact the A221208 central review panel, within 24 hours (except weekends and 
holidays) after images being received, for scheduling a real-time remote review. Reviewers’ 
availabilities (at least monthly) need to be sent to the IROC in advance for this purpose. 
IROC notifies both the participating site and Alliance of the central review result within 24 
hours after receiving the result from the central review panel. If there are any uncertainties 
or the participating site disagrees with the first central review result, a second review by either 
another central reviewer or an adjudicator 
 will be performed. 
This process may take additional 24-48 hours turn-around time, and such review result will be 
used as the final decision for the response determinations. The Alliance A221208 trial committee 
makes decisions of A221208 patient inclusion or exclusion, if a participating site eventually 
disagrees with the central review result. 
Response determinations will be based on the centralized review results and NOT on local 
assessment within this trial. 
For any such related questions, participating sites may directly contact the IROC instead of the 
central reviewer(s), via either the trial email at 
 
 
 


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APPENDIX IV: 
A221208 TUMOR IMAGING PROTOCOLS 
 
Recommended 1.5T Protocol* - Option A – Double Dose of Contrast 
 
3D T1w 
Pre 
Ax 2D 
FLAIR 
Ax 2D DWI 
Contrast 
Preload, or 
DCE 
Ax 2D T2w 
3D T1w 
Post 
DSC-MRI 
Sequence 
IR-GRE 
TSE 
EPI 
Option A: 
0.1 mmol/kg  
 
TSE 
IR-GRE 
GRE-EPI:  
Option A:  0.1 
mmol/kg 
Plane 
Axial 
Axial 
Axial 
 
Axial 
Axial 
Axial 
Mode 
3D 
2D 
2D 
 
2D 
3D 
2D 
TR [ms] 
2100 
>6000 
>5000 
 
>3500 
2100 
1000-1500 
TE [ms] 
Min 
100-140 
Min 
 
100-120 
Min 
25-35ms 
TI [ms] 
1100 
2200 
 
 
 
1100 
N/A 
Flip Angle 
10°-15° 
90°/≥ 160° 
90°/180° 
 
90°/≥ 160° 
10°-15° 
60° 
Frequency 
≥ 172 
≥ 256 
128 
 
≥ 256 
≥ 172 
≥ 96 
Phase 
≥ 172 
≥ 256 
128 
 
≥ 256 
≥ 172 
≥ 96 
NEX 
≥ 1 
≥ 1 
≥ 1 
 
≥ 1 
≥ 1 
1 
Pre-bolus 
Time Points 
 
 
 
 
 
 
30-60 
Total Time 
Points 
N/A 
N/A 
N/A 
 
N/A 
N/A 
>120 
FOV 
256 mm 
240 mm 
240 mm 
 
240 mm 
256 mm 
240 mm 
Slice thickness 
≤ 1.5 mm 
≤ 4 mm 
≤ 4 mm 
 
≤ 4 mm 
≤ 1.5 mm 
As needed for optimal 
tumor coverage 
(Typically 3-5mm) 
Gap/spacing 
0 
0 
0 
 
0 
0 
As needed for optimal 
tumor coverage 
(Typically 0-1) 
Diffusion 
Options 
N/A 
N/A 
B=0, 500, and 
1000 s/mm2 ≥3 
directions 
 
N/A 
N/A 
N/A 
Parallel 
imaging 
Up to 2x 
Up to 2x 
Up to 2x 
 
Up to 2x 
Up to 2x 
Up to 2x 
* 
For contrast agent dosing the option chosen must be consistent between the preload and DSC dose (i.e. 
either option 1 or 2 for both injections). 
 
 


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Recommended 1.5T Protocol* - Option B – Single Dose of Contrast 
 
3D T1w 
Pre 
Ax 2D 
FLAIR 
Ax 2D DWI 
Contrast 
Preload, or 
DCE 
Ax 2D T2w 
DSC-MRI 
3D T1w 
Post 
Sequence 
IR-GRE 
TSE 
EPI 
Option B: 0.05 
mmol/kg 
TSE 
GRE-EPI:  
Option B:  0.05 
mmol/kg 
IR-GRE 
Plane 
Axial 
Axial 
Axial 
 
Axial 
Axial 
Axial 
Mode 
3D 
2D 
2D 
 
2D 
2D 
3D 
TR [ms] 
2100 
>6000 
>5000 
 
>3500 
1000-1500 
2100 
TE [ms] 
Min 
100-140 
Min 
 
100-120 
25-35ms 
Min 
TI [ms] 
1100 
2200 
 
 
 
N/A 
1100 
Flip Angle 
10°-15° 
90°/≥ 160° 
90°/180° 
 
90°/≥ 160° 
60° 
10°-15° 
Frequency 
≥ 172 
≥ 256 
128 
 
≥ 256 
≥ 96 
≥ 172 
Phase 
≥ 172 
≥ 256 
128 
 
≥ 256 
≥ 96 
≥ 172 
NEX 
≥ 1 
≥ 1 
≥ 1 
 
≥ 1 
1 
≥ 1 
Pre-bolus 
Time Points 
 
 
 
 
 
30-60 
 
Total Time 
Points 
N/A 
N/A 
N/A 
 
N/A 
>120 
N/A 
FOV 
256 mm 
240 mm 
240 mm 
 
240 mm 
240 mm 
256 mm 
Slice thickness 
≤ 1.5 mm 
≤ 4 mm 
≤ 4 mm 
 
≤ 4 mm 
As needed for 
optimal tumor 
coverage 
(Typically 3-5mm) 
≤ 1.5 mm 
Gap/spacing 
0 
0 
0 
 
0 
As needed for 
optimal tumor 
coverage 
(Typically 0-1) 
0 
Diffusion 
Options 
N/A 
N/A 
B=0, 500, and 
1000 s/mm2 ≥3 
directions 
 
N/A 
N/A 
N/A 
Parallel 
imaging 
Up to 2x 
Up to 2x 
Up to 2x 
 
Up to 2x 
Up to 2x 
Up to 2x 
* 
For contrast agent dosing the option chosen must be consistent between the preload and DSC dose (i.e. 
either option 1 or 2 for both injections). 
 
 


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Recommended 3T Protocol* - Option A – Double Dose of Contrast 
 
3D T1w 
Pre 
Ax 2D 
FLAIR 
Ax 2D DWI 
Contrast 
Preload, or 
DCE 
Ax 2D T2w 
3D T1w 
Post 
DSC-MRI 
Sequence 
IR-GRE 
TSE 
EPI 
Option A:  0.1 
mmol/kg 
 
TSE 
IR-GRE 
GRE-EPI 
Option A:  0.1 
mmol/kg 
 
Plane 
Axial 
Axial 
Axial 
 
Axial 
Axial 
Axial 
Mode 
3D 
2D 
2D 
 
2D 
3D 
2D 
TR [ms] 
2100 
>6000 
>5000 
 
>2500 
2100 
1000- 1500 
TE [ms] 
Min 
100-140 
Min 
 
80-120 
Min 
25-35ms 
TI [ms] 
1100 
2500 
 
 
 
1100 
N/A 
Flip Angle 
10°-15° 
90°/≥ 160° 
90°/180° 
 
90°/≥ 160° 
10°-15° 
60° 
Frequency 
256 
≥ 256 
128 
 
≥ 256 
256 
≥ 96 
Phase 
256 
≥ 256 
128 
 
≥ 256 
256 
≥ 96 
NEX 
≥ 1 
≥ 1 
≥ 1 
 
≥ 1 
≥ 1 
1 
Pre-bolus 
Time Points 
 
 
 
 
 
 
30-60 
Total Time 
Points 
N/A 
N/A 
N/A 
 
N/A 
N/A 
120 
FOV 
256 mm 
240 mm 
240 mm 
 
240 mm 
256 mm 
240mm 
Slice thickness 
1 mm 
3 mm 
3 mm 
 
3 mm 
1 mm 
As needed for optimal 
tumor coverage 
(Typically 3-5mm) 
Gap/spacing 
0 
0 
0 
 
0 
0 
As needed for optimal 
tumor coverage 
(Typically 0-1) 
Diffusion 
Options 
N/A 
N/A 
B=0, 500, and 
1000 s/mm2 ≥3 
directions 
 
N/A 
N/A 
N/A 
Parallel 
imaging 
Up to 2x 
Up to 2x 
Up to 2x 
 
Up to 2x 
Up to 2x 
Up to 2x 
* 
For contrast agent dosing the option chosen must be consistent between the preload and DSC dose (i.e. 
either option 1 or 2 for both injections). 
 
 


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Recommended 3T Protocol* - Option B – Single Dose of Contrast 
 
3D T1w 
Pre 
Ax 2D 
FLAIR 
Ax 2D DWI 
Contrast 
Preload, or 
DCE 
Ax 2D T2w 
DSC-MRI 
3D T1w 
Post 
Sequence 
IR-GRE 
TSE 
EPI 
Option B:  0.05 
mmol/kg  
TSE 
GRE-EPI 
Option B:  0.05 
mmol/kg 
IR-GRE 
Plane 
Axial 
Axial 
Axial 
 
Axial 
Axial 
Axial 
Mode 
3D 
2D 
2D 
 
2D 
2D 
3D 
TR [ms] 
2100 
>6000 
>5000 
 
>2500 
1000- 1500 
2100 
TE [ms] 
Min 
100-140 
Min 
 
80-120 
25-35ms 
Min 
TI [ms] 
1100 
2500 
 
 
 
N/A 
1100 
Flip Angle 
10°-15° 
90°/≥ 160° 
90°/180° 
 
90°/≥ 160° 
60° 
10°-15° 
Frequency 
256 
≥ 256 
128 
 
≥ 256 
≥ 96 
256 
Phase 
256 
≥ 256 
128 
 
≥ 256 
≥ 96 
256 
NEX 
≥ 1 
≥ 1 
≥ 1 
 
≥ 1 
1 
≥ 1 
Pre-bolus 
Time Points 
 
 
 
 
 
30-60 
 
Total Time 
Points 
N/A 
N/A 
N/A 
 
N/A 
120 
N/A 
FOV 
256 mm 
240 mm 
240 mm 
 
240 mm 
240mm 
256 mm 
Slice thickness 
1 mm 
3 mm 
3 mm 
 
3 mm 
As needed for 
optimal tumor 
coverage 
(Typically 3-5mm) 
1 mm 
Gap/spacing 
0 
0 
0 
 
0 
As needed for 
optimal tumor 
coverage 
(Typically 0-1) 
0 
Diffusion 
Options 
N/A 
N/A 
B=0, 500, and 
1000 s/mm2 ≥3 
directions 
 
N/A 
N/A 
N/A 
Parallel 
imaging 
Up to 2x 
Up to 2x 
Up to 2x 
 
Up to 2x 
Up to 2x 
Up to 2x 
* 
For contrast agent dosing the option chosen must be consistent between the preload and DSC dose (i.e. 
either option 1 or 2 for both injections). 
 
 


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Footnote on GE vs. Siemens vs. Philips – T1 pre and post recommendations 
 
DCE Recommended parameters:  
- 
fast T1-weighted spoiled gradient-recalled echo acquisition  
- 
matrix 128 x 128 mm 
- 
3-5 mm slice thickness 
- 
3-6 second temporal resolution 
- 
minimum 5 minutes acquisition time 
- 
IV gadolinium injection of 0.05 mmol/kg, at 2-4 mL/s, should occur 20 seconds or more after the 
start of the imaging series and should be followed by a saline bolus at the same injection rate.   
- 
25-35 deg flip angle 
 
Abbreviations:  
2DFL, 2-dimensional FLASH (fast low angle shot) gradient recalled echo; 
3D, 2-dimensional; 
 A/P, anterior to posterior;  
ADC, apparent diffusion coefficient;  
Ax, Axial;  
DSC, dynamic susceptibility contrast;  
DWI, diffusion-weighted imaging;  
EPI, echo-planar imaging;  
FLAIR, fluid-attenuated inversion recovery;  
FOV, field of view;  
GE-EPI, gradient-echo echo-planar imaging;  
IR-GRE, inversion-recovery gradient-recalled echo.  
MPRAGE, magnetization prepared rapid gradient-echo;  
NEX, number of excitations or averages;  
PD, proton density;  
R/L, right to left;  
SS-EPI, single-shot echo-planar imaging;  
TE, echo time;  
TI, inversion time;  
TR, repetition time;  
TSE, turbo spin-echo. 
 
 


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APPENDIX V: 
PATIENT INFORMATION SHEET 
PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. This booklet is to be completed at each study visit.   
 
2. The booklet contains 3 sets of questions: 
a. M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) (28 questions) 
b. Dexamethasone Symptoms Questionnaire-Chronic (22 questions) 
c. Linear Analogue Self Assessment (LASA) (5 questions) 
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions. 
  
5. Bring booklet with you to your next clinical visit.  It is very important that you return the booklet 
to us, whether you finish the study or not. 
 
Thank you for taking the time to help 
 
 
 


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APPENDIX VI: 
MD ANDERSON SYMPTOM INVENTORY-BT 
 
 
 


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APPENDIX VII: 
DEXAMETHASONE SYMPTOMS QUESTIONNAIRE-CHRONIC 
 
Dexamethasone Symptom Questionnaire –Chronic (DSQ-Chronic)  
PDMS Number:    Patient Initials:                                 
 
 
Today’s date (day, month, year):     
 
 
 
           
We are interested in some things about you and your health.  Please answer all the questions by circling the 
number that best applies to you.  There are no “right” or “wrong” answers.  The information that you provide 
will remain strictly confidential.   IN THE LAST WEEK:  
Patient question 
Not 
at 
all 
A little 
Quite 
a 
bit 
Very much 
1. Did you have indigestion/heartburn/reflux or discomfort 
in the upper abdomen?   
1 
2 
3 
4 
2. Did you have trouble with sleep? (getting or staying 
asleep)? 
1 
2 
3 
4 
3. Have you felt nauseated? 
1 
2 
3 
4 
4. Have you vomited? 
1 
2 
3 
4 
5. Have you lacked appetite? 
1 
2 
3 
4 
6. Have you had increased appetite? 
1 
2 
3 
4 
7. Have you had hiccups? 
 
1 
2 
3 
4 
8. Have you lost weight? 
 
1 
2 
3 
4 
9. Have you gained weight? 
 
1 
2 
3 
4 
10. Have you felt agitated/nervous? 
 
1 
2 
3 
4 
11. Have you had a rash/acne on your face? 
 
1 
2 
3 
4 
12. Have you had thrush/yeast infection in your mouth? 
 
1 
2 
3 
4 
13. Have you noticed increased roundness of your face? 
 
1 
2 
3 
4 
14. Have you experienced low mood, sadness, depression 
and/or easy crying? 
 
1 
2 
3 
4 
15. Have you experienced increased levels of anger or 
irritability? 
 
1 
2 
3 
4 
16. Have you had difficulty standing from a seated position 
or walking up stairs?  
1 
2 
3 
4 
 
 
 
 
 
 


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Patient question 
Not 
at 
all 
A little 
Quite 
a 
bit 
Very much 
17. Have you had problems with your skin being fragile, 
developed stretch marks or easily bruised? 
1 
2 
3 
4 
18. Have you had headaches? 
1 
2 
3 
4 
19. Are you Diabetic? 
If no, go to Question 21 
 
Yes / No   (please circle) 
 
20a. If yes, was the diabetes diagnosed since you started 
corticosteroids (e.g. dexamethasone, prednisone) 
 
 
Yes / No   (please circle) 
20b. If yes, have you had trouble controlling your blood 
sugars? 
 
1 
2 
3 
4 
 
Patient question 
21.  What other problems have you noticed due to corticosteroids? 
___________________________________________________________________________________________
______________ 
 
___________________________________________________________________________________________
______________ 
 
 
22. Of all the symptoms you’ve experienced due to corticosteroids, please list the 3 you have found the most 
bothersome: 
1. (Most bothersome):_________________________________ 
2. (2nd most bothersome):_______________________________ 
3. (3rd most bothersome):_______________________________ 
 
 
 
 
Patient Signature 
 
 


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APPENDIX VIII: 
LINEAR ANALOGUE SELF ASSESSMENT (LASA) 
Directions: Please circle the number (0-10) best reflecting your response to the following that 
describes your feelings during the past week, including today. 
 
How would you describe: 
 
1. your overall Quality of Life? 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
2. your overall mental (intellectual) well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
3. your overall physical well being?  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
4. your overall emotional well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
5. your overall spiritual well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
 
 
 
 


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APPENDIX IX: 
CORTICOSTEROID MEDICATION LOG 
 
Corticosteroid Medication Log  
 
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
While participating in this study, you will be asked to gradually reduce your corticosteroid 
treatment and fill out the following pill diary to record your schedule of reduction. 
 
SPECIAL INSTRUCTIONS  
1. Take your corticosteroid tablets orally, as instructed by your doctor with or without food. 
2. If a dose is missed, please take the dose as soon as possible, but only if there are 6 or more hours 
remaining before the next dose (if taking two doses per day), or 12 or more hours remaining 
before the next dose (if taking only one dose per day).  
3. If vomiting occurs after taking your corticosteroid, do not take a replacement dose on that day. 
Resume at the next scheduled dose 
4. Corticosteroid tablets should be stored at room temperature 
 
 


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    CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
 
Dose of 
medication 
DATE 
TIME 
TIME 
Number of 
tablets taken 
(AM/PM) 
Comments 
Example 
Dexamethasone 
4 mg 
07/01/2015 
9:00 
AM 
9:00 
PM 
2/2 
 
1 
 
 
 
 
AM 
 
PM 
 
 
2 
 
 
 
 
AM 
 
PM 
 
 
3 
 
 
 
 
AM 
 
PM 
 
 
4 
 
 
 
 
AM 
 
PM 
 
 
5 
 
 
 
 
AM 
 
PM 
 
 
6 
 
 
 
 
AM 
 
PM 
 
 
7 
 
 
 
 
AM 
 
PM 
 
 
8 
 
 
 
 
AM 
 
PM 
 
 
9 
 
 
 
 
AM 
 
PM 
 
 
10 
 
 
 
 
AM 
 
PM 
 
 
11 
 
 
 
 
AM 
 
PM 
 
 
12 
 
 
 
 
AM 
 
PM 
 
 
13 
 
 
 
 
AM 
 
PM 
 
 
14 
 
 
 
 
AM 
 
PM 
 
 
15 
 
 
 
 
AM 
 
PM 
 
 
16 
 
 
 
 
AM 
 
PM 
 
 
17 
 
 
 
 
AM 
 
PM 
 
 
18 
 
 
 
 
AM 
 
PM 
 
 
19 
 
 
 
 
AM 
 
PM 
 
 
20 
 
 
 
 
AM 
 
PM 
 
 
21 
 
 
 
 
AM 
 
PM 
 
 
22 
 
 
 
 
AM 
 
PM 
 
 
23 
 
 
 
 
AM 
 
PM 
 
 
24 
 
 
 
 
AM 
 
PM 
 
 
25 
 
 
 
 
AM 
 
PM 
 
 
26 
 
 
 
 
AM 
 
PM 
 
 
27 
 
 
 
 
AM 
 
PM 
 
 
28 
 
 
 
 
AM 
 
PM 
 
 
29 
 
 
 
 
AM 
 
PM 
 
 
30 
 
 
 
 
AM 
 
PM 
 
 
31 
 
 
 
 
AM 
 
PM 
 
 
32 
 
 
 
 
AM 
 
PM 
 
 
33 
 
 
 
 
AM 
 
PM 
 
 
34 
 
 
 
 
AM 
 
PM 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________    Date:__________  
Comments:_____________________________________________________________ 
 
 
 


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APPENDIX X: 
INTELLECTUAL PROPERTY OPTION TO COLLABORATORS 
The NCI’s “Cancer Therapy Evaluation Program Intellectual Property Option to Collaborators” terms of 
award modifications (as revised April 1, 2011) apply to this study and to any institutions or investigators 
participating in this study or any future study that uses specimens treated with the bevacizumab being 
provided for this study.  Under the terms of the Option, Genentech shall be considered a “Collaborator” 
and Study Drug bevacizumab shall be considered an “Agent” within the meaning of the Option.