Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma
Phase: PHASE2
Conditions: Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Sponsor: Radiation Therapy Oncology Group

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RTOG 1205; version date 10/3/16 
 
RTOG 1205 
 
RANDOMIZED PHASE II TRIAL OF CONCURRENT BEVACIZUMAB AND  
RE-IRRADIATION VERSUS BEVACIZUMAB ALONE AS TREATMENT FOR 
RECURRENT GLIOBLASTOMA 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance for Clinical Trials in Oncology; ECOG-ACRIN Medical Group; and 
SWOG.  
 
Study Chairs (8/24/15) 
Principal Investigator/Radiation Oncology 
Christina Tsien, MD 
Department of Radiation Oncology 
Washington University in St. Louis 
4921 Parkview Place, Campus Box 8224 
St. Louis, MO  63110 
Phone: 314-362-8567/Fax: 314-362-8521 
Email: ctsien@radonc.wustl.edu 
 
Radiation Oncology Co-Chair 
Adam P. Dicker, MD, PhD 
Department of Radiation Oncology 
Jefferson Medical College  
of Thomas Jefferson University 
111 South 11th Street 
Philadelphia, PA 19107-5097   
Phone: 215-955-6700/Fax: 215-503-0013 
E-mail: adam.dicker@jefferson.edu 
 
Medical Oncology Co-Chair 
Jeffrey Raizer, MD 
Northwestern University 
710 N. Lake Shore Drive 
Abbott Hall, Room 1123 
Chicago, IL 60611 
Phone: 312-503-4724/Fax: 312-908-5073 
E-mail: Jraizer@nm.org 
 
Medical Physics Co-Chair 
Martha M. Matuszak, PhD 
University of Michigan 
1500 E. Medical Center Drive 
Ann Arbor, MI  48109 
Phone: 734-936-4309/Fax: 734-936-7859 
E-mail: marthamm@med.umich.edu 
 
Senior Statistician 
Peixin Zhang, PhD 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Phone: 215-940-8881/Fax: 215-928-0153 
Email: ZhangP@NRGOncology.org 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 8 
October 3, 2016 
October 17, 2016 
Closure 
Amendment 7 
 
September 3, 2015 
 
April 28, 2016 
Amendment 7 
September 3, 2015 
September 21, 2015 
Amendment 6 
August 24, 2015 
September 21, 2015 
Amendment 5 
October 9, 2014 
November 3, 2014 
Amendment 4 
June 23, 2014 
November 3, 2014 
Amendment 3 
April 15, 2014 
May 1, 2014 
Amendment 2 
February 27, 2014 
May 1, 2014 
Amendment 1 
November 20, 2013 
December 4, 2013 
Activation 
October 10, 2012 
December 20, 2012 
Group Activation 
October 10, 2012 
November 5, 2012 

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RTOG 1205; version date 10/3/16 
 
 
 
 
Protocol Agents (11/20/13) 
Agent 
Supply 
NSC #  
IND # 
Bevacizumab 
Commercial 
N/A 
Exempt 
 
Participating Sites (11/20/13) 
 US Only 
 Canada Only 
 US and Canada 
 Approved International Member Sites 
 
 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by NRG Oncology nor does NRG Oncology 
assume any responsibility for unauthorized use of this protocol. 
 
 

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RTOG 1205; version date 10/3/16 
 
(10/3/16) 
CTSU CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation can 
be submitted to the CTSU via: 
 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.
org (regulatory documentation 
only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
For regulatory questions call 
the CTSU Regulatory Help 
Desk at 1-866-651-CTSU 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at ctsucontact@westat.com 
See Protocol Section 12.0 for 
data submission 
 
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 https://www.ctsu.org.  
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. 
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of 
the Lead Protocol Organization. 
 
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 – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 

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RTOG 1205; version date 10/3/16 
 
 
 
 
TABLE OF CONTENTS 
 
 
SCHEMA  .................................................................................................................................................. 6 
ELIGIBILITY CHECKLIST  ........................................................................................................................ 7 
1.0 
INTRODUCTION ......................................................................................................................... 12 
1.1  
Overview ..................................................................................................................................... 12 
1.2  
Safety, Efficacy, and Rationale for Combination of Bevacizumab and Re-Irradiation ................ 14 
 
2.0 
OBJECTIVES .............................................................................................................................. 15 
2.1 
Primary Objective ........................................................................................................................ 15 
2.2 
Secondary Objectives ................................................................................................................. 15 
 
3.0 
PATIENT SELECTION ................................................................................................................ 15 
3.1 
Conditions for Patient Eligibility ................................................................................................... 15 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 17 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................. 17 
4.1 
Highly Recommended Evaluations ............................................................................................. 17 
 
5.0 
REGISTRATION PROCEDURES ............................................................................................... 18 
5.1  
Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) Treatment Approach) 18 
5.2 
Pre-Registration Requirements for IMRT Treatment Approach .................................................. 19 
5.3 
Pre-Registration Requirements for 3D-CRT Treatment Approach ............................................. 19 
5.4 
Pre-Registration Requirements for Proton Treatment Approach ................................................ 19 
5.5 
Digital RT Data Submission Using TRIAD .................................................................................. 20 
5.6  
Regulatory Pre-Registration Requirements ................................................................................ 21 
5.7  
Registration ................................................................................................................................. 22 
 
6.0 
RADIATION THERAPY ............................................................................................................... 23 
6.1 
Dose Specifications ..................................................................................................................... 23 
6.2 
Technical Factors [Equipment, energies] .................................................................................... 24 
6.3 
Localization, Simulation, and Immobilization .............................................................................. 24 
6.4 
Treatment Planning/Target Volumes .......................................................................................... 24 
6.5 
Critical Structures ........................................................................................................................ 24 
6.6 
Documentation Requirements ..................................................................................................... 26 
6.7 
Compliance Criteria ..................................................................................................................... 26 
6.8 
R.T. Quality Assurance Reviews ................................................................................................. 26 
6.9 
Radiation Therapy Adverse Events............................................................................................. 26 
6.10 
Radiation Therapy Adverse Event Reporting .............................................................................. 26 
 
7.0 
DRUG THERAPY ........................................................................................................................ 26 
7.1 
Treatment .................................................................................................................................... 26 
7.2 
Bevacizumab Agent Information ................................................................................................. 27 
7.3 
Bevacizumab Dose Modifications ............................................................................................... 33 
7.4 
Modality Review .......................................................................................................................... 35 
7.5 
Adverse Events ........................................................................................................................... 36 
7.6 
CTEP-AERS Expedited Reporting Requirements ...................................................................... 37 
 
8.0 
SURGERY ................................................................................................................................... 39 
 
9.0 
OTHER THERAPY ...................................................................................................................... 39 
9.1 
Permitted Supportive Therapy .................................................................................................... 39 

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RTOG 1205; version date 10/3/16 
 
9.2 
Non-permitted Supportive Therapy ............................................................................................. 39 
 
10.0 
TISSUE/SPECIMEN SUBMISSION ............................................................................................ 39 
10.1 
Tissue/Specimen Submission ..................................................................................................... 39 
10.2 
Specimen Collection for Banking and Translational Research  .................................................. 39 
10.3 
Reimbursement  .......................................................................................................................... 41 
10.4 
Confidentiality/Storage ................................................................................................................ 42 
 
11.0 
PATIENT ASSESSMENTS ......................................................................................................... 42 
11.1 
Study Parameters ....................................................................................................................... 42 
11.2 
Measurement of Response ......................................................................................................... 42 
11.3  
Criteria for Evaluation of Therapy Effectiveness ......................................................................... 43 
11.4 
RANO Response Criteria ............................................................................................................ 43 
11.5  
Criteria for Discontinuation of Protocol Treatment ...................................................................... 45 
 
12.0 
DATA COLLECTION ................................................................................................................... 46 
12.1 
Summary of Data Submission ..................................................................................................... 46 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 46 
 
13.0 
STATISTICAL CONSIDERATIONS ............................................................................................ 47 
13.1  
Study Endpoints .......................................................................................................................... 47 
13.2  
Sample Size and Power Justification .......................................................................................... 47 
13.3 
Patient Accrual ............................................................................................................................ 47 
13.4 
Patient Stratification and Randomization .................................................................................... 48 
13.5  
Analyses Plans ............................................................................................................................ 48 
13.6 
Gender and Minorities ................................................................................................................. 49 
 
REFERENCES ........................................................................................................................................ 51 
APPENDIX I ............................................................................................................................................ 54 
APPENDIX II ........................................................................................................................................... 56 
APPENDIX III .......................................................................................................................................... 57 
 

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RTOG 1205; version date 10/3/16 
 
NRG ONCOLOGY 
 
 
RTOG 1205 
 
Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus  
Bevacizumab Alone as Treatment for Recurrent Glioblastoma 
 
 
SCHEMA (4/15/14) 
 
Bevacizumab-Naïve Recurrent GBM Patients: 
 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
 
Age 
1. <50 
2. ≥50 
 
Karnofsky performance 
status 
1. 60 
2. 70-80 
3. 90-100 
 
Recent resection 
1.Yes 
2. No/biopsy only 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
 
 
 
Arm 1: Bevacizumab alone q 2 weeks (control arm) 
 
Arm 2: Hypofractionated radiotherapy 35 Gy in 10 
fractions with concurrent Bevacizumab q 2 weeks 
(experimental arm) 
 
 
 
See Section 5.0 for radiation therapy credentialing requirements. See Section 7.0 for details/doses of 
bevacizumab. 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Patients with recurrent glioblastoma or variant (gliosarcoma or giant cell glioblastoma etc).  
 
 
 
 
 
 
 
 
 
 
Required Sample Size: 178 
  

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RTOG 1205; version date 10/3/16 
 
ELIGIBILITY CHECKLIST (10/9/14) 
(page 1 of 5) 
 
NRG Oncology Institution #  
RTOG 1205 
Case #  
 
 
 
(Y) 
1. Does the patient have histologically proven diagnosis of glioblastoma or variants 
per section 3.1.1? 
 
 
(Y/NA) 
2. Does patient have progression on contrast-enhanced MRI/CT within 21 days 
prior to registration as defined in section 3.1.1, bullet 1? 
 
 
(Y/N) 
3. Is there an interval of 6 months or greater between completion of prior 
radiotherapy and registration? 
 
 (Y) If No, was one or more of the criteria in section 3.1.1 a, b or c met?      
 
 
(Y/N) 
4. Does the patient have a prior history of standard dose CNS radiation as defined 
in section 3.1.2? 
 
 (Y) If No, was one or more of the criteria in section 3.1.1 a, b or c met?      
 
 
(Y/NA) 
5. Has patient recovered from the toxic effects of prior therapy? 
 
 
(Y/NA) 
6. If patient received prior investigational agent(s) and/or prior cytotoxic therapy was 
there a minimum time of 28 days prior to registration? With the exceptions of 
vincristine (minimum time of 14 days), nitrosoureas (minimum time of 42 days) 
and procarbazine (minimum time of 21 days) 
 
 
(Y/N) 
7. Did the patient have a recent resection (within 5 weeks prior to registration) of the 
glioblastoma? 
If Y: 
_______(Y) Has the patient recovered from the effects of surgery? 
_______(Y/NA) Has a minimum of 7 days elapsed for core or needle biopsy? 
_______(Y) Was a postoperative or intraoperative scan performed prior to 
registration ? 
 
 
(Y) 
8. Was a history and physical examination completed within 14 days prior to 
registration? 
 
 
(Y) 
9. Is the Karnofsky performance status greater than or equal to 60 within 14 days 
prior to registration? 
 
 
(Y) 
10. Is the patient’s age ≥18? 
 
 
(Y) 
11. Was a CBC with differential obtained within 14 days prior to registration with 
adequate bone marrow function as defined in section 3.1.8? 
 
 
(Y) 
12. Is there adequate liver and renal function within 14 days prior to registration as 
defined in section 3.1.8? 
 
 
(N) 
13. Does the patient have proteinuria within 14 days of registration as defined in 
section 3.1.9? 
 
 
(N/NA) 
14. Is the patient pregnant or nursing? 
 

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RTOG 1205; version date 10/3/16 
 
ELIGIBILITY CHECKLIST (9/3/15) 
(page 2 of 5) 
 
NRG Oncology Institution #  
RTOG 1205 
Case #   
 
 
 
(Y/NA) 
15. Was a pregnancy test done within 7 days before registration? 
 
 
(Y/NA) 
16. Is the patient willing to practice effective contraception while on study treatment 
and 6 months after? (women of childbearing potential and men) 
 
 
(Y/N) 
17. Is the patient on full dose anticoagulants? 
If Y: 
_______ (N) Does the patient have active bleeding or a pathological condition 
that carries a high risk of bleeding? 
_______ (Y) Is there an in-range INR (usually between 2 and 3) on a stable dose 
of oral anticoagulant or on a stable dose of low molecular weight 
heparin within 14 days prior to registration? 
 
 
(Y) 
18. Did the patient provide study-specific informed consent prior to study entry? 
 
 
(N) 
19. Has the patient had more than 3 relapses? 
 
 
(N) 
20. Is there  infratentorial or leptomeningeal evidence of recurrent disease? 
 
 
(N) 
21. Does the patient have a recurrent or persistent tumor greater than 6 cm in 
maximum diameter? 
 
 
(N) 
22. Has the patient had prior therapy with an inhibitor of VEGF or VEGFR (including 
bevacizumab)? 
 
 
(Y/N) 
23. Has the patient had prior invasive malignancy (except non- melanomatous skin 
cancer)? 
If Y: 
_______ (Y) Has the patient been disease free for a minimum of 1 year 
 
 
(N) 
24. Does the patient have severe active co-morbidity as in defined in 3.2.6.? 
 
 
(N) 
25. Does the patient have prior allergic reaction to the study drug (Bevacizumab)? 
 
 
(N) 
26. Does the patient have prior history of hypertensive crisis or hypertensive 
encephalopathy? 
 
 
(N) 
27. Does the patient have a history of a non-healing wound, ulcer or bone fracture 
within 90 days (3 months) prior to registration? 
 
 
(N) 
28. Has the patient had gastrointestinal bleeding or any other hemorrhage/bleeding 
event CTCAE, v.4 grade 3 or greater within 30 days prior to registration? 
 
 
(N) 
29. Has the patient had major surgical procedure, open biopsy or significant 
traumatic injury within 28 days prior to registration (with the exception of 
craniotomy)?   
 

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RTOG 1205; version date 10/3/16 
 
ELIGIBILITY CHECKLIST (11/5/12) 
(page 3 of 5) 
NRG Oncology Institution #  
RTOG 1205 
Case #   
 
 
The following questions will be asked at Study Registration:  
IMRT CREDENTIALING AND IGRT CREDENTIALING (for reduced margins only) IS REQUIRED 
BEFORE REGISTRATION. PROTON CREDENTIALING IS REQUIRED IF USING PROTONS. 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical oncologist’s name 
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her urine to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 

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RTOG 1205; version date 10/3/16 
 
ELIGIBILITY CHECKLIST (11/5/12) 
(page 4 of 5) 
NRG Oncology Institution #  
RTOG 1205 
Case #  
 
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 23. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease).  
 
              (Y/N) 24. 
Have you obtained the patient's consent for his or her urine to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 25. 
Have you obtained the patient's consent to allow someone from this institution to 
contact him or her in the future to take part in more research?  
  
               
26. 
Patient’s age (<50/≥50): 
 
 
(1) <50 
 
 
(2) ≥50 
 
               
27. 
Karnofsky performance status: 
(1) 70-80 
(2) 90-100 
(3) 60 
 
              
28.   
(Y/N-biopsy only): Recent resection 
  
              (Y/N) 29. 
Did the patient participate in a previous RTOG GBM trial that collected MGMT  
methylation status? 
 
If yes, what was the RTOG study number? 
 
If yes, what was the patient ID number on the RTOG trial mentioned above? 
 
              (Y/N) 30. 
Did the patient have MGMT analysis performed as routine care by a treating 
physician outside of an RTOG GBM trial (or that was collected during an RTOG 
trial but not required per protocol)? 
 
If yes, what was the result of MGMT analysis? 
(1) Methylated 
(2) Unmethylated 
(3) Invalid 
 
              (Y/N) 31. 
Will IGRT be used for patient positioning? 
 
              (Y/N) 32. 
Will IGRT be used for patient positioning and margin reduction? 
 
33.  
Specify treatment techniques/machine: 
        
(1) 3D-CRT 
 
(2) IMRT 
       
(3) Cyberknife 
       
(4) Protons 
 

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RTOG 1205; version date 10/3/16 
 
 
ELIGIBILITY CHECKLIST (11/5/12) 
(page 5 of 5) 
NRG Oncology Institution #  
RTOG 1205 
Case #  
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 

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RTOG 1205; version date 10/3/16 
 
1.0 
INTRODUCTION 
1.1  
Overview 
Glioblastoma is the most common lethal primary brain tumor in adults (Brandes 2003). Despite 
optimal treatment including surgery, chemotherapy, and radiation, median survival of patients 
with glioblastoma is 14 months. The majority of patients will develop recurrence at a median of 8 
months post treatment (Stupp 2005). 
 
Patients with recurrent glioblastoma have poor prognoses and have been treated with various 
modalities including resection, chemotherapy, or re-irradiation. Prior phase II chemotherapy trials 
were associated with a 6-month progression-free survival of 15% and a median survival of 25 
weeks (Wong 1999, Carson 2007). In 2009, bevacizumab, a humanized monoclonal antibody 
which targets VEGF, was approved by the FDA as a single agent for recurrent glioblastoma. 
 
Vascular proliferation is a notable feature in glioblastoma; therefore, targeting the vascular 
endothelial growth factor (VEGF) is a logical treatment approach (Jain 2007). Anti-VEGF therapy 
can inhibit new vessel growth, lead to vascular regression and vascular normalization, as well as 
directly affect tumor cell function (Ellis 2008). Antiangiogenic therapies rapidly normalize leaky 
abnormal tumor vessels and therefore decrease vasogenic edema as well as the patient’s 
dependence on corticosteroids. This effect may lead to significant improvement in the patient’s 
quality of life (Vredenburgh 2010). 
 
Several clinical trials have evaluated the safety and efficacy of bevacizumab alone or in 
combination with chemotherapy in recurrent gliomas. A single-institution phase II trial 
demonstrated increased response rates and prolonged 6-month progression-free survival 
(Vredenburgh 2007a; Vredenburgh 2007b). Thirty-two patients with recurrent grade III-IV glioma 
(Vredenburgh 2007a) received bevacizumab and irinotecan, showing promising activity with a 6- 
month progression-free survival of 38%. The median overall survival limited to grade IV patients 
was 9.2 months. 
 
In a phase II trial, 48 heavily pretreated recurrent glioblastoma patients received single-agent 
bevacizumab, with a median progression-free survival of 16 weeks, 6-month progression-free 
survival of 29%, and a response rate of 35% based on Macdonald criteria (Kreisl 2009). A 
subsequent randomized, non-comparative phase II trial (BRAIN study) was performed and led to 
the FDA approval of single-agent bevacizumab. Patients with recurrent glioblastoma in first or 
second relapse were randomized to either bevacizumab 10 mg/kg every 2 weeks alone (85 
patients) or in combination with irinotecan (82 patients). The estimated 6-month progression-free 
survival rate was 42.6% and 50.3%, respectively. Median overall survival was 9.2 and 8.7 
months, respectively. The majority of patients in this trial had partial or complete resection (91.8% 
and 91.5%, respectively). A minority of patients (8% and 13%, respectively) were enrolled ≤3 
months following radiotherapy, while 20% and 10%, respectively, were enrolled ≤3 months 
following surgery. Overall, treatment was well tolerated; adverse events related to bevacizumab 
included hypertension, fatigue, and deep vein thrombosis. There was no clear increase in efficacy 
with the addition of irinotecan; however, there was increased toxicity (Friedman 2009). Despite 
the significant increase in response rates and 6-month progression-free survival with single-agent 
bevacizumab, the median overall survival remains 8 to 9 months. 
 
Several phase II trials have attempted to combine bevacizumab with other chemotherapy agents, 
with no significant improvement in outcome. These agents include daily low-dose temozolomide, 
etoposide, erlotinib, and nitrosourea. In fact, these trials identified increased toxicity with no 
improvement in efficacy (Verhoeff 2010; Gilbert 2009; Hasselbach 2010; Reardon 2009; 
Sathornsumetee 2010). Response rates to chemotherapy following bevacizumab failure are 
exceptionally poor. Salvage chemotherapy provided only transient tumor control with an 
estimated 6-month progression-free survival of 2% (Quant 2009). Enrollment in a clinical trial for 
patients with recurrent glioblastoma should be the standard clinical practice and highlights the 
pressing need to identify novel strategies. 
 

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RTOG 1205; version date 10/3/16 
 
Salvage re-irradiation has long been offered as a treatment modality (Hudes 1999, Kim 1997, 
Laing 1993, Grosu 2005, Lederman 2000). Prior results obtained from over 300 glioblastoma 
patients confirmed a 6-month progression-free survival ranging from 28% to 39% and a median 
1-year overall survival of 26% ranging from 18% to 46% (Combs 2005, Nieder 2008, Fogh 2010). 
However, recent advances in RT techniques including fractionated stereotactic radiotherapy 
(FSRT), protons, and IMRT, now allow for highly conformal treatment, which has the potential to 
significantly reduce the toxicity associated with re-irradiation (Fogh 2010).  
 
Several studies report an improvement in 6-month functional status as well as a reduction and 
discontinuation of corticosteroid usage (Laing 1993; Kim 1997; Nieder 2008; VanderSpek 2008). 
Late CNS toxicity was uncommon especially following FSRT. Combs et al reported on 172 
recurrent gliomas with a median time from RT to re-radiation of 10 months. Median tumor size for 
glioblastoma tumors was 47.7 cc. RT dose was 36 Gy in 2 Gy fractions given 5 fractions per 
week. Progression-free survival for 59 glioblastoma patients following re-irradiation was 5 
months, with a median overall survival of 8 months. Factors associated with improved outcome 
included histology, extent of initial resection, and age at primary diagnosis. Treatment was well 
tolerated, with 1 incidence of radiation necrosis (Combs 2005). 
 
Fogh et al reported on 147 high-grade glioma patients treated with FSRT delivering 35 Gy in 10 
fractions. Median time to re-irradiation was 8 months. Somewhat surprisingly, and in contrast with 
other reports, patients who received irradiation within 6 months of initial diagnosis did not 
demonstrate an inferior survival. Median tumor volume was 22 cc. Eighty-four patients underwent 
salvage surgery prior to re-irradiation. Forty-eight patients received concurrent chemotherapy 
such as temozolomide. Median survival was 11 months. Treatment was well tolerated. 
Multivariate analysis suggested younger age and smaller tumor volumes were associated with 
improved outcome (Fogh 2010). 
 
There is a clear rationale for combining bevacizumab with re-irradiation to increase the 
therapeutic ratio through increased antitumor and antivascular effects (Provencio 2010; Lee 
2000). Preclinical data suggest that VEGF is up-regulated in response to radiation; therefore, the 
use of antiangiogenic agents combined with radiation may sensitize both tumors and associated 
vasculature to RT (Gorski 1999). Preclinical studies have demonstrated that antiangiogenic 
agents may uniquely target the radio-resistant and highly tumorigenic cancer stem cells by 
disrupting vascular niches harboring cancer stem cells (Hovinga 2010). Due to its potential 
radioprotective effects, especially the phenomenon of vascular stabilization, the addition of 
bevacizumab may also reduce the toxicity associated with re-irradiation by reducing risk of 
radiation necrosis (Levin 2011). Several phase II and phase III trials have reported on the initial 
safety and tolerability of combining bevacizumab and temozolomide with radiotherapy in primary 
glioblastoma patients (Lai 2010; Vredenburgh 2011).  
 
Preliminary evidence suggests improved outcome with the addition of concurrent and adjuvant 
bevacizumab to re-irradiation. Gutin et al published results regarding 25 patients with recurrent 
grade III-IV gliomas using FSRT and concurrent bevacizumab; with a reported 6-month 
progression-free survival of 65% and median overall survival of 12.5 months. Median time to 
radiation was 15 months. Enhancing tumor volume was ≤ 3.5 cm in maximum diameter. 
Treatment was well tolerated. There was no incidence of radiation necrosis and no additional 
need for corticosteroids following radiation (Gutin 2009). 
 
The Duke group recently reported its single-institution retrospective data on 63 patients with 
recurrent high-grade gliomas, including 49 glioblastoma patients treated with re-irradiation using 
SRS techniques combined with bevacizumab therapy. The treatment regimen was noted to be 
well tolerated. Median time to re-irradiation was 19.6 months. Mean number of systemic therapies 
prior to SRS was 3.6 and mean number of therapies following SRS was 2.9. Median target 
volume was 4.8 cc. The 1-year overall survival in glioblastoma patients who received adjuvant 
(concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant 

14 
RTOG 1205; version date 10/3/16 
 
bevacizumab (p= 0.005). Both age < 50 years and performance status > 70 were associated with 
improved overall survival (Cuneo 2011).  
 
Retrospective single-institutional experience in high-grade glioma patients treated with FSRT 
using 36 Gy in 18 fractions, with concurrent bevacizumab, followed by maintenance bevacizumab 
was recently reported. Overall survival appeared better in patients receiving bevacizumab (12.1 
months) than those who had received either re-irradiation alone or concurrent with temozolomide 
(8.0 months). Treatment was well tolerated, with no incidence of radiation necrosis and one 
incidence of wound dehiscence (Niyazi 2010). 
 
Based on the long history and clinical experience of re-irradiation of recurrent glioblastoma, we 
wish to obtain prospective multi-institutional safety and efficacy data regarding the combination of 
bevacizumab and re-irradiation in improving overall survival in bevacizumab-naïve recurrent 
glioblastoma patients. 
 
Therefore, the primary aim of this study is to provide preliminary evidence of an overall survival 
benefit with the addition of re-irradiation in combination with bevacizumab for patients with 
recurrent glioblastoma in a multi-institutional setting, in the context of a phase II randomized trial 
that will require further confirmation in a phase III trial. 
1.1.1  
Significance of the Current Study 
RTOG 1205 is important in potentially changing the paradigm of treatment in recurrent 
glioblastoma. Despite numerous randomized chemotherapy studies as well as novel targeted 
agents studied to date, no regimens have shown significant improvement in overall survival 
compared to bevacizumab alone. Single-agent bevacizumab is currently the mainstay of 
treatment in recurrent glioblastoma, but the overall survival remains limited at approximately 8 to 
9 months. Responses to therapy following bevacizumab failures are extremely poor. Preclinical 
data suggest that a resistant and invasive phenotype develops following bevacizumab failure, and 
salvage therapy remains ineffective in this context; therefore, this latter patient group will NOT be 
included in our trial. 
 
The goal of this study is to test the hypothesis that re-irradiation combined with an effective 
targeted agent, bevacizumab, will improve the overall survival of bevacizumab-naïve recurrent 
glioblastoma patients. This trial will also be the first prospective multi-institutional study to 
evaluate survival, response, and patterns of failure following re-irradiation. Further, if this trial is 
positive, the implication is that higher radiotherapy doses are potentially feasible and safe, and 
therefore, the addition of bevacizumab and re-irradiation in recurrent gliomas may provide the 
preliminary proof of principle to further study dose-escalated radiation in combination with 
bevacizumab in the upfront treatment of glioblastoma. Additionally, this trial could also potentially 
set the stage for testing additional chemotherapeutic and/or targeted agents with radiation in the 
recurrent glioblastoma setting. This could provide preliminary clinical data to move promising 
agents in the upfront setting in a more efficient manner. 
 
1.2  
Safety, Efficacy, and Rationale for Combination of Bevacizumab and Re-Irradiation 
The safety and efficacy of hypofractionated stereotactic irradiation in combination with 
bevacizumab for recurrent glioblastoma was reported by Gutin et al (2009). The results were 
promising, with a 6-month progression-free survival of 65% and a median overall survival of 12.5 
months. There were no incidences of radiation necrosis noted and there was no need for 
additional corticosteroids following treatment. The treatment was also safe and well tolerated. 
Grade 3 toxicity, including intratumor hemorrhage, wound dehiscence, and bowel perforation, 
was noted in 12% of patients. Retrospective results of hypofractionated stereotactic radiation 
alone using 35 Gy in 10 fractions in 147 high-grade glioma patients were reported by Fogh et al 
(2010). Median survival was 11 months. This underscores the safety and tolerability of this 
approach. 
 
RTOG 0625, a phase II randomized study of bevacizumab and irinotecan or temozolomide, 
enrolled 123 patients and was recently published in abstract form (Gilbert 2009). ACRIN 6637 

15 
RTOG 1205; version date 10/3/16 
 
provided central review of all pre-treatment MRIs. Analysis of the pre-treatment MRI confirmed 
that over 90% of cases had an initial post-contrast T1 MRI tumor diameter of 5 cm or less. A 
statistical analysis was performed using this inclusion criteria (limiting to 5 cm or less), and 
demonstrated a median overall survival of 9.4 months for patients receiving bevacizumab and 
temozolomide and 7.6 months for patients receiving bevacizumab and irinotecan (Wang, RTOG 
0625 summary analysis unpublished data). This preliminary analysis confirms the median survival 
of recurrent glioblastoma treated with bevacizumab at approximately 9 months and a basis for the 
inclusion of tumors limited in size to 5 cm diameter. 
 
Re-irradiation using the newer SRS techniques delivers higher doses of irradiation to a 
considerably more precise target volume, in a single fraction, and with a steep dose gradient 
beyond the tumor. In several series reporting on these novel SRS techniques, overall survival 
was 9 to 11 months. Because of the potential CNS toxicity associated with a single-fraction 
treatment or treatment with very few fractions of large dose per fraction, patients selected for this 
therapy must have small, limited volume recurrences. Fractionation leads to improvement of the 
therapeutic ratio by reducing the risk to normal tissues compared with single-fraction treatments, 
especially for larger tumors (3 to 5 cm) (Brenner 1997, Cho 1999). The linear quadratic (LQ) 
model has been used to calculate the biological equivalent dose using a tumor alpha/beta ratio of 
10 Gy (Mayer 2008). The effect on late normal tissue was calculated using an alpha/beta ratio of 
3 Gy. The proposed schema in this study of 35 Gy in 10 fractions was directly compared to the 30 
Gy in 5 fractions used by Gutin et al and was predicted using biologic modeling to have similar 
antitumor efficacy (47.2 versus 48 Gy with alpha-beta of 10 Gy). However, the 35 Gy in 10 
fractionation scheme is much more favorable in regards to risk of late normal tissue toxicity and is 
likely better tolerated for larger tumors. 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To establish an improvement in overall survival in recurrent GBM patients receiving bevacizumab 
and re-irradiation compared with patients receiving bevacizumab alone. 
 
2.2 
Secondary Objectives 
2.2.1  
To estimate and compare the rate of objective response in patients with measurable disease. 
2.2.2  
To estimate and compare the 6-month progression-free survival rate. 
2.2.3  
To estimate and compare progression-free survival. 
2.2.4  
To estimate and compare the rate of treatment adverse events. 
2.2.5  
To estimate and compare the rate of ≥grade 3 acute or delayed CNS toxicity. 
 
3.0 
PATIENT SELECTION  
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED 
3.1 
Conditions for Patient Eligibility (8/24/15) 
For questions concerning eligibility, please contact the study data manager.  
3.1.1 
Histopathologically proven diagnosis of glioblastoma or variants (gliosarcoma, giant cell 
glioblastoma etc). Patients will be eligible if the original histology was lower-grade glioma and a 
subsequent diagnosis of glioblastoma or gliosarcoma is made. 
 
Patients who did not have recent surgery for their glioblastoma must have shown unequivocal 
radiographic evidence for tumor progression by contrast-enhanced MRI scan (or CT scan for 
patients with non-compatible devices) within 21 days prior to registration as defined in 
Section 11.4.1. 
Note: Patients who did have surgery with a post-operative contrast-enhanced scan falling outside 
the 5-week window prior to registration, per definition of recent surgery in 3.1.4,  must have a 
repeat MRI scan (or CT scan for patients with non-compatible devices) within 21 days prior to 
registration. 
 
Patients must have passed an interval of 6 months or greater between completion of prior 
radiotherapy and registration. If patients have not passed an interval of at least 6 months, 
they may still be eligible if they meet one or more of the following criteria: 

16 
RTOG 1205; version date 10/3/16 
 
a) New areas of tumor outside the original radiotherapy fields as determined by the 
investigator, or 
b) Histologic confirmation of tumor through biopsy or resection, or 
c) Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent with 
true progressive disease, rather than radiation necrosis obtained within 28 days of 
registration AND an interval of at least 90 days between completion of radiotherapy and 
registration. 
 
 
Patients unable to undergo MR imaging because of non-compatible devices can be enrolled 
provided CT scans are obtained and are of sufficient quality. Patients without non-compatible 
devices may not use CT scans performed to meet this requirement. 
3.1.2  
Prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy 
fractions, or equivalent or lower doses. 
 
Patients who have received prior treatment with non-standard RT dose and fractionation, 
interstitial brachytherapy, stereotactic radiosurgery, etc. are eligible as long as the criterion in 
3.1.1 a, b, or c is met or approved by principal investigator.   
3.1.3  
Patients must have recovered from the toxic effects of prior therapy, and there must be a 
minimum time of 28 days prior to registration from the administration of any investigational agent 
or prior cytotoxic therapy with the following exceptions: 
 
14 days from administration of vincristine 
 
42 days from administration of nitrosoureas 
 
21 days from administration of procarbazine 
3.1.4  
Patients having undergone recent resection of their glioblastoma (within 5 weeks prior to 
registration) must have recovered from the effects of surgery. For CNS related core or needle 
biopsies, a minimum of 7 days must have elapsed prior to registration. 
Residual disease following resection of recurrent glioblastoma is not mandated for eligibility 
into the study. To best assess the extent of residual disease post-operatively, a post-
operative or intra-operative MRI scan (or CT scan for patients with non-compatible devices) 
must be performed prior to registration and should be within 96 hours post surgery (although 
24 hours would be optimum).  
3.1.5 
History/physical examination, including neurologic examination, within 14 days prior to 
registration 
3.1.6 
Karnofsky performance status ≥ 60 within 14 days prior to registration 
3.1.7 
Age ≥ 18 
3.1.8 
CBC/differential obtained within 14 days prior to registration, with adequate bone marrow 
function. Adequate bone marrow reserve as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3  
 
Platelets ≥ 75,000 cells/mm3  
 
Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
9.0 g/dl is acceptable.)  
3.1.9 
Acceptable liver (total bilirubin  2.0 mg/dL, and SGOT or AST  2.5 times the upper limit of 
normal) and renal function (serum creatinine  1.8 mg/dL) within 14 days prior to registration.  
 
 
Urine protein: creatinine (UPC) ratio  < 1.0 within 14 days prior to registration OR urine 
dipstick for proteinuria  ≤ 2+ (patients discovered to have  > 2+ proteinuria on dipstick 
urinalysis at baseline must have a UPC ratio done that is <1.0 to be eligible. If the UPC ratio 
is ≥ 1.0 then the patients should undergo a 24-hour urine collection and must demonstrate ≤ 
1g of protein in 24 hours to be eligible). 
 
Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a UPC 
ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is 
calculated using one of the following formulas: 
 [urine protein]/[urine creatinine]: if both protein and creatinine are 
reported in mg/dL 
 [(urine protein) x0.088]/[urine creatinine]: if urine creatinine is reported in 
mmol/L 

17 
RTOG 1205; version date 10/3/16 
 
3.1.10 Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must 
be done within 7 days prior to registration. Effective contraception (men and women) must be 
used in patients of child-bearing potential while on study treatment and for 6 months after. 
3.1.11 Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the 
following criteria:  
 
No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor 
involving major vessels or known varices) 
 
In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable 
dose of low molecular weight heparin, within 14 days prior to registration 
3.1.12 Patient must be able to provide study-specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (4/15/14) 
3.2.1  
More than three relapses 
3.2.2  
Infratentorial, or leptomeningeal evidence of recurrent disease  
3.2.3  
Recurrent or persistent tumor greater than 6 cm in maximum diameter 
3.2.4 
Prior therapy with an inhibitor of VEGF or VEGFR (including bevacizumab) 
3.2.5 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity, or cervix are all 
permissible). 
3.2.6 
Severe, active co-morbidity, defined as follows: 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 
months prior to registration 
 
Transmural myocardial infarction within the last 6 months prior to registration 
 
History of stroke or transient ischemic attack within 6 months prior to registration. 
 
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically 
significant peripheral vascular disease. 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of registration 
 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, 
that laboratory tests for liver function other than screening panel (Section 3.1) and 
coagulation parameters are not required for entry into this protocol. 
 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in this 
protocol may be significantly immunosuppressive.  Protocol-specific requirements may also 
exclude immuno-compromised patients. 
3.2.7 
Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic.  
3.2.8 
Prior allergic reaction to the study drug (Bevacizumab) 
3.2.9 
Prior history of hypertensive crisis or hypertensive encephalopathy. 
3.2.10 History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to 
registration 
3.2.11  Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade 3 or greater 
within 30 days prior to registration 
3.2.12  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
registration (with the exception of craniotomy) 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment 
that do not affect eligibility. 
4.1 
Highly Recommended Evaluations (4/15/14) 
4.1.1  
Baseline MR diffusion and perfusion imaging is optional but strongly recommended as further 
confirmation that the GTV is related to tumor and not radiation effect. The same type of enhanced 

18 
RTOG 1205; version date 10/3/16 
 
scan, i.e., MRI or CT, should be used throughout the period of protocol treatment for tumor 
measurement.  See also Section 11.1.3. 
4.1.2 
The MGMT methylation status as a predictor of outcome will be obtained for the following patient 
groups: 
 
Patients who have already had MGMT performed prior to registration into an /NRG Oncology/ 
RTOG GBM trial collecting MGMT methylation status. 
 
Patients who have had MGMT analysis performed as routine care by a treating physician 
outside of an NRG Oncology/ RTOG GBM trial. 
4.1.3 
Pre-operative contrast-enhanced MRI or CT scan. 
 
5.0 
REGISTRATION PROCEDURES (10/9/14) 
Access requirements for OPEN and TRIAD: 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to 
register (both initial registration and annual re-registration) with CTEP and to obtain a user 
account.  
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures below for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.)  
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
Note: As of Amendment 1 activation, this trial is not utilizing the services of the ITC for 
dosimetry digital treatment data submission. See below for information on installing 
TRIAD for submission of digital RT data prior to enrolling patients. 
 
5.1  
Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) Treatment 
Approach (11/20/13) 
5.1.1  
Institutions that plan to utilize PTV margins of less than 5 mm will also be required to complete 
image-guided radiotherapy (IGRT) credentialing for brain.  
 
In order to utilize IGRT for margin reduction (see Section 6.3), the center must be credentialed for 
its use. This means the institution must have met technology requirements and have provided the 
baseline physics information. This information is available on the NRG Oncology/RTOG website, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205. 
 
In order to become credentialed for brain IGRT, the institution must have already become 
credentialed for either 3DCRT and/or IMRT. Institutions that have not been credentialed by NRG 
Oncology to perform 3DCRT and/or IMRT MUST apply for 3DCRT and/or IMRT credentialing as 
described below in Sections 5.2 and 5.3. 
5.1.2 
IGRT Credentialing Process 
 
IGRT credentialing for brain (review of at least one case) will be required for institutions 
utilizing PTV margins of less than 5 mm (See Section 6.3).  The first step is for the institution 
or investigator to update or complete a new Facility Questionnaire and/or set up an SFTP 
account for digital data submission. See Sectio 12 for details. 
 
Next, the institution must submit a series of daily treatment images along with a spreadsheet 
of IGRT data from an anonymized brain cancer patient. This information is available on the 

19 
RTOG 1205; version date 10/3/16 
 
on 
the 
NRG 
Oncology/RTOG 
website, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205. This series 
must include a minimum of 5 daily pre-treatment images obtained on sequential treatment 
days. Pre-treatment images may include three-dimensional (3D) volumetric images (either 
fan- or cone-beam CT with Megavoltage (MV) or kilovoltage (kV) x-ray or Orthogonal (MV or 
kV) 2D images. These images and the spreadsheet will be reviewed by the Study Chair, 
Christina Tsien, MD, and the Medical Physics Co-chair, Martha Matuszak, PhD, prior to 
certification. 
 
5.2 
Pre-Registration Requirements for IMRT Treatment Approach (2/27/14) 
5.2.1 
In order to utilize IMRT on this study (this includes all CyberKnife treatments), the institution must 
have met specific technology requirements and have provided baseline physics information. 
Instructions for completing these requirements or determining if they already have been met are 
available on the IROC Houston [formerly  the Radiological Physics Center (RPC) web site]. Visit 
http://irochouston.mdanderson.org and select “Credentialing” and “Credentialing Status Inquiry”. 
 
An IMRT phantom study with the IROC Houston must be successfully completed (if the institution 
has not previously met this IMRT credentialing requirement). Instructions for requesting and 
irradiating 
the 
phantom 
are 
available 
on 
the 
IROC 
Houston 
web 
site 
at 
http://irochouston.mdanderson.org; select “Credentialing” and “RTOG”. Upon review and 
successful completion of the phantom irradiation, IROC Houston will notify both the registering 
institution and NRG Oncology that the institution has completed this requirement. Subsequently, 
NRG Oncology will update the RSS database. 
5.2.2 
The institution or investigator must update or complete the electronic Facility Questionnaire 
(available on the IROC Houston web site at http://irochouston.mdanderson.org ) and  then 
complete a credentialing status inquiry form, also found on the IROC Houston, web site to 
determine if your site has met all of the requirements. This will be completed in place of updating 
the previous Facility Questionnaire. When the requirements are met, the site and NRG Oncology 
will be notified. NRG Oncology will then update the RSS database.  Before any cases can be 
entered, a TRIAD account must also have been set up for data submission. 
 
5.3 
Pre-Registration Requirements for 3D-CRT Treatment Approach (2/27/14) 
5.3.1 
Only institutions that have met the technology requirements and that have provided the baseline 
physics information that are described in 3D-CRT Quality Assurance Guidelines may enter 
patients onto this study. 
5.3.2 
The institution or investigator must update or complete a Facility Questionnaire (available on the 
RPC web site at http://irochouston.mdanderson.org) and complete a credentialing status inquiry 
form also found on the IROC Houston web site to determine if your site has met all of the 
requirements. This will be completed in place of updating the previous Facility Questionnaire. 
When the requirements are met the site and NRG Oncology will be notified. NRG Oncology will 
then update the RSS database  prior to entering any cases. A TRIAD account must also have 
been set up for data submission prior to submitting any data. IROC Houston will notify the 
institution and NRG Oncology when all requirements have been met and the institution is eligible 
to enter patients onto this study. NRG Oncology will update the RSS database. 
 
5.4 
Pre-Registration Requirements for Proton Treatment Approach (2/27/14) 
5.4.1  
Proton Credentialing Process  
Proton therapy may be used on this protocol.  Investigators using proton therapy must comply 
with the NCI proton guidelines for the Use of Proton Radiation Therapy in NCI Sponsored 
Cooperative Group Clinical Trials, which are available on the websites of the IROC Houston 
(http://irochouston.mdanderson.org), ATC (http://atc.wustl.edu), and QARC (http://www.qarc.org). 
These requirements include, but are not limited to, completion of a proton facility questionnaire, a 
successful IROC Houston site visit, which identifies the proton technique(s) which can be used, 
annual monitoring of the proton beam calibration, e.g. IROC Houston’s monitoring program. 
5.4.2 
Dose will be reported in Gy (RBE), where 1 Gy(RBE) = proton dose Gy x RBE (radiobiological 
effective dose), RBE = 1.1. 

20 
RTOG 1205; version date 10/3/16 
 
5.4.3 
Radiation doses shall be prescribed using the protocol specified definitions for GTV and CTV.  
For set-up uncertainties and target motion, additional margin (including proximal and distal), 
smearing, and range of modulation will be added on a per beam basis.  Proton treatment plans 
will be based upon a CT scanner for which the institution has defined an imaging protocol for 
protons which establishes the relationship between the CT number and the stopping power ratios. 
5.4.4 
The IROC Houston will coordinate the completion of the proton therapy use approval process in 
conjunction with the appropriate other Quality Assurance Offices for any additional protocol 
specific credentialing requirements.  IROC Houston will notify the institution and NRG Oncology 
when all requirements have been met and the institution is eligible to enter patients onto this 
study. NRG Oncology will update the RSS database. 
5.4.5 
Additional credentialing requirements for this protocol may be found on the IROC Houston  web 
site (http://irochouston.mdanderson.org) by selecting “Credentialing” and “RTOG”. 
5.4.6 
Proton resources for this protocol include: 
 
 
 
Michael T. Gillin, PhD 
Professor 
The University of Texas 
MD Anderson Cancer Center 
Department of Radiation Physics 
713-563-2507/Fax: 713-563-2545 
mgillin@mdanderson.org 
 
 
 
 
Anita Mahajan, MD 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard 
Houston, TX 77030 
713-563-2350 
amahajan@mdanderson.org 
 
5.4.7 
If protons are to be used, review and successful completion of the “Dry-Run” QA test using 
protons is required, the IROC Houston will notify both the registering institution and NRG 
Oncology that the institution has successfully completed this requirement for protons 
 
There are no proton protocol specific credentialing requirements for this protocol.   
 
5.5 
Digital RT Data Submission Using TRIAD (11/20/13) 
TRIAD is the American College of Radiology’s (ACR) image exchange application. 
TRIAD provides sites participating in RTOG clinical trials a secure method to transmit 
DICOM RT and other objects.  TRIAD anonymizes and validates the images as they are 
transferred. 
 
TRIAD Access Requirements 
 
Site physics staff who will submit images through TRIAD will need to be registered with The 
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and 
Access Management (IAM) account. Please refer to Section 5.0 of the protocol for 
instructions on how to request a CTEP-IAM account. 
 
To submit images, the site physics user must have been assigned the 'TRIAD site user' role 
on the relevant Group or CTSU roster. 
 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the NRG 
Oncology/RTOG website Core lab tab.    
 

21 
RTOG 1205; version date 10/3/16 
 
This process can be done in parallel to obtaining your CTEP IAM account username and 
password. 
 
If you have any questions regarding this information, please send an email to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
 
5.6  
Regulatory Pre-Registration Requirements (10/9/14) 
Investigator Registration Requirements  
Prior to the recruitment of a patient for this study, investigators must be registered members of a 
Lead Protocol Organization.  Food and Drug Administration (FDA) regulations and National 
Cancer Institute (NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. Registration requires the submission of: 
 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
 
a current Curriculum Vitae (CV) 
 
a completed and signed Supplemental Investigator Data Form (IDF) 
 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillabe PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
 
Site Registration Requirements [Insert as appropriate] 
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.  Study centers can check the status of their 
registration packets by querying the Regulatory Support System (RSS) site registration status 
page of the CTSU members’ website by entering credentials at https://www.ctsu.org.   
 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the RTOG 1205  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 https://www.ctsu.org 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 
 
Click on the NRG Oncology link to expand, then select trial protocol #RTOG-1205. 
 
Click on the Site Registration Documents link 
 
 
Requirements RTOG 1205 Site Registration: 
 
CTSU IRB Certification CTSU IRB/Regulatory Approval Transmittal Sheet  
 
IRB Approval Letter  
 
IRB/REB Approved Informed Consent (English and native language versions*) *Note: 
Institutions must provide certification/verification of IRB/REB consent translation to NRG 
Headquarters (described below). 
 
IRB/REB registration number renewal information as appropriate. 
 
CTSU RT Facilities Inventory Form  
NOTE:  Per NCI policy all institutions that participate on protocols with a radiation therapy 
component must participate in the Imaging and Radiation Oncology Core (IROC) 

22 
RTOG 1205; version date 10/3/16 
 
monitoring program.  If this form has been previously submitted to CTSU it does not need 
to be resubmitted unless updates have occurred at the RT facility 
 
Submitting Regulatory Documents:  
Submit completed forms along with a copy of your IRB Approval and Informed Consent to the 
CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
Checking Your Site’s Registration Status: 
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 https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Non-English Speaking Canadian and Non-North American Institutions   
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REB approved consent, must be provided in English and 
in the native language. Certification of the translation is optimal but due to the prohibitive costs 
involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation 
consists of the actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational/letterhead stationery that includes the professional title, 
credentials, and signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
5.6.3 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
Prior to clinical trial commencement, Canadian institutions must complete and fax (215-569-0206) 
or e-mail (CTSURegulatory@ctsu.coccg.org) the following Health Canada forms to the CTSU 
Regulatory Office: 
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form.  
5.6.4 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Oncology to receive approval to participate in 
this trial. For more details see link below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx .  
 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling 
patients to this study. 
 
5.7  
Registration (10/9/14) 
5.7.1  
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have 
been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have signed 
and dated all applicable consents and authorization forms.   

23 
RTOG 1205; version date 10/3/16 
 
 
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 
< 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. All site staff will use OPEN to enroll patients to this study.  OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).  
 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
5.7.2 
In the event that the OPEN system is not accessible, participating sites can contact web support 
for assistance with web registration: websupport@acr.org or call the Registration Desk at (215) 
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax 
in the eligibility checklist and will need the registering individual’s e-mail address and/or return fax 
number. This information is required to assure that mechanisms usually triggered by the OPEN 
web registration system (e.g. drug shipment and patient-specific calendar) will occur.  
 
6.0 
RADIATION THERAPY (11/20/13) 
Note:  Intensity Modulated RT (IMRT) Is Allowed.   
Protons are permitted for institutions which have been approved and credentialed for 
protons, as protons may reduce the volume of normal tissue which will be re-irradiated.  (If 
protons are used, to avoid delays resulting from unplanned equipment availability, photon 
therapy may be administered instead of proton therapy.) 
 
Note: As of Amendment 1 activation, this trial is not utilizing the services of the ITC for 
dosimetry digital treatment data submission. See Section 5 for information on installing 
TRIAD for submission of digital RT data PRIOR to enrolling patients. 
 
6.1 
Dose Specifications 
6.1.1  
Photons: Treatment shall consist of 35 Gy delivered in 10 fractions. Target coverage and 
homogeneity limits and deviations are listed in Table 1. 
6.1.2 
Protons - Absorbed dose:  Doses are expressed in units of RBE-weighted absorbed dose, DRBE.  
For protons the RBE is taken to be 1.1.  DRBE = 1.1 x D, where D represents the absorbed dose in 
Gy.  Treatment shall consist of 35 Gy(RBE) delivered in 10 fractions. Target coverage and 
homogeneity limits and deviations are listed in Table 1. 
 
Table 1.  Target Coverage and Dose Limits 
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation Unacceptable 
Volume of PTV covered 
by the prescription dose 
photons 35 Gy – 
protons 35 Gy(RBE) 
Greater than or equal 
to 95% of the PTV 
should receive greater 
than or equal to 
photons 35 Gy – 
protons 35 Gy(RBE) 
Greater than or equal 
to 90% of the PTV 
receiving greater than 
or equal to photons 35 
Gy – protons 35 
Gy(RBE) 
Less than 90% of the 
PTV receiving greater 
than or equal to photons 
35 Gy – protons 35 
Gy(RBE) 
Minimum dose to the 
PTV (0.03 cc) 
Greater than or equal 
to 29.75 Gy (85% of 
Greater than or equal 
to 28 Gy (80% of the 
Less than 28 Gy (80% of 
the prescription dose) – 

24 
RTOG 1205; version date 10/3/16 
 
the prescription dose) 
– protons 29.75 
Gy(RBE) 
prescription dose) – 
protons 28 Gy(RBE); 
Minimum doses of less 
than 28 Gy are 
acceptable if they 
occur due to OAR/PTV 
overlap 
protons 28 Gy(RBE); 
Minimum doses of less 
than 28 Gy are 
unacceptable unless they 
occur in regions of 
OAR/PTV overlap 
Maximum dose to the 
PTV (0.03 cc) 
Less than or equal to 
42 Gy (120% Rx 
Dose) – protons 42 
Gy(RBE) 
Less than or equal to 
45.50 Gy (130% Rx 
Dose) – protons 45.50 
Gy(RBE) 
Greater than 45.50 Gy 
(130% Rx Dose) –
protons 45.50 Gy(RBE) 
 
6.2 
Technical Factors [Equipment, energies]  
The 10 treatment fractions of 3.5 Gy each will be delivered on consecutive treatment days 
(typically 5 fractions per week).  Any FDA cleared external beam radiation delivery system may 
be used (including conventional linear accelerators, cyberknife systems, tomotherapy, proton 
therapy, etc.).  Imaging for treatment planning will be obtained with the patient in the same 
position and immobilization device as for treatment. All patients will be positioned via a 
combination of rigid immobilization and daily image guidance to ensure positioning accuracy of 3 
mm or better, and of a magnitude that justifies the PTV margin applied (the participating 
institutions must document the immobilization and localization methods applied). 
 
6.3 
Localization, Simulation, and Immobilization (10/9/14) 
An MRI and/or CT scanning obtained with the patient immobilized in the treatment position is , 
required for treatment planning.   The image resolution of no worse than 1.5 mm x1.5 mm x 3 
mm.  Immobilization must be rigid (e.g. thermoplastic masks).  For daily treatment, localization 
will include the steps of a) immobilization with the same device used for simulation, and b) daily 
image guidance using at a minimum orthogonal pairs of radiographs aligned to DRRs as a 
computer-assisted process (CT-CBCT alignment is permitted as well).  Institutions utilizing PTV 
margins of less than 5 mm are required to undergo IGRT credentialing for brain (see Section 5.1). 
 
6.4 
Treatment Planning/Target Volumes (10/9/14) 
A GTV will be defined using contrast-enhanced CT and/or MRI images.  The post-operative 
resection cavity will be outlined if no residual enhancing tumor is noted. A CTV expansion of no 
more than 5 mm is optional for lesions measuring less than 3.5 cm in maximum diameter or if this 
is a new lesion, but must be reported when used. Otherwise, no additional CTV expansion will be 
added. A PTV expansion that is justified based on image guidance and immobilization will be 
applied. Regardless of immobilization and localization methods, the PTV expansion should be no 
smaller than 3 mm.  As noted in Section 6.3, institutions utilizing PTV margins of less than 5 mm 
are required to undergo IGRT credentialing for brain (see Section 5.1) and utilize computer-
assisted daily IGRT for all treatment fractions. 
  
If protons are used, an adjustment must be made within the treatment planning process to take 
into account of range uncertainties along the beam direction, following the established practice at 
the specific proton facility, which should be based on the recommendations contained in ICRU 
78, paragraph 5.1.4.4. 
 
Treatment planning using multiple, non-coplanar beams or arc-based therapy is advised. IMRT 
based planning is allowed.  To ensure dose calculation accuracy, the minimum field size used 
should be consistent with the minimum field size commissioned for use at the institution and 
should not be smaller than 2 cm x 2 cm. In any case, the objective of treatment planning is to 
ensure sufficient dose conformity that the normal tissue constraints are met. 
 
6.5 
Critical Structures (2/27/14) 
Normal tissues to be contoured will include the brain, brainstem, optic nerves and chiasm. 
Planning risk volume (PRV) expansions (minimum of 3 mm) should be utilized for optic nerves 

25 
RTOG 1205; version date 10/3/16 
 
and chiasm.  Special consideration should be given to avoid doses greater than the prescription 
dose within the scalp as well as limiting the exit dose through the oral cavity and mucosa. The 
treatment parameters should be modified to optimize the conformity of the prescription isodose 
volume to the target volume while minimizing dose to critical structures.  There are two scenarios 
for normal tissues limits: (1) previous radiation to the local area including critical organs at risk 
and (2) no previous radiation to the local area or organs at risk.  The limits for both scenarios are 
given in Table 2. 
 
Table 2.  Normal Tissue Dose Limits  
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk  
Maximum Dose to PRV for 
Optic Nerves and Chiasm (0.03 
cc) 
Less than or equal to 
20 Gy photons – 20 
Gy(RBE) protons 
Greater than 20 Gy 
but less than or equal 
to  25 Gy photons – 
25 Gy(RBE) protons 
Greater than 25 Gy 
photons – 25 Gy(RBE) 
protons 
Maximum Dose to Brainstem 
(0.03 cc) 
Less than or equal to  
24 Gy photons – 24 
Gy(RBE) protons 
Greater than 24 Gy 
but less than or equal 
to  30 Gy photons – 
30 Gy(RBE) protons 
Greater than 30 Gy 
photons – 30 Gy(RBE) 
protons 
Scenario (2): No previous radiation to the local area or critical organs at risk  
Maximum Dose to PRV for 
Optic Nerves and Chiasm (0.03 
cc) 
Less than or equal to 
35 Gy (the 
prescription dose) 
photons – 35 
Gy(RBE) protons 
Greater than 35 Gy 
but less than or equal 
to 36.75 Gy (105 % of 
the prescription dose) 
photons – 36.75 
Gy(RBE) protons  
Greater than 36.75 Gy 
(105% of the prescription 
dose) photons – 36.75 
Gy(RBE) protons 
Maximum Dose to Brainstem 
(0.03 cc) 
Less than or equal to 
35 Gy (the 
prescription dose) 
photons – 35 
Gy(RBE) protons 
Greater than 35 Gy 
but less than or equal 
to 36.75 Gy (105 % of 
the prescription dose) 
photons – 36.75 
Gy(RBE) protons  
Greater than 36.75 Gy 
(105 % of the 
prescription dose) 
photons – 36.75 
Gy(RBE) protons 
 
 
6.5.1 
Standard Structure Names for TRIAD Submission 
All structures must be submitted and labeled according to the specifications in the table below or 
resubmission will be required. 
 
Standard Name  
Description  
Reference Dose (GY) 
Validation Profile 
GTV_3500  
Residual enhancing tumor or 
post-operative resection 
cavity  
35 
Required 
CTV_3500  
An Optional CTV expansion 
of no more than 5 mm.  
35 
Required 
PTV_3500  
planning target volume; an 
additional margin of 3 to 5 
mm  
35 
Required 
Brain  
Outline of the brain  
 
Required 
OpticChiasm  
Optic Chiasm  
 
Required 
OptChiasm_PRV  
Optic Chiasm Planning Risk 
Volume  
 
Required 
BrainStem  
Brain Stem  
 
Required 
BrainStem_PRV  
Brain Stem Planning Risk 
Volume  
 
Required 

26 
RTOG 1205; version date 10/3/16 
 
OpticNerve_L  
Left Optic Nerve  
 
Required 
OptNrv_L_PRV  
Left Optic Nerve Planning 
Risk Volume  
 
Required 
OpticNerve_R  
Right Optic Nerve  
 
Required 
OptNrv_R_PRV  
Right Optic Nerve Planning 
Risk Volume  
 
Required 
 
 
6.6 
Documentation Requirements 
At the completion of treatment, the following should be forwarded to NRG Oncology: daily 
treatment record and the radiotherapy summary per Section 12.1. In addition, CT/MRI 
documentation must be submitted per Section 12.2. Isodose distributions should be displayed on 
orthogonal planes or, if not possible, on multiple transverse slices through each target. 
 
6.7 
Compliance Criteria 
See Tables 1 and 2 for target and normal tissue compliance criteria. 
 
6.8 
R.T. Quality Assurance Reviews 
 
The Radiation Oncology Co-Chair, Christina Tsien, M.D., will perform an RT Quality Assurance 
Review of cases on an ongoing basis. The final cases will be reviewed within 6 months after this 
study has reached the target accrual or as soon as complete data for all cases enrolled has been 
received at Imaging and Radiation Oncology Core (IROC) Philadelphia, whichever occurs first. 
These reviews will be ongoing and performed at the NRG Oncology semi-annual meetings as 
well as at IROC Philadelphia. 
 
6.9 
Radiation Therapy Adverse Events 
6.9.1 
Acute 
Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or soreness 
of the scalp. Potential acute toxicities include nausea and vomiting as well as temporary 
aggravation of brain tumor symptoms such as headaches, seizures, and weakness. Reactions in 
the ear canals and on the ear should be observed and treated symptomatically; these reactions 
could result in short-term hearing impairment. Dry mouth or altered taste have been occasionally 
reported. 
6.9.2  
Early Delayed 
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1-3 months after radiotherapy treatment.  
6.9.3  
Late Delayed 
Possible late delayed effects of radiotherapy include risk of radiation necrosis, and endocrine 
dysfunction. In addition, neurocognitive deficits, which could lead to mental slowing and 
behavioral change, are possible. Permanent hearing impairment and visual damage are rare. 
Cataracts can be encountered. 
 
6.10 
Radiation Therapy Adverse Event Reporting  
See Section 7.6. 
 
7.0 
DRUG THERAPY 
 
 
Protocol treatment must begin within 14 days after registration. 
 
7.1 
Treatment (10/9/14) 
7.1.1 
Dose Definition 
.Bevacizumab will be administered at a dose of 10 mg/kg every 2 weeks. The patient’s weight 
must be checked prior to each dose of bevacizumab. Doses will be adjusted if there is a > 10% 
change in weight. 
7.1.2 
Technique of Administration 

27 
RTOG 1205; version date 10/3/16 
 
Bevacizumab will be administered intravenously per institutional guidelines with associated pre-
medications.  
7.1.3 
Duration of Treatment  
Initial cycle of bevacizumab must start within 14 days of registration.  A deviation of +/- 3 days is 
permitted. If beyond this timing period, the imaging and work-up will need to be repeated. 
Subsequent bevacizumab doses may be given every 14 days apart  +/- 3 days due to holidays, 
etc. Treatment may be held for > grade 3 toxicities as defined in Section 7.3.  
 
Arm 1: Patients randomized to the bevacizumab alone arm will be administered bevacizumab 
every 2 weeks until disease progression. 
 
Arm 2: Patients randomized to the bevacizumab and re-irradiation arm will receive an initial 
induction dose of bevacizumab (alone without radiation). It will then be followed by concurrent 
bevacizumab and radiation at the next dose which is administered 14 days later. This will allow 
additional time for radiation therapy planning especially in symptomatic patients. Concurrent 
bevacizumab cycle may be given either on the day prior to start of radiation or on day 1 of 
radiation. Bevacizumab will then be continued every 2 weeks until disease progression.   
 
7.2 
Bevacizumab Agent Information (10/3/16) 
Consult the package insert for detailed pharmacologic and safety information. 
7.2.1 
Description and Packaging 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active 
isoforms of human VEGF (or VEGF-A) with high affinity (kd = 1.1 nM). The antibody consists of a 
human IgG1 framework and the antigen-binding complementarity-determining regions from the 
murine anti-VEGF MAb A.4.6.1.16-18. Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and sterile water for injection (SWFI), USP. 
7.2.2 
Administration  
Bevacizumab should be administered as a continuous intravenous infusion using a rate–
regulating device per institutional guidelines with associated pre-medications. Do not administer 
as an IV push or bolus. If no institutional guidelines exist, follow below: 
 
Administer the initial dose over a minimum of 90 minutes.  If no adverse reactions occur, 
administer the second dose over a minimum of 60 minutes. If no adverse reactions occur after 
the second dose, administer subsequent doses over a minimum of 30 minutes. If infusion-related 
adverse reactions occur, all subsequent infusions should be administered over the shortest 
period that was well tolerated. 
7.2.3 
Storage 
Vials contain no preservative and are suitable for single use only. 
7.2.4 
Supply 
Commercially available. 
 
Non-Canadian International Institutions 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study.  
7.2.5 
Adverse Events  
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Event 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 

28 
RTOG 1205; version date 10/3/16 
 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
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 2.4, May 23, 20161 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 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) 
 
 
Blood and lymphatic system 
disorders - Other (renal 
thrombotic microangiopathy)
 
 
Febrile neutropenia 
 
Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
 
 
 
Acute coronary syndrome2
 
 
Cardiac disorders - Other 
(supraventricular 
arrhythmias)3 
 
Cardiac disorders - Other 
(supraventricular arrhythmias)3 (Gr 3)
 
 
Heart failure 
 
 
 
Left ventricular systolic 
dysfunction 
 
 
 
Myocardial infarction2
 
 
 
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) 
 
Infusion related reaction 
 
Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain 
 
Non-cardiac chest pain (Gr 3) 
 
Pain 
 
Pain (Gr 3) 
HEPATOBILIARY DISORDERS 
 
 
 
Gallbladder perforation 
 

29 
RTOG 1205; version date 10/3/16 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
 
Infection9 
 
Infection9 (Gr 3) 
 
 
Infections and infestations - 
Other (necrotizing fasciitis) 
 
 
Infections and infestations - 
Other (peri-rectal abscess) 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 
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 
 

30 
RTOG 1205; version date 10/3/16 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)
 
 
 
Ischemia cerebrovascular2
 
 
Peripheral sensory 
neuropathy14 
 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
 
 
Syncope 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
Hematuria 
 
Hematuria (Gr 3) 
 
Proteinuria 
 
Proteinuria (Gr 2) 
 
 
Renal and urinary disorders 
- Other (nephrotic syndrome)
 
 
 
Urinary fistula 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
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 3) 
 
 
Bronchopleural fistula 
 
 
 
Bronchopulmonary 
hemorrhage 
 
 
Cough 
 
Cough (Gr 3) 
 
Dyspnea 
 
Dyspnea (Gr 2) 
 
Epistaxis 
 
Epistaxis (Gr 3) 
 
Hoarseness 
 
Hoarseness (Gr 3) 
 
 
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 
 
Hypertension 
 
 
Hypertension (Gr 3) 
 
Thromboembolic event 
 
Thromboembolic event (Gr 3) 

31 
RTOG 1205; version date 10/3/16 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)
 
 
 
Vascular disorders - Other 
(arterial thromboembolic 
event)2,16 
 
 
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 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in 
patients with a history of diabetes. 
 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial flutter. 
 
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. 
 
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.  

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RTOG 1205; version date 10/3/16 
 
 
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 - Blood and lymphatic system disorders - Other 
(idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis 
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 (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye disorders - Other 
(vitreous hemorrhage); Eye pain; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; 
Retinal tear; Retinopathy; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; 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 (aseptic necrotic bone); Musculoskeletal and connective tissue disorder - Other (myasthenia 
gravis); Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; 
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; 

33 
RTOG 1205; version date 10/3/16 
 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; 
Leukoencephalopathy; Memory impairment; 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; 
Renal and urinary disorders - Other (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; Pulmonary hypertension; 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. 
 
7.3 
Bevacizumab Dose Modifications (8/24/15) 
7.3.1 
First dose: The dose of bevacizumab will be 10 mg/kg delivered intravenously. There will be no 
dose reduction for bevacizumab. Treatment should be interrupted or discontinued for certain 
adverse events, as described below. If bevacizumab is interrupted for ANY reason for > 8 weeks, 
the patient should discontinue bevacizumab therapy on protocol. 
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE.v4.0 Grade
 
Action To Be Taken 
Allergic reactions 
 
or  
 
Acute infusional reactions/ 
cytokine release syndrome  
 
Grade 1-3 
 
 
If infusion-related or allergic reactions occur, premedications 
should be given with the next dose and infusion time may 
not be reduced for the subsequent infusion.  Follow the 
guidelines in Section 7.3 for bevacizumab  administration.  
 
For patients with grade 3 reactions, bevacizumab  
infusion should be stopped and not restarted on the same 
day.  At the physicians’ discretion, bevacizumab may be 
permanently discontinued or re-instituted with 
premedications and administered no faster than 60 minutes.  
If bevacizumab is re-instituted, the patient should be 
closely monitored for a duration comparable to or 
longer than the duration of the previous reactions.   
Grade 4 
Discontinue bevacizumab  
Arterial Thrombosis 
- Cardiac ischemia/ 
infraction 
- CNS ischemia (TIA, 
Grade 2 ( if new or 
worsened since 
bevacizumab therapy) 
Discontinue bevacizumab  

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RTOG 1205; version date 10/3/16 
 
Event 
CTCAE.v4.0 Grade
 
Action To Be Taken 
CVA) 
- any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 3-4 
Discontinue bevacizumab  
Venous Thrombosis  
 
 
 
Grade 3 
OR 
asymptomatic grade 4 
 
Hold bevacizumab  treatment.  If the planned duration of 
full-dose anticoagulation is < 2 weeks, bevacizumab  
should be held until the full-dose anticoagulation period is 
over. 
 If the planned duration of full-dose anticoagulation is >2 
weeks, bevacizumab  may be resumed during the period 
of full-dose anticoagulation IF all of the criteria below are 
met: 
- The subject must have an in-range INR (usually 2-3) on 
a stable dose of warfarin or be on a stable dose of 
heparin prior to restarting bevacizumab  
- The subject must not have pathological conditions that 
carry high risk of bleeding (eg, tumor involving major 
vessels or other conditions) 
- The subject must not have had hemorrhagic events 
while on study 
 
 If thromboemboli worsen/recur upon resumption of study 
therapy, discontinue bevacizumab  
Grade 4 (symptomatic) Discontinue bevacizumab  
Hypertension* 
 
[Treat with antihypertensive medication as needed.  The goal of BP control should be 
consistent with general medical practice] 
Grade 1  
Consider increased BP monitoring 
Grade 2 asymptomatic 
Begin anti-hypertensive therapy and continue bevacizumab 
-Grade 2 symptomatic 
or Grade 3 
  
 Hold bevacizumab  until symptoms resolve AND BP < 
160/100mmHg 
 
Grade 4 
Discontinue bevacizumab  
Congestive Heart Failure 
Grade 3 
 Discontinue bevacizumab  
Grade 4 
Discontinue bevacizumab 
Proteinuria 
 
[Proteinuria should be monitored by urine dipstick or urine protein creatinine (UPC) 
ratio before every dose of bevacizumab, if dip is > 2 + then a UPC ratio should be 
performed ] 
UPC ratio  
< 3.5 
Continue bevacizumab  
UPC ratio  
> 3.5 
Hold bevacizumab until UPC recovers to < 3.5 
Grade 4 or nephrotic 
syndrome 
Discontinue bevacizumab  
Hemorrhage (CNS or 
pulmonary) 
Grade 2-4 
 Discontinue bevacizumab  

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RTOG 1205; version date 10/3/16 
 
Event 
CTCAE.v4.0 Grade
 
Action To Be Taken 
Hemorrhage (non-CNS; 
non-pulmonary) 
Grade 3 
 
 Patients receiving full-dose anticoagulation should 
discontinue bevacizumab  
 For patients not on full-dose anticoagulation, hold 
bevacizumab until ALL of the following criteria are met: 
- 
the bleeding has resolved and Hb is stable 
- 
there is no bleeding diathesis that would increase 
the risk of therapy 
- 
there is no anatomic or pathologic condition that 
could increase the risk of hemorrhage recurrence. 
 Patients who experience recurrence of grade 3 
hemorrhage should discontinue study therapy 
Grade 4 
Discontinue bevacizumab  
RPLS (reversible posterior leukoencephalopathy 
syndrome or PRES (posterior reversible 
encephalopathy syndrome) 
 Hold bevacizumab  in patients with symptoms/signs 
suggestive of RPLS; subsequent management should 
include MRI scans and control of HTN 
 Discontinue bevacizumab  upon diagnosis of RPLS  
Wound dehiscence requiring medical or surgical 
intervention 
 Discontinue bevacizumab  
GI perforation, GI leak or fistula 
Discontinue bevacizumab  
Bowel obstruction 
Grade 2 requiring 
medical intervention 
 Hold bevacizumab  until complete resolution, with a 
minimum of 4 weeks after surgery.  
 
Grade 3-4 
 Hold bevacizumab until complete resolution 
 If surgery is required, patient may restart bevacizumab 
after full recovery from surgery, and at investigator’s 
discretion 
Other unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
Hold bevacizumab  until symptoms resolve to < grade 1 
Grade 4 
 Discontinue bevacizumab 
 Upon consultation with the study chair, resumption of 
bevacizumab  may be considered if a patient is benefiting 
from therapy and the grade 4 toxicity is transient, has 
recovered to < grade 1 and unlikely to recur with 
retreatment 
 
 
7.4 
Modality Review (11/20/13) 
The Medical Oncology Co-Chair, Jeffrey Raizer, M.D., will perform a Chemotherapy Assurance 
Review of all patients who receive or are to receive chemotherapy in this trial.  The goal of the 
review is to evaluate protocol compliance.  The review process is contingent on timely submission 
of chemotherapy treatment data as specified in Section 12.1. The scoring mechanism is: Per 
Protocol/Acceptable Variation, Not Per Protocol, and Not Evaluable.  A report is sent to each 
institution once per year to notify the institution about compliance for each case reviewed in that 
year. 
 
The Medical Oncology Co-Chair, Jeffrey Raizer, M.D., will perform a Quality Assurance Review 
after complete data for the first 20 cases enrolled has been received at NRG Oncology. Dr. 
Raizer will perform the next review after complete data for the next 20 cases enrolled has been 
received at NRG Oncology. The final cases will be reviewed within 3 months after this study has 
reached the target accrual or as soon as complete data for all cases enrolled has been received 
at NRG Oncology, whichever occurs first. 
 

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RTOG 1205; version date 10/3/16 
 
7.5 
Adverse Events (2/27/14) 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at                          
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via 
either 
the 
CTEP 
web 
site 
(https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613)    ). 
 
7.5.1 
Adverse Events (AEs)  
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements. February 29, 2012.  
7.5.2 
Serious Adverse Events (SAEs) 
Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in 
Section 7.6 will be reported via CTEP-AERS.  SAEs that require 24 hour CTEP-AERS 
notification are defined in the expedited reporting table in Section 7.6.  Contact the CTEP-
AERS Help Desk if assistance is required.  
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in 
any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect; 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy 
of a study participant must be reported via CTEP-AERS in an expedited manner. 
7.5.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS within 30 
days of AML/MDS diagnosis. 
 
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 
 

37 
RTOG 1205; version date 10/3/16 
 
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 via 
CDUS unless otherwise specified.  
 
7.6 
CTEP-AERS Expedited Reporting Requirements (2/27/14) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed 
via 
the 
CTEP 
web 
site, 
https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 . 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once 
internet connectivity is restored, an AE report submitted by phone must be entered electronically 
into CTEP-AERS. 
 
 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies a CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to the NRG Oncology dedicated SAE FAX, 215-717-0990. 
 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS as “expedited reporting NOT required” must still be 
reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS allows submission of all reports regardless of the 
results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the 
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE 
section of the appropriate case report form (see Section 12.1).  
 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 

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RTOG 1205; version date 10/3/16 
 
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. 
Hospitaliz-
ation 
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 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious 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 within 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 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Date: May 5, 2011 

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RTOG 1205; version date 10/3/16 
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND [or Non-CTEP IND]: 
Not applicable. 
 
8.0 
SURGERY 
 
Not applicable to this study. 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication. 
9.1.1 
Anticonvulsants: No limitations in type of anti-convulsants used. 
9.1.2 
Antiemetics: Prophylactic medications are not needed. For nausea, anti-emetics may be used 
based on the treating physician’s preference. 
9.1.3 
Anticoagulants: These may be used for the treatment of DVT’s or PE’s if they occur. Preference 
should be given for LMW Heparins, but Coumadin is allowed. 
9.1.4 
Antidiarrheals: Used as needed per treating physician’s discretion. 
9.1.5 
Analgesics: Used as needed per treating physician’s discretion. 
9.1.6 
Hematopoietic Growth Factors: Used as needed per treating physician’s discretion. 
9.1.7 
Herbal products: Are allowed but patients should inform treating physician and these should be 
recorded. 
9.1.8 
Nutritional supplementation: Are allowed but patients should inform treating physician and these 
should be recorded. 
 
9.2 
Non-permitted Supportive Therapy 
9.2.1  
Patients should avoid the use of medications that have anti-oxidant properties during radiation. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as tissue/specimen submission or quality of life 
assessment. If the patient consents to participate in the tissue/specimen component of the study, 
the site is required to submit the patient’s specimens as specified in Section 10.0 of the protocol. 
Sites are not permitted to delete the tissue/specimen component from the protocol or from the 
sample consent. 
10.1 
Tissue/Specimen Submission  
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. NRG Oncology encourages participants in protocol 
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides 
tissue specimens to investigators for translational research studies. Translational research 
studies integrate the newest research findings into current protocols to investigate important 
biologic questions.  
 
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of 
tissue banking and translational research (highly recommended). 
 
10.2 
Specimen Collection for Banking and Translational Research (Highly Recommended) 
(10/9/14) 
For patients who have consented to participate in the specimen collection component of the 
study. 
 
The following must be provided in order for the case to be evaluable for the NRG Oncology 
Biospecimen Bank: 

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RTOG 1205; version date 10/3/16 
 
10.2.1 Tissue (For collection, processing and shipping information please see Specimen Collection 
Summary below and Appendix III.) 
 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide 
(block); it does not have to be the diagnostic slide itself) 
 
A corresponding paraffin-embedded tissue block of the tumor (the block must match the H&E 
being submitted) or a 2 mm diameter core of tumor tissue, punched from the tissue block 
containing the tumor with a punch tool and submitted in a plastic tube labeled with the 
surgical pathology number. Note: A kit with the punch, tube, and instructions can be obtained 
free of charge from the NRG Oncology Biospecimen Bank. Block or core must be clearly 
labeled with the pathology identification number and block number that corresponds to the 
Pathology Report (see below). 
o 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. 
If the submitted material is reviewed and is not tumor, the site may be assessed a 
protocol violation. 
 
A Pathology Report documenting that the submitted block or core contains tumor. The report 
must include the NRG Oncology protocol number and patient’s case number. The patient’s 
name and/or other identifying information should be removed from the report. The surgical 
pathology numbers and information must NOT be removed from the report. 
 
A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for NRG 
Oncology Biospecimen Bank; if for translational research, this should be stated on the form. 
The form must include the NRG Oncology protocol number and patient’s case number.  
10.2.2 Blood and Urine (For collection, processing and shipping information please see Specimen 
Collection Summary below and Appendix III.) 
 
A Specimen Transmittal Form documenting the type of Biospecimen, the date of collection of the 
biospecimen; the NRG Oncology protocol number, the patient’s case number, time point of 
study, and method of storage, for example, stored at -80 C, must be included. 
10.2.3 Storage Conditions for All Specimens 
Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
 Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one 
week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday). 
 
Please indicate on the ST Form the storage conditions used and time stored. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RTOG 1205; version date 10/3/16 
 
10.2.4 Specimen Collection Summary 
 
Specimens for Banking/Translational Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide 
 
Slide shipped ambient 
A paraffin-embedded tissue 
block of the primary tumor 
taken before initiation of 
treatment or a 2 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool  
Pre-treatment 
Paraffin-embedded 
tissue block or punch 
biopsy  (must match the 
H&E slide being 
submitted)   
Block or punch shipped 
ambient.  Cold packs are 
recommended  during 
warm weather to help 
prevent blocks from 
melting 
 
SERUM: 5-10 mL of whole 
blood in 1 red-top tube and 
centrifuge 
(1) Pre-treatment 
 
(2) 8 weeks after 
treatment initiation 
Frozen serum samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(five to eight) 
Serum sent frozen on dry 
ice via overnight carrier 
PLASMA: 5-10 mL of 
anticoagulated whole blood 
in EDTA tube #1 (purple/ 
lavender top) and 
centrifuge 
(1) Pre-treatment 
 
(2)  8 weeks after 
treatment initiation  
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(five to eight) 
Plasma sent frozen on dry 
ice via overnight carrier 
Whole blood for DNA: 5-10 
mL of anticoagulated whole 
blood in EDTA tube #2 
(purple/ lavender top) and 
mix 
(1) Pre-treatment 
(Note: if site missed this 
timepoint they may collect 
whole blood at any 
timepoint or follow up visit, 
but this must be noted on 
the ST Form) 
 
Frozen whole blood 
samples containing 1.0 
mL per aliquot in 1 mL 
cryovials (three-five) 
Whole blood sent frozen 
on dry ice via overnight 
carrier 
10-20 mL clean-catch urine   
 
(1) Pre-treatment 
 
(2) 8 weeks after 
treatment initiation 
Two 5-10 mL urine 
aliquots in 2 sterile 15 ml 
polypropylene centrifuge 
tubes.  Store frozen at  
-20 or 80 C 
Urine sent frozen on dry 
ice via overnight carrier 
 
10.2.5 Submit materials for Specimen Banking, Translational Research as follows: 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271; RTOG@ucsf.edu 
 
 
10.3 
Reimbursement (4/15/14) 
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program, 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 

42 
RTOG 1205; version date 10/3/16 
 
the requirements/methods specified by the new NCTN Program. This information will be made 
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) 
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from 
the NCI-sponsored Cooperative Group Clinical Trials Program. 
 
10.4 
Confidentiality/Storage  
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.4.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s 
case number only. The NRG Oncology Biospecimen Bank database only includes the following 
information: the number of specimens received, the date the specimens were received, 
documentation of material sent to a qualified investigator, type of material sent, and the date the 
specimens were sent to the investigator. No clinical information is kept in the database. 
10.4.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that submitted 
it. 
  
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters: See Appendix I. See below for additional details. (11/20/13) 
11.1.1 Urine should be assessed via dipstick or random urine creatinine and protein before each dose of 
bevacizumab. If dipstick is > 2 + then a UPC ratio should be performed. 
11.1.2 Vital signs should be assessed before each dose of bevacizumab (on treatment day) to make 
sure there is no increase in blood pressure. 
11.1.3 MR diffusion and perfusion imaging at 8 and 24 weeks post-treatment start is optional but 
strongly recommended. Repeat MR diffusion and perfusion imaging at progression is optional but 
strongly recommended as further confirmation of true tumor progression and not radiation 
necrosis. 
 
11.2 
Measurement of Response  
The primary measure of response will be by serial measures of the product of the two largest 
cross-sectional diameters using MacDonald Criteria. Response will also be evaluated in this 
study using the international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee [JNCI 92(3): 205-216, 2000], see Section 11.4. 
11.2.1  Complete Response (CR) 
Requires all of the following: complete disappearance of the measurable enhancing lesion 
sustained for at least 4 weeks; no new lesions; and no corticosteroids. 
11.2.2  Partial Response (PR) 
Requires all of the following: ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of the measurable enhancing lesion sustained for at least 4 weeks; no 
new lesions; and stable or reduced corticosteroid dose. 
11.2.3  Stable Disease (SD) 
Requires all of the following: does not qualify for complete response, partial response, or 
progression and is receiving stable or decreasing doses of steroids. This will not require a 
confirmatory scan. 
11.2.4  Progression (P) 
Defined by any of the following: ≥ 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions provided that the patient has not had his/her dose of steroids 
decreased since the last evaluation period; and any new lesions. This will not require a 
confirmatory scan. A concomitant decrease in steroid dose will rule out a progression designation 
during the initial 12 weeks after completion of RT.  
 
 

43 
RTOG 1205; version date 10/3/16 
 
11.2.5  Pseudo-progression 
Due to possible radiation effects using large dose per fraction, the initial scan 6 weeks following 
RT should NOT be used to declare progression. In the absence of neurologic worsening OR a 
new distant area of tumor, the initial post-radiation scan should not be used to declare 
progression. Progressive worsening on subsequent imaging studies usually distinguishes true 
progression from pseudo-progression. 
11.2.6 If true progression is determined by subsequent imaging, then the date of progression returns to 
the earlier date with increasing mass. 
 
11.3  
Criteria for Evaluation of Therapy Effectiveness 
11.3.1  Tumor response and regrowth can frequently be difficult to measure directly. Serial neurological 
exams and CT/MRI scans may provide a guide to the actual course. Time interval to progression 
will be measured from registration until deterioration is documented by the individual investigator 
using these guides. The patient should consistently be followed with the same diagnostic imaging 
study (CT or MRI). (NOTE: CT option ONLY for patients unable to undergo MR imaging because 
of non-compatible devices.) 
11.3.2  Overall survival will be measured from registration until death. Progression-free survival will be 
measured from registration until the first occurrence of progression or death. 
11.3.3  The quality of survival will be measured by neurological functional classification and performance 
status. 
11.3.4  Toxicities will be measured using the CTCAE criteria, version 4.0. 
 
11.4 
RANO Response Criteria  
Efficacy determinations using RANO response criteria (Wen 2010) also will be obtained. 
11.4.1 Response Criteria  
 
Radiographic response should be determined in comparison to the tumor measurement obtained 
at pretreatment baseline for determination of response, and the smallest tumor measurement at 
either pretreatment baseline or following initiation of therapy for determination of progression. The 
tables below outline the criteria for radiographic changes following therapy and summarize RANO 
response criteria. In the event that the radiographic changes are equivocal and it is unclear 
whether the patient is stable or has developed progressive disease, it is permissible to continue 
treatment and observe the patient closely, for example at 4 weekly intervals. If subsequent 
imaging studies demonstrate that progression has occurred, the date of progression should be 
the scan at which this issue was first raised.  
 
 
All measurable and non-measurable lesions should be assessed using the same techniques as 
baseline. Ideally patients should be imaged on the same MRI, or least with the same magnet 
strength, for the duration of the study to reduce difficulties in interpreting changes. 
 
 
All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

44 
RTOG 1205; version date 10/3/16 
 
 
Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Complete Response: 
Requires all of the following: 
a) Complete disappearance of all enhancing measurable and non-measurable disease sustained 
for at least 4 weeks.   
b) No new lesions. 
c) Stable or improved non-enhancing (T2/FLAIR) lesions.  
d) Patients must be off corticosteroids (or on physiologic replacement doses only).   
e) Stable or improved clinically. 
Note: Patients with non-measurable disease only cannot have a complete response. The best 
response possible is stable disease. 
Partial Response: 
Requires all of the following: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.  
b) No progression of non-measurable disease.   
c) No new lesions.  
d) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. 
e) The corticosteroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan.  
f) 
Stable or improved clinically. 
 
Note: Patients with non-measurable disease only cannot have a partial response. The best response 
possible is stable disease. 
Stable Disease: 
Requires all of the following: 
a) Does not qualify for complete response, partial response, or progression.   
b) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared to 
baseline scan. In the event that the corticosteroid dose was increased for new symptoms and 
signs without confirmation of disease progression on neuroimaging, and subsequent follow-up 
imaging shows that this increase in corticosteroids was required because of disease 
progression, the last scan considered to show stable disease will be the scan obtained when 
the corticosteroid dose was equivalent to the baseline dose.  
c) Stable clinically. 
Progression:  
Defined by any of the following: 
a) Greater than > 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared to the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids.* 
b) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids compared to baseline scan or best response following initiation of therapy,* not 
due to co-morbid events (e.g. radiation therapy, demyelination, ischemic injury, infection, 
seizures, post-operative changes, or other treatment effects). 
c) Any new lesion. 
d) Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, 
medication side effects, complications of therapy, cerebrovascular events, infection, etc.) or 
changes in corticosteroid dose.  
e) Failure to return for evaluation due to death or deteriorating condition. 
f) 
Clear progression of non-measurable disease.  
*Stable doses of corticosteroids include patients not on corticosteroids 
 
 
 
 

45 
RTOG 1205; version date 10/3/16 
 
 
Summary of RANO Response Criteria 
 
Criterion 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥ 50%  
< 50%  - < 25%  
≥ 25% * 
T2/FLAIR 
Stable or  
Stable or  
Stable or  
* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or  
Stable or  
NA** 
Clinical Status 
Stable or  
Stable or  
Stable or  
* 
Requirement for 
response 
All 
all 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR=complete response; PR=partial 
response; SD=stable disease; PD=progressive disease; FLAIR, fluid-attenuated inversion recovery;  = 
decrease;  = increase 
# Progression occurs when any of the criteria with * is present. 
 
NA**: Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration. 
 
11.4.2 Efficacy Assessments 
 
Progression free survival (PFS) will be defined from the time the patient enters the study until 
there is clinical or radiographic evidence of progressive disease (see definition of PD above). 
 
Overall survival (OS) will be defined from the time the patient enters the study to the date of 
death. Patients not known to have died will be censored for survival as of the last date known 
alive.   
 
PFS and overall survival will be estimated by using the Kaplan-Meier method. 
 
 
The primary endpoint for this study is overall survival. 
 
11.5  
Criteria for Discontinuation of Protocol Treatment 
 
Progression of disease (See Section 11.2) 
 
Unacceptable toxicity to the patient (at the discretion of the treating physician) — Reasons for 
removal must be clearly documented on the appropriate case report form/flow sheet, and 
NRG Oncology data management must be notified. 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 

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RTOG 1205; version date 10/3/16 
 
 
12.0 
DATA COLLECTION 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1600 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will 
be used (first-last). Last names with apostrophes will be identified by the first letter of the last 
name. 
 
12.1 
Summary of Data Submission (10/9/14) 
 
 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks after registration 
Initial Evaluation Form (I1) 
 
Pathology Report (P1) to mail a copy of the 
report to NRG Oncology 
 
 
 
 
 
 
 
Treatment Form (TF) 
At completion of each 8-week period (4 doses of 
bevacizumab per TF form if no protocol 
modification) 
 
 
 
 
 
 
Follow-up Form (F1) 
At the time of progression and at death. AFTER 
progression or treatment discontinuation: every 2 
months for 1 year, then every 6 months for 1 
year, then annually. 
 
 
 
MRI scans and Reports (MR, ME) 
 
Pre-study (complete series) (see Section 12.2) 
 
Progression to TRIAD (see Section 12.2) 
 
 
 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.5 for 
account access and installation instructions) (4/15/14) 
 
Preliminary Dosimetry Information  
 
Digital Data Submission – Treatment  
Within 1 week of 
start of RT  
Digital data submission includes the following, all in DICOM format: 
 
 
CT data, critical normal structures, all GTV, CTV, and PTV contours  
 
 
Digital beam geometry beam sets 
 
 
Single dose file for concurrently treated beams 
 
 
Digital DVH data for all required critical normal structures, GTV, CTV, and 
PTVs for total dose plan  
 
All required structures MUST be labeled per Table in Section 6.5.1. 
 

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RTOG 1205; version date 10/3/16 
 
 
The “RTOG 1205 Datasheet” is available in the Forms section of the of the 
NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1
205. Submit via TRIAD with the digital data listed above. 
 
 
Upon submission of any digital data via TRIAD, complete an online  digital 
data submission form (DDSI) located on the NRG Oncology/RTOG web site at  
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205 
 
 
Item 
Due 
MRI SUBMISSION 
Pre-study MRI (the Scan used to delineate the target 
volumes for planning. Submit the entire series via 
TRIAD  
 
 
 
 
Final Dosimetry Information 
Within 1 week of RT end 
Radiotherapy Form (T1) via the web 
 
Daily Treatment Record (T5) on paper to HQ 
 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES WILL 
BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1  
Study Endpoints (11/20/13) 
13.1.1 Primary Endpoint 
Overall Survival, defined as the interval from randomization to death due to any cause. 
13.1.2  Secondary Endpoints 
 
Objective response 
 
6-month progression-free survival 
 
Progression-free survival, defined as the interval from randomization to progression or death, 
whichever occurs first 
 
Treatment adverse events 
 
Grade 3+ acute or delayed CNS toxicity 
 
13.2  
Sample Size and Power Justification 
The primary objective of this study is to determine whether re-irradiation plus bevacizumab 
(experimental arm) will improve the overall survival compared to bevacizumab alone (control 
arm). The design will be a randomized phase II screening trial as proposed by Rubinstein et al 
(2005). The randomization of experimental and control arms is 1:1. The null hypothesis is that the 
overall survival for both arms is 9 months, based on data from RTOG 0625/ACRIN 6677 and the 
BRAIN study. The alternative hypothesis is that patients receiving IMRT plus bevacizumab will 
have an improvement in overall survival to 13 months, based on the Gutin data. With 160 eligible 
subjects, there will be 80% power to detect a 31% reduction in the hazard ratio to 0.69 at the 
significance level of 0.10 (one-sided).  Analysis will be performed when 135 events (deaths) are 
reported, expected to occur 16 to 21 months after trial closure. Guarding against up to a 10% 
ineligibility rate, the final target accrual for this study will be 178 cases. 
 
13.3 
Patient Accrual 
Based on the monthly accrual for a prior RTOG recurrent glioblastoma phase II study (RTOG 
0625), this study is projected to accrue 10 cases/month. Therefore, the target accrual should be 
completed within 22 months of study activation, allowing slow accrual in the first 6 months.  If the 
average monthly accrual (6 months after trial activation) is less than 5 patients, the study will be 
re-evaluated with respect to feasibility. 
 

48 
RTOG 1205; version date 10/3/16 
 
13.4 
Patient Stratification and Randomization (4/15/14) 
A randomized phase II trial will be conducted for bevacizumab-naïve recurrent GBM patients. Age 
and Karnofsky performance status (KPS) are demonstrated to be prognostic of survival for 
recurrent GBM (Carson 2007). In addition, previous RTOG recurrent GBM trials (RTOG 0625, 
0627) show that age, KPS, and resection type have prognostic value in overall survival. 
Therefore, for this NRG Oncology recurrent GBM study, patients will be stratified by age (<50 vs. 
≥50), KPS (60 vs. 70-80 vs.90-100), and resection type (yes vs. no/biopsy only), and then 
randomized to either the control arm or experimental arm in a permuted block design using the 
method described by Zelen (1974). 
 
13.5  
Analyses Plans 
13.5.1  Statistical Methods 
Overall and progression-free survival rates will be estimated using the Kaplan-Meier method 
(Kaplan 1958), and differences between treatment arms will be tested in the log-rank test (Mantel 
1966).  Overall survival will be measured from the date of randomization to the date of death or, 
otherwise, the last follow-up date on which the patient was reported alive. Progression-free 
survival will be measured from the date of randomization to the date of first progression or death 
or, otherwise, the last follow-up date on which the patient was reported alive. 
 
Objective response rate, grade 3+ toxicities rate, acute or delayed CNS toxicity rate, and 6-month 
progression-free survival rate, will be estimated using an exact binomial distribution together with 
95% confidence interval.  The difference between the 2 groups will be tested using a chi square 
test. In terms of grade 3+ toxicity and acute/delayed toxicity, all patients receiving any protocol 
treatment (bevacizumab or combination of RT with bevacizumab) should be included.  For the 
statistical comparison of the primary endpoint (overall survival), the type I error is set as 0.1 (1-
sided), while for all the secondary endpoints, the statistical comparison between groups will serve 
as an exploratory purpose without multiple comparison adjustment, with type I error of 0.05 (2-
sided) for each comparison. 
 
Multivariate analyses with the Cox proportional hazard model (Cox 1972) for overall and 
progression-free survival will be performed with the stratification variables as fixed variables to 
assess the treatment effect adjusting patient-specific risk factors. The covariates evaluated for the 
multivariate models are assigned protocol treatment, tumor volume at the time of treatment, time 
since original diagnosis, stratification factors, and other prognostic factors. Proportional hazard 
assumptions will be checked using different graphical or time-varying coefficients testing 
methods. If the data clearly do not follow proportional hazards, other statistical models will be 
used to fit the data instead. Possible alternatives are to use the stratified Cox proportional hazard 
model, accelerated failure model, or partition the time axis into sections where proportional 
hazard assumption holds.  
13.5.2  Interim Toxicity and Futility Analysis 
Due to a possible increased incidence of grade 3+ CNS toxicity (possibly, probably, or definitely 
related to treatment) occurring during the first 6 months post RT in the experimental arm, a 
special interim analysis will be performed after the first 20 patients enrolled to the experimental 
arm have a minimum 6-month follow-up. If the incidence of grade 3+ CNS toxicity (based on 
RTOG 0625) is 20% higher, or 30%, in the experimental arm, the trial will be halted due to lack of 
safety. The interim toxicity analysis results will be reported to the NRG Oncology DMC. The DMC 
will then make a recommendation about the trial to the NRG Oncology Group Co-Chairs. 
 
The interim futility analysis will be performed when 50% of the required events (68 deaths) are 
reported. The analysis will be performed on an intent-to-treat basis, with all eligible cases 
included in the treatment arm to which they were randomized regardless of what treatment the 
patients actually received.  The primary endpoint, overall survival, will be tested. The futility will be 
tested using the conditional probability under the alterative hypothesis of detecting the 
hypothesized treatment benefit favoring the experimental arm at the final analysis given the 
observed data. The results from testing the treatment futility will be reported to the NRG Oncology 
DMC. The responsible statistician may recommend early reporting of the results and/or stopping 

49 
RTOG 1205; version date 10/3/16 
 
accrual (if applicable) of the trial if the conditional power is less than 0.1. The accrual rate, 
treatment compliance, safety of the treatments, and the importance of the study are also 
considered in making such a recommendation. The results will be reported to the RTOG DMC 
with the treatment blinded. The DMC will then make a recommendation about the trial to the NRG 
Oncology Group Co-Chair. 
13.5.3  Interim Analysis to Monitor Study Progress 
Interim reports with statistical analyses are prepared every 6 months until the initial manuscript 
reporting the treatment results has been submitted.  The reports contain: 
 
The patient accrual rate with a projected accrual completion date  
 
Accrual by institution 
 
The pretreatment characteristics of accrued patients  
 
The frequency and severity of toxicities  
 
The results of any completed study chair modality reviews 
The interim reports will not contain the results from the treatment comparisons with respect to the 
efficacy endpoints (overall survival, progression-free survival, treatment response).  The NRG 
Oncology DMC will review the accrual to the study and the rate of adverse events on the study at 
least twice per year until the initial results of the study have been presented to the scientific 
community. 
13.5.4  Significance Testing for Final Analysis 
The final analysis will be performed on an intent-to-treat basis, such that all eligible cases on the 
study will be included in the arm to which they were randomized regardless of what treatment the 
patients actually received.  The analysis to report the final results of treatment comparison 
between the experimental arm and the control arm will be undertaken when 135 events (deaths) 
have been reported. A one-sided log-rank test will be performed to test the difference in overall 
survival between the two treatment arms. If the p value is less than protocol-specified 0.10 (one 
sided), the study statistician will reject the null hypothesis and conclude that the experimental arm 
(re-radiation plus bevacizumab) is promising in prolonging overall survival, therefore supporting 
the development of a confirmatory phase III trial comparing this regimen to the current standard 
treatment.   All information reported in the interim analyses to monitor the study progress (above) 
and the treatment compliance with respect to re-radiation and chemotherapy will also be included 
in the final report. 
13.5.5 This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative 
CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 
30, July 31, and October 31. 
 
13.6 
Gender and Minorities 
In conformance with the National Institutes of Health (NIH) Revitalization Act of 1993 with regard 
to inclusion of women and minorities in clinical research, both men and women of all races and 
ethnic groups are eligible for this study. We will also analyze treatment differences by gender, 
race, and ethnicity.  The following table lists the projected accrual for each racial and ethnic group 
based upon previous RTOG recurrent GBM trials. 
 
Projected Distribution of Gender and Minorities 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
10 
13 
23 
Not Hispanic or Latino 
67 
88 
155 
Ethnic Category: Total of all subjects 
77 
101 
178 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
3 
3 
6 
Black or African American 
6 
6 
12 

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RTOG 1205; version date 10/3/16 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
66 
90 
156 
Racial Category: Total of all subjects 
77 
101 
178 
 
 

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RTOG 1205; version date 10/3/16 
 
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Jain RK, di Tomaso E, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610-
622. 
 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53:457-481. 
 
Kim HK, Thornton AF, Greenberg HS, et al. Results of re-irradiation of primary intracranial neoplasms 
with three-dimensional conformal therapy. Am J Clin Oncol.1997;20:358-363. 
 
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus 
irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-4740. 
 
Laing RW, Warrington AP, Graham J, et al. Efficacy and toxicity of fractionated stereotactic radiotherapy 
in the treatment of recurrent gliomas (phase I/II study). Radiother Oncol. 1993;27:22-29. 
 
Lai A, Tran A, Nghiemphu P, et al. Phase II study of bevacizumab plus temozolomide during and after 
radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. 2010;29:142-
148. 
 
Lederman G, Wronski M, Arbit E, et al. Treatment of recurrent glioblastoma multiforme using fractionated 
stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol. 2000;23:155-159. 
 
Lee C-G, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor 
radiation response under normoxic or hypoxic conditions. Cancer Res. 2000;60:5565-5570 
 
Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab 
therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79:1487-
1495. 
 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer 
Chem Rep. 1966;5:163-170. 
 
Mayer R, Sminia P. Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys. 
2008;70:1350-1360. 
 
Nieder C, Astner ST, Mehta MP et al. Improvement, clinical course, and quality of life after palliative 
radiotherapy for recurrent glioblastoma. Am J Clin Oncol. 2008;31:300-305. 
 
Niyazi M, Ganswindt U, Birgit S et al. Irradiation and bevacizumab in high-grade glioma retreatment 
settings. Int J Radiat Oncol Biol Phys. October 27, 2010. Epub ahead of print. 
 
Provencio M, Sanchez A, Garrido P, et al.New molecular targeted therapies integrated with radiation 
therapy in lung cancer. Clin Lung Cancer. 2010;11:91-97. 
 
Quant EC, Norden AD, Drappatz J, et al. Role of a second chemotherapy in recurrent malignant glioma 
patients who progress on bevacizumab. Neuro Oncol. 2009;11:550-555. 
 
Reardon D, Desjardins A, Vredenburgh JJ, et al. Metronomic chemotherapy with daily, oral etoposide 
plus bevacizumab for recurrent malignant glioma: phase II study. Br J Cancer. 2009;101:1986-1994. 
 
Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for 
phase II screening trials. J Clin Oncol. 2005;23:7199-7206. 
 
Sathornsumetee S, Desjardins A, Vredenburgh JJ, et al. Phase II study of bevacizumab and erlotinib in 
patients with recurrent malignant glioma. Neuro Oncol. 2010;12:1300-1310. 

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Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide 
for glioblastoma. New Engl J Med. 2005;352:987-996. 
 
VanderSpek L, Fisher B, Bauman G, et al. 3D conformal radiotherapy and cisplatin for recurrent 
malignant glioma. Can J Neurol Sci. 2008;35:57-64. 
 
Verhoeff JJ, Lavini C, van Linde ME, et al. Bevacizumab and dose-intense temozolomide in recurrent 
high grade glioma. Ann Oncol. 2010;21:1723-1727. 
 
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recurrent malignant glioma. Clin Cancer Res. 2007;13:1253-1259a. 
 
Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent 
glioblastoma multiforme. J Clin Oncol. 2007;25:4722-4729b. 
 
Vredenburgh JJ, Cloughesy T, Samant M, et al, Corticosteroid use in patients with glioblastoma at first or 
second relapse treated with bevacizumab in the BRAIN study. Oncologist. 2010;15:1329-1334. 
 
Vredenburgh JJ, Desjardins A, Reardon DA, et al. The addition of bevacizumab to standard radiation 
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glioblastoma. Clin Cancer Res. 2011:17:4119-4124. 
 
Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients 
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Zelen M. (1974). The randomization and stratification of patients to clinical trials. J Chronic Dis. 27:365-
75. 
 

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APPENDIX I: STUDY PARAMETER TABLES (10/9/14)  
 
 
Pre-Treatment Assessments 
Assessment 
Prior to registration 
Within 14 days prior to 
registration 
Pre-Treatment 
 
Histopath dx 
(P1: pathology 
report to be 
mailed to HQ per 
section 12.0) 
X 
 
 
History 
 
X 
 
Physical 
 
X 
 
Neurological 
exam 
 
X 
 
Tumor imaging 
MRI/CT scan (pts 
without recent 
resection; see 
Section 3.1.1for 
details) (MR 
diffusion and 
perfusion imaging 
strongly 
recommended) 
 
Within 21 days 
 
Tumor imaging 
MRI/CT scan (pts 
with recent 
resection; see 
Section 3.1.4 for 
details) (MR 
diffusion and 
perfusion imaging 
strongly 
recommended) 
And recommended to be within 
96 h post-surgery 
 
 
Karnofsky status 
 
X 
 
CBC w/ 
differential 
 
X 
 
Bilirubin 
SGOT or AST 
 
X 
 
Serum creatinine 
 
X 
 
Urine protein: 
creatinine or urine 
dipstick 
 
X 
 
Serum pregnancy 
test (if applicable) 
 
Within 7 days 
 
MGMT 
methylation status 
(see Section 4 for 
details) 
 
 
X 
Tissue, blood, 
urine for banking 
(if patient 
consents; see 
Section 10 for 
details) 
 
 
X 

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RTOG 1205; version date 10/3/16 
 
Assessments During Treatment 
Assessment 
q8 weeks (± 3 days)
At 8 weeks, 24 weeks, and 
progression 
Physical 
RT arm: weekly during RT 
 
Non-RT arm: q8 weeks 
 
Weight 
X (See 7.1.1; done prior to 
each drug dose) 
 
Neurological exam 
X 
 
Tumor imaging 
MRI/CT scan 
X 
 
Karnofsky status 
X 
 
CBC w/ differential 
X 
 
Urine protein: 
creatinine or urine 
dipstick 
X (See 11.1; done prior to 
each drug dose) 
 
MR diffusion and 
perfusion imaging 
(optional but strongly 
recommended) 
 
X  
Blood pressure 
monitoring 
X (See 11.1; done prior to 
each drug dose) 
 
AE evaluation 
X 
 
Blood, urine for 
banking  
(if patient consents) 
At 8 weeks after treatment 
initiation (± 3 days) 
 
 
 
 
Follow-Up Assessments 
Assessments 
After treatment discontinuation or progression: q8 weeks for 1 year, then q6 
months for 1 year, then annually (± 2 weeks). 
(See Section 12.1 for details) 
Physical 
X 
Karnofsky status 
X 
AE evaluation 
X 
 

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RTOG 1205; version date 10/3/16 
 
APPENDIX II 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 

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RTOG 1205; version date 10/3/16 
 
APPENDIX III (10/9/14) 
 
Appendices for NRG Oncology Biospecimen Collection (as specified by the protocol). 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Blood Collection Kit Instructions 
NRG Oncology Urine Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped in paper  or placed in a cardboard box with padding. Do not wrap 
blocks  with bubble wrap or gauze. Place padding in top of container so that if you shake the 
container the blocks are not shaking If you can hear the block shaking it might break during 
shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address 
(94115). Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. . If possible keep Serum, Plasma, and Whole Bloods in separate 
bags. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens on dry ice via overnight courier to the address above. Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent 
thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples 
can be stored frozen at -80 C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by e-mail: RTOG@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-
5271. 

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RTOG 1205; version date 10/3/16 
 
NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank. The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area. (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block. Twist the punch tool 
once around to separate the plug from the block. Then pull the 
punch tool out of the block. The punch should be filled with tissue 
sample. 
 
 
 
Step 2 
Label the punch tool with the proper specimen ID. Include the 
pathology accession number and block ID.  DON’T remove 
specimen from the punch. 
 
Use a separate punch tool for every specimen. Call or e-mail us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block 
and return the remaining block to your facility.  Please indicate on the submission form the request to 
perform the plug procedure and return of the block. 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For 
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact 
the NRG Oncology Biospecimen Bank by e-mail: RTOG@ucsf.edu or call 415-476-7864/Fax 415-
476-5271. 
 
U.S. Postal Service Mailing Address:  
For Non-frozen Specimens Only 
 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.):  
For Frozen Specimens or Trackable 
shipments 
 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 

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RTOG 1205; version date 10/3/16 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: 
 
One Red Top tube for serum (A) 
 
One Purple Top EDTA tube for plasma (B) 
 
One Purple Top EDTA tube for Whole Blood (C) 
 
Twenty-one (21) 1 ml cryovials 
 
Biohazard bags (3) and Absorbent shipping material (3) 
 
Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal (ST) Form  and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube 
 
Label as many 1ml cryovials (5 to 8) as necessary for the serum collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites 
are unable to process samples at 4C then spinning at room temperature is acceptable if 
done within 2 hours of draw but must be noted on the ST Form. 
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 8) 
labeled with NRG Oncology study and case numbers, collection date/time, protocol time-point 
collected (e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”. If an 
aliquot has less than 0.5 ml in the tube please note the volume on the vial and make a 
note on the ST Form. 
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen 
until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one 
hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the 
plasma collected (5 to 8)  labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “plasma”.  Avoid pipetting up the 
buffy coat layer. If an aliquot has less than 0.5 ml in the tube please note the volume on 
the vial and make a note on the ST Form. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 

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RTOG 1205; version date 10/3/16 
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. If an aliquot has less 
than 1.0 ml in the tube please note the volume on the vial and make a note on the ST 
Form. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
ST Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  

61 
RTOG 1205; version date 10/3/16 
 
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard 
bag.  Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail RTOG@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: RTOG@ucsf.edu  

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RTOG 1205; version date 10/3/16 
 
NRG ONCOLOGY URINE COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of urine specimens. 
Kit Contents: 
 
One (1) Sterile Urine collection cup 
 Two 15 ml polypropylene centrifuge 
tubes 
 
Two 7 ml disposable pipettes 
 Biohazard bags 
 
Absorbent paper towel 
 Parafilm for sealing outside of tubes 
 
Preparation and Processing of Urine Specimens: 
Process: 
 
A clean catch urine specimen will be collected. To collect the specimen, use the following 
instructions: 
o 
Males should wipe clean the head of the penis and females need to wipe between the 
labia with soapy water/cleansing wipes to remove any contaminants.  
o 
After urinating a small amount into the toilet bowl to clear the urethra of contaminants, 
collect a sample of urine in the collection cup. 
o 
After 10-25 mL urine has been collected, remove the container from the urine stream 
without stopping the flow of urine. 
o 
Finish voiding the bladder into the toilet bowl. 
 
Aliquot 5-10 mls of Urine into each of two 15 ml polypropylene centrifuge tubes (disposable 
pipets are provided in the kit). Do not fill with more than 10 mls to avoid cracking of tubes due 
to expansion during freezing. Replace the cap and tighten on the tubes. Make sure the cap is 
not cross-threaded or placed on incorrectly or leaking will occur.  
 
Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
 
Discard remaining Urine and collection cup. 
 
Label the specimen with the NRG Oncology study and case number, collection date and 
time, time point of collection, and clearly mark specimens as “urine”. 
 
Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and 
seal the bag. Freeze and store Urine samples in a -20C or -80C freezer until ready to ship. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with NRG Oncology study and case 
numbers, collection date/time, and time point collected (e.g. pretreatment, post-treatment). 
 
Storage and Shipping: 
Freezing and Storage: 
 
Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days 
of collection. Store at -20C or -80C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 
lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 

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RTOG 1205; version date 10/3/16 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
Samples received thawed will be discarded, and a notification will be sent immediately to the 
Principal Investigator and Clinical Research Assistant of the submitting institution. The institution 
should send a subsequent sample, collected as close as possible to the original planned 
collection date. 
 
For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please 
e-mail RTOG@ucsf.edu or call (415)476-7864 or fax (415) 476-5271. 
 
 
Shipping Address: FedEx/UPS/Courier address (For all frozen samples) 
NRG Oncology Biospecimen Bank San Francisco 
2340 Sutter Street, Room S341, UCSF 
San Francisco, CA  94115 
Contact Phone: (415) 476-7864