rtog 1205 randomized phase ii
untitled h2

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.
rtog 1205 randomized phase ii
study chairs (8/24/15) principal investigator/radiation

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 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 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 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 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  
| 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   |  
| 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
rtog 1205 randomized phase ii
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.  
| (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:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 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. | See Protocol Section 12.0 for  data submission |
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Do not submit study data or  forms to CTSU Data Operations.  Do not copy the CTSU on data  submissions.                                                                                                                             |                                                |
| Contact the CTSU Help Desk  with any OPEN-related questions  at ctsucontact@westat.com                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                     |                                                |
| For regulatory questions call  the CTSU Regulatory Help  Desk at 1-866-651-CTSU  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. |                                                                                                                                                                                                                                     |                                                |
rtog 1205 randomized phase ii
table of contents

| SCHEMA                                                                                                              |                                                                                                                                     |
|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|
| ELIGIBILITY CHECKLIST  .                                                                                            |                                                                                                                                     |
| 1.0                                                                                                                 | INTRODUCTION                                                                                                                        |
| 1.1                                                                                                                 | OVERVIEW .                                                                                                                          |
| 1.2                                                                                                                 | Safety, Efficacy, and Rationale for Combination of Bevacizumab and Re-Irradiation................. 14                               |
| 2.0                                                                                                                 | OBJECTIVES                                                                                                                          |
| 2.1                                                                                                                 | Primary Objective                                                                                                                   |
| 2.2                                                                                                                 | Secondary Objectives .                                                                                                              |
| 3.0                                                                                                                 | PATIENT SELECTION                                                                                                                   |
| 3.1                                                                                                                 | Conditions for Patient Eligibility .                                                                                                |
| 3.2                                                                                                                 | Conditions for Patient Ineligibility .                                                                                              |
| 4.0                                                                                                                 | PRETREATMENT EVALUATIONS/MANAGEMENT                                                                                                 |
| 4.1                                                                                                                 | Highly Recommended Evaluations .                                                                                                    |
| 5.0                                                                                                                 | REGISTRATION PROCEDURES                                                                                                             |
| 5.1                                                                                                                 | Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) Treatment Approach) 18                                           |
| 5.2                                                                                                                 | Pre-Registration Requirements for IMRT Treatment Approach                                                                           |
| Pre-Registration Reguirements for 3D-CRT Treatment Approach .................................................... 19 |                                                                                                                                     |
| 5.3                                                                                                                 | Pre-Registration Reguirements for Proton Treatment Approach ........................................................... 19          |
| 5.4                                                                                                                 | Digital RT Data Submission Using TRIAD .                                                                                            |
| 5.5                                                                                                                 | REGISTRATION REGIS                                                                                                                  |
| 5.6                                                                                                                 |                                                                                                                                     |
| 5.7                                                                                                                 | Registration .                                                                                                                      |
| 6.0                                                                                                                 | RADIATION THERAPY                                                                                                                   |
| 6.1                                                                                                                 | Dose Specifications                                                                                                                 |
| 6.2                                                                                                                 | Technical Factors [Equipment, energies]                                                                                             |
| 6.3                                                                                                                 | Localization, Simulation, and Immobilization .                                                                                      |
| 6.4                                                                                                                 | T Treatment Planning/Target Volumes                                                                                                 |
| 6.5                                                                                                                 | CC                                                                                                                                  |
| 6.6                                                                                                                 | Documentation Requirements .                                                                                                        |
| 6.7                                                                                                                 | Compliance Criteria                                                                                                                 |
| 6.8                                                                                                                 | R.T. Quality Assurance Reviews                                                                                                      |
| Radiation Therapy Adverse Events                                                                                    |                                                                                                                                     |
| 6.9                                                                                                                 | Radiation Therapy Adverse Event Reporting                                                                                           |
| 6.10                                                                                                                | DRUG THERAPY .                                                                                                                      |
| 7.0                                                                                                                 |                                                                                                                                     |
| 7.1                                                                                                                 | T Treatment                                                                                                                         |
| 7.2                                                                                                                 | Bevacizumab Agent Information                                                                                                       |
| 7.3                                                                                                                 | Bevacizumab Dose Modifications .                                                                                                    |
| 7.4                                                                                                                 | Modality Review                                                                                                                     |
| 7.5                                                                                                                 | Adverse Events .                                                                                                                    |
| 7.6                                                                                                                 | CTEP-AERS Expedited Reporting Requirements ......................................................................................37 |
| 8.0                                                                                                                 | SURGERY                                                                                                                             |
| 9.0                                                                                                                 | OTHER THERAPY                                                                                                                       |
| 9.1                                                                                                                 | Permitted Supportive Therapy .                                                                                                      |
| 4                                                                                                                   | 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 |                                                               |
nrg oncology rtog 1205
table of contents

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:  
  
Age  
  
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
eligibility checklist (10/9/14) (page 1
nrg oncology institution # rtog

(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?                                                                                                        |                                                                                                                                                                                                                                                                                                                                                    |
eligibility checklist (9/3/15) (page 2
nrg oncology institution # rtog

(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) 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)   | 21. Does the patient have a recurrent or persistent tumor greater than 6 cm in  maximum diameter?   |
|-------|-----------------------------------------------------------------------------------------------------|  
(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)?  
| (N)   | 26. Does the patient have prior history of hypertensive crisis or hypertensive  encephalopathy?   |
|-------|---------------------------------------------------------------------------------------------------|  
ELIGIBILITY CHECKLIST (11/5/12)
(page 3 of 5)
NRG Oncology Institution \# RTOG 1205
case #
the following questions will be

1. Institutional person randomizing case. 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?    |  
(Y) 2. Has the Eligibility Checklist been completed?  
 4. Date informed consent signed 5. Patient Initials (First Middle Last) 6. Verifying Physician  
| (Y) 3.   | In the opinion of the investigator, is the patient eligible?   |
|----------|----------------------------------------------------------------|
case #
eligibility checklist (11/5/12) (page 4

(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?  (1) 70-80  (2) 90-100  (3) 60                    |
|     | (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)                                                                                        | 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                                                                                  |       |                                                                                                                                                                                                      |  
27. Karnofsky performance status:  
(1) 70-80 (2) 90-100 (3) 60  
(Y/N) 31. Will IGRT be used for patient positioning?
(page 5 of 5)
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 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 6month 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. 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 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.
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1.2 safety efficacy and rationale

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 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.  
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:
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.  
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 postoperative 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
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.
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3.2 conditions for patient ineligibility

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)
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4.0 pretreatment evaluations/management note this

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.
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5.0 registration procedures (10/9/14) access

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.
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5.1 pre-registration requirements for image-guided

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 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.
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5.2 pre-registration requirements for imrt

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.
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5.3 pre-registration requirements for 3d-crt

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.
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5.4 pre-registration requirements for proton

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.  
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. 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.
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5.6 regulatory pre-registration requirements (10/9/14)

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>.
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site registration requirements [insert as

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.
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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
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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) 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
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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)
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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.
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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.  
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://eappsctep.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.
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6.0 radiation therapy (11/20/13) note

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                                                                  | Greater than or equal                                                                                                   | Greater than or equal                                                                                              | Less than 28 Gy (80% of                                                                            |
| PTV (0.03 cc)                                                                        | to 29.75 Gy (85% of                                                                                                     | to 28 Gy (80% of the                                                                                               | the prescription dose) -                                                                           |
| 23                                                                                   | 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                                | Less than or equal to                                                                                                                 |                                                                                                                              |                                                               |
| PTV (0.03 cc)                                      | 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).
(page 5 of 5)
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 computerassisted 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 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  Less than or equal to  (0.03 cc)  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  Less than or equal to  (0.03 cc)  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   |
|-----------------------------|--------------------------------------------------|-----------------------|----------------------|
| Residual enhancing tumor or |                                                  |                       |                      |
| GTV_3500                    | post-operative resection                         | 35                    | Required             |
| cavity                      |                                                  |                       |                      |
| CTV_3500                    | An Optional CTV expansion  of no more than 5 mm. | 35                    | Required             |
| planning target volume; an  |                                                  |                       |                      |
| PTV_3500                    | additional margin of 3 to 5                      | 35                    | Required             |
| mm                          |                                                  |                       |                      |
| 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              |                      |  
| 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   |
(page 5 of 5)
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.
(page 5 of 5)
6.10 radiation therapy adverse event

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 Bevacizumab will be administered intravenously per institutional guidelines with associated premedications.  
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.
(page 5 of 5)
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.
(page 5 of 5)
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
(page 5 of 5)
comprehensive adverse events and potential

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 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                                            |                        |  
| 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                                     | Alanine aminotransferase increased |
| increased                                                                                                                                         | (Gr 3)                                                       |                                    |
| Alkaline phosphatase                                                                                                                              | Alkaline phosphatase increased (Gr                           |                                    |
| increased                                                                                                                                         | 3)                                                           |                                    |
| Aspartate aminotransferase                                                                                                                        | Aspartate aminotransferase                                   |                                    |
| increased                                                                                                                                         | 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                                                                                                                           |                                                              |                                    |  
| 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)                                  |                                                  |  
  
| 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, Intraabdominal 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.  
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; 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                                                         | 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. |
| or  Acute infusional reactions/  cytokine release syndrome                 | 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                                                                                                                                                                                                                                                                                                                                                                                                                            | Discontinue bevacizumab                                                                                                                                                                                                                      |
| worsened since                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                              |
| bevacizumab therapy)                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                              |  
| Event                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | CTCAE.v4.0 Grade                                                                                                                                                                                                                                                                                                                                                                              | Action To Be Taken        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|
| CVA)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                               |                           |
| - any peripheral or  visceral arterial  ischemia/thrombosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Grade 3-4                                                                                                                                                                                                                                                                                                                                                                                     | Discontinue bevacizumab   |
| Venous Thrombosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |  Hold bevacizumab treatment. If the planned duration of                                                                                                                                                                                                                                                                                                                                      |                           |
| Grade 3  OR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | full-dose anticoagulation is < 2 weeks, bevacizumab                                                                                                                                                                                                                                                                                                                                           |                           |
| asymptomatic grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 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  Continue bevacizumab  < 3.5  UPC ratio  Hold bevacizumab until UPC recovers to < 3.5  > 3.5  Grade 4 or nephrotic  Discontinue bevacizumab  syndrome                                        |                           |
| Hemorrhage (CNS or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Grade 2-4                                                                                                                                                                                                                                                                                                                                                                                     |  Discontinue bevacizumab |
| pulmonary)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                               |                           |  
| Event                                                                                                                                                                                                                                                                                                                                                                                                                                          | CTCAE.v4.0 Grade                                                                                                                                                                                                                                                      | Action To Be Taken                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|
| Hemorrhage (non-CNS;                                                                                                                                                                                                                                                                                                                                                                                                                           | Grade 3                                                                                                                                                                                                                                                               |  Patients receiving full-dose anticoagulation should |
| non-pulmonary)                                                                                                                                                                                                                                                                                                                                                                                                                                 | 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                                                                                                                                                                                                                                                                                                                                                                                                 | Discontinue bevacizumab                                                                                                                                                                                                                                              |                                                       |
| intervention  GI perforation, GI leak or fistula                                                                                                                                                                                                                                                                                                                                                                                               | Discontinue bevacizumab                                                                                                                                                                                                                                               |                                                       |
| Bowel obstruction                                                                                                                                                                                                                                                                                                                                                                                                                              | Grade 2 requiring                                                                                                                                                                                                                                                     |  Hold bevacizumab until complete resolution, with a  |
| medical intervention                                                                                                                                                                                                                                                                                                                                                                                                                           | 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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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://eappsctep.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 CTEPAERS **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.
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7.5.3 acute myeloid leukemia (aml)

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 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://eappsctep.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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fda reporting requirements for serious

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.  
| Grade 1          | Grade 2            | Grade 3          |            |
|------------------|--------------------|------------------|------------|
| Hospitalization                  | Grade 4 & 5        |                  |            |
| Timeframes       | Timeframes         | Timeframes       | Timeframes |
| Resulting in     |                    |                  |            |
| Hospitalization  | 10 Calendar Days   |                  |            |
| ≥ 24 hrs         | 24-Hour 5 Calendar |                  |            |
| Not resulting in | Days               |                  |            |
| Hospitalization  | Not required       | 10 Calendar Days |            |
| ≥ 24 hrs         |                    |                  |            |  
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
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expedited ae reporting timelines are

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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9.2 non-permitted supportive therapy

9.2.1 Patients should avoid the use of medications that have anti-oxidant properties during radiation.
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10.0 tissue/specimen submission note patients

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).
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10.2 specimen collection for banking

(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: