NCI/Local Protocol #: RTOG-1122/RTOG NCI Protocol Version Date: October 3, 2016 (Broadcast October 17, 2016)

Transcription

1 For Protocol Amendment 11 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: October 3, 2016 (Broadcast October 17, 2016) Footer The protocol version date was updated Cover Pages The Document History Table was updated to include this amendment. The suite address was updated for Dr. Zhang In response to a CTEP Request for Amendment, the CAEPR for bevacizumab (Version 2.4, May 23, 2016) was revised as follows: Added New Risk: Less Likely: Creatinine increased; Erythroderma Rare but Serious: Avascular necrosis; Gallbladder perforation Increase in Risk Attribution: d to Less Likely from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Dry skin; Generalized muscle weakness; Hyperglycemia; Hypokalemia; Hyponatremia d to Rare but Serious from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Palmar-plantar erythrodysesthesia syndrome Deleted Risk: Less Likely: Cardiac troponin I increased Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Infections and infestations - Other (aseptic meningitis) Provided Further Clarification Footnote # 7 has been altered to read, Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. Footnote #11 has been added and reads, There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 treated with bevacizumab.

2 For Protocol Consent Amendment 11 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: October 3, 2016 (Broadcast October 17, 2016) Global Header What side effects or risks can I expect from being in the study? Minor formatting errors were corrected. The version date was updated for this amendment. Under Possible Side Effects of Bevacizumab, the risk profile for bevacizumab was amended to be consistent with the revised CAEPR for bevacizumab (Version 2.4, May 23, 2016) as follows: Added New Risk: Occasional: Swelling and redness of the skin Rare: Sores in the throat Increase in Risk Attribution: d to Occasional from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Dry Skin; Muscle weakness d to Rare from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Redness, pain or peeling of palms and soles Provided Further Clarification: Damage to the jawbone which may cause loss of teeth (under Occasional) is now being reported as Damage to organs which may cause loss of teeth or loss of motion (under Occasional). PLEASE NOTE: The potential risks listed in the CAEPR for which the relationship to bevacizumab is still undetermined are not required by CTEP to be described in the ICD; however, they may be communicated to patients according to local IRB requirements.

3 For Protocol Amendment 10 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: June 28, 2016 (Broadcast: July 11, 2016) Document footer Document History Table The protocol version was updated. This amendment was added.

4 In response to a CTEP Request for Amendment, the CAEPR for AMG-386 (Version 2.5, April 18, 2016) was revised as follows: Added New Risk: Rare but Serious: Hemorrhage Reported but With Insufficient Evidence for Attribution: Alkaline phosphatase increased; Bloating; Chylothorax; Confusion; Edema cerebral; Hyperkalemia; Hypernatremia; Hypoalbuminemia; Hyponatremia; INR increased; Investigations - Other (granulocyte count decreased); Kidney infection; Lymphedema; Nervous system disorders - Other (left-sided hemineglect); Peripheral ischemia; Peripheral sensory neuropathy; Rectal pain; Spinal fracture; Syncope; Upper respiratory infection; Urinary tract infection; Urinary tract obstruction; Wound infection Increase in Risk Attribution: to Less Likely from Reported but With Insufficient Evidence for Attribution: Hypertension d to Rare but Serious from Reported but With Insufficient Evidence for Attribution: Ascites; Blurred vision; Pleural effusion; Thromboembolic event Deleted Risk: Reported but With Insufficient Evidence for Attribution: Cardiac disorders - Other (intracardiac thrombus) Provided Further Clarification: Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lung neoplasm) and Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (vascular neoplasm) (under Reported but With Insufficient Evidence for Attribution) are now reported as Treatment related secondary malignancy (under Reported but With Insufficient Evidence for Attribution). Bronchopulmonary hemorrhage, Eye disorders - Other (eye hemorrhage), Gastrointestinal hemorrhage, Intracranial hemorrhage, Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage), Renal and urinary disorders - Other (bladder hemorrhage), and Vascular disorders - Other (arterial hemorrhage) (under Reported but With Insufficient Evidence for Attribution) are now reported as Hemorrhage (under Rare but Serious). Footnote 3, Thromboembolic events, including Cerebral venous thrombosis, Jugular vein thrombosis, Peripheral artery thrombosis, Subclavian vein thrombosis, Deep vein thrombosis, Pulmonary embolism, Retinal vascular thrombosis, and Intracardiac thrombus have been observed in AMG 386 (trebananib) trials has been added. Footnote 4 was deleted and the following footnote 5 was added: Hemorrhage events, some of which may be serious, including a Cerebral hemorrhage, Esophageal varices, Hemorrhage, Intracranial hemorrhage, Eye hemorrhage, Gastrointestinal hemorrhage, Arterial hemorrhage, Bronchopulmonary hemorrhage, Bladder hemorrhage, Rectal hemorrhage, and Tumor hemorrhage have been observed in AMG 386 (trebananib) trials.

5 For Protocol Consent Amendment 10 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: June 28, 2016 (Broadcast: July 11, 2016) Header The version date was updated for this amendment. Possible side effects of AMG 386 The risk profile for AMG-386 was amended to be consistent with the revised CAEPR as follows: Added New Risk: Rare and Serious: Bleeding Increase in Risk Attribution: d to Occasional from Reported but With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): High blood pressure which may cause headaches, dizziness d to Rare and Serious from Reported but With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Blurred vision; Fluid in the body Provided Further Clarification: Heart attack which may cause shortness of breath (under Rare) is now reported as Heart attack (under Rare). Blood clot which may cause blindness (under Rare) is now reported as Blood clot which may cause blindness, swelling, pain, or shortness of breath (under Rare).

6 For Protocol Amendment 9 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: September 2, 2015 (Broadcast: September 21, 2015 ) Document footer Document History Table The protocol version was updated. This amendment was added. For Protocol Consent Amendment 9 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: September 2, 2015 (Broadcast: September 21, 2015 ) Header The version date was updated for this amendment. What side effects or risks can I expect from being in the study? The risks and side effects table for Bevacizumab was inadvertently deleted during preparation of Amendment 8. The table has been reinserted.

7 For Protocol Amendment 8 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: July 31, 2015 (Broadcast: August 17, 2015) Document The protocol version was updated. footer Document This amendment was added. History Table Title page Contact information for Peixin Zhang, Phd, at NRG Oncology updated In response to a CTEP Request for Amendment, the CAEPR for AMG-386 (Version 2.4, January 16, 2015) was revised as follows: Added New Risk: Also Reported on AMG 386 Trials But with the Relationship to AMG 386 Still Undetermined: Abdominal infection; Acute coronary syndrome; Anorectal infection; Appendicitis; Bone pain; Cardiac disorders - Other (intracardiac thrombus); Cholecystitis; Colitis; Ear and labyrinth disorders - Other (inner ear fluid); Enterocolitis; Eye disorders - Other (blindness); Eye disorders - Other (central arterial occlusion); Eye disorders - Other (eye hemorrhage); Febrile neutropenia; GGT increased; Gastric ulcer; Gastrointestinal disorders - Other (intestinal ischemia); General disorders and administration site conditions - Other (generalized edema); Glaucoma; Hepatobiliary disorders - Other (hepatitis toxic); Hyperglycemia; Hypocalcemia; Hypoxia; Ileus; Ischemia cerebrovascular; Localized edema; Lung infection; Lymphocyte count decreased; Mania; Metabolism and nutrition disorders - Other (electrolyte imbalance); Mitral valve disease; Multi-organ failure; Neck pain; Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lung neoplasm); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (vascular neoplasm); Nervous system disorders - Other (hemiplegia); Neutrophil count decreased; Papilledema; Pericarditis; Personality change; Pneumonitis; Pulmonary edema; Respiratory, thoracic and mediastinal disorders - Other (obstructive airways disorder); Restrictive cardiomyopathy; Seizure; Sinus tachycardia; Skin and subcutaneous tissue disorders - Other (abnormal hair growth); Skin infection; Skin ulceration; Stroke; Tinnitus; Transient ischemic attacks; Tremor; Tumor pain; Vascular disorders - Other (arterial hemorrhage); Vertigo; Wound complication; Wound dehiscence Decrease in Risk Attribution: d to Less Likely from Likely: Edema limbs d to Reported But Undetermined from Less Likely: Ascites; Blurred vision; Creatinine increased; Pleural effusion

8 For Protocol Consent Amendment 8 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: July 31, 2015 (Broadcast: August 17, 2015) Header The version date was updated for this amendment. What side effects or risks can I expect from being in the study? Possible side effects of AMG 386 At CTEP s request, the text immediately under the heading was amended to be consistent with CTEP s current standard text. The risk profile for AMG-386 was amended to be consistent with the revised CAEPR as follows: Decrease in Risk Attribution: d to Occasional from Common: Swelling of the body d to Reported But Undetermined from Occasional: Fluid in the abdomen which may cause swelling; Blurred vision; Fluid in the chest which may cause shortness of breath Although there is modified risk information for AMG 386, no new risks have been added to the informed consent document (ICD). The amended information is considered to be risks that were already included in the previous version of the CAEPR and would have been communicated to patients in the informed consent document (ICD). In this case, a decrease in the frequency of edema (swelling) limbs, resulted in this risk being moved from likely to less likely, but this risk was previously identified. PLEASE NOTE: The potential risks listed in the CAEPR whose relationship to AMG 386 is still undetermined are not required by CTEP to be described in the ICD; however, they may be communicated to patients according to local IRB requirements.

9 For Protocol Amendment # 7 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: October 22, 2014 (November 3, 2014) Title pages Appendix I (Study Parameter Table) Informed Consent Contact information was updated for Dr. Aldape. The document history table was updated to include Amendment 7. On the second page of the appendix, a line for ALT, AST and Creatinine was added underneath Serum Chemistry. These assessments were intended to be collected during treatment and were inadvertently excluded from this table. The version date was updated for this Amendment. No other changes were made.

10 For Protocol Amendment # 6 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: July 23, 2014 (November 3, 2014) Title pages The document history table was updated to include Amendment In response to a CTEP Request for Amendment, the CAEPR for bevacizumab (Version 2.3, August 1, 2013) was revised as follows: Added New Risk: Less Likely: Dehydration; Wound complication Rare But Serious: Infections and infestations Other (necrotizing fasciitis) Also Reported on Bevacizumab Trials But With the Relationship to Bevacizumab Still Undetermined: Acidosis; Activated partial thromboplastin time prolonged; Agitation; Alopecia; Anxiety; Arachnoiditis; Arterial injury; Arthritis; Ascites; Ataxia; Atelectasis; Atrioventricular block complete; Atrioventricular block first degree; Back pain; Bladder spasm; Blood antidiuretic hormone abnormal; Blurred vision; Bone marrow hypocellular; Bone pain; Breast pain; Bruising; Burn; Carbon monoxide diffusing capacity decreased; Cardiac arrest; Cataract; CD4 lymphocytes decreased; Central nervous system necrosis; Cerebrospinal fluid leakage; Chelitis; Chest wall pain; Cholecystitis; Chronic kidney disease; Cognitive disturbance; Colonic stenosis; CPK increased; Cystitis noninfective; Death NOS; Depressed level of consciousness; Depression; Dermatitis radiation; Dry eye; Dry mouth; Dry skin; Dysesthesia; Dysphagia; Dysphasia; Ear and labyrinth disorders Other (tympanic membrane perforation); Edema face; Edema limbs; Edema trunk; Electrocardiogram QT corrected interval prolonged; Encephalopathy; Enterocolitis; Erectile dysfunction; Esophageal pain; Esophageal stenosis; Extraocular muscle paresis; Extrapyramidal disorder; 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; Facial nerve disorder; Facial pain; Fever; Fibrosis deep connective tissue; Flatulence; Flu like symptoms; Flushing; Forced expiratory volume decreased; Fracture; Gallbladder necrosis; Gallbladder obstruction; Gastrointestinal disorders Other (peritonitis); Generalized muscle weakness; GGT increased; Head soft tissue necrosis; Hearing impaired; Hemolysis; Hepatic necrosis; Hot flashes; Hydrocephalus; Hypercalcemia; Hyperglycemia; Hyperhidrosis; Hyperkalemia; Hypermagnesemia; Hypernatremia; Hyperthyroidism; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia; Hypotension; Hypothyroidism; Hypoxia; Injection site reaction; INR increased; Insomnia; Irregular menstruation; Joint effusion; Keratitis; Leukoencephalopathy; Libido decreased; Lipase increased; Localized edema; Lymphocele; Lymphocyte count decreased; Memory impairment; Multi-organ failure; Muscle weakness lower limb; Muscle weakness

11 upper limb; Musculoskeletal and connective tissue disorder Other (polymyalgia rheumatic); Myocarditis; Nail loss; Nasal congestion; Neck pain; Nervous system disorders Other (increased intracranial pressure); Optic nerve disorder; Oral pain; Pain in extremity; Pain of skin; Pancreatitis; Paresthesia; Pelvic pain; Pelvic soft tissue necrosis; Phlebitis; Photophobia; Photosensitivity; Proctitis; Psychosis; Pulmonary fibrosis; Purpura; Pyramidal tract syndrome; Rash acneiform; Rectal mucositis; Rectal stenosis; Renal and urinary disorders Other (dysuria); Renal and urinary disorders Other (ureterolithiasis); Renal hemorrhage; Respiratory failure; Respiratory, thoracic and mediastinal disorders Other (dry nares); Respiratory, thoracic and mediastinal disorders Other (pulmonary infarction); Restrictive cardiomyopathy; Retinal detachment; Retinal tear; Retinopathy; Right ventricular dysfunction; Serum amylase increased; Skin and subcutaneous tissue disorders Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Soft tissue necrosis lower limb; Somnolence; Stevens-Johnson syndrome; Tinnitus; Tremor; Tumor pain; Typhlitis; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain; Vaginal discharge; Vasculitis; Vasovagal reaction; Watering eyes; Weight gain Increase in Risk Attribution: d to Likely from Less Likely: Neutrophil count decreased d to Less Likely from Reported But Undetermined: Platelet count decreased Decrease in Risk Attribution: d to Reported But Undetermined from Less Likely: Vertigo Provided Further Clarification: Supraventricular tachycardia is now reported as Cardiac disorders Other (supraventricular arrhythmias) and the following footnote (#3) was added, Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. Gastrointestinal anastomotic leak is now reported as Injury, poisoning and procedural complications Other (anastomotic leak) and the following footnote (#10) was added, Anastomotic leak may include Gastrointestinal anastomotic leak; Gastric anastomotic leak; Large intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic leak. Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) reporting requirements: Added: Dehydration; Platelet count decreased; Wound complication Deleted Risk: Also Reported on Bevacizumab Trials But With the Relationship to Bevacizumab Still Undetermined: Pneumonitis; Pneumothorax 12.1 In the Due column of the Cross-Over Treatment Guideline Questionnaire (CO) line, a statement to see Appendix VII for eligibility criteria was added for clarity.

12 For Protocol Consent Amendment #6 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: July 23, 2014 (November 3, 2014) First page The version date was updated Risks and side effects related to The risk profile for bevacizumab was amended to be consistent with the revised CAEPR as follows: bevacizumab Added New Risk: Occasional: Dehydration; Delay in healing of wounds or spontaneous opening of wounds Rare: Flesh-eating bacteria syndrome, an infection in the deep layers of skin Decrease in Risk Attribution: d to Reported But Undetermined from Less Likely (i.e., removed from the Risk Profile): Feeling of spinning or whirling PLEASE NOTE: The potential risks listed in the CAEPR whose relationship to bevacizumab is still undetermined are not required by CTEP to be described in the ICD; however, they may be communicated to patients according to local IRB requirements.

13 For Protocol Amendment # 5 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: April 23, 2014 (Broadcast May 1, 2014) Global Title pages Due to the transition to the NCTN, all RTOG terminology was revised to NRG Oncology terminology where applicable and additional references to RTOG have been removed where no longer applicable. As required by CTEP, references to the Adverse Event Reporting System (AdEERS) have been changed to CTEP Adverse Event Reporting System (CTEP-AERS) throughout the protocol. Peixin Zhang, PhD, was added as the Senior Statistician. The document history table was updated to include Amendment Due to the transition to the NCTN, the Radiologic Physics Center (RPC) was updated to its new name, IROC (Imaging and Radiation Oncology Core) Houston In the Treatment Form (TF) row, (2 doses of bevacizumab and 4 doses of AMG 386/placebo) was added for clarity In the second-to-last sentence, results from Cohort 1 will be reviewed by the RTOG study team was revised to results from Cohort 1 were reviewed by the RTOG study team, to clarify that the Cohort 1 results were already reviewed by RTOG prior to the NCTN transition to NRG. The last paragraph was revised to indicate that the RTOG Data Monitoring and Safety Board is responsible for the phase I portion of the study (completed before the NCTN transition) and the NRG DMC is responsible for the ongoing randomized phase II portion of the study. For Protocol Consent Amendment #5 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: April 23, 2014 (Broadcast May 1, 2014) First page The version date was updated.

14 Will my medical information be kept private? RTOG Headquarters was revised to NRG Oncology Statistics and Data Management Center in the 1 st sentence of the 1 st paragraph; The Radiation Therapy Group was revised to NRG Oncology in the 1 st bullet What are my rights if I take part in this study? In the 3 rd paragraph, RTOG was revised to NRG Oncology.

15 For Protocol Update to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: December 11, 2013; Update Date: January 7, 2014 (Broadcast January 7, 2014) Cover page The update for January 7, 2014, was added to the document history table. Appendix VII 2.1: The second sentence was added as clarification : Formatting was corrected in the last sentence. Appendix VIIA In the heading for Pre-Treatment Assessments, including Cycle 1, Day 1 was added as clarification.

16 For Protocol Amendment # 4 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: December 11, 2013 (Broadcast December 20, 2013) Cover pages The document history table was updated to include Amendment 4. The phone numbers for Drs. Lee, Wen, and Reardon were updated The asterisk and example were added to the table for clarification of dosing for patients weighing 105 kg and above. No changes were made to the informed consent

17 For Protocol Amendment # 3 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: November 27, 2013 (Broadcast December 20, 2013) Global A version date was added to the footer per current RTOG standard. Cover pages The document history table was updated to include Amendment 3. The addresses for Drs. Lee, Wen, and Reardon were updated, The protocol agents table and participating sites list were updated to current RTOG standard. 3.1 A note to consult RTOG Data Management with eligibility questions was added for clarity and Eligibility Checklist question 2 A requirement for a supratentorial component was added for clarity and to be consistent with other RTOG GBM protocols. Subsequent sections were appropriately renumbered and Eligibility Checklist question 3 The last two sentences were added for patients with tumor progression who have surgical resection and Eligibility Checklist question 14 It was clarified that creatinine levels are to be within normal outer institutional limits, but that lower levels are permissible days was deleted, per RTOG standard For clarity, (ie, ) was added after within and Appendix VII/ It was clarified that an open brain biopsy is also considered a major surgical procedure. A 7-day window for recovery from stereotactic biopsy was added, as healing times are shorter than major surgical procedures given the smaller incision required for stereotactic biopsy.

18 4.1, 10.2, , , 12.1 Bolding was added for emphasis. It is mandatory that sites send tumor material used for diagnosis of GBM for central pathology review within 2 months after patient s registration , 7.4, PMB phone and fax numbers were updated If applicable was added after CTSU RT Facilities Inventory Form for clarity. 5.2 In the last bullet, member was added before site for clarity. In the last paragraph, confirmation of registration was deleted because it is not applicable in the OPEN registration system. The window to start treatment on the cross-over arm was expanded from 14 days to 28 days based on feedback from local sites that 14 days was not a feasible time frame given the time required to unblind the patient, to evaluate for eligibility for the cross-over arm, and to send study drug to the local site st paragraph, 1 st sentence: Treatment must begin within 14 days of progression on bevacizumab monotherapy was changed to Treatment must begin within 28 days of radiographic progression on monotherapy and a crossreference to Appendix VII was added for further details. 1 st paragraph, 10 th sentence: within 14 days of progression was changed to within 28 days of progression 1 st paragraph, last 4 sentences: The last 4 sentences were added to clarify timing for imaging needs and to provide instructions for bevacizumab administration during the 28-day window prior to cross-over treatment initiation. 7.3 Further details was clarified as detailed pharmacologic and safety information to be consistent with current RTOG standard. 7.4 A statement was added to consult the investigator brochure for comprehensive pharmacologic and safety information to be consistent with current RTOG standard. The CAEPR for AMG 386 was updated at CTEP s request As broadcast to RTOG sites on 7/5/13, CTEP issued a condensed risk profile and accompanying CAEPR (version 2.3) for AMG 386. The risk profile format for AMG 386 was changed to the new condensed risk profile format, and the version number of the accompanying CAEPR was upgraded from version 2.2 to version 2.3. There were NO changes to the risk information on the CAEPR.

19 The 4 th through 7 th paragraphs of were moved from AMG/Placebo Dose Modifications for Edema/Lymphedema to the end of 7.6. The information is applicable to the general dose modifications section, not just to edema/lymphedema. It was also clarified that dosing can start sooner than Day 15 if the criteria to restart are met , 7.9 The Adverse Events and AdEERs Reporting Requirements sections were updated to current RTOG standard , , 10.3, Specimen submission instructions were updated to current RTOG standard , Appendix I, Appendix VIIA PTT was deleted to be consistent with other RTOG GBM protocols Follow-up Form (F1): A time point was added for 30 days post-treatment because it was inadvertently omitted. 3 rd to last sentence: the phone number was removed; please use the address for questions about installation. Appendix VII/ The definition of adequate renal function was modified to be consistent with eligibility criteria in 3.1. Appendix VIIA The Pre-Treatment header was changed from within 7 days prior to initiating treatment to within 14 days prior In addition, PT, INR, Urine Studies, CBC with differential, and Serum Chemistry were deleted from Day 1 Cycle 1, since they are collected within 14 days of treatment. These timeframes were adjusted and combined because it is not clinically necessary to conduct these assessments 7 days before treatment and then again on Day 1/Cycle 1; within 14 days prior treatment start is sufficient. To be consistent with changes made to 7.2.3, the statement must start within 28 days of radiographic progression on bevacizumab monotherapy was added parenthetically to the During Treatment/Day 1 header.

20 For Protocol Consent Amendment #3 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: November 27, 2013 (December 20, 2013) The CAEPR for AMG 386 was updated at CTEP s request. Risks and side effects related to AMG 386 Risks and side effects related to bevacizumab Consent Form for Use of Tissue, Blood, and Urine for Research: Risk, 2 nd -5 th paragraphs As broadcast to RTOG sites on 7/5/13, CTEP issued a condensed risk profile and accompanying CAEPR (version 2.3) for AMG 386. The risk profile format for AMG 386 was changed to the new condensed risk profile format, and the version number of the accompanying CAEPR was upgraded from version 2.2 to version 2.3. There were NO changes to the risk information on the CAEPR. The format, headings, and terminology were changed to be consistent with CTEP s new guidelines for listing risk profiles in informed consents. There were NO changes to the risk information. Risks associated with central databases were added per current RTOG standard.

21 For Protocol Update to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: February 26, 2013; Update Date: March 13, 2013 (Broadcast March 13, 2013) C hange The cross-reference to was corrected to To avoid confusion: The 3 rd sentence was greyed and indication of the Cohort 1 closure was added, as this text was applicable only to Cohort 1. The 3 rd column of the table was greyed and indication that this information is not applicable to Cohort 2 was added.

22 For Protocol Amendment # 2 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: February 26, 2013 (Broadcast March 13, 2013) C hange Cover pages The document history table was updated to include Amendment 2. Minhee Won has replaced Meihua Wang as the statistician. Eligibility Checklist q 46 and , last bullet Eligibility Checklist q 7, 8, 13, 16 In resp onse to a CTEP Req uest for Amendme nt, patients wit h a history o f venous or arterial thromboembolism within 12 months prior to registration h ave been ex cluded. This change was made to ma ke the proto col co mpliant with the current stand ard AMG 386 protocol template and is not related to new toxicities. Spacing was corrected Eligibility Checklist q 20 for was added Schema, 7.2.1, , 7.9.1, 7.9.2, The protocol was amended to reflect the closure of Cohort 1 and the opening of Cohort In the first sentence, also was added for clarity.

23 C hange In response t o a CTEP Request for A mendment, the CAEPR for AMG 386 (Version 2.2, November 16, 2012) was revised as follows: Added New Risk: Less Likely: Blurred vision Also Reported on Trebananib Trials But With the Relationship to Trebananib Still Undetermined: Abdominal distension; Alopecia; Anemia; Arthralgia; Back pain; Chills; Constipation; Cough; Dehydration; Dizziness; Dry skin; Dysgeusia; Dysphasia; Dyspnea; Epistaxis; Eye disorders Other (eye edema); Fever; Flatulence; Flushing; Gastrointestinal obstruction; Generalized muscle weakness; Headache; Hypertension; Hypomagnesemia; Hypophosphatemia; Hypotension; Insomnia; Mucositis oral; Musculoskeletal and connective tissue disorder - Other (muscle spasms); Myalgia; Nail discoloration; Nail loss; Non-cardiac chest pain; Palmar-plantar erythrodysesthesia syndrome; Platelet count decreased; Pruritus; Rash acneiform; Rash maculo-papular; Respiratory, thoracic and mediastinal disorders - Other (runny nose); Sepsis; Watering eyes; Weight gain; Weight loss; White blood cell decreased Provided Further Clarification: The following footnote was added to Gastrointestinal obstruction, Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, or Small intestinal obstruction and other sites under the GASTROINTESTINAL DISORDERS SOC l was corrected to L for consistency 7.8 In the last paragraph, contact information was updated Per current RTOG stan dard, including a male patient s impregnation of his partner was added afte r any pregnancy. Th e l ast se ntence was deleted b ecause it i s no lo nger accurate. Per current RTOG sta ndard, info rmation on secondary a nd second mali gnancy wa s added , The NOTE in the AE reporting tables was deleted because it is no longer accurate Whole blood was added before DNA for clarity , Appendix IV Campus Box was updated to UCSF Box

24 For Protocol Consent Amendment #2 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: February 26, 2013 (March 13, 2013) Front page A version date was added. The risk profile for AMG 386 was amended to be consistent with the revised CAEPR as follows: Added New Risk: Less Likely: Blurred vision Risks and side effects related to the AMG 386 How many people will take part in the study? What will happen if I take part in this research study? During the study Study Plan About Using Tissue and Blood for Research Per CTEP, although there is modified risk information for AMG 386, the added risk is extre mely similar to risks that were already includ ed in the previo us version of the CAEPR and would have been communicated to patients in the informed consent document (ICD). In this case, blurred vision is more specific information asso ciated with the pre viously identi fied eye disorde r, retin al vascular th rombosis, which may re sult in perm anent impairm ent of vision. When changes such as these are ma de to the ICD (i.e., ch anges as to h ow risk information is p resented and/or additional clarifying information), it is not necessary to su spend enrollment of new subje cts until a revised ICD is reviewed and app roved by the I RB. F or thi s requested amendment, patie nt enrollment may continue before the IRB reviews and approves such chan ges to the informed con sent; however, cha nges to the ICDs can not b e implemented until they are approved by the IRB. PLEASE NOTE: The potential risks listed in the CAEPR whose relationship to AMG-386 is still undet ermined a re n ot requi red by CTEP to be described in the ICD; however, they m ay be comm unicated to p atients according to lo cal IRB requirements. The consent was amended to reflect the closure of Cohort 1 and the opening of Cohort 2.

25 For Protocol Amendment #1 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab with or without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: October 25, 2012 (Broadcast November 8, 2012) C hange Global To comply with CTEP s new formatting/document requirements, the protocol was reformatted and the sample consent was removed from the appendices. The appendices were appropriately renumbered. The informed consent continues to be available via MS Word on the protocol documents section of the main protocol page. Cover pages The document history table was updated to include Amendment 1. The participating sites list was updated to include Canadian sites. Schema For clarity, the ** footnote was expanded and was moved to under the Control Arm For accuracy, No was deleted before prior Canadian institutions were added. Regulatory Pre-Registration Requirements were adjusted to reflect enrollment via OPEN registration. Registration logistics were amended for OPEN enrollment. All enrollment will now occur via OPEN. For logistical purposes, the 4th sentence in the 2nd paragraph was added to provide a window of 3 days.. The agent preparation guidelines were revised at the request of CTEP and Amgen (manufacture of AMG 386) as follows: 1 hour time window from removal from the refrigerator until reconstitution of the drug was extended to 3 hours at room temperature; The dilution of the final IV solution in 50 ml and 100 ml NS was replaced with dilution to a final concentration of 1.2 mg/ml 30 mg/ml; and Use of vial adaptors is permitted but site must use a 0.2 m PES in-line filter during IV administration of AMG386. The 2nd sentence was added to clarify that does is to be determined via the referenced table versus an exact weight calculation. For logistical purposes, the 4th to last sentence was added to provide a window of 3 days. The guidelines concerning for Venous thromboembolic event Grade 3 or pulmonary embolism without vascular compromise or asymptomatic Grade 4 were corrected. For Hypertension Grade 1, and was corrected to and/or. Hypertension Grade 2 was corrected to Hypertension Grade 2 or 3. The paraffin block requirement was removed, as it is not mandatory for submission for central review. Subsequent sections were renumbered P4 submission logistics was clarified It was clarified that tissue banking for future research is an option for all patients, not just those in Cohort 2. Archival tissue was clarified as consisting of slides and/or block. Reference to was added.

26 C Appendix I Appendix VIIA Appendix V hange Cohort 1 or Cross-Over was changed to Cohort 1 and Cross-Over Patients for clarity, and it was clarified that serum collection for PK analysis is mandatory for these patients. Bevacizumab was corrected to open-label AMG 386 in combination with bevacizumab. Reference to Appendix V for kit requests from Covance was added. Cohort 1 or Cross-Over was changed to Cohort 1 and Cross-Over Patients for clarity, and it was clarified that serum collection for antibody analysis is mandatory for these patients. Reference to Appendix V for kit requests from Covance was added. It was clarified that blood banking for future research is an option for all patients, not just those in Cohort 2. The first table was rewritten to incorporate changes made to s as detailed above. The heading of the second table was rewritten for clarity. For logistical purposes, a window of 3 days prior to drug administration was added to during treatment assessments. It was clarified that banking for future research is an option for all patients (Appendix I) and all cross-over patients (Appendix II). Contact information for kit acquisition was updated. For Protocol Consent Amendment #1 to: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab with or without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG 1122 NCI Protocol Version Date: October 25, 2012 (Broadcast November 8, 2012) Why is this study being done? Before you begin the study For clarity, the sentence It is hoped that AMG 386 will kill tumor cells and that it may also block bl ood vessel s that supply the tu mor i n your brain with nu trients and o xygen was moved from the 2 nd -to-last sentence of the 2 nd paragraph to the last se ntence of the 1 st paragraph. For clarity, in the last sentence, used was changed to evaluated. In the 7 th bullet, the first CT was corrected to MRI During the study In the last paragraph, AMG 486 was corrected to AMG 386. About Using Tissue for Research In the third paragraph, it was clarified that banking is an option for any patient, not just those on cohort 2.

27 SUMMARY OF CHANGES Update: June 4, 2012 (Broadcast June 4, 2012) RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma Study Chair: Eudocia Quant Lee, MD, MPH; ; RTOG 1122 was updated as follows: For database needs, Eligibility Checklist questions 18 and 25 were re-worded. Logistics for AMG 386 PK and antibody collection were clarified and corrected. s were made to the following places: 2.2.7: Plasma was corrected to serum, as outlined in : A note was added referring sites to Appendix VI. s 10.4 and 10.5, 2 nd sentences: Blood was corrected to serum. 10.5: Cycle 1 was added before Day , table, Specimens for Pharmacokinetic Analysis and AMG 386 Antibodies section: o A page break was added to further differentiate from specimens to be submitted to the RTOG Biospecimen Resource. o Reference to Appendix VI and IRB approval were added. o Serum for antibody analysis row: Cycle 1 was added before Day : Amgen was corrected to Covance. Appendix I (sample consent), During the Study, last paragraph: o 2 nd sentence: for these purposes was deleted. o 1 st bullet: Cycle 2 was corrected to Cycle 1; and after was deleted; (AMG 386 and AMG 386 antibodies) was deleted. o 2 nd bullet: Day 1 was corrected to Day 1 and 8; (AMG 386) was deleted. o 3 rd bullet: (AMG 386 antibodies) was deleted. Appendix II, Blood for AMG 386 antibodies row: Collection at Cycle 1, Day 1 was added for consistency with other sections of the protocol. Appendix VI: The entire appendix was revised to more clearly describe details for kit acquisition and specimen collection. References: In-text references and corresponding citations were corrected as needed for accuracy and were styled per current RTOG standard. 5.0: A statement was added that the protocol is open to US institutions only : The weblink was added for accessing the Online Agent Order Process (OAOP) and training manual. 12.0: The location of the Specimen Transmittal Form on the RTOG website was corrected.

28 For Protocol Amendment 11 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: October 3, 2016 Footer The protocol version date was updated Cover Pages The Document History Table was updated to include this amendment. The suite address was updated for Dr. Zhang In response to a CTEP Request for Amendment, the CAEPR for bevacizumab (Version 2.4, May 23, 2016) was revised as follows: Added New Risk: Less Likely: Creatinine increased; Erythroderma Rare but Serious: Avascular necrosis; Gallbladder perforation Increase in Risk Attribution: d to Less Likely from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Dry skin; Generalized muscle weakness; Hyperglycemia; Hypokalemia; Hyponatremia d to Rare but Serious from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Palmar-plantar erythrodysesthesia syndrome Deleted Risk: Less Likely: Cardiac troponin I increased Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution: Infections and infestations - Other (aseptic meningitis) Provided Further Clarification Footnote # 7 has been altered to read, Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. Footnote #11 has been added and reads, There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the age of 18 treated with bevacizumab.

29 For Protocol Consent Amendment 11 of: RTOG 1122, Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma NCI/Local Protocol #: RTOG-1122/RTOG 1122 NCI Protocol Version Date: October 3, 2016 Global Header What side effects or risks can I expect from being in the study? Minor formatting errors were corrected. The version date was updated for this amendment. Under Possible Side Effects of Bevacizumab, the risk profile for bevacizumab was amended to be consistent with the revised CAEPR for bevacizumab (Version 2.4, May 23, 2016) as follows: Added New Risk: Occasional: Swelling and redness of the skin Rare: Sores in the throat Increase in Risk Attribution: d to Occasional from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Dry Skin; Muscle weakness d to Rare from Also Reported on Bevacizumab Trials But With Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Redness, pain or peeling of palms and soles Provided Further Clarification: Damage to the jawbone which may cause loss of teeth (under Occasional) is now being reported as Damage to organs which may cause loss of teeth or loss of motion (under Occasional). PLEASE NOTE: The potential risks listed in the CAEPR for which the relationship to bevacizumab is still undetermined are not required by CTEP to be described in the ICD; however, they may be communicated to patients according to local IRB requirements.