The Document History Table was updated to include this amendment. The CTSU contact information table was updated.

Transcription

1 For Protocol Amendment #8 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI/Local Protocol #: RTOG 1205/RTOG 1205 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 CTSU contact information table was updated 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 #8 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI/Local Protocol #: RTOG 1205/RTOG 1205 NCI Protocol Version Date: October 3, 2016 (Broadcast October 17, 2016) Header What side effects or risks can I expect from being in the study? The version date was updated. The introductory paragraphs were updated to current NCI standard text. 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 #7 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI/Local Protocol #: RTOG-1205/RTOG 1205 NCI Protocol Version Date: September 3, 2015 (Broadcast: September 21, 2015) Document Footer Document History table Informed Consent The protocol version date was updated This amendment was added. Question 17: Added within 14 days prior to registration at the end of the second indented subquestion. This was done to make material consistent with the same material covered in No changes to the text of the sample consent; the version date of the consent was changed to be consistent with the amendment of the protocol.

4 For Protocol Amendment #6 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI/Local Protocol #: RTOG-1205/RTOG 1205 NCI Protocol Version Date: August 24, 2015 (Broadcast: March 18, Revised from original date September 21, 2015.) Document The protocol version date was updated Footer Document This amendment was added. History table Cover page Suite # for Peixin Zhang updated to 1720 Jeffery Raizer s address was updated The following text was added to clarify eligibility information: Last line of first bullet: 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 or approved by principal investigator was added to the end of the bulleted sentence to provide clarification Second bullet: within 14 days prior to registration was added to further clarify patient selection criteria Treatment Modification for Bevacizumab-Related Adverse Events table s were made to correct errors: Row titled Hypertension Sub-row 3: Following Grade 2 asymptomatic the text but diastolic BP < 100 mmhg was removed Sub-row 4: Grade 2-3 was replaced with Grade 2 symptomatic or Grade 3 and then Symptomatic OR Diastolic BP > 100mmHg was removed Sub-row 4: 90mmHg* was replaced with 100mmHg Footnoted list below table was removed. Text was as follows: Current CTCAE definitions used by CTEP (eg, hypertensive crisis)

5 For Protocol Consent Amendment #6 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: August 24, 2015 (Broadcast: March 18, Revised from original date September 21, 2015.) Header About Using Tissue for Research The version date was updated for this amendment. The following sentence was removed because the website being referred to no longer exists: An information sheet about using tissue for research is available at tissue research.

6 For Protocol Amendment #5 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: October 9, 2014 (November 3, 2014) Title pages Question Appendix I: Assessments During Treatment Appendix I: Assessments During Treatment and Follow-Up Assessments The document history table was updated to include Amendment 5. The protocol has been amended to allow participation by the entire network of adult NCTN organizations. Alliance, ECOG-ACRIN, and SWOG member sites that are not NRG Oncology members may register patients to the trial using the Oncology Patient Enrollment Network (OPEN) registration system and credit Alliance, ECOG-ACRIN or SWOG. The protocol and forms will be available on the CTSU member website, and CTSU contact information was added. Contact information was updated for Dr. Tsien. The possibility for intra-operative scan was added, because an increasing number of institutions now have this capability. Text was updated to current standard for protocols posted on the CTSU member website. The first three sentences of 6.3 and first sentence of 6.4 were written to clarify intent. An MRI and/or CT simulator scan does not need to done with contrast in the treatment position. It is acceptable to obtain a CT simulator scan without contrast and then fuse with a diagnostic contrast-enhanced MRI. To allow for proper dose adjustments based on patient weight changes, instructions were added to indicate that the patient s weight must be checked prior to each bevacizumab dose. The time point for optional serum, plasma and urine collection for banking was corrected from 6 weeks after treatment completion to 8 weeks after treatment initiation Appendix III Biospecimen collection logistics were updated to current standard.

7 12.1 Next to Pathology Report, a note was added to mail a copy of the report to NRG Oncology. In the Assessment column, a note concerning P1 submission was added. In the Assessment column, the cross reference for MGMT methylation status was corrected to 4. Appendix I: Pre-Treatment Assessments The column for within 7 days prior to registration was changed to pre-treatment, and MGMT methylation status and tissue, blood, urine for banking were placed in that column. The one assessment that is required within 7 days prior to registration (serum pregnancy test) is now noted in the 14 days prior to registration column. For clarity, the optional MRI diffusion and perfusion imaging was removed from its own assessment line and added to the tumor imaging without and with recent resection lines. For Protocol Consent Amendment #5 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: October 9, 2014 (November 3, 2014) First page The version date was updated Consent Form for Use of Tissue for Research/ About Using Tissue for Research In the second paragraph, the description and weblink for the tissue information sheet was updated. In the third paragraph, the time point for optional blood and urine collection for banking was corrected from 6 weeks after treatment completion to 8 weeks after treatment initiation.

8 For Protocol Amendment # 4 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: June 23, 2014 (Broadcast November 3, 2014) Title pages The document history table was updated to include Amendment 4., q. 21 The redundant question mark was removed The spelling of HIPAA was corrected 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;

9 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 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

10 For Protocol Consent Amendment #4 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: June 23, 2014 (November 3, 2014) First page Possible side effects of radiation to the brain Possible side effects of bevacizumab The version date was updated The format and headings were changed to be consistent with CTEP s current guidelines for listing risk profiles in informed consents. No content changes were made. The risk profile for bevacizumab was amended to be consistent with the revised CAEPR as follows: 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.

11 For Protocol Amendment #3 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: April 15, 2014 (May 1, 2014) Global 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. Title pages Peixin Zhang, PhD, was added as the Senior Statistician. The document history table was updated to include Amendment 3. Schema p.1 q 9 p. 4 q p.1 q Appendix I p.1 q Appendix I p.1 q 7 Appendix I Karnofsky performance status (KPS) was lowered to allow enrollment of patients with KPS 60. This change was made to permit inclusion of clinically neurologically stable patients with lower performance status due to unrelated events, such as chronic back pain. The change was also made because patients with the potential to benefit from re-irradiation may be more symptomatic. The pre-registration window for contrast-enhanced MRI or CT scan (non-compatible devices) showing unequivocal radiographic evidence for tumor progression was expanded from within 14 days of registration to within 21 days. Corresponding changes were made to Appendix I, second column. This change was made to account for inability to obtain a repeat MRI in a timely fashion and/or difficulty obtaining insurance reimbursement for a 2 nd MRI. The timeline for recent resection was expanded from 30 days to 5 weeks. The 30- day pre-registration timeline for post-operative MRI was removed. Corresponding changes were made to Appendix I, first column. These changes were made so that patients undergoing surgical resection do not have to undergo a repeat scan. The and Appendix I were corrected to correspond with the existing text indicating that the 96-hour post-surgery timeframe is a recommendation, not a requirement. Baseline platelet count was lowered from 100,000 to 75,0000 cells/m 3, because the lower count is not expected to compromise patient safety.

12 p.2 q The number of permitted relapses was expanded from two to three. This change was made to accommodate physicians who prefer not to enroll patients on standard arm bevacizumab alone until the patient has tried several non-bevacizumab containing regimens, due to the lack of response following failure from bevacizumab alone. p.2 q p. 21, q The exclusion of multifocal disease was removed. Patients previously presenting with multi-focal disease will no longer specifically be excluded. Several centers enrolling patients requested further clarification regarding this section. Therefore, the change was made to provide the necessary clarification and accommodate those patients presenting with clear evidence of tumor progression who would otherwise meet eligibility criteria including the rigid tumor size criteria. Recurrent or persistent tumor 5 cm or less was increased to 6 cm or less; the normal tissue limits remain prioritized over tumor. Based on experience treating larger tumor sizes up to 6 cm using this dose and fractionation without observed brain toxicity, the study chairs do not anticipate this adjustment will impact toxicity or increase planning difficulty Appendix I Pre-operative contrast-enhanced MRI or CT scan was added to the list of Highly Recommended Evaluations in 4.1.3, and a corresponding addition was made to Appendix I In the second paragraph, the RPC was updated to IROC Houston, because it was inadvertently not changed to the new name in Amendment Due to the transition to the NCTN, RTOG Headquarters was updated to IROC (Imaging and Radiation Oncology Core) Philadelphia where applicable 10.3 Reimbursement was updated to current standard text.

13 12.2 TRIAD submission instructions were updated to current standard text. For Protocol Consent Amendment #3 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: April 15, 2014 (May 1, 2014) First page The version date was updated Will my medical information be kept private? In the first bullet, the Radiation Therapy Group was changed to NRG Oncology.

14 For Protocol Amendment #2 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: February 27, 2014 (Broadcast May 1, 2014) Global 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. Due to the for the transition to the National Clinical Trials Network (NCTN), the title pages were revised to include our new organization name, NRG Oncology. Title pages A sentence was added beneath the title specifying NRG Oncology as leading the trial with participation of the network of NCTN researchers: the Alliance, ECOG-ACRIN, and SWOG. The document history table was updated to include Amendment , 5.3, 5.4, 5.6 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, and corresponding web site. Credentialing logistics were revised as appropriate The table was updated per current submission needs. Informed Consent No changes

15 For Protocol Amendment #1 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: November 20, 2013 (Broadcast December 4, 2013) Title Pages The document history table was updated to include Amendment 1. Dr. Raizer s title was modified from Neuro-Oncology Co-Chair to Medical Oncology Co-Chair for clarity. Minhee Won has replaced Meihua Wang as the statistician. The protocol agents table and participating sites list were updated to current RTOG standard. 3.1 A note to consult RTOG Data Management was added for clarity. 5.0 RTOG is now using TRIAD to collect RT digital data. TRIAD provides sites participating in RTOG clinical trials with a secure method to transmit DICOM RT and other digital data. TRIAD anonymizes and validates the images and information objects as they are transferred via the internet. The first 2 paragraphs were added to update the protocol with access requirements for OPEN, Medidata Rave, and TRIAD , IGRT pre-registration requirements were updated to current RTOG standard IMRT pre-registration requirements were updated to current RTOG standard D-CRT pre-registration requirements were updated to current RTOG standard. 5.5, 6.0, 6.5.1, 12.1, 12.2 The protocol was updated to include logistics for TRIAD use for RT digital data submission If applicable was added after CTSU RT Facilities Inventory Form for clarity. The phone number for the PMB was updated.

16 Instructions for Canadian and international institutions were updated to current RTOG standard In the 1 st two paragraphs, OPEN registration text was updated to current standard. In the 4 th paragraph, the 1 st bulleted item was updated to be consistent with changes made in 5.0. In the 4 th paragraph, last bulleted item, member was added before site for clarity and password authorization instructions were added for non- RTOG member sites OPEN registration text was updated to current standard. 7.2 Further details was clarified as detailed pharmacologic and safety information to be consistent with current RTOG standard It was clarified that the administration instructions are to be followed for sites without relevant institutional guidelines , 11.1, Appendix I (Assessments During Treatment) Instructions for monitoring proteinuria were corrected to be consistent across sections. 7.4 Dr. Raizer s title was modified from Neuro-Oncology Co-Chair to Medical Oncology Co-Chair for clarity The Adverse Events and AdEERs Reporting Requirements sections were updated to current RTOG standard. 7.6 In the last paragraph before the table, phase 1 was corrected to phase 2 and Specimen collection was added before component because it was inadvertently omitted.

17 10.2.1, , Appendix III Specimen submission instructions were updated to current RTOG standard For clarity, complete series was added next to pre-study MRI scans and reports In the last bullet, Grade 3 was corrected to Grade 3+. For Protocol Consent Amendment #1 to: RTOG 1205, Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma NCI Protocol Version Date: November 20, 2013 (Broadcast December 4, 2013) Front page A version date was added. Consent Form for Use of Tissue, Blood, and Urine for Research: About Using Tissue for Research Consent Form for Use of Tissue, Blood, and Urine for Research: Risks, 2 nd -5 th paragraphs The first paragraph was rewritten to clarify that patients will have already had a biopsy. Risks associated with central databases were added per current RTOG standard.