peters @duke.edu Sub-Investigator(s) Annick Desjardins, M.D. annick.desjardins@dm.duke.edu Henry Friedman, M.D. henry.friedman@duke.edu Darell Bigner, M.D. darell.bigner@duke.edu Dina Randazzo, D.O. dina.randazzo@dm.duke.edu John Sampson, M.D., Ph.D. john.sampson@duke.edu Gary Archer, Ph.D. gary.archer@duke.edu Elizabeth Reap, Ph.D. elizabeth.reap@duke.edu Luis Sanchez -Perez, Ph.D. luis.sanchez -perez@duke.edu Peter Fecci, M.D., Ph.D. peter.fecci@duke.edu Statistician James E. Herndon II, Ph.D. james.herndon@duke.edu Lead Study Coordinator Stevie Threatt , C.R.C. stevie.threatt@duke.edu Regulatory Coordinator Rachel Hesler, Ph.D. rachel.hesler@duke.edu Data Manager Eric Lipp eric.lipp@duke.edu Original version: 04/02 /2015 Amended version 1: BMS Modification Requests 06/09/2015 Amended version 2: PRTBTC PRC Modification Requests 07/24/2015 Duke Cancer Institute CONFIDENTIAL Page 2 Amended version 3: CPC Modifications and PI -initiated corrections 08/24/2015 .Added abbreviation (Section 4); Removed research summary (Section 5); Updated study schema (Section 6 ); Added more background on nivolumab (Section 7 ); Moved randomization (Sections 9 , 12, 15); Moved surgery (Sections 9 , 12); Removed specific Td manufacturer (Sections 9, 10, 12); Corrected dose of Td/Saline for pre- conditioning (Sections 9, 12); Corrected cell concentration error (Section 10); Corrected name of pharmacy dispensing Td (Section 10 ); Removed specific research nurse name (Section 10); Updated Tests & Procedures Table (Section 12); Corrected # of vaccines for primary analysis (Section 15). Amended version 4: CPC Modifications Request 9/8/2015 Clarified rationale for surgery following nivo lumab ± DC vaccine and subjects will be removed if surgery must be performed prior to plan (Sections 7, 9 and 12). Amended version 5: FDA Modification Requests 9/16/2015 Clinical benefit in Section 12.2.1 is clarified; tolerating study drug in same section also clarified; Time point as listed in the PRTBTC Imagi ng SOP is clarified in Section 18.3. Amended version 6: PI modification requests 1/20/2016 Included Apheresis blood work prior to each leukapheresis (Section 12); updated the blood work drawn prior to leukapheresis and each inf usion of nivolumab (Section 12), corrected the total number of vaccines required for replacement of patients for primary endpoint evaluation (Section 15.7); and updated the documents in the appendices by removing them from protocol and uploading as separate attachments in eIRB (Section 18). Amended vers ion 7: PI modification requests 2/4/2016 Use of antihistamines before, during and following vaccine `administration recommendation (Section 12.7.3). Amended versio n 8: PI modification requests 5/12/2016 Overall formatting change to meet FDA standards for electronic submission (entire document); Changed Primary Study Coordinator ( Cover Page); Removed reference to “alone” from Group 2 description since giving nivolumab alone is done prior to randomization (Sections 7.3 & 9.1.6 ); Clarified blood draws (immune monitoring, and pre- nivo) timing, volume, and tubes , and removed CCL3 blood assessments (Sections 6, 8, 9.1, 12.1, 12.2, 12.7.5 & 15.6); Clarified subjects whose cells fail to qualify will not undergo repeat leukapheresis (Section 9.1); Described how Td booster will be administered on all enrolled subjects , removed saline injections during Td pre- conditioning (Sections 9.1,12.2); Changed timing of study treatments to allow more approximation and flexibility (Section 9.1, 9.1.4, & 15); Changed listing Dr. John Sampson to simply Duke Neurosurgeon (Sections 9.1 & 12.2); Updated AE and SAE collection to starting at time of consent through to 30 days after study ends, and includes leukapheresis (Sections 9.1.3, 9.1.4, 12 .6.2, 13 .1, & 13.2.1); Added language regarding a deviation log for non- reportable events for missed appointments (Section 9.1.4); Clarified that research team will document concomitant medications, not just study coordinator (Section 9.1.5); Added more language on nivolumab infusion and timing (Section 9.2); Updated location of leukapheresis (Section 10.1); Cla rified eligibility criteria (Section 11 ); Increased dexamethasone from 2 mg/day to 4 mg/day (Section 11.2); Updated the Schedule of Events table(s) (Section 12); Removed WHO Performance Status (Sections 12.1 & 18.6); Simplified description of standard of care MRI (Sections 12.1 & 12.2.1); Removed references to a medical monitor (Sections 12.2.2 & 12.2.3); Changed nivolumab dose interruption timing from >6 weeks to >8 weeks (Section 12.2.2); Removed steroid usage as a Duke Cancer Institute CONFIDENTIAL Page 3 criterion for early withdrawal and moved to own section (Sections 12.6.1 & 12.7.4); Added description of vital sign monitoring with nivolumab and vaccine administrations (Section 12.7.2); Changed the wording from “bi -weekly” to ev ery other week (QOW) (Sections 4, 6, and 15 ); Clarified that TUMS are given three times a day instead of “with meals” (Section 12.2); Updated consenting by PI to include her designee (Section 16.3); and fixed minor edits and formatting errors (throughout). Amended version 9: PI modification requests 8/5/2016 Use of b evacizumab in subjects that develop inflammation was added (Section 9.1.6); Use of Antihistamines (Section 9.1.4) and Use of Corticosteroids (Section 9.1.5 ) were moved from Study Assessments (Section 12.7) to Study Design (Section 9.1); added definition of WBRT to the List of Abbreviations ; changed Primary Regulatory Coordinator to Rachel Hesler; clarification of the timing of MRIs and tests and procedures at Nivolumab infusion #1 (Section 12 ); Removed reference to BMS Guidelines in appendices in inclusion criteria (Section 11.1 ) and fixed minor formatting errors (throughout). Amended version 10: PI modification requests 8/29/2016 Due to a change in the quality control timeline, the vaccine schedule for Group II subjects was changed to 3 vaccines prior to surgery and 5 vaccines after surgery, keeping the total number of vaccines at 8 ( Section 6, Section 9.1 , Section 12, Section 15); Changes were made to Group I vaccine timeline to keep consistent ( Section 6, Section 9.1, Section 12); As a result of these changes to the vaccine timeline, the immune monitoring timeline was updated (Section 6 , Section 9.1 , Section 12 ) and the primary safety analyses will now focus on all subjects who complete at least 3, not 4, vaccinations or terminate early due to unacceptable toxicity (Section 9.1, Se ction 15 ); Clarified that Nivolumab will be infused over 30- 60 minutes (Section 9.2); Clarified that the surgery is for de- bulking purposes (Section 7.3); fixed minor formatting errors (throughout). Amended version 11: PI modification requests 02/13/2017 At leukapheresis #2, subjects (group 1 and group 2) do not need to have a physical exam, neuro exam, KPS, O2 saturation (Section 12). Subjects will continue to receive these exams at the Nivolumab infusion after leukapheresis #2 (1 day to 2 weeks later) ; Corrected Table 3 to indicate that patients who have completed at least 3 (not 4) vaccinations will be included in safety analysis (Section 15.7); For subjects whose first leukapheresis yields 8 or more vaccines, the duration of the second leukapheresis can be 2 hours instead of 4 hours (Section 12.2) ; Complications following resection added to definition of unacceptable toxicity (Section 9.1); Vital signs will be taken right after injection of DC vaccine, not 30- 60 minutes post vaccine (Section 12.7.2, Section 12); In the Criteria for Early Withdrawal section (Section 12.6. 1), correction of reference to section defining unacceptable toxicity ( Section 9.1.1) instead of nivolumab discontinuation criteria ( Section 12.2.2) ; added that a subject can continue on one study drug if the other study drug is discontinued due to unacceptable toxicity; Removed restatement of the definition of unacceptable toxicity and instead referred to definition in Section 9.1.1 (Section 15.4.1 ); Correction of reference #112 (Section 17) Amended version 12 03/15/2017 PI changed (title page and Section 13.2.1 ) Pro00065241: AVERT Version: 20170 315 Duke Cancer Institute CONFIDENTIAL Page 4 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ....................................................................................................................... 4 2 LIST OF FIGURES ...............................................................................................................................