CLINICAL RESEARCH ROTOCOL A proof-of-principle study of hyperbaric oxygen as a radiosensitizer prior to stereotactic radiosurgery for brain metastases Principal Investigator: Alan Hartford, M.D., Ph.D., FACR Section of Radiation Oncology Dartmouth-Hitchcock Medical Center One Medical Center Drive Lebanon, NH 03756 603-650-6600 Co-investigators Jay Buckey, M.D. (hyperbaric medicine) David Gladstone, Sc.D. (radiation physics) Gregory Russo, M.D. (radiation oncology) Clifford Eskey, M.D., Ph.D. (neuroradiology) Arti Gaur, Ph.D. (neurobiology and translational science) Ben Williams, Ph.D. (radiation physics and radiobiology) Biostatistical Support Tor Tosteson, Ph.D. (biostatistics) Zhongze Li, M.S. (biostatistics) Radiology Clifford Eskey, M.D., Ph.D. (neuroradiology) Pathology Research staff Divya Ravi, M.S. Suzanne Vaughn, R.N., O.C.N. Funding Sponsor: NCCC-Clinical Translational Research Program Dartmouth-Hitchcock Medical Center Study Product: Hyperbaric oxygen as radiosensitizer for SRS treatment Protocol Number: D12129 IND Number: Not applicable Initial Version: [7 June 2012] V1 Amended: [07 November 2014] V6 Amended: [17 August 2012] V2 Amended: [20 January 2015] V7 Amended: [25 July 2013] V3 Amended: [18 April 2018] V8 Amended: [28 February 2014] V4 Amended: [11 April 2019] V9 Amended: [17 October 2014] V5 Amended: [17 March 2020] V10 CONFIDENTIAL [HBO – SRS for brain mets] Page ii Version: 10 – 17 March 2020 Table of Contents STUDY SUMMARY..........................................................................................................1 1 INTRODUCTION.......................................................................................................2 1.1 BACKGROUND ......................................................................................................2 1.2 INVESTIGATIONAL AGENT.......................................................................................7 1.3 PRECLINICAL DATA ...............................................................................................7 1.4 CLINICAL DATA .....................................................................................................8 1.5 DOSE RATIONALE AND RISK/BENEFITS. ..................................................................9 2 STUDY DESIGN......................................................................................................10 2.1 GENERAL DESIGN...............................................................................................10 2.1.1 Study Objectives...........................................................................................10 2.1.2 Study Flowchart............................................................................................10 2.2 PRIMARY STUDY ENDPOINTS ...............................................................................11 2.3 SECONDARY STUDY ENDPOINTS ..........................................................................11 2.4 FURTHER EXPLORATORY STUDY ENDPOINTS........................................................12 3 SUBJECT SELECTION AND WITHDRAWAL .......................................................13 3.1 INCLUSION CRITERIA ...........................................................................................13 3.2 EXCLUSION CRITERIA..........................................................................................14 3.3 SUBJECT RECRUITMENT AND SCREENING.............................................................15 3.4 EARLY WITHDRAWAL OF SUBJECTS......................................................................15 3.4.1 When and How to Withdraw Subjects ..........................................................15 3.4.2 Data Collection and Follow-up for Withdrawn Subjects................................15 3.4.3 Replacement of withdrawn subjects .............................................................16 4 STUDY INTERVENTION.........................................................................................16 4.1 DESCRIPTION .....................................................................................................16 4.2 TREATMENT REGIMEN.........................................................................................16 4.3 ACUTE HBO TOXICITY.........................................................................................16 4.4 PRIOR AND CONCOMITANT THERAPY....................................................................17 5 STUDY PROCEDURES (SEE ATTACHED TABLE, SECTION 14.1)....................17 5.1 VISIT 1 – “INITIAL CONSULTATION VISIT” ................................................................17 5.2 VISIT 2 – “PRETREATMENT VISIT” .........................................................................18 5.3 VISIT 3 – “SRS TREATMENT VISIT” ......................................................................18 5.3.1 Principles: .....................................................................................................18 5.3.2 Equipment:....................................................................................................18 5.3.3 Protocol Volume Target Definitions: .............................................................19 5.3.4 Gross Tumor Volume (GTV):........................................................................19 5.3.5 Planning Target Volume (PTV):....................................................................19 5.3.6 Timing of Radiotherapy:................................................................................19 5.3.7 Target Dose:.................................................................................................19 5.3.8 Normal Tissue Tolerance:.............................................................................19 5.3.9 Optional Blood Draw for Markers..................................................................19 5.4 FOLLOW-UP VISITS..............................................................................................20 CONFIDENTIAL [HBO – SRS for brain mets] Page iii Version: 10 – 17 March 2020 6 STATISTICAL PLAN ..............................................................................................20 6.1 STATISTICAL METHODS .......................................................................................20 6.2 SAMPLE SIZE DETERMINATION.............................................................................22 6.3 SUBJECT POPULATION(S) FOR ANALYSIS..............................................................22 7 SAFETY AND ADVERSE EVENTS........................................................................22 7.1 DEFINITIONS.......................................................................................................22 7.2 RECORDING OF ADVERSE EVENTS .......................................................................25 7.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .........25 7.3.1 Investigator reporting: notifying the IRB........................................................26 7.4 STOPPING RULES ...............................................................................................26 8 DATA HANDLING AND RECORD KEEPING........................................................27 8.1 CONFIDENTIALITY ...............................................................................................27 8.2 SOURCE DOCUMENTS .........................................................................................27 8.3 CASE REPORT FORMS ........................................................................................27 8.4 RECORDS RETENTION.........................................................................................28 9 STUDY MONITORING, AUDITING, AND INSPECTING........................................28 9.1 SAFETY AND DATA MONITORING ..........................................................................28 9.2 ON-SITE MONITORING ........................................................................................28 9.3 AUDITING AND INSPECTING ..................................................................................28 10 ETHICAL CONSIDERATIONS ...............................................................................29 11 STUDY FINANCES.................................................................................................29 11.1 FUNDING SOURCE ..............................................................................................29 11.2 CONFLICT OF INTEREST.......................................................................................29 12 PUBLICATION PLAN .............................................................................................29 13 REFERENCES........................................................................................................29 14 ATTACHMENTS .....................................................................................................32 14.1 TABLE SUMMARIZING STUDY PROCEDURES/FLOWCHART ........................................32 14.2 SAE REPORTING FORM ......................................................................................33 14.3 HBO TREATMENT PROTOCOL (INCLUDING “DRY RUN”)...........................................33 14.4 QUALITY OF LIFE INSTRUMENTS ...........................................................................34 14.4.1 St. Louis University Mental Status (SLUMS) exam...................................34 14.4.2 EORTC QLQ C-30 ....................................................................................35 14.4.3 EORTC QLQ 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