Protocol #: CL-PTL 105 PROTOCOL TITLE : Open -label Phase II Trial of Adjuvant bishRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine (FANG™) for High -Risk Stage III/IV Ovarian Cancer NCT 01309230 PROTOCOL DATE : September 25, 2015 CONFIDENTIAL Information and data included in this protocol contain trade secr ets and privileged or confidential information which is the pr operty of Gradalis, Inc. No person is authorized to make it public without written permission of Gradalis, Inc. These restrictions on dis closure will apply equally to all future information supplied to you, which is indicated as privileged or confidential. This material may be disclosed to and used by your staff and associates as may be necessary to conduct this clinical study. PROTOCOL TITLE: Open-label Phase II Trial of Adjuvant bi- shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine (FANG™) for High Risk Stage III/IV Ovarian Cancer Protocol #: CL-PTL 105 STUDY AGENT: Vigil™ formerly known as FANG™ (bi-shRNAfurin and GMCSF Autologous Tumor Cell Vaccine) SPONSOR: Gradalis, Inc. 2545 Golden Bear Drive, Suite 110 Carrollton, TX 75006 Phone: (214) 442-8124 Fax: (214) 442-8101 PROTOCOL DATE: Amendment #9 dated September 25, 2015 Amendment #8 dated June 19, 2014 Amendment #7 dated January 9, 2014 Amendment #6 dated April 15, 2013 Amendment #5 dated January 31, 2013 Amendment #4 dated May 1, 2012 Amendment #3 dated October 5, 2011 Amendment #2 dated June 23, 2011 Amendment #1 dated February 18, 2011 Initial Protocol dated November 16, 2010 Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 2 INVESTIGATOR PROTOCOL SIGNATURE PAGE Protocol Title: Open-label Phase II Trial of Adjuvant bi-shRNA furin and GMCSF Augmented Autologous Tumor Cell Vaccine (FANG™) for High Risk Stage III/IV Ovarian Cancer Protocol #: CL-PTL 105 SPONSOR: Gradalis, Inc. 2545 Golden Bear Drive, Suite 110 Carrollton, TX 75006 Phone: (214) 442-8124 Fax: (214) 442-8101 Protocol Date Amendment #9 dated September 25, 2015 Amendment #8 dated June 19, 2014 Amendment #7 dated January 9, 2014 Amendment #6 dated April 15, 2013 Amendment #5 dated January 31, 2013 Amendment #4 dated March 29, 2012 Amendment #3 dated October 5, 2011 Amendment #2 dated June 23, 2011 Amendment #1 dated February 18, 2011 Initial Protocol dated November 16, 2010 I have read and understand the contents of the indicated clinical protocol and will adhere to the trial requirements as present ed, including all st atements regarding confidentiality. In addition, should I choose to participate as an investigator, I and my sub-investigator(s) agree to conduc t the study as outlined herein, in accordance with Good Clinical Practices (GCP s), the Declaration of Helsinki, in compliance with the obligations and requirem ents of clinical investigators and all other requirements listed in Title 21 Code of Federal Regul ations (CFR) Part 312. ________________________ _______ Name of Investigator (please print) Signature of Investigator __________________ _____________ Date Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 3 TABLE OF CONTENTS INVESTIGATOR PROTOCOL SIGNATURE PAGE ....................................................... 2 ABBREVIAT IONS........................................................................................................... 5 SYNOPSIS ............................................................................................................ 7 1.0 INTRODUCT ION ................................................................................................ 11 1.1 Immune Therapy in Cancer ..................................................................... 11 1.2 Immune Function Capacity in Cancer Pa tients ........................................ 12 1.3 Immune Function Capacity in Ovarian Cancer Patients........................... 13 1.4 Background on Transforming Growth Factors beta (TGF β) ..................... 14 1.5 Background on GMCSF ........................................................................... 16 1.6 Background on Gene Vacci nes in C ancer ............................................... 17 1.7 Blockade of multiple TFG β isoforms is needed to reverse immunosuppre ssion ................................................................................. 19 1.8 Background on TAG (TGF 2 antisense and GMCS F vaccine) ................ 20 1.9 Background on Furin................................................................................ 26 1.10 Phase I Re sults ........................................................................................ 35 2.0 STUDY RAT IONALE ......................................................................................... 43 3.0 OBJECTIVES ................................................................................................. 45 3.1 Primary objec tive(s) ................................................................................. 45 3.2 Secondary objec tive(s) ............................................................................ 45 4.0 STUDY DESIGN ................................................................................................. 45 4.1 Design ...................................................................................................... 45 5.0 STUDY POPULA TION ....................................................................................... 46 5.1 Sample Si ze ............................................................................................. 46 5.2 Inclusion Cr iteria ...................................................................................... 46 5.3 Exclusion Cr iteria ..................................................................................... 47 5.4 Withdrawal ............................................................................................... 48 6.0 INVESTIGATIONAL PLAN ................................................................................ 49 6.1 Patient Registrati on and Enrollm ent ........................................................ 49 6.2 Tumor Procur ement ................................................................................. 50 6.3 Vaccine Manufac turing ............................................................................ 50 6.4 Study Treatment Ad ministra tion ............................................................... 51 6.5 Toxicity ..................................................................................................... 53 6.6 Schedule of Assessments ........................................................................ 53 7.0 CONDUCT OF TH E STUDY .............................................................................. 57 7.1 Ethics and Regulatory Considerat ions ..................................................... 57 7.2 IRB and IB C ............................................................................................. 57 7.3 Written Informed Consent ........................................................................ 58 7.4 Confidentiality of Reco rds ........................................................................ 59 Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 4 7.5 Modification of Protocol ............................................................................ 59 7.6 Protocol Questions and Deviat ions .......................................................... 59 8.0 EVALUATION OF TUMORS .............................................................................. 60 8.1 Disease Evaluation .................................................................................. 60 9.0 DRUG INFORM ATION ....................................................................................... 60 9.1 Investigational Produc t............................................................................. 60 9.2 Safety A nalysis ........................................................................................ 61 9.3 Concomitant Therapy ............................................................................... 62 10.0 OCCUPATIONAL SAFETY................................................................................ 62 11.0 ADVERSE EVE NTS ........................................................................................... 63 11.1 Adverse Event and Serious Adve rse Event Defi nitions............................ 63 11.2 Attribution of Causalit y ............................................................................. 64 11.3 Expected Side Effects .............................................................................. 64 11.4 Recording of an Ad verse Ev ent ............................................................... 65 11.5 Serious Adverse Ev ent Repor ting ............................................................ 65 12.0 PATIENT COMPLETION AND WITHDRAWAL ................................................. 66 12.1 Indication for Taking Pa tients Off Study ................................................... 66 13.0 DATA EVALUAT ION ......................................................................................... 66 13.1 Statistics and Estimat ed Sample Size ..................................................... 66 13.2 Definition of Eval uable Pati ents ............................................................... 67 13.3 Time to Recurrence of Disease (TTR) ..................................................... 68 13.4 Time to Treatment Failure ........................................................................ 68 13.5 Survival .................................................................................................... 69 14.0 STUDY RECO RDS ............................................................................................ 69 14.1 Documentat ion ......................................................................................... 69 14.2 Case Report Form (CRF) Procedur es ..................................................... 70 APPENDIX A .......................................................................................................... 71 ECOG Performance St atus Scale ................................................................... 71 APPENDIX B .......................................................................................................... 72 Schedule Of Asse ssment s .............................................................................. 72 APPENDIX C .......................................................................................................... 73 NCI Common Toxicity Criteria For Adverse Events (CTCAE), Version 3.0 ..... 73 APPENDIX D .......................................................................................................... 74 FACT-O, Vers ion 4 .........................................................................................