74 REFERENC ES .......................................................................................................... 77 Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 5 ABBREVIATIONS Abbreviation Term AE Adverse event ALT Alanine transaminase (also referred to as SGPT) ANC Absolute neutrophil count APC Antigen Presenting Cells AST Aspartate transaminase (also referred to as SGOT) BUN Blood urea nitrogen CBC Complete blood count CD Cluster of differentiation CMV Cytomegalovirus CO 2 Total carbon dioxide CR Complete response CRF Case report form CTCAE Common Toxicity Criteria for Adverse Events CTL Cytotoxic T lymphocyte DC Dendritic cell(s) DTH Delayed-type hypersensitivity ECOG PS Eastern Cooperative Oncology Group Performance Score ELISA Enzyme-Linked ImmunoSorbent Assay ELISPOT Enzyme-Linked ImmunoSorbent Spot ER Endoplasmic reticulum FANG™ bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine FL Flt-3-Ligand GMCSF Granulocyte Macrophage-Col ony Stimulating Factor GMP Good Manufacturing Practice GVAX GMCSF Secreting autol ogous or allogenic tumor vaccine HLA Human Leukocyte Antigen IBC Institutional Biosafety Committee IEC Independent Ethics Committee IL Infiltrating lymphocytes IRB Institutional Review Board LAK Lymphokine-activated killer Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 6 Abbreviation Term LD Longest diameter LLC Large latent complex LPI Lead Principal Investigator MARY CROWLEY Mary Crowley Cancer Research Centers MHC Major histocompatability complex MLR Mixed lymphocyte reaction MR Mannose receptor NCI National Cancer Institute NED No evidence of disease NK Natural Killer NKT Natural Killer T cell(s) NSCLC Non small cell lung cancer PCR Polymerase chain reaction PD Progressive disease PI Principal Investigator PR Partial response PS Performance Status RECIST Response Evaluation Criteria in Solid Tumors SCLC Small cell lung cancer SD Stable disease SLC Small latent complex STMN1 Stathmin 1 TAA Tumor Associated Antigens TAP transporter associated with Ag processing TGF Transforming growth factor-  TIL Tumor infiltrating lymphocytes TNF Tumor necrosis factor Treg Regulatory T cell TTR Time to recurrence ULN Upper limits of normal WNL Within normal limits Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 7 SYNOPSIS Summary: Despite a gradual improvement in t heir overall survival over the past decade, approximately 75% of women with Stage IIIC ovarian cancer who achieve a complete clinical response will relapse as will 50% of those achieving pathologic complete response at a medi an time of 18-24 months. Phase III studies of both maintenance and consolidation therapeutic interventions have not translated into an overall survival advantage. Preliminary studies of immunotherapy in patients with ovarian cancer suggest target accessibility (potential immunogenicity) to immune mediated approaches. In an effort to overcome limitations of immunostimu latory cancer vaccines, we designed a novel autologous whole cell vaccine, Vigil™ formerly known as FANG™, incorporating the rhGMCSF tr ansgene and the bifunctional shRNA furin (to block proprotein conversion to active TGF 1 and  2) to 1) address the inability to fully identify cancer associated antigens, 2) effect antigen recogni tion by the immune system (i.e. antigen immunogen), 3) enhance effector potency, and 4) subvert endogenous cancer-induced immune resistance. A Phase I assessment of Vigil™ vaccine in 33 advanced solid tumor patients (1 of them being a pediatric patient 15 years of age) receiving ≥1 vaccination (at a dose of 1.0 x 10 7 or 2.5 x 107 cells/injection/month for a maximum of 12 vaccinations) demonstrated safety of the Vi gil™ vaccine. Furthermore, proof of principle was established in the manuf actured vaccines with increased mean GMCSF expression post-transfection to 1135 pg/106 cells/ml and knockdown of furin, TGF 1 and TGF 2 at 78%, 93%, and 95%, respec tively). In addition, although a Phase I study, the data sugges ted an overall survival benefit. Given the preliminary Phase II evidence of prolongation of ti me to relapse in randomized Vigil™ vs. No Vigil™ tr eated patients (p=0.005), as of this amendment all patients screening for enrollment into the main portion of the trial (including those who previously had tumor tissue harvested), will receive Vigil™ vaccine and will no longer be r andomized. An extensive Phase II/III protocol is designed to more definitively assess benefit. Additional safety data in ovarian cancer patients receiving 1x10 7 cells/ID injection on a monthly basis (maximum 12) is required. This is a Phase II open-label study of maintenance intradermal autologous Vigil™ cancer vaccine administered to women with Stage III/IV epithelial ovarian cancer who attain a clinical complete response (including a post-treatment, prevaccination baseline serum CA-125 level of ≤ 20 units/ml) after surgical cytoreduction and a total of six courses of front-line (pre- and post- or post- surgical) doublet chemotherapy. Patients meeting eligibilit y criteria will receive at least 5 but no more than 6 cycles of NCCN Category 1 chemotherapy. Thereafter, patients will receive Vigil TM vaccine at a dose of 1.0 x 107 cells/injection for minimum of 4 to a maximum of 12 vaccinations (based on number of vaccine doses manuf actured and patient eligib ility. Trial endpoints Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 8 include time to recurrence (TTR), doc umentation of immune responses, and correlation of immune respons e and clinical effect. Objective(s): Primary Objectives :  To assess time to recurrence (TTR) following the administration of bi- shRNAfurin and GMCSF autologous tumor cell (Vigil™) vaccine. Secondary Objectives :  To identify and determine the effect of Vigil™ autologous tumor cell vaccine on immune surrogate markers.  To assess the predictive potential of initial tumor infiltrating lymphocyte (TIL) and tumor associated macrophage (TAM) phenotypes.  To enlarge the safety database of Vi gil™ autologous tumor cell vaccine in patients with minimal disease. Methodology : This is a Phase II open-label trial of Vig il™ autologous tumor cell vaccine. Tumor will be harvested at the time of surgical debulking (standard of medical care). Patients achieving clinical complete re sponse (CR) following primary surgical debulking and doublet chemotherapy will be stratified for i) surgical stage (Stage IV or suboptimal debulking (>1 cm residual) Stage III disease versus Stage III patients with optimal debulking (<1 cm residual)) and ii) post-operative chemotherapy, pre-vaccine CA -125 of greater than 10 but less than or equal to 20 U/mL versus 0 ≤10 U/ml then randomized 2:1 (N ote: patients with Stage IIIc ovarian cancer will be additionally evaluat ed as a subset using descriptive statistical endpoint only). Patients will receive 1.0 x 10 7 cells / intradermal injection of gene transfected autologous tumor cells, Vigil™, once a month for up to 12 doses as long as sufficient material is available. A minimum harvest aliquot to produce 4 monthly injections will be requ ired for entry into the study. These patients will be managed in an outpatient setting. He matologic function, liver enzymes, renal function and electrolyt es will be monitored monthly. Immune function analysis including ELISPOT analysi s of cytotoxic T cell function to autologous tumor antigens will be monitored at ( ≤24 hours before) tissue harvest, ≤24 hours before the first cycle chemotherapy (post debulking), ≤24 hours before the third cycle chemotherapy (post debulki ng), baseline (screening); prior to Vigil™ injection at Months 2, 4, 6 and EOT. CA-125 will be monitored at baseline, every month for t he first year, every 3 months ± 2 weeks for the second and third year. Number of Patients: Approximately fifty (50) pat ients with high risk Stage III/IV ovarian cancer. Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 9 Inclusion Criteria: 1. Histologically confirmed Stage III/I V papillary serous or endometrioid ovarian cancer. 2. Per Amendment #8, tr eatment naïve, high risk ovarian cancer will no longer be stratified, but the follo wing information will be collected: a. Stage IV or suboptimal (>1 cm residual) Stage III disease versus Stage III patients with optimal ( ≤1 cm residual) disease, b. CA-125 ≤10 U/ml versus CA-125 greater than 10 to 20 U/ml c. IP chemotherapy versus IV chemotherapy 3. Clinically defined CR (no cancer related symptoms, normal physical examination and CT scan abdomen/pelvi s and chest x-ray, and CA-125 ≤ 20 U/ml) following completion of surg ical debulking. Patients enrolled must complete at least 5 but no more than 6 cycles platinum/taxane adjuvant or interval debulking + chem otherapy (or chemotherapy as per recommendations of NCCN guidelines , category 1 (IP chemotherapy included)). (Patients who complete surgery/chemother apy with a CA-125 >20 U/mL pre-randomizati on have the option of being followed up to 2 months if serial CA-125 values continue to decrease at a rate of ≥50% per month. 4. Availability of “golf-ball” size ~ 10-30 grams tissue at time of primary surgical debulking. 5. Successful manufacturing of 4 vials of Vigil™ vaccine. 6. Recovered from all clinically relevant toxicities related to prior protocol specific therapy (i ncluding neuropathy ≤Grade 2). 7. ECOG performance status (PS) 0-2 prior to tumor debulking laparotomy. 8. ECOG PS 0-1 prior to Vigi l™ vaccine administration. 9. Normal organ and marrow function as defined below: Absolute granulocyte count ≥ 1,500/mm3 Absolute lymphocyte count ≥ 200/mm3 Platelets ≥ 75,000/mm3 Total bilirubin ≤ 2 mg/dL AST(SGOT)/ALT(SGPT) ≤ 2x institutional upper limit of normal Creatinine < 1.5 mg/dL 10. Patients must be off all “statin” drugs for ≥ 2 weeks prior to initiation of therapy. Ability to understand and the willingness to sign a written informed consent document for tissue harvesting. 11. Ability to understand and the willi ngness to sign a written informed protocol specific consent. Exclusion Criteria: 1. Surgery involving general anesthes ia, radiotherapy, or immunotherapy within 4 weeks prior to randomization. Chemotherapy within 3 weeks prior to Vigil™ vaccine administration. St eroid therapy within 1 week prior to vaccine administration. 2. Patients must not have received any other investigational agents within 4 weeks of Vigil™ vaccine administration. Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 10 3. Patients with history of brain metastases. 4. Patients with compromised pulmonary disease. 5. Short term (<30 days) c oncurrent systemic steroids ≤ 0.25 mg/kg prednisone per day (maximum 7.5 mg/ day) and bronchodilators (inhaled steroids) are permitted; other steroid regimens and/or immunosuppressives are excluded. 6. Prior splenectomy. 7. Prior malignancy (excluding nonm elanoma carcinomas of the skin and carcinoma in situ cervix) unless in remission for ≥ 2 years. 8. Kaposi’s Sarcoma. 9. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic conges tive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychia tric illness/social situations that would limit compliance wit h study requirements. 10. Patients with known HIV. 11. Patients with chronic H epatitis B and C infection. 12. Patients with uncontrolled autoimmune diseases. Medication and Doses: Autologous Vigil™ vaccine will be supplied by Gradalis, Inc. Patients will receive 1.0 x 10 7 cells via intradermal injection one day each month, ≥3 weeks following completion of doublet chemotherapy (no longer than 2.5 months post chemotherapy), for a maximu m of 12 doses as long as sufficient material is available and s ubject is clinically stable. Duration: If sufficient material is available, the patient may continue therapy up to 12 doses, unless disease progression is documented (see Section 4.0, Study Design). If the pat ient experiences ≥ Grade 2 toxicity (excluding Grade 3 injection site reaction), they may cont inue on treatment with doses delayed or reduced if, in the opinion of the PI, this is considered to be in the best interest of the patient. Efficacy Assessments:  Time to disease recurrence  Immune surrogate markers  Quality of Life (FACT-O, Version 4) Safety Assessments:  Physical examination, performance st atus, height, weight, temperature, blood pressure, and pulse  Toxicity: CTCAE v 3.0 Protocol # CL-PTL 105 CONFIDENTIAL AM #9 09/25/15 Page 11 INTRODUCTION 1.0 Immune Therapy in Cancer 1.1 For decades immune-based therapies have been investigated in many types of cancer, including melanoma, prostate, renal cell, non-Hodgkin’s lymphoma, bladder cancer, and renal cell carci noma (Quan, Dean et al. 1997; Alexandroff, Jackson et al.