September 19, 2018 Page | 33 5.11 Assessment of Outcomes 5.11.1 Safety Assessments. NCI CTCAE version 4 will be used to assess toxicities in all patients in this study. Careful toxicity assessments will be performed with s tandard laboratory studies (CBC, BUN, creatinine, electrolytes, and LFTs) before each treatment. In addition, a medical history and physical examination will be performed monthly. Three unusual toxicities can occur with anti -PD-1 therapy. These include induction of autoimmunity (nephritis, colitis, pneumonitis, and endocrinopathies). Careful, frequent clinical evaluatio n for the development of autoimmunity symptoms will be performed. Detailed plans for management of these toxicities will be present in the clinical protocol. Patients who develop uncontrolled grade 3/4 pneumonitis will permanently discontinue IPI- NIVO OR N IVO. Patients will be treated in the Moffitt Clinical Research Unit, which is staffed by nurses experienced in the management of infusion reactions and cytokine release syndrome. We are also very experienced in managing the toxicities associated with immu ne checkpoint inhibitors as we have treated over 200 lung cancer patients with either anti -PD-1 or anti -PD- L1 therapy since June 2011. All SAEs with a determination of SAE -relatedness to the investigational therapy will be reported as described in the data and safety -monitoring plan detailed in the protocol. 5.11.2 Clinical Efficacy. Radiographic assessments will be performed at the end of vaccines 1 -3 (“first 3 vaccines”) and twice in patients receiving vaccines 4 -6 (“second three vaccines”). First , after vaccine 4 and t hen, after all 6 vaccines. Subsequently, assessments will be done every 12 weeks. Response will be assessed primarily using the response evaluat ion criteria in solid tumors (RECIST v1.1 ). Response rate, overall survival, and progression- free survival will be determined. Subjects with progressive disease by RECIST but without rapid clinical deterioration may continue to be treated at the discretion of the investigator. The immune related ( ir)RECIST will also be used secondarily for research purposes only . This is a modification of RECIST and allows measurement of response patterns unique to immune therapy, such as tumor progression of index lesions and appearance of new lesions prior to tumor regression 85. Patients who are found to have stable disease (SD), partial response (PR), or complete response (CR) will continue on study until evidence of disease progression, intolerance, or withdrawal from study. 5.11.3 Immunological Efficacy Criteria used to determine the presence of immune responses: Individual patient will be considered responders if at any time point the response in IFN-γ ELIPOT assay is higher than 30 spots per 2 × 105 AND the response in IFN-γ ELISPOT to ALVAC p53 is more than 2 SD Protocol: Version 8.0. September 19, 2018 Page | 34 higher than the response to corresponding ALVAC control at the same time point AND 2 SD higher than the corresponding response at the ba se line (before start of the treatment). s 5.11.4 Biomar ker Testing A pre-treatment tumor biospy will be performed (mandatory) and utilized to evaluate tumor p53 biomarker status . To be eligible for the study, patients must have a favorable tumor p53 biomarker profile defined by ≥ 50% p53 positive tumor cells by immunohistochemistry. Tumor p53 biomarker evaluations may be performed with either original or recurrent tumor although samples from recurrent disease are preferred. The mandatory pre- treatment tumor biopsy specimen will be used to evaluate p53 protein expression using a CLIA -certified p53 assay . If sufficient tumor sample remains available, additional immunohistochemistry evaluations will be performed for PD-1, PDL -1, PDL -2 protein expression as well as tumor i nfiltration by immune cells expressing CD3, CD8, CD4, CD25, FoxP3, CD11b, and CD56. Tumor mutational burden will also be evaluated using Foundation One CDx , if possible depending on tissue availability. Simultane ously, all efforts will be made to collect archival tumor tissue from previous biopsies, either in the form of a FFPE block or unstained slides ( ideally 5 -10, but any number will be acceptable depending on availability). Protocol: Version 8.0. September 19, 2018 Page | 35 6.0 TRIAL FLOW CHART All laboratory studies, visits and procedures included in these Flow chart have a +/ - 7 day window. This rule applies in addition to any existing window included for specific laboratory studies, visits or procedures at the discretion of the investigators. Scree ning Leuko pheresi s #1A,E Visit #1C,E Visit #2 Visit #3 Visit #4 Visit #5 Leuko pheresis #2B,E Visit #6D,E Visit #7 Visit #8 Visit #9 Visit #10 Visit #11 Visit #12 Visit #13,F + End of Study VisitG Induction Immunotherapy Maintenance Immunotherapy Wk -4 to 0 Wk -3 to 0 Wk 1 C1 D1 Wk 3 C1D15 Wk 4 C2D1 Wk 5 C2D8 Wk 7 C3D1 Wk 8 to 12 Wk 10 C4D1 Wk 13 C5D1 Wk 1 5 C5D15 Wk 17 C6D1 Wk 19 C6D1 5 Wk 21 C7D1 Wk 23 C7D15 Wk 2 5, + C8,+ D1 ICF1 X H+P2 X X X X X X X X MD3 visit X X X X X X X Mid-Level visit X X X X X X X X X X CTC7 visit X X X X X X X X X X X X X X X X X Concurrent Medications X X ……………………………………………………………………………………………………………………………….… X X Adverse event (AE) evaluationCC X X …………………………………………………………………….. …………………………………………………………… X X CBC, diff X X X X X X X X X X X X X X CMP X X X X X X X X X X X X X X Mg X X4 X LDH X X X X PT/INR, PTT X X4 X Thyroid studies13 X X X X EKG , U/A X X4 Pregnancy test X X4 X4 CT chest/abd .6 X X X X X6 X Brain MRI5,8 X5 X5 X5 X5 NivolumabAA X X X X XAA X X X Ipilimumab X X X X Ad.p53 -DCBB X X X XBB X X Immune response evaluation9 X X10 X X X Image guided core biopsy11 X Tumor Biomarker s (p53 IHC)12 X Life-expectancy >4 months X 1 Informed consent form (ICF) must be signed within 3 week s of first leukopheresis (start of study) Protocol: Version 8.0. September 19, 2018 Page | 36 2 Brief history and physical (H+P) to include vital signs (VS), weight (W), height (H) and performance status (PS) and AE evalu ation on Mid-Level visits and Full H+P on MD visits. 3 Can also be performed by protocol assigned Mid- Level: Nurse Practitioner (NP) or Physician Assistant (PA) 4 Only need repeated if leukopheresis being performed more than 4 weeks since a prior test performed 5 Only re quired for patients with CNS symptoms suspicious of brain metastasis or for patients known to have untreated brain metastasis. Otherwise it is only required if clinically indicated per treating physician discretion 6 Starting with visit #1 3 and beyond, while only receiving maintenance nivolumab, patients will have restaging CT scans every 3 months 7 When the patient is seen by the MD, then only a clinical trials coordinator (CTC) visit will be required. For all other appointments, a Mid Level (Mid L) visit will be required 8 The type and site of any other imaging scan will only be performed when clinically indicated, at the discretion of the treati ng physician 9 Including MDSC determination 10 Not necessary if blood drawn at screening 11 Tumor biopsy is mandatory. Ideally, 4 -6 core samples should be obtained. A lesser number of cores (1- 3) will be acceptable in cases where patient safety so requires or if in the judgement of the physician performing the biopsy less number of cores should be performed. . Simultaneously, all efforts will be made to collect archival tumor tissue from previous biopsies, either in the form of a FFPE block or unstained slides (ideally 5 -10, but any number will be acceptable depending on availability) . 12 Tumor Biomarker Testing for p53 expressio n at enroll ment is required. Tumor p53 biomarker evaluations can be performed with either original or recurrent tumor although samples from recurrent disease are preferred. Additional biomarkers will also be performed depending on tissue availability as per section 5.11.4. 13 See Table 5, (T3, T4 and TSH) A First leukopheresis should occur within 2-3weeks of completing screening evaluation (date of the last screening test perf ormed) B Second leukopheresis should occur within 2-3weeks of completing restaging evaluation C Visit #1 should be scheduled within 2week of leukopheresis #1 D Visit #5 should be scheduled within 2 week of leukopheresis #2 E For clarity and consistency pu rposes, if visits #1 and/or #5 occur more than 2 weeks from leukopheresis, they will still be considered to occur on weeks 1 and/or 10 respectively F patients will be seen on a monthly schedule after visit #1 3 G The mandatory Safety Follow -Up Visit (End of trial, EOT) should be conducted approximately 30- 45 days after the last dose of trial treatment or before the initiation of a new anti -cancer treatment, whichever comes first (End of trial, EOT). AA Nivolumab is administered at a fixed dose of 480 mg e very 4 weeks during the maintenance period until PD BB First booster vaccine (vaccine #4) should be administered with the first cycle of maintenance immunotherapy (C5D1), in combin ation with single agent (maintenance) nivolumab. The subsequent second and t hird booster vaccines will be administered 4 weeks later, on C7D1 and C9D1, respectively with the corresponding dose of nivolumab. CC The study stopping criteria incorporated to the protocol are applicable (as described in …..) ONLY PRIORr to D1C3. NOTE: IN CASE THAT, DURING THE CONDUCTION OF THE TRIAL, A DISCREPANCY WAS NOTED BETWEEN THE PROTOCOL CONTENT AND THIS CALENDAR, THE INFORMATION OR REQUIREMENTS INCLUDED IN THE CALENDAR WILL BE FOLLOWED Protocol: Version 8.0. September 19, 2018 Page | 37 6.1 TRIAL FLOW CHART: Second Course Phase (Retreatment Period) All laboratory studies, visits and procedures included in these Flow chart have a +/ - 7 day window. This rule applies in addition to any existing window included for specific laboratory studies, visits or procedures at the discretion of the investigators. Screening Visit #1 Visit #2 Visit #3 Visit #4 Visit #5 Visit #6 Visit #7 Visit #8,A + End of Study VisitB Induction Immunotherapy Maintenance Immunotherapy Wk -4 to 0 Wk 1 C1 D1 Wk 4 C2D1 Wk 7 C3D1 Wk 10 C4D1 Wk 13 C5D1 Wk 17 C6D1 Wk 21 C7D1 Wk 25, + C8 +D1 H+P14 X X20 X X X X X X X X MD15/Mid - Level visit X X20 X X X X X X X X CTC18 visit X X X X X X X X X X Concurrent Medications X X …………………………………………………………………………………….… X X AE evaluation X X …………………………..…………………………………………………………… X X CBC, diff X X X X X X X X X X CMP X X X X X X X X X X Pregnancy test X CT chest/abd.17 X X X X17 X Brain MRI16,19 X16 X16 X16 X16 NivolumabAA X X X X XAA X X X Ipilimumab X X X X 14 Brief history and physical (H+P) to include vital signs (VS), weight (W), height (H) and performance status (PS) and AE evalu ation on Mid-Level visits or MD visits. Protocol: Version 8.0. September 19, 2018 Page | 38 15 Can also be performed by protocol assigned Mid- Level: Nurse Practitioner (NP) or Physicia n Assistant (PA) 16 Only required for patients with CNS symptoms suspicious of brain metastasis or for patients known to have untreated brain met astasis. Otherwise it is only required if clinically indicated per treating physician discretion 17 At the time of visits #8 and beyond, while only receiving maintenance nivolumab, patients will have restaging CT scans every 3 months 18 When the patient is seen by the MD, then only a clinical trials coordinator (CTC) visit will be required. For all other appoi ntments, a M id Level (Mid L) visit will be required 19 The type and site of any other imaging scan will only be performed when clinically indicated, at the discretion of the treati ng physician 20 This visit is not necessary if screening visit performed within 4 weeks of D1C 1 A patients will be seen on a monthly schedule after visit #8 B The mandatory Safety Follow -Up Visit (End of trial, EOT) should be conducted approximately 30- 45 days after the last dose of trial treatment or before the initiation of a new anti- cancer treatment, whichever comes first (End of trial, EOT). AA Nivolumab is administered at a fixed dose of 480 mg every 4 weeks until PD Protocol: Version 8.0. September 19 , 2018 Page | 39 7.0 TRIAL PROCEDURES 7.1 Trial Procedures The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.