95% exact confidence intervals will also be presented. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 71 of 95 For Arm 6 Cohorts C and D, PFS will be calculated as the time between first dose of HS -110 and the date of PD, as defined by RECIST 1.1 or death, whichever occurs first. For patients with no recorded post -baseline tumor assessments, PFS will be censored a t day 1 . For those who remain alive and have no PD, PFS will be censored on the date of last evaluable tumor assessment. Kaplan -Meier curves will be produced separately for each Cohort in Arms 5 and 6 . Analysis details are provided in the SAP. These analys es will be conducted on the ITT population. A secondary examination of response will be performed using the Per Protocol population and the Adenocarcinoma population . 16.6. Secondary Efficacy Endpoints and Analyses Objective Response Rate Defined as the propo rtion of patients achieving a best overall response of complete response (CR) or partial response (PR) by RECIST 1.1 .These response rates will be summarized for each cohort using counts and percentages. 95% exact confidence intervals will also be presente d. A second, exploratory measure of ORR, iORR, will be calculated using the principles of iRECIST. For Arm 6, the rate of improvement in RECIST 1.1 response from SD to CR/PR will also be presented. This analysis will be conducted on the Safety population. A secondary examination of response will be performed using the Per Protocol population and the Adenocarcinoma population. Overall Survival OS will be calculated as the duration of survival from the date of first HS -110 dosing into the study to the date of death from any cause or will be censored on the date the patient was last known to be alive. Progression -Free Survival PFS will be calculated as the time between the date of first dose of HS -110 and the date of PD, as defined by RECIST 1.1 or death, whichever occurs first. A second , exploratory measure of PFS , iPFS, will be calculated as the time between the date of first dose of HS -110 and the date of iCPD as defined by iRECIST or death, whicheve r occurs first. For patients with no recorded post-baseline tumor assessments, PFS/iPFS will be censored at the day of first dose . For those who remain alive and have no PD, PFS /iPFS will be censored on the date of last evaluable tumor assessment. Kaplan -Meier curves will be produced separately for each Cohort in Arms 5 and 6 . Analysis details are provided in the SAP . Duration of Response DOR will be calculated from the time of first confirmed response (CR or PR) until radiographic PD by RECIST 1.1 . A second , exploratory DOR measure, iDOR , will be calculated as the time of first confirmed response (iCR or iPR) until iCPD as defined by iRECIST . Disease Control Rate DCR is defined as the proportion of pa tients whose best overall respons e is PR, CR, or SD, as defined by RECIST 1.1. A second , exploratory DCR rate, iDCR, is defined as the proportion of patients whose best overall response is iPR, iCR, or iSD, as defined by iRECIST . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 72 of 95 6-month Durable Response Rate 6 mo DRR is defined a s the percent age of responders with durable responses lasting at least 6 months from time of initial response by RECIST 1.1 . A second , exploratory DRR measure , 6 mo iDRR, is defined as the percentage of responders with durable responses lasting at least 6 m onths from the time of initial response by iRECIST. 12-month Durable Response Rate 12 mo DRR is defined a s the percent age of responders with durable responses lasting at least 12 months from the time of initial response by RECIST 1.1 . A second , exploratory DRR measure, 12 mo iDRR, is defined as the percentage of responders with durable responses lasting at least 12 months fr om the time of initial response by iRECIST. 6-month Overall Survival 6m OS will be calculated as the proportion of patients who are alive at 6 months following the date of first dose of HS -110 and will be presented as a median with exact 95% CI. 12-month Overall Survival 12m OS will be calculated as the proportion of patients who are alive at 12 months following the date of first dose of HS -110 and will be presented as a median with exact 95% CI . 6-month Progression Free Survival 6m PFS will be calculated as the proportion of patients who have not progressed at 6 months following the date of first dose of HS -110 and will be presented as a median with exact 95% CI. 12-month Progression Free Survival 12m PFS will be calculated as the proportion of patients who have not progressed at 12 months following the date of first dose of HS -110 and will be presented as a median with exact 95% CI. Safety and Tolerability Safety will be measured as the frequency of TEAEs/SAEs , including CS abnormal laboratory parameters, ECGs, PEs, and vitals in patients receiving at least one dose of HS-110. 16.7. Exploratory Endpoints and Analyses The following endpoints will be evaluated: • As outlined in section 16.6, efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyz ed using the principals of iRECIST to produce iORR, iPFS, iDOR, iDCR, and iDRR. • Peripheral blood IR will be measured by ELISPOT to detect an increase of 2 -fold over baseline of IFNγ and/or granzyme B (gzB) positive T cells, as well as analysis of surface markers that define NK and T cell subsets of activation, memory and exhaustion by flow cytometry . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 73 of 95 • Evaluation of tumor tissue obtained for presence of TILs (%) and correlation of pre- and post -treatment TIL levels with clinical outcomes . • Evaluation of tumor tissue obtained for percent expression of PD -L1 on tumor cells and correlation of pre - and post -treatment PD -L1 expression with clinical outcomes. • Evaluatio n of peripheral blood TMB to measure the number of mutations within the tumor genome and correlation of TMB levels with clinical outcomes. Other exploratory analys es of peripheral blood and tumor tissue to determine immune changes and response to treatment may be conducted as new technology emerges. Exploratory endpoints will be summarized descriptively at each scheduled sampling time point . Appropriate transformations may be undertaken in cases were the data are not Normally distributed. 16.8. Safety Analys es The analys es will be completed for the Safety population. Adverse Events Treatment emergent AEs are AE which occur on or after the first dose of study medication. The Medi cal Dictionary for Regulatory Activities (MedDRA) will be used for the coding of AEs. TEAEs, serious or CTCAE Grade 3 or 4 TEAEs, and TEAEs related to HS-100 will be summarized overall and by system organ class and preferred term by treatment group. These will summarize the number of events and the number and percent of patients with a given event. In addition, the number and percent of patients with TEAEs will be tabulated by maximum severity. A summary of all TEAEs by system organ class and preferred term occurring in at least 5% of patients in each Arm will be tabulated . Laboratory Assessments All laboratory -based data will be presented as listings of all values as well as abnormal results judged to be clinically significant , which will also be reported a s AEs. Numeric summaries of all observed and change from baseline laboratory evaluations will be provided (e.g. , by visit and treatment arm), including chemistry , hematology , and Troponin I or Troponin T results. Vital Signs Numeric summaries of all observed and change from baseline vital signs will be provided by time point and treatment group, including blood pressure, heart rate, respiratory rate, and temperature. ECGs Numeric summaries of all observed and change from base line in ECG parameters will be provided by time point and treatment arm , including heartrate, QRS duration (msec), QT interval (msec), QTcF interval (msec), and PR interval (msec) and the overall assessment of normal, abnormal, not clinically significant, and abnormal, clinically significant. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 74 of 95 Other Assessments Other collected data not specifically mentioned, including physical examinations (PEs) and protocol deviations, will be presented in patient listings. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 75 of 95 17. DESCRIPTION OF ETHIC AL CONSIDERATIONS RELAT ED TO THE TRIAL. The study will be conducted in accordance with all applicable regulatory requirements, including a US IND, and Sponsor will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency i n accordance with applicable country -specific regulatory requirements or local regulations, where applicable, prior to a site initiating the study in that country. The study will also be conducted in accordance with 21 CFR parts 50, 54, 56, and 312, ICH GCP, all local, regional and federal regulatory requirements, all applicable patient privacy requirements, and the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following: • IRB/EC/IBC review and favorable opinion /approval to conduct the study and of any subsequent relevant amending documents • Patient informed consent • Investigator reporting requirements A copy of the site -specific proposed ICF should be submitted to the Sponsor for review and comment before submissi on to the IRB/EC. The study should not begin until the ICF has been reviewed and approved by the Sponsor and until the document has been approved by the IRB/EC of record . The ICF shall contain all the elements of informed consent specified in the above regulations and guidance . Written informed consent will be obtained for each patient before he or she can participate in the study. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 76 of 95 18. DIRECT ACCESS TO SOU RCE DATA/DOCUMENTS 18.1. Study M onitoring In accordance with applicable regulations and GCP, the S ponsor will perform quality control and assurance checks. Before enrolling any patient into this study, the S ponsor (or designees) will review the protocol, the IB, draft CRFs and instructio ns for their completion, and significant protocol sections (i.e. reporting AEs and SAEs ) with the Investigator . A qualified designee of the Sponsor will monitor the conduct of the study at reasonable intervals by visiting the site and /or by contacting the site by telephone and e -mail. The Investigator agrees that qualified representatives of the Sponsor and regulatory agencies will have, both during and after this study, direct access to review medical records pertinent to the clinical study as specified by regulations. Patients will not be identified by name in documents that leave the study site, and confidentiality of information in both study and medical records will be preserved to the extent that is required by regulations. The Sponsor will monitor the study consistent with the demands of the study and site activity to ensure that the: • Data are authentic, accurate, and complete; • Safety and rights of patients are being protected; • Study is conducted in accordance with the currently approved protocol , any other study agreements, GCP, and all applicable regulatory requirements. 18.2. Protocol Deviations In general, a protocol deviation is an inadvertent excursion from or non -compliance with the IRB/EC -approved protocol. The Investigator is responsible for ensuring the study is conducted in accordance with the protocol and should not implement any changes to the protocol unless it is required to eliminate an immediate hazard to the patient. If the deviation affects the safety or the rights of the patient, th e Sponsor must be notified immediately. Other deviations outside of these categories will be reported to the IRB/EC in accordance with local requirements, as applicable. Deviations that fall into the following categories will be captured on the CRFs for in clusion in the CSR : • Entered into the study without meeting eligibility criteria . • Developed withdrawal criteria during the study and was not withdrawn . • Received wrong treatment or incorrect dose . • Received excluded concomitant treatment . • Failed to collect data essential to the interpret ation of primary endpoints for the study . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 77 of 95 19. QUALITY CONTROL AND QUALITY ASSURANCE To ensure compliance with GCP and all applicable regulatory requirements, the S ponsor may conduct one or more quality assuranc e audits. Regulatory agencies may also conduct regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the Investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 78 of 95 20. DATA HANDLING AND RE CORDKEEPING 20.1. Retention of Records Following clos ure of the study, the Investigator or the head of the medical institution, where applicable, must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records m ust be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The Investigator must assure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re -generating a hard copy, if required. Furthermore, the Investigator must ensure there is an acceptable back up of these reproductions and that an acceptable quality control process exists for making these reproductions. These records should be retained for not less than 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of th e investigational product. These documents should be retained for a longer period; however, if required by applicable regulatory requirements or by an agreement with the Sponsor. Thereafter, records will not be destroyed without giving the Sponsor prior written notice and the opportunity to further store such records. The Investigator must notify Sponsor of any changes in the archival arrangements, including, but not limited to, the following: archive at an off -site facility, change in office and archive lo cation, transfer of ownership of the records in the event the Investigator leaves the site. 20.2. Provision of Study Results and Information to Investigators When required by applicable regulations, the Investigator signatory for the clinical study report (CSR) will be determined at the time the report is written. When the CSR is completed, Sponsor will provide the Investigator with a summary of the study results. 20.3. Data Management The data collection tool for this study will be Sponsor -defined CRFs. Patient data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. After the Sponsor receives the CRFs, the Sponsor’s Medical Monitor (or designee) will review the data for safety information, and the Sponsor’s clin ical data associates (or designees) will review them for logical consistency and will use automated programs to help identify missing data, selected protocol violations, out -of-range data, and other inconsistencies. Requests for data clarification or corre ction will be forwarded to the investigative site for timely resolution. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 79 of 95 20.4. Study and Site Closure Upon completion or premature discontinuation of the study, the Sponsor (or designee(s) will conduct site closure activities with the Investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and Sponsor procedures. In addition, Sponsor reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons, including, but not limited to, safety or ethical issues or severe non-compliance. For this multicenter study, this can occur at one or more sites. If Sponsor determines such action is needed, Sponsor will discuss this with the Investigator or the head of the medical institution, where a pplicable, including the reasons for taking such action. When feasible, Sponsor will provide advance notification to the Investigator or the head of the medical institution, where applicable, of the impending action prior to its taking effect. Sponsor will promptly inform all other Investigators or the head of the medical institution, where applicable, and/or institutions conducting the study if the study is suspended or prematurely discontinued for safety reasons. Sponsor will also promptly inform the regu latory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the Investigator or the head of the medical institution, where applicable, must inform the IRB/EC prompt ly and provide the reason for the suspension or premature discontinuation. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 80 of 95 21. LIST OF REFERENCES 1. SEER Cancer Statistics Review, 1975 -2014. National Cancer Institute., 2017. 2017, at https://seer.cancer.gov/csr/1975_2014/ .) 2. Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S. Metastatic non -small - cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow -up. Annals of oncology : offici al journal of the European Society for Medical Oncology / ESMO 2014;25 Suppl 3:iii27 -39. 3.