Figure 1. Study Design 5.0 PARTICIPANT SELECTION 5.1 Inclusion Criteria Patients must meet all of the following inclusion criteria to be enrolled into the study: 1. Histologically or cytologically confirmed non -small cell lung adenocarcinoma 2. Received at least 2 and no more than 3 prior lines of systemic therapy for Stage IV or recurrent incurable NSCLC, in cluding cytotoxic chemotherapy, molecularly -targeted agents, or immunotherapy. Prior adjuvant or neoadjuvant chemotherapy or definitive chemoradiation for locally advanced disease does not count as a line of therapy as long as the last administration of t he regimen occurred at least 12 months prior to enrollment. A repeat course of a prior line of systemic therapy does not count as an additional line of therapy. Maintenance systemic therapy or palliative radiotherapy to single sites of disease will not b e considered an additional regimen. 3. Suitable, in the opinion of the investigator, for conventional single agent chemotherapy 4. Documented disease progression at study entry 5. Age ≥ 18 years 6. ECOG performance status (PS) ≤ 1; ECOG PS=2 patients may be considere d after discussion with the Medical Monitor 7. CNS metastases may be permitted after discussion with the Medical Monitor but must be treated and neurologically stable. Patients must be on a stable or dec reasing dose of corticosteroids and/or have no requirement for anticonvulsants for 14 days prior to screening. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 31 of 84 8. Lab parameters:  Albumin ≥ 2.5 mg/dL  Total Bilirubin < 1.5 mg/dL unless known Gilbert’s syndrome  Alanine transaminase (ALT), and aspartate transaminase (AST) ≤3.0 × upper limits of normal (ULN) or ≤5 × ULN in the case of liver metastases.  Calculated or measured creatinine clearance >35 mL/minute per the Cockcroft -Gault formula  Absolute neutrophil count ≥ 1,500/mm3  Hemoglobin ≥ 9 g/dL  Platelet count ≥ 100,000/mm3 9. Willing and able to comply with the protocol and sign informed consent , including weekly clinic visits to receive injections for 12 weeks followed by every -3-week visits thereafter for up to 12 months if randomized to the experimental group . 10. Female patients who are of childbearing p otential and fertile male patients must agree to use an effective form of contraception (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) with their sexual partners throughout study participation. Female patients of childbearing potential must test negative for pregnancy prior to enrolling in the trial. 5.2 Exclusion Criteria Patients that meet any of the following exclusion criteria are not eligible to be enrolled into the study: 1. Received systemic anticancer therapy (including cytotoxic chemotherapy, monoclonal antibodies, immunotherapy, and tyrosine kinase inhibitors ( TKIs )) or radiation therapy within the previous 14 days 2. Received m ore than 3 lines of prior conventional therapy for advanced disease . 3. Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or intercurrent illness, unrelated to the tumor, requiring active therapy . Testing is not required in the absence of history. 4. Any condition requiring concurrent systemic immunosuppressive therapy 5. Known immunodeficiency disorders, either primary or acquired 6. Known leptomeningeal disease 7. Other active malignancies 8. Prior treatment with a cancer vaccine for this indi cation 9. Pregnant or breastfeeding Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 32 of 84 6.0 STUDY PROCEDURES A signed, written informed consent form that is currently approved by an IRB /EC/IBC must be obtained from the potential patient before he/she can participate in any study -specific procedures, including stu dy- specific screening procedures. Patients will be enrolled and randomized once all screening procedures have been completed , and it is determined that the patient meets all eligibility criteria. 6.1 Schedule of Assessments (SOA) In general, the schedule of a ssessments is divided into 3-week cycles with the first 12 weeks being the induction period and the remainder being the maintenance period . Patients in the experimental group may visit the clinic m ore frequently than patients in the control group during t he induction period in order to permit the weekly treatment with viagenpumatucel -L and safety assessment o f the combination with CY . REST OF PAGE INTENTIONALLY LEFT BLANK Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 33 of 84 Schedule of Assessments NOTE: Visits marked in bold are mandatory for all patients. 1 Baseline procedures may be combined with the Week 1 visit, so long as all procedures are performed prior to dosing. 2 Patients randomized to the control group need not be seen in the clinic at these time points if standard practice dictates such. Patients randomized to the experimental group will still be seen. 3 Full physical exam will be performed at screen ing and EOT. Exams at Weeks 4, 7, 10, and 13 are limited to vital signs and symptoms. 4 Samples to be drawn prior to dosing. For pati ents randomized to the control group, if 100mL cannot be safely drawn due to cytopenia, 40mL of heparinized blood may be excl uded. 5 Hematology and Chemistry assessments need repeating at Baseline only if the Screening visit was performed > 2 weeks prior to the first dose. Induction Maintenance Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Procedure Screen Baseline1 Wk 1 Wk 22 Wk 32 Wk 4 Wk 52 Wk 62 Wk 7 Wk 82 Wk 92 Wk 10 Wk 112 Wk 122 Wk 13 Wk 16 Wk 19 Wk 22 Wk 28 Wk 31 Wk 40 Wk 49 Wk 52 EOT LTFU Study Day -28 to -1 -7 to 1 1 8±2 15±2 22±2 29±2 36±2 43±2 50±2 57±2 64±2 71±2 78±2 85±2 106±3 127±3 148±7 190±7 211±7 274±7 337±7 358±7 +28 ±7 Q3 mo Baseline Documentation Informed Consent X Eligibility Assessment X Randomization X Medical History X ECOG PS X X Pre-existing symptoms X X X Safety Assessments Physical Exam inc. vital signs3 X X X X X X 12-lead ECG X X X X Laboratory Studies Immunologic Response (mL)4 100 100 100 100 100 100 Blood Hematology X X5 X X X X X X X X X X X X X X X X X Serum Chemistry X X5 X X X X X X X X X Urinalysis X X X X X X X X X X Pregnancy Test X X Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 34 of 84 NOTE: Visits marked in bold are mandatory for all patients. 6 Baseline procedures may be combined with the Week 1 visit, so long as all procedures are performed prior to dosing. 7 Patients randomized to the control group need not be seen in the clinic at these timepoints if standard practice dictates such 8 Scans will be performed every 9 weeks for the first 28 weeks and t hen every 12 weeks thereafter. irCR, irPR and irPD will be confirmed w ith a second tumor assessment a fter at least 4 weeks. 9 Radiological assessments will continue, where possible, for patients withdrawing due to clinical progression but prior to irR C determined progression and for patients who remain on treatment after confirmed irPD . 10 Patients are to be monitored on site for 30 minutes following each dose. 11 Physician’s Choice options should be given with dose and route according to investigator’s standard practice until progression. 12 Tumor biopsies will be obtained in consenting patients randomized to the experimental group at Baseline and Week 13 . Archival biopsy tissue may be provided if available. 13 Subsequent anticancer therapy will be colle cted. Induction Maintenance Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Procedure Screen Baseline6 Wk 1 Wk 27 Wk 37 Wk 4 Wk 57 Wk 67 Wk 7 Wk 87 Wk 97 Wk 10 Wk 117 Wk 127 Wk 13 Wk 16 Wk 19 Wk 22 Wk 28 Wk 31 Wk 40 Wk 49 Wk 52 EOT LTFU Study Day -28 to -1 -7 to 1 1 8±2 15±2 22±2 29±2 36±2 43±2 50±2 57±2 64±2 71±2 78±2 85±2 106±3 127±3 148±7 190±7 211±7 274±7 337±7 358±7 +28 ±7 Q3 mo Tumor Assessments CT scan or MRI8 X X X X X X X9 Dosing Vaccine10 X X X X X X X X X X X X X X X X X Metronomic CY X*7 X*7 X*7 X*7 X*7 X*7 Physician’s Choice (Control Group)11 SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC SOC Other Clinical Assessments Tumor Biopsy12 X X Adverse Events X X X X X X X X X X X X X X X X X X X X X X Concomitant Medications X X X X X X X X X X X X X X X X X X X X X X X X X13 Survival X Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 35 of 84 6.2 Screening Procedures The following procedures must be conducted <4 weeks prior to the first dose of study medication :  Written informed consent  Verify eligibility criteria  Patient demographics  ECOG PS – discuss with Medical Monitor any patients with ECOG = 2  Clinically significant m edical history , including prior treatments, concomitant medications , and pre-existing symptoms  Physical examinatio n (including weight, vital signs [heart rate, temperature, respiratory rate and blood pressure] )  12-lead ECG  Blood hematology, serum chemistry, and urinalysis  Urine or serum pregnancy test for female patients of childbearing potential  Tumor assessment , including CT scan or MRI , to document baseline index lesions for irRC and target and non -target lesions for RECIST 6.3 On-Study Procedures Study -related procedures and assessments performed during treatment on study are detailed as follows and in the Schedule of Assessments table (see Section 6.1). 6.3.1 Baseline Assessments (Day -7 to 1) The following procedures will be performed after all t he previous screening procedures hav e been completed and prior to dosing. These assessments may occur on the same day as dosing, so long as the collection of biopsy tissue and blood samples occurs PRIOR to dosing. Reassessment of ECOG PS (and discussion with Medical Monitor for patients whose ECOG PS has changed since Screening (see Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 36 of 84  Appendix 1 . ECOG Performance Status Scale ))  Record pre-existing symptoms and concomitant medications  Blood hematology and serum chemistry only if the screening visit was performed >2 weeks prior to the first dose Once the patient has met all of the eligibility requirements for the study, the patient will be randomized. Each patient will be assigned a unique study number and will be considered enrolled on the study at the time of randomization.  Baseline tumor biopsy (where consent has been provided in patient s randomized to the experimental group ; archival biopsy tissue may be provided if available . Note: Provide at least 4, non-stained, 10 micron sections for analysis of shared tumor antigen expression, expression of MHC class I, and expression of immunosuppressive molecules . If slides are not available, formalin - fixed paraffin embedded ( FFPE ) tissue (50 microns) is also acceptable .) 6.3.2 Visit Assessments 6.3.2.1 Week 1 Assessment s (Day 1) The following procedures will be performed after all t he previous screening and baseline procedures have been completed.  Update of concomitant medications and pre -existing symptoms  Blood draw for baseline immunologic response obtained prior to dosing  Patients randomized to the experimental group o Administration of vaccine o Monitor patients on site for potential acute reactions for 30 minutes after vaccine administration o Metronomic CY administrati on (taken at home )  Patients randomized to the control group o Physician’s choice, depending on schedule (described in section 7.2)  Record adverse events 6.3.2.2 Week 2, 6, 8 and 12 Assessments The following procedures will be performed at Week 2 (Day 8 ± 2 ), Week 6 (Day 36 ± 2 ), Week 8 (Day 50 ± 2) and Week 12 ( Day 78 ± 2). Note that patients in the control group need not be seen in the clinic if standard practice dictates such :  Blood hematology  Patients randomized to the experimental group o Administration of vaccine o Monitor patients on site for potential acute reactions for 30 minutes after vaccine administration  Patients randomized to the control group Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 37 of 84 o Physician’s choice, depending on schedule  Record adverse events  Record concomitant medications 6.3.2.3 Week 3, 5, 9 and 11 Assessments The following procedures will be performed at Week 3 (Day 15 ± 2), Week 5 (Day 29 ± 2), Week 9 (Day 57 ± 2) and Week 11 (Day 71 ± 2). Note that patients in the control group need not be seen in the clinic if standard practice dictates such :  Blood hematology  Patients randomized to experimental group o Administration of vaccine o Monitor patients on site for potential acute reactions for 30 minutes after vaccine administration o Metronomic CY administration (taken at home )  Patients randomized to the control group o Physician’s choice, depending on schedule  Record adverse events  Record concomitant med ications 6.3.2.4 Week 4 Assessments The following procedures will be performed at Week 4 (Day 22 ± 2):  Vital Signs , with physical exam targeted to signs and symptoms  Blood draw for immunologic response obtained prior to dosing  Blood hematology , serum chemistry, an d urinalysis  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.5 Week 7 Assessments The following procedures will be performed at Week 7 (Day 43 ± 2):  Vital Signs , with physical exam targeted to signs and symptoms  Blood hematology , serum chemistry, and urinalysis Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 38 of 84  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration o Metronomic CY administration (taken at home )  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.6 Week 10 Assessments The following procedures will be performed Week 10 (Day 64 ± 2):  Vital Signs, with physical exam targeted to signs and symptoms  12-lead ECG  Blood draw for immunologic response obtained prior to dosing  Blood hematology , serum chemistry, and urinalysis  Tumor Assessment by CT scan or MRI - irCR, irPR and irPD will be confirmed with a second tumor assessment at least 4 weeks later  Patients in experimental group o Administrati on of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.7 Week 13 Assessments The following procedures will be performed at Week 1 3 (Day 85 ± 2):  Vital Signs , with physical exam targeted to signs and symptoms  Blood draw for immunologic response obtained prior to dosing  Blood hematology , serum chemistry, and urinalysis  Patients in experimental group o Tumor biopsy (in consenting patients . Note: Provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of infiltrating T cells . If slides are not available, FFPE tissue (50 microns) is also acceptable .) o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 39 of 84  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.8 Week 16 Assessments The following procedures will be performed at Week 16 (Day 106 ± 3):  Patients in experimental group o No experimental therapy  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse eve nts  Record concomitant medications 6.3.2.9 Week 19 Assessments The following procedures will be performed Week 19 (Day 127 ± 3):  12-lead ECG  Tumor Assessment by CT scan or MRI – irCR, irPR and irPD will be confirmed with a second tumor assessment at least 4 weeks later  Patients in experimental group o No experimental therapy  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.10 Week 2 2 Assessments The following procedures should be completed at Week 2 2 (Day 148 ± 7):  Blood draw for immunologic response obtained prior to dosing  Blood hematology , serum chemistry, and urinalysis  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactio ns for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on drug and schedule  Record concomitant medications Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 40 of 84  Record adverse events 6.3.2.11 Week 28 Assessments The following procedures should be completed at Week 28 (Day 190 ± 7):  Tumor Assessment by CT scan or MRI – irCR, irPR and irPD will be confirmed with a second tumor assessment at least 4 weeks later .  Patients in experimental group o No experimental therapy  Patients in the control group o Physician’s choice, depending on drug and schedule  Record adverse events  Record concomitant medications 6.3.2.12 Week 31 Assessments The following procedures should be completed at Week 31 (Day 211 ± 7):  Blood hematology , serum chemistry, and urinalysis  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on drug and schedule  Record concomitant medications  Record adverse events 6.3.2.13 Week 40 Assessments The following procedures should be completed at Week 40 (Day 274 ± 7):  Blood hematology , serum chemistry, and urinalysis  Tumor Assessment by CT scan or MRI – irCR, irPR and irPD will be confirmed with a second tumo r assessment at least 4 weeks later .  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on drug and schedule  Record concomitant medications  Record adverse events Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 41 of 84 6.3.2.14 Week 49 Assessments The following procedures should be completed at Week 49 (Day 337 ± 7):  Blood hematology , serum chemistry, and urinalysis  Patients in experimental group o Administration of vaccine o Monitor patient on site for potential acute reactions for 30 minutes after vaccine administration  Patients in the control group o Physician’s choice, depending on schedule  Record concomitant medications  Record adverse events 6.3.2.15 Week 52 Assessments The following procedures should be completed at Week 52 (Day 358 ± 7):  Tumor Assessment by CT scan or MRI – irCR, irPR and irPD will be confirmed with a second tumor assessment at least 4 weeks later .  Patients in experimental group o No experime ntal therapy  Patients in the control group o Physician’s choice, depending on schedule  Record adverse events  Record concomitant medications 6.3.3 End of Treatment Visit ( Day 28 ± 7 post last dose) The following procedures should be completed approximately 4 weeks following last dose of vaccine , including patients who discontinue vaccine dosing prematurely.  Physical examination (including weight, vital signs)  12-lead ECG  Blood draw for immunologic response  Blood hematology , serum chemistry, and urinalysis  Urine or serum pregnancy test for female patients of childbearing potential  Record adverse events  Record concomitant medications 6.3.4 Long -term Follow -up Visits All patient s will be followed for survival until study termination or death , whichever occurs first . Radiol ogical assessment s will continue, where possible, for patients withdrawing due to clinical Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 42 of 84 progression but prior to irRC determined progression or for patients who continue on treatment beyond confirmed irPD . Survival data as well as information on any ne w anticancer therapy initiated after disease progression will be collected via phone call approximately every 3 months. Since OS is the primary endpoint of this study, follow -up continue s even if subjects participate in other experimental studies or recei ve other treatment. 6.4 Safety Assessments Safety will be assessed throughout the study by a qualified physician, physician assistant , or nursing staff. Measurements used to evaluate safety will include history, physical examination, vital signs, clinical laboratory tests , urinalysis, 12 -lead ECG , and monitoring for AEs. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 .03 (NCI -CTCAE v4.03) NCI, 2010 . Laboratory measurements that deviate clinically significantly (as determined by the investigator) from previous measurements may be repeated. If warranted, additional or more frequent testing than is specified in the protocol should be done to provide ade quate documentation of AEs and the resolution of AEs. 6.4.1 Physical Examination Medical and physical examinations must be performed by a qualified physician, nurse practitioner, or physician assistant and should include a thorough review of all body systems at Screening and at the End of Treatment ; exams at Weeks 4, 7, 10, and 13 are limited to vital signs and symptoms. Physical examinations will include vital signs. Blood pressure, heart rate, respiratory rate, and temperature will be measured after resting i n a semi -supine or supine p osition . 6.4.2 Clinical Laboratory Evaluations Patients will have blood samples collected for routine clinical laboratory testing. The clinical laboratory parameters will be analyzed at the site’s local laboratory. Laboratory assess ments to be co mpleted will include hematology , serum chemistry and urine or serum pregnancy test (females of childbearing potential) and will be defined as following:  Serum Chemistry: To include sodium, calcium, total protein, albumin, creatinine, blood ur ea nitrogen, total bilirubin, alkaline phosphatase, AST, ALT, potassium, c hloride, bicarbonate, lactate dehydrogenase, and glucose.  Hematology : To include white blood cell (WBC) with differential, platelet count, hemoglobin, and red blood cell (RBC) count.  Urine or serum pregnancy test : See section 6.4.6 below for further details.  Additional laboratory assessments may be conducted throughout the study as medically necessary. 6.4.3 Urinalysis Patients will have urine samples collected for routine urinalysis. The urinalysis will include color, appearance, and dipstick for specific gravity, protein, white blood cell -esterase, glucose, ketones, urobilinogen, nitrite, WBC, R BC, and pH. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 43 of 84 6.4.4 ECG The following parameters from 12 -lead electrocardiograms will be evaluated: heart rate, PR interval, QRS duration, QT interval, and QTcF interval. 6.4.5 Injection Site Reactions The grading scale for injection site reactions (ISRs) used in this trial can be found in A ppendix 4. Grade 1 ISRs consisting of mild redness, erythema and swelling around the injection site are anticipated. Grade 1 reactions should dissipate over several days to a week with no special treatment. All ISRs should be recorded on the Injection Site Reaction CRF page. If an unusual or Grade 3 or 4 ISR occurs, attempts to obtain photographs at the peak of severity and at follow -up visits that show resolution over time are encouraged. A ruler should be in the field of view to allow measurement of the size of the reaction. If the patient consents, the de -identified photograph(s) should be appended to the CRF . 6.4.6 Pregnancy All female patients of childbearing potential will have a urine or serum pregnancy test performed at Screen ing and at the End of T reatment follow -up visit. Female patients who become pregnant during the study should discontinue study medication immediately. The patient will receive counseling from the investigator or designee regarding the nature of the study medication and the potential risk on fetal development. 6.4.6.1 Time Period for Collecting Pregnancy Information The time period for collecting information on whether a pregnancy occurs is from the Screening visit to 4 weeks after the last dose of study medication. Information on pregnancies identified prior to study drug administration does not need to be reported to Heat Biologics. 6.4.6.2 Action to be Taken if Pregnancy Occurs The investigator will notify Heat Bi ologics , or designee, within 1 week of learning of a patient’s pregnancy. The patient will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to Heat Biologics , or designee . Ge nerally, follow -up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported . While pregnancy itself is not considered to be an AE or serious adverse event ( SAE ), any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE/SAE section 8.1). A spontaneous abortion after th e first trimester will be reported as an SAE . Furthermore, any SAE occurring as a result of a post -study pregnancy and that is considered reasonably related to the investigational product by the investigator will be reported to Heat Biologics. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 44 of 84 6.4.6.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study Subject The investigator w ill attempt to collect pregnancy information on any female partner of a male study patient who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to Heat Biologics , or designee, within 1 week of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to Heat Biologics , or designee . Generally , follow -up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy after the first trimester will be reported. 6.5 Efficacy Assessments 6.5.1 Tumor Assessments Tumor response assessments will incorporat e results from radiographic tumor assessment (CT scans or MRI) and physical examination, where appropriate , and will follow both immune -related response criteria (irRC),67 which ha ve been previously defined to describe the unique response patterns observed with immunotherapeutic agents, and conventional RECIST 1.1 criteria .68 All clinical decision -making ( e.g. determination of progression) will follow definitions of irRC only. The i dentification of index and new lesions (irRC) and target plus non -target lesions (RECIST criteria) will be documented at baseline , and r epeat scans will be performed every 9 weeks until Week 28 and then every 12 weeks thereafter , unless clinical signs of p rogression necessitate earlier scanning . The same method used at screening must be used throughout the study . Bone scans are NOT acceptable for determination of disease status , and suspected bone lesions must be confirmed by CT/MRI . PET scanning is strongly discouraged for the purposes of disease evaluation , and any proposed use should be discussed with the Medical Monitor prior to baseline scanning . A centralized review of scans will be done during the course of this study. The data from the blinde d independent review will be used for the response endpoints, rather than local reads. Further details are provided in the imaging charter. 6.5.1.1 Immune Criteria for Tumor Assessment Whereas conventional RECIST criteria consider any new measurable lesion to indicate PD, irRC is based on changes in total tumor burden from the baseline (nadir, for irPD) tumor assessment, regardless of any initial increase in baseline lesions or the appea rance of new lesions. This practice of determining next treatment steps based on the overall tumor burden is reasonably consistent with standard of care in the advanced clinical setting of the current study and is therefore suitable for application to bot h the experimental and control groups for clinical decision -making . In accordance with immune criteria, a t the baseline tumor assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions ( 5 lesions per organ, u p to 10 visc eral lesions + 5 cutaneous index lesions ) is calculated. At ea ch subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm ; up to 5 new lesions per organ, 10 visce ral lesions) are added together to prov ide the total tumor burden: Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 45 of 84 Tumor Burden = SPDindex lesions + SPDnew, measurable lesions Decreases in tumor burden must b e assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening). Each investigator will assess disease r esponse (complete response [irCR], partial response [irPR], stable disease [irSD], and pro gressive disease [irPD]) using ir RC criteria outlined in Appendix 2. Patients determined to have irCR, irPR, or irPD will have an additional confirmatory scan performed at least 4 weeks after the initial scan. If a patient is classified as having irPD at a post -baseline tumor assessment, then confirmation of irPD by a second scan in the absence of rapid clinical deterior ation is required. The definition of confirmation of progression represents an increase in tumor burden ≥25% compared with the nadir at 2 conse cutive time points at least 4 weeks apart. The disease response measures will allow for the calculation of the immu ne-related disease control rate and 6-month disease control rate (irDCR and 6m -irDCR ), whic h includes irCR, irPR, and irSD ; immune -related overall response rate (irORR), which includes ir CR and irPR ; immune -related progression -free survival (irPFS) ; and immune -related time to progression (irTTP) . 6.5.1.2 RECIST Criteria for Tumor Assessment At the baseline tumor assessment, tumor lesions/lymph nodes will be categorized as measurable or non - measurable with measurable tumor lesions recorded according to the longe st diameter in the plane of measurement (except for pathological lymph nodes, which are measured in the shortest axis) . When more than 1 measurable lesion is present at baseline , all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should be identified as targ et lesions. For the purposes of this study, a maximum of 2 lymph nodes are permitted as target lesions, irrespective of the organ systems from which they originate. Target lesions should be sele cted on the basis of their size (lesions with the longest diameter) . A sum of the diameters for all target lesions will be calculated and reported as the baseline sum diameters. All other lesions (or sites of disease) , including pathological lymph nodes , should be ident ified as non - target lesions and should also be recorded at baseline . Measurements are not required and these lesions should be f ollowed as ‘present’, ‘absent’, or ‘unequivocal progression’ . Disease response (com plete response (CR) , partial response (PR), stable disease (SD), and progressive disease (PD )) will be assessed as outlined in Appe ndix 3 . The disease response measures will allow for the calculation of the disease control rate and 6 -month disease control rate (DCR and 6mDCR ), which includes CR, PR, and SD ; the overall response rate (ORR), which includes CR and PR ; progression -free survival (PFS) ; and time to progression (TTP) . 6.5.2 Immunologic Response Peripheral blood s amples will b e obtained prior to the first study treatment , at Week s 4, 10, 13, and 22, and at EOT in all patients . All samples will be shipped to and processed by one or more central laborator ies. Ninety (90) mL heparinized blood and 10 mL of non -heparinized blood will be drawn at each time point and used for analysis as outlined below. Peripheral blood mononuclear cells (PBMC s) will be isolated from Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 46 of 84 heparinized blood samples by Ficoll separation. Isolated PBMC s will be utilized for immunophenotyping analysis using flow cytometry , DNA isolatio n and subsequent TCR sequencing, intracellular cytokine analysis, and for ELISPOT assays as described below. Serum collected from non -heparinized blood samples will be stored for batch analysis of antibody titers and serum cytokines/chemokines . In addition to the analyses specified below, subsequent exploratory mechanistic analyses, the nature of which will be determined by emerging PBMC and tumor biopsy data on the immuno logical environment pre- and post -vaccine and/or CY administration , may also be performed. 6.5.2.1 Production of Interferon -gamma from CD8+ T Cells ( ICS Assay) The immune response will be evaluated by antigen -specific flow cytometry and/or ELISPOT analysis for IFNγ production by patient T cells. These ICS assays will be done under Good Laboratory Practice (GLP )-like conditions using standard operating procedures and validating assays with standardized negative and positive controls. Processing of all patient samp les by a single facility in large batches will be performed to minimize assay variability between samples. Thawed and i solated PBMCs will be challenged or restimulated with specific tumor vaccine antigens as follows:  PBMCs alone (negative control)  PBMCs + PMA + Ionomycin (positive control)  PBMCs + viagenpumatucel -L whole cell lysates or AD100 -HLA A1 -gp96 -Ig (vaccine)  PBMC + a cocktail of known shared antigens , including MAGE -A3, CT7, XAGE -1b, XAGE -1d A maximum of 4 stimulation conditions at each time point per blood sample will be set up. For the flow cytometry assay, following in vitro stimulation, cells will be harvested and labeled with antibodies to cell surface markers, including CD4 and CD8, and then fixed and permeabilized and stained for the indicated intracellular markers, including IFNγ and gzB. Samples will be analyzed by flow cytometry immediately after staining. For the ELISPOT assay, the frozen PBMCs will be thawed, antigen challenged , and plated for analysis of IFNγ and granzyme B ( gzB) production by ELISPOT assay and analyzed in triplicate for each time point for each patient. If cells are limiting, IFNγ analysis will be prioritized. Following incubation, samples will be quantitated i n an automated ELISPOT reader. The frequency of IFN  producing CD8+ cells is thought to mirror the frequency of cytotoxic CD8+ cells. However , cytotoxicity is primarily mediated by perforin and granzymes following granule exocytosis. In some instances IFN γ secretion and granule exocytosis are uncoupled. Therefore , the direct measurement of gzB secretion by ICS may provide a more direct readout for antigen -specific granule exocytosis and cytotoxicity. For clinical efficiency it may be important to detect both IFN secretion and gzB exocytosis. Antigen specificity of the ICS response will be evaluable by comparing responses generated using the various stimulator cell populations and specific NSCLC shared antigens as indicated. This will also enable separa tion of the ‘allo -antigen’ specific response with the potential parent cell line tumor -antigen -specific Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 47 of 84 response. Positive responses will be defined as a greater than 2-fold increase in the number of IFNγ -positive CD8+ T cells compared to baseline. 6.5.2.2 PBMC Counts Total PBMC counts will be obtained from each patient from 2 sources. First, blood hematology will be performed for each patient according to the schedule of assessments in Section 6.1 at the clinical centers. Second, the peripheral blood phenotyping analysis (described below) will be performed quantitatively for each of the markers indicated, providing a secondary measure of PBMC subsets defined by expression of the indivi dual markers indicated. Total PBMC counts may be utilized as a surrogate endpoint for the overall health of a patient’s immune system. 6.5.2.3 Phenotyping of Blood Lymphocyte Subsets Following alkaline lysis of red blood cells using standard proced ures, peripheral blood samples will be stained using antibodies specific for the following cell markers : CD3, CD4, CD8, CD 19, CD25, CD45, CD56 , and FoxP3 . Samples will be analyzed by multicolor flow cytometry using standard procedures. Flow cytometric analysis of patient peripheral blood samples will quantitatively determine the frequency and number of lymphocytes (CD45+), B cells (CD45+CD3 -CD19+), helper T cells (CD45+CD3+CD4+), cytotoxic T cells (CD45+CD3+CD8+), T-regs (CD3+CD4+CD25+FoxP3 +), and NK cells (CD45+CD56+) at baseline and over the course of therapy. In addition a T cell activation panel (CD4, CD8, Ki67, perforin, IFNγ) will be performed before and after in vitro stimulation with PMA/ionomycin, a T -reg panel (CD4, CD25, FoxP3, CD127, CD45 -RA), a myeloid suppressor cell panel (CD39, CD11b, CD124, CD45, HLA - DR, CXCR4), and T cell suppression panel (CD4, CD8, CTLA -4, PD -1, Tim -3) will be performed on freshly isolated PBMC. 6.5.2.4 TCR Sequencing ELISPOT and intracellular cytokine assays are frequently used to monitor patient immune response to immunotherapy, despite the knowledge that th ese assay s have not previously been strongly predictive of clinical response. Thus, prognostic immune monitoring assays are highly desired. If TCR clones are present that recognize antigens introduced by viagenpumatucel -L, clonal expansion of these cells is indicative of effective vaccination and potentially predictive for the presence of patient tumor -antigen - specific T cells. TCR genomic DNA extracted from tumor tissue and PBMCs will be amplified and sequenced using Adaptive Biotechnologies Corp . (www.adaptivebiotech.com ) immunoSEQ assay. The current study is designed to explore the feasibility of application of this approach to later phase studies. In addition, data generated using this approach during this study may later be compiled with a larger data set to investigate the prognostic significance of individual TCR sequences befo re and during treatment with viagenpum atucel -L. Although this assay is potentially predictive of a clinical response, it remains an exploratory endpoint in this trial because this analysis can only be confirmed once expansion of individual T cell clones i s found to correlate (or not) with improved patient survival. Thus, the TCR sequencing data will be analyzed both Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 48 of 84 before the survival data has matured in order to ascertain whether there are conserved sequences expanded for patients with similar HLA types but also to determine whether a clonal TCR signature emerges that has the potential to be used as a predictive biomarker for response in subsequent trials. 6.5.2.5 Analysis of Infiltrating T C ells (Post-Treatment Tumor Biopsy ) For the cohort of patients who unde rgo post -treatment biopsies , the tissue will be examined for the presence of TILs. Two-color fluorescence immunohistochemistry (IHC) and multicolor fluorescence -activated cell sorting analysis will be used for quantification of CD8 + T cells and measuremen t of their activation status (CD69 -expression) and cytotoxic activity (CD107a -expression) in situ. These data will be correlated with clinical response. 6.5.2.6 Antigen Screening of Baseline or Archival Tumor Biopsy A baseline or archival biopsy sample (all patients for whom this is available) containing at least 4, non - stained, 10 micron sections will be collected for the purpose of screening the tissue for representative antigen expression (LAGE -1, NY -ESO -1, MAGE -[A1-10], CT7, CT10, GAGE , etc.), expre ssion of MHC class I, and expression of immunosuppressive molecules , including , for example, CTLA -4, PD -L1 and PD - 1, by mRNA expression and/or IHC analysis . If slides are not available, FFPE tissue ( 50 microns) is also acceptable. These data will be ret rospectively correlated with immune response to determine if a particular antigen expression profile may predict response to treatment. The tumor arrays will be processed by IHC and PCR according to standard methods. Bound antibodies will be visualized by using the avidin -biotin complex method according to the recommendations of the supplier (Vectastatin Elite ABC Kit; Vector Laboratories Inc., Burlingame, CA). Diaminoben zidine will be used as chromogen. 57B staining will be classified as follows: no sta ining; “weak,” indicating low - intensity staining regardless of positive cell percentages or medium -intensity staining of no more than 20% of cells; “moderate,” indicating medium -intensity staining of more than 20% of cells or high -intensity staining of no more than 20% of cells; “strong,” indicating high -intensity staining of more than 20% of cells. Only moderately and strongly positive cases will be considered positive. For PCR -based analysis, total RNA will be isolated from collected tissue samples and reverse transcribed to cDNA using standard methods. The expression of tumor antigens from cDNA samples will then be interrogated using real -time PCR and a variety of specific tumor antigen probes. 6.6 Patient Completion and Withdrawal 6.6.1 Patient Completion Patients may contin ue to receive study drugs for 12 months, until death, or until they meet the criteria for treatment discontinuation . Patients will continue to be followed beyond discontinuation of treatment for subsequent therapies and survival. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 49 of 84 6.6.2 Discontinuation from Study Treatment Every effort must be made by study personnel to keep patients on study treatment . However, a patient will be discontinued prior to completion of the study treatment for any of the following reasons:  Grade 4 adverse event (or Grade 3 adverse event at the Principal Investigator’s discretion ) assessed as definitely or probably related to therapy for patients in the experimental group  Pregnancy  Termination of the study by Heat Biologics  Intercurrent illness that prevents further administration of treatment Patients may also be discontinued prior to completion of the study treatment for any of the following reasons:  Progressive disease , according to irRC by a confirmed scan or significant clinical progression at an earlier time point, if judged by the investigator to be in the patient’s best interests . Patients who experience progressive disease in the absence of clinical deterioration may continue to receive study treatment.  Significant deviation from protocol on the part of the patient (includes lack of compliance)  Significant protocol violation on the part of the investigator Patients may withdraw consent for participation in the study at any time. Additionally, the invest igator may withdraw a patient at his/her discretion. If a patient prematurely discontinues study treatment for any reason, the patient will continue to be followed for study endpoints, unless consent for this is withdrawn. If the patient withdraws consent for continued follow up, the investigator must make every effort to perform the EOT assessments 4 weeks following the last dose of vaccine , even if the patient has initiated other anticancer treatment . The explanation of why the patient is discontinuing s tudy treatment should be documented in the CRF . If the patient discontinues study treatment due to toxicity, “Adverse Event” will be recorded as the primary reason for withdrawal. If a patient is prematurely discontinued from the study at any time due to an AE or SAE, the patient must be followed until resolution to Grade 2 or less, unless it is unlikely to improve because of underlying disease . If a patient fails to return for the necessary visits or discontinues prematurely from treatment, a genuine effort should be made to determine the reason why. For a patient lost to follow -up there should be at least 2 documented attempts to contact the patient. 6.6.3 Patient Withdrawal from Study In accordance with International Conference on Harmonization (ICH) Good Cl inical Practice (GCP) Guidelines, a patient has the right to withdraw from the study at any time for any reason without prejudice to his/her future medical care by the physician or at the institution. The investigator and sponsor also have the right to wi thdraw patients from the study treatment, as describe d below or for safety, behavioral , or Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 50 of 84 administrative reasons. Note that withdrawal of consent for treatment is not the same as withdrawal of consent for survival follow -up. 6.6.4 Replacement of Patients Patien ts will not be replaced. An overage of patients has been included in the sample size to allow for patients who do not accrue an event for the primary efficacy analysis . 7.0 STUDY DRUG All production, formulation, and packaging of the investigational agent will be in accordance with applicable current Good Manufacturing Practice (cGMP) and meet applicable criteria for use in humans. 7.1 Experimental Group 7.1.1 Viagenpumatucel -L (HS-110) Viagenpumatucel -L is a cell line derived from a human lung adenocarcinoma biops y of a lung cancer patient and that cell line is designated as AD100. The cell line derived from that patient has been kept in culture in standard medium and is free of contamination by mycoplasma, virus, or other adventitious agents. AD100 was transfect ed with the plasmid cDNA ‘B45 -neo-gp96Ig -HLA A1’. Preparation of the drug product includes expansion of batches of cells with testing for presence of expression of HLA -A1 by fluorescent -activated cell sorter and gp96 -Ig by enzyme -linked immunosorbent assay (ELISA). Cells are harvested, washed, resuspended in buffer, and irradiated at 12,000 rad to render cell replication incompetent while maintaining biological activity, i.e., expression of certain proteins . Samples are withdrawn for biological and safety analysis, and the remaining aliquots are frozen and stored at < -120C. Viagenpumatucel -L is provided as single -dose vials either 1) as concentrated frozen liquid, which will require dilution by the pharmacist with sterile saline , or 2) as fully -diluted frozen liquid not requiring additional dilution . In either case the final drug product will consist of 10 million cells resuspended in 0.6 mL buffered saline containing human serum albumin (HSA), dimethyl sulfoxide ( DMSO ), and pentastarch. Overfill of 0.1 mL is factored into each vial to allow extraction of the full 0.5 mL dose for patient administration. Additional detail can be found in the Pharmacy Manual. Each viagenpumatucel -L dose of 0.5 mL will be divided into 5 injections (0.1 mL per injection) and administered as 5 spatially divided intradermal injections in the same extremity to increase volume distribution and enhance antigen presentation to lymph node regions. Vaccine dosing will rotate injection site extremities every 4 timep oints: antero -lateral left thigh, antero -lateral right thigh, left shoulder and right shoulder. Viagenpumatucel -L will be given weekly for 12 weeks followed by every 9 weeks until progression or up to one year, whichever occurs first . Missed doses may b e made up if the missed dose is given at least 4 days before the subsequent dose. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 51 of 84 7.1.2 Cyclophosphamide Cyclophosphamide (Cytoxan) is a synthetic antineoplastic alkylating agent chemically related to the nitrogen mustards. It interfere s with the growth of susceptible rapidly proliferating malignant cells, via a mechanism of actio n involv ing cross -linking of tumor cell DNA. It is widely used in a range of hematological and solid malignancies (including lymphomas, multiple myeloma, mycosi s fungoides, neuroblasto ma, small cell lung carcinoma , ovary and breast adenocarcinoma ), usually at doses of 10mg/kg or higher (600-750 mg/m2). Cyclophosphamide tablets are white with blue flecks and will be supplied at a dosage of 50 mg cyclophosphamide (anhydrous). Additional information can be found in the package insert.62 Cyclophosphamide should be taken once daily every other week for 12 weeks P.O. with food and a large glass of water in the morning . Missed doses will not be made up. 7.2 Control Group 7.2.1 Physician’s Choice s Investigators may choose from the following restricted list of treatment options: vinorelbine, erlotinib, gemcitabine , paclitaxel, docetaxel , or pemetrexed if the patient has not previously received it. The treatment regimens will be given in nominal 21 day cycles with dose and route according to investigator’s standard practice until progression. Additional information can be found in the respective package inserts. 7.3 Treatment Assignment and Stratification Patients will be randomized centrally using a stratified block design into the experimental group or the control group. Patients will be strat ified according to their ECOG PS: either PS ≤ 1 or PS=2 and previous treatment with a checkpoint inhibitor (strata: yes vs. no) . Patients will then be placed into blocks of 6 and randomized 2 to 1. Each patient will be assigned a unique study number at screening and will be considered enrolled in the study at the time of randomization through IXRS. 7.4 Study Drug Handling and Accountability Physician’s choice regimens will not be supplied by the sponsor and will be sourced at each institution individually ac cordi ng to its standard procedure. The following subsection s apply to the experimental group only. 7.4.1 Preparation Viagenpumatucel -L must be thawed and labeled prior to injection. Preparation of the product and labeling procedures will be described in the Pharmacy Manual. 7.4.2 Labeling Study drug vials /bottles will be labeled with the product name, the dose ide ntification number, storage requirements , and the statement "Caution: New Drug --Limited by Federal (or United States) law to investigational use." Addi tional country -level requirements may be included on the carton label. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 52 of 84 7.4.3 Storage Viagenpumatucel -L must be stored at ≤ -120C in liquid nitrogen storage (a Dewar unit). If liquid nitrogen storage is not available at the investigative site, a unit will be supplied by the study sponsor. The sponsor will also arrange for replacement of the liquid nitrogen at regular intervals to ensure that the proper storage temperature is maintained throughout the study. Cyclophosphamide will be stored at room temperature. 7.4.4 Product Accountability The investigator or designee , where applicable , will be responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all app licable regulatory requirements, the investigator or designated site staff (e.g., investigational drug pharmacist) must maintain current investigational product accountability records throughout the course of the study. These records will contain the foll owing information:  Date, quantity , and vial /bottle number(s) received from and returned to the sponsor (if applicable)  Patient Study ID number, date, quantity, and vial /bottle number(s) of agent dispensed  Date, quantity , and vial /bottle number(s) of accide ntal loss of study agent (if applicable)  Date, quantity, and vial /bottle number(s) investigational product destroyed per institutional guidelines (if applicable)  Documentation of storage conditions These inventories must be made available for inspection by the study monitor. The investigator will be responsible for ensuring that all used and unused trial supplies are accounted for. At the end of the trial the study monitor will also collect the original investigational agent dispensing record. A copy of the dispensing record should be kept at the site and maintained with the study records. 7.4.5 Occupational Safety Precautions should be taken to avoid direct contact with the investigational product. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be available to the investigator for viagenpumatucel -L. 7.5 Concomitant Medications All concomitant medications , including prescription and over -the-counter medications taken during the 14 days before the date of first dose, during the study treatment, and through 4 weeks post the last dose of study drug , will be documented. Any concomitant medication(s), including herbal or vitamin preparations, taken during the study will be recorded in the CRF. At a minimum, the drug name, dose, and the dates of administration will be recorded. Caffeine consumption and supplemental oxygen use will also be collected. 7.5.1 Permitted M edications Local and/or s ystemic injection reactions may be treated with anti -allergics, antipyretics and/or analgesics in accord ance with standard local practice and investigator’s clinical judgment. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 53 of 84 Pre-treatment of the vaccine injection site with anesthetic cream is allowed only after the Week 1 vaccine administration has been performed without it and injection pain has been documented as an adverse event. For patients randomized to the control group, g ranulocyte colony -stimulating factor (G -CSF) is allowed at the investigator’s discretion according to local institutional guidelines. For patients randomized to the experimental group, G -CSF should be given only after a patient experiences Grade 3 neutropenia. 7.5.2 Prohibited Medications In principle, steroid therapy is not permitted , but patients who are on a stable low dose of steroids ( e.g. those with brain metastases ; low dose is defined as daily steroid  prednisone 10mg ) may be considered on an individual bas is after consultation with the Medical M onitor . Topical and inhalation steroids will be permitted. No concomitant chemotherapy , immunotherapy, immunosuppressive or other anticancer therapy will be permitted prior to discontinuation from treatment in the study. Erlotinib, vinorelbine , paclitaxel , and docetaxel are all substrates for the CYP3A4 cytochrome p450 isozyme. Caution should be exercised when using any of these agents with strong inhibitors ( e.g. ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, eryth romycin, telithromycin, itraconazole, and nefazadone ) or inducers ( e.g. carbamazepine, rifampin, phenytoin, and St. John’s Wort ) of the CYP3A4 pathway. Administration of other concomitant investigational agents , for any indication, is not permitted while o n this study. During long-term follow -up there are no prohibited medications, and patients may enroll in any investigational study for which they are eligible. 7.5.3 Supportive Care Patients should receive full supportive care during the study, including transfu sions of blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, and other care as deemed appropriate and in accordance with t heir institutional guidelines . 7.6 Treatment of Investigational Product Overdose There have been no cases of overdose with viagenpumatucel -L. Treatment of any suspected or confirmed overdose with viagenpumatucel -L should be symptomatic , and supportive care is recommended in cases where overdose is suspected. As described in the Investigato r’s Brochure for viagenpumatucel -L, Heat Biologics does not recommend specific treatment for overdose or toxicity; however, the investigator should use appropriate clinical judgment in treating the overdose. For the purposes of this study, an overdose of viagenpumatucel -L is defined as any dose 50 % greater than the intended dose for that patient. Appropriate Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 54 of 84 supportive care measures may need to be provided to address these potential toxicities in the event of an overdose. 7.7 Dose Modifications Any AE ≥ Grad e 3 possible, probably, or definitely related to one or more study drugs will be discussed with the Medical Monitor before continuing with dosing, with the following exceptions, for which no discussion with the Medical Monitor will be required:  Local inje ction site reactions lasting < 72 hours including pain, redness, swelling, induration, or pruritus  Systemic injection reactions lasting < 72 hours of fever, myalgia, headache, or fatigue No dose modifications of viagenpumatucel -L will be permitted. It is not anticipated that any significant toxicity is likely to arise in patients who receive CY. However, should any Grade 3 adverse events occur, which are considered by the investigator to be related to CY, then the dose of CY will be delayed until the toxi city has resolved to at least Grade 1 (any concurrent viagenpumatucel -L therapy will continue uninterrupted). If the dose of CY has to be delayed for more than 2 consecutive weeks of dosing ( i.e a 4 week period overall), then CY dosing will be discontinue d in that patient (although viagenpumatucel -L therapy will continue, in accordance with the provisions of the protocol ). There is no provision in the protocol for a dose reduction with CY. Control group regimens will be given at full strength with dose reductions as needed for management of toxicity according to the investigator’s standard of care. 8.0 SAFETY MONITORING All patients will be assessed for pre-existing symptoms during screening (f rom the date of signature of informed consent to immediately prior to first dose of study drug) . Symptoms will be documented as AEs from the first dose of study drug until 4 weeks after the last dose of study drug or until death, whichever occurs first. Any AEs occurring after this time period will also be reported, if in the opinion of the investigator, the event is deemed related to study drug. All AEs will be followed until the event has subsided or, in the case of permanent impairment, until the cond ition stabilizes. 8.1 Adverse Events (AE) and Serious Adverse Events (SAE) The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the investigator or site staff will be res ponsible for detecting, documenting and reporting AEs and SAEs, as detailed in both this section of the protocol and in the AE/SAE section of the study procedures manual . AEs should only be recorded for up to 4 weeks following the last dose of study medic ation, unless the AE is considered definitely, probably , or possibly related to the study medication , which requires that the AE be reported regardless of the amount of time that has passed since receiving the last dose of study medication. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 55 of 84 8.1.1 Definition of an AE An adverse event is any untoward medical occurrence associated with the use of a medicinal product in humans, whether or not considered related to the medicinal product (21 CFR 312.32 (a)). Note: an AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a medicinal product . For marketed medicinal products, this also includes failure to produce expected benefits ( i.e., lack of ef ficacy), abuse, or misuse. A suspected adverse reaction (SAR) is defined as any AE for which there is reasonable possibility that the drug caused the AE (21 CFR 312.32 (a)). An AE or SAR is considered unexpected if it is not listed in the Investigator ’s Brochure or is not listed at the specificity or severity that has been observed or, if an Investigator ’s Brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the curr ent application (21 CFR 312.32 (a)). 8.1.2 Definition of an SAE The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH -E2a March 1995, as implemented by the US FDA, defines a SAE or serious adverse drug experience as any untoward medical occurrence that at any dose:  Results in death (i.e., the AE actually causes or leads to death)  Is life -threatening (with regards to determining if an AE is serious, “life -threatening” is defined as an AE for which the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe. If either the investigator or the spon sor believes that an AE meets the definition of life -threatening, it will be considered life -threatening)  Requires i npatient hospitalization or prolongation of existing hospitalization  Results in p ersistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  Results in a c ongenital anomaly/birth defect  Results in a ny “other” important medical event. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in othe r situations, such as important medical events that may not be immediately life -threatening or result in death or hospitalization but may jeopardize the patient or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 56 of 84 8.1.3 Disea se-Related Events or Outcomes Not Qualifying as SAEs An event that is part of the natural course of the disease under study (i.e., disease progression) should not be reported as an SAE. Death due to disease progression is to be recorded on the Death CRF page and not as a SAE. However, if the progression of the underlying disease is greater than what would normally be expected for the patient, or if the investigator considers that there was a causal relationship between treatment with viagenpumatucel -L or protocol design/procedures and the disease progression, then it must be reported as an SAE. Any new primary cancer must be reported as an SAE. 8.1.4 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other abnormal assessments (e.g., ECGs or vital signs) that are judged by the investigator as clinically significant will be recorded as AEs and SAEs if they meet the definition of an AE or SAE. Cl inically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically si gnificant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the patient’s condition, or that are present or detected at the star t of the study and do not worsen, will not be reported as AEs or SAEs. The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant. 8.1.5 Repo rting Adverse Events The investigator will record all directly observed AEs and all AEs spontaneously reported by the study patient on the Adverse Event CRF . In addition, each study patient will be questioned about AEs. Each AE should be described in deta il on the Adverse Event CRF and SAEs on a Serious Adverse Event form and include the following information: start and stop dates, CTCAE v. 4 .03 grading, relationship to study medication, action taken, and outcome. AEs should be recorded from time of first dose up to 4 weeks following the last dose of study medication regardless of the causal relationship to the study medication. AEs considered possibly, probably , or definitely related to study medication should be recorded at any time regardless of when t hey occurred. The investigator will also assess the possible relationship between the AE and any of the study medication s as well as any concomitant medications according to the following criteria:  Definitely related: AE and administration of 1 or more study product s are related in time, and a direct association can be demonstrated .  Probably related: AE and administration of 1 or more study products are reasonably related in time, and AE is more likely explained by study product than other reasons.  Possibly related: AE and administration of 1 or more study products are reasonably related in time, and AE can be explained equally well by causes other than study product. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 57 of 84  Unlikely related: Potential relationship between AE and 1 or more study products could exist (i.e., the possibility cannot be excluded), but AE is most likely explained by causes other than study product  Not related: AE is clearly explained by another cause not related to any study product. Event outcome will be recorded using the f ollow ing categories:  Recovered/resolved  Recovering/resolving  Not recovered/not resolved  Recovered/resolved with sequelae  Fatal  Unknown 8.1.6 Prompt Reporting of SAEs All SAEs, whether or not considered related to study drug, must be reported by telephone within 24 hours to the Medical Monitor listed on page 2 of this protocol. During the initial phone call, the Medical Monitor will require the following patient information:  Patient identification , including patient study number, initials, and sex  Date of first study drug dose  Total dose and number of doses administered  Date and amount of last study drug dose  Whether the patient was taking study drug at the time of the AE  Date, duration, and description of AE  Events and/or symptoms leading up to the AE  Action taken, i ncluding whether patient was withdrawn from study  Concomitant therapy , including doses, routes, and regimens  Pertinent laboratory data  Medical history , including time on study prior to AE and history that might be related to the AE  Study drug status (e.g., interrupted, discontinued, dose changed) In addition to the above information, the Medical Monitor will require the investigator's assessment of the following:  Severity of the AE  Investigator's assessment of the relationship of the AE to study treatment  Outcome of the AE Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 58 of 84 Any oral report of SAEs must be followed within 48 hours by a detailed, written report signed by the investigator. Any necessary follow -up must be submitted within a reasonable time thereafter. The sponsor will promptly report SAEs related to viagenpumatucel -L or CY to the FDA and other applicable regulatory agencies in accordance with Title 21 of the CFR, Part 312.32 (21 CFR 312.32) and local regulatory requirements. The investigator should also comply with any applicable requirements related to the reporting of SAEs to the IRB/EC. The investigator will provide an SAE follow -up report to the sponsor. In this report, the investigator is to assess and record the SAE in detail, including the date and time of onset, description, intensity, duration, outcome, etiology, relationship to st udy drug, and action taken. Any SAEs that continue at the patient’s last study visit must be followed until the event resolves or follow -up is agreed to be adequate by the investigator, Medical Monitor, and sponsor. The clinical site i nvestigator and the Medical Monitor will review each SAE report and evaluate the relationship of the SAE to study treatment and to underlying disease. Based on the investigator’s and sponsor’s assessment of the SAE, a decision will be made concerning the need for further act ion. The primary consideration governing further action is whether new findings affect the safety of patients participating in the clinical study. If the discovery of a new SAE related to viagenpumatucel -L and/or CY raises concern over the safety of cont inued administration of study drug to patients, the sponsor will take immediate steps to notify the FDA and all investigators participating in clinical studies of viagenpumatucel - L. Further action that may be required includes the following:  Modification o f the protocol  Discontinuation or suspension of the study  Modification of the existing consent form and informing current study participants of new findings  Addition of any newly identified viagenpumatucel -L related AEs to the list of expected AEs to the Investigator’s Brochure 8.2 Data Monitoring Committee The Data Monitoring Committee will be responsible for review of data from the interim analys es as well as ongoing safety evaluation. This team will meet regularly to review continuing safety data, and a description of the membership, roles and responsibilities, and data to be reviewed will be outlined in a separate charter. 8.3 Trial Stopping Rules Under any of the following circumstances, dosing for all patients randomized to the experimental group will hal t immediately until a thorough investigation has been conducted by the Data Monitoring Committee , and the team agrees that it is safe to continue. At the discretion of the team, the FDA or other Health Regulatory Agencies may be consulted.  In the event of a death within 24 hours of vaccination that cannot be clearly attributed to another cause Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 59 of 84  If at any time during the study 3 or more subjects randomized to the treatment group experience any anaphylactic reactions, a full -thickness ulceration/necrosis, or any AE  Grade 3 possibly, probably , or definitely related to study drug with the following exceptions: o Local injection site reactions lasting < 72 hours, including pain, redness, swelling, induration, or pruritus o Systemic reactions lasting < 72 hours of fever, myalgia, headache, or fatigue  In the event of any unexpected Grade 4 toxicities, assessed as possibly, probably , or definitely related to viagenpumatucel -L 9.0 STATISTICAL CONSIDERATIONS 9.1 General Statistical Considerations Baseline demographic data as well as all exploratory endpoints will be presented descriptively as means, medians, or proportions with appropriate measures of variance. All efficacy analyses will be based on the intention t o treat ( ITT) population unless otherwise specified. Survival curves for the primary endpoint of OS (and others where appropriate, including PFS and TTP) will be generated by the method of Kaplan - Meier and compared with the log -rank test. In an explorato ry analysis, the weighted log rank test will also be used. The weighted log rank test preserves the statistical power that is lost due to a potential lag time effect in efficacy with immunotherapeutic agents.69 In a supporting analysis, the hazard ratio with appropriate 95% CI for the risk of death between the experimental and control group will be estimated using multivariate Cox Proportional Hazard regression. To identify the set of baseline factors with the greate st potential for association with OS, those with a p -value of ≤ 0.25 in a simple univariate Cox regression w ith the dependent variable, will be retained for further consideration. This is a recommended approach for removing weak prognostic covariates so that a more manageable set of variables can be analyzed via multivariate techniques .70 After this univariate screening process, the final independent variables with a p < 0.05 will be retained in the final model through a backwards elimination process . As a final exploratory analysis, restric ted mean survival times will be generated as descri bed by Royston and Parmer .71 Restricted mean survival time estimation is recommended in cases where the proportional hazards assumption is in doubt. The binary secondary endpoints ( i.e. survival at 6 months and 12 months) will be presented as odds ratios with ap propriate 95% CI. The overall analysis will include a univariate comparison of prespecified baseline features (including age and PS) . All of the analyses will be performed using SAS® Version 9.1 (or later). Prospective subset analyses will include the following: 1) Evaluation of the difference in treatment outcomes in the per -protocol population, as defined below, who had an immune response defined as an increase of IFNγ -positive CD8+ cells great er than 2- fold over baseline compared to those who did not. 2) Evaluation of the difference in treatment outcomes in the per -protocol population, as defined below, who were previously treated with a checkpoint inhibitor versus checkpoint -naïve patients. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 60 of 84 9.2 Sampl e Size Approximately 1 23 patients will be randomized in a 2:1 ratio to the experimental or the control group . Approximately 20-30 centers will enroll patients. Simulation studies have suggested that a 2 to 3 month delay in the separation of survival curves with experimental immunotherapeutic drugs can reduce the available statistical power of 15 to 20%.72 Therefore, the statistical power in the current study was adjusted for this anticipated loss. This sample size was based on the hypothesis that the combination of viagenpumatucel -L and CY versus the control group will result in a significant increase in OS. The overall sample size in this study is expected to b e 123 patients, randomized in a 2 to 1 manner into the experimental and control group s (82 vs 41 randomized to provide 59 events in the experimental group and 33 events in the control group) . By assuming an alpha of 10% (one tailed), th e study should have a final 80% power (assuming a 15% initial loss ) to detect a 50% reduction (i.e. HR = 0. 50) in the risk of death between the experimental and control group s (median OS in the experimental group of 10 months vs. 5 months in the control group ) over a 3.5 year trial period . 9.3 Analysis Populations Study populations are defined as follows: Per-protocol population: defined as all randomized patients who have not had a major protocol deviation as defined in section 10.3 . Intent ion to Treat (ITT) : defined as all randomized patients summarized by randomized treatment. As Treated (AT) : defined as all randomized patients who receive at least 1 dose of randomiz ed treatment , and summarized by treatment received. Other sub -populations of patients for secondary and exploratory analyses may be defined at the time of statistical analysis and will be identified in any reporting of results. 9.4 Accountability, Demographics, and Baseline Characteristics Accountability information will be summarized , including the number of en rolled patients , dosed patients , and patients withdrawn by reason. Descriptive information on demographics and baseline data , including age, sex, weight, height, physical examination , and medical history , will be provided in a summary table. Summaries w ill be provided by treatment group and overall for the AT and ITT population classifications. 9.5 Interim Analyses Two exploratory interim analys es will be performed after approximately 14 and 41 patients randomized to the experimental group have had blood sam ples taken at Week 10. For the 41 patient analysis only, the trial may be discontinued, or modified as necessary, if fewer than 50% of patients in the experimental group experience a peripheral blood immunologic response (IR) via intracellular cytokine st aining (ICS) of IFNγ - positive CD8+ cells greater than 2 -fold over baseline unless there is evidence of clinical or immunologic Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 61 of 84 activity in secondary endpoints . For example, if the overall response rate suggested clinical activity, the trial may still proce ed as written. Neither of the interim analyses will examine overall survival. 9.6 Primary Efficacy Endpoints and Analyses 9.6.1 Overall Survival (OS) The primary efficacy parameter is OS, calculated as the duration of survival from the date of randomization 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 . The primary a nalysis will be conducted when 92 survival events have occurred. Analysis details are provided in Section 9.1. 9.7 Secondary Efficacy Endpoints and Analyses 9.7.1 Safety Safety is defined as the proportion of AE/SAE in patients receiving viagenpumatucel -L and low -dose CY compared to the proportion of AE/SAE in patients receiving Physician’s Choice . 9.7.2 Immune -related overall disease control rate (irDCR) irDCR is defined as the proportion of participants whose immune -related best overall response is immune - related partial response (irPR), immune -related complete response (irCR), or immune -related stable disease (irSD) , as defined by ir RC. Differences in irDCR between the experimental and control group s will be presented as odds ratios with 95% CI. 9.7.3 Overall d isease control rate (DCR) DCR is defined as the proportion of participants whose best overall response is partial response ( PR), complete response ( CR), or stable disease ( SD) by RECIST criteria. Differences in DCR between the experimental and control groups will be presented as odds ratios with 95% CI. 9.7.4 6-month immune -related disease control rate (6m -irDCR) 6m-irDCR is defined as the proportion of participants whose immune -related best response is irPR, irCR, or irSD 6 months following randomization. Differences in 6m -irDCR between the experimental and control groups will be presented as odds ratios with 95% CI. 9.7.5 6-month disease c ontrol rate (6mDCR) 6mDCR is defined as the proportion of participants whose best response using RECIST criteria is PR, CR, or SD 6 months following randomization. Differences in 6mDCR between the experimental and control groups will be presented as odds ratios with 95% CI. 9.7.6 Immune -related overall response rate (irORR) irORR is defined as the number of participants with irCR or irPR, divided by total participants in the data set. Differences in ir ORR between the experimental and control group s will be pres ented as odds ratios with 95% CI. Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 62 of 84 9.7.7 Overall response rate (ORR) ORR is defined as the number of participants with CR or PR, divided by total participants in the data set. Differences in ORR between the experimental and control group s will be presented as odds ratios with 95% CI. 9.7.8 Immune -related Progression -Free Survival (irPFS) irPFS will be calculated as the time between randomization and date of immune -related progressive disease (irPD) as defined by irRC or death, whichever occurs first. For patients with no recorded post baseline tumor assessments, irPFS will be censored at randomization. For those who remain alive and have no irPD, irPFS will be censored on the date of last evaluable tumor assessment. Kaplan -Meier curves will be produced separately for each treatment group along with the estimated rate of patients without disease progression or death at each time point. Analysis details are provided in Section 9.1 . 9.7.9 Progression -Free Survival (PFS) PFS will be calculated as the time between randomization and the date of progressive disease ( PD), as defined by RECIST 1.1 or death, whichever occurs first . For patients with no recorded post -baseline tumor assessmen ts, PFS will be censored at randomization. For those who rem ain 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 treatment group along with the estimated rate of patients without disease progression or death at each time point. Analysis details are provided in Section 9.1 . 9.7.10 Immune -related Time to Progression (irTTP) irTTP is defined as the time between the date of randomization and the date of irPD. Kaplan -Meier curves will be produced separately in an exploratory analysis for each treatment group along with the estimated rate of patients without disease progression at each time point. 9.7.11 Time to Progression (TTP) TTP is defined as the time between the date of randomization and the date of RECIST documented PD. Kaplan -Meier curves will be produced separately in an exploratory analysis for each treatment group along with the estimated rate of patients without disease progression at each time point. 9.7.12 6-month overall survival (6mOS) 6mOS will be calcu lated as the proportion of patients who are alive at 6 months after randomization and presented as an odds ratio with 95% CI in the ITT population . 9.7.13 12-month overall survival (12mOS) 12mOS will be calculated as the proportion of patients who are alive at 12 months after randomization and presented as an odds ratio with 95% CI in the ITT population . 9.7.14 Immun ologic Response (IR) IR is defined as the p eripheral blood immunologic response via flow cytometry and/or ELISPOT of IFNγ - positive CD8+ cells greater than 2-fold over baseline . The exploratory parameters associated with IR will Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 63 of 84 be presented descriptively as means, medians, or proportions with appropriate measures of variance . Appropriate transformations will be undertaken in cases where the data are not nor mally distributed. These analyses will be completed using the per -protocol population. 9.8 Exploratory Endpoints and Analysis The following endpoints will be evaluated in patients completing at least 9 weeks of study medication :  Peripheral blood immunologic r esponse (analysis of surface markers, CD3, CD4, CD8, CD 19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and gzB.  Total PBMC counts by flow cytometry , including lymphocyte subsets (B cells, helper T -cells, cytotoxic T -cells, NK cells and T -regs)  Evaluation of tumor tissue obtained from pre -treatment biopsy or archival biopsy tissue for shared tumor antigen expression (LAGE -1, NY-ESO -1, MAGE -[A1-10], CT 7, CT10, GAGE, etc .), expression of MHC class I, and expression of immunosuppressive molecules , including , for example, CTLA -4, PD -L1 and PD -1, by mRNA expression and/or IHC analysis  Evaluation of tumor tissue obtained from post -treatment biopsy for presence of TILs  Evaluation of tumor tissue and PBMCs for T cell receptor sequencing to determine correlation between clonally expanded T cell populations and other endpoints Particular at tention will be paid to determining the presence of an association between individual TCR clones as determined by deep sequencing of patient TCR and OS. Because clinical responses to viagenpumatucel -L are expected to be driven by the stimulation of antigen -specific CD8+ T cell clones that recognize antigens introduced by viagenpumatucel -L that are commonly expressed by an individual patient tumor, this analysis may provide a more specific surrogate for IR than traditional ELISPOT or ICS assays. In addition , other recent vaccine trials have demonstrated a relationship between the frequency and activation status of patient NK cells and OS (TG4010, Transgene/Novartis) . Thus, this relationship will also be analyzed for viagenpumatucel -L in the current study using Cox Proportional Hazard regression in an exploratory manner . Exploratory endpoints will be summarized descriptively by time point of collection as described in preceding sections . Appropriate transformations will be undertaken in cases were the data are not normally distributed. 9.9 Safety Analysis The analysis will be completed for the As T reated population . 9.9.1 Adverse Events Treatment emergent adverse events (TEAEs) will be defined as events that occur on or after the first dose of study medication . The M edical Dictionary for Regulatory Activities (MedDRA) coding dictionary will be used for the coding of AEs. TEAEs, serious or CTC AE Grade 3 or 4 TEAEs, and TEAEs related to therapy 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, Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 64 of 84 the number and percent of patients with TEAEs will be provided by maximum severity. A summary of all TEAEs by system organ class and preferred term occurring in at least 5% of patients in either treatment group will be provided . 9.9.2 Laboratory Assessments All laboratory -based data will be presented as listings of all values as well as abnormal results judged to be clinically sig nificant, which will also be reported as AEs. Numeric summaries of all observed and change from baseline laboratory evaluations will be provided by visit and treatment group , including chemistry, hematology, and urinalysis results. No inferential compari sons are planned. 9.9.3 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. No inferential analyses are planned for vital signs. 9.9.4 ECGs and Physical Examination Physical examination data and changes will be presented as listings. ECG results will be presented as listings and summarized by treatment group and visit based on incidence of clinically significant abnormalities. No inferential comparisons across treatment groups are planned. 9.9.5 Other Assessments Other collected data not specifically mentioned, including physical examinations and protocol deviations , will be presented in patient listings. 10.0 STUDY CONDUCT CONSIDERATIONS 10.1 Regulatory and Ethical Considerations The study will be conducted in accordance with all applicable regulatory re quirements, including a US IND, and Heat Biologics will obtain favorable opinion/approval to conduct the study from the appropr iate regulatory agency in 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 GCP, all applica ble 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 informed consent document should be submitted to the sponsor for review and comment before submission to the IRB /EC. The study should not begin un til the document has been reviewed by the sponsor and until the document has been approved by the IRB /EC. The informed Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 65 of 84 consent document shall contain all the elements of informed consent specified in the regulations. Written informed consent will be obta ined for each patient before he or she can participate in the study. 10.2 Quality Control (Study Monitoring) In accordance with applicable regulations and GCP, Heat Biologics will perform quality control and assurance checks. Before enrolling any patient into this study, sponsor personnel (or designees) and the investigator will review the protocol, the brochure for clinical investigators, the CRFs and instructions for their c ompletion, the procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A qualified representative of the sponsor will monitor the conduct of the study by visiting the site and by contacting the site by telephone. The inve stigator 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 permitted by regulations. Patients will not be id entified by name in documents that leave the study site, and confidentiality of information in medical records will be preserved unless disclosure is required by regulations. Heat Biologics will monitor the study consistent with the demands of the study a nd site activity to verify 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 and any other study agreements, GCP, and all applicable regulatory requirements. 10.3 Protocol Deviations In general, a protocol deviation is an inadvertent excursion to, or non -compliance with, the IRB /EC approved protocol . The investigator is responsible for ensuring the study is conducted in accordance with the procedures described in this 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 of the patient, the 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. D eviations that fall into the following cate gories will be captured on the CRFs.  Entered into the study without meeting e ligibility criteria  Developed withdrawal criteria during th e study and was not withdrawn  Received wro ng treatment or incorrect dose  Received excluded concomitant treatment  Failed to collect data necessary to interpret primary endpoints Heat Biologics, Inc. Investigational Product: V iagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 66 of 84 10.4 Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, Heat Biologics may conduct 1 or more quality assurance audits. Regulatory agencies may also conduct regulatory inspection of this study.