A Ph ase 2, Multicenter, Randomized Study to Evaluate the Safety and Efficacy of Viagenpumatucel -L (HS-110) in Combination with Low Dose ( Metronomic) Cyclophosphamide Versus Chemotherapy Alone in Patients with Non-Small Cell Lung Adenocarcinoma after Failure of Two or Three Previous Treatment Regimens for Advanced Disease Protocol HS110 -201 Amendment History: Date Version Amendment Number Amendment Type 07 Mar 2014 1.0 Initial Protocol Not applicable 18 April 2014 2.0 1 Non-substantial 03 Sept 2014 3.0 2 Non-substantial 29 Oct 2014 4.0 3 Non-substantial CONFIDENTIAL Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the execution of the ethical review of the study, without written authorization from the sponsor. It is however, permissible to provide information to a participant to obtain informed consent. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 2 of 84 Sponsor: Meli ssa Price, PhD Heat Biologics, Inc. 801 Capitola Drive, Suite 12 Durham , NC 27713 Tel: +1-919-240-7133 Email: mprice@heatbio.com Medical Monitor: James Bal sley, M.D. Drug Safety Solutions 5205 Indigo Moon Way Raleigh, NC 27613 Tel: +1-410-708-7609 Fax: +1-919-844-6948 Email: jbalsley@drugsafety.biz Principal Investigator : Roger B. Cohen , M.D. Professor, Division of Hematology -Oncology Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philade lphia, PA 19104 Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 4 of 84 INVESTIGATOR PROTOCOL AGREEMENT PAGE Protocol Number: HS110 -201 Protocol Title: A Phase 2, Multicenter, Randomized Study to Evaluate the Safety and Efficacy of Viagenpumatucel -L (HS -110) in Combination with Low Dose (Metronomic) Cyclophosphamide Versus Chemotherapy Alone in Patients with Non -Small Cell Lung Adenocarcinoma after Failur e of Two or Three Previous Treatment Regimen s for Advanced Disease Version/Date: Version 4.0 (29 October 2014 ) I understand that all documentation provided to me by Heat Biologics, Inc., or its designated representative(s) concerning this study that has not been published previously will be kept in the strictest confidence. This documentation includes the study protocol, investigator’s brochure, case report forms, and other scientific data. This study will not commence without the prior written approval of a properly constituted Institutional Review Board (IRB) or Ethics Committee (EC) , and Institutional BioSafety Committee (IBC). No changes will be made to the study protocol without the prior written approval of Heat Biologics, Inc., and the IRB , EC, and/or IBC, except where necessary to eliminate an immediate hazard to the patient. I have read and understand the clinical protocol and agree to conduct the clinical study in compliance with the protocol, Good Clinical Practice, and applicable local regulat ory requirements. Principal Investigator Name, printed: ____________________________________________ Principal Investigator Signature: _________________________________________________ Date: ________________________ Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 5 of 84 CLINICAL PROTOCOL SYNOPSIS Sponsor: Heat Biologics, Inc. Protocol No. HS110 -201 Name of Study Drug: Viagenpumatucel -L (HS-110) Phase of Development: Phase 2 Trial title A Phase 2, Multicenter, Randomized Study to Evaluate the Safety and Efficacy of Viagenpumatucel -L (HS -110) in Combination with Low Dose (Metronomic) Cyclophosphamide Versus Chemotherapy Alone in Patients with Non -Small Cell Lung Adenocarcinoma after Failur e of Two or Three Previous Treatment Regimens for Advanced Disease Study Objective(s) Primary Objective:  To evaluate overall survival Secondary Objectives:  To evaluate the safety of the combination of viagenpumatucel -L and low -dose cyclophosphamide (CY)  To evaluate immune -related overall response rate (irORR), (complete response and partial response) and also overall response rate (ORR) by RECIST  To evaluate immune -related disease control rate (irDCR) (complete response, partial response, and stable dise ase) and also disease control rate (DCR) by RECIST at 6 months following randomization and overall  To evaluate immune -related progression -free survival (irPFS) and also progression -free survival (PFS) by RECIST  To evaluate immune -related time to progressi on (irTTP) and also time to progression (TTP) by RECIST  To evaluate the proportion of patients who are alive at 6 months following randomization  To evaluate the proportion of patients who are alive at 12 months following randomization  To characterize the peripheral blood immunologic response via intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on IFNγ-positive CD8+ cells following vaccination Exploratory Objectives: To evaluate exp loratory endpoints , which may include:  Peripheral blood i mmunologic response by flow cytometry and ELISPOT  Total peripheral blood mononuclear cell ( PBMC ) counts by flow cytometry , including lymphocyte subsets  Evaluation of tumor tissue obtained from pre -treatment biopsy or archival biopsy tissue for shared tumor antigen expression , expression of major histocompatibility complex ( MHC ) class I, and expression of immunosuppressive molecules  Evaluation of tumor tissue obtained from post-treatment biopsy for presence of tumor -infiltrating T lymphocytes (TILs)  Evaluation of tumor tissue and PBMCs for T cell receptor (TCR) sequencing to determine correlation between clonally expanded T cell populations and other endpoints Trial centers Up to 30 centers Total sample size Approximatel y 123 patients will be randomized 2 to 1 into the experimental and control group , respectively. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 6 of 84 Trial design Patients who have failed 2 or 3 prior lines of therapy for incurable or metastatic disease will be randomized 2:1 to 1 of the following treatment groups : Experimental Group : Viagenpumatucel -L plus metronomic CY (82 patients) Control Group : Physician’s Choice (PC) (41 patients)  Vinorelbine  Erlotinib  Gemcitabine  Paclitaxel  Docetaxel  Pemetrexed Patients randomized to the experimental group will be treated during an induction phase with combination metronomic CY and viagenpumatucel -L weekly for 12 weeks followed by monotherapy viagenpumatucel -L in the maintenance phase once every 9 weeks for up to 12 months or until discontinuation from study treatment, at which time patients will be followed for overall survival. Patients randomized to the control group will be treated with a PC regimen until discontinuation from study treatment, at which time patients will be followed for overall survival. Patients with progressive disease by irRC at an assessment may continue on treatment until the next assessment if judged by the investigator to be in the patient’s best interest . While treatment may continu e beyond irPD , statistical analysis will still follow strict definitions as defined in section 6.5.1 Tumor Assessments . Blood samples will be taken to evaluate the CD8+ immune response in PBMCs and their correlation to overall survival. Patients will have samples drawn prior to the first study treatment, at Weeks 4, 10, 13, and 22 , and at End of Treatment (EOT). Where considered appropriate by the investigator, patients randomized to the experimental group will be invited to consent for biopsies pre -treatment and at Week 13 (i.e. after completion of 12 weeks of treatment) for exploratory biomarker analysis. Patients will also be asked to consent to provide archival biopsy tissue if av ailable. Examination of tumor samples will enable screening for expression of MHC class I (necessary for any immunologic response), expression of immunosuppressive molecules , including , for example, CTLA -4, PD -L1, and PD -1 (informative for future possible combination studies), expression of tumor antigens that are known to be expressed by viagenpumatucel -L, presence of TILs, and T -cell receptor (TCR) sequencing. Patients will be monitored for safety with adverse event (AE) reporting, clinical laboratory parameters (hematology, liver function, electrolytes, renal function, and urinalysis), 12 -lead electrocardiogram (ECG) recording, vital signs, and physical exams. Efficacy assessments will include survival, tumor evaluation, and immune response. Tumor assessments will be done at screening, every 9 weeks until Week 28, and every 12 weeks thereafter until progression, unless clinical signs of progression necessitate earlier assessment . Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 7 of 84 Dosing regimen , form and route Experimental Group  Viagenpumatucel -L: 1 x 107 cells weekly for 12 weeks followed by injections every 9 weeks for up to 12 months or until discontinuation from study treatment , whichever occurs first . Viagenpumatucel -L is provided as single -dose vials either 1) as concentrated frozen liquid, which will require dilution by the pharmacy with sterile saline, or 2) as fully -diluted frozen liquid not requiring additional dilution. In either case the final d rug product will consist of 10 million cells resuspended in buffered saline containing human serum albumin (HSA), dimethyl sulfoxide ( DMSO ), and pentastarch. Each vaccine dose of 0.5 mL will be divided into 5 injections (0.1 mL per injection) and administ ered as 5 spatially divided intradermal injections in the same extremity to increase volume distribution and enhance antigen presentation to lymph node regions. Dosing will rotate injection site extremities every 4 timepoints: antero -lateral left thigh, a ntero -lateral right thigh, left shoulder and right shoulder.  CY: One 50mg tablet administered orally daily for 7 days on alternating weeks for a total of 6 weeks of therapy over 12 weeks Control Group Therapy to be given in nominal 21 day cycles with dose and route according to investigator’s standard practice until progression  Vinorelbine  Erlotinib  Gemcitabine  Paclitaxel  Docetaxel  Pemetrexed Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 8 of 84 Eligibility criteria Inclusion Criteria: 1. Histologically or cytologically confirmed non-small cell lung adenocarcinoma 2. Received at least 2 and no more than 3 prior line s of systemic therapy for Stage IV or recurrent incurable NSCLC , including cytotoxic chemotherapy, molecular ly-targeted agents , or immunotherapy . Prior adjuvant or neoadj uvant chemotherapy or definitive chemoradiation for locally advanced disease does not count as a line of therapy as long as the last administration of the regimen occurred at least 12 months prior to enrollment. A repeat course of a prior line of systemic therapy does not count as a n additional line of therapy. Maintenance systemic therapy or palliative radiotherapy to single sites of disease will not be 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 s tatus (PS) ≤ 1; ECOG PS=2 patients may be considered 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 req uirement for anticonvulsants for 14 days prior to screening . 8. Lab parameters:  Albumin ≥ 2 .5 mg/dL  Total Bilirubin < 1.5 mg/dL unless known Gilbert’s syndrome  Alanine transaminase (ALT), and a spartate 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 ne utrophil count ≥ 1,5 00/mm3  Hemoglobin ≥ 9 g/dL  Platelet count ≥ 100,000/mm3 9. Willing and able to comply with the protocol and sign informed consent , including weekl y 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 potential 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 th eir sexual partners throughout study participation. Female patients of childbearing potential must test negative for pregnancy prior to enrolling in the trial. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 9 of 84 Exclusion Criteria: 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 il lness, 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 l eptomeningeal disease 7. Other active malignancies 8. Prior treatment with a cancer vaccine for this indication 9. Pregnant or breastfeeding Safety monito ring All patients will be assessed for pre-existing symptoms during screening (from 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 t o study drug. All AEs will be followed until the event has subsided or, in the case of permanent impairment, until the condition stabilizes. The Data Monitoring Committee will assess safety of the vaccine on an ongoing basis during trial enrollment and dosing. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 10 of 84 Statistical Methods Patients will be randomized centrally using a stratified block design according to ECOG PS (strata: ECOG PS ≤ 1 vs. 2) and previous treatment with a checkpoint inhibitor (strata: yes vs. no) This sample size is based on the hypothesis that the combination of vaccine and CY versus physician’s choice will result in a significant increase in overall survival . The sample size in this study will be 1 23 patients randomized in a 2 to 1 manner into the experimental and control groups (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 ), the study should have a n 80% power to detect a 50% reduction in the risk of death ( median overall survival ( OS) of 10 months in the treatment group vs 5 months in the control group ; HR = 0 .50). The primary analysis will be conducted when 92 survival events have accrued. The primar y endpoint will be overall survival. Survival curves will be generated by the method of Kaplan -Meier and compared with the log -rank test. In an exploratory analysis, the weighted log rank test will also be used. The weighted log rank test preserves the statistical power that is lost due to the potential lag time effect in efficacy with immunotherapeutic agents. In a supporting analysis, the hazard ratio for the risk of death between the experimental and control group s will be estimated using multivariate Cox Proportional Hazards regression. Independent variables with a p<0.05 will be retained in the final model. As a final exploratory analysis, restricted mean survival times will be generated. The secondary binary efficacy endpoints will be reported as odds ratios with 95% confidence intervals (CI). The additional exploratory endpoints will be evaluated descriptively as means, medians and proportions with appropriate measures of variance. Two interim analyse s will be performed after appro ximately 14 and 41 patients randomized to the experimental group have had blood samples taken at Week 10 ( i.e. after completion of 9 weeks of treatment). For the 41 patient analysis only, t he trial will be discontinued, or modified as necessary, if fewer than 50% of patients in the experimental group experience a peripheral blood immunologic resp onse (IR) via ICS of IFNγ -positive CD8+ cells greater than 2 -fold over baseline unless there is evidence of clinical or immunolo gic activity in secondary endpoints. For example, if the overall response rate suggested clinical activity, the trial may still proceed as written. Neither of the interim analyses will examine overall survival. Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 11 of 84 Efficacy Parameters Primary Endpoints:  Overall Survival (OS): OS will be 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 Secondary Endpoints:  Safety: Safety is defined as the number of adverse events (AE)/seri ous adverse events (SAE) in patients receiving viage npumatucel -L and low -dose CY.  Immune -related overall disease control rate (irDCR): irDCR is defined as the proportion of patients whose immune -related best overall response is immune -related partial response (irPR), immune -related complete response (irCR), or immune -related stable disease (irSD). irSD = does not meet criteria for irCR or irPR, in the absence of immune -related progressive disease (irPD) .  Overall Disease Control Rate (DCR): DCR is defined as the proportion of patients whose best overall response using RECIST criteria is partial response (PR), complete response (CR), or stable disease (SD). SD = does not meet criteria for CR or PR, in the absence of pr ogressive disease (PD) .  6-month immune -related disease control rate (6m -irDCR): 6m-irDCR is defined as the proportion of patients whose immune -related best response is irPR, irCR, or irSD 6 months following randomization.  6-month Disease Control Rate (6mDCR): 6mDCR is defined as the proportion of patients whose best response using RECIST is PR, CR, or SD 6 months following randomization.  Immune -related Overall Response Rate (irORR): irORR is defined as the number of patients with irCR or irPR, divided by total participants in the data set.  Overall Response Rate (ORR): ORR is defined as the number of patients with CR or PR by RECIST, divided by total patients in the data set.  Immune -related Progression -Free Survival (irPFS): irPFS will be calculated as the time between randomization and the date of irPD or death, whichever occurs first.  Progression -Free Survival (PFS): PFS will be calculated as the time between randomization and the date of PD as defined by RECIST or death, whichever occurs first.  Immune -related time to progression (irTTP): irTTP is defined as the time between the date of randomization and the date of irPD.  Time to progression (TTP): TTP is defined as the time between the date of randomization and the date of RECIST documented P D.  6-month overall survival (6mOS): 6mOS will be calculated as the proportion of patients who are alive at 6 months foll owing randomiz ation  12-month overall survival (12mOS): 12mOS will be calculated as the proportion of patients who are alive at 12 months fol lowing randomiz ation  Immunologic response (IR): Peripheral blood immunologic response via intracellular cytok ine staining (ICS) by flow cytometry and/or ELISPOT of IFNγ -positive CD8+ cells greater than 2-fold over baseline Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 12 of 84 Exploratory Endpoints :  Peripheral blood i mmunologic response (analysis of surface markers, CD3 , CD4 , CD8 , CD19, CD25, CD45, CD56, FoxP3 , and degranulation) and stimulation analysis via ICS of IFNγ and granzyme B (gzB) .  Total PBMC counts by flow cytometry , including lymphocyte subsets (B cells, helper T cells, cytotoxic T cells, natural killer ( NK) cells and regulatory T cells ( T-regs))  Evaluation of tumor tissue obtained from pre -treatment biopsy or archival biopsy tissue for shared tumor antigen expressi on (LAGE -1, NY-ESO -1, MAGE -[A1-10], CT7, 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 immunohistochemi stry (IHC) analysis  Evaluation of tumor tissue obtained from post-treatment biopsy for presence of TILs  Evaluation of tumor tissue and PBMCs for TCR sequencing to determine correlation between clonally expan ded T cell populations and other endpoints Heat Biologics, Inc. Investigational Product: Viagenpumatucel -L Protocol HS110 -201 CONFIDENTIAL Version 4.0; 29 -Oct-2014 Page 13 of 84 TABLE OF CONTENTS LIST OF ABBREVIATIONS ................................ ................................