Conditions: Non Small Cell Lung Cancer
Keywords: lung cancer gp96 vaccine immunotherapy Heat Biologics cyclophosphamide vinorelbine erlotinib gemcitabine paclitaxel docetaxel pemetrexed
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
Determine whether viagenpumatucel-L combined with low-dose cyclophosphamide prolongs survival in patients with NSCLC who failed 2 or 3 prior lines of therapy for incurable or metastatic disease compared with chemotherapy alone.

Detailed description:
This study will test whether vaccination with viagenpumatucel-L combined with low-dose cyclophosphamide will prolong the survival of patients with non-small cell lung cancer (NSCLC) who have failed 2 or 3 prior lines of therapy for incurable or metastatic disease compared with chemotherapy alone. Patients will be randomized 2 to 1 into the viagenpumatucel-L arm and the chemotherapy alone arm, respectively.

Arms:
arm 1: Viagenpumatucel-L (HS-110) given as 1\*10\^7 cells for 12 weekly injections followed by injections every 9 weeks for up to 12 months or until discontinuation from study treatment, whichever occurs first, plus metronomic cyclophosphamide therapy for the first 12 weeks. arm 2: Patients will be treated with a physician's choice regimen until progression.

Interventions: intervention 1: Viagenpumatucel-L intervention 2: Metronomic Cyclophosphamide intervention 3: Physician's Choice Regimen (Vinorelbine, Erlotinib, Gemcitabine, Paclitaxel, Docetaxel, Pemetrexed)
Intervention descriptions: intervention 1: Vaccine derived from irradiated human lung cancer cells genetically engineered to continually secrete gp96-Ig intervention 2: One 50mg tablet administered orally daily for 7 days on alternating weeks for a total of 6 weeks of therapy over 12 weeks intervention 3: Physician will select one of the following to be given in nominal 21 day cycles with dose and route according to investigator's standard practice:

* Vinorelbine
* Erlotinib
* Gemcitabine
* Paclitaxel
* Docetaxel
* Pemetrexed

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
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 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. 
 
 


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Protocol HS110-201 
 
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Sponsor: 
Melissa 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 Balsley, 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 
Philadelphia, PA 19104 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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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 Failure of Two or Three Previous Treatment Regimens 
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 regulatory requirements.  
 
Principal Investigator Name, printed: ____________________________________________ 
 
Principal Investigator Signature: _________________________________________________ 
 
Date: ________________________ 
  
 


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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 Failure 
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 disease) 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 progression (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 exploratory endpoints, which may include: 
 
Peripheral blood immunologic 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 
Approximately 123 patients will be randomized 2 to 1 into the experimental and control group, 
respectively. 


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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 continue 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 available.  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. 


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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 drug 
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 administered 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, antero-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 


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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 lines of systemic therapy for Stage IV or 
recurrent incurable NSCLC, including 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 the 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 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 status (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 decreasing dose of 
corticosteroids and/or have no requirement 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 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 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 their sexual 
partners throughout study participation. Female patients of childbearing potential must 
test negative for pregnancy prior to enrolling in the trial.  


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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 more 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 indication 
9. Pregnant or breastfeeding 
Safety 
monitoring 
 
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 to 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. 


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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 123 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 an 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 primary 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 groups 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 analyses will be performed after approximately 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, the trial will be discontinued, or modified 
as necessary, if fewer than 50% of patients in the experimental group experience a peripheral 
blood immunologic response (IR) via ICS of IFNγ-positive CD8+ cells greater than 2-fold over 
baseline unless there is evidence of clinical or immunologic 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. 


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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)/serious adverse events 
(SAE) in patients receiving viagenpumatucel-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 progressive 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 PD.   
 
6-month overall survival (6mOS): 6mOS will be calculated as the proportion of patients 
who are alive at 6 months following randomization 
 
12-month overall survival (12mOS): 12mOS will be calculated as the proportion of 
patients who are alive at 12 months following randomization 
 
Immunologic response (IR): Peripheral blood immunologic response via intracellular 
cytokine staining (ICS) by flow cytometry and/or ELISPOT of IFNγ-positive CD8+ cells 
greater than 2-fold over baseline  


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Exploratory Endpoints: 
 
Peripheral blood immunologic 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 expression (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 immunohistochemistry (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 expanded T cell populations and other endpoints 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ..................................................................................................................... 17 
1.0 
BACKGROUND ............................................................................................................................. 20 
1.1 
Non-Small Cell Lung Cancer ...................................................................................................... 20 
1.2 
Vaccine-based Immunotherapy for NSCLC................................................................................ 21 
1.2.1 
Background..........................................................................................................................21 
1.2.2 
Vaccines in development for NSCLC .................................................................................22 
1.3 
Description of Investigational Agent HS-110 ............................................................................. 23 
1.4 
Prior Human Experience ............................................................................................................. 23 
2.0 
RATIONALE .................................................................................................................................. 25 
2.1 
Background Rationale ................................................................................................................. 25 
2.2 
Study-Specific Rationale ............................................................................................................. 26 
2.3 
Justification of Study Drug Administration Strategy .................................................................. 26 
2.3.1 
Viagenpumatucel-L .............................................................................................................26 
2.3.2 
Cyclophosphamide (CY) .....................................................................................................27 
2.4 
Rationale for Performing Tumor Biopsies .................................................................................. 27 
3.0 
OBJECTIVES ................................................................................................................................. 28 
3.1 
Primary Objective ........................................................................................................................ 28 
3.2 
Secondary Objectives .................................................................................................................. 28 
3.3 
Exploratory Objectives ................................................................................................................ 28 
4.0 
TRIAL DESIGN .............................................................................................................................. 29 
5.0 
PARTICIPANT SELECTION ........................................................................................................ 30 
5.1 
Inclusion Criteria ......................................................................................................................... 30 
5.2 
Exclusion Criteria ........................................................................................................................ 31 
6.0 
STUDY PROCEDURES ................................................................................................................. 32 
6.1 
Schedule of Assessments (SOA) ................................................................................................. 32 
6.2 
Screening Procedures .................................................................................................................. 35 
6.3 
On-Study Procedures ................................................................................................................... 35 
6.3.1 
Baseline Assessments (Day -7 to 1) ....................................................................................35 
6.3.2 
Visit Assessments ................................................................................................................36 


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6.3.3 
End of Treatment Visit (Day 28 ± 7 post last dose) ............................................................41 
6.3.4 
Long-term Follow-up Visits ................................................................................................41 
6.4 
Safety Assessments ..................................................................................................................... 42 
6.4.1 
Physical Examination ..........................................................................................................42 
6.4.2 
Clinical Laboratory Evaluations ..........................................................................................42 
6.4.3 
Urinalysis .............................................................................................................................42 
6.4.4 
ECG .....................................................................................................................................43 
6.4.5 
Injection Site Reactions .......................................................................................................43 
6.4.6 
Pregnancy ............................................................................................................................43 
6.5 
Efficacy Assessments .................................................................................................................. 44 
6.5.1 
Tumor Assessments .............................................................................................................44 
6.5.2 
Immunologic Response .......................................................................................................45 
6.6 
Patient Completion and Withdrawal ........................................................................................... 48 
6.6.1 
Patient Completion ..............................................................................................................48 
6.6.2 
Discontinuation from Study Treatment ...............................................................................49 
6.6.3 
Patient Withdrawal from Study ...........................................................................................49 
6.6.4 
Replacement of Patients ......................................................................................................50 
7.0 
STUDY DRUG ............................................................................................................................... 50 
7.1 
Experimental Group .................................................................................................................... 50 
7.1.1 
Viagenpumatucel-L (HS-110) .............................................................................................50 
7.1.2 
Cyclophosphamide ..............................................................................................................51 
7.2 
Control Group .............................................................................................................................. 51 
7.2.1 
Physician’s Choices .............................................................................................................51 
7.3 
Treatment Assignment and Stratification .................................................................................... 51 
7.4 
Study Drug Handling and Accountability ................................................................................... 51 
7.4.1 
Preparation ...........................................................................................................................51 
7.4.2 
Labeling ...............................................................................................................................51 
7.4.3 
Storage .................................................................................................................................52 
7.4.4 
Product Accountability ........................................................................................................52 
7.4.5 
Occupational Safety .............................................................................................................52 
7.5 
Concomitant Medications ............................................................................................................ 52 
7.5.1 
Permitted Medications .........................................................................................................52 


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7.5.2 
Prohibited Medications ........................................................................................................53 
7.5.3 
Supportive Care ...................................................................................................................53 
7.6 
Treatment of Investigational Product Overdose .......................................................................... 53 
7.7 
Dose Modifications ..................................................................................................................... 54 
8.0 
SAFETY MONITORING ............................................................................................................... 54 
8.1 
Adverse Events (AE) and Serious Adverse Events (SAE) .......................................................... 54 
8.1.1 
Definition of an AE .............................................................................................................55 
8.1.2 
Definition of an SAE ...........................................................................................................55 
8.1.3 
Disease-Related Events or Outcomes Not Qualifying as SAEs ..........................................56 
8.1.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs .56 
8.1.5 
Reporting Adverse Events ...................................................................................................56 
8.1.6 
Prompt Reporting of SAEs ..................................................................................................57 
8.2 
Data Monitoring Committee ........................................................................................................ 58 
8.3 
Trial Stopping Rules .................................................................................................................... 58 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................................ 59 
9.1 
General Statistical Considerations ............................................................................................... 59 
9.2 
Sample Size ................................................................................................................................. 60 
9.3 
Analysis Populations ................................................................................................................... 60 
9.4 
Accountability, Demographics, and Baseline Characteristics ..................................................... 60 
9.5 
Interim Analyses .......................................................................................................................... 60 
9.6 
Primary Efficacy Endpoints and Analyses .................................................................................. 61 
9.6.1 
Overall Survival (OS) ..........................................................................................................61 
9.7 
Secondary Efficacy Endpoints and Analyses .............................................................................. 61 
9.7.1 
Safety ...................................................................................................................................61 
9.7.2 
Immune-related overall disease control rate (irDCR) .........................................................61 
9.7.3 
Overall disease control rate (DCR) .....................................................................................61 
9.7.4 
6-month immune-related disease control rate (6m-irDCR) .................................................61 
9.7.5 
6-month disease control rate (6mDCR) ...............................................................................61 
9.7.6 
Immune-related overall response rate (irORR) ...................................................................61 
9.7.7 
Overall response rate (ORR) ...............................................................................................62 
9.7.8 
Immune-related Progression-Free Survival (irPFS) ............................................................62 
9.7.9 
Progression-Free Survival (PFS) .........................................................................................62 


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9.7.10 
Immune-related Time to Progression (irTTP) .....................................................................62 
9.7.11 
Time to Progression (TTP) ..................................................................................................62 
9.7.12 
6-month overall survival (6mOS) ........................................................................................62 
9.7.13 
12-month overall survival (12mOS) ....................................................................................62 
9.7.14 
Immunologic Response (IR) ................................................................................................62 
9.8 
Exploratory Endpoints and Analysis ........................................................................................... 63 
9.9 
Safety Analysis ............................................................................................................................ 63 
9.9.1 
Adverse Events ....................................................................................................................63 
9.9.2 
Laboratory Assessments ......................................................................................................64 
9.9.3 
Vital Signs ...........................................................................................................................64 
9.9.4 
ECGs and Physical Examination .........................................................................................64 
9.9.5 
Other Assessments ...............................................................................................................64 
10.0 
STUDY CONDUCT CONSIDERATIONS .................................................................................... 64 
10.1 
Regulatory and Ethical Considerations ....................................................................................... 64 
10.2 
Quality Control (Study Monitoring) ............................................................................................ 65 
10.3 
Protocol Deviations ..................................................................................................................... 65 
10.4 
Quality Assurance ....................................................................................................................... 66 
10.5 
Study and Site Closure ................................................................................................................ 66 
10.6 
Records Retention ....................................................................................................................... 66 
10.7 
Provision of Study Results and Information to Investigators ...................................................... 67 
10.8 
Data Management ........................................................................................................................ 67 
Appendix 1. ECOG Performance Status Scale ............................................................................................ 68 
Appendix 2: Immune-related Response Criteria ......................................................................................... 69 
Appendix 3. The Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines ............................ 70 
Appendix 4. Grading Scale for Injection Site Reactions ............................................................................. 72 
Appendix 5. Amendment Change Log ........................................................................................................ 73 
REFERENCES ............................................................................................................................................ 81 
 
 
 


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LIST OF ABBREVIATIONS 
6mDCR 
6-month Disease Control Rate 
6m-irDCR 
6-month Immune-Related Disease Control Rate 
AE(s)  
Adverse event(s) 
ALT 
 
Alanine aminotransferase 
ANA  
Antinuclear antibodies 
AST 
 
Aspartate aminotransferase 
AT 
 
As treated 
CBC  
Complete blood count 
CFR 
 
Code of Federal Regulations 
cGMP  
Current Good Manufacturing Practice 
CI 
 
Confidence interval 
CRF 
 
Case report form 
CT 
 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
 
Cytotoxic T lymphocytes 
CTLA4 
Cytotoxic T-lymphocyte associated antigen 4 
CR 
 
Complete response 
CY 
 
Cyclophosphamide 
DC 
 
Dendritic cells 
DCR  
Disease control rate 
DMSO  
Dimethyl sulfoxide 
EC 
 
Ethics Committee 
ECG  
Electrocardiograms 
ECOG  
Eastern Cooperative Oncology Group 
ELISA  
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-linked immunosorbent spot 
EOT 
End of Treatment 
ER 
Endoplasmic reticulum 
ESR 
 
Erythrocyte sedimentation rate 
EX 
 
Excluded Patients 
FDA  
Food and Drug Administration 
FFPE  
Formalin-fixed paraffin embedded 
GCP  
Good Clinical Practice 
GLP 
 
Good Laboratory Practice 
G-CSF  
Granulocyte colony-stimulating factor 
gzB 
 
Granzyme B 
HIV 
 
Human immunodeficiency virus 
HLA  
Human leukocyte antigen 
HSA  
Human serum albumin 
IBC 
 
Institutional Bioethics Committee 
ICH 
 
International Conference on Harmonization 
ICS 
 
Intracellular Cytokine Staining 
IFN  
Interferon gamma 
IHC 
 
Immunohistochemistry 


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IR 
 
Immunologic Response 
IRB 
 
Institutional Review Board 
irCR 
 
Immune-Related Complete Response 
irDCR  
Immune-Related Overall Disease Control Rate 
irORR  
Immune-Related Overall Response 
irPD 
 
Immune-Related Progressive Disease 
irPFS  
Immune-Related Progression Free Survival 
irPR 
 
Immune-Related Partial Response  
irRC 
 
Immune-Related Response Criteria 
irSD 
 
Immune-Related Stable Disease 
ISR 
 
Injection Site Reaction 
ITT 
 
Intention to treat 
 
i.v. 
 
Intravenous 
IXRS  
Interactive Response System 
LTFU  
Long-term Follow-up 
MedRA 
Medical Dictionary for Regulatory Activities 
MHC  
Major histocompatibility complex 
MRI 
 
Magnetic resonance imaging 
mRNA  
Messenger Ribonucleic Acid 
MSDS  
Material safety data sheet 
NCI 
 
National Cancer Institute 
NK 
 
Natural killer 
NSCLC 
Non-small cell lung cancer 
ORR  
Overall Response Rate 
OS 
 
Overall Survival 
PBMC  
Peripheral blood mononuclear cell 
PC 
 
Physician’s Choice 
PCR 
 
Polymerase Chain Reaction 
PD 
 
Progressive Disease 
PD-1  
Programmed death 1 receptor 
PD-L1  
Programmed death ligand 1 
PFS 
 
Progression-Free Survival 
P.O. 
 
Per os 
PR 
 
Partial Response 
PS 
 
Performance Status 
RBC  
Red blood cell 
SAE 
 
Serious adverse event 
SAR  
Suspected adverse reaction 
SD 
 
Stable Disease 
SOA  
Schedule of Assessments 
T-reg  
Regulatory T cell 
TCR 
 
T-cell Receptor 
TEAE  
Treatment emergent adverse event 
TIL 
 
Tumor Infiltrating Lymphocyte 
TKI 
 
Tyrosine Kinase Inhibitor 


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ULN  
Upper limit of normal 
US 
 
United States 
WBC  
White blood cell 
 
 


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1.0 
BACKGROUND 
1.1 
Non-Small Cell Lung Cancer 
The annual incidence of non-small cell lung cancer (NSCLC) in the United States is the third highest of all 
malignancies, with ~200,000 cases being recorded in 2012.1  More than 50% of patients have local or distant 
metastatic disease at diagnosis, and in stage IV the disease is almost uniformly fatal with a 5-year survival 
of <5%.2  The overall annual mortality from lung cancer worldwide is 1.4 million, which is higher than that 
from colon, breast, and prostate carcinoma combined.  Despite a number of therapeutic advances in the last 
decade, response to first line and subsequent therapy for advanced NSCLC remains suboptimal.  
Patients with metastatic or recurrent NSCLC who lack a relevant mutation are usually treated with 
platinum-containing doublet chemotherapy (with or without the anti-VEGF antibody bevacizumab 
[Avastin]).3 Patients with EGFR or EML4-ALK mutations generally do better with appropriate molecularly 
targeted therapies, compared to wild type patients treated with doublet chemotherapy, but even these 
patients eventually progress and end up requiring conventional cytotoxic chemotherapy.4,5 
With standard contemporary regimens, including maintenance therapy in the first line setting, median 
survival of patients with advanced NSCLC in 2013 was in the range of 12-16 months.6,7  Despite 
improvements in the first line management of advanced NSCLC, all patients will eventually progress or 
remain refractory to initial therapy and at least 50 percent will then subsequently receive second line 
treatment, usually consisting of docetaxel, erlotinib or pemetrexed.8   
An increasing proportion of these patients are also becoming candidates for third and fourth line 
interventions. However, despite a growing tendency toward more aggressive treatment of later stages of the 
disease, outcomes are limited as response to currently available therapies significantly diminishes at each 
successive stage of treatment.  One large recent series of Western patients showed that response rates were 
reduced from a first line figure of 20.9% to a second line value of 16.3%, a  third line one of  2.3% and a 
fourth line outcome of 0%. The disease control rate (response plus stable disease) also decreased 
dramatically from first- to fourth-line treatment.9  A similar recent study in Japanese patients showed that 
69.3%, 38.4%, 17.7%, and 6.0% of patients received second-, third-, fourth-, and fifth-line chemotherapy, 
respectively, with median survival times of 15.3 months, 12.8 months, 12.0 months and 9.9 months 
respectively.  Overall response rates and disease control rates with third- and fourth-line chemotherapy 
were 17.0% and 34.4% and 11.3% and 24.5%, respectively.10 
The relatively poor responses seen in the third and fourth line setting are due to a combination of progressive 
biological resistance of the underlying tumor arising from successive prior regimens of chemotherapy11,12 
and a decline in the performance status of patients, due to treatment and disease related morbidities.13,14,15 
The increasing proportion of patients being delivered to the third line arena, combined with a lack of 
effective strategies with which to treat them, collectively create a significant clinical need for additional 
third line and beyond treatment interventions, which are mechanistically novel and of inherently low 
toxicity. Vaccine-based immunotherapy is one such candidate to meet the demands of this particular 
therapeutic challenge and is the subject of the current trial in patients with advanced NSCLC being treated 
in the third line setting. 


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1.2 
Vaccine-based Immunotherapy for NSCLC 
1.2.1 
Background 
While some types of tumors, such as renal carcinoma and melanoma, are traditionally thought to be 
immunogenic, as evidenced by documented spontaneous clinical regressions and durable responses to high-
dose immunomodulatory agents, such as interleukin-2, evidence for an immune role in NSCLC has 
historically been less compelling, although substantial clinical evidence is now emerging to support this 
proposition.  
In particular, the observation of objective responses following immunotherapy in patients with highly 
refractory NSCLC validates this approach in a preliminary manner suggesting that additional 
immunological strategies for tumor control, such as vaccines, are worth pursuing in the clinic.16   
Vaccination approaches to immunotherapy focus on the induction of innate (natural killer [NK] cell) 
responses and tumor-specific T lymphocytes by various means.  The first FDA-approved therapeutic cancer 
vaccine (Provenge, Dendreon Corp) consists of a patient autologous preparation of antigen presenting cells 
that have been pulsed with a single antigen (prostatic acid phosphatase) in vitro. These cells are then re-
infused into patients and were shown to increase overall survival in patients with advanced prostate cancer. 
This approach is an example of an autologous vaccine and requires significant processing of patient material 
for each individualized treatment. This paradigm leads to increased cost of therapy, prolongs the period in 
which a patient may be off-treatment and is encumbered by the potential for manufacturing failure or 
shortfalls.  
Another class of vaccine with a range of agents in various phases of clinical development includes 
allogeneic, cell-based therapy. One of the first in this class consisted of granulocyte-macrophage colony-
stimulating factor (GM-CSF) transfected tumor cells used as vaccines through indirect presentation of 
tumor antigen to T cells by dendritic cells (DC).17,18,19,20 Other examples include tumor cells transfected 
with B7.1 (CD80),21,22,23,24,25,26 human leukocyte antigen (HLA) molecules,27,28 or anti-sense transforming 
growth factor β2 (TGF-β2) DNA constructs or tumor cells decorated with bacterial sugar residues. What 
all of these approaches have in common, is that the transfer of tumor antigens from the injected vaccine 
construct to the patient immune system is an unregulated and random event.   
Upon administration to patients, the allogeneic cells are destroyed by the patient’s immune system and the 
resulting tumor cell fragments are endocytosed by tissue resident macrophages. Typically, antigens that are 
interpreted by the patient’s immune system in this manner are subsequently displayed on major 
histocompatibility complex (MHC) class II, resulting predominantly in a CD4+ helper T cell-mediated (not 
CD8+ cytotoxic T cell-mediated) immune response. This is a critical distinguishing characteristic between 
the current approach with viagenpumatucel-L, which exclusively leads to tumor antigen transfer to MHC I 
and activation of a CD8+ cytotoxic T cell-mediated response (discussed further below).  
 


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1.2.2 
Vaccines in development for NSCLC 
There are two vaccines currently in clinical development for the treatment of potentially curable earlier 
stage NSCLC. The MAGE-A3 vaccine is being evaluated in the treatment of resectable stage I–IIIA 
NSCLC29 and MUC 1 liposomal-BLP25 in unresectable stage IIIB NSCLC after definitive 
chemoradiation.30,31,32  MAGE-A3 is an antigen specifically associated with various solid tumors, including 
NSCLC, while MUC1 is a membrane-bound glycoprotein that becomes overexpressed and undergoes 
aberrant glycosylation with malignant transformation of diverse tumor types, including NSCLC. 
One of the common features of the MAGE-A3 and the MUC-1 vaccines is that they each target only a 
single antigen. Although up to 50 percent of patient tumors may express either MAGE-A3 and/or MUC-1, 
the expression of these antigens within an individual tumor is rarely uniform. This observation is 
representative of the underlying genetic heterogeneity of advanced cancer and predicts that even patients 
who are ‘positive’ for an individual antigen may have a significant tumor burden that is also antigen 
‘negative’. Following treatment with a single-antigen vaccine, it is reasonable to predict that, even in the 
presence of a robust immune response, MAGE-A3 or MUC-1 negative tumor cells will be resistant to the 
tumor-specific immune response. 
Various strategies have therefore been devised to circumvent this limitation, including more diverse antigen 
targeting with allogeneic tumor cell vaccines, such as belagenpumatucel–L and viagenpumatucel-L.   
Belagenpumatucel-L is a tumor cell vaccine made with four irradiated NSCLC cell lines (two 
adenocarcinoma lines, one squamous and one large-cell carcinoma line) modified with TGF-β2 antisense 
plasmid. Belagenpumatucel-L is currently being clinically evaluated in NCSLC in the advanced disease 
setting,33 along with two other vaccine approaches. TG4010 is a recombinant viral vector genetically 
modified to express MUC1 and interleukin-2,34,35,36 while the EGF vaccine (CIMAvax EGF) consists of 
human recombinant EGF combined with a Neisseria meningitis-derived carrier protein and an 
immunoadjuvant.37,38 
Overall therefore, a variety of vaccine approaches is being evaluated in NSCLC in a range of clinical 
contexts, including adjuvant, maintenance and first line treatment settings. While none of these has yet 
received the validation of a successful phase III trial outcome, the promise of the results demonstrated in 
phase II trials attests to the growing clinical evidence supporting the utility of vaccine-based treatment 
strategies in this tumor type. 
Viagenpumatucel-L is distinct from other competitive approaches in clinical testing as it is an allogeneic 
cell-based vaccine containing a broad range of NSCLC tumor antigens combined with a specific mechanism 
for the transport of these antigens to patient antigen presenting cells for the generation of a specific CD8+ 
cytotoxic T cell response (described below).  
In this trial, viagenpumatucel-L is used in conjunction with metronomic low dose cyclophosphamide.  
Although it is anticipated that administration of viagenpumatucel-L alone will be associated with a 
substantial CD8+ response, one important mechanism that tumors use for defense against anti-tumor T cells 
is the recruitment of regulatory T cells (T-regs) to the tumor microenvironment. T-regs are the population 
of T cells that serves to protect from autoimmune disease and are frequently co-opted by tumors for their 


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own defense. Cyclophosphamide specifically inhibits T-reg function. In studies dating back to the 1970s, 
it has been shown that while treatment with high-dose cyclophosphamide leads to tumor cell killing through 
direct chemical cytotoxicity, treatment with low-dose cyclophosphamide (<200 mg/m2) leads to tumor cell 
death via (amongst other mechanisms) inhibition of T-regs and subsequent facilitation of cytotoxic T cell-
mediated killing.39,40 
1.3 
Description of Investigational Agent HS-110 
Viagenpumatucel-L is a whole cell vaccine derived from a human lung adenocarcinoma cell line AD100, 
containing HLA-A1 and gp96-Ig that is both species (human) and indication (lung cancer)-specific, that 
has been irradiated to render cell replication incompetent while maintaining biological activity.   
Gp96 is a member of the heat shock protein family and has evolved specific characteristics that are 
advantageous for a therapeutic cancer vaccine. Similar to other heat shock proteins, gp96 is an intracellular 
protein that functions as a protein chaperone to facilitate the proper folding of other cellular proteins. In 
contrast to other heat shock proteins, gp96 is restricted to the endoplasmic reticulum (ER) via expression 
of a KDEL ER retention sequence on its C-terminal end. Within the ER, gp96 has exposure to a majority 
of proteins and antigens that eventually are displayed on MHC I. This property is likely to have influenced 
the evolution of a secondary role for gp96 as a molecular warning system for necrotic cell death.  
Because gp96 is an ER-restricted protein, it is typically released from cells only upon physical destruction 
or necrotic cell death.  Upon release from a dying cell, extracellular gp96 is able to interact with a series of 
receptors, including Toll-like receptors (TLR) -2 and -4 on the surface of antigen presenting cells. 
Engagement of TLR-2 and -4 provides an adjuvant signal to a patient’s antigen presenting cells. 
Simultaneously, gp96 is able to bind to the endocytic scavenger receptor, CD91, to facilitate internalization 
of gp96 together with whatever protein cargo it bound within the dying cell. Any antigens brought into an 
antigen presenting cell by gp96 are then transferred to MHC I, through the cross-presentation pathway, for 
induction of a CD8+ T cell-mediated cytotoxic T cell response.   
Heat Biologic’s ImPACT technology seeks to replicate this natural mechanism by engineering gp96 to 
become a secretable molecule through the replacement of the KDEL retention signal with a secretory 
sequence from an immunoglobulin molecule. The resulting gp96-Ig fusion protein can then be transfected 
into a tumor cell line that contains a profile of antigens that are specific for a given tumor type and used to 
stimulate a CD8+ T cell response toward those antigens. In the case of viagenpumatucel-L, Heat Biologics 
has screened a series of NSCLC cell lines to prioritize antigens that are known to be shared amongst a high 
proportion of patients with NSCLC (including MAGEA3, NYESO1, etc.) and selected the AD100 cell 
line based on these shared antigen expression characteristics.  
1.4 
Prior Human Experience 
A first-in-humans Phase 1 study to examine the safety and immunogenicity of viagenpumatucel-L has been 
conducted in patients with stage IV, or recurrent NSCLC who had failed at least one line of standard 
chemotherapy.41 The study was closed prematurely for administrative reasons.  Follow-up continued 
through April 2011 for the 18 vaccinated patients across 3 different dose-schedule (DS) cohorts and is 
summarized here.  All cohorts had up to 3 6-week courses of treatment.  The DS-1 cohort (11 patients) 


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received > 4 x 107 cells (~ 5.7 x 105 cells/kg) every other week (up to 9 vaccinations), the DS-2 cohort (4 
patients) received > 2 x 107 cells (~ 2.9 x 105 cells/kg) weekly (up to 18 vaccinations), and the DS-3 cohort 
(3 patients) received > 1 x 107 cells (~ 1.4 x 105 cells/kg) twice weekly (up to 36 vaccinations).  
Two DS-3 patients completed the planned 3-course treatment.  Five patients (2 DS-1 and 3 DS-2) completed 
2 courses before being taken off treatment due to progressive disease, and 8 DS-1 patients completed 1 
course before progression.  Three patients, 1 in each cohort, died (2) or progressed (1) before completing 
the first course of vaccination.  
Most adverse events were Grade 1 or Grade 2. Five adverse events among 3 treated patients were Grade 3 
rectal hemorrhage, dyspnea, chest pain, pneumonia and fatigue.  
By April 2011, 14 patients had died and 4 surviving patients had been followed for a median of 10.6 months 
(range 2.6 to 16.6).  The Kaplan-Meier estimate of median survival was 8.0 months (95% confidence 
interval [CI]: 6.7 to 18.2), and the 6, 12, and 24-month overall survival (OS) rates were 77.8% (95% CI: 
51.1 to 91.0%), 41.9% (95% CI: 19.1 to 63.3%), and 11.2% (95% CI: 0.8 to 37.3%), respectively.  Although 
comparison is limited due to incomplete accrual to DS-2 and DS-3, 2 of 4 DS-2 patients and 2 of 3 DS-3 
patients have survived longer than the median survival time of 7.1 months for the 11 DS-1 patients.  Time 
to progression for DS-2 and DS-3 patients also appears to compare favorably with the median progression-
free survival (PFS) of 1.3 months for DS-1 patients.   
Patient immune responses were monitored in this trial using peripheral blood samples isolated from each 
patient before treatment and at 3 additional timepoints throughout the trial (6, 12 and 18 weeks).  Using 
these samples, individual immune responses were measured by ELISPOT assays to determine the presence 
of an immune response characterized by production of IFNγ by patient CD8+ T cells.  Of the 18 patients 
enrolled in the trial, at least 2 samples (baseline and either week 6, 12 and/or 18) were available for 15 of 
the 18 patients on the trial.  
Of the 15 patients with samples that were able to be analyzed and compared to baseline, 11 of the 15 
demonstrated a doubling or greater (in some cases upwards of 100-fold increases) of a CD8+ T cell-
mediated, vaccine-specific immune response.  Furthermore, there was no increase in CD4+ T cell-mediated 
immunity, confirming preclinical findings that the effect of the gp96-Ig approach is limited to CD8+ 
cytotoxic T cell responses.   
When the survival of the immune responders (11/15 patients) was compared to that of the non-responders 
(4/15), it was observed that the immune responder overall survival was 16.5 months as compared to 4 
months in the immune non-responder group.  These data provide a possible link between increased vaccine-
specific cytotoxic T cell responses and increased survival, which will be explored further in the current 
study.    


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2.0 
RATIONALE 
2.1 
Background Rationale 
As advanced NSCLC is an incurable condition all patients given first and second line therapy will 
eventually relapse, or remain refractory from the outset. Consequently, treatment in the third and fourth line 
arena is an important and expanding area of overall medical management, with approximately 40% of 
patients who receive initial therapy for advanced disease going on to third line or higher treatment.42 
Furthermore, patient perspectives are increasingly exceeding those of physicians, in favor of a greater 
preference for more prolonged treatment into the latest stages of the disease,43,44 with almost 50% and 25% 
of patients undergoing active therapy within the last 4 and 2 weeks of their lives, respectively.45 
Although objective response rates and PFS fall precipitously after second line therapy,9 recently completed 
randomized trials with a placebo arm (MISSION and ZEPHYR), suggest that the median survival of 
patients in the post-second line setting is now as long as 8 months,46,47 which compares highly favorably 
with previous estimates of just 3-4 months,48 although there is as yet no clear evidence that survival is 
significantly improved by existing therapeutic interventions.49  
The fact that a growing proportion of patients are reaching third, fourth and even fifth line settings10 and 
the finding that over 50% of overall median survival may now reside in the post-second line context mean 
that the third line and beyond space is a significant and evolving area of therapeutic potential in the overall 
management of advanced NSCLC. 
While current National Comprehensive Cancer Network (NCCN) guidelines recommend several options 
for first-line and second-line therapies, only erlotinib is endorsed as a third-line therapy in unselected 
patients.50 Additionally crizotinib has been approved, essentially for any line of therapy, in patients with an 
EML4/ALK translocation.51 However, recent clinical results have shown that, at least in the second line 
setting, erlotinib treatment leads to inferior outcomes, when compared to chemotherapy, in patients with 
wild type EGFR status.52,53 Furthermore, crizotinib is only suitable for the 4-5% of NSCLC patients who 
actually have an EML4/ALK abnormality.54 Therefore, for the vast majority of patients without mutated 
disease who lack corresponding molecularly targeted therapy, treatment options are significantly limited 
and substantially sub-optimal in the post- second line setting. 
A variety of molecularly target approaches55 and chemotherapy strategies are currently employed 
empirically in the third and fourth line setting. Chemotherapy-based regimens include platin, or non-platin-
based doublet therapy and also mono-therapy with agents, such as paclitaxel, docetaxel, vinorelbine, 
gemcitabine and pemetrexed.56  
However, in practice the range of treatment choices actually available to patients is severely constrained by 
co-morbidities, often arising from prior first or second line therapy. For example, pemetrexed use may be 
complicated in patients with renal impairment57 or uncontrolled effusions,58 while docetaxel may be contra-
indicated in patients with residual neuropathy from prior platin-based therapy.59 Many patients also have a 
significantly high risk of febrile neutropenic complications from chemotherapy, a liability compounded by 
poor performance status and advanced age,60 which are frequently characteristic features of patients in the 
more advanced stages of NSCLC. 


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Overall, therefore, the range of clinically useful agents is extremely limited in the third line and further 
setting. Although no agents have so far shown a survival advantage in the third line context, second line 
agents, such as docetaxel and pemetrexed, have shown improved survival despite achieving very low 
response rates, suggesting that most of the utility derived in the later stages of NSCLC is from disease 
stabilization,9 an ideal mechanistic setting for a vaccine-based therapeutic approach. It is therefore 
anticipated that a vaccine, such as viagenpumatucel-L (HS-110), could offer superior efficacy to currently 
available third line strategies with a comparable or better safety profile. 
The current trial will examine the clinical utility of a vaccine-based therapy compared to a range of widely 
used conventional third line agents.  
2.2 
Study-Specific Rationale 
Summarizing the background information in the sections above, the rationale for this study of 
viagenpumatucel-L in combination with metronomic low-dose cyclophosphamide (CY) is as follows:   
(1) Recent and paradigm-changing clinical data suggest that effective NSCLC immunotherapy is feasible 
and that under the right circumstances NSCLC cells may, in fact, become susceptible to attack by cytotoxic 
T lymphocytes (CTL).    
(2) Secreted gp96-Ig from viagenpumatucel-L combines adjuvant activity with polyvalent peptide 
specificity and activates DC, NK cells, and CTL.  As a result tumor cells can be killed by NK cell-specific 
mechanisms and by MHC-restricted CD8+ CTL activity.  The activation of DC and NK cells by 
viagenpumatucel-L may also counteract the generation of immunosuppressive T-regs.   
(3) Viagenpumatucel-L stimulates antigen cross presentation via the CD91 receptor, TLR2 and TRL4 on 
DC and macrophages (as described above).  Allogeneic NSCLC cells are known to share public tumor 
antigens, including MAGEA3, MUC1, NY-ESO-1 and others.  Therefore allogeneic, gp96-secreting 
tumor cells used as a vaccine (such as viagenpumatucel-L) are expected to generate NK and CTL activity 
against the patient’s autologous tumor through common expression of selected shared tumor antigens.   
(4) The rationale for administering viagenpumatucel-L in combination with low-dose metronomic CY is 
based on the presumption that a majority of established tumors have developed an active mechanism of 
immune evasion.  For some tumors this may include direct expression or recruitment of cells expressing 
CTLA-4 or PD-L1.  In many cases, this immunosuppression may also be mediated by T-regs.  The use of 
low-dose metronomic CY (50 mg, PO, QD, 1 week on/1 week off) has been demonstrated to provide 
prolonged suppression of both T-reg numbers and function without having direct cytotoxic effects on tumor 
cells.61 
2.3 
Justification of Study Drug Administration Strategy 
2.3.1 
Viagenpumatucel-L  
The initial Phase 1 study in lung cancer examined 3 dosing schedules: twice weekly, weekly and once every 
2 weeks. The twice weekly and weekly dosing schedules were determined to produce the most desirable 
immune response (at least a doubling of CD8+ numbers from baseline).  The weekly dosing schedule was 


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selected for this trial as it represents the schedule with greatest patient acceptability for frequency of 
treatment visits.  
The dose of 1x 107 cells was selected for this trial.  The 1x107 cells is half the dose that was used in the 
Phase 1 trial (DS-2 cohort).  Murine data suggested that lower doses may produce sufficient immune 
response and may even result in superior clinical effects, and, therefore, the lower dose of 1x107 cells was 
chosen.  Additionally, this lower dose is prudent from a safety perspective as this trial is the first testing the 
combination with metronomic low-dose CY.   
Vaccine will be administered weekly as 5 x 0.1mL intradermal injections (see Section 7.1). The selection 
of the route of administration is based on the hypothesis that split doses stimulate stronger immune 
responses by allowing vaccine antigens to reach more regional lymph nodes (where immune responses are 
generated).  The vaccine will be administered intradermally to enhance stimulation of cellular immune 
responses as compared to subcutaneous or intramuscular immunization.  
2.3.2 
Cyclophosphamide (CY) 
When administered at conventional cytotoxic doses (10-15 mg/kg intravenously), CY usage is associated 
with significant clinical toxicity, including myelosuppression (predominantly leukopenia and neutropenia 
and less frequently anemia or thrombocytopenia), hemorrhagic cystitis, nausea, vomiting, diarrhea, 
anorexia, alopecia, skin pigmentation and allergic reactions.62 
However, at the dose proposed for the current study (50 mg daily on alternate weeks) the predominant 
toxicity is expected to be mild neutropenia or leukopenia, based upon extensive experience in the literature 
with the use of low-dose metronomic CY in a range of malignancies, including breast, prostate and lung 
cancer. Typically, grade 3 or higher hematological toxicities have been documented in less than 5% of 
patients in these studies and grade 3 or higher non-hematological toxicities in less than 2%, supporting the 
contention that low-dose CY, as proposed for the current study, is a safe and well tolerated 
intervention63,64,65,66  
2.4 
Rationale for Performing Tumor Biopsies 
In order for an allogeneic cell-based vaccine to lead to a clinical response in a treated cancer patient, that 
vaccine must not just stimulate a tumor-antigen-specific immune response as detected by circulating 
lymphocytes in the peripheral blood, but those lymphocytes must infiltrate the tumor microenvironment in 
order to kill tumor cells.  Patients who are predicted to respond to viagenpumatucel-L are those whose 
tumors express antigens that are known to overlap with the shared antigens contained within the AD100 
cell backbone of viagenpumatucel-L.  In addition, it is predicted that those patients whose tumors express 
a number of antigens that are shared with viagenpumatucel-L will have improved clinical responses as 
compared to those patients whose tumors only share 1 or 2 antigens with viagenpumatucel-L.  Furthermore, 
it is possible that the likelihood of a patient having a clinical response to treatment with viagenpumatucel-L 
could be predicted by the presence and extent of tumor infiltration by CD8+ T cells, determined in turn by 
the degree of correlation found with shared individual antigens between patient tumors and 
viagenpumatucel-L.  Consequently, acquisition of tumor tissue is essential to histologically examine tumor 
antigen expression and generate predictive information on which patients are most likely to have a clinical 


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response, and thus inform optimal patient selection for future trials.  Archival biopsy tissue, if available, 
will be acceptable for the pre-treatment tumor antigen analysis. 
3.0 
OBJECTIVES 
3.1 
Primary Objective 
To evaluate overall survival  
3.2 
Secondary Objectives 
 
 To evaluate the safety of the combination of viagenpumatucel-L and low-dose 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 disease) 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 progression (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  
3.3 
Exploratory Objectives 
 To evaluate exploratory endpoints, which may include: 
o Peripheral blood immunologic response by flow cytometry and ELISPOT 
o Total peripheral blood mononuclear cell (PBMC) counts by flow cytometry, including 
lymphocyte subsets 
o Evaluation of tumor tissue obtained from pre-treatment biopsy or archival biopsy tissue for 
shared tumor antigen expression, expression of MHC class I, and expression of 
immunosuppressive molecules 
o Evaluation of tumor tissue obtained from post-treatment biopsy for presence of tumor-
infiltrating T lymphocytes (TIL) 
o Evaluation of tumor tissue and PBMCs for T cell receptor (TCR) sequencing to determine 
correlation between clonally expanded T cell populations and other endpoints 
 


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4.0 
TRIAL DESIGN 
Patients who have failed 2 or 3 prior lines of therapy for advanced 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) 
Therapy to be given in nominal 21 day cycles with dose and schedule according to investigator’s 
standard practice 
 
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 discontinued from treatment and followed for overall survival as 
defined by irRC, at which time patients will be discontinued from treatment and followed for overall 
survival.  Patients randomized to the control group will be treated with a PC regimen until 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 continue 
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 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 for exploratory biomarker analysis.  Patients 
will also be asked to consent to provide archival biopsy tissue if available.  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 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 


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every 12 weeks thereafter until progression, unless clinical signs of progression necessitate earlier 
assessment.  The overall study design is summarized below in Figure 1. 
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, including 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 the 
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 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 status (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 decreasing dose of corticosteroids and/or 
have no requirement for anticonvulsants for 14 days prior to screening.  


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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 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 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 more 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 indication 
9. Pregnant or breastfeeding 
 


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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 study-
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 assessments 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 more frequently than patients in the control group during the induction period in order to 
permit the weekly treatment with viagenpumatucel-L and safety assessment of the combination with CY.  
 
 
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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 screening 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 patients randomized to the control group, if 100mL cannot be safely drawn due to cytopenia, 40mL of heparinized blood may be excluded. 
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 
 


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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 then every 12 weeks thereafter.  irCR, irPR and irPD will be confirmed with a second tumor assessment after at least 4 weeks. 
9 Radiological assessments will continue, where possible, for patients withdrawing due to clinical progression but prior to irRC 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 collected. 
 
 
 
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 


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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 medical history, including prior treatments, concomitant medications, and 
pre-existing symptoms  
 
Physical examination (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 the previous screening procedures have 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  
 


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 
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 patients 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 Assessments (Day 1)  
The following procedures will be performed after all the 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 administration (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 


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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 medications 
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, 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 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 


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 
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 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 
6.3.2.7 Week 13 Assessments 
The following procedures will be performed at Week 13 (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 


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 
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 events 
 
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 22 Assessments 
The following procedures should be completed at Week 22 (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 reactions for 30 minutes after vaccine administration 
 
Patients in the control group 
o Physician’s choice, depending on drug and schedule 
 
Record concomitant medications 


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 
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 
tumor 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 


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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 experimental 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 patients will be followed for survival until study termination or death, whichever occurs first.  
Radiological assessments will continue, where possible, for patients withdrawing due to clinical 


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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 new 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 continues even if subjects participate in other experimental studies or 
receive 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 adequate 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 in a semi-supine or supine position.  
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 assessments to be completed 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 urea 
nitrogen, total bilirubin, alkaline phosphatase, AST, ALT, potassium, chloride, 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, RBC, and pH.   


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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 Appendix 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 
Screening and at the End of Treatment 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 Biologics, 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.  Generally, 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 the 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. 


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6.4.6.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study Subject 
The investigator will 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 incorporate 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 have 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 identification of index and new lesions (irRC) and target plus non-target lesions (RECIST criteria) will 
be documented at baseline, and repeat scans will be performed every 9 weeks until Week 28 and then every 
12 weeks thereafter, unless clinical signs of progression 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 blinded 
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 appearance 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 both the 
experimental and control groups for clinical decision-making.  
In accordance with immune criteria, at the baseline tumor assessment, the sum of the products of the two 
largest perpendicular diameters (SPD) of all index lesions (5 lesions per organ, up to 10 visceral lesions + 
5 cutaneous index lesions) is calculated. At each 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 visceral lesions) are added 
together to provide the total tumor burden: 


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Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index 
lesions at screening). 
Each investigator will assess disease response (complete response [irCR], partial response [irPR], stable 
disease [irSD], and progressive disease [irPD]) using irRC 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 deterioration is required.  The 
definition of confirmation of progression represents an increase in tumor burden ≥25% compared with the 
nadir at 2 consecutive time points at least 4 weeks apart.  
The disease response measures will allow for the calculation of the immune-related disease control rate and 
6-month disease control rate (irDCR and 6m-irDCR), which includes irCR, irPR, and irSD; immune-related 
overall response rate (irORR), which includes irCR 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 longest 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 target 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 selected 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 identified as non-
target lesions and should also be recorded at baseline.  Measurements are not required and these lesions 
should be followed as ‘present’, ‘absent’, or ‘unequivocal progression’.   
Disease response (complete response (CR), partial response (PR), stable disease (SD), and progressive 
disease (PD)) will be assessed as outlined in Appendix 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 samples will be obtained prior to the first study treatment, at Weeks 4, 10, 13, and 22, and 
at EOT in all patients.  All samples will be shipped to and processed by one or more central laboratories.  
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 (PBMCs) will be isolated from 


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heparinized blood samples by Ficoll separation.  Isolated PBMCs will be utilized for immunophenotyping 
analysis using flow cytometry, DNA isolation 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 immunological 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 samples by a single facility in large batches will 
be performed to minimize assay variability between samples. 
Thawed and isolated 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 in 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 IFNγ 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 
separation of the ‘allo-antigen’ specific response with the potential parent cell line tumor-antigen-specific 


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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 individual 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 procedures, peripheral blood samples will be 
stained using antibodies specific for the following cell markers: CD3, CD4, CD8, CD19, 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 these assays 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 before and during treatment with 
viagenpumatucel-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 is found to 
correlate (or not) with improved patient survival.  Thus, the TCR sequencing data will be analyzed both 


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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 Cells (Post-Treatment Tumor Biopsy) 
For the cohort of patients who undergo 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 measurement 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.), 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.  If slides are not available, FFPE tissue (50 microns) is also 
acceptable.  These data will be retrospectively 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).  Diaminobenzidine will 
be used as chromogen.  57B staining will be classified as follows: no staining; “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 continue 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.   


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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 investigator 
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 study 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 Clinical 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 withdraw patients from the study treatment, as described below or for safety, behavioral, or 


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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 
Patients 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 biopsy 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 transfected 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 timepoints: 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 be made up if the missed dose is given at least 4 days 
before the subsequent dose.   


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7.1.2 
Cyclophosphamide 
Cyclophosphamide (Cytoxan) is a synthetic antineoplastic alkylating agent chemically related to the 
nitrogen mustards.  It interferes with the growth of susceptible rapidly proliferating malignant cells, via a 
mechanism of action involving cross-linking of tumor cell DNA.  It is widely used in a range of 
hematological and solid malignancies (including lymphomas, multiple myeloma, mycosis fungoides, 
neuroblastoma, 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 Choices 
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 stratified 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 according to its standard procedure.  The following subsections 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 identification number, storage 
requirements, and the statement "Caution: New Drug--Limited by Federal (or United States) law to 
investigational use."  Additional country-level requirements may be included on the carton label.   


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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 applicable 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 following 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 accidental 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 Medications 
Local and/or systemic injection reactions may be treated with anti-allergics, antipyretics and/or analgesics 
in accordance with standard local practice and investigator’s clinical judgment.   


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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, granulocyte 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 basis after consultation with the Medical Monitor.  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, erythromycin, 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 on 
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 transfusions of blood and blood 
products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, and other care as 
deemed appropriate and in accordance with their 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 Investigator’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 


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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 ≥ Grade 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 injection 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 toxicity 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 discontinued 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 (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 to study drug.  All AEs will be followed until the event has subsided 
or, in the case of permanent impairment, until the condition 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 responsible 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 medication, 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.  


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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 efficacy), 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 current 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 sponsor believes that an AE meets the definition of life-threatening, it will be 
considered life-threatening) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
Results in a congenital anomaly/birth defect 
 
Results in any “other” important medical event.  Medical or scientific judgment should be exercised 
in deciding whether reporting is appropriate in other 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. 


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8.1.3 
Disease-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.  Clinically 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 significant 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 start 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 
Reporting 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 detail 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 they occurred.  
The investigator will also assess the possible relationship between the AE and any of the study medications 
as well as any concomitant medications according to the following criteria: 
 
Definitely related: AE and administration of 1 or more study products 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. 


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 
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 following 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, including 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 


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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 study 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 investigator 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 action.  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 continued 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 of 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 analyses 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 halt 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 


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 
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 to 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 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 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 greatest 
potential for association with OS, those with a p-value of ≤ 0.25 in a simple univariate Cox regression with 
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, restricted mean survival times will be generated as described 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 appropriate 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 greater 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. 


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9.2 
Sample Size  
Approximately 123 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 be 123 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 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 groups (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. 
Intention 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 randomized 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 enrolled 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 will be provided by 
treatment group and overall for the AT and ITT population classifications. 
9.5 
Interim Analyses 
Two exploratory interim analyses will be performed after approximately 14 and 41 patients randomized to 
the experimental group have had blood samples 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 staining (ICS) of IFNγ-
positive CD8+ cells greater than 2-fold over baseline unless there is evidence of clinical or immunologic 


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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. 
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 analysis 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 irRC.  Differences in irDCR between the experimental and control groups will be 
presented as odds ratios with 95% CI.  
9.7.3 
Overall disease 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 control 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 irORR between the experimental and control groups will be presented as odds ratios 
with 95% CI.   


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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 groups 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 
assessments, PFS will be censored at randomization.  For those who remain alive and have no PD, PFS will 
be censored on the date of last evaluable tumor assessment.  Kaplan-Meier curves will be produced 
separately for each 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 calculated 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 Immunologic Response (IR) 
IR is defined as the peripheral 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 


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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 normally 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 response (analysis of surface markers, CD3, CD4, CD8, CD19, 
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], 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 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 attention 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 Treated 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 Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary will 
be used for the coding of AEs.  TEAEs, serious or CTCAE 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, 


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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 significant, 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 comparisons 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 requirements, including a US 
IND, and Heat Biologics will obtain favorable opinion/approval to conduct the study from the appropriate 
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 applicable patient privacy requirements, and 
the guiding principles of the Declaration of Helsinki.  This includes, but is not limited to, the following: 
 IRB/EC/IBC review and favorable opinion/approval to conduct the study and of any subsequent 
relevant amending documents 
 Patient informed consent 
 Investigator reporting requirements 
A copy of the site-specific proposed informed consent document should be submitted to the sponsor for 
review and comment before submission to the IRB/EC.  The study should not begin until the document has 
been reviewed by the sponsor and until the document has been approved by the IRB/EC.  The informed 


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consent document shall contain all the elements of informed consent specified in the regulations.  Written 
informed consent will be obtained 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 completion, 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 investigator agrees that qualified representatives of the sponsor and regulatory agencies will have, both 
during and after this study, direct access to review medical records pertinent to the clinical study as 
permitted by regulations.  Patients will not be identified 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 and 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.  Deviations that fall into the following categories will be captured on the CRFs.   
 
Entered into the study without meeting eligibility criteria 
 
Developed withdrawal criteria during the study and was not withdrawn 
 
Received wrong treatment or incorrect dose 
 
Received excluded concomitant treatment 
 
Failed to collect data necessary to interpret primary endpoints 


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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.  
Such audits/inspections can occur at any time during or after completion of the study.  If an audit or 
inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any relevant issues. 
10.5 
Study and Site Closure 
Upon completion or premature discontinuation of the study, the Site Monitor will conduct site closure 
activities with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, 
and Heat Biologics procedures. 
In addition, Heat Biologics reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons, including, but not limited to, safety or ethical issues or severe non-compliance.  For 
this multicenter study, this can occur at 1 or more sites.  If Heat Biologics determines such action is needed, 
Heat Biologics will discuss this with the investigator or the head of the medical institution, where 
applicable, including the reasons for taking such action, at that time.  When feasible, Heat Biologics will 
provide advance notification to the investigator or the head of the medical institution, where applicable, of 
the impending action prior to its taking effect. 
Heat Biologics will promptly inform all other investigators or the head of the medical institution, where 
applicable, and/or institutions conducting the study if the study is suspended or prematurely discontinued 
for safety reasons.  Heat Biologics will also promptly inform the regulatory authorities of the suspension or 
premature discontinuation of the study and the reason(s) for the action.  If required by applicable 
regulations, the investigator or the head of the medical institution, where applicable, must inform the 
IRB/EC promptly and provide the reason for the suspension or premature discontinuation. 
10.6 
Records Retention 
Following closure of the study, the investigator or the head of the medical institution, where applicable, 
must maintain all site study records, except for those required by local regulations to be maintained by 
someone else, in a safe and secure location.  The records must be maintained to allow easy and timely 
retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review 
of data in conjunction with assessment of the facility, supporting systems, and staff.  Where permitted by 
local laws/regulations or institutional policy, some or all of these records can be maintained in a format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.  The investigator must assure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including regenerating a hard 
copy, if required.  Furthermore, the investigator must ensure there is an acceptable back up of these 
reproductions and that an acceptable quality control process exists for making these reproductions. 
These records should be retained for not less than 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an ICH region 
or at least 2 years have elapsed since the formal discontinuation of clinical development of the 


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investigational product.  These documents should be retained for a longer period, however, if required by 
applicable regulatory requirements or by an agreement with the sponsor.  Thereafter, records will not be 
destroyed without giving the sponsor prior written notice and the opportunity to further store such records. 
The investigator must notify Heat Biologics of any changes in the archival arrangements, including, but not 
limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the 
investigator leaves the site. 
10.7 
Provision of Study Results and Information to Investigators 
When required by applicable regulations, the investigator signatory for the clinical study report will be 
determined at the time the report is written.  When the clinical study report is completed, Heat Biologics 
will provide the investigator with a full summary of the study results.  The investigator is encouraged to 
share the summary results with the patients, as appropriate.  In addition the investigator will be given 
reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the 
results for the entire study at the Heat Biologics site or other mutually agreeable location. 
10.8 
Data Management 
The data collection tool for this study will be Heat Biologics-defined CRFs.  Patient data necessary for 
analysis and reporting will be entered/transmitted into a validated database or data system.   
After the sponsor receives the CRFs, the sponsor’s Medical Monitor (or designee) will review the data for 
safety information, and the sponsor’s clinical data associates (or designees) will review them for logical 
consistency and will use automated programs to help identify missing data, selected protocol violations, 
out-of-range data, and other inconsistencies.  Requests for data clarification or correction will be forwarded 
to the investigative site for timely resolution. 
 


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Appendix 1. ECOG Performance Status Scale 
 
ECOG PERFORMANCE STATUS73 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed 
or chair 
5 
Dead 
Credit: the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 
 
 
 


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Appendix 2: Immune-related Response Criteria 
The overall response according to irRC is derived from time point response assessments based on tumor 
burden as follows below:67  
 
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions) 
confirmed by a repeat, consecutive assessment at least 4 weeks from the date first documented.  
New non-measurable lesions do not indicate progression, but preclude irCR. 
 
irPR, decrease in tumor burden > 50% relative to baseline confirmed by a consecutive assessment 
at least 4 weeks after first documentation 
 
irSD, not meeting criteria for irCR or irPR, in absence of irPD  
 
irPD, increase in tumor burden > 25% relative to nadir (minimum recorded tumor burden) 
confirmed by a repeat, consecutive assessment at least 4 weeks from the date first documented.  
New measurable lesions do not automatically define disease progression but are incorporated into 
the total tumor burden.   
 
Derivation of irRC Overall Responses 
Measurable Response 
Nonmeasurable response 
Overall response 
Index 
and 
new, 
measurable 
lesions 
(tumor 
burden),* % 
Non-index lesions 
New, 
nonmeasurable 
lesions 
Using irRC 
↓100  
↓100 
↓100  
↓≥50  
↓≥50  
↓<50 to <25↑  
↓<50 to <25↑  
≥25↑ 
Absent 
Stable 
Unequivocal 
progression 
Absent/Stable 
Unequivocal 
progression 
Absent/Stable 
Unequivocal 
progression 
Any 
Absent 
Any 
Any 
Any 
Any 
Any 
Any 
Any 
irCR†  
irPR† 
irPR† 
irPR† 
irPR† 
irSD 
irSD 
irPD† 
*Decreases assessed relative to baseline, including measurable lesions only (>5 × 5 mm). 
†Assuming complete and partial response (irCR and irPR) and progression (irPD) are confirmed by a 
second, consecutive assessment at least 4 wk apart. 


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Appendix 3. The Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines 
The overall response according to RECIST 1.1 is derived from time-point response assessments based on 
tumor burden as follows below.68  
Evaluation of target lesions: 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of non-target lesions: 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
Evaluation of Overall Time Point Response for Patients with Measurable Disease at Baseline 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, NE = 
Inevaluable 
*When target lesions show SD/PR and some subset of non-target lesions is inevaluable, a careful decision 
must be made whether to call the overall response at this time point SD/PR or NE. This is based on whether 
the inevaluable lesions, if they showed growth, could cause an overall response of PD in the context of the 


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other lesion responses seen. If the inevaluable non-target lesions comprise a significant proportion of the 
overall disease burden, the appropriate time point response is NE. 


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Appendix 4. Grading Scale for Injection Site Reactions 
The grading scale is derived from the FDA Guidance for Industry 
(http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccin
es/ucm074775.htm#TOXICITYGRADINGSCALETABLES) 
 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life 
Threatening 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
Emergency room 
visit or 
hospitalization 
Erythema/Redness 
2.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling* 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
 
* Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 
 


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Appendix 5. Amendment Change Log 
Protocol Change 
Section Affected 
Version Where 
Implemented 
Added amendment history 
Title page 
Version 2.0, 
Amendment 1 
Added pregnancy assessments 
Protocol synopsis (Eligibility criteria), 5.1 
Inclusion Criteria, 6.1.1 SOA Stage A, 
6.1.2 SOA Stage B, 6.2 Screening 
Procedures, 6.3.4 End of Treatment Visit, 
6.5.2 Clinical Laboratory Evaluations, 
6.5.6 Pregnancy (including 6.5.6.1-
6.5.6.3), 6.7.3 Discontinuation 
Version 2.0, 
Amendment 1 
Added respiratory rate to vital signs 
6.2 Screening Procedures, 6.5.1 Physical 
Examinations, 9.8.3 Vital Signs 
Version 2.0, 
Amendment 1 
Added docetaxel as a physician's 
choice regimen 
Protocol synopsis (Trial design; Dosing 
regimen, form and route), 4.0 Trial 
Design, 6.1.1 SOA Stage A, 6.1.2 SOA 
Stage B, 7.2.1 Physican's Choices, 7.5.2 
Prohibited Medications 
Version 2.0, 
Amendment 1 
Eliminate immune monitoring and 
blood banking after Week 22 in Stage 
A and Week 19 in Stage B 
6.1.1 SOA Stage A, 6.1.2 SOA Stage B, 
6.3.2.13 Week A31 Assessments and 
every 9 weeks thereafter, 6.3.3.10 Week 
B28 Assessments and every 9 weeks 
thereafter, 6.6.2 Immunological Response 
Version 2.0, 
Amendment 1 
Updated treatment period to 1 year; 
previously listed as 2 years 
Protocol synopsis (Trial design; Dosing 
regimen, form and route; Eligibility 
criteria), 4.0 Trial Design, 5.1 Inclusion 
Criteria, 6.3.2.11 Week A25 Assessments 
and every 9 weeks thereafter, 6.3.3.9 
Week B25 Assessments and every 9 
weeks thereafter, 6.3.3.10 Week B28 
Assessments and every 9 weeks thereafter, 
6.7.1 Patient Completion 
Version 2.0, 
Amendment 1 
Updated eligibility requirement from 
two lines of conventional therapy to 
two lines of therapy, including 
conventional therapy, targeted 
therapy, immunotherapy, or 
investigational therapy administered 
through a clinical trial 
Protocol synopsis (Trial design), 4.0 Trial 
Design 
Version 2.0, 
Amendment 1 
Added abstinence as an acceptable 
form of contraception 
Protocol synopsis (Eligibility criteria), 5.1 
Inclusion Criteria 
Version 2.0, 
Amendment 1 
Remove Stage B for patients 
randomized to the control group 
Protocol synopsis (Trial design), 4.0 Trial 
Design, 6.1.2 Schedule of Assessments; 
6.3.3 Stage B Assessments; 6.7.3 Study 
Discontinuation 
Version 2.0, 
Amendment 1 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Remove blood banking for patients 
randomized to the control group 
6.1.1, 6.1.2 Schedule of Assessments; 6.3 
On-study Procedures 
Version 2.0, 
Amendment 1 
Remove Blood for exploratory 
analysis from Stage B table - 
duplicate entry to "Immunologic 
Response" entry 
6.1.2 Schedule of Assessments;  
Version 2.0, 
Amendment 1 
Add Hematology and Chemistry to 
BL procedures if screening labs done 
>2 weeks prior to first dose 
6.1.1 Schedule of Assessments; 6.3.1 
Baseline Assessments 
Version 2.0, 
Amendment 1 
Add language that pre-medication 
with anesthetic cream is allowed 
7.5.1 Permitted Medications 
Version 2.0, 
Amendment 1 
Updated the Schedule of Events 
descriptions to match the tables 
6.3 On Study Procedures 
Version 2.0, 
Amendment 1 
Remove Weeks B4, B5, B8 and B9 
visits to be consistent with text 
indicating weekly clinic visits for 12 
weeks followed by every 3 weeks 
thereafter 
6.1.2 SOA – After First Progression; 6.3 
On Study Procedures 
Version 2.0, 
Amendment 1 
Modification of schedule of Vital 
Signs and targeted Physical Exam in 
Stage B to align with the ECGs 
6.1.2 SOA – After First Progression; 6.3 
On Study Procedures; 6.5.1 Physical 
Examination 
Version 2.0, 
Amendment 1 
Update title 
Cover page, Sponsor Protocol Approval 
page, Investigator Protocol Agreement 
page, Synopsis 
Version 3.0, 
Amendment 2 
Expanded on reference to serum 
collected for immunologic response 
6.5.2 Immunologic Response 
Version 3.0, 
Amendment 2 
Note that cyclophosphamide is 
administered every other week for 12 
weeks 
7.1.2 Cyclophosphamide 
Version 3.0, 
Amendment 2 
Prohibit dose modifications of 
viagenpumatucel-L but allowed dose 
reductions of Physician’s Choice 
drugs as needed for management of 
toxicity according to the 
investigator’s standard of care 
7.7 Dose Modifications (formerly Dose 
Delays) 
Version 3.0, 
Amendment 2 
Remove radiotherapy as a prior 
regimen for eligibility 
Synopsis, 5.1 Inclusion Criteria 
Version 3.0, 
Amendment 2 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Reduce viagenpumatucel-L dosing in 
the maintenance period from every 3 
week s to every 9 weeks 
Synopsis; 4.0 Trial Design; 6.1 SOA; 
6.3.2.8-12 Assessments at Weeks 16, 19, 
22+9x, 25+9x, and 28+9x 
Version 3.0, 
Amendment 2 
Do not treat any patients after 
progression 
Synopsis, 2.1 Background Rationale, 2.2 
Study-Specific Rationale, 3.2 Secondary 
Objectives, 4.0 Trial Design (including 
Figure 1), 6.1 SOA, 6.3.4 LTFU Visits, 
6.4.1 Physical Examination, 6.5.1 Tumor 
Assessments, 6.6.3 Discontinuation from 
Study Treatment, 7.2.1 Physician’s 
Choices, 9.6 Secondary Efficacy 
Endpoints and Analyses 
Version 3.0, 
Amendment 2 
Add 6-month immune-related disease 
control rate and 6-month disease 
control rate as study endpoints 
Synopsis; 3.2 Secondary Objectives; 
Figure 1; 9.6.2-5 irDCR, DCR, 6m-
irDCR,and 6mDCR 
Version 3.0, 
Amendment 2 
Remove known allergy to soy or egg 
products as an exclusion criteria 
Synopsis, 5.2 Exclusion Criteria 
Version 3.0, 
Amendment 2 
Biopsy only collected in patients 
randomized to viagenpumatucel-L 
Synopsis, 4.0 Trial Design, 6.1 SOA, 6.3.1 
Baseline Assessments 
Version 3.0, 
Amendment 2 
Move post-treatment biopsy to Week 
13 
Synopsis, 4.0 Trial Design, 6.1 Schedule 
of Assessments, 6.3.2.6-7 Assessments at 
Weeks 10 and 13 
Version 3.0, 
Amendment 2 
Stop immune response testing in 
patients receiving physician’s choice 
regimens after Week 1 
Synopsis; 4.0 Trial Design; 6.1 SOA; 
6.3.2.4-7 Assessments at Weeks 4, 7, 10, 
and 13; 6.3.2.10 Assessments Week22+9x, 
6.3.3 EOT, 6.5.2 Immunologic Response 
Version 3.0, 
Amendment 2 
Remove dose and route requirements 
for physician’s choice regimens 
Synopsis, 6.1 SOA, 7.2.1 Physician’s 
Choices 
Version 3.0, 
Amendment 2 
Update Sponsor address 
Contact Page 
Version 3.0, 
Amendment 2 
Allow patients on stable low dose 
steroids after consulting Medical 
Monitor 
7.5.2 Prohibited Medications 
Version 3.0, 
Amendment 2 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Add pemetrexed as a physician’s 
choice 
Synopsis, 4.0 Trial Design, 7.2.1 
Physician’s Choices 
Version 3.0, 
Amendment 2 
Add interim analysis 
Synopsis, 4.0 Trial Design, 8.3 Trial 
Stopping Rules 
Version 3.0, 
Amendment 2 
Allow patients who have received 3 
prior lines of therapy 
Synopsis, 5.1 Inclusion Criteria 
Version 3.0, 
Amendment 2 
Allow patients to provide archival 
biopsy tissue 
Synopsis, 2.4 Rationale for Performing 
Tumor Biopsies, 3.3 Exploratory 
Objectives, 4.0 Trial Design, 6.1 SOA, 
6.5.2.5 Antigen Screening of Baseline or 
Archival Tumor Biopsy, 9.7 Exploratory 
Endpoints and Analysis 
Version 3.0, 
Amendment 2 
Moved exploratory objectives to a 
separate section (rather than a subset 
of secondary endpoints) 
Synopsis, 3.3 Exploratory Objectives 
Version 3.0, 
Amendment 2 
Added grading scale for injection site 
reactions 
Appendix 4. Grading Scale for Injection 
Site Reactions 
Version 3.0, 
Amendment 2 
Added Data Monitoring Committee 
Synopsis, 8.2 Data Monitoring 
Committee, 8.3 Trial Stopping Rules 
Version 3.0, 
Amendment 2 
Allow G-CSF 
7.5.1 Permitted Medications 
Version 3.0, 
Amendment 2 
Indicated where randomization will 
occur (at baseline) 
6.1 Schedule of Assessments, 6.3.1 
Baseline Assessments 
Version 3.0, 
Amendment 2 
Updated and expanded the 
maintenance visit 
6.1 Schedule of Assessments, 6.3.2.10-15 
Assessments at Weeks 22, 28, 31, 40, 49, 
and 52 
Version 3.0, 
Amendment 2 
Added concomitant medication 
assessment 
6.3.1 Baseline Assessments 
Version 3.0, 
Amendment 2 
Removed volumes of samples 
collected 
6.3.2 Visit Assessments (throughout) 
Version 3.0, 
Amendment 2 
Specified CT and MRI for tumor 
assessments 
6.3.2 Visit Assessments (throughout) 
Version 3.0, 
Amendment 2 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Take immune response samples from 
all patients 
Synopsis, 4.0 Trial Design, 6.1 SOA, 
6.3.2.4 Week 4 Assessments, 6.3.2.6 
Week 10 Assessments, 6.3.2.7 Week 13 
Assessments, 6.3.2.10 Week 22 
Assessments, 6.3.3 End of Treatment 
Visit, 6.5.2 Immunologic Response 
Version 4.0, 
Amendment 3 
Eliminate immune response and 
blood banking at Weeks 7 and 40 
Synopsis, 4.0 Trial Design, 6.1 SOA, 
6.3.2.5 Week 7 Assessments, 6.5.2 
Immunologic Response 
Version 4.0, 
Amendment 3 
Combine immune response and blood 
banking into a single category 
Former section 6.5.3, Schedule of 
Assessments, 6.5.2 Immunologic 
Response,  
Version 4.0, 
Amendment 3 
Update immunologic response 
methodology and endpoints 
Synopsis, 6.5.2 Immunologic Response, 
9.7 Exploratory Endpoints and Analysis 
Version 4.0, 
Amendment 3 
Indicate preference for tissue sections 
rather than FFPE 
6.3.1 Baseline Assessments, 6.3.2.7 Week 
13 Assessments, 6.5.2.5 Antigen 
Screening of Baseline or Archival Tumor 
Biopsy 
Version 4.0, 
Amendment 3 
Describe make up doses of vaccine 
and CY 
7.1.1 Viagenpumatucel-L (HS-110), 7.1.2 
Cyclophosphamide 
Version 4.0, 
Amendment 3 
Clarify steroid therapy use and define 
low-dose steroid therapy 
7.5.2 Prohibited Medications 
Version 4.0, 
Amendment 3 
Indicate that patients in the 
experimental arm should receive G-
CSF only after a Grade 3 neutropenia 
7.5.1 Permitted Medications 
Version 4.0, 
Amendment 3 
Indicate that patients may not receive 
other investigative therapies 
7.5.2 Prohibited Medications 
Version 4.0, 
Amendment 3 
Not require patients with progressive 
disease to discontinue study treatment 
6.6.3 Discontinuation from Study 
Treatment 
Version 4.0, 
Amendment 3 
Indicate that dose should be taken 
with food and water in the morning 
7.1.2 Cyclophosphamide 
Version 4.0, 
Amendment 3 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Indicate that only patients in the 
experimental group should 
discontinue study treatment for a 
Grade 4 event definitely or probably 
related to therapy 
6.6.3 Discontinuation from Study 
Treatment 
Version 4.0, 
Amendment 3 
Indicate in that Grade 3 or greater 
adverse events or unexpected Grade 4 
toxicities should be assessed as 
possibly, probably, or definitely 
related to study drug to stop the trial 
8.3 Trial Stopping Rules 
Version 4.0, 
Amendment 3 
Indicate that patients in the control 
group can have a reduced volume of 
blood collected for immune response 
6.1 SOA 
Version 4.0, 
Amendment 3 
Exclude patient with any condition 
requiring active steroid or other 
immunosuppressive therapy 
Synopsis, 5.2 Exclusion Criteria 
Version 4.0, 
Amendment 3 
Exclude patients with prior treatment 
with a cancer vaccine 
Synopsis, 5.2 Exclusion Criteria 
Version 4.0, 
Amendment 3 
Include patients with no more than 3 
lines of prior therapy 
Synopsis, 5.1 Inclusion Criteria 
Version 4.0, 
Amendment 3 
Collect information on caffeine 
consumption and supplemental 
oxygen use 
7.5 Concomitant Medications 
Version 4.0, 
Amendment 3 
Interim analysis for trial stopping will 
occur after 41 patients in the 
experimental group have had blood 
samples taken at Week 10 
Synopsis, 4.0 Trial Design 
Version 4.0 
Amendment 3 
Added exploratory analysis after 14 
patients in the experimental group 
have had blood samples taken at 
Week 10. 
Synopsis, 4.0 Trial Design 
Version 4.0, 
Amendment 3 
Specify that cyclophosphamide 
should be taken by mouth 
7.1.2 Cyclophosphamide 
Version 4.0, 
Amendment 3 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Long-term follow-up will be until 
study termination or death, whichever 
occurs first 
6.3.4 Long-term Follow-up Visits 
Version 4.0, 
Amendment 3 
Stress that follow-up needs to 
continue even if patients initiate other 
therapy 
6.3.4 Long-term Follow-up Visits 
Version 4.0, 
Amendment 3 
Changed the order of Patient 
Withdrawal from Study and 
Discontinuation from Study 
Treatment 
6.6.2 Discontinuation from Study 
Treatment, 6.6.3 Patient Withdrawal from 
Study 
Version 4.0, 
Amendment 3 
Point out that withdrawal of consent 
for treatment is not the same as 
withdrawal of consent for follow-up 
6.6.3 Patient Withdrawal from Study 
Version 4.0, 
Amendment 3 
Removed “other than 
viagenpumatucel-L” from the 
sentence on concomitant 
investigational agents 
7.5.2 Prohibited Medications 
Version 4.0, 
Amendment 3 
Noted that during follow-up there are 
no prohibited medications and 
patients may enroll in any appropriate 
investigational study 
7.5.2 Prohibited Medications 
Version 4.0, 
Amendment 3 
Updated safety from number of 
AE/SAE to proportion of AE/SAE  
9.6.1 Safety 
Version 4.0, 
Amendment 3 
Prior adjuvant or neoadjuvant 
chemotherapy or definitive 
chemoradiation with curative intent, 
or a repeat course of a prior line of 
systemic therapy does not count as a 
prior line of therapy if last 
administration occurred at least 12 
months prior to enrollment  
Synopsis, 5.1 Inclusion Criteria 
Version 4.0, 
Amendment 3 
State when the primary analysis will 
be conducted 
Synopsis, 4.0 Trial Design, 9.5.1 Overall 
Survival 
Version 4.0, 
Amendment 3 


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Protocol Change 
Section Affected 
Version Where 
Implemented 
Added Heat Biologics logo 
Cover page 
Version 4.0, 
Amendment 3 
Defined AEs to be recorded as 
possibly, probably, or definitely 
related to study medication 
8.1.5 Reporting Adverse Events 
Version 4.0, 
Amendment 3 
 
 


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