Clinical trial NCT02439450
Conditions: Non-small Cell Lung Cancer
Keywords: lung cancer gp96 vaccine immunotherapy Heat Biologics Nivolumab checkpoint inhibitor
Sponsor: Heat Biologics
Start date: 2015-04-15; Completion date: 2022-11-04
Enrollment: 121 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test whether vaccination with viagenpumatucel-L combined with strategies to modulate the immune response is safe for patients with non-small cell lung adenocarcinoma or squamous cell carcinoma for incurable or metastatic disease.

Detailed description:
This study will test whether vaccination with viagenpumatucel-L combined with strategies to modulate the immune response is safe for patients with non-small cell lung adenocarcinoma or squamous cell carcinoma for incurable or metastatic disease. These methods collectively use the body's immune system to target the patient's own tumor. Immunosuppression hinders that response, and may develop in NSCLC patients in a variety of ways, such as activation of checkpoint pathways in the tumor microenvironment. Drugs that disrupt checkpoint molecule signaling like anti-PD-1 monoclonal antibodies nivolumab, may release this brake on the immune system. Tumor expression of PD-L1 plays an important role in patient response to checkpoint inhibitors; in general, clinical response to checkpoint inhibitors requires tumor expression of PD-L1 and presence of Tumor Infiltrating Lymphocytes (TIL). Combining viagenpumatucel-L with anti-PD-1 agents may enhance the vaccine's anti-tumor activity while prolonging or increasing the efficacy of the checkpoint inhibitor.

Arms: arm 1: Patients naïve to checkpoint inhibitor (CPI) therapy will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 viable cells/ 0.5 mL for 18 weeks and bi-weekly nivolumab infusions. After 18 weeks of treatment, patients will continue on monotherapy standard of care nivolumab until confirmed disease progression or unacceptable toxicity, whichever occurs first. After the completion of 18 weeks of combination therapy, patients may receive either nivolumab dosing schedule listed in the current approved package insert (every 2 weeks or every 4 weeks) per Investigator discretion. arm 2: HS-110 dosing to be initiated at/before the start of the 3rd maintenance treatment cycle, or within 19 weeks of front-line pembrolizumab monotherapy. Patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 viable cells/0.5 mL for 13 weeks in combination with SOC pembrolizumab every 3 weeks. Following the 13-week priming period, HS-110 injections will be administered for boosting every 3 weeks in combination with SOC pembrolizumab until confirmed disease progression or unacceptable toxicity, whichever occurs first. arm 3: Patients with prior checkpoint inhibitor (CPI) therapy will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 viable cells/ 0.5 mL for 18 weeks and bi-weekly nivolumab infusions. After 18 weeks of treatment, patients will continue on monotherapy standard of care nivolumab until confirmed disease progression or unacceptable toxicity, whichever occurs first. After the completion of 18 weeks of combination therapy, patients may receive either nivolumab dosing schedule listed in the current approved package insert (every 2 weeks or every 4 weeks) per Investigator discretion. arm 4: HS-110 dosing to be initiated at/before the start of the 3rd maintenance treatment cycle, or within 19 weeks of front-line pembrolizumab monotherapy. Patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 viable cells/0.5 mL for 13 weeks in combination with SOC pembrolizumab + pemetrexed every 3 weeks. Following the 13-week priming period, HS-110 injections will be administered for boosting every 3 weeks in combination with SOC pembrolizumab + pemetrexed until confirmed disease progression or unacceptable toxicity, whichever occurs first.
Interventions: intervention 1: Viagenpumatucel-L intervention 2: Nivolumab intervention 3: Pembrolizumab intervention 4: Pemetrexed
Intervention descriptions: intervention 1: Vaccine derived from irradiated human lung cancer cells genetically engineered to continually secrete gp96-Ig intervention 2: Nivolumab 240mg IV q2weeks for 18 weeks or until disease progression or unacceptable toxicity. After the completion of 18 weeks of combination therapy, patients may receive either nivolumab dosing schedule listed in the current approved package insert (every 2 weeks or every 4 weeks) per Investigator discretion. intervention 3: The recommended dose of KEYTRUDA (pembrolizumab) is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. intervention 4: The recommended dose of ALIMTA (pemetrexed) when administered with carboplatin and pembrolizumab for the initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 administered as an intravenous infusion over 10 minutes prior to carboplatin on Day 1 of each 21-day cycle for 4 cycles. Pembrolizumab should be administered prior to ALIMTA when given on the same day.

Protocol documents:
Prot_SAP_000.pdf: 
Heat Biologics, Inc. 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
Page 1 of 95 
 
 
 
 
 
 
CLINICAL PROTOCOL 
A PHASE 1B/2 STUDY OF VIAGENPUMATUCEL‑L (HS-110) IN COMBINATION 
WITH MULTIPLE TREATMENT REGIMENS IN PATIENTS WITH NON‑SMALL 
CELL LUNG CANCER (THE “DURGA” TRIAL) 
 
Protocol Number:  
 
HS110-102 
Version and Date:  
 
Amendment #6, 24 May 2019 
Previous Versions: 
 
 
 
Amendment #5, 05 September 2018 
 
 
 
 
 
 
 
 
 
Amendment #4, 07 December 2017 
 
 
 
 
 
 
 
 
 
Amendment #3, 21 November 2016 
 
 
 
 
 
 
 
 
 
 
 
Amendment #2, 11 December 2015 
 
 
 
 
 
 
 
 
 
Amendment #1, 02 July 2015 
 
 
Initial Protocol, 30 December 2014 
 
Investigational Product: 
 
Viagenpumatucel-L (HS-110) 
IND Number: 
 
14814 
Indication: 
 
Non-Small Cell Lung Cancer (NSCLC) 
Development Phase: 
 
1b/2 
Principal Investigator:  
 
Daniel Morgensztern, MD 
Sponsor:  
 
Heat Biologics, Inc. 
 
 
801 Capitola Drive, Suite 12 
Durham, NC 27713 
 
 
Tel: +1-919- 794-7914 
 
 
 
 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
Information in this document is confidential and should not be disclosed without the written 
consent of Heat Biologics, Inc. except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting this clinical study. It is permissible to disclose 
information only to your Institutional Review Board or Ethics Committee, study personnel directly 
involved with conducting this study, or participants in the study to obtain informed consent.  


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Persons to whom information is disclosed must be notified that the information is confidential and 
proprietary to Heat Biologics, Inc. 
 
Sponsor:  
 
 
 
Lori McDermott 
Vice-President, Clinical Development  
 
 
 
 
 
 
 
Heat Biologics, Inc. 
801 Capitola Drive, Suite 12 
Durham, NC 27713 
Tel: +1-919-794-8950 
Email: lmcdermott@heatbio.com 
 
 
Medical Monitor: 
 
James Balsley, MD  
ProPharma Group 
5205 Indigo Moon Way 
Raleigh, NC 27613 
Tel: +1-410-708-7609 
Fax: +1-919-844-6948 
Email: james.balsley@propharmagroup.com 
 
 
Principal Investigator: Daniel Morgensztern, MD 
Associate Professor, Division of Oncology 
Department of Medical Oncology 
Washington University School of Medicine in St. Louis 
St. Louis, MO 63110 
Tel: +1-314-747-7948 
Email: danielmorgensztern@wustl.edu 
 
 


Heat Biologics, Inc. 
 
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Protocol HS110-102 
 
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1. 
INVESTIGATOR’S AGREEMENT 
Protocol Number: HS110-102 
Protocol Title: 
A Phase 1b/2 Study of Viagenpumatucel-L (HS-110) in Combination with 
Multiple Treatment Regimens in Patients with Non-Small Cell Lung Cancer 
(The “DURGA” Trial) 
 
Amendment #:  
6 
 
Version Date:  
24 May 2019 
 
I have read and understood Protocol HS110-102 Amendment 6 (dated 24 May 2019) and agree to 
conduct the study as outlined and in accordance with the principles of Good Clinical Practice as 
described in the International Conference on Harmonization Guidelines (ICH E-6) and Form FDA 
1572, including the archiving of essential documents. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 




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3. 
SYNOPSIS 
Name of Sponsor/Company: 
Heat Biologics, Inc. 
Name of Investigational Product: 
Viagenpumatucel-L (HS-110) 
Title of Study:  
A Phase 1b/2 Study of Viagenpumatucel-L (HS-110) in Combination with Multiple Treatment Regimens in 
Patients with Non-Small Cell Lung Cancer (The “DURGA” Trial) 
Study center(s): Up to 25 U.S. centers 
Phase of development: 1b/2 
Primary Objectives: 
Phase 1b: To characterize the safety and tolerability of vaccination with HS-110 in combination with multiple 
immune modulating strategies in patients with non-small cell lung cancer (NSCLC). 
Phase 2, Arm 5: To evaluate Objective Response Rate (ORR) by RECIST 1.1 (Response Evaluation Criteria in 
Solid Tumors). 
Phase 2, Arm 6: To evaluate Progression Free Survival (PFS) by RECIST 1.1  
Secondary Objectives: 
• 
To evaluate overall survival (OS), objective response rate (ORR), progression free survival (PFS), 
duration of response (DOR), durable response rate (DRR) and disease control rate (DCR) per RECIST 
1.1. 
• 
Arm 5: To characterize the safety and tolerability of HS-110 in combination with nivolumab in 
patients with NSCLC. 
• 
Arm 6: To characterize the safety and tolerability of HS-110 in combination with pembrolizumab ± 
pemetrexed in patients with NSCLC. 
Exploratory Objectives: 
• 
Efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyzed using the principals of 
iRECIST to produce iORR, iPFS, iDOR, iDCR, and iDRR. 
• 
To characterize the peripheral blood immunologic response (IR) via Enzyme-Linked ImmunoSpot 
(ELISPOT) analysis. 
• 
To determine total peripheral blood mononuclear cell (PBMC) counts, including lymphocyte subsets. 
• 
To evaluate archival and fresh biopsy tissue for presence of tumor-infiltrating lymphocytes (TIL), 
level of programmed cell death ligand (PD-L1) expression, correlation of pre- and post-treatment TIL 
and PD-L1 measurements with clinical outcomes, and expression of immune active cell subsets and 
molecules. 
• 
To examine tumor mutation burden and other exploratory analysis of peripheral blood and tumor 
tissue to determine immune changes and response to treatment 


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Trial Design: This is a master protocol, intended to evaluate multiple immune modulation strategies in 
combination with HS-110; subsequent treatment arms will be added by amendment as supporting data as these 
combination therapies mature. Patients will be assigned to treatment arms based on the fit to eligibility criteria.  
As of Amendment 4, the Phase 1b portion of the trial (consisting of the first 15 patients to receive HS-110 in 
combination with nivolumab) is complete. Subsequent patients and cohorts will be considered Phase 2. Treatment 
Arm 1 (HS-110 plus oxygen, n=1 patient) has been discontinued. Patients in previously designated Arms 2, 3, and 
4 all received HS-110 + nivolumab but had different TIL status. Patients from these arms have now been 
reclassified as Arm 5, and further enrollment into this arm is ongoing.   
As of Amendment 5, the patient population under study was expanded to include front line patients who have 
received immunotherapy (with or without chemotherapy), who have not progressed clinically or radiographically 
(per RECIST 1.1) at the most recent imaging assessment, and who will begin maintenance immunotherapy with 
SOC pembrolizumab ± pemetrexed. HS-110 will be added to their immunotherapy maintenance regimen, and must 
be initiated on or before maintenance cycle 3 (after completion of platinum chemotherapy), or no later than week 
19 (if receiving front line pembrolizumab monotherapy). 
Patients who meet all eligibility criteria will be enrolled to the below treatment arms and cohorts, until the total 
sample size for Phase 2 is met (n=105) in addition to the Phase 1b sample size (n=15) for a total study sample size 
of approximately 120 evaluable patients:  
Arm 5: HS-110 plus SOC nivolumab (n=100, to include 15 phase 1b patients and 85 phase 2 patients)   
Arm 6: HS-110 plus SOC pembrolizumab ± pemetrexed (n=up to 20 phase 2 patients).  
Arm 5 patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a 
dose of 1 × 107 viable cells/ 0.5 mL for 18 weeks and nivolumab infusions administered every two weeks. After 18 
weeks of treatment, patients will continue on monotherapy SOC nivolumab until confirmed disease progression or 
unacceptable toxicity, whichever occurs first. After the completion of 18 weeks of combination therapy, patients 
may receive either nivolumab dosing schedule listed in the current approved package insert (every 2 weeks or every 
4 weeks) per Investigator discretion.  
Arm 5 patients will be scanned radiographically at Screening, Week 9, Week 18, and every 8 weeks thereafter until 
confirmed disease progression.  
Arm 6 patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a 
dose of 1  107 viable cells/0.5 mL for 13 weeks in combination with SOC pembrolizumab ± pemetrexed every 3 
weeks. Following the 13-week priming period, HS-110 injections will be administered for boosting every 3 weeks 
in combination with SOC pembrolizumab ± pemetrexed until confirmed disease progression or unacceptable 
toxicity, whichever occurs first. 
Arm 6 patients will be scanned radiographically at Screening and every 9 weeks thereafter until confirmed disease 
progression. 
For all study patients, the scan schedule will continue until confirmed iCPD as defined by iRECIST, after which 
they will be followed for OS. Using the principles of iRECIST, patients with unconfirmed disease progression 
(iUPD) should continue on study treatment until confirmed progression (iCPD) unless clinical progression 
necessitates otherwise. 
For all study patients, screening tumor samples (archival or fresh) and on-treatment biopsy tumor samples may be 
screened for expression of immune active cell subsets and molecules, expression of PD-L1 on tumor cells, and 


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evaluation for the presence of TILs. Pre- and post-treatment TIL and PD-L1 levels with be correlated with clinical 
outcomes. 
Peripheral blood samples will be taken to evaluate tumor mutation burden and immune cell subsets for correlation 
with clinical outcomes.  
Safety will be assessed by frequency of adverse events (AEs), evaluation of clinical laboratory parameters 
(hematology, liver function, electrolytes, troponin, and renal function), vital signs, electrocardiogram (ECG), and 
physical exams (PEs). 
Efficacy will be assessed by measures of OS as well as ORR, DOR, DCR, DRR and PFS by RECIST 1.1.   
Number of evaluable patients (planned): Up to 120  
Phase 1b: 15 patients (completed in 2017) 
Phase 2:  Up to 105 patients  
Inclusion criteria: 
1. Age ≥ 18 years. 
2. Histologically or cytologically confirmed non-small cell lung adenocarcinoma or squamous cell 
carcinoma. Patients with mixed histology other than adeno-squamous are not eligible. 
3. At least one site of measurable disease by CT scan or MRI as defined by RECIST 1.1. [Note: criteria not 
applicable to Arm 6 patients who have achieved 100% reduction in target lesions.] 
 
4. Arm 5: Received at least one prior line of therapy, but no more than 3 lines of therapy, for incurable (i.e. 
unresectable) or metastatic NSCLC, including cytotoxic chemotherapy, molecularly-targeted agents, or 
immunotherapy. One prior line of an FDA-approved checkpoint inhibitor (CPI) therapy is permitted, 
however a treatment period with CPI of at least 4 months is required. 
OR 
Arm 6: Received front line immunotherapy (with or without chemotherapy) for incurable (i.e. 
unresectable) or metastatic NSCLC and did not progress clinically or radiographically per RECIST 1.1 
at most recent imaging assessment,  and will begin maintenance immunotherapy with SOC 
pembrolizumab ± pemetrexed. [Note: HS-110 dosing to be initiated at/before the start of the 3rd 
maintenance treatment cycle, or within 19 weeks of front-line pembrolizumab monotherapy.] 
5. Life expectancy of at least 18 weeks. 
6. Arm 5: Documented disease progression at study entry 
OR 
Arm 6: Documented Stable Disease, Partial Response, Complete Response (SD/PR/CR) per 
RECIST 1.1 after a minimum of 9 to 12 weeks of front line immunotherapy (with or without 
chemotherapy).  
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
8. Central Nervous System (CNS) metastases may be permitted after discussion with the Medical Monitor 
and must meet the following conditions: 


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a. 
Patient must be treated and radiographically and neurologically stable. Stable CNS metastases are 
defined by the return of neurological symptoms to baseline, use of no more than 10 mg of prednisone 
or equivalent per day, and no evidence of new or active brain lesions in the repeated scan prior to 
study entry. 
b. Brain lesions must have been previously irradiated, including whole brain radiation therapy or 
radiosurgery.  
c. All radiation treatment (except for localized stereotactic palliative therapy) must be completed at least 
4 weeks prior to enrollment.  
9. Lab parameters: 
− 
Albumin ≥ 2.5 g/dL. 
− 
Total Bilirubin < 3.0 × upper limit of normal (ULN) unless patient has Gilbert’s syndrome. 
− 
Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × 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. 
10. Willing and able to comply with the protocol and sign informed consent, including office visits for weekly 
HS-110 injections for 18 weeks (Arm 5) or weekly HS-110 injections for 13 weeks followed by every 3 
week boosting injections until disease progression (Arm 6). 
11. 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. 
12. Willing and able to provide either archival or fresh biopsy sample at Screening, and fresh tumor biopsy at 
Week 10 when feasible. Archival tissue used at Screening must be representative of the patient’s current 
disease state unless written authorization from the Sponsor is obtained. Note that the fresh biopsy at Week 
10 may be waived with written authorization from the Sponsor. 
13. Arm 5: Suitable for treatment with nivolumab per the current approved package insert. 
OR 
Arm 6: Suitable for front line maintenance treatment with pembrolizumab ± pemetrexed per the current 
approved package inserts. 
 
Exclusion Criteria: 
1. Arm 5: Received systemic anticancer therapy within 21 days prior to first dose of study drug. 
2. Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or concurrent 
illness, unrelated to the tumor, requiring active therapy. Testing is not required in the absence of history. 
3. Any condition requiring concurrent systemic immunosuppressive therapy. 
4. Known immunodeficiency disorders, either primary or acquired. 
5. Known leptomeningeal disease. 


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6. Active malignancies within 12 months, with the exception of those with a negligible risk of metastasis or 
death, and treated with expected curative outcome. 
7. Pregnant or breastfeeding. 
8. Prior participation in a clinical study of HS-110. 
9. Active, known, or suspected autoimmune disease at any time prior to study entry. 
10. Received a live vaccine within 30 days prior to first dose of study drug. 
11. Significant cardiovascular disease:  
a. 
Baseline Left Ventricular Ejection Fraction (LVEF) below lower limit of normal range per 
institutional standard by ECHO or MUGA to be obtained within 30 days prior to first dose of study 
drug 
b. History of myocardial infarction within 1 year of enrollment 
c. 
History of heart failure within 2 years of enrollment, or at any time if due to auto-immune causes or 
prior immunotherapy treatment, unless pre-approved by the medical monitor 
d. A clinically significant ECG abnormality, including PR interval of >260 ms, any evidence of heart 
block, or a baseline prolonged QTc interval (e.g., a repeated demonstration of a QTc interval 
>480 ms) to be obtained within 30 days prior to first dose of study drug 
12. Refractory to immunotherapy (clinical or radiographic progression after 12 weeks or less of 
immunotherapy). 
 
Investigational product, dosage and mode of administration:  
HS-110 (viagenpumatucel-L) is provided as fully-diluted, frozen liquid not requiring additional dilution. The final 
drug product will consist of 10 million cells resuspended in buffered saline containing human serum albumin 
(HSA), dimethyl sulfoxide (DMSO) and pentastarch. Dosing will rotate injection site extremities at every time 
point: antero-lateral left thigh, antero-lateral right thigh, left shoulder, and right shoulder. 
Arm 5: 
HS-110   
Patients will receive a dose of 1 × 107 HS-110 cells per 0.5 mL administered as 5 spatially divided intradermal 
injections (≤ 0.1 mL per injection) once weekly for 18 weeks, or until confirmed radiographic or clinical 
progression or unacceptable toxicity, whichever occurs first.  
Nivolumab  
Patients will receive SOC nivolumab every 2 weeks during the 18-week combination treatment period or 
until PD or unacceptable toxicity, whichever occurs first. After 18 weeks of combination treatment, SOC 
nivolumab may be administered per either dosing schedule in the current approved nivolumab package insert 
(every 2 weeks or every 4 weeks) per Investigator discretion. 
Arm 6: 
HS-110  
Patients will receive a dose of 1 × 107 HS-110 cells per 0.5 mL administered as 5 spatially divided intradermal 
injections (≤ 0.1 mL per injection) once weekly for 13 weeks in combination with SOC pembrolizumab +/- 


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pemetrexed every 3 weeks. Following the 13-week priming period, HS-110 injections will be administered 
for boosting every 3 weeks in combination with pembrolizumab +/- pemetrexed until confirmed radiographic 
or clinical progression or unacceptable toxicity, whichever occurs first. 
Pembrolizumab ± Pemetrexed  
Patients in this group will receive SOC every 3 weeks per the pembrolizumab and pemetrexed package 
inserts for the treatment of NSCLC.  
 
Safety Parameters: 
Primary Endpoint: 
Phase 1b: Safety and Tolerability: Measured by the frequency of treatment emergent adverse events 
(TEAEs)/serious adverse events (SAEs), including clinically significant (CS) abnormal laboratory parameters, 
ECGs, PEs, and vital signs in patients receiving at least 1 dose of HS-110.  
Efficacy Parameters: 
Primary Endpoints: 
Phase 2: Arm 5- Objective Response Rate: Defined as the number of patients achieving a best overall response 
of complete response (CR) or partial response (PR) by RECIST 1.1, divided by the total number of enrolled 
patients. This will be calculated for each cohort. Note that ORR will be a secondary endpoint for Arm 6. 
Phase 2: Arm 6- Progression-Free Survival: Calculated as the time between the date of first dose of HS-110 and 
the date of PD as defined by RECIST 1.1 or death, whichever occurs first. For patients with no recorded 
post-baseline tumor assessments, PFS will be censored at the day of first dose. For those who remain alive and 
have no PD, PFS will be censored on the date of last evaluable tumor assessment. This will be calculated for each 
cohort. Note that PFS will be a secondary endpoint for Arm 5. 
Secondary Endpoints: 
Overall Survival (OS): Calculated as the duration from date first dose of HS-110 to date of death from any cause 
or will be censored on the date the patient was last known to be alive. 
Duration of Response (DOR): Calculated from the time of first response (CR or PR) until radiographic PD (per 
RECIST 1.1) or clinical deterioration requiring a change of treatment. 
Disease Control Rate (DCR): Defined as the proportion of evaluable patients whose best overall response is PR, 
CR, or SD by RECIST 1.1.  
Durable Response Rate (DRR/): Defined as the % of responders (CR or PR) with durable responses lasting at 
least 6 months from time of initial response. DRR will be calculated at 6 and 12 months. 
OS Rate: Defined as the proportion of patients who are alive at 6, 12, and 24 months following first dose of HS-
110.PFS Rate: Defined as the proportion of patients who have not progressed at 6 and 12 months following first 
dose of HS-110. 
Safety and Tolerability: Measured by the frequency of TEAEs/SAEs including CS abnormal laboratory 
parameters, ECGs, PEs, and vital signs in patients receiving at least 1 dose of HS-110. 
Exploratory Endpoints: 


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Efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyzed using the principals of iRECIST to 
produce iORR, iPFS, iDOR, iDCR, and iDRR. 
Peripheral blood IR will be measured by ELISPOT to detect an increase of 2-fold over baseline of IFNγ and/or 
granzyme B (gzB) positive T cells, as well as analysis of surface markers that define NK and T cell subsets of 
activation, memory and exhaustion by flow cytometry.   
Evaluation of tumor tissue obtained for presence of TILs and correlation of pre- and post-treatment TIL levels with 
clinical outcomes. 
Evaluation of tumor tissue obtained for expression of PD-L1 on tumor cells and correlation of pre- and post-
treatment PD-L1 expression with clinical outcomes. 
Evaluation of peripheral blood TMB to measure the number of mutations within the tumor genome and correlation 
of TMB levels with clinical outcomes. 
Other exploratory analysis of peripheral blood and tumor tissue to determine immune changes and response to 
treatment may be conducted as new technology emerges. 
Statistical methods: 
Study populations are defined as follows: 
Safety Population: all patients who receive at least 1 dose of HS-110. 
Per-Protocol (PP) Population: all patients who have received at least 6 doses of HS-110, and who have a pre-
treatment tumor assessment and at least one post-treatment tumor assessment. 
Adenocarcinoma Population: all patients in the PP who have adenocarcinoma histology 
The Phase 1b portion is an exploratory substudy with safety as a primary endpoint. In Phase 2, the results from 
each cohort in Arm 5 and Arm 6 will be tabulated separately. 
Arm 5 will include 2 cohorts, with a primary endpoint of ORR for each cohort: 
- Cohort A: CPI naïve patients  (n=40) 
- Cohort B: CPI progressor patients (n=60). Note that this Cohort will be permitted to over-enroll based on 
patient availability. 
 
Arm 6 is an exploratory arm that will include up to 20 patients in 2 cohorts pending patient availability. The 
primary endpoint for each cohort will be PFS. The distribution of patients between these cohorts will not be 
controlled:   
 
- Cohort C: Maintenance pembrolizumab 
- Cohort D: Maintenance pembrolizumab + pemetrexed  
 
Each cohort (A, B, C and D) will be analyzed including patients of all histology types, and then again including 
only adenocarcinoma patients. 
Analyses will be performed within each of the cohorts to identify differences in strata for each of the following 
factors, provided sufficient data exists: 
• 
Histology: adenocarcinoma and squamous cell carcinoma  
• 
PD-L1 status: negative (<1%) and positive (≥1%) based on tumor cell expression  


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• 
TIL status: high (> 10%) and low (≤ 10%)  
• 
Tumor Mutation Burden: high (10 or more mutations) and low (less than 10 mutations) 
Additional factors, such as line of treatment or presence of injection site reactions, may be added to statistical 
models used for analyses; the method of pooling and testing for interaction among the different factors for the 
different cohorts will be described in detail in the SAP.   
With a total enrollment into this hypothesis-generating clinical trial of up to 120 patients across the two treatment 
arms, this study should have sufficient patients to identify likely subgroups for whom the addition of HS-110 to 
SOC appears have a clinically meaningful benefit over SOC alone. No formal hypothesis testing will be performed. 
Baseline demographic and clinical data (safety and efficacy) as well as all exploratory endpoints will be 
summarized using descriptive statistics (means, medians, proportions, standard deviations, minima, and maxima). 
Time-to-event endpoints (PFS/iPFS, OS) will be calculated using Kaplan-Meier methodology. All summaries of 
binary efficacy endpoints such as immune response, DCR/iDCR and ORR will be presented with exact 95% CI for 
each cohort.  
 


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4. TABLE OF CONTENTS  
1. 
INVESTIGATOR’S AGREEMENT ........................................................................................3 
2. 
SPONSOR PROTOCOL APPROVAL PAGE .........................................................................4 
3. 
SYNOPSIS ...............................................................................................................................5 
4. 
TABLE OF CONTENTS .......................................................................................................13 
4.1. List of Tables ..............................................................................................................18 
4.2. List of Figures .............................................................................................................18 
4.3. Abbreviations and Acronyms .....................................................................................19 
4.4. Statement of Compliance ............................................................................................23 
5. 
INTRODUCTION ..................................................................................................................24 
5.1. Non-Small Cell Lung Cancer .....................................................................................24 
5.2. Vaccine Monotherapy Approaches for NSCLC .........................................................25 
5.3. Vaccine Combination Approaches to NSCLC ...........................................................25 
5.4. Description of Investigational Agent, HS-110 ...........................................................26 
5.5. Prior Human Experience with HS-110 .......................................................................27 
6. 
STUDY RATIONALE ...........................................................................................................29 
6.1. Study Specific Rationale .............................................................................................29 
6.2. Justification of HS-110 Dose Selection ......................................................................30 
6.3. Rationale for Obtaining Archival Tissue and Performing Tumor Biopsies ...............31 
6.4. Rationale for Inclusion of Squamous Cell Carcinoma Patients ..................................31 
6.5. Rationale for Checkpoint Inhibitor Progressor Patients and First Line 
Maintenance Patients ......................................................................................32 
6.6. Rationale for First Line Maintenance Dosing ............................................................33 
7. 
INVESTIGATIONAL PLAN .................................................................................................34 
7.1. Overall Study Design ..................................................................................................34 
7.2. Study Treatments ........................................................................................................35 
8. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................37 
8.1. Primary Objectives .....................................................................................................37 
8.2. Secondary Objectives .................................................................................................37 
8.3. Exploratory Objectives ...............................................................................................37 
9. 
SELECTION AND WITHDRAWAL OF PATIENTS ..........................................................38 
9.1. Subject Inclusion Criteria ...........................................................................................38 


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9.2. Subject Exclusion Criteria ..........................................................................................40 
9.3. Patient Completion and Withdrawal ...........................................................................41 
 
Patient Completion .............................................................................41 
 
Discontinuation from Study Treatments .............................................41 
 
Patient Withdrawal from Study ..........................................................42 
10. STUDY PROCEDURES ........................................................................................................43 
10.1. 
Screening Procedures and Baseline (Day -28 to Day -1) ...............................43 
 
Baseline Assessments (Day -7 to Day 1) ............................................44 
10.2. 
Arm 5: On Study Treatment Procedures ........................................................44 
 
Week 1 Assessments (Day 1) .............................................................44 
 
Week 2 Assessments ...........................................................................45 
 
Week 3 Assessments ...........................................................................45 
 
Week 4 Assessments ...........................................................................45 
 
Week 5, 6, 8, and 11 Assessments ......................................................46 
 
Week 7 and 13 Assessments ...............................................................46 
 
Week 9 and 18 Assessments ...............................................................46 
 
Week 10 and 16 Assessments .............................................................46 
 
Week 12, 14, 15, and 17 Assessments ................................................47 
10.3. 
Arm 5: End of Treatment (EOT) Visit ...........................................................47 
10.4. 
Arm 5: Follow-up Procedures ........................................................................47 
 
Post-HS-110 Follow Up (After HS-110 treatment until 
disease progression) ............................................................................47 
 
Survival Follow-Up (Progressive Disease until Death) ......................47 
10.5. 
Arm 6: On Study Treatment Procedures ........................................................48 
 
Week 1 Assessments (Day 1) .............................................................48 
 
Week 2 Assessments ...........................................................................48 
 
Week 3 Assessments ...........................................................................48 
 
Week 4 Assessments ...........................................................................49 
 
Week 5, 6, 8, 9, 11 and 12 Assessments .............................................49 
 
Week 7 and 13 Assessments ...............................................................49 
 
Week 10 Assessments .........................................................................49 
 
Boosting Visits and Assessments (Week 14 to EOT) ........................50 


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10.6. 
Arm 6: End of Treatment ................................................................................50 
10.7. 
Arm 6: Survival Follow-Up (Progressive Disease until Death) .....................50 
10.8. 
Schedule of Activities (SOA) .........................................................................50 
11. TREATMENT OF PATIENTS ..............................................................................................55 
11.1. 
Description of Study Drug ..............................................................................55 
11.2. 
Prior and Concomitant Medications ...............................................................55 
11.3. 
Permitted Medications ....................................................................................55 
 
Prohibited Medications .......................................................................55 
 
Supportive Care ..................................................................................56 
11.4. 
Treatment of Investigational Product Overdose .............................................56 
11.5. 
Dose Adjustment Criteria ...............................................................................56 
12. STUDY DRUG MATERIALS AND MANAGEMENT .......................................................57 
12.1. 
HS-110 ............................................................................................................57 
12.2. 
Study Drug Storage .........................................................................................57 
12.3. 
Study Drug Preparation ..................................................................................58 
12.4. 
Labeling ..........................................................................................................58 
12.5. 
Study Drug Accountability .............................................................................58 
12.6. 
Occupational Safety ........................................................................................58 
13. ASSESSMENT OF SAFETY .................................................................................................59 
13.1. 
Physical Examination .....................................................................................59 
13.2. 
Clinical Laboratory Evaluations .....................................................................59 
13.3. 
Injection Site Reactions ..................................................................................60 
13.4. 
Cardiac Monitoring .........................................................................................60 
13.5. 
Pregnancy .......................................................................................................61 
 
Time Period for Collecting Pregnancy Information ...........................61 
 
Action to be Taken if Pregnancy Occurs ............................................61 
 
Action to be Taken if Pregnancy Occurs in a Female Partner 
of a Male Study Subject ......................................................................61 
14. ASSESSMENT OF EFFICACY ............................................................................................62 
14.1. 
Tumor Assessments ........................................................................................62 
 
RECIST 1.1 and iRECIST for Tumor Assessment ............................62 
14.2. 
Immunologic Response (IR) ...........................................................................63 


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14.3. 
Production of Interferon-gamma and Granzyme B from PBMCs 
(ELISPOT) ......................................................................................................63 
14.4. 
Phenotyping Phenotypic Analysis of Blood Lymphocyte Subsets by 
FACS ..............................................................................................................64 
14.5. 
Analysis of Infiltrating T-Cells (Post-Treatment Tumor Biopsy) ..................64 
14.6. 
Tumor Mutation Burden Analysis ..................................................................64 
15. SAFETY MONITORING ......................................................................................................65 
15.1. 
Adverse and Serious Adverse Events .............................................................65 
 
Adverse Event (AE) ............................................................................65 
 
Serious Adverse Event (SAE) ............................................................65 
 
Disease-Related Events or Outcomes not Qualifying as SAEs ..........66 
 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as AEs and SAEs ...........................................................66 
15.2. 
Relationship to Study Drug ............................................................................66 
15.3. 
Reporting Adverse Events ..............................................................................67 
15.4. 
Prompt Reporting of SAEs .............................................................................67 
15.5. 
Study Review Committee and Data Monitoring Committee ..........................68 
16. STATISTICS ..........................................................................................................................69 
16.1. 
General Statistical Considerations ..................................................................69 
16.2. 
Sample Size ....................................................................................................69 
16.3. 
Analysis Populations ......................................................................................70 
16.4. 
Disposition, Demographics, and Baseline Characteristics .............................70 
16.5. 
Primary Efficacy Endpoint and Analysis .......................................................70 
 
Phase 1b: Safety and Tolerability .......................................................70 
 
Phase 2: Objective Response Rate (Arm 5 Cohorts A/B) and 
Progression Free Survival (Arm 6 Cohorts C/D) ...............................70 
16.6. 
Secondary Efficacy Endpoints and Analyses .................................................71 
 
Objective Response Rate ....................................................................71 
 
Overall Survival ..................................................................................71 
 
Progression-Free Survival ..................................................................71 
 
Duration of Response .........................................................................71 
 
Disease Control Rate ..........................................................................71 
 
6-month Durable Response Rate ........................................................72 


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12-month Durable Response Rate ......................................................72 
 
6-month Overall Survival ...................................................................72 
 
12-month Overall Survival .................................................................72 
 
6-month Progression Free Survival ....................................................72 
 
12-month Progression Free Survival ..................................................72 
 
Safety and Tolerability .......................................................................72 
16.7. 
Exploratory Endpoints and Analyses..............................................................72 
16.8. 
Safety Analyses ..............................................................................................73 
 
Adverse Events ...................................................................................73 
 
Laboratory Assessments .....................................................................73 
 
Vital Signs ..........................................................................................73 
 
ECGs ...................................................................................................73 
 
Other Assessments ..............................................................................74 
17. DESCRIPTION OF ETHICAL CONSIDERATIONS RELATED TO THE TRIAL. ..........75 
18. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.....................................................76 
18.1. 
Study Monitoring ............................................................................................76 
18.2. 
Protocol Deviations ........................................................................................76 
19. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................77 
20. DATA HANDLING AND RECORDKEEPING ...................................................................78 
20.1. 
Retention of Records ......................................................................................78 
20.2. 
Provision of Study Results and Information to Investigators .........................78 
20.3. 
Data Management ...........................................................................................78 
20.4. 
Study and Site Closure....................................................................................79 
21. LIST OF REFERENCES ........................................................................................................80 
APPENDIX 1: ECOG PERFORMANCE STATUS SCALE .......................................................82 
APPENDIX 2: GRADING SCALE FOR INJECTION SITE REACTIONS ...............................83 
APPENDIX 3: THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1) GUIDELINES AND GUIDLELINES FOR RESPONSE 
CRITERIA FOR USE IN TRIALS TESTING IMMUNOTHERAPEUTICS 
(IRECIST) ...................................................................................................................84 
APPENDIX 4: AMENDMENT JUSTIFICATION AND CHANGE LOG ..................................88 
 
 
 


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4.1. 
List of Tables 
Table 1: 
Comparison of ImPACT to Other Immunotherapies ..................................................29 
Table 2: 
Schedule of Activities (Arm 5: HS-110+ Nivolumab) ...............................................51 
Table 3: 
Schedule of Activities (Arm 6: HS-110 + Pembrolizumab +/- Pemetrexed) .............53 
Table 4: 
Investigational Product ...............................................................................................55 
 
4.2. 
List of Figures 
Figure 1: 
Structure of ImPACTTM Vaccine, HS-110 ..................................................................27 
Figure 2: 
Number of Common Antigens between HS-110, Squamous and 
Adenocarcinoma in NSCLC .......................................................................................32 
Figure 3: 
Study Design ...............................................................................................................35 
 
 
 


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4.3. 
Abbreviations and Acronyms 
  
Abbreviation  
Definition 
12mOS 
12-month overall survival 
6mOS 
6-month overall survival 
A2AR 
A2A adenosine receptor 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
AMP 
Adenosine monophosphate 
ANA 
Antinuclear antibodies 
APC 
Antigen presenting cell 
AST 
Aspartate aminotransferase 
cAMP 
Cyclic adenosine monophosphate 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
Current good manufacturing practices 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T-lymphocyte 
CTLA-4 
Cytotoxic T-lymphocyte associated antigen 4 
CPI 
Checkpoint Inhibitor 
DC 
Dendritic cell 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
DMSO 
Dimethyl sulfoxide 
DRR 
Durable Response Rate 


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Abbreviation  
Definition 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor  
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-linked immunosorbent spot 
EOT 
End of treatment 
ER 
Endoplasmic reticulum 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin embedded 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
gzB 
Granzyme B 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HSA 
Human serum albumin 
IBC 
Institutional Biosafety Committee 
ICF 
Informed consent form 
IO 
Immuno-oncology 
i.v. 
Intravenous 
ICH 
International Conference on Harmonisation 
ICS 
Intracellular cytokine staining 
IDMC 
Independent data monitoring committee 
IDO 
Indoleamine-2,3-dioxygenase 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon-γ 
IHC 
Immunohistochemistry 
IR 
Immunologic response 
IRB 
Institutional Review Board 


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Abbreviation  
Definition 
iCPD 
Confirmed Disease Progression based on immune responses assigned using 
iRECIST 
iCR 
Complete Response based on immune responses assigned using iRECIST 
iUPD 
Unconfirmed Disease Progression based on immune responses assigned 
using iRECIST  
iPR 
Partial Response based on immune responses assigned using iRECIST 
iRECIST 
Response Evaluation Criteria in Solid Tumors for use in trials testing 
immunotherapeutics 
iSD 
Stable Disease based on immune responses assigned using iRECIST 
ISR 
Injection site reaction 
IST 
Investigator-sponsored trial 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
mAbs 
Monoclonal antibodies 
MAGE-A1 
Melanoma-associated antigen 1 
Mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSDS 
Material safety data sheet 
MUC1 
Mucin-1 (tumor associated antigen) 
MUGA 
Multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network  
NCI 
National Cancer Institute 
NK 
Natural killer 
Non-iCR/non-iUPD 
Neither criteria for iCR or iPD have been met 
NOS 
Not otherwise specified 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 


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Abbreviation  
Definition 
PD 
Progressive disease 
PD-1 
Programmed death receptor 1 
PD-L1 
Programmed death ligand 1 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PP 
Protocol population 
PR 
Partial response 
PS 
Performance status 
QoL 
Quality of Life 
RBC 
Red blood cell 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RR 
Response rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
SD 
Stable disease 
SOA 
Schedule of activities 
SOC 
Standard-of-care 
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TGF 
Transforming growth factor 
TIL 
Tumor infiltrating lymphocytes 
TKI 
Tyrosine kinase inhibitor 
TLR 
Toll-like receptor 
T-reg 
Regulatory T-cell 
TrPAL 
Triple positive activated lymphocytes (CD16 + CD56 + CD69+) 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 
 
 


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4.4. 
Statement of Compliance 
 
This trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following the United States (US) Code of Federal 
Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 11, 50, 54, 56, 
and Part 312). 
 
The protocol, informed consent form (ICF), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB)/ Ethics Committee (EC) for review 
and approval.  Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled.  Any amendment to the protocol and ICF will require review and approval 
by the IRB/EC prior to implementation.  In addition, a determination will be made regarding 
whether a new ICF needs to be obtained from participants who already provided consent using a 
previously approved ICF. 
 


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5. 
INTRODUCTION 
5.1. 
Non-Small Cell Lung Cancer 
The annual incidence of non-small cell lung cancer (NSCLC) in the United States is estimated at 
~222,500 cases in 2017 and remains the deadliest malignancy worldwide. Most NSCLC patients 
have local or distal metastatic lesions upon diagnosis (stage IV) and the disease has a poor  5-year 
survival rate of 5.2%.1 Despite a number of therapeutic advances in the last decade, response to 
first-line and subsequent therapy for advanced NSCLC remains sub-optimal. 
Treatment strategies include consideration regarding tumor histology, molecular pathology, age, 
and comorbidities. In patients without mutations of epidermal growth factor receptor (EGFR), 
anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) rearrangements, first-line therapy 
generally includes platinum-based doublet chemotherapy, with or without the anti-vascular 
endothelial growth factor (VEGF) antibody, bevacizumab. Patients with mutations can 
significantly delay disease progression by treatment with molecularly targeted agents, therefore 
treatment with tyrosine kinase inhibitors (TKIs) should be considered a first line treatment in this 
patient population2.  The programmed death-1 (PD-1) inhibitor pembrolizumab (KEYTRUDA) 
has recently been approved by the FDA as a first line single agent therapy in patients with 
programmed cell death ligand-1 (PD-L1) expression more than 50% with negative or unknown 
results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements. In addition, 
pembrolizumab is now used in combination with carboplatin/pemetrexed (PARAPLATIN® among 
others/ALIMTA®) as first-line therapy for patients with advanced non-squamous NSCLC or 
NSCLC not otherwise specified (NOS) based on the Keynote-021 results.3 
The current standard of care (SOC) for second line therapy of NSCLC includes treatment with 
monoclonal antibody (mAB) immune checkpoint inhibitors (CPI) such as nivolumab (OPDIVO®), 
pembrolizumab and atezolizumab. These checkpoint inhibitors have delivered objective responses 
of ~20% in an unselected NSCLC population, with impressive clinical results in a subset of 
programmed death ligand 1 (PD-L1) positive patients. Specific subgroup analysis of single agent 
nivolumab found response rates in previously treated (second line) non-squamous patients to be 
17 to 20%, and in squamous patients to be 14.5 to 20%4,5. PD-L1 expression is often associated 
with T-cell activation and patients with a low level of existing tumor-infiltrating lymphocytes 
(TIL) appear to be less likely to respond to checkpoint inhibition. In fact, 60-70% of NCSLC 
patients are TIL-negative, which may be a contributing factor in the low overall response rate to 
checkpoint therapy in this unselected patient population.  
These observations support the hypothesis that tumor-specific T-cell activation enhances the 
clinical activity of checkpoint therapy. HS-110 represents a novel way to stimulate a CD8+ T-cell 
response toward tumor associated antigens to enhance checkpoint therapy in treating NSCLC. This 
trial will include both CPI naïve and CPI progressor patients.  The relatively poor responses seen 
with second-line and subsequent treatments are due to a combination of progressive biological 
resistance of the underlying tumor arising from successive regimens of chemotherapy and a decline 
in the performance status of patients, due to treatment- and disease-related morbidities.  
The large and increasing population of patients being delivered checkpoint inhibitor therapy to the 
post-first-line setting, opens an opportunity to combine an immunostimulatory vaccine, HS-110, 


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to create a potential synergist treatment. Since the historical objective response rate (ORR) for 
nivolumab as second line agent in NSCLC is 20%, this is a population that could derive benefit 
from the immunostimulating ability of HS-110 in combination with nivolumab. Immune CPI 
progressor patients have an unknown response rate to nivolumab as a single agent in the second-
line setting. It is currently recommended for second-line therapy per National Comprehensive 
Cancer Network (NCCN) Clinical Practice Guidelines in Oncology™, but there is an insufficient 
quantity of data stating the exact ORR of nivolumab after a patient has progressed on first-line 
pembrolizumab. It can be understood logically to be a lower response, as the patient previously 
progressed while on the CPI in the first-line setting. 
HS-110 in previous human trials in NSCLC was found to be safe and immunogenic. This 
mechanistically novel technology and inherent low toxicity profile in combination with nivolumab 
in the second-line setting has potential to fill an unmet need in this population.  
5.2. 
Vaccine Monotherapy Approaches for NSCLC 
Vaccines have the potential to trigger a durable antitumor response with minimal toxicity, thus 
presenting an attractive alternative for NSCLC treatments. Vaccine-based therapy utilizing an 
autologous or allogeneic antigenic stimulus to promote endogenous antitumor immune activation 
is currently being heavily investigated in the clinic. Melanoma-associated antigen 3 (MAGE-A3) 
and mucin 1 glycoprotein (MUC1) are antigens specifically associated with various solid tumors, 
including NSCLC. 6,7 Two vaccines, designed to target these antigens, have been unsuccessful in 
treating potentially curable, earlier stage NSCLC in recent phase 3 trials. The MAGE-A3 vaccine 
failed to extend disease-free survival in patients with MAGE-A3-positive tumors, and no gene-
signature-defined patient subsets could be identified that may have experienced clinical benefit.8,9 
The L-BLP25 vaccine administered in combination with cyclophosphamide, failed to show an 
overall survival (OS) advantage against placebo in unresectable stage IIIB NSCLC after definitive 
chemoradiation.7,10  
Although up to 50% of patient tumors may express either MAGE-A3 and/or MUC1, the expression 
of these antigens within an individual tumor is rarely uniform, reflecting the underlying genetic 
heterogeneity of tumors, and suggests that patients who may be positive for a particular molecular 
signature and/or antigen may also have a significant tumor burden that is negative for those same 
molecular targets, thus leading to ineffective treatment for single-agent therapies. Following 
treatment with a single-antigen vaccine, even in the presence of a robust immune response, 
MAGE-A3 or MUC1 negative tumor cells may be resistant to a tumor-specific immune response. 
Furthermore, these trials did not enrich their patient population through selection for specific 
biomarkers that may exist in certain patients who may have benefitted from either of these 
therapies.   
5.3. 
Vaccine Combination Approaches to NSCLC 
Tumor heterogeneity, as evidenced by the recurrence of tumors after single-agent 
chemotherapeutic interventions, strongly suggests that a multi-targeted approach may be more 
successful; however, combinations with traditional chemotherapeutic agents alone remains 
difficult due to the overt toxicity caused by those agents. Due to the lack of such toxicity with 
vaccine therapies, this is an attractive therapeutic option being investigated.  


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Recent phase 3 results of tumor cell vaccine, belagenpumatucel-L, showed that while the vaccine 
failed to improve OS across the entire study population, an additional subset analysis suggested 
that there was a survival benefit for belagenpumatucel-L treated patients who had recently 
completed front-line chemotherapy and in those who received front-line combination radiation 
chemotherapy.11,12 Additionally, TG4010 (a recombinant viral vector genetically modified to 
express MUC1 and interleukin-2 [IL-2]), added to first-line chemotherapy, resulted in an increase 
in OS in NSCLC patients.13 Furthermore, a better clinical outcome was observed in 
TG4010-treated patients with a normal percentage of triple positive activated lymphocytes 
(CD16 + CD56 + CD69+ [TrPAL]) when compared to patients with a high percentage of TrPAL.  
The vaccine combination approaches of the current trial are predicated on an assumption that 
significant localized immunosuppression exists within the tumor microenvironment, mediated 
mainly by regulatory T-cells (T-regs), predominately driven by checkpoint pathway dysregulation, 
intra-tumor hypoxia, and extracellular adenosine. The consequent down-regulation of the 
CD4 + CD8 + T-cell population results in a formidable degree of tumor immunodefense against 
tumor-directed vaccine strategies. A number of studies have consistently suggested elevated T-reg 
levels in NSCLC and a direct association with both an adverse prognostic outcome and response 
to therapy, findings of direct relevance to the currently proposed therapeutic strategy, predicated 
as it is on T-cell targeting.14,15 T-regs in NSCLC also appear to exhibit particularly high levels of 
PD-L1 and CTLA-4, supporting their pivotal role in the control of the neoplastic immune milieu 
and further implicating them as suitable targets for therapeutic immuno-intervention.15,16 
5.4. 
Description of Investigational Agent, HS-110 
HS-110 (viagenpumatucel-L) is an allogeneic, cell-based immunotherapy containing a broad range 
of NSCLC tumor antigens (up to 66 known cancer testis antigens) combined with a specific 
mechanism for the transport of these antigens to patient antigen-presenting cells that results in a 
specific CD8+ cytotoxic T-cell response.  
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, endogenous gp96 is restricted to the 
endoplasmic reticulum (ER) via expression of a KDEL (target peptide sequence) ER retention 
sequence on its C-terminus. Within the ER, gp96 is exposed 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.17 
Endogenous gp96 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 TLR-4 on the surface of antigen presenting 
cells, and engagement of TLR-2 and -4 provides an adjuvant signal. 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.18 


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Heat Biologics’ 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 HS-110, 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. Figure 1 illustrates that structure of HS-110. 
Figure 1: 
Structure of ImPACTTM Vaccine, HS-110 
 
Figure 1: Schematic diagram showing the structure of HS-110. This vaccine has a cellular backbone (AD100 cell line) 
which has been modified with a gp96-Ig expression plasmid. Tumor cell antigen-gp96-Ig complexes are secreted by 
the cell in order to deliver a pan-antigenic antitumor response 
5.5. 
Prior Human Experience with HS-110 
A first-in-human Phase 1 investigator-initiated, single-center, open-label study to examine the 
safety and immunogenicity of HS-110 was conducted in patients with stage IV or recurrent 
NSCLC who failed at least one line of standard chemotherapy. The primary objective of this study 
was to evaluate the safety of HS-110 vaccine in patients with advanced NSCLC, and secondary 
objectives were to study the immune response to vaccination, monitor clinical responses, and 
recommend a dose-schedule (DS) combination for further testing in an initial clinical trial of 
vaccine efficacy.  
A total of 36 patients were to be assigned to receive HS-110 administered as an intradermal 
injection following one of 3 DS regimens, designed to deliver equivalent numbers of cells for up 
to 18 weeks. Patients were treated with one of 3 dose-schedule (DS) combinations,    
• DS-1: > 4 × 107 cells every other week for 6 weeks with up to 3 courses and 
9 vaccinations. 
• DS-2: > 2 × 107 cells weekly for 6 weeks with up to 3 courses and 18 vaccinations. 
• DS-3: > 1 × 107 cells twice-weekly for 6 weeks with up to 3 courses and 36 
vaccinations. 
Nineteen (19) of the planned 36 patients enrolled in the study; 1 patient withdrew prior to receiving 
treatment and 18 received study treatment (n=11 patients in DS-1, n=4 patients in DS-2, and n=3 
patients in DS-3). The first 7 patients were enrolled in the DS-1 cohort, and those enrolled 
subsequent were assigned to each of the DS cohorts in a 1:1:1 ratio. This study was closed to 


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enrollment at the mid-way point following a strategic decision to focus on further development 
under a commercial Investigational New Drug (IND) application. Data from this study have been 
published.19 
Four patients died due to disease progression, and 4 patients reported a total of 6 serious adverse 
events (SAEs), none of which were considered by the Investigator to be treatment-related. Five 
SAEs were reported by 3 (16.7%) treated patients, which included rectal hemorrhage, dyspnea, 
chest pain, and lung infection (pneumonia), all of which were severe (Grade 3) in nature. One of 
these patients also reported a Grade 3 event of fatigue. The patient who did not receive treatment 
experienced a SAE of respiratory disorder, which resulted in study discontinuation.  
The majority of adverse events (AEs) were Grade 1 or Grade 2, the most frequent of which were 
induration (n=18, 100%), rash (n=16, 88.9%), pruritus and pain (n=5 each, 28%).  
Overall, a total of 14 patients died and the 4 surviving patients have 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 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, 2 (0.5%) patients who 
received weekly vaccines (DS-2) and 2 (66.7%) of those receiving vaccine 2 times per week (DS-
3) have survived longer than the median survival time of 7.1 months for the 11 patients who were 
vaccinated every other week (DS-1). 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. Although there were no objective responses by Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1, 7 of 15 evaluable patients exhibited stable disease (SD) after a single course 
of therapy; 3 of these patients had durable SD of greater than 3 years.  
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. Peripheral blood samples were collected 
from each patient prior to treatment and at 6-, 12-, and 18-week time points. Immune response was 
characterized by production of Interferon-gamma (IFNγ) by patient CD8 + T-cells and assayed by 
Enzyme-Linked ImmunoSpot (ELISPOT). Of the 15 evaluable patients, 11 (73.3%) 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 by ELISPOT, 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, 73.3%) was compared to that of the non-responders (4/15, 26.7%), it was observed that 
the immune responder OS was 16.5 months vs. 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. 


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6. 
STUDY RATIONALE 
6.1. 
Study Specific Rationale 
The combination of HS-110 and nivolumab is hypothesized to evoke a synergistic effect, based on 
the theory that checkpoint inhibitors work best in PD-L1 positive tumors in the presence of TIL. 
Studies in mice have shown that the combination of PD-1 blockade and gp96-Ig vaccination results 
in a potent increase in the number of CD8 + cytotoxic T-cells.20  Emerging data from the ongoing 
DURGA trial shows increased TIL after HS-110 vaccine. Thus, combining HS-110 with anti-PD-1 
agents may enhance the vaccine’s anti-tumor activity while prolonging or increasing the efficacy 
of the checkpoint inhibitor.  
HS-110 is distinct from other competitive vaccine approaches in clinical testing as it is an 
allogeneic, cell-based immunotherapy 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. It is, 
therefore, likely that HS-110 will represent a more effective antigenic stimulus than many other 
existing vaccine constructs.  
HS-110 is based on Heat Biologics’ ImPACT™ technology, a gp96-Ig fusion protein expression 
construct, which when expressed, leads to the secretion of gp96-bound cellular specific antigens. 
The backbone cell line for HS-110, AD100, was selected based on its antigenic profile which 
overlaps with the antigenic profiles in a large proportion of NSCLC patient tumor samples. 
Extracellular gp96 activates a CD8 + T-cell mediated immune response in 2 distinct manners: 1) 
by functioning as an adjuvant to activate dendritic cells (DC) via TLR-2 and TLR-4 and 2) by 
functioning as an antigen carrier for antigen cross presentation to CD8 + T-Cells via the endocytic 
scavenger receptor, CD91. These characteristics make gp96 unique because it can both activate 
and deliver chaperoned antigens by an antigen presenting cell (APC) to MHC I in order to elicit a 
CD8 + T-cell mediated immune response. A comparison of our ImPACT approach to other vaccine 
monotherapies is shown in Table 1 below.  
 
Table 1: 
Comparison of ImPACT to Other Immunotherapies 
Criteria 
ImPACT Therapy 
Other Allogeneic 
Autologous 
Cell-based 
Pan-antigen delivery 
✓ 
Some 
Some 
Targeted delivery of 
antigens to APC in 
vivo 
✓ 
 
Some 
Exclusive cytotoxic 
CD8 + T-cell response 
✓ 
 
Some 
Dual antigen 
carrier/adjuvant 
✓ 
 
 


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Criteria 
ImPACT Therapy 
Other Allogeneic 
Autologous 
Cell-based 
Rapid and efficient 
new product 
development 
✓ 
Some 
 
Low manufacturing 
cost of goods sold 
✓ 
Some 
 
 
Thus, the rationale for the evaluation of HS-110 in combination with multiple immune modulating 
strategies is as follows: 
• Recent and paradigm-changing clinical data support the feasibility of effective NSCLC 
immunotherapy when NSCLC cells become susceptible to attack by cytotoxic T 
lymphocytes (CTL). 
• Secreted gp96-Ig from HS-110 combines immune adjuvant activity with polyvalent 
peptide specificity, activating DC, NK cells, and CTLs, and resulting in death of tumor 
cells by NK cell-specific mechanisms and by MHC-restricted CD8 + CTL activity. The 
activation of DC and NK cells by HS-110 may also counteract the generation of 
immunosuppressive T-regs. 
• This master protocol design facilitates the testing of novel combinations of 
immunotherapies in a small number of patients in order to characterize the safety 
profile and immune response to advance promising new combination regimens into 
larger expansion cohorts. 
• The combination of HS-110 with anti-PD-1 checkpoint inhibitors may enhance the 
efficacy of the vaccine by accelerating the immune system response with PD-L1, which 
is expressed on the surface of many tumor cells. Likewise, given that patients require 
TIL to respond to checkpoint inhibitor therapy, the combination may enhance or 
prolong their activity by inducing TIL presence in patients who do not have TIL at 
baseline. Though the exact TIL threshold is uncertain, for patients with baseline TIL, 
HS-110 may drive further activation and clonal expansion of antigen-specific and 
activated CD8 + T-cells, leading to a higher quality immune response of TIL. 
6.2. 
Justification of HS-110 Dose Selection 
As indicated in the initial phase 1 investigator-sponsored trial (IST), the weekly (2 × 107 cells) and 
twice weekly (1 × 107 cells) dosing schedules were determined to produce the most desirable 
immune response (at least a doubling of CD8 + numbers from baseline). The weekly dosing 
regimen was selected for this trial as a starting point, as it represents the schedule with greatest 
patient acceptability for frequency of treatment visits. Further, the choice of the lower dose is 
prudent from a safety perspective as this trial is the first testing HS-110 in combination with 
multiple treatment regimens that incorporate additional immunomodulation. Furthermore, murine 
and simian data suggest that lower doses may produce sufficient immune response with possibly 
superior clinical effects.21 Specifically, the murine dose-ranging studies indicated that production 


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of approximately 400 ng gp96-Ig per million cells (15-20 micrograms [mcg] per kg on a weight 
basis) provided the optimal dose. Production of approximately 5-10 mcg gp96-Ig per million cells 
(1-2.5 mcg per kg on a weight basis) in a macaque dose-ranging study provided the optimal dose. 
Thus, there is not an expectation of a typical dose-escalation in larger mammals as is anticipated 
for most antibodies or small molecules where receptor saturation is predictive of efficacy. In the 
case of HS-110, no significant difference in immune response was detected between the 3 doses 
in the phase 1 IST and longer anecdotal survival was observed in 2 of 3 patients who received the 
10 million cells per dose, twice-weekly treatment schedule. Finally, improvements in the 
cell-freezing protocol have increased the viability of the frozen cells. Thus, we concluded that the 
10 million cells weekly dosing regimen was most appropriate for this phase 1b combination study. 
The selection of the multi-injection intradermal route of administration for HS-110 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. 
6.3. 
Rationale for Obtaining Archival Tissue and Performing Tumor 
Biopsies 
In order for an allogeneic cell-based vaccine to elicit to a clinical response, it must not only 
stimulate a tumor-antigen-specific immune response as detected by circulating lymphocytes in the 
peripheral blood, but those lymphocytes must also infiltrate the tumor microenvironment. A 
response to HS-110 is expected in patients whose tumors express antigens that overlap with the 
antigens contained within the AD100 cell backbone of HS-110. In addition, the response of 
patients with tumors that express numerous antigens shared with HS-110 is expected to surpass 
the response of those with tumors that only share 1 or 2 antigens with HS-110. Furthermore, 
clinical response to HS-110 may be predicted by the presence and extent of tumor infiltration by 
CD8 + T-cells. Thus, archival or fresh biopsy tissue will be obtained for pre-treatment tumor 
analysis, and a fresh biopsy sample should be collected for post-treatment analysis when feasible 
(unless written authorization from the Sponsor is obtained).  
6.4. 
Rationale for Inclusion of Squamous Cell Carcinoma Patients 
While the AD100 line selected for HS-110 was derived from adenocarcinoma, an example of 
evaluating upregulated gene expression between NSCLC adenocarcinoma and squamous cell 
carcinoma has been depicted below (Figure 2) showing overlap of 14 antigens between 
adenocarcinoma tumor bank data and HS-110, and an overlap of 10 antigens between squamous 
cell carcinoma tumor bank antigen expression and HS-110. Thus, multiple shared antigens 
between HS-110 and squamous cell carcinoma support the rationale for inclusion of squamous cell 
carcinoma patients in this clinical trial. 


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Figure 2: 
Number of Common Antigens between HS-110, Squamous and 
Adenocarcinoma in NSCLC 
 
Figure 2: HS-110 was derived from AD100 cell line from adenocarcinoma; HS-110 has 14 antigens in 
common with adenocarcinoma and HS-110. In addition, HS-110 has 10 antigens in common with 
squamous NSCLC. 
6.5. 
Rationale for Checkpoint Inhibitor Progressor Patients and First 
Line Maintenance Patients 
Currently, pembrolizumab is the only checkpoint inhibitor approved for first-line treatment in 
NSCLC in patients with ≥ 50% PD-L1 expression. It has shown an improvement in ORR, but there 
are still patients that have PD. This is an area of unmet need and response rates to additional 
checkpoint inhibitors in the second and third line, specifically monoclonal antibodies (mAbs) such 
as nivolumab, pembrolizumab, and atezolizumab are unknown.  
Combining HS-110 with anti-PD-1 agents may enhance the vaccine’s anti-tumor activity while 
prolonging or increasing the efficacy of the checkpoint inhibitor. The combination of HS-110 and 
nivolumab is hypothesized to evoke a synergistic effect, based on the theory that checkpoint 
inhibitors work best in PD-L1 positive tumors in the presence of TIL. Studies in mice have shown 
that the combination of PD-1 blockade and gp96-Ig vaccination results in a potent increase in the 
number of CD8 + cytotoxic T-cells.20  Emerging data from this ongoing DURGA trial shows 
increased TIL after HS-110 vaccine and increased tumor expression of PD-L1. Therefore, 


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combining this treatment for CPI progressor patients affords the opportunity to determine if HS-
110 can stimulate PD-L1 expression on the tumor, and improve efficacy of nivolumab. 
6.6. 
Rationale for First Line Maintenance Dosing 
Patients in first line maintenance phase run the risk of disease progression, some of which can be 
attributed to the continuous generation of exhausted and inadequate numbers of tumor specific 
effector T cells. The goal of adding HS-110 along with PD-1/L1 blockade in the maintenance 
phase is to ensure a higher probability that tumor growth will be controlled by the continuous 
generation of antigen specific CD8+ T cells, and rescue of this activated CD8+ T cells from 
exhaustion. Many patients fail to receive second-line therapy due to rapid progression of disease, 
decrease in their performance status, or increase cancer-related symptoms. By treating patients 
with HS-110 along with PD-1 blockade in the maintenance phase of first line therapy, the window 
of opportunity for immune driven treatment benefit may be augmented and extended. Exhausted 
tumor specific T cells maybe refractory or resistant to complete rescue by PD-1 blockade therapy 
alone and require additional activation and expansion of new tumor specific sets of CD8+ T cells. 
It can therefore be surmised that concomitant dosage of HS-110 along with checkpoint blockade 
in the first line maintenance phase until progression can ensure an ongoing and expanded adaptive 
immune response as opposed to CPI treatment alone. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a master protocol, intended to evaluate multiple immune modulation strategies in 
combination with HS-110; subsequent treatment arms will be added by amendment as supporting 
data for these combination therapies mature. Patients will be assigned to treatment arms based on 
the fit to eligibility criteria. 
As of Amendment 4, the Phase 1b portion of the trial (consisting of the first 15 patients to receive 
HS-110 in combination with nivolumab) is complete. Subsequent patients and cohorts will be 
considered Phase 2. Treatment Arm 1 (HS-110 plus oxygen, n=1 patient) has been discontinued. 
Patients in previously designated Arms 2, 3, and 4 all received HS-110 + nivolumab but had 
different TIL status.  Patients from these arms have now been reclassified as Arm 5, and further 
enrollment into this arm is ongoing.   
As of Amendment 5, the patient population under study will be expanded to include front line 
patients who have received immunotherapy (with or without chemotherapy), who have not 
progressed clinically or radiographically (per RECIST 1.1) at the most recent imaging assessment, 
and who will begin maintenance immunotherapy with SOC pembrolizumab ± pemetrexed. HS-
110 will be added to their immunotherapy maintenance regimen, and must be initiated on or before 
maintenance cycle 3 (after completion of platinum chemotherapy), or no later than week 19 (if 
receiving front line pembrolizumab monotherapy). 
Patients who meet all eligibility criteria will be enrolled to the below treatment arms and cohorts 
(n=120):  
Arm 5 HS-110 plus SOC nivolumab (n=100, to include 15 phase 1b patients and 85 phase 2 
patients).  
Arm 6 HS-110 plus SOC pembrolizumab ± pemetrexed (n=up to 20 phase 2 patients). 
Arm 5 patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL 
injections at a dose of 1 × 107 viable cells/0.5 mL for 18 weeks and nivolumab infusions 
administered every two weeks. After 18 weeks of treatment, patients will continue on monotherapy 
SOC nivolumab until confirmed disease progression or unacceptable toxicity, whichever occurs 
first. After completion of 18 weeks of combination therapy, patients may receive either nivolumab 
dosing schedule listed in the package insert (every 2 weeks or every 4 weeks) per Investigator 
discretion.  
Arm 5 patients will be scanned radiographically at Screening, Week 9, Week 18, and every 8 
weeks thereafter until confirmed disease progression. 
Arm 6 patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL 
injections at a dose of 1 × 107 viable cells/0.5 mL for 13 weeks in combination with SOC 
pembrolizumab ± pemetrexed every 3 weeks. Following the 13-week priming period, HS-110 
injections will be administered for boosting every 3 weeks in combination with SOC 
pembrolizumab or SOC pembrolizumab/pemetrexed until confirmed disease progression or 
unacceptable toxicity, whichever occurs first.  


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Arm 6 patients will be scanned radiographically at Screening and every 9 weeks thereafter until 
confirmed disease progression. 
For all study patients, the scan schedule will continue until confirmed disease progression (iCPD) 
as defined by iRECIST, after which they will be followed for OS. Using the principles of iRECIST, 
patients with unconfirmed disease progression (iUPD) should continue on study treatment until 
confirmed progression (iCPD) unless clinical progression necessitates otherwise. 
For all study patients, screening tumor samples (archival or fresh) and on-treatment biopsy tumor 
samples (when feasible to obtain) will be screened for expression of immune active cell subsets 
and molecules, expression of PD-L1 on tumor cells and evaluation for the presence of TILs. Pre- 
and post-treatment TIL and PD-L1 levels with be correlated with clinical outcomes. 
Peripheral blood samples will be taken to evaluate tumor mutation burden and immune cell subsets 
for correlation with clinical outcomes. 
Safety will be assessed by frequency of adverse events (AEs), evaluation of clinical laboratory 
parameters (hematology, liver function, electrolytes, troponin, and renal function), vital signs, 
electrocardiogram (ECG), and physical exams (PEs). 
Efficacy will be assessed by measures of OS, ORR, DOR, DCR, DRR and PFS by RECIST 1.1. 
The overall study design is summarized below in Figure 3. 
 
Figure 3: 
Study Design 
  
  
7.2. 
Study Treatments 
Each patient will be assigned a unique patient identification number at screening; this unique 
identifier will be recorded on all CRFs and ancillary documents specific to the patient. Prospective 
patients will be considered enrolled in the study on the date of their first dose of HS-110.   
Patients enrolled in Arm 5 will receive HS-110  administered concomitantly with nivolumab. HS-
110 0.5 mL will be administered intradermally as weekly injections for 18 weeks. Standard of care 
nivolumab will be given intravenously every 2 weeks until the HS-110 administration period is 


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complete, after which nivolumab may be administered either every 2 weeks or every 4 weeks (per 
Investigator’s discretion) in accordance with the current approved nivolumab Package Insert.  
Patients enrolled in Arm 6 will receive HS-110 plus SOC pembrolizumab ± pemetrexed. HS-110 
will be administered concomitantly with maintenance pembrolizumab +/- pemetrexed. HS-110 0.5 
mL will be administered intradermally as weekly injections for 13 weeks, followed by 0.5 mL 
intradermal injections every 3 weeks. Treatment with HS-110 and pembrolizumab +/- pemetrexed 
will continue until confirmed disease progression or unacceptable toxicity, whichever occurs first. 
Patients’ participation in this study may continue 2 years or longer. The duration of the nivolumab, 
pembrolizumab, and pembrolizumab/pemetrexed treatments are standard of care (SOC) and will 
continue along with radiology scans until confirmed disease progression or unacceptable toxicity. 
Following confirmed disease progression, patients will be followed by telephone or office visit for 
survival approximately every 3 months.  


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8. 
STUDY OBJECTIVES AND PURPOSE 
8.1. 
Primary Objectives 
Phase 1b: To characterize the safety and tolerability of HS-110 in combination with 
multiple immune modulating strategies in patients with NSCLC. 
Phase 2, Arm 5: To evaluate Objective Response Rate (ORR) by RECIST 1.1 in each 
cohort. 
Phase 2, Arm 6: To evaluate progression free survival (PFS) by RECIST 1.1 in each 
cohort. 
8.2. 
Secondary Objectives 
• To evaluate overall survival (OS), objective response rate (ORR), progression free 
survival (PFS), duration of response (DOR), durable response rate (DRR) and disease 
control rate (DCR) per RECIST 1.1. 
• Arm 5: To characterize the safety and tolerability of HS-110 in combination with 
nivolumab in patients with NSCLC.  
• Arm 6: To characterize the safety and tolerability of HS-110 in combination with 
pembrolizumab ± pemetrexed in patients with NSCLC. 
8.3. 
Exploratory Objectives 
• Efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyzed using the 
principals of iRECIST to produce iORR, iPFS, iDOR, iDCR, and iDRR. 
• To characterize the peripheral blood immunologic response (IR) via Enzyme-Linked 
ImmunoSpot (ELISPOT) analysis. 
• To determine total peripheral blood mononuclear cell (PBMC) counts, including 
leukocyte subsets that define NK and T cell subsets of activation, memory and 
exhaustion. 
• To evaluate archival and fresh biopsy tissue for presence of tumor-infiltrating 
lymphocytes (TILs), level of PD-L1 expression, correlation of pre- and post-treatment 
TIL and PD-L1 measurements on tumor cells with clinical outcomes, and expression 
of immune active cells and molecules.  
• To examine tumor mutation burden and other exploratory analysis of peripheral blood 
and tumor tissue to determine immune changes and response to treatment. 


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9. 
SELECTION AND WITHDRAWAL OF PATIENTS 
The study population will consist of two distinct patient types. Arm 5 will include metastatic 
NSCLC patients that have failed first line therapy and are undergoing second line therapy or 
greater. The patients can have adenocarcinoma or squamous cell NSCLC and be checkpoint 
inhibitor (CPI) naïve or CPI progressor. Arm 6 will include metastatic NSCLC patients who have 
received immunotherapy (with or without chemotherapy) in the front line, who have not 
progressed clinically or radiographically (per RECIST 1.1) at the most recent imaging assessment, 
and who will begin initiation of maintenance immunotherapy with standard of care (SOC) 
pembrolizumab ± pemetrexed. [Note: HS-110 dosing to be initiated at/before the start of the 3rd 
maintenance treatment cycle, or within 19 weeks of front-line pembrolizumab monotherapy.] 
The sections below list all of the inclusion and exclusion criteria patients must meet to proceed 
with enrollment, and they must voluntarily provide written consent to participate in the study. 
9.1. 
Subject Inclusion Criteria 
 Patients must meet all of the following inclusion criteria to be enrolled into the study: 
1. Age ≥18 years. 
2. Histologically or cytologically confirmed diagnosis of non-small cell lung adenocarcinoma 
or squamous cell carcinoma. Patients with mixed histology other than adeno-squamous are 
not eligible. 
3. At least one site of measurable disease by CT scan or MRI as defined by RECIST 1.1. 
[Note: criteria not applicable to Arm 6 patients who have achieved 100% reduction in 
Target Lesions.] 
4. Arm 5: Received at least one prior line of therapy, but no more than three prior lines of 
therapy, for incurable (i.e. unresectable) or metastatic NSCLC, including cytotoxic 
chemotherapy, molecularly-targeted agents, or immunotherapy. One prior line of FDA-
approved checkpoint inhibitor (CPI) therapy is permitted, however a treatment period with 
CPI of at least 4 months is required. 
OR 
Arm 6: Received front line immunotherapy (with or without chemotherapy) for incurable 
or metastatic NSCLC and did not progress clinically or radiographically per RECIST 1.1 
at the most recent imaging assessment, and will begin maintenance immunotherapy with 
SOC pembrolizumab ± pemetrexed. [Note: HS-110 dosing to be initiated at/before the start 
of the 3rd maintenance treatment cycle, or within 19 weeks of front-line pembrolizumab 
monotherapy.] 
5. Life expectancy of at least 18 weeks. 
6. Arm 5: Documented disease progression at study entry. 
OR 


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Arm 6: Documented Stable Disease, Partial Response, Complete Response (SD/PR/CR) 
per RECIST 1.1 after a minimum of 9 to 12 weeks of front line immunotherapy (with or 
without chemotherapy). 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
8. Central Nervous System (CNS) metastases may be permitted after discussion with the 
Medical Monitor and must meet the following conditions: 
a. Patient must be treated and radiographically and neurologically stable. Stable CNS 
metastases are defined by the return of neurological symptoms to baseline, use of no 
more than 10 mg of prednisone or equivalent per day, and no evidence of new or active 
brain lesions in the repeated scan prior to study entry. 
b. Brain lesions must have been previously irradiated, including whole brain radiation 
therapy or radiosurgery.  
c. All radiation treatment (except for localized stereotactic palliative therapy) must be 
completed at least 4 weeks prior to enrollment.  
9. Lab parameters: 
• Albumin ≥ 2.5 g/dL. 
• Total Bilirubin < 3.0 × upper limit of normal (ULN) unless patient has Gilbert’s 
syndrome. 
• Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × 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. 
10. Willing and able to comply with the protocol and sign informed consent, including office 
visits for weekly HS-110 injections for 18 weeks (Arm 5) or weekly HS-110 injections for 
13 weeks followed by every 3 week boosting injections until disease progression (Arm 6). 
11. 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. 
12. Willing to provide either archival or fresh biopsy sample at Screening, and fresh tumor 
biopsy at Week 10 when feasible. Archival tissue used at Screening must be representative 
of the patient’s current disease state unless written authorization from the Sponsor is 
obtained. Fresh biopsy at Week 10 may be waived with written authorization from the 
Sponsor. 


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13. Arm 5: Suitable for treatment with nivolumab per the current approved package insert. 
OR 
Arm 6: Suitable for front line maintenance treatment with pembrolizumab ± pemetrexed 
per the current approved package inserts. 
9.2. 
Subject Exclusion Criteria 
Patients that meet any of the following exclusion criteria are not eligible to be enrolled into the 
study: 
1. Arm 5: Received systemic anticancer therapy within 21 days prior to first dose of study 
drug. 
2. Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections 
or concurrent illness, unrelated to the tumor, requiring active therapy. Testing is not 
required in the absence of history. 
3. Any condition requiring concurrent systemic immunosuppressive therapy. 
4. Known immunodeficiency disorders, either primary or acquired. 
5. Known leptomeningeal disease. 
6. Active malignancies within 12 months, with the exception of those with a negligible risk 
of metastasis or death, and treated with expected curative outcome. 
7. Pregnant or breastfeeding. 
8. Prior participation in a clinical study of HS-110. 
9. Active, known, or suspected autoimmune disease. 
10. Received a live vaccine within 30 days prior to first dose of study drug. 
11. Significant cardiovascular disease: 
a. Baseline Left Ventricular Ejection Fraction (LVEF) below lower limit of normal range 
per institutional standard by ECHO or MUGA within 30 days prior to first dose of 
study drug. 
b. History of myocardial infarction within 1 year of enrollment. 
c. History of heart failure within 2 years of enrollment, or at any time if due to auto-
immune causes or prior immunotherapy treatment, unless pre-approved by the medical 
monitor. 
d. A clinically significant ECG abnormality, including PR interval of >260 ms, any 
evidence of heart block, or a baseline prolonged QTc interval (e.g., a repeated 
demonstration of a QTc interval >480 ms) within 30 days prior to first dose of study 
drug. 
12. Refractory to prior immunotherapy (clinical or radiographic progression after 12 weeks or 
less of immunotherapy). 


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9.3. 
Patient Completion and Withdrawal 
 
Patient Completion 
Patients in Arm 5 will receive a combination of weekly injections of HS-110 and nivolumab 
infusions every two weeks for 18 weeks. After 18 weeks of treatment, patients will continue on 
monotherapy SOC nivolumab until disease progression or unacceptable toxicity, whichever occurs 
first. After 18 weeks of combination therapy, SOC nivolumab may be administered according to 
either dosing schedule in the nivolumab package insert (every 2 weeks or every 4 weeks) per 
Investigator discretion. Arm 5 patients will be scanned radiographically at Screening, Week 9, 
Week 18, and every 8 weeks thereafter until confirmed disease progression. 
Patients in Arm 6 will receive weekly injections of HS-110 for 13 weeks in combination with SOC 
pembrolizumab ± pemetrexed infusions administered every 3 weeks. Following the 13-week 
priming treatment period, HS-110 injections will be administered for boosting every 3 weeks in 
combination with SOC pembrolizumab ± pemetrexed until confirmed disease progression or 
unacceptable toxicity, whichever occurs first. Arm 6 patients will be scanned radiographically at 
Screening and every 9 weeks thereafter until confirmed disease progression.  
After confirmed disease progression, patients will be followed for collection of subsequent anti-
cancer therapies and survival status every 3 months. This may be done via telephone or office visit.  
 
Discontinuation from Study Treatments 
Every effort must be made by study personnel to keep patients on study treatment(s); however, a 
patient will be discontinued prior to completion of HS-110 treatment for any of the following 
reasons: 
• Grade 4 AE(s) considered by the Investigator to be related to study treatment (or Grade 
3 AE(s) at the Investigator’s discretion) assessed as related to treatment, except for 
“expected” AEs with nivolumab or pembrolizumab or pembrolizumab/pemetrexed 
treatment, as per the package inserts. 
• Pregnancy. 
• Termination of the study by the Sponsor. 
• Intercurrent illness that prevents further administration of treatment. 
• Patient withdrawal of consent. 
Patients may also be discontinued prior to completion of the study treatment for any of the 
following reasons: 
• Progressive disease, according to iRECIST 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.  
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 specifically withdrawn.  


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Amendment 6, 24 May 2019 
 
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A reason for discontinuation must be documented in the case report form (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, unless it is unlikely to improve 
because of underlying disease. 
 
Patient Withdrawal from Study 
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 for scheduling a follow-up visit. 
In accordance with the International Conference on Harmonisation (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 study treatment, as 
described above or for safety, behavioral, or administrative reasons.  
If the patient does not have enough data to be considered evaluable (received at least 6 doses of 
HS-110 and had a pre-treatment tumor assessment and at least one post-treatment tumor 
assessment) an additional patient may be enrolled into the study. 


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CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
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10. 
STUDY PROCEDURES 
This study will be conducted in compliance with the protocol, GCP, and applicable regulatory 
requirements. A current, signed and dated informed consent form (ICF) that has been approved by 
an IRB/IEC must be obtained from the potential patient before he/she can participate in any 
study-specific procedures, including study-specific screening procedures.  
A patient will be considered enrolled on the date of the first dose of HS-110. 
For Arm 5 patients, the study will generally be conducted in 4 periods, as follows: Screening, On 
Study (receiving HS-110 treatment), Post-HS-110 Follow-up (no longer receiving HS-110 
treatment, but not yet progressed), and Survival Follow-up (after confirmed disease progression).  
For Arm 6 patients, the study will generally be conducted in 3 periods, as follows: Screening, On 
Study (priming and boosting until progression), and Survival Follow-up (after confirmed disease 
progression). 
10.1. 
Screening Procedures and Baseline (Day -28 to Day -1) 
The following procedures and assessments must be conducted within approximately 4 weeks (Day 
-28 to Day -1) prior to the first dose of study medication.  
For each potential patient, the following procedures and assessments will be performed by 
qualified study staff.   
These procedures and assessments may occur on the same day as dosing, as long as the collection 
of biopsy tissue and blood samples occurs PRIOR to dosing with any study drug and recorded 
appropriately to verify. Qualified study personnel should obtain the following: 
• A current IRB/IEC-approved ICF must be signed and dated before any study-related 
procedures are performed.   
• Complete medical history including prior treatments and surgeries, prior medications, 
and pre-existing clinical signs and symptoms 
• Patient demographics (age, sex, race and ethnicity) 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) (Appendix 1) 
• Full physical examination (PE) including height and weight, and an evaluation of all 
body systems (Section 13.1) 
• Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• Draw blood for hematology, serum chemistry, and troponin I or T (Section 13.2) 
• Blood draw for baseline immunological response (Section 14.2) 
• Serum or urine pregnancy test for female patients of childbearing potential (Section 
13.2) 
• Tumor assessment, including CT scan or MRI, to document target and non-target 
lesions by RECIST 1.1 and iRECIST. (Section 14.1.1) 


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• Mandatory archival or fresh tissue collection. Note that sample must be obtained via 
incisional, excisional or core needle biopsy. A fine needle aspiration is not acceptable 
for archival or fresh biopsy. Additional tissue collection and preparation procedures are 
provided in a separate Biopsy Manual. 
• Electrocardiogram (ECG) 
• Echocardiogram (ECHO) or Multiple-Gated Acquisition (MUGA) Scan with left 
ventricular ejection fraction (LVEF) (Section 13.4) 
• Verify eligibility criteria via inclusion and exclusion criteria per Section 9.1 and 
Section 9.2. 
 
Baseline Assessments (Day -7 to Day 1) 
The following procedures will be performed after all the previous screening procedures have been 
completed and prior to dosing.   
• Reassessment of ECOG PS (Appendix 1) 
• Record pre-existing symptoms as medical history and prior medications. 
• Hematology and serum chemistry only if the Screening Visit was performed more than 
2 weeks prior to the first dose (Section 13.2) 
• Serum or urine pregnancy testing for females of child-bearing potential only if the 
Screening Visit was performed more than 2 weeks prior to the first dose (Section 13.2) 
• Re-Verify eligibility criteria via inclusion and exclusion criteria per Section 9.1 and 
Section 9.2 
10.2. 
Arm 5: On Study Treatment Procedures  
Study-related procedures and assessments performed during treatment on study are detailed as 
follows and in the Schedule of Activities (SOA; Table 2). This period of the study is generally 
considered to be the combination treatment period from Day 1 through Week 18, but could be 
shorter in duration if HS-110 is prematurely discontinued.  
 
Week 1 Assessments (Day 1) 
The following procedures will be performed after all the previous Screening and Baseline 
procedures have been completed: 
• Update of prior medications and pre-existing symptoms as medical history 
• Reconfirm eligibility prior to dosing 
• Blood draw for tumor mutation burden (TMB) obtained prior to dosing (Section 14.6). 
Note that Cohort B patients enrolled prior to Amendment 5 that did not have a week 1 
TMB sample collected should have a one-time TMB lab drawn at the next feasible visit 
(i.e. Week 4, 10, 16 or post-HS110/survival follow-up). 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 


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• Administration of HS-110 
• Monitor patients on site for potential acute reactions for 30 minutes after HS-110 
administration (first dosing only) 
• Administration of SOC nivolumab per package insert 
• Record any AEs experienced by patient 
• Record concomitant medications 
 
Week 2 Assessments  
The following procedures will be performed at Week 2 (Day 8 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• Vital signs, with abbreviated PE (Section 13.1) targeted to signs and symptoms  
• Administration of HS-110 
• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 3 Assessments 
The following procedures will be performed at Week 3 (Day 15 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• ECG conducted prior to dosing 
• Vital signs, with abbreviated PE targeted to signs and symptoms 
• Administration of HS-110 
• Administration of SOC nivolumab, per package insert 
• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 4 Assessments 
The following procedures will be performed at Week 4 (Day 22 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• Vital signs, with abbreviated PE targeted to signs and symptoms   
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Administration of HS-110  
• Record AEs experienced by the patient 
• Record concomitant medications 


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Amendment 6, 24 May 2019 
 
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Week 5, 6, 8, and 11 Assessments 
The following procedures will be performed at Week 5 (Day 29 ± 3), Week 6 (Day 36 ± 3), Week 8 
(Day 50 ± 3), and Week 11 (Day 71 ± 3).  
• Vital signs, with abbreviated PE targeted to signs and symptoms (Weeks 5 and 11 only)  
• Administration of HS-110 
• Administration of SOC nivolumab (Weeks 5 and 11 only), per package insert 
• Record AEs experienced by the patient 
• Record concomitant medications 
 
Week 7 and 13 Assessments 
The following procedures will be performed at Week 7 (Day 43 ± 3), and Week 13 (Day 85 ± 3): 
• Vital signs, with abbreviated PE targeted to signs and symptoms (Week 7 only). 
• Blood draw for IR prior to dosing (Section 14.2) 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Administration of HS-110 
• Administration of SOC nivolumab, per package insert 
• Record AEs experienced by the patient 
• Record concomitant medications 
 
Week 9 and 18 Assessments 
The following procedures will be performed at Weeks 9 (Day 57 + 3) and Week 18 (Day 120 ± 3): 
• Tumor assessment by CT scan or MRI and evaluation of tumor response using RECIST 
1.1 and iRECIST (Section 14.1.1) 
•  Administration of HS-110 
• Administration of SOC nivolumab (only on Week 9), per package insert 
• Record AEs experienced by the patient 
• Record concomitant medications 
 
Week 10 and 16 Assessments 
The following procedures will be performed at Week 10 (Day 64 ± 3) and Week 16 (Day 106 ± 3): 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Tumor biopsy (Week 10 only) to be obtained when feasible unless written authorization 
from the Sponsor is obtained. Note that sample must be obtained via incisional, 
excisional or core needle biopsy. A fine needle aspiration is not acceptable. Additional 
tissue collection and preparation procedures are provided in a separate Biopsy Manual. 


Heat Biologics, Inc. 
 
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Protocol HS110-102 
 
CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
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• Administration of HS-110 
• Record AEs experienced by the patient 
• Record concomitant medications 
 
Week 12, 14, 15, and 17 Assessments 
The following procedures will be performed at Week 12 (Day 78 ± 3), Week 14 (Day 92 ± 3), Week 
15 (Day 99 ± 3), and Week 17 (Day 113 ± 3).  
• Vital signs, with abbreviated PE targeted to signs and symptoms (Week 15 only) 
• Administration of HS-110 
• Administration of SOC nivolumab, per package insert (Weeks 15 and 17 only) 
• Record AEs experienced by the patient 
• Record concomitant medications 
10.3. 
Arm 5: End of Treatment (EOT) Visit  
The following procedures should be completed approximately 3 to 4 weeks following last dose of 
HS-110, including patients who discontinue dosing prematurely. If patient completes all 18 weeks 
of HS-110 treatment, the EOT Visit should occur at Week 21 or 22. 
• Full PE (including height and weight) 
• Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• Blood draw for IR (Section 14.2) 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Record AEs experienced by the patient 
• Record concomitant medications 
10.4. 
Arm 5: Follow-up Procedures  
 
Post-HS-110 Follow Up (After HS-110 treatment until disease progression) 
The off-treatment follow-up period for Arm 5 is defined as the time when patients have 
discontinued or completed HS-110 treatment and are receiving SOC treatment with nivolumab 
monotherapy, which is administered per Investigator discretion according to the package insert 
dosing regimens of either every 2 weeks or every 4 weeks. During this time, radiological 
assessments will continue every 8 weeks until confirmation of iCPD by iRECIST. Any AEs 
deemed related to study drug will also be recorded.  
 
Survival Follow-Up (Progressive Disease until Death) 
The survival follow-up period refers to the time between the confirmation of PD and patient death. 
Patients will be followed for OS. Survival status and subsequent anti-cancer therapy will be 


Heat Biologics, Inc. 
 
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Protocol HS110-102 
 
CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
Page 48 of 95 
 
 
collected approximately every 3 months in a clinic visit or by telephone if the patient is no longer 
attending clinic visits at the investigative site. 
10.5. 
Arm 6: On Study Treatment Procedures  
 
Week 1 Assessments (Day 1) 
The following procedures will be performed after all the previous Screening and Baseline 
procedures have been completed, with HS-110 dosing beginning no later than the start of the 3rd 
maintenance treatment cycle, or more than 19 weeks from the start of front-line treatment for 
patients receiving pembrolizumab monotherapy: 
• Update of prior medications and pre-existing symptoms as medical history 
• Reconfirm eligibility prior to dosing 
• Blood draw for tumor mutation burden obtained prior to dosing (Section 14.6) 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• Administration of HS-110 
• Monitor patients on site for potential acute reactions for 30 minutes after HS-110 
administration (first dose only) 
• Administration of SOC pembrolizumab ± pemetrexed per package inserts  
• Record any AEs experienced by patient. 
• Record concomitant medications. 
 
Week 2 Assessments 
The following procedures will be performed at Week 2 (Day 8 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• Vital signs, with abbreviated PE (Section 13.1) targeted to signs and symptoms  
• Administration of HS-110 
• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 3 Assessments 
The following procedures will be performed at Week 3 (Day 15 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• ECG conducted prior to dosing 
• Vital signs, with abbreviated PE targeted to signs and symptoms 
• Administration of HS-110 


Heat Biologics, Inc. 
 
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CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
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• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 4 Assessments 
The following procedures will be performed at Week 4 (Day 22 ± 3): 
• Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Vital signs, with abbreviated PE targeted to signs and symptoms 
• Administration of HS-110 
• Administration of SOC pembrolizumab ± pemetrexed per package inserts  
• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 5, 6, 8, 9, 11 and 12 Assessments 
The following procedures will be performed at Week 5 (Day 29 ±3),Week 6 (Day 36 ± 3), Week 
8 (Day 50 ± 3), Week 9 (Day 57 ± 3), Week 11 (Day 71 ±3) and at Week 12 (Day 78 ± 3): 
• Administration of HS-110 
• Record AEs experienced by patient 
• Record concomitant medications 
• Week 9 only: Tumor assessment by CT scan or MRI and evaluation of tumor response 
using RECIST 1.1 and iRECIST (Section 14.1.1) 
 
Week 7 and 13 Assessments 
The following procedures will be performed at Week 7 (Day 43 ± 3) and Week 13 (Day 85 ± 3): 
• Blood draw for immunological response obtained prior to dosing (Section 14.2) 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Vital signs, with abbreviated PE targeted to signs and symptoms (Week 7 only) 
• Administration of HS-110 
• Administration of SOC pembrolizumab ± pemetrexed per package insert  
• Record AEs experienced by patient 
• Record concomitant medications 
 
Week 10 Assessments 
The following procedures will be performed at Week 10 (Day 64 ± 3): 


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Protocol HS110-102 
 
CONFIDENTIAL 
 
 
Amendment 6, 24 May 2019 
 
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• Vital signs, with abbreviated PE targeted to signs and symptoms 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Administration of HS-110 
• Administration of SOC pembrolizumab ± pemetrexed per package insert  
• Record AEs experienced by patient 
• Record concomitant medications 
• Tumor biopsy collected when feasible unless written authorization from the Sponsor 
is obtained. Note that sample must be obtained via incisional, excisional or core 
needle biopsy. A fine needle aspiration is not acceptable. Additional tissue collection 
and preparation procedures are provided in a separate Biopsy Manual. 
 
Boosting Visits and Assessments (Week 14 to EOT) 
Following the 13-week priming period, HS-110 injections will be administered for boosting every 
3 weeks (± 3 days) in combination with SOC pembrolizumab ± pemetrexed until confirmed disease 
progression. During this time, radiological assessments will continue every 9 weeks until 
confirmation of iCPD per iRECIST. Concomitant medications and AE/SAEs will also be recorded. 
10.6. 
Arm 6: End of Treatment  
The following procedures should be completed approximately 3 to 4 weeks following last dose of 
HS-110, including patients who discontinue dosing prematurely.  
• Full PE (including height and weight) 
• Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• Blood draw for IR (Section 14.2) 
• Blood draw for hematology and serum chemistry (Section 13.2) 
• Record AEs experienced by the patient 
• Record concomitant medications 
10.7. 
Arm 6: Survival Follow-Up (Progressive Disease until Death) 
The survival follow-up period refers to the time between the confirmation of PD and patient death. 
Patients will be followed for OS. Survival status and subsequent anti-cancer therapy will be 
collected approximately every 3 months in a clinic visit or by telephone if the patient is no longer 
attending clinic visits at the investigative site. 
10.8. 
Schedule of Activities (SOA) 
Table 2 outlines the clinical assessments and treatments by week for Arm 5 receiving HS-110 in 
combination with nivolumab and Table 3 outlines the clinical assessments and treatments by week 
for Arm 6 receiving HS-110 in combination with pembrolizumab ± pemetrexed. 


Heat Biologics, Inc. 
 
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CONFIDENTIAL 
Amendment 6, 24 May 2019 
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Table 2: 
Schedule of Activities (Arm 5: HS-110+ Nivolumab) 
                                                 
1 EOT should be completed approximately 3 to 4 weeks following last dose of HS-110, including for patients who discontinue dosing prematurely. 
2 Baseline procedures may be combined with Week 1 visit, as long as they are performed prior to dosing. 
3 Full physical exam will be performed at Screening and EOT and includes obtaining the patient’s height and weight, and an assessment of the following body systems: HEENT, Pulmonary, 
Cardiovascular, Musculoskeletal, Abdominal/Gastrointestinal, Lymphatic, Neurological, Dermatologic, and Genito-urinary systems.  Abbreviated physical exams will be conducted at Weeks 2, 3, 4, 
5, 7, 11, and 15 and are limited to vital signs and symptoms unless otherwise clinically indicated. 
4 Blood draw for hematology requires 5 mL and serum chemistry requires 5 mL; hematology assessments include white blood cell (WBC) with differential, platelet count, hemoglobin, red blood cell 
(RBC) count and absolute neutrophils; 
chemistry includes
 
serum
 assessment of sodium, calcium, total protein, albumin, creatinine, blood urea nitrogen (BUN), total bilirubin, alkaline phosphatase, 
AST, ALT, potassium, chloride, sodium bicarbonate, lactate dehydrogenase, and glucose. 
5 Repeat assessment at Baseline only if Screening Visit was performed > 2 weeks prior to dosing. 
6 Blood draw for Troponin I or T requires 5 mL (performed at Screening and Weeks 1 through 4). 
7 Urine or serum pregnancy test. Blood draw for serum pregnancy test for women of childbearing potential requires 1 mL (performed at Screening and Baseline prior to dosing). 
8 Blood draw for TMB requires 20 ml of blood at Week 1 prior to dosing. 
9 Cohort B Patients who enrolled prior to Amendment 5 and did not have a week 1 TMB sample drawn should have this sample collected at the next feasible visit.. 
10 Blood draw for IR requires 50 mL of blood (performed at Screening and at Weeks 7, 13 and EOT). 
11 Tissue biopsy sample collection may be archival or fresh at screening, and fresh tissue collected at Week 10 when feasible. 
 
Activity 
Screening 
Week 
EOT1 
Post-HS-
110 FU 
Survival 
FU 
D-28 to D-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
 
 
Study Day 
 
Baseline2 
D-7 to D1 
8   
±2 
15  
±3 
22   
±3 
29  
±3 
36  
±3 
43  
±3 
50 
±3 
57 
±3 
64 
±3 
71 
±3 
78 
±3 
85 
±3 
92 
±3 
99 
±3 
106 
±3 
113 
±3 
120 
±3 
+21 to 
28 
Q8 weeks Q3 months 
Informed 
Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE with vitals 
X3 
 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X3 
 
 
Hematology4 and 
serum chemistry4 
X 
X5 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Troponin I or T6 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test7  
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Mutation 
Burden Lab8 
 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic 
Response Lab10 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Tissue Sample 
Collection11 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
Amendment 6, 24 May 2019 
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12 Tumor assessment will be evaluated by RECIST 1.1 and iRECIST 
13 Only subsequent anti-cancer therapy will be recorded 
14 30 minute observation after first dose only 
15 Nivolumab will be administered every 2 weeks while receiving HS-110 treatment 
16 Nivolumab dosing schedule during Post-HS-110 Follow Up determined per Investigator discretion 
17 AEs/SAEs to be recorded up to 4 weeks after the last administration of HS-110, and followed until resolution (unless not resolvable due to underlying disease) 
18 Only AEs deemed related to study drug will be recorded  
 
Activity 
Screening 
Week 
EOT1 
Post-HS-
110 FU 
Survival 
FU 
 
D-28 to D-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
 
 
Study Day 
 
Baseline2 
D-7 to D1 
8   
±2 
15 
±3 
22   
±3 
29 
±3 
36 
±3 
43 
±3 
50 
±3 
57 
±3 
64 
±3 
71 
±3 
78 
±3 
85 
±3 
92 
±3 
99 
±3 
106 
±3 
113 
±3 
120 
±3 
+21 to 
28 
Q8 weeks Q3 months 
Tumor 
Assessment by 
CT or MRI12 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Q8 weeks 
from wk 18 
 
ECG 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA 
with LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
X13 
HS-110 
Administration  
 
 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
SOC Nivolumab 
administration15 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Q2 or Q4 
weeks16 
 
Record 
AEs/SAEs17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Table 3: 
Schedule of Activities (Arm 6: HS-110 + Pembrolizumab +/- Pemetrexed) 
                                                 
19 EOT should be completed approximately 3 to 4 weeks following last dose of HS-110, including premature/early termination of HS-110 treatment. 
20 Baseline procedures may be combined with Week 1 visit, as long as they are performed prior to dosing. 
21 Full physical exam will be performed at Screening and EOT and includes obtaining the patient’s height and weight, and an assessment of the following body systems: HEENT, Pulmonary, 
Cardiovascular, Musculoskeletal, Abdominal/Gastrointestinal, Lymphatic, Neurological, Dermatologic, and Genito-urinary systems.  Abbreviated physical exams will be conducted at Weeks 2, 3, 4, , 
7, and 10 are limited to vital signs and symptoms unless otherwise clinically indicated. 
22 Blood draw for hematology requires 5 mL and serum chemistry requires 5 mL; hematology assessments include white blood cell (WBC) with differential, platelet count, hemoglobin, red blood cell 
(RBC) count and absolute neutrophils; 
chemistry includes
 
serum
 assessment of sodium, calcium, total protein, albumin, creatinine, blood urea nitrogen (BUN), total bilirubin, alkaline phosphatase, 
AST, ALT, potassium, chloride, sodium bicarbonate, lactate dehydrogenase, and glucose.  
23 Repeat assessment at Baseline only if Screening Visit was performed > 2 weeks prior to dosing. 
24 Blood draw for Troponin I or T requires 5 mL (performed at Screening and Weeks 1 through 4). 
25 Blood draw for serum pregnancy test for women of childbearing potential requires 1 mL (performed at Screening and Baseline prior to dosing). 
26 Blood draw for TMB requires 20 ml of blood at Week 1 prior to dosing. 
27 Blood draw for IR requires 50 mL of blood (performed at Screening and at Weeks 7, 13 and EOT). 
28 Tissue biopsy sample collection may be archival or fresh at screening, and fresh tissue collected at Week 10 when feasible. 
 
Activity 
Screening 
Week 
Boosting EOT19 
Survival 
FU 
D-28 to D-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
 
Study Day 
 
Baseline20 
D-7 to D1 
8 ±2 
15 ±3 22 ±3 29 ±3 36 ±3 43 ±3 50 ±3 57 ±3 64 ±3 71 ±3 78 ±3 85 ±3 Q3 weeks 
±3 
+21 to 
28 
Q3 
months 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE with vital signs 
X21 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X19 
 
Hematology22 and 
serum chemistry22 
X 
X23 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Troponin I or T24 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test25 
(serum or urine) 
X 
X23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Mutation 
Burden Lab26 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunologic 
Response Lab27 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Tissue Collection28 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 


Heat Biologics, Inc. 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 54 of 95 
 
 
                                                 
29 EOT should be completed approximately 3 to 4 weeks following last dose of HS-110, including premature/early termination of HS-110 treatment. 
30 Tumor assessment will be evaluated by RECIST 1.1 and iRECIST.  Qualifying imaging assessment for Arm 6 may be completed up to 6 weeks prior to first HS-110 administration. 
31 Only subsequent anti-cancer therapy will be recorded. 
32 30 minute observation after first dose only. 
33 Pembrolizumab +/- pemetrexed will be administered every 3 weeks per package insert.  
34 AEs/SAEs to be recorded up to 4 weeks after the last administration of HS-110, and followed until resolution (unless not resolvable due to underlying disease). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activity 
Screening 
Week 
Boosting EOT29 
Survival 
FU 
Day -28 to D-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
 
Study Day 
 
Baseline D-7 to 
D1 
8 ±2 
15 ±3 22 ±3 29 ±3 36 ±3 43 ±3 50 ±3 57 ±3 64 ±3 71 ±3 78 ±3 85 ±3 Q3 weeks 
±3 
+21 to 
28 
Q3 
months 
Tumor Assessment 
by CT or MRI30 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Q9 weeks 
from 
week 9 
 
 
ECG 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA 
with LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X31 
HS-110 vaccination  
 
 
X32 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SOC 
Pembrolizumab +/- 
pemetrexed 
administration33 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Record AEs/SAEs34 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 55 of 95 
11. 
TREATMENT OF PATIENTS 
11.1. 
Description of Study Drug 
Table 4: 
Investigational Product 
PARAMETER 
PRODUCT INFORMATION 
INN/USAN name 
Viagenpumatucel-L 
Code Name 
HS-110 
Dosage Form 
Suspension for Injection (ready-to-use or concentrated) 
Strength / Dose 
1 × 107 viable cells/ 0.5 mL 
Route of Administration 
Intradermal 
Dosing Regimen 
Arm 5: Weekly, 5 intradermal 0.1 mL injections for 18 weeks 
Arm 6: Weekly, 5 intradermal 0.1 mL injections for 13 weeks 
followed by 5 intradermal 0.1mL injections every 3 weeks 
until disease progression or unacceptable toxicity (whichever 
occurs first) 
How Supplied 
Ready-to-use single-dose vial: 0.6 mL (includes 0.5 mL dose 
plus 0.1 mL overage) 
Storage Conditions 
≤ - 120⁰C  
Stored in liquid nitrogen vapor phase 
11.2. 
Prior and Concomitant Medications 
All prior and 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. Subsequent anti-cancer therapy will 
also be collected during off-treatment follow up and survival follow up. 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.  
11.3. 
Permitted Medications 
Local and/or systemic injection reactions may be treated with antihistamines, antipyretics, and/or 
analgesics in accordance with standard local practice and Investigator’s clinical judgment. 
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 AE. 
 
Prohibited Medications 
In principle, steroid therapy is not permitted, but use of steroids for TEAEs may be considered 
after consultation with the Medical Monitor. Patients receiving replacement doses of 
corticosteroids for adrenal insufficiency should not have their replacement dose withheld. Arm 6 
patients receiving SOC pemetrexed may receive steroids as recommended per Package Insert. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 56 of 95 
Topical and inhaled steroids will be permitted. Other than protocol-defined agents, no concomitant 
chemotherapy, immunotherapy, immunosuppressive or other anticancer therapy will be permitted 
while receiving study treatments. 
Administration of other concomitant investigational agents, for any indication, is not permitted 
while on this study. 
During survival follow-up there are no prohibited medications, and patients may enroll in any 
investigational study for which they are eligible. 
 
Supportive Care 
Patients should receive full supportive care during the study, including transfusions of blood and 
blood products; treatment with antibiotics, antiemetics, antidiarrheals, and analgesics; and other 
care as deemed appropriate and in accordance with their institutional guidelines. 
11.4. 
Treatment of Investigational Product Overdose 
There have been no cases of overdose with HS-110. Treatment of any suspected or confirmed 
overdose with HS-110 should be symptomatic, and supportive care is recommended in cases where 
overdose is suspected. As described in the Investigator’s Brochure (IB) for HS-110, the Sponsor 
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 HS-110 is defined as any dose 50% greater than the intended dose for that patient. 
Appropriate supportive care measures may need to be provided to address these potential toxicities 
in the event of an overdose. 
11.5. 
Dose Adjustment Criteria 
Any Grade 3 or higher AE determined to be treatment-related (HS-110 and/or nivolumab and/or 
pembrolizumab ± pemetrexed) will be discussed with the Medical Monitor before continuing with 
dosing, with the following exceptions: 
• 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 
• For patients in Treatment Arm 5: known and manageable reactions considered 
“expected” with nivolumab per the package insert 
• For patients in Treatment Arm 6: known and manageable reactions considered 
“expected” with pembrolizumab and/or pemetrexed per the package inserts. 
Where judged appropriate by the Investigator (after discussion with the Medical Monitor) a dose 
delay may be necessary for ≥ Grade 3 AEs until resolution of the toxicity (to Grade 1 or less). 
HS-110: No dose modifications of HS-110 will be permitted. 
Nivolumab, pembrolizumab and pemetrexed: Dose modifications are permitted according to 
their package inserts. If nivolumab, pembrolizumab and/or pemetrexed is discontinued due to 
toxicity, patients may continue to receive HS-110. This approach is consistent with results showing 
clinical benefit in patients even after toxicity-related treatment discontinuation. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 57 of 95 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
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. 
12.1. 
HS-110 
HS-110 is provided as single-dose vials containing fully-diluted frozen liquid not requiring 
additional dilution. The final drug consists of 10 million cells resuspended in 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 HS-110 dose totaling 1 × 107 cells per dose will be administered as 5 spatially divided 
intradermal injections (≤ 0.1 mL per injection) in the same extremity to increase volume distribution 
and enhance antigen presentation to lymph node regions. Vaccine dosing will rotate injection site 
extremities at every time point: antero-lateral left thigh, antero-lateral right thigh, left shoulder, 
and right shoulder. Missed doses may be made up if the missed dose is given at least 4 days before 
the subsequent dose. All doses will be administered at the Investigator site. 
In Arm 5, HS-110 will be administered weekly for 18 weeks.  
In Arm 6, HS-110 will be administered weekly for 13 weeks. Following the 13-week priming 
period, HS-110 injections will be administered for boosting every 3 weeks in combination with 
SOC pembrolizumab ± pemetrexed until confirmed disease progression or unacceptable toxicity 
(whichever occurs first).   
12.2. 
Study Drug Storage 
The activity of HS-110 is critically dependent on the viability of the cells in the preparation and 
vials must be stored at cryogenic temperature (≤ - 120⁰ C) in liquid nitrogen vapor phase. The 
product is supplied to the clinical site from the clinical supply depot via shipments in liquid 
nitrogen dry-shipper units which are validated to maintain temperature for 10 days. Upon arrival, 
the product must be transferred to controlled liquid nitrogen storage at the clinical site for 
continued storage. If liquid nitrogen storage is not available at the investigative site, a unit will be 
supplied by the 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. 
Study staff must take care to minimize temperature excursions during transfer of the product from 
shipping containers to controlled ultralow temperature storage on site. The product should not be 
retrieved from cryogenic storage until the study subject is present and available for dosing. When 
removing a product carton from storage to retrieve a vial for dosing, any doses remaining in the 
carton must be returned to ≤ - 120ºC immediately. 
Additional study drugs (nivolumab, pembrolizumab, pemetrexed) will be commercially supplied 
and stored according to instructions in their current approved package inserts.  


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
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12.3. 
Study Drug Preparation 
HS-110 must be thawed and the syringes labeled prior to injection. Preparation of the product and 
syringe labeling procedures is described in the Pharmacy Manual. Note that HS-110 must be 
administered within 2 hours of removing from liquid nitrogen dewar. 
12.4. 
Labeling 
HS-110 is 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. 
Additional study drugs (nivolumab, pembrolizumab, and pemetrexed) are used as commercially 
supplied; labelling is not applicable. 
12.5. 
Study Drug 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., 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 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) of study drug destroyed per institutional 
guidelines (if applicable and approved by Sponsor). 
• Documentation of storage conditions. 
These inventories must be made available for inspection by the study monitor, auditors and/or 
regulatory inspectors. The Investigator is responsible for ensuring that all used and unused clinical 
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. 
12.6. 
Occupational Safety 
Precautions should be taken to avoid direct contact with the study drug. A Material Safety Data 
Sheet (MSDS) describing occupational hazards and recommended handling precautions will be 
provided to the Investigator. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 59 of 95 
13. 
ASSESSMENT OF SAFETY 
Safety data will be collected throughout the study by a qualified physician, physician assistant, or 
nursing staff. Measurements used to evaluate safety will include medical history, physical 
examination, vital signs, clinical laboratory tests, ECGs, and evaluation of AEs. AEs will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.03 (NCI CTCAE v4.03).22 
Clinically significant abnormal laboratory parameters (as determined by the Investigator) may be 
repeated. If warranted, additional or more frequent testing than is specified in the protocol if 
warranted by the physician to monitor and treat AEs and should be documented in the study record 
until resolution. 
13.1. 
Physical Examination 
PEs must be performed by a qualified physician, nurse practitioner, or physician assistant and 
should include a thorough review of all body systems at Screening (Day -28 to Day -1) and at the 
EOT Visit. Body systems to be evaluated include Head, Eyes, Ears, Nose and Throat (HEENT), 
Pulmonary, 
Cardiovascular, 
Musculoskeletal, 
Abdominal/Gastrointestinal, 
Lymphatic, 
Neurological, Dermatologic, and Genito-urinary systems. In addition, the full PE will include 
obtaining the patient’s height and weight. 
Abbreviated PEs will be conducted at Weeks 2, 3, 4, 5, 7, 11, 15 for arm 5, and at Weeks 2, 3, 4, 
7, and 10 for arm 6. Abbreviated PEs are limited to vital signs and physical symptoms unless 
otherwise clinically indicated. Vital signs include blood pressure, heart rate, respiratory rate, and 
temperature, and will be measured after resting in a semi-supine or supine position. 
13.2. 
Clinical Laboratory Evaluations 
Blood samples will be collected for routine clinical laboratory testing and cardiovascular 
monitoring.  The clinical laboratory parameters will be analyzed at the site’s local laboratory. 
Laboratory assessments to be completed will include serum chemistry, hematology, Troponin I or 
T, and urine or serum pregnancy test (females of childbearing potential), and are defined as 
follows: 
• Serum Chemistry (5 mL): To include sodium, calcium, total protein, albumin, 
creatinine, blood urea nitrogen (BUN), total bilirubin, alkaline phosphatase, AST, 
ALT, potassium, chloride, sodium bicarbonate, lactate dehydrogenase, and glucose. 
• Hematology (5 mL): To include white blood cell (WBC) with differential, platelet 
count, hemoglobin, red blood cell (RBC) count and absolute neutrophils. 
• Troponin I or T (5 mL): See Section 13.4 for further details. 
• Urine or serum (1 mL) pregnancy test: See Section 13.5  for further details. 
• Additional laboratory assessments may be conducted throughout the study as medically 
necessary. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
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13.3. 
Injection Site Reactions 
The grading scale for injection site reactions (ISRs) used in this trial can be found in Appendix 2. 
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, regardless of grade, should be recorded on the Injection Site Reaction CRF 
page, including a photograph of each reaction where feasible. If an unusual, Grade 3, or Grade 4 
ISR occurs, attempts to obtain photographs at initial report and at follow-up visits, which show 
resolution over time, are encouraged. A ruler should be in the field of view to allow measurement 
of the size of the reaction. De-identified photograph(s) should be appended to the CRF. 
13.4. 
Cardiac Monitoring 
Troponin I or T and ECGs will be used in the first month of the study to monitor for signs of 
immune-related cardiotoxicity as per Table 2. The following actions should be taken in the event 
of changes in cardiac monitoring tests: 
- 
Isolated Troponin I or T elevation:  
o Delay HS-110 and additional study drug treatment (nivolumab, pembrolizumab, or 
pembrolizumab/pemetrexed). 
o Assess patient for new onset of chest pain, shortness of breath, orthopnea (shortness 
of breath when lying down), or syncope. 
o Perform ECG and ECHO to evaluate for new evidence of heart block, reduction in 
LVEF, pericardial effusion, or other abnormalities.  
o Repeat Troponin I or T in 2-3 days. 
o If new symptoms have developed and/or repeat troponin remains elevated (above 
upper limit of normal per institution), consider discontinuation of therapy and 
cardiology consultation.  In this event contact Medical Monitor to discuss the case. 
o If Troponin decreases with no other clinically significant findings, treatment can be 
restarted after discussion and approval by Medical Monitor. 
- 
ECG evidence of heart block: 
o Delay HS-110 and additional study drug treatment (nivolumab, pembrolizumab, or 
pembrolizumab/pemetrexed).  
o Assess patient for new onset of chest pain, shortness of breath, orthopnea (shortness 
of breath when lying down), and syncope. 
o Perform ECHO to evaluate for reduction (> 10% reduction from baseline or below 
lower limit of normal per institution) in LVEF, pericardial effusion, or other 
abnormalities.  
o Repeat ECG in 2-3 days. 
o If new symptoms have developed and/or repeat ECG remains abnormal consider 
discontinuation of therapy and cardiology consultation.  In this event contact Medical 
Monitor to discuss the case. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 61 of 95 
o Treatment must be permanently discontinued in confirmed cases of acute onset heart 
block. All cases must be discussed with Medical Monitor. 
13.5. 
Pregnancy 
All female patients of childbearing potential will have a urine or serum pregnancy test performed 
at the Screening and Baseline Visits. 
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.  
 
Time Period for Collecting Pregnancy Information 
All pregnancy information should be collected from the time of Screening Visit (up to Day -28 
prior to study drug administration) to 4 weeks after the last dose of study medication. Patients with 
pregnancies identified during screening will be recorded as screen failures. 
 
Action to be Taken if Pregnancy Occurs 
The Investigator will notify the Sponsor, or designee, within 24 hours 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 the Sponsor, 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 SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE 
and SAE Section 15.1). 
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 
study drug by the Investigator will be reported to the Sponsor. 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. 
 
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 male study patient’s female 
partner who becomes pregnant while participating in this study. The Investigator will record 
pregnancy information on the appropriate form and submit it to the Sponsor, or designee, within 
24 hours 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 
the Sponsor 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. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 62 of 95 
14. 
ASSESSMENT OF EFFICACY 
14.1. 
Tumor Assessments 
Tumor response assessments will incorporate results from radiographic tumor assessment (CT 
scans or MRI) of the chest, abdomen, and pelvis as well as physical examination, where 
appropriate, and will follow RECIST 1.1 and iRECIST criteria. PET scans will also be collected 
if obtained but are not required per protocol. 
The identification of target plus non-target lesions by CT or MRI will be documented at Screening, 
and repeat scans will be performed at Week 9, Week 18 and then every 8 weeks thereafter (Arm 
5), or at Screening and every 9 weeks (Arm 6) until confirmed iCPD per iRECIST, unless clinical 
signs of progression necessitate earlier scanning. 
The same method used at Screening must be used throughout the study whenever possible. 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. 
 
RECIST 1.1 and iRECIST 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.  
Radiographic assessment (CT scan or MRI) will be performed as follows: 
Arm 5: Screening, Week 9, Week 18, and every 8 weeks thereafter until confirmed disease 
progression; 
Arm 6: Screening and every 9 weeks until confirmed disease progression 
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 via RECIST 1.1 and iRECIST will be assessed as outlined in Appendix 3.  
The determination of iRECIST response uses the same guidelines to determine measurable or non-
measurable lesions. The concept change for iRECIST is the resetting of the bar if RECIST 1.1 
progression is followed at the next assessment by tumor shrinkage. This approach allows atypical 
responses, such as delayed responses that occur after pseudoprogression, to be identified, further 
understood, and better characterized. Refer to Appendix 3 for further details. 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 63 of 95 
The disease response measures will allow for the calculation of the ORR, PFS, and DCR. The 
ORR includes CR/iCR, and PR/iPR. PFS is the time between treatment assignment and the date 
of PD/iPD or death, whichever comes first. The DCR includes responses of PR/iPR, CR/iCR or 
SD/iSD.  
14.2. 
Immunologic Response (IR) 
Peripheral blood samples (50 mL) will be collected at Screening,Week 7, Week 13, and EOT. All 
samples will be shipped to and processed by Heat Biologics, Inc. or its designee. 
Forty (40) mL heparinized blood and 10 mL of non-heparinized blood will be drawn at each of the 
above time points and used for analysis as outlined below. PBMCs will be isolated from 
heparinized blood samples by Ficoll separation. Isolated PBMCs will be utilized for 
immunophenotyping and functional analysis using fluorescence activated cell sorting (FACS) and 
ELISPOT assays as described below. A subset of isolated PBMCs will by lysed in nucleic acid 
preservative buffers for downstream analysis of molecular signatures. Serum collected from 
non-heparinized blood samples will be stored for batch analysis of antibody titers to HLA-A1, in 
non-HLA-A1 positive patients 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-study treatment, may also be performed. 
14.3. 
Production of Interferon-gamma and Granzyme B from PBMCs 
(ELISPOT) 
The immune response will be evaluated by antigen-specific ELISPOT analysis for IFNγ and 
Granzyme B production by patient cells. These ELISPOT assays will be conducted in our research 
facility.  
Previously cryopreserved and thawed PBMCs will be challenged or restimulated with specific 
tumor vaccine antigens as follows: 
• PBMCs + PMA + Ionomycin (positive control). 
• PBMCs + HS-110 whole cell lysates  
• PBMCs + a n overlapping cocktail of known shared antigens, which may include 
Survivin, TTK, NY-ESO-1, CEP55, MAGEA1, MAGEA3, MAGEA6, MAGEA12, 
MAGEB1, MAGEC1, MAGEC2, CXORF61, GAGE1, BAGE1, CTCFL, DDX43, 
SSX1, SSX4, and HORMAD 1. 
For the ELISPOT assay, the frozen PBMCs will be thawed, antigen challenged, and plated for 
analysis of IFNγ and GzB production by two color enzymatic ELISPOT assay and analyzed in 
duplicate per time point for each patient. Following incubation, samples will be quantitated in an 
automated ELISPOT reader. 
The frequency of IFN producing PBMC 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 ELISPOT may provide a more direct readout for 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 64 of 95 
antigen-specific granule exocytosis and cytotoxicity. Antigen specificity of the ELISPOT response 
will be evaluated 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 response. 
Positive responses will be defined as a greater than two-fold increase in the number of 
IFNγ-positive PBMC compared to baseline. 
14.4. 
Phenotyping Phenotypic Analysis of Blood Lymphocyte Subsets by 
FACS 
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 +), T-cells (CD45 +, CD3 +, CD8 +), regulatory T-cells (CD3 +, CD4+, CD25+, 
FoxP3 +), and NK cells (CD45 +, CD56 +, CD3-) at baseline and over the course of therapy. In 
addition, a NK/T-cell activation panel (Ki67, CD137, CD27, CD28), memory panel (CD27, Cd28, 
CD45 RA, CD197, CD57) and exhaustion panel (CTLA4, PD-1, Tim3, TIGIT) will be performed. 
14.5. 
Analysis of Infiltrating T-Cells (Post-Treatment Tumor Biopsy) 
Post-treatment biopsies will be collected at week 10, when feasible, and the tissue will be examined 
for the presence of TILs. Multicolor fluorescence immunohistochemistry (IHC) will be used for 
quantification of infiltrating CD3+, CD4+ and FOXP3+ T-cells and measurement of their 
activation status, Ki67 and PD-1 expression, and cytotoxic activity (gzB expression) in situ. These 
data will be correlated with clinical response. 
14.6. 
Tumor Mutation Burden Analysis 
Tumor Mutation Burden (TMB) is the number of coding somatic base substitution and indel 
mutations occurring in a tumor specimen, per megabase (Mb) of coding genome assessed. 
Approximately 20 mLs of whole blood will be collected using cell free DNA collection tubes at 
the Week 1 visit prior to dosing. Samples will be shipped to, and analyzed by, Foundation 
Medicine using their FoundationACT® circulating tumor DNA (ctDNA) assay. Note that Cohort 
B patients enrolled prior to Amendment 5 that did not have a week 1 TMB sample collected should 
have this one-time lab drawn at the next feasible visit (i.e. Week 4, 10, 16 or post-HS110/survival 
follow-up). 
 
 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 65 of 95 
15. 
SAFETY MONITORING 
15.1. 
Adverse and Serious Adverse Events 
All patients will be assessed for pre-existing symptoms during screening (from the date of 
signature of ICF 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 (EOT) 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 resolved or, in the case of permanent impairment, until the condition 
stabilizes. 
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. 
 
Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of a medicinal product in 
humans, whether or not considered related to the medicinal product (Code of Federal Regulations 
(CFR) Title 21 part 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]). 
 
Serious Adverse Event (SAE) 
The 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. 


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• 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. 
 
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 study drug 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. 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry and hematology) or other abnormal 
assessments (e.g., vital signs) that are judged by the Investigator as clinically significant (CS) will 
be recorded as AEs and SAEs if they meet the definition of an AE or SAE. CS 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, 
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 CS. 
15.2. 
Relationship to Study Drug 
The Investigator, or other qualified physician designee, will assess the possible relationship 
between the AE/SAE and any of the study medications, as well as any concomitant medications 
according to the following criteria: 
• Related: AE and administration of one or more study products are related in time, and 
AE is explained by one or more study products. 
• Not related: AE is explained by another cause not related to any study product. 


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Event outcome will be recorded using the following categories: 
• Recovered/resolved. 
• Not recovered/not resolved. 
• Recovered/resolved with sequelae. 
• Fatal. 
• Unknown. 
15.3. 
Reporting Adverse Events 
The Investigator will record all directly observed AEs and all AEs spontaneously reported by the 
study patient. In addition, each study patient will be questioned about any AEs they have 
experienced during each study visit. 
Each AE should be described in detail in the patient’s medical record and on the “Adverse Event” 
CRF and SAEs on a “Serious Adverse Event” form and include the following information: start 
and stop dates and times, 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 
related to study medication should be recorded at any time regardless of when they occurred. 
15.4. 
Prompt Reporting of SAEs 
All SAEs, whether or not considered related to study drug, must be reported within 24 hours to the 
Medical Monitor listed on page 2 of this protocol. During the initial report, the Medical Monitor 
will require the following patient information as available: 
• 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 and which drug(s) 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 due to the event. 
• 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). 


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• In addition to the above information, the Medical Monitor will require the Investigator's 
assessment of the following: 
− Severity of the AE. 
− Relationship of the AE to study treatment. 
− Outcome of the AE. 
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 as soon as reasonably possible. The 
Sponsor will promptly report SAEs related to HS-110 or additional study drug to the FDA and 
other applicable regulatory agencies in accordance with 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 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 Medical Monitor’s 
(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 HS-110 and/or 
additional study drug 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 HS-110. 
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 HS-110 related AEs to the list of expected AEs to 
the Investigator’s Brochure. 
15.5. 
Study Review Committee and Data Monitoring Committee 
In the phase 1b portion of the study, a Study Review Committee provided ongoing safety 
evaluations and recommendation for advancement into phase 2. Moving forward, a fully 
constituted and independent Data Monitoring Committee (DMC) will review ongoing safety and 
efficacy of phase 2 patients. A full description of the membership, roles, and responsibilities of the 
DMC will be outlined in a separate charter. 
Ad-hoc meetings will also occur if the Sponsor, Medical Monitor, or Investigator believes a safety 
issue has arisen during the course of the trial that may warrant further review or trial alteration. 


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16. 
STATISTICS 
16.1. 
General Statistical Considerations 
Patients will be analyzed according to the following cohorts for Arm 5: 
• Cohort A, composed of all CPI naïve patients (n=40, including 15 phase 1b patients).   
• Cohort B, composed of all CPI progressor patients (n=60). Note that this cohort will be 
permitted to over-enroll. 
Patients will be analyzed according the following cohorts for Arm 6. Distribution will not be 
controlled within the two cohorts (n=up to 20 based on patient availability): 
• Cohort C, composed of all patients receiving maintenance pembrolizumab 
• Cohort D, composed of all patients receiving maintenance pembrolizumab + pemetrexed 
Each cohort (A, B, C and D) will be analyzed including patients of all histology types, and then 
again including only adenocarcinoma patients. 
Analyses will be performed within each of the cohorts to identify differences in strata for each of 
the following factors if sufficient data exists: 
• Histology: adenocarcinoma and squamous cell carcinoma 
• PD-L1 status: negative (<1%) and positive (≥1%) based on tumor cell expression  
• TIL status: high (> 10%) and low (≤ 10%) 
• Tumor Mutation Burden: high (10 or more mutations) and low (less than 10 mutations) 
Additional factors, such as line of treatment or presence of injection site reactions, may be added 
to statistical models used for analyses; the method of pooling and testing for interaction among the 
different factors will be described in detail in the SAP.   
The intent of this clinical investigation is to establish the ORR and quantify the duration of PFS 
across the various subsets in NSCLC patients who receive HS-110.  
Categorical variables will be summarized by frequency distributions (number and percentage of 
patients), while continuous variables will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum and maximum). All binary clinical endpoints such as immune 
response, DCR and ORR will be presented as point estimates with 95% CI for each cohort. Time-
to-event endpoints (PFS, OS) will be calculated using Kaplan-Meier methodology.  
TEAEs will be summarized in an overall summary of treatment-emergent adverse events (TEAEs), 
as well as tables summarized all TEAEs (by SOC and PT), TEAEs related to HS-110, TEAEs 
related to the combination therapy (nivolumab, pembrolizumab, or pembrolizumab/pemetrexed, 
serious TEAEs, serious TEAEs related to the combination therapy, and grade 3+ TEAEs.  Listings 
of all TEAEs, serious TEAEs, and TEAEs leading to discontinuation will also be presented. 
16.2. 
Sample Size  
Within Arm 5, Cohorts A and B are planned to enroll 40 and 60 patients, respectively. Note that 
Cohort B will be permitted to over-enroll based on patient availability. The phase 1b patients 


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(n=15) will be included in the sample size for Cohort A. The distribution of patients, relative to 
enrollment, will not be controlled within Arm 6 (Cohorts C and D) but is planned to be up to 20 
total based on patient availability. Response will be summarized for various combinations of 
factors in an exploratory manner.  With a total enrollment into this clinical investigation of up to 
120 patients, this study should provide sufficient precision to provide a characterization of the 
likely efficacy subsets to be used in a larger study. 
16.3. 
Analysis Populations 
Study populations are defined as follows: 
 
Safety Population:  defined as all patients who receive at least 1 dose of HS-110. 
Per-Protocol (PP): defined as all patients who have received at least 6 weekly doses of HS-110 in 
combination with either nivolumab (given with every other HS-110 dose) or pembrolizumab 
(given with every third HS-110 dose during priming), and who have a pre-treatment tumor 
assessment and at least one post-treatment tumor assessment. 
Adenocarcinoma Population:  defined as all patients in the PP who had adenocarcinoma histology. 
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. 
16.4. 
Disposition, Demographics, and Baseline Characteristics 
Disposition information will be summarized, including the numbers of dosed patients, and patients 
withdrawn by reason, as well as the reason for discontinuation from treatment. 
Descriptive information on demographics and baseline characteristics, including age, sex, weight, 
height, physical examination, and baseline ECOG score will be provided in a summary table. 
Summaries will be provided by treatment group and overall for the Safety and Per Protocol 
populations. 
16.5. 
Primary Efficacy Endpoint and Analysis 
Safety/tolerability is the primary endpoint for the phase 1b portion of this study. For the phase 2 
portion of this study, the primary endpoint for Arm 5 cohorts is ORR and the primary endpoint for 
Arm 6 cohorts is PFS. 
 
Phase 1b: Safety and Tolerability 
Safety will be measured by the frequency of treatment emergent adverse events (TEAEs)/serious 
adverse events (SAEs), including clinically significant (CS) abnormal laboratory parameters, 
ECGs, PEs, and vitals in patients receiving at least one dose of HS-110. 
 
Phase 2: Objective Response Rate (Arm 5 Cohorts A/B) and Progression Free 
Survival (Arm 6 Cohorts C/D) 
For Arm 5 Cohorts A and B, ORR will be defined as the proportion of patients achieving a best 
overall response of complete response (CR) or partial response (PR) by RECIST 1.1. These 
response rates will be summarized for each cohort using counts and percentages.  95% exact 
confidence intervals will also be presented.   


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For Arm 6 Cohorts C and D, PFS will be calculated as the time between first dose of HS-110 and 
the date of PD, as defined by RECIST 1.1 or death, whichever occurs first. For patients with no 
recorded post-baseline tumor assessments, PFS will be censored at day 1. For those who remain 
alive and have no PD, PFS will be censored on the date of last evaluable tumor assessment. 
Kaplan-Meier curves will be produced separately for each Cohort in Arms 5 and 6. Analysis details 
are provided in the SAP. 
These analyses will be conducted on the ITT population.  A secondary examination of response 
will be performed using the Per Protocol population and the Adenocarcinoma population.  
16.6. 
Secondary Efficacy Endpoints and Analyses 
 
Objective Response Rate  
Defined as the proportion of patients achieving a best overall response of complete response (CR) 
or partial response (PR) by RECIST 1.1.These response rates will be summarized for each cohort 
using counts and percentages.  95% exact confidence intervals will also be presented. A second, 
exploratory measure of ORR, iORR, will be calculated using the principles of iRECIST. For Arm 
6, the rate of improvement in RECIST 1.1 response from SD to CR/PR will also be presented. 
This analysis will be conducted on the Safety population.  A secondary examination of response 
will be performed using the Per Protocol population and the Adenocarcinoma population.  
 
Overall Survival 
OS will be calculated as the duration of survival from the date of first HS-110 dosing into the study 
to the date of death from any cause or will be censored on the date the patient was last known to 
be alive. 
 
Progression-Free Survival  
PFS will be calculated as the time between the date of first dose of HS-110 and the date of PD, as 
defined by RECIST 1.1 or death, whichever occurs first. A second, exploratory measure of PFS, 
iPFS, will be calculated as the time between the date of first dose of HS-110 and the date of iCPD 
as defined by iRECIST or death, whichever occurs first. For patients with no recorded 
post-baseline tumor assessments, PFS/iPFS will be censored at the day of first dose. For those who 
remain alive and have no PD, PFS/iPFS will be censored on the date of last evaluable tumor 
assessment. Kaplan-Meier curves will be produced separately for each Cohort in Arms 5 and 6. 
Analysis details are provided in the SAP. 
 
Duration of Response  
DOR will be calculated from the time of first confirmed response (CR or PR) until radiographic 
PD by RECIST 1.1.  A second, exploratory DOR measure, iDOR, will be calculated as the time 
of first confirmed response (iCR or iPR) until iCPD as defined by iRECIST. 
 
Disease Control Rate 
DCR is defined as the proportion of patients whose best overall response is PR, CR, or SD, as 
defined by RECIST 1.1.  A second, exploratory DCR rate, iDCR, is defined as the proportion of 
patients whose best overall response is iPR, iCR, or iSD, as defined by iRECIST.  


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6-month Durable Response Rate 
6 mo DRR is defined as the percentage of responders with durable responses lasting at least 6 
months from time of initial response by RECIST 1.1. A second, exploratory DRR measure, 6 mo 
iDRR, is defined as the percentage of responders with durable responses lasting at least 6 months 
from the time of initial response by iRECIST. 
 
12-month Durable Response Rate 
12 mo DRR is defined as the percentage of responders with durable responses lasting at least 12 
months from the time of initial response by RECIST 1.1. A second, exploratory DRR measure, 12 
mo iDRR, is defined as the percentage of responders with durable responses lasting at least 12 
months from the time of initial response by iRECIST. 
 
6-month Overall Survival 
6m OS will be calculated as the proportion of patients who are alive at 6 months following the date 
of first dose of HS-110 and will be presented as a median with exact 95% CI. 
 
12-month Overall Survival 
12m OS will be calculated as the proportion of patients who are alive at 12 months following the 
date of first dose of HS-110 and will be presented as a median with exact 95% CI. 
 
6-month Progression Free Survival 
6m PFS will be calculated as the proportion of patients who have not progressed at 6 months 
following the date of first dose of HS-110 and will be presented as a median with exact 95% CI. 
 
12-month Progression Free Survival 
12m PFS will be calculated as the proportion of patients who have not progressed at 12 months 
following the date of first dose of HS-110 and will be presented as a median with exact 95% CI. 
 
Safety and Tolerability 
Safety will be measured as the frequency of TEAEs/SAEs, including CS abnormal laboratory 
parameters, ECGs, PEs, and vitals in patients receiving at least one dose of HS-110. 
16.7. 
Exploratory Endpoints and Analyses 
The following endpoints will be evaluated: 
• As outlined in section 16.6, efficacy parameters of ORR, PFS, DOR, DCR, and DRR 
will be analyzed using the principals of iRECIST to produce iORR, iPFS, iDOR, 
iDCR, and iDRR. 
• Peripheral blood IR will be measured by ELISPOT to detect an increase of 2-fold 
over baseline of IFNγ and/or granzyme B (gzB) positive T cells, as well as analysis of 
surface markers that define NK and T cell subsets of activation, memory and 
exhaustion by flow cytometry.   


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• Evaluation of tumor tissue obtained for presence of TILs (%) and correlation of 
pre- and post-treatment TIL levels with clinical outcomes. 
• Evaluation of tumor tissue obtained for percent expression of PD-L1 on tumor cells 
and correlation of pre- and post-treatment PD-L1 expression with clinical outcomes. 
•  Evaluation of peripheral blood TMB to measure the number of mutations within the 
tumor genome and correlation of TMB levels with clinical outcomes. 
Other exploratory analyses of peripheral blood and tumor tissue to determine immune changes and 
response to treatment may be conducted as new technology emerges. 
Exploratory endpoints will be summarized descriptively at each scheduled sampling time point. 
Appropriate transformations may be undertaken in cases were the data are not Normally 
distributed. 
16.8. 
Safety Analyses 
The analyses will be completed for the Safety population.   
 
Adverse Events 
Treatment emergent AEs are AE which occur on or after the first dose of study medication. The 
Medical Dictionary for Regulatory Activities (MedDRA) will be used for the coding of AEs. 
TEAEs, serious or CTCAE Grade 3 or 4 TEAEs, and TEAEs related to HS-100 will be summarized 
overall and by system organ class and preferred term by treatment group. These will summarize 
the number of events and the number and percent of patients with a given event. In addition, the 
number and percent of patients with TEAEs will be tabulated by maximum severity. A summary 
of all TEAEs by system organ class and preferred term occurring in at least 5% of patients in each 
Arm will be tabulated. 
 
Laboratory Assessments 
All laboratory-based data will be presented as listings of all values as well as abnormal results 
judged to be clinically significant, which will also be reported as AEs. Numeric summaries of all 
observed and change from baseline laboratory evaluations will be provided (e.g., by visit and 
treatment arm), including chemistry, hematology, and Troponin I or Troponin T results.  
 
Vital Signs 
Numeric summaries of all observed and change from baseline vital signs will be provided by time 
point and treatment group, including blood pressure, heart rate, respiratory rate, and temperature.  
 
ECGs 
Numeric summaries of all observed and change from baseline in ECG parameters will be provided 
by time point and treatment arm, including heartrate, QRS duration (msec), QT interval (msec), 
QTcF interval (msec), and PR interval (msec) and the overall assessment of normal, abnormal, not 
clinically significant, and abnormal, clinically significant.   


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Other Assessments 
Other collected data not specifically mentioned, including physical examinations (PEs) and 
protocol deviations, will be presented in patient listings. 
 


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17. 
DESCRIPTION OF ETHICAL CONSIDERATIONS RELATED 
TO THE TRIAL. 
The study will be conducted in accordance with all applicable regulatory requirements, including 
a US IND, and Sponsor will obtain favorable opinion/approval to conduct the study from the 
appropriate regulatory agency 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 21 CFR parts 50, 54, 56, and 312, ICH GCP, 
all local, regional and federal regulatory requirements, all applicable patient privacy requirements, 
and the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the 
following: 
• IRB/EC/IBC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amending documents 
• Patient informed consent 
• Investigator reporting requirements 
A copy of the site-specific proposed ICF should be submitted to the Sponsor for review and 
comment before submission to the IRB/EC. The study should not begin until the ICF has been 
reviewed and approved by the Sponsor and until the document has been approved by the IRB/EC 
of record. The ICF shall contain all the elements of informed consent specified in the above 
regulations and guidance. Written informed consent will be obtained for each patient before he or 
she can participate in the study. 
 
 
 


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18. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
18.1. 
Study Monitoring 
In accordance with applicable regulations and GCP, the Sponsor will perform quality control and 
assurance checks. Before enrolling any patient into this study, the Sponsor (or designees) will 
review the protocol, the IB, draft CRFs and instructions for their completion, and significant 
protocol sections (i.e. reporting AEs and SAEs) with the Investigator. A qualified designee of the 
Sponsor will monitor the conduct of the study at reasonable intervals by visiting the site and/or by 
contacting the site by telephone and e-mail. 
The Investigator agrees that qualified representatives of the Sponsor and regulatory agencies will 
have, both during and after this study, direct access to review medical records pertinent to the 
clinical study as specified by regulations. Patients will not be identified by name in documents that 
leave the study site, and confidentiality of information in both study and medical records will be 
preserved to the extent that is required by regulations. 
The Sponsor will monitor the study consistent with the demands of the study and site activity to 
ensure that the: 
• Data are authentic, accurate, and complete; 
• Safety and rights of patients are being protected; 
• Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP, and all applicable regulatory requirements. 
18.2. 
Protocol Deviations 
In general, a protocol deviation is an inadvertent excursion from or non-compliance with the 
IRB/EC-approved protocol. The Investigator is responsible for ensuring the study is conducted in 
accordance with the protocol and should not implement any changes to the protocol unless it is 
required to eliminate an immediate hazard to the patient. 
If the deviation affects the safety or the rights of the patient, 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 for inclusion in the CSR: 
• Entered into the study without meeting eligibility criteria. 
• Developed withdrawal criteria during the study and was not withdrawn. 
• Received wrong treatment or incorrect dose. 
• Received excluded concomitant treatment. 
• Failed to collect data essential to the interpretation of primary endpoints for the study. 
 


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19. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct one 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. 
 


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20. 
DATA HANDLING AND RECORDKEEPING 
20.1. 
Retention of Records 
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 re-generating a hard copy, if required. 
Furthermore, the Investigator must ensure there is an acceptable back up of these reproductions 
and that an acceptable quality control process exists for making these reproductions. 
These records should be retained for not less than 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period; however, if required by applicable regulatory requirements or by an agreement with the 
Sponsor. Thereafter, records will not be destroyed without giving the Sponsor prior written notice 
and the opportunity to further store such records. 
The Investigator must notify Sponsor of any changes in the archival arrangements, including, but 
not limited to, the following: archive at an off-site facility, change in office and archive location, 
transfer of ownership of the records in the event the Investigator leaves the site. 
20.2. 
Provision of Study Results and Information to Investigators 
When required by applicable regulations, the Investigator signatory for the clinical study report 
(CSR) will be determined at the time the report is written. When the CSR is completed, Sponsor 
will provide the Investigator with a summary of the study results.   
20.3. 
Data Management 
The data collection tool for this study will be Sponsor-defined CRFs. Patient data necessary for 
analysis and reporting will be entered/transmitted into a validated database or data system. 
After the Sponsor receives the CRFs, the Sponsor’s Medical Monitor (or designee) will review the 
data for safety information, and the Sponsor’s 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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20.4. 
Study and Site Closure 
Upon completion or premature discontinuation of the study, the Sponsor (or designee(s) will 
conduct site closure activities with the Investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and Sponsor procedures. 
In addition, Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons, including, but not limited to, safety or ethical issues or severe 
non-compliance. For this multicenter study, this can occur at one or more sites. If Sponsor 
determines such action is needed, Sponsor will discuss this with the Investigator or the head of the 
medical institution, where applicable, including the reasons for taking such action. When feasible, 
Sponsor will provide advance notification to the Investigator or the head of the medical institution, 
where applicable, of the impending action prior to its taking effect. 
Sponsor will promptly inform all other Investigators or the head of the medical institution, where 
applicable, and/or institutions conducting the study if the study is suspended or prematurely 
discontinued for safety reasons. Sponsor will also promptly inform the 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. 
 


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21. 
LIST OF REFERENCES 
1. SEER Cancer Statistics Review, 1975-2014. National Cancer Institute., 2017. 2017, at 
https://seer.cancer.gov/csr/1975_2014/.) 
2. Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S. Metastatic non-small-
cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Annals of oncology : official journal of the European Society for Medical Oncology / 
ESMO 2014;25 Suppl 3:iii27-39. 
3. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 
cohort of the open-label KEYNOTE-021 study. The Lancet Oncology 2016;17:1497-508. 
4. Feld E, Horn L. Emerging role of nivolumab in the management of patients with non-small-
cell lung cancer: current data and future perspectives. Onco Targets and Therapy 2017;10:3697-
708. 
5. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2013;31:1021-8. 
6. Vansteenkiste JF, Zielinski M, Dahabreh IJ, et al. Association of gene expression signature 
and clinical efficacy of MAGE-A3 antigen-specific cancer immunotherapeutic as adjuvant 
therapy in resected stage IB/II non-small cell lung cancer.  ASCO Annual Meeting; 2008 May 
30-June 3, 2008; Chicago, IL. 
7. Butts CA, Socinski MA, Mitchell P, et al. START: A phase III study of L-BLP25 
(Tecemotide) cancer immunotherapy for unresectable stage III non-small cell lung cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2013;31:abstr 7500. 
8. GlaxoSmithKline. Investigational MAGE-A3 antigen-specific cancer immunotherapeutic 
does not meet first co-primary endpoints in MAGRIT, a phase III non-small cell lung cancer 
clinical trial. London, UK2014. 
9. GlaxoSmithKline. Update on phase III clinical trial of investigational MAGE-A3 antigen-
specific cancer immunotherapeutic in non-small cell lung cancer. London, UK2014. 
10. Butts C, Socinski MA, Mitchell PL, et al. Tecemotide (L-BLP25) versus placebo after 
chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-
blind, phase 3 trial. The Lancet Oncology 2014;15:59-68. 
11. Nemunaitis J, Nemunaitis M, Senzer N, et al. Phase II trial of Belagenpumatucel-L, a TGF-
beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer 
(NSCLC) patients. Cancer gene therapy 2009;16:620-4. 
12. Giaccone G, Bazhenova LA, Nemunaitis J, et al. A phase III study of belagenpumatucel-L, 
an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. 
European journal of cancer (Oxford, England : 1990) 2015;51:2321-9. 
13. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line 
chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. The Lancet 
Oncology 2011;12:1125-33. 


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14. Ganesan A-P, Johansson M, Ruffell B, et al. Tumor-Infiltrating Regulatory T Cells Inhibit 
Endogenous Cytotoxic T Cell Responses to Lung Adenocarcinoma. The Journal of Immunology 
2013;191:2009-17. 
15. Woo EY, Yeh H, Chu CS, et al. Cutting edge: Regulatory T cells from lung cancer patients 
directly inhibit autologous T cell proliferation. Journal of immunology (Baltimore, Md : 1950) 
2002;168:4272-6. 
16. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 
expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating 
lymphocytes and their PD-1 expression. Clinical cancer research : an official journal of the 
American Association for Cancer Research 2004;10:5094-100. 
17. Murshid A, Gong J, Stevenson MA, Calderwood SK. Heat shock proteins and cancer 
vaccines: developments in the past decade and chaperoning in the decade to come. Expert review 
of vaccines 2011;10:1553-68. 
18. Strbo N, Garcia-Soto A, Schreiber TH, Podack ER. Secreted heat shock protein gp96-Ig: 
next-generation vaccines for cancer and infectious diseases. Immunologic research 2013;57:311-
25. 
19. Raez LE, Walker GR, Baldie P, et al. CD8 T cell response in a phase I study of therapeutic 
vaccination of advanced NSCLC with allogeneic tumor cells secreting endoplasmic reticulum-
chaperone gp96-Ig-peptide complexes. Advances in Lung Cancer 2013;Vol.02No.01:10. 
20. Fromm G, De Silva S, Giffin L, Xu X, Rose J, Schreiber TH. P206 Gp96-Ig/costimulator 
(OX40L, ICOSL, or 4-1BBL) combination vaccine improves T cell priming and enhances 
immunity, memory, and tumor elimination. Journal for Immunotherapy of Cancer 2016;4:116. 
21. Strbo N, Vaccari M, Pahwa S, et al. Novel vaccination modality provides significant 
protection against mucosal infection by highly pathogenic SIV. Journal of immunology 
(Baltimore, Md : 1950) 2013;190:2495-9. 
22. Institute NC. Common Terminology Criteria for Adverse Events (CTCAE) v4.03. In: 
Services USDoHaH, ed.2010. 
23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, England : 
1990) 2009;45. 
24. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. The Lancet Oncology;18:e143-e52. 
25. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination 
Immune Checkpoint Blockade. The New England journal of medicine 2016;375:1749-55. 
 
 


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APPENDIX 1: ECOG PERFORMANCE STATUS SCALE 
 
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, MD, Group Chair 


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APPENDIX 2: GRADING SCALE FOR INJECTION SITE REACTIONS  
 
Local Reaction to 
Injectable Product 
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 
0.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling* 
0.5-5 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 3: THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST 1.1) GUIDELINES AND GUIDLELINES FOR 
RESPONSE CRITERIA FOR USE IN TRIALS TESTING 
IMMUNOTHERAPEUTICS (IRECIST) 
 
RECIST 1.1 
The objective response according to RECIST 1.1 is derived from time-point response assessments 
based on tumor burden as follows below.  
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 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
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 = Not Evaluable 
When target lesions show SD/PR and some subset of non-target lesions are considered not 
evaluable, 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 lesions that are not evaluable, if they showed growth, 
could cause an overall response of PD in the context of the other lesion responses seen. If the 
non-target lesions that are not evaluable comprise a significant proportion of the overall disease 
burden, the appropriate time point response is NE. 
 
* Please refer to the complete New response evaluation criteria in solid tumours: Revised RECIST 
guidelines – version 1.1 for further details23. 
 
iRECIST 
The guidelines continue to recommend use of RECIST 1.1 to define whether tumor lesions are 
measurable or non-measurable and the principles used to determine objective tumor response are 
largely unchanged from RECIST 1.1. The concept change for iRECIST is the resetting the bar if 
RECIST 1.1 progression is followed at the next assessment by tumor shrinkage. 
 
iRECIST defines unconfirmed progress (iUPD) on the basis of RECIST 1.1 principles; however, 
iUPD requires confirmation on repeat imaging no less than 4 weeks later, which is done on the 
basis of observing either a further increase in size (or in the number of new lesions) in the lesion 
category in which progression was first identified in (i.e., target or non-target disease), or 
progression (defined by RECIST 1.1) in lesion categories that had not previously met RECIST 1.1 
progression criteria. However, if progression is not confirmed, but instead tumor shrinkage occurs 
(compared with baseline), which meets the criteria of iCR, iPR, or iSD, then the bar is reset so that 
iUPD needs to occur again (compared with nadir values) and then be confirmed (by further growth) 
at the next assessment for iCPD to be assigned. If no change in tumor size or extent from iUPD 
occurs, then the time point response would again be iUPD. This approach allows atypical 
responses, such as delayed responses that occur after pseudoprogression, to be identified, further 
understood, and better characterized. 
 


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However, many aspects of new lesion assessment are unique to iRECIST. If a new lesion is 
identified (thus meeting the criteria for iUPD) and the patient is clinically stable, treatment should 
be continued. New lesions should be assessed and categorized as measurable or non-measurable 
using RECIST 1.1 principles.  
 
The algorithm for patients with no previous iUPD is identical to RECIST 1.1. For patients with 
iUPD at the last time point response, the next time point response is dependent on the status of all 
lesions, including target, non-target, new lesion target, and new lesion non-target; on whether any 
increase in size has occurred (either a further increase in size or a sufficient increase to assign a 
new iUPD if the criteria were not previously met); or the appearance of additional new lesions. 
 
Assignment of time point response using iRECIST 
 
Time point 
response with 
no previous 
iUPD in any 
category 
Time point response with previous iUPD in any 
category * 
Target lesions: iCR; non-target 
lesions: iCR; new lesions: no  
iCR 
iCR 
Target lesions: iCR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iPR 
iPR 
Target lesions: iPR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iPR 
iPR 
Target lesions: iSD; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iSD 
iSD 
Target lesions: iUPD with no change, 
or with a decrease from last time 
point; non-target lesions: iUPD with 
no change, or decrease from last time 
point; new lesions: yes  
Not Applicable 
New lesions confirm iCPD if new lesions were 
previously identified and they have increased in size 
(≥5 mm in sum of measures for new lesion target or 
any increase for new lesion non-target) or number; if 
no change is seen in new lesions (size or number) from 
last time point, assignment remains iUPD  
Target lesions: iSD, iPR, iCR; non-
target lesions: iUPD; new lesions: no  
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in the size of non-target disease 
(does not need to meet RECIST 1.1 criteria for 
unequivocal progression)  
Target lesions: iUPD; non-target 
lesions: non-iCR/non-iUPD, or iCR; 
new lesions: no  
 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in sum of measures ≥5 mm; 
otherwise, assignment remains iUPD  
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no  
 
iUPD 
Remains iUPD unless iCPD is confirmed based on a 
further increase in previously identified target lesion 
iUPD in sum of measures ≥5 mm or non-target lesion 
iUPD (previous assessment need not have shown 
unequivocal progression)  
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes  
 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of a further increase in previously identified target 
lesion iUPD sum of measures ≥5 mm, previously 
identified non-target lesion iUPD (does not need to be 


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Time point 
response with 
no previous 
iUPD in any 
category 
Time point response with previous iUPD in any 
category * 
unequivocal), or an increase in the size or number of 
new lesions previously identified  
Target lesions: non-iUPD or 
progression; non-target lesions: non-
iUPD or progression; new lesions: yes  
iUPD 
Remains iUPD unless iCPD is confirmed on the basis 
of an increase in the size or number of new lesions 
previously identified  
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no 
pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete response, partial response, and stable 
disease would be the same. *Previously identified in assessment immediately before this time point. “i” indicates 
immune responses assigned using iRECIST. iCR=complete response. iPR=partial response. iSD=stable disease. 
iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither CR nor PD have been met. 
iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumors. 
 
 
Please refer to the complete Guidelines for iRECIST24. 
 
 
 
 


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APPENDIX 4: AMENDMENT JUSTIFICATION AND CHANGE LOG 
Amendment 6 Justification 
Amendment 6 is designed to provide clarification and improve ease of operationalization of 
Amendment 5 across multiple sites with differing practices of front-line patient management. In 
general, the timing to initiate additive HS-110 to front line maintenance will be restricted by weeks 
and/or cycles rather than be tethered to the timing of imaging scans. Amendment 6 also clarifies 
that the primary endpoint of PFS added in Amendment 5 only applies to the newly added Arm 6 
cohorts in front-line maintenance; original Arm 5 patients (Cohorts A & B) will retain the same 
primary endpoint (ORR) which has been in place since the inception of the trial. Additionally, 
Amendment 6 modifies the allocation of patients to Cohorts B, C, and D due to operational 
considerations but does not affect the total sample size for the trial. Lastly, Amendment 6 offers 
clarification around frequently asked questions with regard to eligibility criteria, allows for retro-
active collection of TMB samples for Cohort B patients enrolled prior to Amendment 5, as well as 
modifies the Arm 6 PE schedule to better align with physician visits.  
Amendment 5 Justification: 
Amendment 5 expands the patient population to include patients receiving front line 
pembrolizumab ± pemetrexed, as well as relaxes the eligibility criteria for CPI Progressors. Per 
Investigator feedback, the minimum CPI treatment duration requirement for Arm 5 CPI progressor 
patients is lowered from 6 months to 4 months. Additionally, the term CPI relapsed is being 
corrected to CPI progressor, which is more clinically relevant.  
To enhance compliance with protocol procedures, the Week 10 tumor biopsy may be waived with 
written authorization from the Sponsor. 
To further characterize the patient population, Tumor Mutation Burden (TMB) testing will be 
performed for exploratory analysis. TMB is a biomarker which has been associated with response 
to immunotherapy in multiple disease types. TMB measures the number of mutations within a 
tumor genome, and tumors which harbor more mutations have been shown to have a greater 
likelihood of response to immunotherapy. 
Amendment 4 Justification: 
Amendment 4 corrects the study design by taking the current 4-arm trial and combining the 3 TIL 
classified arms into one treatment arm receiving HS-110 and nivolumab. This design contains 
treatment arm cohorts based on previous immune checkpoint inhibitor exposure. The TIL status 
and response to treatment will still be analyzed as an exploratory endpoint and the statistical plan 
was amended to support the change in trial design. This amendment also broadens the histological 
type of NSCLC to include squamous cell in addition to adenocarcinoma.  While the AD-100 line 
selected for HS-110 was derived from adenocarcinoma, an evaluation of upregulated gene 
expression between NSCLC adenocarcinoma and squamous cell carcinoma have multiple shared 
antigens between HS-110 and squamous cell carcinoma, thus supporting the rationale for inclusion 
of squamous cell carcinoma patients in this clinical trial. In addition, the long-term follow-up scans 
were defined to every 8 weeks and iRECIST evaluation criteria was added. Visit windows were 
expanded to allow for weekends and holidays, and the text throughout has been streamlined and 
rearranged for compliance with the ICH E6 guidelines and NIH-FDA protocol template. 
Amendment 3 Justification: 


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Amendment 3 addresses the exclusion criteria and safety monitoring secondary to the recent 
publication of myocarditis with combination immunotherapy treatment.25 It also realigns the 
physical exam schedule for consistency with nivolumab dosing days. 
Amendment 2 Justification: 
Amendment 2 changes address the issue of biopsies that are not evaluable in the ongoing cohorts. 
Recent experience suggests 25-40% of biopsies will not be evaluable. Patients without an 
evaluable pre-treatment biopsy are currently being balanced between the two arms in a “next man 
up” fashion without knowing their TIL status. Arm 4 will allow these patients to continue to 
receive while maintaining the appropriate sample size of Arms 2 and 3. This Arm also acts as an 
overflow for patients who consent to study participation and meet the eligibility criteria for a cohort 
that is filled. Finally, Amendment 2 will allow prospective revision of the expansion cohort 
selection criteria based on emerging response data from the trial. 
Amendment 1 Justification: 
In the period since the HS110-102 protocol was initiated, the treatment paradigm for this 
population has undergone a substantial change with the approval of checkpoint inhibitors for 
treatment of NSCLC. The main change in Amendment 1 is in response to that changing landscape: 
addition of study arms to assess the combination of viagenpumatucel with nivolumab 
(administered per current, approved labeling). Because nivolumab is an approved therapy for this 
indication and theophylline is not, the option for combination with theophylline is being 
discontinued (no patients were enrolled in the theophylline arm of the study.) Amendment 1 also 
introduces mandatory biopsies for the study arms prescribing the 2-drug combination of 
viagenpumatucel with nivolumab; this requirement is implemented to define the characteristics of 
the enrolled population and to allow comparison to emerging literature on patients who typically 
respond to checkpoint inhibitors (see Section 2.3 for more information). Finally, Amendment 1 
allows for expansion (of up to 30 patients) for any combination treatments that show efficacy 
signals. 
DURGA Amendment Change Log 
Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Amendment 2 
Updated protocol template; moved 
information to a new template; moved 
sections to fit content of new template 
All 
Sections 
 
Closed oxygen + HS-110 arm 
6.1  
 Overall Study Design 
Converted expansion cohorts to official 
Phase 2 study 
6.1 6.3 
and 14  
 Overall Study Design,  
Treatment Assignment, and 
Statistics 
 
Updated background information. 
Excluded discussion of hypoxia and 
adenosine pathway  
3  
 Synopsis 


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Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Removed oxygen as a combination 
drug; removed oxygen-related 
assessments 
4.1,4.2.2, 
5.3, 6, 8.2, 
9.4, 10.2, 
10.4, 11.3, 
12.8, and 
14.8  
 Study Specific Rationale, Oxygen (former), 
Exploratory Objectives, Investigational Plan, 
Subject Exclusion Criteria; Dose 
Modifications (former); Oxygen (former), 
Study Drug Storage, ABG Panel (former), 
Antigen Screening of Baseline or Archival 
Tumor Biopsy (former), Exploratory 
Endpoints (former) and Analyses (former) 
 
Updated schedule of assessments to 
reflect removal of oxygen endpoints and 
change in frequency of CT/MRI scans 
7  
 Study Procedures 
Added Cohort C for patients who cannot 
be entered into Cohort A or B 
6.1  
 Overall Study Design 
Added rationale for Cohort C 
4.4  
Rationale for Arm 4 
Added the possibility of using archival 
tissue for the pre-treatment biopsy 
6.1 and8.1   Overall Study Design and Subject Inclusion 
Criteria 
Added TCR repertoire characterization 
by sequencing as an exploratory 
endpoint 
5.3, 6.1, 
12.1.2, 
and 14.7  
Exploratory Objectives, Overall Study 
Design, Characterization of TCR Repertoire, 
and Exploratory Endpoints and Analyses 
Added correlation of pre- and post-
treatment TIL levels with clinical 
outcomes to exploratory objectives 
5.3, 6.1, 
and 14.7  
 Exploratory Objectives, Overall Study 
Design, and Exploratory Endpoints and 
Analyses 
Removed references to irRC for tumor 
assessments 
12.1, 12.2,  
14.7.2, 
and  
Appendix 
2 (former) 
 Tumor Assessments, Immune Criteria for 
Tumor Assessment (former), and 
Progression Free Survival (former),  
 
 
Added references for RECIST 1.1 for 
tumor assessments 
12.1, 
12.1.1, 
14.6.5, 
14.7, and 
Appendix 
3 
Tumor Assessments; RECIST 1.1 for Tumor 
Assessment; Progression-Free Survival, and 
Exploratory Endpoints 
 
Updated amendment change log 
Appendix 
4 
 
Revised language to allow prospective 
revision of the expansion cohort 
selection criteria  
6.3  
 Treatment Assignment 
 
Updated study drug information 
9.1 and 
10.1  
 Description of Study Drug and HS-110 (HS-
110) 
 


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Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Updated information for study drug 
storage 
10.2  
 Study Drug Storage 
Added objective response rate as the 
primary endpoint for Phase 2 
5.1 and 
14.5.2  
 Primary Objective and Phase 2: Objective 
Response Rate 
 
Updated statistical considerations 
relative to planned analyses 
14  
 Statistics 
Periodic editorial changes, including, 
updating Synopsis 
Multiple 
sections 
Throughout document 
Amendment 3 
Revised cardiac exclusion criteria 
secondary to recent publications of 
myocarditis with combination 
immunotherapy treatment 
8.2  
 Subject Exclusion Criteria 
Added cardiac safety monitoring 
secondary to recent publications of 
myocarditis with combination 
immunotherapy treatment 
7.2, 7.4, 
and 11.5  
 On-study Procedures, Schedule of 
Assessments, and Cardiac Monitoring 
Revised Physical Exam schedule to be 
consistent with nivolumab dosing days. 
7.2, 7.4, 
and 11.1  
 
On-study Procedures, Schedule of 
Assessments, and Physical Examination 
Amendment 4 
Corrected study design with the correct 
use of ‘treatment arms’ by combining 
the previous TIL-defined treatment arms 
(#2, 3, and 4) into one single treatment 
arm of nivolumab plus HS-110 (arm 
#5), and correlating TIL status to 
clinical outcomes by statistical analysis. 
6 and 14  
 Investigational Plan and Statistics 
Modified the eligibility criteria by 
removing exclusion criteria #12 which 
prohibited the entry of patients who 
received prior treatment with immune 
checkpoint inhibitors, and replacing 
with criteria to exclude patients who are 
refractory to checkpoint inhibitors. 
8.2  
 Subject Exclusion Criteria 
Modified the eligibility criteria by 
amending inclusion criteria #1 to allow 
squamous cell histology in addition to 
adenocarcinoma. 
8.1  
 Subject Inclusion Criteria 
Corrected study design by removing 
references to ‘cycles’. 
Multiple 
Sections 
Throughout document 


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Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
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Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Updated cardiac monitoring testing to 
allow Troponin T in lieu of Troponin I 
as per facility standard of care. 
7.2, 7.4, 
and 11.5  
On-study Procedures, Schedule of 
Assessments, and Cardiac Monitoring 
Updated the frequency of follow-up 
assessments and post-HS-110 
radiological scans to every 8 weeks 
rather than every 9 to 12 weeks.  
Multiple 
sections 
including  
7.2 and 
7.4  
 On-study Procedures and Schedule of 
Assessments 
Clarified the difference in follow up 
between ‘post-HS-110’ as off-treatment 
follow up, and ‘post-nivolumab’ as 
survival follow up. 
Multiple 
sections 
including  
7.2 and 
7.4  
 On-study Procedures and Schedule of 
Assessments 
Updated study endpoints to include 
Duration of Response and updated 
statistical plan based on amended study 
design. 
5, 14, and 
16  
 Trial Objectives and Purpose and Statistics 
 
iRECIST analysis criteria added. 
Multiple 
sections 
and 
Appendix 
3 
Throughout the document iRECIST was 
added in addition to RECIST 1.1 evaluations. 
Defined criteria for RECIST and iRECIST 
were added to Appendix 3. 
Streamlining of text throughout 
document for clarity and adding/re-
arranging text for compliance with ICH 
E6 guideline and NIH-FDA protocol 
template. 
Multiple 
sections 
 Throughout the document 
Expansion of visit windows, including 
EOT, to allow for weekends and 
holidays. Added text/assessments to 
ensure completeness and consistency 
between SOA and other sections of 
protocol. 
10 and 
Table 2  
 Study Procedures and Schedule of Activities 
 
Removal of option to conduct study 
visits at home with qualified home 
health personnel. 
10 and 
12.1  
 Study Procedures and HS-110 
Removal of intradermal testing. 
10 and 
Table 2 
Study Procedures and Schedule of Activities 
Removal of immune response lab draw 
at Week 4 and replacement at Week 1 
prior to dosing.  
10 and 
Table 2 
Study Procedures and Schedule of Activities 
Removal of pregnancy test at EOT visit 
and replacement at Baseline visit. 
10 and 
Table 2 
Study Procedures and Schedule of Activities 


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Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 93 of 95 
Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Addition of enrollment flowsheet 
Appendix 
5 
Appendix 5 
Amendment 5 
Expansion of patient population to 
include front line patients who have 
received immunotherapy with or 
without chemotherapy, who did not 
progress at the first imaging assessment 
and who will begin maintenance 
immunotherapy with pembrolizumab ± 
pemetrexed (Arm 6). 
Synopsis, 
7.1, 
Figure 3, 
7.2, 9, 9.1, 
9.2 
Trial Design, Overall Study Design, Study 
Treatments, Selection and Withdrawal of 
Patients, Subject Inclusion Criteria, Subject 
Exclusion Criteria 
Addition of study procedures (including 
treatment) and follow-up for Arm 6.  
9.3.1, 
10.5, 10.6, 
10.7, 11.5, 
12, 12.4, 
13.4, 14.1, 
14.1.1, 
15.6, 
Table 3  
Patient Completion, Arm 6: Treatment and 
Follow-up Procedures, Dose Adjustment 
Criteria, Study Drug Materials and 
Management, Labeling, Tumor Assessments, 
RECIST 1.1 and iRECIST for Tumor 
Assessment, Stopping Rules, Schedule of 
Activities (Arm 6: HS-110 + Pembrolizumab 
±Pemetrexed),  
Changed the primary endpoint to PFS, 
and assigned ORR as a secondary 
endpoint. 
Synopsis, 
7.1, 8.1, 
8.2, 16.5, 
16.6 
Trial Design, Overall Study Design, Primary 
Objectives, Secondary Objectives, Primary 
Efficacy Endpoints and Analysis, Secondary 
Efficacy Endpoints and Analysis 
Addition of option for Sponsor waiver 
for collection of Week 10 biopsy.  
Synopsis, 
6.3, 7.1, 
9.1, 
10.2.8, 
14.6, 16.7, 
Table 2 
Trial Design, Rationale for Obtaining 
Archival Tissue and Performing Tumor 
Biopsies, Overall Study Design, Inclusion 
Criteria, Week 10 and 16 Assessments, 
Analysis of Infiltrating T Cells (Optional 
Post Treatment Tumor Biopsy), Exploratory 
Endpoints and Analyses, Schedule of 
Activities (Arm 5: Treatment and Follow-up 
Procedures) 
Tumor Mutation Burden (TMB) testing 
added as exploratory analysis. 
Synopsis, 
14.9, 16.7 
Exploratory Endpoints, Tumor Mutation 
Burden Testing, Exploratory Endpoints and 
Analysis 
Modified and streamlined statistical 
methodology without formal hypothesis 
testing. 
Synopsis, 
16.1, 16.2, 
16.3, 16.4, 
16.5, 16.6, 
16.7, 16.8 
Overall Study Design, General Statistical 
Considerations, Sample Size, Analysis 
Populations, Disposition, Demography and 
Baseline Characteristics, Primary Efficacy 
Endpoints and Analysis, Secondary Efficacy 
Endpoints and Analysis, Exploratory 
Endpoints and Analysis, Safety Analysis 


Heat Biologics, Inc. 
 
 
Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 94 of 95 
Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
Separation of efficacy endpoints 
between RECIST 1.1 and iRECIST. 
Synopsis, 
8.1, 8.2, 
16.5, 16.6 
Trial Design, Primary Objectives, Secondary 
Objectives, Primary Efficacy and Endpoints 
and Analysis, Secondary Efficacy Endpoints 
and Analysis 
Removal of Appendix 5.  
Appendix 
5 
Level 2 Flowchart / Minimum Enrollment 
Requirements for the Initial Examination of 
Response by the DMC (version 1.0) 
Removal of histology-based cohorts in 
Arm 5, and addition of enrollment caps 
for Treatment Arm 5 cohorts and Arm 
6. 
Synopsis, 
7.1, 16.1 
Trial Design, Overall Study Design, General 
Statistical Considerations 
Change in terminology from ‘subjects’ 
to ‘patients’. 
N/A 
Various throughout document 
Change in terminology from ‘relapsed’ 
to ‘progressor’. 
N/A 
Various throughout document 
Modification of existing eligibility 
criteria from a 6-month CPI requirement 
to a 4 month CPI requirement. 
Synopsis, 
9.1 
Subject Inclusion Criteria 
Removal of Week 19 visit for Arm 5. 
10.2, SOA Arm 5: On Study Treatment Procedures  
 
Removal of exploratory testing 
involving TCR repertoire, major 
histocompatibility (MHC) class I 
expression, and characterization of neo-
antigens. 
Synopsis, 
7.1, 8.3, 
14.4, 16.7 
Trial Design, Overall Study design, 
Exploratory Endpoints, Exploratory 
Endpoints and Analysis, Phenotyping 
Phenotypic Analysis of Blood Lymphocyte 
Subsets by FACS 
Reference to Investigational Product as 
‘HS-110’ from ‘Viagenpumatucel-L’ 
N/A 
Various throughout document 
Change in terminology from ‘Off-
Treatment Follow-Up’ to ‘Post-HS-110 
Follow-Up’ period. 
N/A 
Various throughout document 
Revised nivolumab dosing schedule in 
Arm 5 Post-HS-110 Follow-Up period. 
7.1, 7.2, 
9.3.1,  
Overall Study design, Study Treatments, 
Patient Completion,  
Removal of immune response lab draw 
at Week 1 prior to dosing and 
replacement with TMB. 
10.2.1, 
Table 2 
Week 1 Assessments (Day 1), Schedule of 
Activities (Arm 5: Treatment and Follow-up 
Procedures) 
Amendment 6 
Clarification of timing for addition of 
HS-110 to front-line maintenance 
treatment. 
9.0, 9.1.9, 
10.1, 
10.5.1 
Synopsis, Selection and Withdraw of 
Patients, Subject Inclusion Criteria, 
Screening Procedures and Baseline, Week 1 
Assessments 
Clarification that original primary 
endpoint of ORR will still apply to Arm 
5 Cohorts A & B, and the recently 
8.1, 
16.5.2, 
16.6 
Synopsis, Primary Objectives, Primary 
Efficacy Endpoints; Secondary Efficacy 
Endpoints 


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Viagenpumatucel-L 
Protocol HS110-102 
 
CONFIDENTIAL 
Amendment 6, 24 May 2019  
Page 95 of 95 
Protocol Change 
Affected 
Section(s) 
Numbers 
Section Titles 
added PFS will only the primary 
endpoint for the new Arm 6 Cohorts C 
& D. Also corrected the omission of 6 
and 12 month PFS endpoints. 
Increase in Cohort B Sample Size from 
40 to 60 with option for over-enrollment 
based on patient availability; Decrease 
in Cohort C/D Sample Size from 40 to 
up to 20 based on patient availability. 
Total trial sample size remains 
unchanged. 
7.1, 
Figure 3,  
Synopsis, Overall Study Design, Study 
Design 
Clarifying remarks inserted to eligibility 
criteria. 
9.1, 9.2 
Synopsis, Subject Inclusion Criteria, Subject 
Exclusion Criteria 
Modified Injection Site Reaction 
Grading Scale to capture more ISRs. 
Appendix 
2 
Injection Site Reaction Grading Scale 
Added exclusion criteria for patients 
who have received more than 3 lines of 
treatment for metastatic NSCLC. 
9.2 
Synopsis, Subject Exclusion Criteria 
Clarification on TMB collection when 
not obtained at Week 1. 
10.2.1, 
Table 2, 
14.6 
Week 1 Assessments, Arm 5 Schedule of 
Assessments, Tumor Mutation Burden 
Alignment of Arm 6 PE with physician 
visits. 
10.5.5, 
10.5.8, 
Table 3 
Week 5 & 11 Assessments, Week 10 
Assessments; Arm 6 Schedule of 
Assessments