A Phase II Randomized Study of Safety and Efficacy of a Multiple Antigen Vaccine (STEMVAC) in Non-Small-Cell Lung Cancer Patients
Phase: PHASE2
Conditions: Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8
Sponsor: University of Washington

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PROTOCOL
UNIVERSITY OF WASHINGTON, DEPARTMENT OF MEDICINE, DIVISION OF ONCOLOGY
AND
VA PUGET SOUND HEALTH CARE SYSTEM
Current Version Date:  11/13/2023
CVI Protocol 151
A Phase II Randomized Study of Safety and Efficacy of a Multiple Antigen Vaccine (STEMVAC) in Non-
Small-Cell Lung Cancer Patients 
University of Washington Researchers:
Shaveta Vinayak, MD
PI - Associate Professor
Division of Oncology, UW
(206) 616-0583
Rafael Santana-Davila, M.D.
Co-PI -Associate Professor
Division of Oncology, UW
(206) 606-2048
Mary L. Disis, M.D.
Professor 
Division of Oncology, UW
Member FH
(206) 616-1823
William R. Gwin, M.D.
Assistant Professor
Division of Oncology, UW
(206) 221-5956
Andrew Coveler, M.D.
Associate Professor
Division of Oncology, UW
(206) 221-7509
John B. Liao, M.D., PhD
Associate Professor
GYN/ONC, UW
(206) 543-3915
Katelyn Jones
Research Study 
Coordinator
Division of Oncology, UW 
(206) 685-9903
Jennifer Childs, M.P.H.
Research Coordinator
Division of Oncology, UW
(206) 616-2305
Kris Kauno, CCRC
Research Coordinator
Division of Oncology, UW
(206) 543-3829
Lawrence Ngo
Research Coordinator
Division of Oncology, UW
(206) 606-1303
Ying Liu, PhD
Biostatistician
Division of Oncology, UW
(206) 221-0869
Emergency (24 hour) pager for University of Washington Patients:  Rafael Santana-Davila, (206) 314-9194
External Performance site researchers:
Solomon A. Graf, M.D.
Attending Physician/VA PI
VA Puget Sound Health 
Care System
(206) 277-6829
Jeannine Barton
Lead Clinical Research 
Coordinator
VA Puget Sound Health 
Care System
(206)-277-3101
 Emergency (24 hour) numbers for VA:  Jeannine Barton (206) 369-5743 or 1-800-329-8387 and ask the VA operator 
to page the on-call oncologist.

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Protocol Signature Page
’
Site Principal Investigator s Agreement
I have read “A Phase II Randomized Study of Safety and Efficacy of a Multiple Antigen Vaccine (STEMVAC) in Non-
Small-Cell Lung Cancer Patients”. 
I have fully discussed the objectives of this trial and the contents of this protocol with the Sponsor representative. 
I agree to conduct the study as outlined herein and in accordance with International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP), with applicable Food and Drug Administration (FDA) regulations set forth in 
21 Code of Federal Regulations (CFR) Parts 50,54, and 312, and all other applicable regulatory requirements. 
Principal Investigator Name: ____________________________________ 
____________________________________             _____________________ 
Signature 
                    Date 

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TABLE OF CONTENTS
Study Synopsis.............................................................................................................................................4
List of Appendices.......................................................................................................................................8
Abbreviations...............................................................................................................................................9
Introduction................................................................................................................................................11
Background................................................................................................................................................12
Objectives ..................................................................................................................................................15
Agent Information .....................................................................................................................................16
Vaccine Administration…………………………………………………………………………………  18
Patient Selection ........................................................................................................................................20
Experimental Design .................................................................................................................................21
Plan of Treatment ......................................................................................................................................23
Withdrawal from Study Treatment............................................................................................................27
Evaluation and Management of Toxicity Related to the Study Treatment ...............................................27
Accrual and Criteria for Premature Study Termination ............................................................................30
Statistical Considerations...........................................................................................................................31
Safety Reporting ...……………………………………………………………………………………… 35 
Administrative Considerations ..................................................................................................................35
References..................................................................................................................................................38

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STUDY SYNOPSIS
Title
A Phase II Randomized Study of Safety and Efficacy of a Multiple 
Antigen Vaccine (STEMVAC) in Non-Small-Cell Lung Cancer 
Patients 
Study Population
Patients with histologically-confirmed diagnosis of stage IV non-small 
cell lung cancer (NSCLC), that are not eligible for approved targeted 
therapies, have completed 3 - 4 cycles of chemoimmunotherapy 
(induction treatment), have achieved responsive or stable measurable 
disease and are receiving or are candidates to continue maintenance 
treatment with pembrolizumab +/- pemetrexed; the treatment would be 
dependent on histology.  Patients will be enrolled after induction 
chemoimmunotherapy, and will have received no more than 2 cycles of 
maintenance pembrolizumab +/- pemetrexed. Patients will be 
randomized to one of two research treatments given concurrently with 
maintenance therapy.  
Rationale
Immunotherapy is a significant treatment advance for NSCLC patients 
and the only therapy that can lead to a long term survival, although this 
occurs in less than 20%[1].  The current standard of care for patients 
with 
NSCLC 
is 
chemoimmunotherapy 
with 
carboplatin, 
pemetrexed/paclitaxel and pembrolizumab.  These regimens were 
studied in two Phase III trial, which randomized patients to either 
chemotherapy plus immunotherapy (pembrolizumab) vs. chemotherapy 
alone.  In patients with non-squamous histology the combination arm 
showed a clear survival advantage with a median overall survival of 22 
months vs 10.7 months for those who received chemotherapy alone (HR 
0.56 [95% CI 0.45-0.70], P < .00001)[2].   In patients with squamous 
histology  the combination arm showed a survival advantage with a 
median overall survival of  17.1 months versus 11.6 for those patients 
treated with chemotherapy alone (HR, 0.71 (95% CI: 
However, it is also clear that the majority of patients will have a limited 
response and die from their disease within 2 years.  New therapies are 
needed to stimulate an immune response against the cancer that could in 
turn lead to long term responses in all patients.
Vaccines are able to induce tumor specific immunity and increase CD8 
tumor infiltrating T-cells (TIL).  High levels of TIL predicts response to 
immune checkpoint inhibitors (ICI) therapy in animal models and lung 
cancer patients[3, 4].  Unfortunately, high levels of TIL, defined as 
>50% of tumor stromal lymphocytes, are found in less than 10% of 
patients and less than a quarter of NSCLC patients have any evidence of 
TIL.  Vaccine induced TIL could “jump start” the immune system to 
stimulate further clinical responses with concurrent pembrolizumab.  
Vaccines targeting biologically relevant antigens could recognize and 
eliminate lung cancer cells which have undergone epithelial to 
mesenchymal transition (EMT); a process which promotes metastases in 
lung cancer.

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We developed a multi-antigen vaccine, STEMVAC, that targets proteins 
in the EMT pathway. We have identified epitopes within the sequence 
of non-mutated-tumor antigens that selectively induce Type 1 Th1 
immunity which supports generation of CD8 cytolytic T-cells (CTL)[5]. 
Th1 selective epitopes significantly inhibit cancer growth by causing a 
marked influx of CD8 TIL[6, 7].  
We hypothesize that immunizing patients with advanced NSCLC with 
measurable disease after induction chemoimmunotherapy while 
receiving immune checkpoint inhibitors will generate tumor tracking 
Type I T-cells resulting in increased activated CD8 TIL.  To further 
study this hypothesis, we propose a randomized Phase 2 study in which 
patients with NSCLC that have completed 3 - 4 cycles of induction 
treatment will be randomized to treatment with STEMVAC+GM-CSF 
or GM-CSF alone concurrently with pembrolizumab +/- pemetrexed.
Objectives
Primary
1.
To 
determine 
whether 
intradermal 
(ID) 
injection 
of 
STEMVAC+GM-CSF vaccination increases the percentage of 
CD8+ TIL in patients with advanced NSCLC compared to 
patients who receive ID GM-CSF alone.  
2.
 To evaluate safety of STEMVAC immunization and concurrent 
pembrolizumab +/- pemetrexed maintenance therapy in patients 
with advanced NSCLC.
Secondary
1. To evaluate the magnitude of the immune response generated to 
STEMVAC when given in combination with pemetrexed and 
pembrolizumab maintenance therapy. 
2. To determine whether vaccine induced T-cells traffic to tumor 
and can eliminate cancer cells which have undergone EMT.
3. To 
evaluate 
potential 
clinical 
efficacy 
of 
STEMVAC 
immunization by comparing overall response rate between both 
arms.
4. To determine whether vaccination increases CD8 T-cell 
activation markers (GZB, CD127 and PD1) and Type I immune 
cells (CD4 Th1) in the tumor. 
Study Design
This is a randomized Phase II study in patients with advanced NSCLC 
who have completed induction therapy without progression and have 
measurable disease.
Patients receiving maintenance pembrolizumab +/- pemetrexed (per 
standard 
of 
care) 
will 
be 
randomized 
to 
one 
of 
two  
treatments:

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     ARM 1: ID administration of 300 mcg/dose STEMVAC admixed 
                    with 100 mcg/dose of GM-CSF 
     
     ARM 2: ID administration of 100 mcg/dose GM-CSF alone 
Patients will undergo a core biopsy (fresh tissue biopsy is preferred; 
archival tissue can be used if fresh tissue core is not feasible (only if 
there sufficient archival tissue) of their tumor prior to the assigned 
immunization arm and again three weeks after their third vaccine.  
Patients may also receive up to 1 additional booster vaccine (with the 
same treatment arm originally assigned) approximately 9 weeks after the 
third vaccine.
Number of Patients
The study will accrue up to 40 patients with at least 20 patients per arm.  
Replacements are possible. 
Outcome Measures
Primary Endpoints
1. Percentage of CD8+ TIL in patients between the two arms. 
Immunohistochemical (IHC) staining for CD3, CD4, and CD8 
will be performed on the biopsies collected pre-treatment and 
post 3 vaccine administration.
2. Safety will be assessed per Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0, physical exam and laboratory 
tests.
Secondary Endpoints
1. STEMVAC 
induced 
immunity 
in 
combination 
with 
pembrolizumab +/- pemetrexed. Chemoimmunotherapy might 
impact the immune response generated to STEMVAC. We will 
measure the magnitude of the Th1 STEMVAC specific immune 
response using IFN-g ELISPOT.
2. T-cells traffic to tumor and can eliminate cancer cells which 
have undergone EMT. We will assess TCR-beta (TCRb) gene 
usage in both T-cell lines expanded from peripheral blood and in 
the tumor biopsy, and the expression of EMT related genes in the 
tumor after vaccination with STMEVAC+GM-CSF or GM-CSF 
alone.
3. Clinical Efficacy of the vaccine. We will evaluate clinical 
response three weeks after the 3rd vaccine using RECIST 1.1. 
Although the study is not powered to definitively address overall 
response rate (ORR), data generated may give some indication of 
clinical utility.
4. T-cell activation and Type I lymphocyte markers will be 
evaluated by IHC staining in pre- and post-vaccine biopsies. We 
will evaluate CD4+Tbet+ (Th1), CD4+GATA3+ (Th2) and 

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activation markers (GZB, CD127, and PD-1) on CD8 T-cells in 
tumor biopsies.

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List of Appendices
Appendix A 
ECOG Performance Scale
Appendix B
Calendar of Events
Appendix C
Data and Safety Monitoring Plan
Appendix D
NCCN Guidelines for Menopause Status

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Abbreviations
AE
Adverse Event
ANA
Antinuclear antibodies
ANC
Absolute neutrophil count
APC 
Antigen presenting cells
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CNS
Central Nervous System
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTL
Cytolytic T-cell
Co-PI
Co - Principal Investigator
DSMP
Data and Safety Monitoring Plan
EDTA
Ethylenediaminetetraacetic acid
EMT
Epithelial to mesenchymal transformation
FH
Fred Hutchinson 
FH/UW CC 
IRB
Fred Hutchinson /University of Washington Cancer Consortium Institutional Review Board
HLA
Human leukocyte antigen
HRPO
Human Research Protections Office
ICI
Immune checkpoint inhibitor
ID
Intradermal
IFN-g
Interferon-gamma
IHC
Immunohistochemistry
IND
Investigational New Drug
MDSC
Myeloid Derived Suppressor Cells

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Abbreviations, continued
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIH
National Institutes of Health
NIH OBA
National Institutes of Health Office of Biotechnology Activities
NSCLC
Non-small cell lung cancer
ORP
Office of Research Protections
rhuGM-CSF
recombinant human granulocyte-macrophage colony stimulating factor; GM-CSF; 
LEUKINE® (sargramostim)
SAE
Serious Adverse Event
Th
T helper cells
Th1
T helper 1 cells
Th2
T helper 2 cells
TIL
Tumor infiltrating lymphocytes
Treg
T regulatory cell
ULN
Upper limit of normal
UPN
Unique patient number
USAMRMC
United States Army Medical Research and Material Command
UW
University of Washington
UW IBC
University of Washington Institutional Biosafety Committee
UW TRU
University of Washington Translational Research Unit
UW IDS
University of Washington Investigational Drug Pharmacy
UW IT
University of Washington Information Technology

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1. INTRODUCTION
Lung cancer remains the leading cause of cancer mortality within the Veterans Affairs Health Administration[8] 
and the United States accounting for 24% of all cancer deaths[9]. In 2020 it is estimated that there will be 
228,820 new cases and 135,720 deaths within the United States. Lung cancer is composed of different 
histologies of which non-squamous makes the preponderance of cases. The majority of patients present with 
metastatic disease for which treatment is offered to alleviate symptoms and prolong life but is not curative, and 
most patients die from their disease within 2 years of diagnosis[2].
Immunotherapy through immune checkpoint inhibition has dramatically changed the paradigm of how we treat 
this disease and it’s the only therapy that has been shown to provide a subset of patients with long term 
outcomes.  Surviving more than 5 years with NSCLC was extremely rare before the era of immunotherapy, now 
although difficult to estimate given the novelty of this therapy, it appears that close to 20% patients treated with 
checkpoint inhibitors are alive 5 years after diagnosis[1].  However, the great majority of patients experience 
only a small benefit and ultimately die from their disease. 
Vaccines developed for the treatment of cancer have been in therapeutic human clinical trials for several years 
and are, at last, showing some success in randomized Phase III studies[10, 11].  To be effective, vaccines must 
arm the immune system to target and destroy the disease-causing agent.  The mechanisms of immune evasion 
by non-small cell lung cancer (NSCLC) are currently poorly understood. In an effort to provide more patients 
with therapies that can achieve long term survival, development of new immunotherapeutic agents, such as 
vaccines, that can overcome cancer resistance is of paramount importance.  We have developed a multi-antigen 
polyepitope vaccine, STEMVAC, targeting immunogenic proteins involved in epithelial to mesenchymal 
transition (EMT); a process which promotes metastases in lung cancer.  We hypothesize that immunizing 
patients with advanced NSCLC, after an initial response to chemo-immunotherapy will generate tumor 
trafficking Type I T-cells resulting in increased activated CD8 tumor infiltrating T-cells (TIL).  
Recent evidence indicates that Type I immunity, associated with the production of interferon-gamma (IFN-g), is 
needed for cancer eradication.  Type I immunity enhances cross priming at the site of cancer initiation by 
activating local antigen presenting cells (APC) to more efficiently present immunogenic proteins or tumor 
antigens to T cells.  Cross priming is the primary method by which immunity is generated against cancer as 
tumor cells do not express the recognition molecules needed for immune activation.  IFN-g is primarily secreted 
by CD4+ T-helper 1 cells (Th1).  Vaccine strategies designed to elicit tumor antigen specific Th1 immunity 
have the potential to generate epitope spreading (a broadening of immunity to additional antigens), concurrently 
stimulate antigen specific cytotoxic CD8+ T cells, and establish immunologic memory.  Immunologic memory 
will ensure that the destructive immune response will deploy when the antigen is expressed in the future.  
We have identified 5 stem cell/EMT proteins (CDH3, CD105, YB-1, MDM2 and SOX2) that are overexpressed 
in lung cancer and associated with poor survival.  We have created a vaccine, STEMVAC, composed of 
extended Th1 epitopes derived from these proteins.  Vaccination in lung and breast mouse models has shown 
immunization with STEMVAC antigen sequences to be safe and inhibit tumor growth.  We have recently 
completed a Phase I study where we enrolled 32 patients to determine the safety and potential efficacy of up to 
3 escalating dose-levels of STEMVAC.  All 3 doses had an acceptable safety profile with the majority of 
adverse events being grades 1 and 2.
We propose a Phase II randomized clinical trial administering one of two treatment arms (1) STEMVAC+GM-
CSF or (2) GM-CSF alone in patients with advanced non-squamous NSCLC who have completed induction 

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therapy without progression, have measurable disease and continue on pemetrexed/pembrolizumab maintenance 
(per standard of care).
Our primary endpoints are to assess whether intradermal (ID) injection of STEMVAC+GM-CSF vaccination 
increases the percentage of CD8+ TIL in patients with advanced NSCLC compared to patients who receive ID 
GM-CSF alone and the safety of immunization with concurrent pemetrexed/pembrolizumab maintenance 
therapy in patients with advanced NSCLC.  The secondary objectives are to evaluate the magnitude of the 
response induced by STEMVAC concurrent with pemetrexed/pembrolizumab maintenance therapy, determine 
whether vaccine induced T-cells traffic to tumor and can eliminate cancer cells which have undergone EMT, to 
evaluate the clinical efficacy of the vaccine by comparing overall response in both arms, and determine whether 
vaccination with STEMVAC increases T-cell activation markers and Type I immune cells.    
2. BACKGROUND
2.A. Role of immunotherapy in non-small cell lung cancer (NSCLC) treatment.  Lung cancer is the leading 
cause of death from cancer, accounting for almost one third of all cancer deaths.  The most common type of 
lung cancer is NSCLC that constitutes 85% of all lung cancer cases.  Most patients are diagnosed at late-stage, 
when the treatments have a limited efficacy and treatment is palliative.  For many years, approaches to improve 
outcome and survival focused on decreasing smoking rates, identification of early biomarkers and development 
of new imaging techniques for early detection, although without much success.  Immunotherapy launched a 
new era in the treatment of NSCLC. Immune checkpoint inhibitor (ICI) monoclonal antibodies have changed 
the standard of care for metastatic NSCLC.  The combination of chemotherapy and pembrolizumab as first line 
therapy for advanced PD-L1 positive NSCLC patients has significantly increased progression free and overall 
survival as compared to chemotherapy[2].  The overall response rate to combination immuno-chemotherapy is 
48% as compared to 19% for chemotherapy alone in patients with non-squamous lung cancer and 62.6% vs 
38.4% in patient with squamous NSCLC.  Unfortunately, most clinical responses are transient and although 
patients are living longer, by 20 months after the initiation of treatment less than a quarter of patients are free of 
disease and the majority eventually succumb to NSCLC[2,50].  Our aim is to improve the success of 
immunotherapy to all patients. 
2.B. Vaccines to elicit tumor specific Type I T-cells in NSCLC. There has been intense interest in defining 
the predictors of response to ICI in NSCLC in an attempt to optimize immunotherapy for all patients with the 
disease.  Three markers predict outcome: (1) tumor mutational burden, (2) PD-L1 expression in the tumor, and 
(3) CD8+ tumor infiltrating lymphocytes (TILs).  Tumors with high mutational burden have a higher likelihood 
of processing and presenting those mutations in class I MHC molecules for the generation of CD8 cytotoxic T-
cells (CTL).  Mutations can appear foreign to the immune system and elicit a more “viral-like” response.  About 
50% of all NSCLC have the level of mutations needed to potentially stimulate recognition of mutation related 
antigens[12].  Patients with PD-L1 expression of or above 50% of the tumor cells have increased rate of 
response to treatment with ICI, although responses are usually partial and most of them stop responding and 
relapse.  Population based studies of tumor immune infiltrates have defined the type of immune response 
needed for clinically effective anti-tumor immunity; a high density of Type I T-cells, both CD4+ (Th1) and 
CD8+ that have trafficked to tumor, have penetrated the stroma, and are of a memory phenotype[13, 14].  
Investigators studying factors that predict response to ICI in NSCLC have found Type I immunity, especially 
CD8 TIL, present in the tumor at the time of treatment indicates responders.  The reality, however, is that high 
levels of TIL, defined as >50% of tumor stromal lymphocytes, are found in less than 10% of patients and about 
a quarter of NSCLC patients have no evidence of TIL[15, 16].  The tumor microenvironment in many NSCLC 
patients is Type II (Th2), characterized by T regulatory (Treg) cells, neutrophils and type 2 macrophages that 
prevent an efficient Type I response and contribute to escape from the immune system[17, 18].    

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In order to increase the response rate to ICI we need strategies to generate Type I T-cells, especially CD8 T-
cells, in patients with NSCLC who have not completely responded to immuno-chemotherapy.  Methods to 
increase Type I TIL at the time of maintenance pemetrexed/pembrolizumab in patients with measurable disease 
may stimulate further clinical responses as T-cells are elicited.  Vaccines able to induce a strong Type I immune 
response could increase the CD8 T-cells infiltrating the tumor and improve responses to ICI. 
2.C. T-helper Type I (Th1) vaccines as a vehicle for lung cancer treatment.  What antigens should we target 
in a lung cancer vaccine?  Lung cancer has one of the highest mutation rates of all types of cancer.  Mutations 
can elicit immune response, as they look foreign to the immune system.  However, mutations in NSCLC are 
highly heterogeneous not only between patients but also within the tumor, which makes difficult to define a 
vaccine based on mutated antigens that could succeed in most of the patients.  In contrast, overexpressed non-
mutated proteins in NSCLC are commonly shared between patients, as overexpression respond to the 
requirements of the tumor cells to grow and divide.  Non-mutated tumor antigens have long been studied in 
cancer vaccines.  Overexpression of the protein alters the manner in which immunogenic epitopes are displayed 
in MHC molecules as compared to the protein expressed at a basal level thus making immune recognition tumor 
specific[19].  Unfortunately, a barrier to the successful clinical application of vaccines targeting non-mutated 
tumor associated proteins is the finding that specific regions (epitopes) of these antigens induce T-regulatory 
(Treg) cells which are expanded when the epitopes are included in a vaccine formulation.  The result is a 
suppression of therapeutically effective immunity[6, 20, 21].
Our group has focused on the development of vaccines specifically designed to elicit CD4+ T-cells for several 
reasons; (1) Type I CD4+ T-cell responses, Th1, can significantly alter the immune microenvironment to 
support a dominant cytotoxic T-cell response and epitope spreading which is a broadening of the immune 
response to multiple antigens in the tumor through enhanced cross-priming by cytokine activated antigen 
presenting cells (APC), (2) CD4 T-cell epitopes can be identified which bind with high affinity across multiple 
HLA-DR alleles (promiscuous epitopes) to create a universal vaccine which can be processed by diverse HLA 
and (3) appropriately primed CD4 T-cells establish immunologic memory which is essential for anti-tumor 
efficacy[22, 23].  We have developed a novel method of Class II (CD4) epitope identification that included 
functional screening to identify Th2 or Treg inducing epitopes with the aim of editing out those sequences to 
allow unfettered Type I immunity to be generated.  Our model antigen was Insulin Growth Factor Binding 
Protein (IGFBP)-2 which we had defined as immunogenic in patients with cancer and a protein associated with 
increased metastases[6].  We identified putative Class II interacting sequences via a multi-algorithm approach 
to ensure responsiveness across diverse HLA alleles [24].  Secondly, we conducted population-based screening 
of predicted IGFBP-2 epitopes for Type I and II cytokine secretion to determine sequences that elicit Th2 or 
Treg using samples reflective of diverse HLA types (>95% population coverage (n=40)).  We found that there 
were sequences of IGFBP-2 that, across most individuals studied, elicited primarily IFN-gamma (g) (Th1) or 
IL-10 (Th2) responses.  IGFBP-2 is highly homologous between mouse and man (82%).  Mice immunized with 
Th1 selective or Th2 selective sequences of IGFBP-2 developed a similar restricted phenotype of response as 
we observed in human T-cells in in vitro culture.  Immunization with the Th1 selective vaccine significantly 
inhibited the growth of an implanted syngeneic epithelial tumor (p<0.01), while immunization with the Th2 
selective epitopes had no effect on tumor growth (p>0.05 to control).  When equal concentrations of the two 
vaccines were admixed and then used to immunize, the Th2 inducing vaccine completely abrogated the anti-
tumor effect of the Th1 selective vaccine [6].  We have subsequently shown our Th1 selective vaccines induce 
tumor specific immunity and increase CD8+ TIL in animal models[7].  These data demonstrate that unless 
regulatory sequences are removed from vaccines targeting non-mutated tumor associated proteins effective 
immunity cannot be generated due to the immune-dominance of self-regulatory peptides.  

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2.D. STEMVAC: a Th1 vaccine targeting the epithelial to mesenchymal transition (EMT).  EMT is a 
process by which anchorage dependent cancer cells develop the capacity to metastasize and become drug 
resistant as a stem cell-like phenotype emerges[25].  Metastases and the development of drug resistance are two 
of the main factors leading to relapse and death in NSCLC.  EMT is a common process in metastatic NSCLC.  
Evidence of circulating tumor cells which have undergone EMT are present in most patients at this stage [26].  
Tumor EMT signatures are associated with a lack of T-cell infiltration in NSCLC[27].  The presence of EMT 
increases expression of multiple immunosuppressive cytokines, including IL-10 and TGF-beta and the 
upregulation of numerous secondary immune checkpoint proteins[27].  Elimination of NSCLC cells that have 
undergone EMT may both limit metastasis and augment immunity.  
We have identified several proteins on the EMT pathway, CDH3, CD105, YB-1, MDM2, and SOX2, which are 
important in lung cancer progression and are overexpressed in NSCLC as compared to normal lung tissue. 
CDH3 is highly expressed in more than 60% of NSCLC tumors[28].  High CDH3 expression has been 
significantly associated with metastasis, stage, shorter disease-free survival (DFS) and overall survival (OS) 
compared with low expression.  CD105 upregulation correlates with neo-vascularization and angiogenesis and 
is highly expressed during EMT[29].  CD105 overexpression may define EMT in NSCLC.  YB-1 is a protein 
involved in transcription and translation and is overexpressed in 50% of advanced NSCLC.  YB-1 over-
expression in lung cancer is associated with the development of metastasis and inferior OS[30].  MDM2 is also 
overexpressed in about 50% of NSCLC[31].  As a mediator of drug resistance, MDM2 overexpression is 
associated with reduced DFS and OS in multivariate analysis (p<0.01 for both comparisons)[32].  SOX2 
overexpression is found in more than a third of NSCLC and is an independent predictor of poor prognosis[33].  
Inhibition of SOX2 expression inhibits the migration and invasion of cancer cells in culture[34].  We 
hypothesize that proteins overexpressed in stem cells or in EMT can serve as vaccine candidates.  We have used 
the Th screening method described before to identify epitopes that preferentially elicit Type I but not Type II 
cytokines for each of the 5 antigens included in the vaccine.  These Th1 inducing epitopes are encoded in 
STEMVAC.
2.E. STEMVAC is immunogenic and safe in a Phase I clinical trial.  We have performed a Phase I dose 
escalation study of 150mcg, 300mcg, and 600mcg of intradermal (ID) STEMVAC with 100mcg GM-CSF in 
patients with advanced stage breast cancer (NCT02157051).  Vaccines were given once a month for 3 
immunizations followed by 2 booster immunizations at 6 and 9 months.  Thirty patients were enrolled (10/arm) 
and the primary objectives of the study were to determine the safety and optimal immunogenic dose of 
STEMVAC.  Secondary objectives were to determine whether booster vaccines enhanced the level of immunity 
achieved and whether Treg cells or myeloid derived suppressor cells (MDSC) were elicited or impacted vaccine 
outcomes.  Immunity was assessed by IFN-g and IL-10 ELISPOT.  STEMVAC was immunogenic and we 
defined the 300mcg dose as optimal.  IFN-g STEMVAC specific immune responses were detected at all dose 
levels and no increase in IL-10 secreting STEMVAC specific T-cells was observed.  Flow cytometry evaluation 
revealed no increase in Treg levels, MDSC, or increase in PD-1 expression on either CD4 or CD8 T-cells.  The 
150mcg dose was the least immunogenic, while he 300mcg and 600mcg doses were equally immunogenic.  
STEMVAC immunization was safe, 98% of all adverse events (AE) were grade 1 or 2.  Of the possibly, 
probably, or definitely related AEs the most common included injection site reaction (30%), flu-like symptoms 
after vaccination (18%), transient leukopenia (18%), transient lymphopenia (9%), arthralgia (9%) and fatigue 
(9%).  There were 4 grade 3 events that consisted of transient lymphopenia temporally related to vaccination.  
Further, there was no clinical evidence of the development of autoimmunity.  Several measures assessing the 
potential of subclinical autoimmunity were made evaluating serum antinuclear antibodies (ANA), C3, anti-
dsDNA, and TSH at each time point.  Only one grade 1 autoimmune AE was recorded on the study; a 
conversion of an ANA from 0 to a titer of 1:40 which corrected spontaneously on subsequent testing.

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These data suggest that plasmid-based DNA vaccination, using sequences derived from tumor associated 
proteins such as those included in STEMVAC, which contain numerous Th1 epitopes, can be safely 
administered and result in long lived immunity.
2.F. GM-CSF as an immunotherapeutic in lung cancer and a vaccine adjuvant.  We included a GM-CSF 
alone control arm due to the potential anti-tumor activity of GM-CSF alone in NSCLC. Granulocyte-
macrophage colony-stimulating factor (GM-CSF) is a cytokine secreted by multiple cells including 
macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts.  This potent cytokine 
facilitates the maturation and migration of dendritic cells to lymph nodes and enables the presentation of tumor-
associated antigens to generate a T-cell response.  GM-CSF has been evaluated alone or in combination with 
radio- or chemo-therapy in several malignancies[35, 36].  NSCLC patients treated with an EGFR inhibitor in 
combination with radiotherapy and GM-CSF showed a significantly increased objective response (ORR 95.2% 
vs. 71.4%, p<0.05) compared to those patients treated with the EGFR inhibitor alone. Treatment with 
radiotherapy and GM-CSF significantly increased CD3+ and CD4+ T-cells (p<0.05) in blood, and improved 
one-year progression free survival (p=0.047)[37].  Combination of GM-CSF with radiotherapy has shown to 
induced immune mediated tumor regression at metastatic sites distant to the irradiated field (abscopal effect).  
In a phase II trial to evaluate abscopal response induced by radiotherapy + GM-CSF in patients with solid 
metastatic tumors, including lung cancer, 27% of patients presented abscopal responses, defined as a reduction 
of at least 30% in any measurable non-irradiated lesion >1cm.  Those patients with abscopal response also 
showed improved overall survival (20.98 vs 8.33 months)[38].  
Incorporation of adjuvants to vaccines increases their immunogenicity. As a vaccine adjuvant, GM-CSF 
upregulates co-stimulatory (CD80 and CD86) and MHC class II molecules, activating dendritic cells (DCs), 
CD4+ and CD8+ T-cells[39].  GM-CSF has been tested in numerous animal and human trials as vaccine 
adjuvant for anti-tumor immunotherapy in prostate, skin, breast and lung cancer[40, 41].  GM-CSF drives the 
activation of macrophages to an M1-like pro-inflammatory phenotype in vitro[42-44], producing chemokines 
for leukocyte recruitment[45] and pro-inflammatory cytokines[42].  These molecular signals contribute to the 
role of GM-CSF in the differentiation and activation of T helper (Th) type 1 and Th17 cells, further promoting 
pro-inflammatory events[46].  The use of GM-CSF as an adjuvant to the plasmid-based STMEVAC vaccine, 
which contain numerous Th1 epitopes, could potentiate the T helper (Th) type 1 immunity.
3.  OBJECTIVES
3.A. Primary objectives
1. To determine whether intradermal (ID) injection of STEMVAC+GM-CSF vaccination increases the 
percentage of CD8+ TIL in patients with advanced NSCLC compared to patients who receive ID GM-CSF 
alone.   
2. To evaluate safety of STEMVAC immunization and concurrent pembrolizumab and/or pemetrexed 
maintenance therapy in patients with advanced NSCLC.
3.B. Secondary objectives
1. To evaluate the magnitude of the immune response to STEMVAC when given in combination with 
pembrolizumab and/or pemetrexed maintenance therapy. 
2. To determine whether vaccine induced T-cells traffic to tumor and can eliminate cancer cells which have 
undergone EMT.
a.
To evaluate by TCR beta (TCRb) sequencing in matched peripheral blood mononuclear cells 
(PBMC) of patients and in biopsy TILs whether the same TCRb clones in blood are found in 
abundance in tumor. 

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b. Biopsies before and after vaccination will be compared to determine if vaccination modulates 
the EMT gene signature in the tumor.
3. To evaluate potential clinical efficacy of STEMVAC immunization by comparing overall response rate 
between both arms.
4. To determine whether vaccination increases CD8 T-cell activation markers (GZB, CD127 and PD1) and 
Type I immune cells (CD4 Th1) in the tumor. 
4.  AGENT INFORMATION
4.A. Multi-antigen vaccine
The plasmid-based DNA vaccine we will use clinically is called STEMVAC (IND 16249, Sponsor: Mary L. 
Disis, M.D.).  The STEMVAC fusion protein is 352 amino acids in length and contains epitopes derived from 
the CD105, Yb-1, SOX2, CDH3, and MDM2 proteins.  The epitopes range from 32 to 92 amino acids in length.  
4.A.1. Synthesis and characterization
STEMVAC for clinical use has been amplified, quantified and vialed by the Biologics Production Facility at the 
Fred Hutchinson under Good Manufacturing Practice laboratory conditions.
4.A.2 Formulation and stability
The vaccine is vialed as a single dose containing DNA suspended in tromethamine/EDTA (TE) as a stabilizing 
buffer.  The vaccine formulation is labeled to accurately reflect the product identity, concentration, lot number 
and fill date.  These labels are attached to vials immediately post-fill.  Vials will be subjected to microbial, 
sterility and stability testing to ensure safety and stored at -20 ± 5ºC until use.
4.A.3. GM-CSF
Recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF; Sargramostatin, 
LEUKINE) will be used as adjuvant admixed with STEMVAC or administered alone and will be obtained by 
commercial suppliers and stored at their specifications.  
GM-CSF is a growth factor that supports the survival, clonal expansion, and differentiation of hematopoietic 
progenitor cells including dendritic APCs.  In general, the use of GM-CSF and rhuGM-CSF is associated with 
little toxicity when administered intravenous or subcutaneous injection.  It is generally well tolerated at doses 
ranging from 50-500 mcg/m2/day.  Severe toxicity is extremely rare in patients treated with rhuGM-CSF.  For 
the current study, rhuGM-CSF will be used at a total injection dose of 100 mcg.
Administration of rhuGM-CSF may aggravate fluid retention in patients with pre-existent edema, capillary leak 
syndrome, or pleural or pericardial effusions.  In some patients with pre-existing renal or hepatic dysfunction, 
elevation of the serum creatinine or bilirubin and hepatic enzymes has occurred during rhuGM-CSF 
administration.  Dose reduction or interruption of rhuGM-CSF administration has resulted in a decrease to 
pretreatment values.  Occasional transient and reversible supraventricular arrhythmia has been reported in 
uncontrolled studies, particularly in patients with a previous history of cardiac arrhythmia.  Stimulation of 
marrow precursors with rhuGM-CSF may result in a rapid rise in white blood cell count.  If rhuGM-CSF is 
being used for the purpose of hematopoietic reconstitution, dosing should be stopped if the absolute neutrophil 
count (ANC) exceeds 20,000/cm3.  The dose being used in this study should not have an effect on ANC levels.  
RhuGM-CSF may stimulate the growth of myeloid malignancies; therefore caution must be exercised in its use 
in these malignancies or myelodysplastic syndromes.  Our group has given over 1100 vaccine injections mixed 
with 100 mcg GM-CSF to patients on previous studies.  During those studies patients sometimes complained of 

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mild to moderate flu like symptoms (fever, chills, achy, fatigue) for 1 – 2 days following vaccination which may 
be related to the use of GM-CSF.
Patients with contraindications to receiving rhuGM-CSF will not be eligible for study as noted in Section 6.B.3.  
Contraindications will include: (1) previous allergic reactions to GM-CSF, (2) laboratory values outside of an 
adequate range as described in Section 6.A.11 and (3) cardiac conditions as described in Section 6.B.1.
RhuGM-CSF is a sterile, white, preservative-free lyophilized powder in 250 mcg vials.  Reconstituted rhuGM-
CSF (Sargramostim, LEUKINE) will be used as adjuvant admixed with STEMVAC plasmid-based vaccine or 
given alone at the 100 mcg/dose.  This will be administered intradermally. 
4.A.4. Availability
STEMVAC for clinical use has been vialed by the Biologics Production Facility at the Fred Hutchinson under 
good manufacturing practice (GMP) laboratory conditions.
RhuGM-CSF is a sterile, white, preservative-free lyophilized powder in 250 mcg vials and is obtained by 
commercial suppliers and stored at their specifications.  Each pharmacy will order this per their own procedures.
The STEMVAC vaccine is supplied as frozen vials and each vial carries a label bearing the drug identification 
and conditions for storage.  The site pharmacy will prepare and dispense the vaccine for administration per a 
standard operating procedure established by the University of Washington Investigational Drug Service (UW 
IDS) by pulling a single vial vaccine from the freezer and thawing it slowly at room temperature.  The rhuGM-
CSF (Sargramostim, LEUKINE) will be reconstituted in sterile preservative free water.  To admix vaccine with 
GM-CSF, it will be added to an empty vial and then the vaccine is added to that.  The vial is rotated gently to 
mix.  The dose will be divided into 3 Tuberculin Safety Syringes or 3 1 mL syringe with .01mL graduation with 
a 27 gauge, ½ inch needle for a total of 3 intradermal injections (2 syringes x 0.33 mL and 1 syringe x 0.34) each 
for intradermal injection. For rhuGM-CSF alone, it will be reconstituted and divided into two Tuberculin Safety 
Syringes or divided into two 1 mL syringe with .01mL graduation with 0.20ml each as described above.
4.A.5. Agent distribution
STEMVAC will be managed by the University of Washington Investigational Drug Service (UW IDS) as 
delegated by the IND Sponsor.  UW IDS will be responsible for the study drug disposition (drug receipt, transfer 
or return) and shall be documented on the Investigational Drug Accountability Record.  UW and VA Puget 
Sound will each obtain the adjuvant, rhuGM-CSF (Sargramostim, LEUKINE) directly.
The prepared vaccine is stored at the University of Washington, Gene and Cell Therapy Laboratory (UW 
GCTL), a GMP facility, until it is transported to the UW IDS where it will be dispensed to UW patients or 
shipped/transported to VA Puget Sound for administration.  Vaccine shipped/transported to VA Puget Sound 
will be sent/transported overnight on dry ice.  Once received at VA Puget Sound the chain of custody the 
vaccine stored in the research freezer per label specifications and documentation should be completed.  We are 
planning 2 shipments over the study, but if an additional request needs to be made VA Puget Sound should 
contact UW IDS using the contact information below:
Investigational Drug Services
Reference Study Number: RG1013946
FAX: 206-598-4901
Phone: 206-598-6054

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4.A.6. Agent accountability
The Principal Investigator, Shaveta Vinayak, or a responsible party designated by the co-PI, must maintain a 
record of the inventory and disposition of all agents received.  The PI is required to maintain adequate records of 
receipt, dispensing and final disposition of study agent.  This responsibility has been delegated to UW IDS as 
well as dispensing records by the site pharmacy.  Include on receipt record from whom the agent was received 
and to whom study agent was shipped, date, quantity and batch or lot number.  On dispensing record, note 
quantities and dates study agent was dispensed.
4.A.7. Storage
Vials of the vaccine will be subjected to microbial, sterility and stability testing to ensure safety and stored at 
-20ºC ± 5ºC until use.  The product will be stored in freezers with alarmed temperature controls at both the  UW 
GCTL and site pharmacies at temperature -20°C ± 5°C.
The GM-CSF will be stored per package insert.  It should not be frozen or shaken. 
4.B. Concurrent pembrolizumab +/- pemetrexed maintenance therapy 
In patients with non-squamous disease pemetrexed will be administered IV every 3 weeks, at 500 mg/m2.  This 
is part of the standard of care, administered by the patient’s own oncologist. Commercial supply will be used, 
and the administration of this agent and the supportive care needed (i.e. steroids, folate, vitamin b12 and anti-
nausea medications) will follow institutional guidelines.  Steroid use should not exceed  7 days.
Pembrolizumab will be administered IV every 3 weeks, at a fixed dose of 200 mg.  This is part of the standard 
of care, administered by the patient’s own oncologist, and commercial supply will be used, and the 
administration of this agent will follow institutional guidelines.
5.  VACCINE ADMINISTRATION
Vaccines will be administered on an outpatient basis at the University of Washington Translational Research 
Unit (UW TRU) or the VA Puget Sound Health Care System (VA Puget Sound).  The vaccine will be 
administered on day 14 (+ 3 days) after maintenance therapy. 
5.A. Final vaccine preparation
The STEMVAC vaccine is supplied in single-use vials as a sterile, frozen solution.  Each single-use vial has a 
final concentration of 1mg/mL or 0.5 mg of DNA / 1 mL TE.  Each STEMVAC vaccine will carry a label 
bearing the drug identification and conditions for storage.  For Arm 1 we will reconstitute recombinant human 
GM-CSF (rhuGM-CSF, Sargramostim) will be used as adjuvant admixed with the STEMVAC plasmid based 
vaccine (see table below for details of preparation).
           ARM 1: STEMVAC Vaccine Admixed 
with GM-CSF (nominal strength STEMVAC 
300 mcg + 100 mcg GMCSF)
STEMVAC Vaccine 
Vial Dosage    
Number 
of 
ID 
Injections per dose
Original/First Batch: 302.2 mcg STEMVAC + 
99.4 mcg GM-CSF
1 mg/1 mL
2 ID injections x 0.35 
mL
New/Second Batch Lot: 301.3 mcg STEMVAC 
+ 99.3 mcg GM-CSF
0.5 mg/1 mL
3 ID injections (2 x 0.33 
mL and 1 x 0.34 mL)
ARM 2: 100 mcg of GM-CSF

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5.B. Vaccine administration
Standard precautions should be taken when handling the vaccine/GM-CSF.  Gloves and lab coats should be 
worn per the standard of the clinic administering the vaccine.  Caution should be taken when handling the 
vaccine that is prepared by the pharmacy in syringes.  Sharps containers should be readily available.  The 
vaccine is administered as 2 intradermal injections for the 1mg/1mL vial dosage  3 intradermal (ID) injections 
for the 0.5mg/1mL vial dosage.  It should be injected slowly to avoid any vaccine leaking out from under the 
skin.  Standard reporting procedures should be implemented as needed per the standard of the clinic. Trained 
medical staff will administer vaccines using professional standards of medication administration that include:
•
Right patient, right vaccine, right dose, right route, right site.
•
Personnel who will administer vaccines will have received training and education on vaccine 
administration and disposal before providing vaccines to patients.
One dose of the vaccine may be given in the same general area approximately every three weeks along with a 
with a booster vaccine.  Patients will be monitored for a minimum of 60 minutes post vaccine administration.  
Acute hypersensitivity and/or anaphylactic reactions are very rare with reported rates ranging from 0.22 - .065 
per 100,000 doses of vaccinations. Additionally, anaphylactic reactions to vaccines should they occur, usually 
appear within 5 to 60 minutes.  
5.C. Contraindications
Patients should not be pregnant or become pregnant throughout the remainder of the study.  Patients should not 
concurrently enroll in any other treatment study.  Participants scheduling a non-study-related vaccination 
(COVID-19, flu, shingrix, etc.) should ensure a minimum of 14 days between the vaccine dose and any 
STEMVAC vaccination.
5.D. Concomitant Medications
Throughout the duration of the study patients should not be on other cytotoxic chemotherapy aside from 
pemetrexed, systemic steroids (aside from those prescribed with pemetrexed or for immune related adverse 
events), monoclonal antibodies (with the exception of pembrolizumab), and/or other biologic therapy.  
Systemic steroid therapy of  7 days is considered chronic use for this protocol.  If a patient needs to be on 
systemic steroids  7 days please consult the IND sponsor before withdrawing the patient from the study.  
Topical, ocular, intra-articular, intranasal, inhalational corticosteroids (with minimal systemic absorption) and 
treatment for an immune-related adverse event are allowed (Section 10.A).
Bisphosphonates, such as denosumab, are permitted.  All medications (prescription and over-the-counter), 
vitamin and mineral supplements, and/or herbs taken by the patient will be documented in their study chart and 
may include: start and stop dates, dose, route of administration, and indication. Medications taken for a study 
procedure (e.g., biopsy) should also be included.
5.E. Dose Modifications/Delay
5.E.1.  Vaccine
There are no dose modifications for the vaccine as part of this protocol.  There may be allowances for the timing 
of the administration of vaccine to accommodate for special circumstances (i.e. illness).  There may be vaccine 
administration interruptions due to holding of pemetrexed and/or pembrolizumab.  If there are immune related 
adverse events (irAE) that are treated with systemic steroids at the time of scheduled vaccine, the vaccine 
administration should also be delayed.  Any delay of vaccine, will be pre-approved by a PI, study physician, 
physician extender and/or IND sponsor and documented in the patient study chart.

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The study team and the patient’s oncology team will communicate any changes in the patient’s treatment plan.  
Changes will be discussed with the study physician, PI/Co-PI, physician extender and/or IND sponsor in 
regards to vaccine administration. 
5.E.2. Pemetrexed
After the first administration pemetrexed may be reduced, interrupted, or discontinued at the patient’s 
clinicians’ discretion per the approved product labels and local regulations.  If pemetrexed is interrupted or 
discontinued, pembrolizumab may be continued.
5.E.3. Pembrolizumab
Based on existing clinical study data, most immune related adverse events (irAEs) were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive care.  
When an irAE is suspected every effort should be made to discard other possible etiologies that are non- 
immune related.  The ASCO/NCCN guidelines should be followed to manage irAE[33] at the patient’s 
oncologists’ discretion.  
6. PATIENT SELECTION
6.A. Inclusion criteria
1. Histologically-confirmed diagnosis of stage IV non-squamous or squamous NSCLC.
2. Have measurable disease based on RECIST 1.1 within one month of first vaccine. Target lesions situated in 
a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
3. Have completed 3 - 4 cycles of chemoimmunotherapy, without evidence of progressive disease.  
Pembrolizumab has to be included in at least 3 of these cycles.
4. Have not received more than 2 cycles of maintenance pembrolizumab and/or pemetrexed and be a candidate 
for continuation of this therapy.
5. At least 1 site of disease that could be biopsied during treatment.  This site should not be a site that is used 
to determine measurable disease for efficacy purposes.  Lesions that will be biopsied should not be on a 
previously irradiated area unless progression has been demonstrated in such lesions. 
6. Patients must be at least 28 days post systemic steroids prior to enrollment, unless this is a steroid 
administered concurrently with chemotherapy or used as part of prophylaxis to prevent IV contrast 
reactions. 
7. Patients must have ECOG Performance Status Score of 0 or 1 (Appendix A).
8. Patients must have recovered from major infections and/or surgical procedures, and in the opinion of a 
PI/Co-PI/study physician/physician extender, not have any significant active concurrent medical illnesses 
precluding protocol treatment.
9. Willing to undergo up to two serial biopsies while on study. 
10. Estimated life expectancy of more than 6 months.
11. Adequate laboratory values within 60 days of first vaccination defined as follows:
a.
WBC  3000/mm3
b. Lymphocyte count  800/mm3
c.
Platelet count  75,000/mm3
d. Hgb  9 g/dl 
e.
Serum creatinine  1.2 mg/dl or creatinine clearance > 50 ml/min
f.
Total bilirubin  1.5 mg/dl.
g. AST/SGOT  2 times upper limit of normal (ULN) or SGOT  5 times upper limit of normal (ULN) in 
the presence of liver metastasis 

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12. If female of childbearing potential has a negative urine or serum pregnancy test within 72 hours prior to 
receiving the first dose of study medication. 
13. All patients who are having sex that can lead to pregnancy must agree to contraception for the duration of 
study.  
14. Patients must be at least 18 years of age.
6.B. Exclusion criteria
1. Patients with any of the following cardiac conditions:
a.
Symptomatic restrictive cardiomyopathy
b. Unstable angina within 4 months prior to enrollment
c.
New York Heart Association functional class III-IV heart failure on active treatment 
d. Symptomatic pericardial effusion
2. Patients with central nervous system (CNS) metastasis that have not been treated.  Patients with previously 
treated brain metastases may participate provided they are clinically stable for at least 4 weeks and, have no 
evidence of new or enlarging brain metastases and also are off steroids for 2 weeks prior to dosing with 
study medication. 
3. Patients with any contraindication to receiving rhuGM-CSF based products.
4. Patients with any clinically significant autoimmune disease that requires active treatment with 
immunosuppressants.  Replacement therapy (e.g., thyroxine, insulin) is not considered a form of systemic 
treatment.  Administration of systemic steroids (i.e., for allergic reactions, CT scans, or the management of 
irAEs) is allowed.
5. Has a known history of another prior invasive malignancy within 2 years, except subjects with early stage 
cancer that has undergone potentially curative therapy with no evidence of that disease recurrence for 2 
years since initiation of that therapy.
6. Patients who are simultaneously enrolled in any other treatment study.
7. Patients who are pregnant or breastfeeding.
8. Patients with genetic driver alterations (e.g EGFR, ALK, ROS1, BRAF, MET ex 14, RET) for which 
targeted treatment exist and are FDA approved, except if the subject is not eligible or has progressed 
through those therapies. 
7.  EXPERIMENTAL DESIGN
7.A. Study design
This is a Phase II randomized study to examine the safety and efficacy of in patients with advanced NSCLC 
who have completed induction therapy without progressive disease and have measurable disease and are 
continuing on maintenance pembrolizumab +/- pemetrexed.
Patients receiving concurrent pembrolizumab +/- pemetrexed (per standard of care) will be randomized to 
either:
ARM 1: STEMVAC 301.59 mcg + GMCSF 99.2 mcg (nominal strength STEMVAC  300 mcg + 100 mcg 
GMCSF) administered at day 14 (+3 days) of the 21-day cycle for a series of 3 vaccines and a 
booster vaccine. 
ARM 2: ID administration of GM-CSF alone, administered at day 14 (+3 days) of the 21- day cycle for a     
  series of 3 vaccines and a booster vaccine.
Twenty patients will be enrolled per arm, STEMVAC and GM-CSF or GM-CSF alone.  First vaccine will be 
administered approximately two weeks after pembrolizumab +/- pemetrexed infusion.  The next two vaccines 

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approximately two weeks after each infusion.  Imaging and biopsy will be done prior to the first vaccination 
(archived tissue may be used at the discretion of the Clinical PI) and approximately three weeks after the 3rd 
vaccine.  One additional booster will be given approximately 9 weeks after last vaccine.  Blood for 
immunologic monitoring will be done prior or at vaccine 1, and at evaluation 1 (three weeks after 3rd vaccine, 
week 10), evaluation 2/second booster vaccine (week 16) and post booster evaluation (week 19).  Those booster 
patients will have an additional visit and blood draw.  Toxicity evaluations will be performed at each patient 
visit.  
The study schema is shown below:
7.B. Sample size
The study will accrue at least 40 patients who will be randomized sequentially to one of the two arms (20 
patients/arm). Additional patients may be enrolled to replace patients who fail to complete the study in order to 
meet the target accrual of 40 patients.
7.C. Outcome measures  
Primary endpoints: 
1. Percentage of CD8+ TIL will be evaluated by immunohistochemistry (IHC) on tumor biopsies pre- and 
post-vaccine.  Immunohistochemical (IHC) staining for CD3, CD4, and CD8 will be performed on the 
biopsies collected pre-treatment and post 3 vaccine administrations. The mean of the number of CD8+ T-
cells from an evaluation of 4 high powered fields will be determined for each sample and reported as a % of 
total CD3+ cells.  Tissue staining and cell quantification will be performed by qualified personnel blinded to 
the study randomization and clinical outcome.  
2. Safety of STEMVAC immunization and concurrent pembrolizumab and/or pemetrexed maintenance therapy 
in patients with NSCLC will be evaluated using the modified NCI toxicity criteria.  Toxicity evaluation will 
be based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0, physical exam and 
laboratory tests and documented for each patient visit. Complete physical examination will be performed at 
Arm1
n=20
Bx, Blood &
Imaging
V1
V2
V3
Bx, Blood &
Imaging
B
Blood
Blood
MT
MT
MT
Enroll & 
Randomize
Week
1
2
3
4
5
6
7
8
9
         10….......
16
19
MT
MT
MT
Arm2
n=20
Bx, Blood &
Imaging
V1
V2
V3
Bx, Blood &
Imaging
B
Blood
Blood
Arm 1 -Vaccine (STEMVAC + GM-CSF)
Arm 2 - GM-CSF Alone
V - Vaccine
MT - Maintenance Treatment
Bx - Biopsy
B- Booster

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each vaccine visit.  Laboratory tests including renal function tests, uric acid, blood counts, serum glucose, 
and liver function tests will be evaluated.  ANA, anti-C3, ds-DNA antibodies, and a thyroid panel will be 
evaluated at each time-point.  Laboratory tests will be done prior to vaccination and at 3, 9 and 12 weeks 
after the third vaccine (12 weeks or 3 weeks post booster for those receiving the booster vaccine).
Secondary endpoints:
1. To determine the magnitude of the immune response to STEMVAC when given in combination with 
pemetrexed and pembrolizumab maintenance therapy. Chemoimmunotherapy might impact the immune 
response generated to STEMVAC. We will measure the magnitude of the Th1 STEMVAC specific immune 
response using IFN-g ELISPOT.  The magnitude of Th1 response will be defined for each antigen in 
STEMVAC for each patient as the value of the corrected spots per well (CSPW) (CSPW= [(mean of spots 
in the antigen stimulated wells) – (mean of antigens for the no-antigen negative control wells)] for the same 
time point).  The antigens to be evaluated are: 1ug/mL protein antigens (recombinant proteins are available 
on all of the EMT associated proteins), human myoglobin (negative control), 0.5U/mL tetanus toxoid 
(positive control), and the epitopes encompassed within the vaccine at 10ug/mL.  
2. To evaluate if vaccine induced T-cells traffic to tumor and eliminate tumor cells that have undergone EMT 
transformation. 
a.
TCR sequencing will be performed in T-cell lines specific for STEMVAC antigens generated 
from peripheral blood mononuclear cells (PBMC) of patients and in biopsy TILs.  We will 
evaluate matched T-cells from PBMCs and biopsies from the patients to determine whether the 
same TCR-beta (TCRb) clones in blood are found in abundance in tumor. 
b. Expression of EMT related genes will be analyzed by qPCR using the Human EMT RT² Profiler 
PCR Array, which includes 84 genes related to the EMT process. Gene expression profiles from 
biopsies before and after vaccination will be compared to determine if vaccination modulates the 
EMT gene signature in the tumor.
3. To evaluate the clinical efficacy of the vaccine.  We will evaluate clinical response approximately one 
month after the 3rd vaccine using RECIST 1.1.  Although the study is not powered to definitively address 
overall response rate (ORR), data generated may give some indication of clinical utility.
4. To determine whether vaccination increases CD8 T-cell activation markers (GZB, CD127 and PD-1) and 
Type I (CD4 Th1) immune cells.  Tumor microenvironment in NSCLC patients is frequently Type II, 
characterized by T regulatory (Treg) cells, neutrophils and type 2 macrophages that prevent an efficient 
Type I response and contribute to escape from the immune system.  T-cell activation markers and Type I 
immune cells will be evaluated by IHC staining in pre- and post-vaccine biopsies.  We will evaluate 
CD4+Tbet+ (Th1), CD4+GATA3+ (Th2) and activation markers (GZB, CD127, and PD-1) on CD8 T-cells. 
The % of change in these populations will be described similarly as CD8+ TIL. 
8. PLAN OF TREATMENT (SEE APPENDIX B) 
Standard-of-care laboratory evaluations done prior to signing consent may qualify for baseline evaluations if 
they have been conducted within 60 days prior to first vaccine.  In addition, we can use CT scans within 60 
days.  All baseline evaluations must be completed before study agent is dispensed.
8.A. Initial/baseline evaluation (may be performed up to 60 days prior to vaccine visit)
1. Sign consent form before initiation of study procedures
2. Medical history and complete physical examination which includes weight, vital signs, baseline symptom 
assessment and ECOG scoring (Appendix A)

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3. CT of chest and abdomen (per standard of care) and read by RECIST 1.1, pelvic CT scans are required if 
there is evidence of disease there.
4. CT or ultrasound guided core biopsy of tumor – to be done prior to receiving vaccine (archived tissue may 
be used at the discretion of the Clinical PI provided there is sufficient tissue to evaluate the primary 
endpoints of the trial.)
5. Clinical labs 
a.
Complete blood count with differential and platelet count 
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin
8.B. Chemoimmunotherapy (administered per standard of care by the patient’s oncologist)
Pembrolizumab at a fixed dose of 200 mg +/- pemetrexed at a dose of 500 mg/m2 will be administered every 21 
days.  Rate of administration and pre-medications such as folic acid, vitamin b12, antiemetics and steroids will 
be administered under local custom. Patients should have a physical examination (which includes weight, vital 
signs,), laboratory evaluation (including a complete blood count with differential and platelet count, 
comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, alkaline 
phosphatase, and total bilirubin) before each chemotherapy administration.
8.C. Immunizations 
1. A physical examination will be done prior to each vaccination which will include weight, vital signs, 
vaccine symptom/toxicity assessment.  May use initial evaluation results prior to vaccine 1.
2. Females who are having sex that can lead to pregnancy must have a negative urine pregnancy test prior to 
vaccination.  This excludes patients who have undergone permanent sterilization (i.e., tubal ligation, 
hysterectomy or menopause as defined per the NCCN Guidelines. See Appendix D).
3. Clinical labs prior to vaccine (may use initial evaluation results prior to vaccine 1) 
a.
Complete blood count with differential and platelet count (initial evaluation labs may be used prior to 
vaccine 1)
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin (eligibility labs, if available may be used prior to vaccine 1)
c.
Autoimmune labs: ANA, C3, anti-dsDNA, and thyroid function tests
4. Tetanus diphtheria (Td) immunization if one has not been administered within six months-prior to first 
vaccine only.  If patient has a history of an allergic reaction to the Td immunization, one will not be given 
and patient can still continue to be in the study as there are other positive controls used for immune assays.
5. Research blood  
a.
Prior to first vaccine, approximately 200 ml for immunologic monitoring as described in Section 8.H.
6. Vaccinations will be administered ID on Day 14 (+3 days) post pembrolizumab +/- pemetrexed infusion.
a.
All vaccines will be administered in the outpatient setting at the University of Washington Translational 
Research Unit (UW TRU) and VA Puget Sound
b. Post-immunization monitoring:  Patients will be observed for a minimum of 60 minutes post 
immunization and post-vaccine vital signs will be documented (See Section 8.H. below)  
8.D. First follow up post vaccine (approximately 3 weeks post third vaccine) – Evaluation 1
1. A physical examination will be performed which will include weight, vital signs, symptom/toxicity 
assessment as well as: 
a.
Complete blood count with differential and platelet count
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin
c.
Immunotherapy labs: ANA, C3, anti-dsDNA, and thyroid function tests

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2. Research blood
a.
Approximately 200 ml for immunologic monitoring as described in Section 8.H.                     
3. CT or Ultrasound guided core biopsy of tumor 
4. CT of chest and abdomen (and pelvis if there is evidence of disease there) performed per standard of care 
and read by RECIST (shortly prior to or shortly after this visit).  
a.
Patients without progressive disease will continue receiving chemoimmunotherapy treatment under 
the care of their treating physician with further restaging under their guidance.
8.E. Booster vaccine - second follow up post vaccine (approximately 9 weeks post third vaccine) – 
Evaluation 2
1. A physical examination will be performed which will include weight, vital signs, symptom/toxicity   
    assessment as well as:
a.
Complete blood count with differential and platelet count
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin
c.
Autoimmune labs: ANA, C3, anti-dsDNA, and thyroid function tests
2. Females who are having sex, that can lead to pregnancy, must have a negative urine pregnancy test 
3. Research blood draw (for immunologic monitoring)
a.
Approximately 200 ml of blood will be collected as described in Section 8.H. below
4. This will be the last study visit for those not receiving the booster vaccine (for those off-study treatment)
5. Booster vaccine administration for those patients still on study treatment
a.
This vaccine will be the same as the one administered in Section 8.C
b. As much as possible each dose of vaccine will be administered within the same draining lymph node site
c.
All vaccines will be administered in the outpatient setting at the UW TRU and VA Puget Sound
d. Post-immunization monitoring:  Patients will be observed for a minimum of 60 minutes post 
immunization and post-vaccine vital signs will be documented (See Section 8.H. below)
8.F. Post Booster vaccine evaluation (approximately 3 weeks post booster vaccine)
1.A physical examination will be performed which will include weight, vital signs, symptom/toxicity    
assessment as well as:
a.
Complete blood count with differential and platelet count
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, BUN, AST, ALT, 
alkaline phosphatase, and total bilirubin
c.
Autoimmune labs: ANA, C3, anti-dsDNA, and thyroid function tests
2. Research blood draw (immunologic monitoring)
a.
Approximately 200 ml of blood will be collected as described in Section 8.H. below
8.G. Long-Term Follow-Up
A request for records will be sent to the patient’s primary oncologist twice yearly from end of study visits for a 
total of 5 years.  This information will be put in the study chart which is kept in a locked filing cabinet in a 
secured building.  Information requested will include:
a.
Most recent laboratory evaluation (CBC, CMP) 
b. Patient’s disease free and overall survival status
c.
Recent clinical notes which may include history and physical exam notes
Notes will be reviewed by study team for vaccine toxicity and followed up with the patient’s primary 
physician if indicated.

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Study charts are kept for 30 years after the close of the study per University of Washington policy.  VA Puget 
Sound study will be utilizing both electronic and paper research charts which are kept for at least 6 years after 
the fiscal year in which the study was closed at VA in accordance with RCS 10-1.
We will be looking for possible autoimmune symptoms (e.g. unexplained rash, dry eyes, unexplained diarrhea) 
within the above collected records.
We will encourage patients to notify us if they become pregnant after they complete study visits.
8.H. Management of potential study risks
Although patients have a small chance of experiencing an allergic-type reaction to the vaccine, if a reaction 
were to happen, it would usually occur within one hour of the vaccination.  For this reason, all patients will 
undergo observation and monitoring of vital signs for a minimum of 60 minutes post-vaccination. 
Large volume research blood draws (up to 200 ml) are required at designated study visits for immunologic 
monitoring.  The amount of blood obtained for immunologic monitoring assays at designated time points is in 
strict adherence with guidelines set by the BloodWorks NW and are associated with minimal risks.  However, 
as with any large volume blood draw patients should be well hydrated prior to the blood draw.  Thus, during the 
consent process, and at subsequent visits, patients will be instructed to hydrate sufficiently prior to visits 
requiring large volume blood draws.  As part of the study we will be evaluating the laboratory values, such as 
hematocrit.  If the patient’s prior hematocrit value was  30 we will proceed with the large volume blood draw 
at the subsequent visit.
Patients will receive two biopsies which are not part of regular treatment.  A biopsy can result in adverse events 
including pain, discomfort, bleeding, swelling, scarring, bruising, and infection, dependent on the site of 
disease.  We will attempt to minimize risk by closely evaluating accessible lesions.  Patients will be given a 
separate surgical consent form for this hospital procedure. 
8.I. Storing samples for future testing 
If any research blood is left over after the study’s immunologic monitoring, it may be stored for future research 
related to the development of other immunotherapies.  The choice to store any leftover samples is up to the 
patient and whatever their decision, it will not affect their participation in this study.  The VA Puget Sound will 
not be participating in sample storage for future testing.  At the end of the study all samples provided by VA 
Puget Sound will need to be documented as destroyed by the University of Washington and that documentation 
will be keep in the subject’s research chart and recorded on the appropriate VA Research and Development 
(R&D) sub-Committee closure paperwork.
8.J. Randomization
Patients will be randomized by the University of Washington staff delegated by Co-PI, Shaveta Vinayak.  
Patients will be randomized using block randomization method to ensure a balance in sample size with two 
treatment groups over time. Specifically, with a block size of 4, we have six possible sequences; these are 
AABB, ABAB, ABBA, BAAB, BABA, and BBAA, where A and B stands for Arm 1 or 2, respectively. A list 
of 10 random numbers will be generated within the range of 1 to 6. Each number refers to one of the sequences 
allocations in each block. 

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9. WITHDRAW FROM STUDY TREATMENT
9.A. Patient Withdrawal
Patients may decide to withdraw from the study treatment at any time and for any reason, at which time all 
research-related treatment procedures will then cease.  Patients, who have persistent grade 3 or 4 toxicity (of a 
two week or greater duration) related to the vaccine, at time of withdrawal from study treatment, will continue 
to be followed until toxicity resolves or returns to baseline for that patient.  We will continue to follow them for 
disease status as conducted by their primary physician according to conventional practice standards.  If the 
patient is willing, we will continue to draw research blood per protocol timelines.  Prior to blood draw, labs will 
be reviewed by study physician/physician extender for patients receiving cytotoxic chemotherapy or 
immunosuppressive agents. Study physicians/physician extender will assess if blood draw would be safe for 
these patients, and what amount may be drawn (not to exceed 200 ml).  Once patients have withdrawn from 
treatment, they will continue to be followed in Long Term Follow Up unless they have withdrawn their consent. 
Withdrawal will be reported in the annual renewal report to all appropriate agencies.  We will report the reason 
for the withdrawal if known and whether it was related to the study.
9.B. Study Physician Withdrawal
A PI/Co-PI/Study Physician/Physician Extender, or IND sponsor may deem it appropriate to remove a patient 
from study participation for toxicity (as described in Section 11- Accrual and Criteria for Premature Study 
Termination), recurrent disease, study non-compliance, current illnesses or therapy, or other reasons.  Patients, 
who have persistent grade 3 or 4 toxicity (of a two week or greater duration), at time of withdrawal from study 
treatment, will continue to be followed until toxicity resolves or returns to baseline for that patient.
Patients may continue to be followed for disease status as conducted by their primary physician according to 
conventional practice standards.  If applicable, patients who are no longer being vaccinated may continue to be 
followed for immunity and research blood may be requested as described in above.  If a co-PI/Study 
Physician/Physician Extender withdraws the patient from study, it will be reported in the annual renewal report 
to all appropriate agencies.  We will report the reason for the withdrawal and whether it was related to the study.
9.C. Discontinuation of Study Treatment
The study may be discontinued if the toxicity rate criteria, as described in Section 11 – Accrual and Criteria for 
Premature Study Termination, are met.  If the study is discontinued for toxicity all research-related treatment 
procedures will cease.  We will continue to monitor clinically significant toxicity until the toxicity resolves or 
returns to an individual’s baseline.  
If patients are willing, we will continue to follow them for disease status and/or research blood to follow 
immunity as described in Section 8.G. above.  We will report the study termination to the Fred Hutchinson 
/University of Washington Cancer Consortium Institutional Review Board and VA Puget Sound Health Care 
System IRB #1 at the time we become aware of the discontinuation (with 10 days). 
10. EVALUATION AND MANAGEMENT 
OF 
TOXICITY 
RELATED TO THE 
STUDY 
TREATMENT
Patients will be asked to report local injection site reactions and systemic reactions.  Toxicity will be evaluated 
according to the CTEP CTCAE v5.0 and the Data and Safety Monitoring Plan (DSMP) as described in 
Appendix C. At each visit, evaluation for toxicity will include, but is not limited to: complete blood count 
(CBC), serum electrolytes, creatinine, BUN, liver function tests, and a physical examination.  Study 
physicians/physician extender will attribute adverse events and its relatedness.  Adverse events may be related 
to the STEMVAC, GM-CSF, pemetrexed and/or pembrolizumab or all of them or neither of them. 

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For grade 1 or 2 vaccine-related reactions, patients may be treated with acetaminophen or Benadryl as clinically 
indicated at the discretion of the study clinician.  For grade 3 or greater adverse events, using the CTEP CTCAE 
v5.0, that are considered definitely, probably, or possibly related to the vaccine (other than those listed below in 
Table 3), we have defined a stopping boundary rule as described in Section 11 – Accrual and Criteria for 
Premature Study Termination.  
We will begin to evaluate and record systemic reactions from the time of confirmed eligibility through End of 
Treatment visit.
10.A. Vaccines
Risk of STEMVAC Vaccine
UW has given over 1100 peptide/DNA plasmid vaccine injections in previous studies, and below are some 
possible risks: 
Table 1: STEMVAC Expected Adverse Events 
Likely
Less Likely
Rare, some may be serious
Pain and discomfort during 
vaccine administration
Redness and tenderness at 
injection site (this usually goes 
away in 1-2 days)
Itching at vaccine site
Fatiguea, b
Headache
Flu-like symptoms
Muscle pain
Nauseaa, b
Chills
Diarrheaa, b
Allergic reaction, including shortness of 
breath, dizziness, a feeling of fainting, 
hives, and difficulty breathing caused by 
swelling of the mouth, face tongue, or 
throat
Seizures
Severe allergic reaction to the vaccine may 
require medication, lead to hospitalization, 
and may result in death
a Also common and expected in pemetrexed and/or pembrolizumab.
b Also common and expected with pembrolizumab
Risk of Granulocyte-Macrophage Colony Stimulating Factor (rhuGM-CSF, Sargramostim)
GM-CSF is a man-made protein that is almost identical to a protein the body makes, and will be mixed and 
injected with the vaccine. GM-CSF is also known as an adjuvant. In our previous vaccine studies that used GM-
CSF, patients sometimes complained of mild to moderate flu like symptoms (fever, chills, achiness, and fatigue) 
for 1-2 days after vaccination that may be related to the use of GM-CSF. The possible risks listed below are for 
a larger and more frequent doses of GM-CSF than will be given in this study.

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Table 2: GM-CSF Expected Adverse Events
Likely
Less likely
Rare, some may be serious
Local reactions at the site of 
the injection
Low grade fever (< 100.5oF)a, b
Chills
Pain in the bones, muscles, chest, 
abdomen, chest, or joints
Nauseaa, b
Vomitinga, b
Diarrheaa, b
Flu-like symptoms including 
fatiguea, weakness, headache
Decreased appetitea, b
Increased white blood cell count
Kidney and liver problems
Local reaction at the site of 
injection
Rashes
Liver enlargement
Low blood pressure
Fluid retention (including fluid in lungs or 
around the heart)
Blood clotting, including blood clots in the 
leg veins that can break loose and go to the 
lung
Increased platelets, low albumin, increase of 
liver enzymes
Rapid or irregular heartbeat or other heart 
problems
Allergic reaction, including shortness of 
breath, dizziness, a feeling of fainting, hives, 
and difficulty breathing caused by swelling 
of the mouth, face, tongue or throat
Worsening 
of 
pre-existing 
fluid 
accumulation in arms and legs, in the lungs 
and around the heart that may result in 
breathing problems and heart failure
Temporary loss of consciousness
a Also common and expected in pemetrexed and/or pembrolizumab.
b Also common and expected with pembrolizumab
Based on our previous Phase I study with STEMVAC, Grade 3 or higher adverse events occurred in 2% of the 
vaccinated patients. Table 3 shows those Grade 3 or higher adverse events that are expected and allowable in 
this Phase II study. 
Table 3. Vaccine related expected and allowable Grade 3 and 4 Related Toxicities (CTEP CTCAE v5.0) that 
are not included in the stopping rule.
Category
Toxicity/AE
Allowable 
Duration
General disorders and administration site 
conditions
Flu-like symptoms
1 week
Musculoskeletal and connective tissue 
disorders
Arthralgia
1 week
Myalgia
1 week
Investigations
Lymphocyte count 
decreased
2 weeks
Thrombocytopenia*
1 weeks
Blood and lymphatic system disorders
Anemia*
1 weeks

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Category
Toxicity/AE
Allowable 
Duration
Investigations
White blood cells 
decreased
2 weeks
*Also common and expected in pemetrexed and/or pembrolizumab.
We would consider steroid administration for grade 3 or 4 adverse immune related events that have been 
reported with other immune based therapies, i.e. ipilimumab [47].  Examples of such immune related AEs 
include; rash, diarrhea/colitis, and hepatitis. The following dose schedule may be used:
Day 1:
Intravenous Solu-Medrol at 1 mg/kg
Day 2:
Intravenous Solu-Medrol at 1 mg/kg
Day 3-4:
Prednisone at 30 mg BID PO q day
Day 5-6:
Prednisone at 15 mg BID PO q day
Day 6-7:
Prednisone at 10 mg BID PO q day
Day 7-8:
Prednisone at 10 mg PO q day
Day 8-9:
Prednisone at 5 mg PO q day
10.B. Pemetrexed
Pemetrexed is a type of chemotherapy called an anti-folate. As a chemotherapy, it is believed to help to kill or 
slow the growth of cancer cells. Table 4 provides expected adverse events related to the combination of 
pembrolizumab +/- pemetrexed.[2, 48]
10.C. Pembrolizumab
Pembrolizumab is an immunotherapy and it works with your immune system to help fight certain cancers by 
blocking the PD-1 pathway and to help prevent cancer cells from hiding. Pembrolizumab helps the immune 
system do what it was meant to do: detect and fight cancer cells.
Table 4. Expected adverse events related to pemetrexed and/or pembrolizumab (Events occurring in 
 of 
patients being treated with pemetrexed and/or pembrolizumab with carboplatin).[2, 48]
Fatigue
Decreased appetite
Neutropenia
Peripheral edema
Fever
Vomiting 
Asthenia 
Dyspnea
Constipation
Cough
Rash
Dysgeusia
Diarrhea
Nausea 
Pruritus
Anemia
Thrombocytopenia
Dizziness 
Increased lacrimation
Increased blood 
creatinine
Increased alanine 
aminotransferase
Increased aspartate 
aminotransferase
Alopecia
Peripheral 
neuropathy
11. ACCRUAL AND CRITERIA FOR PREMATURE STUDY TERMINATION 
We have completed a Phase I study where we evaluated the safety of the vaccine at 3 different doses.  All three 
doses exhibited a satisfactory safety profile with the majority of adverse events were grade 1 and 2. 
Although the chance is low, the trial will be stopped based on two continuous toxicity monitoring rules for 
adverse events of interest (Table 5).  Current standard of care with pemetrexed/pembrolizumab therapy induces 

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a broad spectrum of adverse events as indicated in Table 4 above. Up to 99.8% of the patients treated with 
pemetrexed/pembrolizumab presented with adverse events, and 67.2% of them presented Grade 3 or higher 
adverse events[2].  We have defined a list of adverse events of interest (Table 5) as described in Gandhi et 
al.[2]. The adverse events of interest are defined as those with an immune-related cause and are considered 
regardless of attribution to a trial drug by a PI/Co-PI. Grade 3 or higher adverse events of interest were reported 
in 8.9% of patients treated with pemetrexed/pembrolizumab[2]. 
Table 5. Expected adverse events of interest 
Two continuous monitoring rules for toxicity will be used to ensure stopping trial if the observed toxicity rate 
exceed a threshold. For the investigation arm with STEMVAC the two continuous toxicity monitoring rules 
assume that adverse event of interest (Table 5) probability is not more than 20% for grade 3 and no more than 
10% for grade 4.  The maximum number of grade 3 or 4 toxicity events of interest for every patient enrolled at a 
specific timepoint is shown in Tables 6 and 7. The trial will be stopped if the number of AE of interest is equal 
to or exceeds boundary (bn) out of n patients with completed follow-up. This is a Pocock-type stopping 
boundary that yields the probability of crossing the boundary at most 0.05 when the rate of AE of interest is 
equal to the acceptable rate (<20% for grade 3 AE rate and <10% for grade 4 AE rate).[49] 
Table 6. Toxicity monitoring for grade 3 AE of interest
Table 7. Toxicity monitoring for grade 4 AE of interest
12. STATISTICAL CONSIDERATIONS
12.A. Statistical analysis plan
This is a phase II randomized study of STEMVAC+GM-CSF or GM-CSF administered ID concurrently with 
pembrolizumab +/- pemetrexed maintenance therapy. 
Primary endpoints
1. Determine whether ID STEMVAC+GM-CSF vaccination increases the percentage of CD8+ TIL in patients 
with advanced NSCLC compared to patient who receive ID GM-CSF alone by immunohistochemistry 
(IHC). The mean of the number of CD8 T-cells will be determined by IHC for each biopsy sample, at 
baseline and after the third vaccine, as a % of total CD3 cells. Two-sample Student’s t-test with a 1-sided 
0.05 significance level will be used to assess the difference.  The distribution of the differences of CD8 T-
cells between baseline and post treatment will be examined to check the normality assumption and outliers.  
If the outliers are substantial or the distribution is skewed, Wilcoxon nonparametric test will be used to 
assess the difference between the two treatment arms.  Depending on the correlation between baseline and 
Hypothyroidism
Colitis
Hypophysitis
Thyroiditis
Pneumonitis
Severe skin reaction
Pancreatitis
Type 1 diabetes mellitus
Hyperthyroidism
Nephritis
Adrenal insufficiency
Infusion reaction
Hepatitis
Myositis
Number of patients, n
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Boundary, bn
-
-
3
4
4
4
5
5
5
6
6
6
7
7
7
8
8
8
9
9
Number of patients, n
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Boundary, bn
-
2
3
3
3
3
4
4
4
4
4
4
5
5
5
5
5
6
6
6

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post-treatment measures, alternative analytical method will be adopted using an ordinary least square 
regression for the post-treatment CD8 T-cells percentage while adjusting for the baseline measure.  
2. Evaluate safety of STEMVAC immunization and concurrent pembrolizumab and/or pemetrexed 
maintenance therapy in patients with advanced NSCLC. Safety of STEMVAC immunization and concurrent 
pembrolizumab and/or pemetrexed maintenance therapy in patients with NSCLC will be evaluated using the 
modified NCI toxicity criteria.  Toxicity evaluation will be based on Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0, physical exam and laboratory tests. Complete physical examination will be 
performed at each vaccine visit and will include weight, vital signs, vaccine symptom/toxicity assessment.  
Laboratory tests including complete blood count with differential and platelet counts, and comprehensive 
metabolic panel for renal function, uric acid, serum glucose, and liver function will be evaluated.  Anti-
ANA, anti-C3, ds-DNA antibodies, and a thyroid panel will be also evaluated at each time-point.  All 
clinically significant adverse events (including lab abnormalities) will be graded on a scale of 1-5 and 
documented.  
Secondary endpoints
1. Determine the magnitude of the immune response to STEMVAC when given in combination with 
pemetrexed and pembrolizumab maintenance therapy. The Th1 STEMVAC antigen specific immune 
response will be determined by IFN-g ELISPOT. The magnitude of Th1 response will be defined for each 
antigen in STEMVAC for each patient as the value of the corrected spots per well (CSPW) (CSPW= [(mean 
of spots in the antigen stimulated wells) – (mean of antigens for the no-antigen negative control wells)] for 
the same time point). The antigens to be evaluated are: 1ug/mL protein antigens (recombinant proteins are 
available on all of the EMT associated proteins), human myoglobin (negative control), 0.5U/mL tetanus 
toxoid (positive control), and the epitopes encompassed within the vaccine at 10ug/mL. An increase in the 
number of peptide or protein specific IFN-g producing spots that is statistically different than no antigen 
and/or controls (p<0.05) will be taken as an indication of vaccinated immune response. T-test among the 2 
groups (vaccine and adjuvant alone) will be conducted to evaluate immune response if skewness is not 
observed. 
2. Evaluate if vaccine induced T-cells traffic to tumor and eliminate tumor cells that have undergone EMT 
transformation.  Patients from the STEMVAC arm with the most robust antigen specific responses will 
undergo peripheral blood T-cell expansion and blood and tumor TCR sequencing.  Shannon diversity index 
will be summarized and the Clopper-Pearson confidence interval will be computed for the rate of T-cell 
trafficking among the 10 patients subject to TCRb sequencing.  If we observe antigen specific responses at 
high level in the patients receiving GM-CSF alone, Fisher exact test will be used to compare the rates of 
expansion of T-cell clones in PBMC from the vaccine arm and PBMC from the control arm.  Logistic 
regression will be used to compare the rates between arms if adjusting for the baseline rates. The expression 
of EMT genes in tumor biopsies will be compared between all patients in the two arms, adjusting for their 
respective baseline levels, with multiple testing adjustment for declaring significance.  For each EMT 
marker, the differences of gene expressions pre- and post-vaccination will be assessed for association with 
the differences of antigen-specific, pre- and post-vaccination CD8 TIL (or the presence of GZB positive 
cells), stratified by treatment arm.  A significant negative association accounting for multiple testing will 
support the hypothesis that CD8 TIL eliminates cancer cells that have undergone EMT.
3. Evaluate potential clinical efficacy of STEMVAC immunization by comparing overall response rate 
between both arms. We will evaluate potential clinical response approximately one month after the 3rd 
vaccine using RECIST 1.1.  In a Phase III trial the ORR observed with maintenance pemetrexed was 3% 
[57].  There is no clinical trial that has studied ORR due to pembrolizumab in the maintenance setting, 

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however, the median time to response when pembrolizumab is added to chemotherapy is 2.2 months [1].  
Further response after the induction treatment is likely to be low.  We would assume an ORR less than 5% 
would be attributed to maintenance therapy.  An informal comparison will be conducted to compare the 
ORR between the two arms, with the Fisher exact test to account for small sample size.  Additional analyses 
will be conducted to evaluate other efficacy endpoints, which include progression free survival (PFS) and 
overall survival (OS).  Time-to-event variables are analyzed using the Kaplan-Meier method.  Kaplan-Meier 
estimates of the survival function with 95% CIs at specific time points (using Greenwood’s formula for the 
standard error) will be computed.  Comparisons of PFS and OS in the two arms will be conducted by the 
log-rank test.
4. Determine whether vaccination increases CD8 T-cell activation markers (GZB, CD127 and PD1) and Type 
I immune cells (CD4 Th1) in the tumor. CD8 T-cell activation and Type I immune cells will be evaluated by 
IHC staining in pre- and post-vaccine biopsies. We will evaluate CD4+Tbet+ (Th1), CD4+GATA3+ (Th2) 
and activation markers (GZB, CD127, and PD-1) on CD8 T-cells. The % of change in these populations will 
be described similarly as CD8+ TIL.  Similar analyses comparative to the CD8 in the primary objective will 
be conducted. In brief, two-sample T-tests or the Wilcoxon test will be utilized to compare the absolute 
change of T-cell activation markers and the Type I immune cells from baseline based on the normality of 
the data. 
12.B. Sample size
Primary endpoints:
1. Determine whether intradermal (ID) injection of STEMVAC+GM-CSF vaccination increases the percentage 
of CD8+ TIL in patients with advanced NSCLC compared to patients who receive ID GM-CSF alone by 
IHC. Determine the percentage of CD8+ TIL in patients between the two arms. With a proposed sample size 
of 20 subjects per treatment arm (40 subjects total), the study has  0.80 power to detect a  0.80-standard-
deviation difference in the maximum absolute change from baseline in % CD8 TIL in the experimental arm 
relative to the control arm. 
2. Evaluate safety of STEMVAC immunization and concurrent pembrolizumab and/or pemetrexed 
maintenance therapy in patients with advanced NSCLC.  Toxicity evaluation will be based on Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0, physical exam and laboratory tests.   
Secondary endpoints:
1. Determine the magnitude of the immune response to STEMVAC when given in combination with 
pemetrexed and pembrolizumab maintenance therapy.  The Th1 STEMVAC antigen specific immune 
response will be determined by IFN-g ELISPOT.  A proposed sample size of 20 patients per group provide 
80% power to detect a statistically significant difference (at the one-sided level of 0.05) if the true effect 
size is one standard deviation, correcting the multiple comparisons using Bonferroni method. Effect size is 
defined as the difference in mean specific T-cell response level divided by the common standard deviation.
2. Evaluate if vaccine induced T-cells traffic to tumor and eliminate tumor cells that have undergone EMT 
transformation.  We will assess TCR-beta (TCRb) gene usage in both T-cell lines expanded from peripheral 
blood and in the tumor biopsy, and the expression of EMT related genes in the tumor after vaccination with 
STMEVAC+GM-CSF or GM-CSF alone.  We hypothesize a successful therapeutic immunization would be 
the ability to detect vaccine induced T-cells clones in the majority of immunized patients (80%) or at least a 
minimum of half the patients analyzed.  With 10 patients included in this analysis, we will have a standard 
error of 0.13 if the true rate of T-cell clone trafficking to tumor is 80% and a standard error 0.16 if the true 
rate of trafficking is 0.5, the minimal rate we would expect for a clinically efficacious vaccine.  

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3. Evaluate potential clinical efficacy of STEMVAC immunization by comparing overall response rate 
between both arms. We will evaluate clinical response approximately one month after the 3rd vaccine using 
RECIST 1.1.  Although the study is not powered to definitively address overall response rate (ORR), data 
generated may give some indication of clinical utility.  In a Phase III trial the ORR observed with 
maintenance pemetrexed was 3% [57].  There is no clinical trial that has studied ORR due to 
pembrolizumab in the maintenance setting, however, the median time to response when pembrolizumab is 
added to chemotherapy is 2.2 months [1].  Further response after the induction treatment is likely to be low.  
We would assume an ORR less than 5% would be attributed to maintenance therapy.  With 20 patients in 
the STEMVAC arm, we have >80% power to detect a significant difference if the response rate in the 
STEMVAC arm is > 23% compared to 5% response rate as the historical control rate.  
4. Determine whether vaccination increases CD8 T-cell activation markers (GZB, CD127 and PD1) and Type 
I immune cells (CD4 Th1) in the tumor. CD8 T-cell activation markers and Type I immune cells will be 
evaluated by IHC staining in pre- and post-vaccine biopsies.  With the proposed sample size of 20 patients 
per group, we have more than 80% power to detect a statistically significant difference (at the one-sided 
level of 0.05) in mean specific T cell immune response and in CD8 T-cell activation markers if the true 
effect size is one standard deviation. Multiple-testing will be accounted for using the Bonferroni procedure.
12.C. Projected gender and ethnic distribution
The ethnic and gender distribution chart below (Table 8) reflects estimates of race and gender of the population 
to be included in this study.  The ethnic and gender distribution reflects estimates that are based on the 
Washington State Department of Health - Washington State Cancer Registry data released on March 2020. The 
data was filtered on incidence, Lung and Bronchus (how it is categorized in database), 4 year time period (2013-
2017), and race. Based on this data we calculated the following: Hispanic (2.4%), White (88.1%), Asian (4.4%), 
Black or African American (2.4%), American Indian/Alaska Native (< 1%), and Native Hawaiian or Other 
Pacific Islander (1.1%).
Table 8.  Distribution of ethnicity and gender.
TARGETED/PLANNED ENROLLMENT: Number of Subjects
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
1
2
Not Hispanic or Latino
19
19
38
Ethnic Category: Total of All Subjects *
20
20
40
Racial Categories
American Indian/Alaska Native
0
0
0
Asian
1
1
2
Native Hawaiian or Other Pacific Islander 
0
0
0
Black or African American 
1
1
2
White
18
18
36
Racial Categories: Total of All Subjects *
20
20
40

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13. SAFETY REPORTING
For definitions of adverse events, reference Appendix C.  Mary L. (Nora) Disis, M.D., UW CVI, is the IND 
sponsor of this trial.  Any serious adverse event (SAEs) will need to be reported to Dr. Disis within 24 hours of 
learning of the event.
Mary L. (Nora) Disis, M.D.
University of Washington
IND Sponsor
ndisis@u.washington.edu 
Phone: 206-616-1823
Fax: 206-221-5529
The following information will be included when calling Dr. Disis:
Date and time of the SAE
Date and time of the SAE report
Name of reporter
Call back phone number Affiliation/Institution conducting the study DCP protocol number
Title of protocol
Description of the SAE, including attribution to drug and expectedness
Mary L. (Nora) Disis, M.D.
University of Washington
IND Sponsor
ndisis@u.washington.edu
Phone: 206-616-1823
14. ADMINISTRATIVE CONSIDERATIONS
14.A. Institutional review board
In accordance with federal regulations, an Institutional Review Board that complies with the regulations in 21 
CFR 56 must review and approve this protocol and the informed consent form prior to initiation of the study.
14.B. Consent
A PI/Co-PI/Study Physician or their designated physician extender (Nurse Practitioner/Physician Assistant) or 
study coordinator per institutional policy, must explain verbally and in writing the nature and duration of the 
study and possible consequences of the treatment.  Patients must also be informed that they may withdraw from 
the study at any time and for any reason without jeopardizing their future treatment.   This should be 
documented by the consenting physician or physician extender in a consent note and signed.
14.C. Reporting adverse events related to the vaccine
Patients are monitored for the development of vaccine toxicities by assessing adverse events with serum 
chemistries, liver function studies, complete blood counts and physical exams.  All clinically significant adverse 
events (including lab abnormalities) are graded on a scale of 1-5 and attribution is assigned as to its relation to 
the vaccines.  We will begin to evaluate and record systemic adverse events from the time of confirmed 
eligibility through End of Treatment visit.  We will record adverse events that are reported to us by the patient, 
caregivers, and clinical support staff.

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Post visit AEs will be reported using the NCI’s CTEP CTCAE v5.0.  A copy of the CTEP CTCAE v5.0 can be 
downloaded from the CTEP homepage (http://ctep.info.nih.gov).  Guidelines for AE reporting to the FDA and 
the NCI are described in the DSMP, Appendix C.  The Monitoring Plan (as mandated by the National Institutes 
of Health (NIH)/National Cancer Institute (NCI)) Policy and Procedure for this phase II study is described in 
Appendix C.  
SAEs are communicated to the PI/Co-PI, Fred Hutchinson/University of Washington Cancer Consortium 
(FH/UW CC IRB), IND Sponsor, FDA, Medical Monitor, University of Washington Institutional Biosafety 
Committee (UW IBC), UW TRU, and FH Biologic Production, VA Puget Sound Health Care System IRB#1 
and U.S. Army Medical Research and Materiel Command Human Subjects Research Review Board 
(USAMRMC) Office of Research Protections (ORP) Human Research Protection Office (HRPO).  A status 
report including accrual, AEs and death information will be reviewed by the PI/Co-PI every 6 months and the 
FH/University of Washington Cancer Consortium Data and Safety Monitoring Committee (DSMC) annually. In 
addition, the study will be monitored by the Clinical Research Support Services according to the FH /University 
of Washington– Cancer Consortium monitoring plan.
14.D. Confidentiality of patient records
All eligible patients will be assigned a unique patient number (UPN) that will not contain any personally 
identifying information, such as name, initials, medical record number, social security number, etc.  To 
maintain confidentiality, we protect the link between the patients’ personal identifying information and UPN 
number by limiting who has access to the patients’ chart documentation.  Only delegated clinical research staff 
has access to the data, which remain locked at all times when not in use or kept on secured servers with 
permission access to only approved clinical research staff.
All hard copy research records collected on potential and enrolled patients are stored in a locked filing cabinet in 
a locked office that can only be accessed by approved clinical research staff when not in use.  This staff 
includes: co-PIs/study physician(s), physician extenders and designated clinical research staff.  These are also 
the only people that have access to the link between the patients’ personal identifying information and their 
assigned UPN codes. Any electronic VA research charts or data will be kept on VA secured servers and 
protected by VA IT in accordance with VA regulations and policies.
In terms of the protections and security of electronic clinical data, it is being performed by the University of 
Washington Information Technology (UW IT) Services.  The UW and VA IT information security policy is to 
protect information and information systems. It also ensures compliance with UW/VA policy and state and 
federal regulations.  
14.E. Study team roles and responsibilities
Drs. Vinayak (PI) and Santana-Davila, Co-PI in collaboration with Dr. Disis (IND Sponsor) will be responsible 
for the oversight of the study.  Dr. Vinayak is responsible for the overall conduct of the study and Dr. Santana-
Davila will be specifically responsible for the clinical evaluations for the study.  The PI/Co-PI collaborate on  
the preparation and implementation of the protocol with the PI being responsible for PI study required signatures 
(i.e. adverse event log at end of study, etc.). The PI/Co-PI also analyze the results of the study data.  Drs. 
Vinayak and Santana-Davila are responsible for ensuring that all information and documentation related to the 
conduct and safety of the study is disseminated to the proper agencies in the proper timeframe. Dr. Vinayak and 
Santana-Davila will delegate tasks to qualified research staff for this study as needed at UW.  Dr. Graf will 
delegate tasks to the research staff at VA Puget Sound.  

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Research physicians/physician extenders per institutional policy will be delegated to perform physical exams, 
and collect, review, and attribute adverse events per protocol. In addition, they will be available to answer 
patient study related questions. They collaborate attentively with the research staff to ensure the safety and 
efficacy of the patient.
Research Nurses/Coordinators will be responsible for recruitment, initial screening, baseline event collection, 
coordination of clinical treatment, study visits and follow up. They may do medication/adverse event collection 
review with patients and ensure it is entered into the database in a timely manner, so as to have real time data to 
review and report any safety concerns or trends. They will be responsible for maintaining regulatory 
documentation to the various agencies involved with this research and assist with ensuring that all research team 
members are following the protocol and all regulations.
All clinical research staff are required to complete the following training:
1.
Human Subjects Protections
2.
HIPAA
3.
Good Clinical Practice

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Appendix A. ECOG Performance Scale
Performance status: Patients will be assessed according to the current ECOG performance scale (Table 9).
Table 9.  ECOG performance scale
Grade
Description
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
As published in Am. J. Clin. Oncol: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. 
The ECOG/Zubrod Performance Status is in the public domain therefore available for public use.  To duplicate 
the scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 

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Appendix B. Calendar of Events
Table 10.  Calendar of events
Visit Time Point
Procedures
Initial visit/Biopsy
Some procedures may be done up to 60 
days prior to the first vaccine
Informed Consent
Medical history and complete physical examination
Vitals signs-including weight
Clinical labsa, b
Urine pregnancy test (if applicable)
CT or Ultrasound guided core needle biopsy of 
tumor (archived tissue may be used at the discretion of 
the Clinical PIs)
RECIST 1.1
VACCINE 1 c
14 days (+ 3) post pembrolizumab +/- 
pemetrexed infusion
Complete physical examinationd may use initial 
evaluation results prior to vaccine 1.
Vitals signs-including weight 
Urine pregnancy test (if applicable)
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Research blood: approximately one cup
Tetanus diphtheria (Td) vaccine
Vaccine 1 (STEMVAC+GM-CSF or GM-CSF alone)
After vaccine monitoring for allergic reaction for a 
minimum of one hour
Maintenance treatment
Approx. 7 days after vaccine 1
Pembrolizumab +/- pemetrexed
VACCINE 2 c 
14 days (+ 3) post pembrolizumab +/-  
pemetrexed infusion 
Complete physical examination
Vitals signs-including weight
Assess for any side effects
Urine pregnancy test (if applicable)
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Vaccine 2 (STEMVAC+GM-CSF or GM-CSF alone)
After vaccine monitoring for allergic reaction for a 
minimum of one hour
Maintenance treatment
Approx. 7 days after vaccine 2
Pembrolizumab +/- pemetrexed
VACCINE 3 c
14 days (+ 3) post pembrolizumab +/- 
pemetrexed infusion 
Complete physical examination
Vitals signs-including weight 
Assess for any side effects
Urine pregnancy test (if applicable)
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Vaccine 3 (STEMVAC+GM-CSF or GM-CSF alone)
After vaccine monitoring for allergic reaction for a 
minimum of one hour

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Visit Time Point
Procedures
Maintenance treatment
Approx. 7 days after vaccine 3
Pembrolizumab +/- pemetrexed
EVALUATION 1 – At least 3 weeks after 
THIRD vaccine 
Complete physical examination
Vitals signs-including weight 
Assess for any side effects
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Research blood: approximately one cup
Imaging – CT scan per standard of care
RECIST 1.1
CT or Ultrasound guided core biopsy of tumor Chest 
x-ray
BOOSTER VACCINE 
EVALUATION 2 - At least 9 weeks after 
THIRD vaccine 
Complete physical examination
Vitals signs-including weight
Assess for any side effects
Urine pregnancy test (if applicable and receiving 
booster vaccine)
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Research blood: approximately one cup
For those on study treatment:
o
Booster Vaccine (STEMVAC+GM-CSF or 
GM-CSF alone)
o
After vaccine monitoring for allergic reaction 
for a minimum of one hour
POST BOOSTER EVALUATION- At 
least 3 weeks after BOOSTER vaccine 
Complete physical examination
Vitals signs-including weight
Assess for any side effects
Clinical labsb
ANA, C3, anti-dsDNA, thyroid function test
Research blood: approximately one cup
LONG TERM FOLLOW-UP
Twice yearly for 5 years after last visit
Request records from the patient’s oncologist
aCan use standard of care laboratory evaluations if performed 60 days prior to prior to the vaccine visit
bCBC with differential: white blood cells, red blood cells, platelets; Comprehensive metabolic panel 
(CMP): sugar (glucose) level, electrolyte and fluid balance, kidney function, liver function
cVaccine administered Day 14 (+3 days) after pembrolizumab and/or pemetrexed infusion
dMay use physical exam that was done prior to vaccine 1
eRecords may include: most recent laboratory evaluation, patient’s disease status, and recent clinical 
notes with medical history/physical exam(s)

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Appendix C. Data and Safety Monitoring Plan
A. PURPOSE
To ensure that the Cancer Vaccine Institute follows NIH/NCI/CTEP/FDA guidelines with respect to: (1) 
accurate assessment and timely reporting of adverse drug reactions associated with investigational drugs, (2) 
adherence to protocol, and (3) accurate reporting of data.  The DSMP will be approved by FH/UW CC IRB in 
Seattle, Washington.
This is a multi-center clinical study including the FH/UW Consortium and the VA Puget Sound Health Care 
System. The PI for this project are responsible for every aspect of the design, delegating 
responsibility/authority, study conduct and final analysis of the protocol.  The PI, or delegated qualified 
research staff, will document that each external performance site is qualified to conduct the trial and conforms 
to all relevant regulations and guidelines. The PI, or delegated trained research staff, will obtain copies of VA 
Puget Sound IRB approval and will have the responsibility for receiving the information required for adverse 
event reporting and safety monitoring, and disseminating that information to the appropriate FH/UW 
committees.  Regulations defining the responsibilities for assessment and reporting of AEs, SAEs, and 
unexpected AEs are defined by the Code of Federal Regulations:  21 CFR 312.32 and CTEP CTCAE v5.0 
published by CTEP, a division of the NCI/NIH.  A matrix of reporting requirements and schedules is at the 
CTEP web-site at http://ctep.infi.nih/gov. 
This clinical study will rely upon the monitoring of the trial by the PI in conjunction with a Research Nurse, a 
Statistician, an Independent Medical Monitor and an Independent Study Monitor assigned by the Clinical 
Research Support of the FH/UW CC IRB. The trial PI/Co-PI will establish and carry out procedures for 
assessing protocol compliance, data accuracy and completeness, and full and timely reporting of safety data.  
VA Puget Sound acknowledges their responsibilities for data and adverse event reporting.  Study monitors will 
be required to complete either on-site or remote monitoring visits with the VA Puget Sound Health Care System 
study coordinator to review VA study data and VA medical records.  VA Puget sound will provide the CRF 
source data to the UW study team by secured fax or secured email and all provided data is in accordance with 
applicable sub-award grant application provisions for the conduct of this study at the external participating site.
There is an Independent Medical Monitor for this study.  The Medical Monitor, Cristina P. Rodriguez, will be 
informed that study enrollment has begun and become familiar with the study.  The Medical Monitor will 
review the study approximately every 6 months throughout the study treatment period with a PI/Co-PI, 
Research MD(s), Research Nurse(s), Research Coordinator(s), and/or other related clinical research staff.  The 
Medical Monitor will review patient recruitment and retention, adherence to protocol, follow-up, data quality, 
and participant risk versus benefit.  The Medical Monitor has the authority to stop the research protocol in 
progress, remove individual human subjects from the research protocol, and take whatever steps necessary to 
protect the safety and well-being of human subjects and recommend actions that may need to be reported to the 
IRB. 
If a SAE occurs the PI will be notified along with the FH/UW CC IRB, VA Puget Sound Health Care System 
IRB #1, IND Sponsor, FDA, Medical Monitor, UW IBC, UW TRU, FH Biologic Production, and U.S. Army 
Medical Research and Materiel Command Human Subjects Research Review Board (USAMRMC) Office of 
Research Protections (ORP) Human Research Protection Office (HRPO). 
B. OBJECTIVES
1. To ensure that the PI, Co-PIs and Clinical Research Staff follow federal and institutional regulatory 
guidelines with respect to timely reporting of adverse reactions associated with investigational drugs

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2. To define classification of adverse drug reactions as expected or unexpected
3. To define classification of adverse drug reactions as serious or non-serious
4. To define monitoring and stopping rules based on adverse drug reactions reports
5. To ensure compliance and accuracy of documentation of adverse drug reactions reportable to: (1) FH/UW 
CC IRB, (2) IND Sponsor, (3) FDA, (4) Medical Monitor, (5) UW IBC, (6) UW TRU, (7) FH biological 
production, (8) VA Puget Sound Health Care System IRB #1, and (9) USAMRMC ORP HRPO. 
C. ADVERSE EVENT REPORTING POLICY AND PROCEDURES
Evaluation of AEs: AEs are graded on a scale of 1-5 and attribution is assigned using the CTEP CTCAE v5.0 
which uses descriptive terminology.  Information pertaining to toxicity is recorded.
If a particular significant AE severity/intensity is not specifically graded by the CTEP CTCAE v5.0, the PI, Co-
PI, study physicians and/or physician extenderare to revert to the general definitions of Grade 1 through Grade 5 
and use his or her best medical judgment.
The 5 general grades are:
Grade 1: Mild
Grade 2: Moderate
Grade 3: Severe
Grade 4: Life-threatening or disabling
Grade 5: Death related to AE
Patients are monitored for the development of toxicities by assessing AEs with physical examinations and 
serum chemistries, liver function studies, and complete blood counts at baseline and prior to each vaccine and at 
post vaccine evaluation visits.  The development of connective tissue disorders and laboratory autoantibody 
responses will also be clinically assessed for the development of anti-DNA antibodies (ANA, C3, thyroid 
function tests, and anti-dsDNA).  
Abnormal laboratory findings and other abnormal investigational findings may not be reported as AEs unless 
they are clinically significant, associated with clinical signs and symptoms, lead to treatment discontinuation or 
are considered otherwise medically important by a PI and/or Co-PI. 
If an abnormality fulfills these criteria, the identified medical condition (e.g. anemia) should be reported as the 
AE rather than the abnormal value itself (e.g. low hemoglobin).
For patients who are hospitalized, due to their disease, a PI, Co-PI, study physician, physician extender or IND 
sponsor will review their records and determine what may relevant event(s), procedures, and medications shall 
be documented in the study record.
1. Definitions of AEs:
a.
AE - any unfavorable and unintended sign (including abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medical treatment or procedure regardless of whether it is 
considered related to the medical treatment or procedure. 
An AE may include: 
an exacerbation of a pre-existing illness
an increase in frequency or intensity of a pre-existing episodic event or condition
a condition detected or diagnosed after study drug administration
continuously persistent disease or symptoms that were present at baseline and worsen following 
the start of the study

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An AE does not include: 
medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or transfusion); 
however, the condition that leads to the procedure may be an AE
pre-existing diseases, conditions, or laboratory abnormalities present or detected at the start of 
the study that do not worsen
hospitalizations or procedures that are done for elective purposes not related to an untoward 
medical occurrence (e.g., hospitalizations for cosmetic or elective surgery or social/convenience 
admissions)
the disease being studied or signs/symptoms associated with the disease unless more severe than 
expected for the patient's condition
overdose of study drug without any clinical signs or symptoms
b. Expected AE - an event that may be reasonably anticipated to occur as a result of the study procedure 
and is described in the Investigator Brochure and/or consent form. Expected AEs for this study are listed 
in Section 10.A. Tables 1-5. 
c.
Unexpected AE - an AE that is not described in the Investigator Brochure and/or consent form and is 
unanticipated.  An event that might have been anticipated but is more serious than expected or occurs 
more frequently than expected, would be considered an unexpected AE.
d. Life-threatening AE - the patient was at substantial risk of dying at the time of the AE or it is suspected 
that the use or continued use of the product would have resulted in the patient’s death.
e.
Serious AE - grade 4 or 5 toxicity or any AE occurring at any dose that results in any of the following 
outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization due to the AE, a persistent or significant disability/incapacity or a congenital 
anomaly/birth defect.
f.
Hospitalizations that do not meet these criteria are: 
social reason in the absence of an AE
surgery or procedure planned prior to entry into the trial
Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations; for example, important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above. Any AE is considered a 
SAE if it is associated with clinical signs or symptoms judged by a PI and/or Co-PI to have a 
significant clinical impact. 
Note: Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
2. Scale of scoring AEs 
a.
Grade 1 = mild AE
b. Grade 2 = moderate AE
c.
Grade 3 = severe adverse event
d. Grade 4 = life-threatening or disabling AE
e.
Grade 5 = death related to AE
3. Attribution of AE
a.
5 (definite): the AE is clearly related to the investigational agent.  
b. 4 (probable): the AE is likely related to the investigational agent.
c.
3 (possible): the AE may be related to the investigational agent.

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d. 2 (unlikely): the AE is doubtfully related to the investigational agent.
e.
1 (unrelated): the AE is clearly NOT related to the investigational agent.
4. SAE event reporting
a.
This procedure is outlined below by regulatory agency (Table 11).
FH/UW CC IRB – We will follow the current AE reporting policy of our institutional IRB.
VA Puget Sound Health Care System IRB#1 – We will follow the current AE reporting policy of our 
institutional IRB.
FDA (for trials using an Investigational New Drug (IND)) – SAEs will be reported per 21 CFR 312.32 by 
telephone or facsimile transmission (using either the narrative format, the MedWatch Form 3500A as soon 
as possible but no later than seven calendar days after initial receipt of the information concerning the event.  
All unexpected, SAEs are reported in writing (using either the narrative format, the MedWatch Form 3500A 
to the FDA Center for Biologics within 15 calendar days after initial receipt of the information concerning 
the event. Yearly written progress reports to the FDA will summarize expected or non-serious unexpected 
AEs.
Independent Medical Monitor - At a minimum, the medical monitor should comment on the outcomes of 
SAEs and relationship of the SAE to the vaccine or prepare an unbiased written report of the event.  They 
should also indicate whether they agree with the details of the report provided by the study PI and/or Co-PI.  
SAE’s determined by either the PI/Co-PI or medical monitor to be possibly or definitely related to 
participation and reports of events resulting in death must be promptly forwarded to the USAMRMC ORP 
HRPO (usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil).
UW IBC - We will follow the current AE reporting policy of the UW IBC.
UW TRU - The UW TRU will receive copies of the documents submitted to the FH/UW CC IRB within 7-
10 calendar days.
FH Biologic Production - The FH Biologic Production will receive copies of the documents submitted to the 
using either the narrative format, the MedWatch Form 3500A, or using the Genetic Modification Clinical 
Research Information System within 7-15 calendar days.
USAMRMC ORP HRPO – although we will report expected and unexpected serious and unexpected 
serious/fatal events to the FHCRC/UW CC IRB, we will also report these unanticipated events to the 
USAMRMC ORP HRPO promptly by email (usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil), 
reported by telephone (301-619-2165), or by facsimile (301-619-7803) to the HRPO.
Follow-up reports will need to be completed until resolution of the unanticipated event that was not 
available at the time of initial reporting.

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Table 11. AE reporting
Expected
Expected
Unexpected
Unexpected
Non-Serious
Serious
Non-Serious
Serious (including grade 
4 & 5 toxicity)
Attribution * 
(Possible, 
Probable, Definite)
Attribution * 
(Possible, 
Probable, 
Definite)
Attribution * 
(Possible, 
Probable, Definite)
Attribution * (Possible, 
Probable, Definite)
FH/UW CC 
IRB
Continuation 
Review Report
Continuation 
Review Report
Continuation 
Review Report
FH AE Expedited 
Reporting Form – ASAP 
but within 7 days
VA Puget 
Sound Health 
Care IRB #1
Continuation 
Review Report
Continuation 
Review Report
Continuation 
Review Report
FH AE Expedited 
Reporting Form – ASAP 
but within 7 days and VA 
UPIRTSO form within 5 
days and if resulted in 
death within 24 hours.
FDA
Annual Progress 
Report
Annual Progress 
Report
Annual Progress 
Report
FDA Form 3500A or 
Narrative Format – 
ASAP but within 7 days) 
Medical 
Monitor
Bi-annual Meeting 
(twice a year)
Bi-annual 
Meeting (twice a 
year)
Bi-annual Meeting
FH AE Expedited 
Reporting Form – ASAP 
but within 7 days
UW IBC
Routine Report, as 
appropriate
Routine Report, 
as appropriate
Routine Report, as 
appropriate
ASAP within 7 days – 
MedWatch Form 3500A 
or Narrative Format) 
UW TRU
Copy of 
Continuation 
Review Report if 
requested
Copy of 
Continuation 
Review Report if 
requested
Copy of 
Continuation 
Review Report if 
requested
Copy of FH AE 
Expedited Reporting 
Form
FH biological 
production
Yearly FDA 
Progress Report if 
requested 
Yearly FDA 
Progress Report if 
requested
Yearly FDA 
Progress Report if 
requested 
ASAP within 7 days – 
MedWatch Form 3500A 
or Narrative Format) 
USAMRMC 
Annual Progress 
Annual Progress 
Annual Progress 
By FAX once we learn of 

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Expected
Expected
Unexpected
Unexpected
Non-Serious
Serious
Non-Serious
Serious (including grade 
4 & 5 toxicity)
Attribution * 
(Possible, 
Probable, Definite)
Attribution * 
(Possible, 
Probable, 
Definite)
Attribution * 
(Possible, 
Probable, Definite)
Attribution * (Possible, 
Probable, Definite)
ORP HRPO
Report
Report
Report
the event
5. Procedure for reporting SAEs:
a.
Identify the classification/attribution of the AEs as defined above using the CTEP CTCAE v5.0.
b. After appropriate medical intervention has been instituted, the PI or his/her designee will be notified 
within 24 hours.
c.
File appropriate reports immediately by phone/fax with appropriate agencies, as described in Table 11.
d. Notify the patient’s primary physician or referring physician within a medically appropriate timeframe, 
depending on the classification of the AE.
e.
Submit written reports to appropriate agencies.
f.
Document the AE in the patient’s research file, using a progress note to describe the event and 
treatment, if appropriate.
g. File copies of all forms/correspondence relating to the AE in the patient’s research file.
D. CLINICAL TRIALS MONITORING, STOPPING RULES AND OPERATIONAL PROCEDURES 
Adverse Events and subject safety will be reviewed continuously. The PI will ensure that the DSMP is followed 
and that the AEs are properly monitored and accurately reported to the appropriate regulatory agencies in a 
timely manner. A status report including accrual, AEs and death information will be reviewed by a PI every 6 
months and the FH/University of Washington Cancer Consortium Data and Safety Monitoring Committee 
annually. In addition, the study will be monitored by the Clinical Research Support Services according to the 
FH /University of Washington– Cancer Consortium monitoring plan. 
1. Clinical data documentation
a.
Internal study monitoring:
Clinical labs are evaluated at each patient visit for the development of toxicity (AEs) related to the 
vaccine.  Clinically significant abnormal lab values may be faxed to the patient’s physician.  
A Research Physician, physician extender or a PI/Co-PI sees each patient at each visit with the 
following evaluations being completed: toxicity evaluation, physical assessment and AEs summary 
(these evaluations are part of the source documentation that is filled out at each visit). Grade 1 and 2 
non-serious and expected AEs will be reviewed with the PI or designee regularly at clinical meetings.  
All other AEs will be reported to the PI or designee at the time they become known and reported as 
outlined above in Section C. 
Each patient research file is audited for completeness, legibility, and accuracy.  Audits may be 
conducted by a designated clinical research staff member(s) on an ongoing basis. 
b. Biannual review with the independent Medical Monitor:

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The Medical Monitor will meet/or conference call with the PI or designee, and other members of the 
clinical team, approximately every 6 months.   All patients are reviewed for AEs. Conduct of the study 
is reviewed for any practice changes and documentation of proper notification of changes as appropriate 
to the IRB and FDA. 
c.
Biannual study audit: 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of 
this plan, Fred Hutch Clinical Research Support coordinates data and compliance monitoring conducted 
by consultants, contract research organizations, or Fred Hutch employees unaffiliated with the conduct 
of the study. Independent monitoring visits occur at specified intervals determined by the assessed risk 
level of the study and the findings of previous visits per the institutional DSMP. In addition, protocols 
are reviewed at least annually and as needed by the Consortium Data and Safety Monitoring Committee 
(DSMC), Fred Hutch Scientific Review Committee (SRC), and the Fred Hutch/University of 
Washington Cancer Consortium Institutional Review Board (IRB). The review committees evaluate 
accrual, adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan 
for studies actively enrolling or treating patients. The IRB reviews the study progress and safety 
information to assess continued acceptability of the risk-benefit ratio for human subjects. Approval of 
committees as applicable is necessary to continue the study. The trial will comply with the standard 
guidelines set forth by these regulatory committees and other institutional, state, and federal guidelines.
2. Data validity/integrity
Systems to insure data integrity have been put into place to provide multiple checks to data entry.  Patient 
eligibility is initially reviewed by the Research Coordinator/Research Nurse and a PI or designee during the 
screening portion of the study.  The chart is then reviewed by a study physician/physician extender after the 
consent conference and before study procedures start.  It is then ultimately signed off on by a PI or designee. 
Additionally, research data will be reviewed biannually by the Independent Medical Monitor and Study 
Monitor.
Clinical laboratory monitoring data is reviewed by a qualified clinician (Research MD, physician extender, 
Research Nurse and/or PI/Co-PI) and any abnormalities are assessed. Patient records are kept in the 
patient’s research file and reviewed at biannual monitoring visits.  Data is taken from the patient’s source 
documentation, the patient’s research file, and entered into a database which links data to patient by a UPN 
and is accessible by password code only.  Data entry is made by the Research Coordinator/designated 
clinical research staff member and is verified at end of study by the Research Nurse/designated clinical 
research staff member by reviewing source documents and case report forms and reconciling them to the 
study database.  A percentage of all data entry is reviewed by a member of the clinical research team and the 
Independent Study Monitor.  
The trial will be stopped based on two continuous toxicity monitoring rules for adverse events of interest as 
defined in Section 11 - Table 5.  The two continuous toxicity monitoring rules assume that the adverse event 
of interest (Table 5) probability is not more than 20% for grade 3 and no more than 10% for grade 4. The 
threshold to stop the trial, defined as the maximum number of grade 3 or 4 toxicity events of interest for 
every patient enrolled at a specific timepoint is shown in Tables 6 and 7. The trial will be stopped if the 
number of AE of interest is equal to or exceeds boundary (bn) out of n patients with completed follow-up.

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Appendix D. NCCN Guidelines for Menopause Status
The National Comprehensive Cancer Network (NCCN) defines menopause as “generally the permanent 
cessation of menses, includes a profound and permanent decrease in ovarian estrogen synthesis.” According 
to their guideline, the criteria for determining menopause are:
Prior bilateral oophorectomy
60 or older
Age less than 60 years; amenorrheic for 12 or more months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression; and follicle-stimulating hormone (FSH) and 
plasma estradiol in the postmenopausal range.
If taking tamoxifen or toremifene, and age is under 60 years, then FSH and plasma estradiol 
level should be in the postmenopausal range.
It is not possible to assign menopausal status to women who are receiving a leuteinizing 
hormone-releasing hormone agonist or antagonist. In women premenopausal at the time of 
adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.