Conditions: Squamous Cell Carcinoma of the Head and Neck
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
To evaluate safety, immunogenicity and anti-tumor responses of intradermally delivered SNS-301 added to checkpoint inhibitor therapy in locally advanced unresectable or metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN) patients.

Detailed description:
This is a Phase 1/2, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of SNS-301 delivered intradermally in addition to pembrolizumab in patients with locally advanced unresectable or metastatic/recurrent SCCHN. The trial population consists of patients with locally advanced unresectable or metastatic/recurrent SCCHN who are currently receiving checkpoint inhibitor (CPI) therapy (Cohort A) or are naïve to CPI therapy (Cohort B). Patients who are currently receiving CPI therapy must have a best response of stable disease (SD) or first evidence of progressive disease (PD) after a minimum of 12 weeks of treatment with a CPI. Patients receiving a CPI other than pembrolizumab will be switched over to pembrolizumab at the time of entering this study. Patients receiving pembrolizumab in the first line setting must be PD-L1 positive.

Arms:
arm 1: * SNS-301
* Pembrolizumab

Interventions: intervention 1: SNS-301 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Day 0, Week 3, Week 6, Week 9 then every 6 weeks (±3 days) for 6 additional doses, thereafter every 12 weeks (±3 days) up to 24 months. intervention 2: Pembrolizumab (200 mg dose) IV infusion will be administered over 30 minutes every 3 weeks up to 24 months or Pembrolizumab (400 mg dose) IV will be administered over 30 minutes every 6 weeks up to 24 months.

Protocol document:
Prot_000.pdf: 
SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 1 of 132 
 
An Open-Label, Multi-Center Trial of SNS-301 Added to 
Pembrolizumab in Patients with Locally Advanced Unresectable 
or Metastatic/Recurrent Squamous Cell Carcinoma of the Head 
and Neck 
 
Study product:  
SNS-301 
IND number:  
16963 
Protocol number:  
SNS301-2-2 
Phase:  
1/2 
Version:  
4.0 
Final Protocol Date: 
November 6, 2020 
Study Sponsor: 
Sensei Biotherapeutics 
620 Professional Drive 
 
Gaithersburg, MD 20879 
Regulatory Statement 
This study will be performed in compliance with the protocol and in accordance with Good Clinical Practice 
(International Conference on Harmonization, Guidance E6 (R2), March 2018), principles of human subject protection, 
and applicable country-specific regulatory requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential 
and may not be disclosed unless such disclosure is required by applicable laws and regulations. In any event, persons for 
whom this information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that 
is indicated as privileged or confidential. 


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SPONSORS PROTOCOL SIGNATURE PAGE 
 
 
Sponsor: 
Sensei Biotherapeutics 
Address: 
620 Professional Drive 
Gaithersburg, MD 20879 
Protocol Title 
An Open-Label, Multi-Center Trial of SNS-301 Added to 
Pembrolizumab in Patients with Locally Advanced Unresectable or 
Metastatic/Recurrent Squamous Cell Carcinoma of the Head and Neck 
Protocol 
Number 
SNS-301-2-2 
Protocol 
Version: 
Final Protocol 
Date:  
Version 4.0 
 
November 6, 2020 
I approved the protocol and confirm that the protocol follows the current ICH/GCP guidelines. 
 
 
 
_______________________________________________________________________________ 
Marie-Louise Fjaellskog, MD, PhD 
 
Date 
Chief Medical Officer 
Sensei Biotherapeutics 
 
23 November 2020


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TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY............................................................................................................. 6 
 
CLINICAL PROTOCOL SYNOPSIS ............................................................................................... 6 
 
SCHEMA .................................................................................................................................. 22 
2. 
TERMS, ACRONYMS, ABBREVIATIONS ............................................................................ 23 
3. 
INTRODUCTION ........................................................................................................................ 27 
 
BACKGROUND ........................................................................................................................ 27 
 
Pharmaceutical and Therapeutic Background .............................................................. 27 
 
Pre-Clinical, Clinical Trials and Other Ongoing Trials ................................................ 28 
 
RATIONALE ............................................................................................................................ 29 
 
Rationale for the Trial and Selected Subject Population ............................................... 29 
 
Rationale for Companion Diagnostic and Translational Biomarkers ........................... 31 
 
Rationale for Dose Selection/Regimen ........................................................................... 31 
 
BENEFIT/RISK ......................................................................................................................... 32 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................................ 33 
 
STUDY OBJECTIVES ................................................................................................................ 33 
 
Primary Objectives......................................................................................................... 33 
 
Secondary Objective....................................................................................................... 33 
 
Exploratory Objective .................................................................................................... 33 
 
STUDY ENDPOINTS ................................................................................................................. 33 
 
Primary .......................................................................................................................... 33 
 
Secondary ....................................................................................................................... 34 
 
Exploratory .................................................................................................................... 34 
5. 
STUDY DESIGN .......................................................................................................................... 34 
 
RESEARCH HYPOTHESES ........................................................................................................ 34 
 
OVERALL DESIGN................................................................................................................... 34 
 
END OF STUDY DEFINITION.................................................................................................... 36 
6. 
STUDY POPULATION .............................................................................................................. 36 
 
EXCLUSION CRITERIA ............................................................................................................ 38 
 
SCREEN FAILURES .................................................................................................................. 40 
 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................ 40 
7. 
STUDY INTERVENTION .......................................................................................................... 40 
 
STUDY INTERVENTION(S) ADMINISTRATION ......................................................................... 40 
 
Study Treatment Description .......................................................................................... 40 
 
Dosing, Administration and Preparation ....................................................................... 41 
 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ....................................................... 42 
 
Acquisition and Accountability ...................................................................................... 42 
 
Formulation, Appearance, Packaging and Labeling for SNS-301 and Pembrolizumab43 


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Product Storage and Stability ........................................................................................ 43 
 
RANDOMIZATION AND BLINDING .......................................................................................... 43 
 
CONCOMITANT THERAPY ....................................................................................................... 43 
 
Allowed concomitant treatments .................................................................................... 44 
 
Prohibited Medications or Treatments During Study .................................................... 44 
 
Rescue Medication ......................................................................................................... 44 
 
DOSE MODIFICATION AND/OR INTERRUPTION ....................................................................... 44 
8. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/ 
WITHDRAWAL .................................................................................................................................. 45 
 
DISCONTINUATION OF STUDY INTERVENTION ....................................................................... 45 
 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ..................................... 45 
 
LOST TO FOLLOW-UP ............................................................................................................. 45 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 46 
 
EFFICACY ASSESSMENTS ....................................................................................................... 46 
 
Tumor Assessment .......................................................................................................... 46 
 
SAFETY ASSESSMENTS ........................................................................................................... 50 
 
Demographics and Medical History .............................................................................. 50 
 
Physical Examinations ................................................................................................... 50 
 
Eastern Cooperative Oncology Performance Status ..................................................... 50 
 
Vital Signs ...................................................................................................................... 50 
 
Electrocardiograms........................................................................................................ 50 
 
Clinical Safety Laboratory Assessments ........................................................................ 50 
 
Hepatitis and HIV Screening ......................................................................................... 51 
 
Pregnancy Test ............................................................................................................... 52 
 
Urinalysis ....................................................................................................................... 52 
 
TSH, T3 and FT4 ............................................................................................................ 52 
 
Creatine Phosphokinase (CPK) ..................................................................................... 52 
 
HPV/EBV Testing ........................................................................................................... 52 
 
PD-L1 Testing ................................................................................................................ 52 
 
Immunogenicity Assessments ......................................................................................... 52 
 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................................. 56 
 
Definition of Adverse Event (AE) ................................................................................... 56 
 
Definition of Serious Adverse Event (SAE) .................................................................... 56 
 
Classification of an Adverse Event ................................................................................ 58 
 
Adverse Event Reporting ................................................................................................ 59 
 
Serious Adverse Event Reporting ................................................................................... 59 
 
Serious and unexpected suspected adverse reaction ...................................................... 60 
 
Unanticipated (Serious) Adverse Device Effect (UADE) ............................................... 61 
 
Dose-Limiting Toxicities ................................................................................................ 61 
 
Stopping Rules ................................................................................................................ 62 
 
Adverse Events of Special Interest ................................................................................. 62 
 
Guidance for Investigators for Patients on Anti-coagulants ......................................... 62 
 
Reporting of Pregnancy ................................................................................................. 63 
 
Time Period and Frequency for Event Assessment and Follow-Up .............................. 63 
10. STATISTICAL CONSIDERATIONS ....................................................................................... 63 


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STATISTICAL HYPOTHESES .................................................................................................... 63 
 
SAMPLE SIZE DETERMINATION .............................................................................................. 64 
 
POPULATIONS FOR ANALYSES ............................................................................................... 64 
 
STATISTICAL ANALYSES ........................................................................................................ 65 
 
General Methods ............................................................................................................ 65 
 
Efficacy Analyses ........................................................................................................... 65 
 
Safety Analyses ............................................................................................................... 66 
 
Other Analyses ............................................................................................................... 66 
 
INTERIM ANALYSES ............................................................................................................... 66 
 
Safety Committee ............................................................................................................ 67 
11. SUPPORTING DOCUMENTATION & OPERATIONAL CONSIDERATIONS ............... 67 
 
REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS ................................... 67 
 
Regulatory and Ethical Issues ........................................................................................ 67 
 
Financial Disclosure ...................................................................................................... 68 
 
Informed Consent Process ............................................................................................. 68 
 
Data Protection .............................................................................................................. 68 
 
Committee Structure....................................................................................................... 69 
 
Data Quality Assurance ................................................................................................. 69 
 
Source Documents .......................................................................................................... 70 
 
Study and Site Closure ................................................................................................... 70 
 
Publication Policy .......................................................................................................... 70 
12. REFERENCE LIST ..................................................................................................................... 71 
APPENDIX A: TUMOR ASSESSMENT CRITERIA ..................................................................... 72 
APPENDIX B: ECOG PERFORMANCE STATUS ........................................................................ 85 
APPENDIX C: SUMMARY OF CHANGES .................................................................................... 86 
APPENDIX E: PRINCIPAL INVESTIGATOR SIGNATURE OF AGREEMENT PAGE ...... 132 
 
 
 


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1. PROTOCOL SUMMARY 
 Clinical Protocol Synopsis 
Protocol Title:  An Open-Label, Multi-Center Trial of SNS-301 Added to Pembrolizumab in Patients 
with Locally Advanced Unresectable or Metastatic/Recurrent Squamous Cell Carcinoma of the Head 
and Neck 
Sponsor:  Sensei Biotherapeutics 
                  620 Professional Drive 
                  Gaithersburg, MD  20879 
Protocol Number: SNS-301-2-2 
Trial Phase: 1/2 
Estimated Number of Trial Centers and Countries/Regions: Up to 15 sites in the U.S. 
Formulation: 
1. SNS-301 (1X1011 particles in 1ml ID injection) 
2. Pembrolizumab (200 mg or 400 mg dose IV infusion over 30 minutes)  
 
Research Hypotheses: SNS-301 delivered by intradermal injection (ID) using the 3M® hollow 
microstructured transdermal system (hMTS) device in addition to  pembrolizumab, will be generally safe, 
well tolerated, immunogenic and lead to anti-tumor responses in adult patients with locally advanced 
unresectable or metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN)  
 
Objectives and Endpoints: 
Primary Objectives: 
Associated Primary Endpoints: 
1. To determine the safety and tolerability of 
SNS-301 delivered by intradermal injection 
(ID) using the 3M® hollow microstructured 
transdermal system (hMTS) device in 
addition to pembrolizumab among patients 
with locally advanced unresectable or 
metastatic/recurrent SCCHN 
• 
All adverse events (AEs) by CTCAE v5  such 
as clinically significant changes in safety 
laboratory parameters from baseline: CBC 
with Differential; Chemistry Panel; Urinalysis; 
T3, Free T4 and TSH; creatine phosphokinase 
(CPK ) and including adverse events of special 
interest (AESI) classified by system organ 
class (SOC), preferred term (PT), severity and 
relationship to drug 
 
2. To evaluate the anti-tumor activity of SNS-301 
delivered by intradermal injection (ID) using the 
3M® hollow microstructured transdermal system 
(hMTS) device in addition to pembrolizumab in 
patients with locally advanced unresectable or 
metastatic/recurrent SCCHN 
 
 
 
 
 
 
• 
Objective response rate (ORR) by immune 
Response Evaluation Criteria in Solid Tumors 
(iRECIST)  
• 
Objective response rate (ORR) by Response 
Evaluation Criteria (RECIST) version 1.1 by 
investigator review   
• 
Duration of Response (DoR) as assessed by 
RECIST version 1.1 and iRECIST 
• 
Disease control rate (DCR) as assessed by 
RECIST version 1.1 and iRECIST 


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• 
Progression Free Survival (PFS) as assessed by 
RECIST version 1.1 and iRECIST  
• 
Overall Survival (OS) 
 
Secondary Objective 
Associated Secondary Endpoints 
To evaluate preliminary immune response to 
SNS-301 delivered by intradermal injection 
(ID) using the 3M® hollow microstructured 
transdermal system (hMTS) device in 
addition to pembrolizumab in  patients with 
locally advanced unresectable or 
metastatic/recurrent SCCHN 
 
 
 
• 
Antigen-specific cellular immune responses 
that may be assessed by but not limited to: 
Interferon-γ secreting T lymphocytes in 
peripheral blood mononuclear cells (PBMCs) 
by ELI Spot 
• 
Anti-SNS-301 antibody response 
• 
Assessment of pro-inflammatory and 
immunosuppressive elements in neoplastic and 
adjacent normal tissue, where feasible 
 Exploratory Objective 
Associated Exploratory Endpoints 
To evaluate tumor and immune biomarkers and 
their association with treatment outcome 
(antitumor activity and/or safety) in patients with 
locally advanced unresectable or 
metastatic/recurrent SCCHN 
 
 
 
 
 
 
• 
Immune related gene expression in the tumor 
• 
Expression of tumor specific oncoproteins 
including but not limited to ASPH 
• 
Correlation of serum ASPH level as 
determined by ELISA with tissue expression 
using IHC 
• 
miRNA profiling to predict treatment efficacy 
evaluating pre and post-treatment peripheral 
blood samples as well as urine samples 
• 
Cytokine and chemokine profiles in urine pre- 
and post-treatment and longitudinally 
throughout the trial  
• 
TCR sequencing of PBMCs for diversity 
and putative antigen specificity 
• 
CtDNA analysis and tracking for progression 
Trial Population: 
The trial population consists of patients with locally advanced unresectable or metastatic/recurrent SCCHN 
who are currently receiving a CPI therapy (Cohort A) or are naïve to CPI therapy (Cohort B).  Patients who 
are currently receiving CPI therapy must have a best response of stable disease (SD) or first evidence of 
progressive disease (PD) after a minimum of 12 weeks of treatment with a CPI.   Patients receiving first-line 
pembrolizumab monotherapy must be PD-L1 positive. Patients receiving a CPI other than pembrolizumab 
will be switched over to pembrolizumab at the time of entering this study.  
 
Sample Size: Approximately up to 30 patients will be enrolled into each cohort on the trial.  
 
This is a two-stage clinical trial with the primary efficacy endpoint of objective response per iRECIST. 
Patients enrolled in the first stage will need to be deemed evaluable at 12 weeks, meeting the definition for 
the efficacy evaluable analysis set; at least one dose of treatment and the Week 12 efficacy assessment or 
progression prior to Week 12.  Approximately15 patients may be enrolled in the first stage and evaluated for 
objective response (futility assessment) at 12 weeks. All patients will participate in the overall efficacy 
analysis. If warranted, based on response, up to an additional 15 patients may be enrolled in each cohort in 
the second stage.      
 


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See Section 10 for an explanation of the 2-stage enrollment. 
 
The study enrollment is expected to last approximately 18-24 months. 
 
Study Design: 
This is a Phase 1/2, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary 
clinical efficacy of SNS-301 delivered intradermally in addition to pembrolizumab in patients with locally 
advanced unresectable or metastatic/recurrent SCCHN. A safety run-in will be performed using a modified 
rolling six design which will enroll up to 6 patients and these patients will be included in the first stage of 
trial assessments pending they meet criteria set forth above. 
 
After consenting to participate in this clinical trial, participants will be screened for enrollment.  A tissue 
sample is required for ASPH expression testing from either a fresh biopsy or archival tissue from a previous 
biopsy.  Ideally, a pre-treatment tissue sample obtained after initiation of ongoing pembrolizumab, 
nivolumab or other CPI therapy and first dose of SNS-301 and pembrolizumab on this current clinical trial 
will be collected.  Patients are requested to provide archival tissues from a prior biopsy or surgery that is 
treatment -naïve including prior 1) chemotherapy, radiation and 2) anti PD(L)-1 treatment-naïve, pending 
availability. The patient may start study treatment prior to receiving the ASPH expression results from the 
fresh biopsy or archival tissue from a previous biopsy.  An on-treatment biopsy is required when medically 
feasible, after the third dose of the study treatment, treatment week 6.  Additionally, up to two optional 
biopsies may be obtained in select cases at any time during the study, if medically feasible. For patients who 
progress as determined per RECIST1.1/iRECIST criteria, an optional biopsy will be obtained at the time of 
disease progression.  
 
Patients will be enrolled into one of two cohorts depending on whether they are currently on a CPI or if they 
are naïve to CPI therapy as per the flow diagram below. 
 
 
 
 


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The following procedures will be performed: 
 
1. For eligible patients, the study treatment of SNS-301 in addition to pembrolizumab will be initiated 
on Day 0 (First dose).   
2. SNS-301 will be dosed approximately 1 hour after IV infusion of pembrolizumab for the first dose. 
Subsequent doses of SNS-301 and pembrolizumab can be dosed in any order. If pembrolizumab is 
discontinued by the Investigator prior to 24 months, treatment with SNS-301 vaccine therapy may 
continue for up to 24 months in patients without disease progression. 
3. Tumor biopsies will be collected at the time of screening and at Week 6 (± 3 days and at first 
evidence of radiographic or clinical disease progression if clinically deemed feasible. Patients who 
are unable to undergo biopsy sample collection during treatment but otherwise meet criteria listed in 
the protocol may continue to receive study treatment.  
4. SNS-301 will be administered intradermally using the 3M micro-needle device.  The dosing 
schedule will be as follows: Day 0, Week 3, Week 6, Week 9 then every  6 weeks (±3 days) for 6 
additional doses, thereafter every 12 weeks (±3 days) until confirmed disease progression, 
unacceptable toxicity, deemed intolerable by the investigator or up to 24 months in patients without 
disease progression. 
5. Pembrolizumab will be administered either every 3 weeks or every 6 weeks until confirmed disease 
progression, unacceptable toxicity, deemed intolerable by the investigator or up to 24 months in 
patients without disease progression.   
6. Imaging will be performed at 6 weeks (± 7 days) calculated from the first dose and will continue to 
be performed every 6 weeks (± 7 days), for the first 54 weeks, or earlier if clinically indicated. 
Thereafter, imaging will be performed approximately every 12 weeks (± 7 days). Imaging timing 
should follow calendar days and should not be adjusted for delays or changes in treatment 
administration dates. 
7. In patients who discontinue trial therapy for any reason other than radiologically defined confirmed 
progression, tumor imaging should be performed at the time of treatment discontinuation (± 4 
weeks). If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, 
then additional tumor imaging at treatment discontinuation is not required. 
8. Patients will be followed for all adverse events (AEs) for 30 days and for adverse events of special 
interest (AESI) and serious adverse events (SAEs) occurring up until 90 days after the last dose of 
study treatment or until the start of a new anti-cancer treatment, whichever comes first.  If the 
investigator becomes aware of an AESI or SAE that is considered related to study treatment after 
discontinuation from the trial, those events should be reported to the Sponsor within 24 hours. 
9. All patients who experience disease progression, have unacceptable toxicity or start a new anti-
cancer therapy and are discontinued from the trial will be followed for survival and subsequent anti-
cancer therapy. Patients should be contacted (i.e. by telephone) every 3 months to assess for survival 
status for up to 3 years, until death or patient withdraws consent. A pregnancy test is also required 
for WOCBP every 3 months.  
10. Patients who discontinue from study treatment for reasons other than disease progression (e.g., 
toxicity) will continue scheduled tumor assessment until disease progression, withdrawal of consent, 
or start of new anti-cancer therapy, death, or trial termination by Sponsor, whichever occurs first. 
 
Safety Run-In: A safety run-in will be performed using a modified rolling six design which will enroll up to 
six patients (safety lead-in patients).  A Safety Committee will review data from the Safety Run-In.  (Refer 
to Section Safety Committee).  
 
Once the first three patients of these six patients have completed Week 6 assessments, in the absence of any 
dose-limiting toxicity (DLT), enrollment may proceed through stage 1. However, if prior to the first three 
patients completing Week 6, a single patient from the first six experiences a DLT, then enrollment will be 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 10 of 132 
 
limited to six patients until all six patients have reached Week 6 and are assessed for DLT. If no additional 
patients, of these six, experience a DLT within the 6-week safety run in period, then enrollment may proceed 
to completion. 
If a second of these first six patients experiences a DLT within the first six weeks, enrollment will stop, and 
the Sponsor’s medical monitor, in addition to the PI and Investigator(s) at the patients’ site(s) will discuss 
the case, and a decision will be made whether to modify the trial or to cease further enrollment. If enrollment 
is ceased, it will only be reinitiated after amendment of the protocol and approval of the amended protocol 
by the IRB. 
Safety run-in patients that withdraw from the study for reasons other than a DLT, prior to the end of the 
safety run-in period, will be replaced. The end of the safety run-in period is defined as the earliest of the 
following: 
• 
The first three patients in cohort A have all completed Week 6 with no DLTs experienced by any of 
the safety run-in patients in that cohort (up to six); enrollment may then proceed to completion; 
• 
All six patients of the safety run-in phase, in cohort A, have completed week six with only one 
patient having experienced a DLT; enrollment may then proceed to completion; 
• 
Two or more of the safety run-in patients, have experienced DLTs prior to completing Week 6; 
enrollment will be suspended. 
Dose-Limiting Toxicities (DLTs) are defined in protocol  
 
Because this trial is treating patients with SNS-301 and pembrolizumab for the first time, there will be a 
waiting period of one week between enrollment of the first patient and the second patient. 
 
Stopping Rules 
The trial will be stopped if any adverse experience of any related death, grade 4 autoimmune toxicity or any 
grade 4 toxicity that is considered to have a causal relationship to study drug.  Any related death, grade 4 
autoimmune toxicity and any grade 4 toxicity that is considered to have a causal relationship to study drug 
will be submitted to regulatory agencies within the expedited safety reporting criteria. 
 
Study treatment: 
Study treatment include:  
1. SNS-301 (1x1011 dose/1ml) ID injection using the 3M® hollow microstructured transdermal system 
(hMTS) device will be administered on Day 0, Week 3, Week 6 and Week 9 (± 3 days) then every 6 
weeks (±3 days) for 6 additional doses, and thereafter every 12 weeks (±3 days) until confirmed disease 
progression, unacceptable toxicity, deemed intolerable by investigator or up to 24 months in patients 
without disease progression. 
2. Pembrolizumab (200 mg dose) IV infusion over 30 minutes every 3 weeks or Pembrolizumab (400 
mg dose) IV infusion over 30 minutes every 6 weeks will be administered until confirmed disease 
progression, unacceptable toxicity, deemed intolerable by investigator or up to 24 months in patients 
without disease progression.  When possible, pembrolizumab should be given on the same schedule 
as SNS-301. The investigator should consult the sponsor if there are questions regarding aligning the 
study treatment schedule. 
 
 
 
 


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For the purpose of this protocol, study treatment is defined as SNS-301 added on to pembrolizumab, 
when given according to the US package insert. Refer to 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf for most recent package 
insert. 
 
 
Statistical Methods: 
 
Sample Size Justification:   
Each cohort will enroll in two stages.  Within each cohort, approximately 15 participants may be 
enrolled in Stage 1 and an additional approximately 15 participants may be enrolled in Stage 2, if 
expanded. The sample size for each cohort and stage is based on Simon’s two-stage design for tests of 
one proportion.  
 
Analysis Populations:   
Safety Analysis Set: 
The safety analysis will be based on the Safety Analysis Set, which comprises all patients who receive 
at least 1 dose of the study treatment or component of the study treatment.  
 
Efficacy-Evaluable Analysis Set: 
The primary efficacy analysis will be based on the Efficacy-Evaluable Analysis Set, which comprises 
all patients who receive at least 1 dose of the study treatment or component of the study treatment and 
have a post baseline response assessment per iRECIST at Week 12. Patients who discontinued 
treatment prior to Week 12 due to disease progression will be included. Patients who do not have a post 
baseline response assessment conducted will not be included in the analysis of efficacy. 
 
Safety Run-In Set: 
All patients who receive at least 1 dose of the study treatment or component of the study treatment apart 
of the safety run-in. 
 
Immunologic Analysis Set: 
All patients who receive at least 1 dose of the study treatment or component of the study treatment and 
have at least one valid post-baseline immunologic assessment available. 
 
General Methods: 
All summarizations will be presented separately for each cohort, and over all subjects combined. 
 
For continuous variables, descriptive statistics (number (n), mean, median, standard deviation, 
minimum and maximum) will be presented. For categorical variables, frequencies and percentages will 
be presented. For time-to-event variables, percentages of patients experiencing that event will be 
presented and median time-to-event will be estimated using the Kaplan-Meier method. As appropriate, 
a 95% CI will be presented. Graphical displays will be presented, as appropriate. All data collected will 
be presented in by-patient data listings.  
 
Patients demographic characteristics including age, gender, and race will be analyzed, with categorical 
variables summarized in frequency tables while continuous variables summarized using mean (standard 
deviation) and median (range).   
 
Safety evaluations will be based on the incidence, severity, attribution and type of AEs, and changes in 
the patient’s vital signs, and clinical laboratory results. Summarization of toxicity data will focus on 
incidence of any serious adverse events, adverse events, drug-related adverse events, and adverse events 


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leading to discontinuation or death, and will be presented in tabular form by system organ class and 
preferred term. Adverse events will be assessed for severity according to the NCI CTCAE, version 5.0. 
 
Objective response rate (ORR) is defined as the proportion of patients with a confirmed best response 
of CR or PR by iRECIST. 
 
 
 
 
Inclusion Criteria: 
 
In order to be eligible for participation in this trial, the patient must: 
1. Provide signed IRB approved informed consent in accordance with institutional guidelines.  
2. Be 18 years of age or older on the day of signing the informed consent, and able and willing to 
comply with all trial procedures. 
3. Have histologically or cytologically documented locally advanced unresectable or 
metastatic/recurrent SCCHN and meet the criteria of either Cohort A or B. 
Cohort A:  Patients with Ongoing CPI Therapy 
a. Patients currently receiving a checkpoint inhibitor (CPI; anti-PD-1 and anti-PD-L1 agents).  
b. Patients currently receiving a CPI must be considered by Investigator to have the potential to 
derive clinical benefit from continued treatment with pembrolizumab. 
c. Based on RECIST 1.1/iRECIST criteria on current CPI treatment (prior to initiation of this 
study), patients must have a best response of  stable disease (SD) or first evidence of 
progressive disease (PD) after a minimum of 12 weeks of a CPI. 
d. Patients on other CPI therapy than pembrolizumab must be willing to switch over to 
pembrolizumab therapy. 
Cohort B:  Patients without Previous CPI Therapy 
a. Patients must be checkpoint inhibitor naïve (anti-PD-1 and anti-PD-L1 agents)  
b. Patients should receive study treatment as first line (PD-L1 positive) or as second line (PD-L1 
negative) systemic therapy in the advanced/metastatic setting. 
4. Have measurable disease, as defined by RECIST version 1.1 (investigator assessment). 
5. Have a performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Performance 
Scale. 
6. Have a life expectancy of ≥ 3 months. 
7. Be willing to provide a pre-treatment tissue sample obtained after initiation of ongoing CPI therapy 
(Cohort A, only) and before first dose of SNS-301 and pembrolizumab on this current clinical trial 
unless clinically contra-indicated per treating physician. Patients unable to provide pre-treatment 
biopsy while on CPI will be evaluated on a case-by-case basis for enrollment pending Sponsor 
consultation (Cohort A, only). Patients are requested to also provide archival tissue from a prior 
biopsy or surgery that is treatment –naïve including prior 1) chemotherapy, radiation and/or 2) anti-
PD(L)-1 treatment-naïve, pending availability.  Tissue provided pre-treatment (fresh or archival) will 
be used to determine ASPH expression. Additionally, an on-treatment biopsy is required unless 
clinically contraindicated, after the third dose of study treatment at week 6. For patients who progress 
as determined per RECIST1.1/iRECIST criteria, an optional biopsy may be obtained at the time of 
disease progression.  
8. Have an ECG with no clinically significant findings such as stage 2b and 3 heart block, any history of 
ventricular arrhythmias or NYHA heart failure within the past 6 months, and QTc prolongation > 500 
ms or as deemed clinically significant by the investigator and performed within 28 days prior to first 
dose.   


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 13 of 132 
 
9. Demonstrate adequate organ function: hematological, renal, hepatic, coagulation parameters as 
defined below and obtained within 28 days prior to the first study treatment. Adequate hematologic 
and end-organ function: 
 
System 
Laboratory Value 
Hematological 
 
 
Absolute neutrophil count (ANC) 
≥1500/ µL 
Platelets 
≥100,000/ µL 
Hemoglobin 
≥9 g/dL, or ≥5.6 mmol/L without transfusion or 
EPO dependency within 7 days  
Renal 
 
Creatinine OR 
Calculated creatinine clearance                           
≤ 1.5 x upper limit of normal (ULN) OR 
≥ 30 mL/min for patient with creatinine level > 
1.5 x institutional ULN 
Note: Creatinine clearance should be calculated 
per Cockcroft-Gault formula 
Hepatic 
 
Total bilirubin 
≤ 1.5 x ULN OR                                                    
Direct bilirubin ≤ ULN for patients with total 
bilirubin levels > 1.5 x ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 x ULN OR 
≤ 5 x ULN for patients with liver metastases 
Coagulation 
 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
Activated Partial Thromboplastin Time  
(aPTT) 
≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
 
10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use two highly effective contraceptive methods that result in a combined failure rate of 
< 1% per year during the treatment period and for at least 180 days after the last dose of study 
treatment: 
• 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of ovaries 
and/or uterus) 
• 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal 
ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices 
• 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
  
For male patients: Agree that during the period specified above, men will not father a child. Male 
patients must remain abstinent (refrain from heterosexual intercourse with women of childbearing 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 14 of 132 
 
potential),   must be surgically sterile (e.g., vasectomy) or use contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for at least 180 days after the last dose of 
study treatment.  
 
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from trial entry: 
 
Cancer-specific Exclusion Criteria: 
1. Any approved anti-cancer therapy including chemotherapy, targeted small molecule therapy or 
radiation therapy within 2 weeks prior to trial Day 0; or if patient has not recovered (i.e., Less than or 
equal to grade 1 or returned to baseline level) from adverse events due to a previously administered 
agent; the following exceptions are allowed: 
• 
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 
days prior to baseline imaging 
• 
Hormone-replacement therapy or oral contraceptives 
• 
Patients with grade 2 neuropathy or grade 2 alopecia 
2. Patients with evidence of rapid progression on prior therapy (if applicable) resulting in rapid clinical 
deterioration should be excluded from participation in the trial. 
3. Currently participating and receiving trial therapy or has participated in a trial of an investigational 
agent and/or has used an investigational device within 28 days prior to Day 0. 
Note: Patients who have entered the follow-up phase of an investigational trial may participate as 
long as it has been 28 days since the last dose of the previous investigational agent or device.  
4. Uncontrolled tumor-related pain 
• 
Patients requiring pain medication must be on a stable regimen at trial entry; 
• 
Symptomatic lesions amenable to palliative radiotherapy per investigator’s discretion (e.g., 
bone metastases or metastases causing nerve impingement) should complete treatment at least 
7 days prior to enrollment 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures 
(once monthly and more frequently) 
• 
Patients with indwelling catheters (e.g., PluerX) are allowed  
6. Malignancies other than indications open for enrollment within 3 years prior to Day 0, with the 
exception of those with negligible risk of metastasis or death treated with expected curative outcome, 
undergoing active surveillance or treatment-naïve for indolent tumors. 
 
General Medical Exclusion Criteria 
 
7. Pregnant or lactating or intending to become pregnant or father children within the projected duration 
of the trial starting with the screening visit through 180 days after the last dose of pembrolizumab 
and/or SNS-301. 
8. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized 
antibodies or fusion proteins.  
9. Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the PD-1/PD-L1 inhibitor formulation. 
10. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.   
11. History or any evidence of interstitial lung disease such as idiopathic pulmonary fibrosis, organizing 
pneumonia (e.g., bronchiolitis obliterans), drug induced or active non-infectious   pneumonitis, 
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 15 of 132 
 
• 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted  
12. History of HIV. HIV antibody testing recommended per investigator’s clinical suspicion.   
13. Active hepatitis B (hepatitis B surface antigen reactive) or active hepatitis C (HCV qualitative RNA 
detected); testing recommended per investigator’s clinical suspicion. 
14. Severe infections within 4 weeks prior to enrollment, including, but not limited to, hospitalization for 
complications of infection, bacteremia, or the presence of any active infection requiring systemic 
therapy. 
15. Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 0 
• 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or 
to prevent chronic obstructive pulmonary disease exacerbation) are eligible 
16. History or current evidence of any condition, therapy or laboratory abnormality that in the opinion of 
the treating investigator might confound the results of the trial or interfere with the patient’s 
participation for the full duration of the trial.  
17. Prior allogeneic stem cell or solid organ transplant. 
18. Received a live, attenuated vaccine within 28 days prior to randomization or anticipation that such a 
live attenuated vaccine will be required during the trial. 
Note: Influenza vaccination should be given during influenza season only (approximately October to 
March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days 
prior to Day 0, during treatment, or within 90 days following the last dose of study treatment.  
19. Known previous or ongoing, active psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.  
20. Prisoner or patient who is compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (i.e. infectious disease) illness. 
21. Treatment with systemic immunomodulating agents (including but not limited to IFNs, IL-2, 
ipilimumab) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to first dose, 
excluding current CPI therapy.  
22. Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) 
within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic 
immunosuppressive medication during the course of the study, with the following exceptions: 
• 
Patients who received acute, low-dose (≤ 10 mg/day) systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 
hours of corticosteroids for a contrast allergy) are eligible for the study  
• 
Patients who received inhaled, topical and intranasal steroids are eligible for the study 
• 
Patients who received mineral corticosteroids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) for asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study.  
 
 
 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 16 of 132 
 
Table 1: Trial Schedule of Events 
Pembrolizumab Schedule – Every 3 weeks 
 
Screeninga 
 
Cycle 
1 
Day 0 
 
Cycle 2 
Week 3 
 
Cycle 3 
Week 6 
 
Cycle 
4 
Week 
9 
 
Every 3 
weeks 
 
Every 6 weeks 
 
Discontinuatio
n VisitPb 
 
Follow-up 
 
Day -28 to 
Day -1 
Signed Informed 
Consent Form(s) 
X 
 
 
 
 
 
 
 
 
Medical, surgical, and 
cancer histories, 
including 
demographic 
f
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Complete Physical 
examPd 
X 
 
 
 
 
 
 
 
 
Targeted Physical 
examPe 
 
Xf 
Xf 
Xf 
Xf 
Xf 
 
X 
 
ECOG performance 
statusPf 
X 
X 
X 
X 
X 
X 
 
X 
 
HIV, Hep B and Hep C 
serologyPg 
X 
 
 
 
 
 
 
 
 
Concomitant 
MedicationsPh 
X 
X 
X 
X 
X 
X 
 
X 
 
Anticoagulant specific 
drug and/or 
anticoagulant factor 
Xa levelsi 
X 
X 
X 
X 
X 
At week 12 then, Q6w until week 
45, thereafter Q12w 
X 
 
For patients on anticoagulants only 
Vital Signs and 
WeightPj 
X 
X 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
12-lead ECGPk 
X 
 
 
 
 
 
 
 
 
Tumor ImagingPl 
X 
Q6w from Day 0 until ~12 months, there after Q12w 
 
 
RECIST/iRECIST 
X 
Q6w from Day 0 until~12 months, there after Q12w 
 
 
HematologyPm 
X 
XPf 
XPf 
XPf 
XPf 
XPf 
 
X 
 
Serum ChemistryPn 
X 
XPf 
XPf 
XPf 
XPf 
XPf 
 
X 
 
Coagulation Panel 
(aPTT, INR) 
X 
 
 
 
 
 
 
 
 
UrinalysisPo 
X 
 
 
X 
 
 
X 
X 
 
PregnancyPp 
X 
X 
X 
X 
X 
X 
 
X 
X 
TSH, T3 and  Free T4Pq 
X 
 
 
X 
 
 
X 
 
 
CPK 
X 
 
 
 
 
 
 
X 
 
HPV/EBV, if unknown 
X 
 
 
 
 
 
 
 
PDL-1 
X 
 
 
 
 
 
 
 
Blood samples for 
immunology 
assessmentsr 
 
X 
X 
X 
X 
At week 12, then Q6 weeks until 
Week 36 and Q12w thereafter as 
well as at disease progression 
 
 
Tumor specimens 
X 
 
 
X 
PUp to 2 optional biopsies and at 
disease progression 
 
 
Adverse Eventst 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pembrolizumabu 
 
X 
X 
X 
X 
X 
 
 
 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 17 of 132 
 
SNS-301Pv 
 
X 
X 
X 
X 
After week 9, Q6w for 6 more 
doses (week 45), thereafter Q12w 
until PD or 24 months if no PD 
 
 
Survival and new anti-
cancer therapy follow-
upPw 
 
 
 
 
 
 
 
 
X 
 
Note: Assessments scheduled on the days of study treatment should be performed before the study treatment unless otherwise 
noted.  
 
Pa 
PWritten informed consent can be obtained up to 28 days prior to Day 0 and is required for performing any trial-specific tests or 
procedures. However,  tumor tissue collection (archived or fresh) can exceed 28 days to ensure that sufficient time is available for 
obtaining the requested sample for trial purposes.  Additionally, a pre-screening informed consent is available to obtain archived 
tumor tissue prior to the  study’s primary consent. Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Day 0 may be used for screening assessments rather than repeating such tests. 
Screening labs (CBC and chemistry) may be used for Day 0 if they are within 10 days of Day 0. 
Pb 
P Patients who discontinue early from study treatment (i.e.,  progression, adverse event, etc.), will be asked to return to the clinic 
within 30 days after the last dose for a treatment discontinuation visit.  
Pc 
PCancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Previous progression data should be collected as 
well. Demographic information includes sex, age, and self-reported race/ethnicity. HPV, EBV, reproductive status and 
smoking/alcohol history should also be captured.   
Pd A complete physical exam will include head, eyes, ears, nose, throat and cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal and neurological systems.  Height and weight will also be collected.  Any signs and symptoms, other 
than those associated with a definitive diagnosis, should be collected at baseline and during the study.    
e A targeted, symptom-directed exam will be performed, as clinically indicated. 
 
f ECOG performance status, targeted physical exam, and local laboratory assessments may be obtained ≤ 72 hours before each 
dosing visit.  
 
Pg 
PPatients should be tested for HIV locally prior to the inclusion into the trial only based on  investigator’s clinical suspicion for 
HIV infection and HIV-positive patients will be excluded from the clinical trial. Hepatitis B surface antigen, anti-HBc antibody, 
anti-HBs antibody, and Hepatitis C antibody immunoassays should be tested only per investigator’s clinical suspicion during 
screening and tested locally. In patients who have positive serology for the anti-HBc antibody, HBV DNA should be tested prior 
to Day 0. 
Ph
P Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications 
the patient has used within the 7 days prior to the screening visit should be documented. At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded. 
i Specific anticoagulant drug and/or anticoagulant factor Xa levels will be obtained only on patients receiving anticoagulant therapy.  
Drug levels will also be obtained at any time of clinical bleeding.  Traditional testing methods can be used for warfarin, heparin 
(e.g., PT/INR, aPTT, TT).  Novel oral anticoagulants may require anticoagulant factor Xa levels or anticoagulant drug specific 
level testing.  See sections Concomitant Medications & Guidance for Investigators for Patients on Anti-coagulants for additional 
information. 
 
jVital signs include heart rate, respiratory rate, blood pressure, and temperature. For first infusion of pembrolizumab, the patient’s 
vital signs should be determined within 60 minutes before the start of the infusion. If clinically indicated, vital signs should be at 
15, 30, 45, and 60 minutes (± 5 minutes for all timepoints) after the start of the infusion, and 30 (± 10) minutes after the infusion. 
For subsequent infusions, vital signs will be collected within 60 minutes before the start of the infusion and at 30 (± 5) minutes 
after the infusion. Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
trial physician if they develop such symptoms.   
kECG recordings will be obtained during screening and as clinically indicated at other time points. Patients should be resting and 
in a supine position for at least 10 minutes prior to ECG collection.  
l Examinations performed as standard of care prior to obtaining informed consent and within 28 days of first dose of study treatment 
may be used rather than repeating tests. All measurable and evaluable lesions should be assessed and documented at the screening 
visit. Tumor imaging should be performed by computed tomography (CT), but may be performed by magnetic resonance imaging 
(MRI) if CT is contraindicated, but the same imaging technique should be used in patient throughout the trial. CT scans (with 
oral/IV contrast unless contraindicated) must include chest, abdomen and pelvis. The investigator must review before dosing at the 
next visit. Patients will undergo tumor assessments every 6 weeks (±7 days) for the first 54 weeks (approximately 12 months) 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 18 of 132 
 
following first dose of study treatment, or earlier if clinically indicated. After 54 weeks, tumor assessments will be required every 
12 weeks (±7 days). Patients who discontinue from treatment for reasons other than disease progression (e.g., toxicity) will continue 
scheduled tumor assessments until disease progression, start of new-anti cancer therapy, withdrawal of consent, or death. 
Investigators may perform additional scans or more frequent assessments if clinically indicated. Patients who continue treatment 
beyond radiographic or clinical disease progression will be monitored with a follow-up scan at the next scheduled tumor assessment. 
Imaging timing should follow calendar days and should not be adjusted for delays or changes in treatment administration dates.  
The Sponsor may request digitized scans from patients during the study. 
Pl m 
PHematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (absolute 
counts of neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells (if any)), and platelet count. A manual 
differential can be done if clinically indicated.  
n  
PSerum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or CO2, calcium, 
phosphorus, glucose, total bilirubin (direct bilirubin only if total bilirubin is elevated), ALT, AST, alkaline phosphatase, lactate 
dehydrogenase, total protein, and albumin. 
o Urinalysis includes specific gravity, pH, glucose, protein, ketones, blood, and a microscopic exam if abnormal results are noted. 
Urinalysis to be performed every 6 weeks. 
p 
PSerum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed 
and documented as negative within 72 hours prior to each dose.  
q 
PThyroid function tests will be performed before first dose and every 6 weeks thereafter.  
P 
rImmunology samples are to be drawn at Day 0, Week 3, Week 6, Week 9, Week 12, then Q6 weeks until Week 36 and thereafter 
every 12 weeks until disease progression, as well as at disease progression.  If  the patient is unable to have samples obtained at the 
protocol specified visit (i.e., COVID19 related) then an unscheduled sample may be drawn. 
sA pre-treatment tumor tissue sample will be analyzed for ASPH expression. After signing of the Informed Consent Form, tumor 
tissue should be submitted to the Sponsor in a timely manner.  A pre-treatment sample is defined as a specimen obtained after 
initiation of ongoing  CPI therapy and before first dose of SNS-301 and pembrolizumab on this current clinical trial. Patients are 
requested to provide archival tissue from a prior biopsy or surgery that is treatment –naïve including prior 1) chemotherapy, 
radiation and/or 2) anti-PD(L)-1 treatment-naïve, pending availability.  Tumor tissue should be of good quality based on total and 
viable tumor content. Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-needle aspiration may be acceptable 
pending Sponsor approval however, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. For core 
needle biopsy specimens, at least three cores should be submitted for evaluation. The patient may start study treatment prior to 
receiving the ASPH expression results from the fresh biopsy or archival tissue from a previous biopsy.  All patients will undergo a 
mandatory tumor biopsy sample collection, if clinically feasible as determined by the trial investigator, at the Week 6 (at the time 
of third dose +/- 3 days). Additionally, up to two optional biopsies may be obtained at any time during the study, if medically 
feasible. A biopsy may also be obtained at the first evidence of radiographic or clinical disease progression (i.e., not proceeded by 
meaningful tumor regression). For patients who respond and subsequently progress, an optional biopsy may be obtained at the time 
of disease progression. Patients who are unable to undergo biopsy sample collection but otherwise meet criteria outlined in protocol 
may continue to receive study treatment.  If  the patient is unable to have the biopsy at the protocol specified visit (i.e., COVID19 
related) then an unscheduled biopsy may be performed. 
tAEs will be collected from the time of informed consent until 30 days after the last dose of study treatment or until initiation of 
another anti-cancer therapy, whichever occurs first. SAEs and AESIs will be collected from the time of informed consent until 90 
days after the last dose of study treatment of until initiation of anti-cancer therapy, whichever occurs first.  
u Pembrolizumab will be given every 3 weeks until confirmed disease progression, unacceptable toxicity, deemed intolerable by 
investigator or up to 24 months in patients without disease progression. The window for each visit is ± 3 days unless otherwise 
noted. A 60 minutes observation period is recommended for the first dose and 30 minutes for subsequent doses.  
v SNS-301 is administered every 3 weeks until week 9 (ie.,4 doses). Then every 6 weeks for 6 more doses (until week 45). Thereafter 
it will be administered every 12 weeks until confirmed disease progression, unacceptable toxicity, deemed intolerable by 
investigator or up to 24 months in patients without disease progression. The window for each visit is ± 3 days unless otherwise 
noted. A 30-minute observation period is recommended after each study treatment. 
P 
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinical visits approximately 
every 3 months for up to 3 years, until death, lost to follow-up, withdrawal of consent, or trial termination by Sponsor. All patients 
will be followed for survival and new anticancer therapy information unless the patient requests to be withdrawn from follow-up; 
this request must be documented in the source documents and signed by the investigator. If the patient discontinues study treatment 
without documented clinical disease progression, every effort should be made to follow up regarding survival, progression (, and 
new anti-cancer therapy. 
 
 
 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 19 of 132 
 
Pembrolizumab Schedule – Every 6 weeks 
 
 
Screeninga 
 
Cycle 1 
Day 0 
 
Cycle 2 
Week 3 
 
Cycle 3 
Week 6 
 
Cycle 4 
Week 9 
 
Every 6 
weeks 
 
Every 12 
weeks 
 
Discontinuation 
VisitPb 
 
Follow-up 
 
Day -28 to 
Day -1 
Signed Informed 
Consent Form(s) 
X 
 
 
 
 
 
 
 
 
Medical, surgical, and 
cancer histories, 
including demographic 
informationPc 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Complete Physical 
examPd 
X 
 
 
 
 
 
 
 
 
Targeted Physical 
examPe 
 
Xf 
Xf 
Xf 
Xf 
Xf 
 
X 
 
ECOG performance 
statusPf 
X 
X 
X 
X 
X 
X 
 
X 
 
HIV, Hep B and Hep C 
serologyPg 
X 
 
 
 
 
 
 
 
 
Concomitant 
MedicationsPh 
X 
X 
X 
X 
X 
X 
 
X 
 
Anticoagulant specific 
drug and/or 
anticoagulant factor Xa 
levelsi 
X 
X 
X 
X 
X 
After week 12, Q6w until 
week 42, thereafter Q12w 
X 
 
For patients on anticoagulants only 
Vital Signs and WeightPj 
X 
X 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
12-lead ECGPk 
X 
 
 
 
 
 
 
 
 
Tumor ImagingPl 
X 
Q6w from Day 0 until ~12 months, there after Q12w 
 
 
RECIST/iRECIST 
X 
Q6w from Day 0 until ~12 months, there after Q12w 
 
 
HematologyPm 
X 
XPf 
XPf 
XPf 
XPf 
XPf 
 
X 
 
Serum ChemistryPn 
X 
XPf 
XPf 
XPf 
XPf 
XPf 
 
X 
 
Coagulation Panel 
(aPTT, INR) 
X 
 
 
 
 
 
 
 
 
UrinalysisPo 
X 
 
 
X 
 
X 
 
X 
 
PregnancyPp 
X 
X 
X 
X 
X 
X 
 
X 
X 
TSH, T3 and  Free T4Pq 
X 
 
 
X 
 
X 
 
 
 
CPK 
X 
 
 
 
 
 
 
X 
 
HPV/EBV, if unknown 
X 
 
 
 
 
 
 
 
PDL-1 
X 
 
 
 
 
 
 
 
Blood samples for 
immunology 
assessmentsr 
 
X 
X 
X 
X 
At week 12, then Q6 
weeks until Week 36 and 
Q12w thereafter as well as 
at disease progression 
 
 
Tumor specimenss 
X 
 
 
X 
P 
Up to 2 optional biopsies  
and at disease 
progression 
 
 
Adverse EventsPt 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pembrolizumabu 
 
X 
 
X 
 
X 
 
 
 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 20 of 132 
 
SNS-301Pv 
 
X 
X 
X 
X 
After week 12, Q6w for 6 
more doses (week 45), 
thereafter Q12w until PD 
or 24 months if no PD 
 
 
Survival and new anti-
cancer therapy follow-
upPw 
 
 
 
 
 
 
 
 
X 
Note: Assessments scheduled on the days of study treatment should be performed before the study treatment unless otherwise 
noted.  
 
Pa 
PWritten informed consent can be obtained up to 28 days prior to Day 0 and is required for performing any trial-specific tests or 
procedures. However,  tumor tissue collection (archived or fresh) can exceed 28 days to ensure that sufficient time is available for 
obtaining the requested sample for trial purposes.  Additionally, a pre-screening informed consent is available to obtain archived 
tumor tissue prior to the study’s primary consent.   Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Day 0 may be used for screening assessments rather than repeating such tests. 
Screening labs (CBC and chemistry) may be used for Day 0 if they are within 10 days of Day 0. 
Pb 
P Patients who discontinue early from study treatment (i.e., progression, adverse event, etc.), will be asked to return to the clinic 
within 30 days after the last dose for a treatment discontinuation visit.  
Pc 
PCancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Previous progression data should be collected as 
well. Demographic information includes sex, age, and self-reported race/ethnicity. HPV, EBV, reproductive status and 
smoking/alcohol history should also be captured.   
Pd A complete physical exam will include head, eyes, ears, nose, throat and cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal and neurological systems.  Height and weight will also be collected.  Any signs and symptoms, other 
than those associated with a definitive diagnosis, should be collected at baseline and during the study.    
e A targeted, symptom-directed exam will be performed, as clinically indicated. 
 
f ECOG performance status, targeted physical exam, and local laboratory assessments may be obtained ≤ 72 hours before each 
dosing visit.  
 
Pg 
PPatients should be tested for HIV locally prior to the inclusion into the trial only based on investigator’s clinical suspicion for 
HIV infection and HIV-positive patients will be excluded from the clinical trial. Hepatitis B surface antigen, anti-HBc antibody, 
anti-HBs antibody, and Hepatitis C antibody immunoassays should be tested only per investigator’s clinical suspicion during 
screening and tested locally. In patients who have positive serology for the anti-HBc antibody, HBV DNA should be tested prior 
to Day 0. 
Ph
P Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications 
the patient has used within the 7 days prior to the screening visit should be documented. At subsequent visits, changes to current 
medications or medications used since the last documentation of medications will be recorded. 
i Specific anticoagulant drug and/or anticoagulant factor Xa levels will be obtained only on patients receiving anticoagulant therapy.  
Drug levels will also be obtained at any time of clinical bleeding.  Traditional testing methods can be used for warfarin, heparin 
(e.g., PT/INR, aPTT, TT).  Novel oral anticoagulants may require anticoagulant factor Xa levels or anticoagulant drug specific 
level testing.  See sections Concomitant Medications & Guidance for Investigators for Patients on Anti-coagulants for additional 
information. 
 
jVital signs include heart rate, respiratory rate, blood pressure, and temperature. For first infusion of pembrolizumab, the patient’s 
vital signs should be determined within 60 minutes before the start of the infusion. If clinically indicated, vital signs should be at 
15, 30, 45, and 60 minutes (± 5 minutes for all timepoints) after the start of the infusion, and 30 (± 10) minutes after the infusion. 
For subsequent infusions, vital signs will be collected within 60 minutes before the start of the infusion and at 30 (± 5) minutes 
after the infusion. Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
trial physician if they develop such symptoms.   
kECG recordings will be obtained during screening and as clinically indicated at other time points. Patients should be resting and 
in a supine position for at least 10 minutes prior to ECG collection.  
l Examinations performed as standard of care prior to obtaining informed consent and within 28 days of first dose of study treatment 
may be used rather than repeating tests. All measurable and evaluable lesions should be assessed and documented at the screening 
visit. Tumor imaging should be performed by computed tomography (CT), but may be performed by magnetic resonance imaging 
(MRI) if CT is contraindicated, but the same imaging technique should be used in patient throughout the trial. CT scans (with 
oral/IV contrast unless contraindicated) must include chest, abdomen and pelvis. The investigator must review before dosing at the 
next visit. Patients will undergo tumor assessments every 6 weeks (±7 days) for the first approximately 12 months following first 
dose of study treatment, or earlier if clinically indicated. After approximately one year, tumor assessments will be required every 
12 weeks (±7 days). Patients who discontinue from treatment for reasons other than disease progression (e.g., toxicity) will continue 


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scheduled tumor assessments until disease progression, start of new-anti cancer therapy, withdrawal of consent, or death. 
Investigators may perform additional scans or more frequent assessments if clinically indicated. Patients who continue treatment 
beyond radiographic or clinical disease progression will be monitored with a follow-up scan at the next scheduled tumor assessment. 
Imaging timing should follow calendar days and should not be adjusted for delays or changes in treatment administration dates.  
The Sponsor may request digitized scans from patients during the study. 
Plm 
PHematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (absolute 
counts of neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells (if any)), and platelet count. A manual 
differential can be done if clinically indicated.  
n  
PSerum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or CO2, calcium, 
phosphorus, glucose, total bilirubin (direct bilirubin only if total bilirubin is elevated), ALT, AST, alkaline phosphatase, lactate 
dehydrogenase, total protein, and albumin. 
o Urinalysis includes specific gravity, pH, glucose, protein, ketones, blood, and a microscopic exam if abnormal results are noted. 
Urinalysis to be performed every 6 weeks. 
p 
PSerum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed 
and documented as negative within 72 hours prior to each dose.  
q 
PThyroid function tests will be performed before first dose and every 6 weeks thereafter.  
P 
r Immunology samples are to be drawn at Day 0, Week 3, Week 6, Week 9, 12, then Q6 weeks until Week 36 and thereafter every 
12 weeks until disease progression, as well as at disease progression.   
s A pre-treatment tumor tissue sample will be analyzed for ASPH expression. After signing of the Informed Consent Form, tumor 
tissue should be submitted to the Sponsor in a timely manner.  A pre-treatment sample is defined as a specimen obtained after 
initiation of ongoing pembrolizumab, nivolumab or other CPI therapy and before first dose of SNS-301 and pembrolizumab on this 
current clinical trial. Patients are requested to provide archival tissue from a prior biopsy or surgery that is treatment –naïve 
including prior 1) chemotherapy, radiation and/or 2) anti-PD(L)-1 treatment-naïve, pending availability.  Tumor tissue should be 
of good quality based on total and viable tumor content. Acceptable samples include core needle biopsies for deep tumor tissue or 
lymph nodes or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-needle 
aspiration may be acceptable pending Sponsor approval however, brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable. For core needle biopsy specimens, at least three cores should be submitted for evaluation. The patient may start 
study treatment prior to receiving the ASPH expression results from the fresh biopsy or archival tissue from a previous biopsy. All 
patients will undergo a mandatory tumor biopsy sample collection, if clinically feasible as determined by the trial investigator, at 
the Week 6 (at the time of third dose of SNS-301 +/- 3 days). Additionally, up to two optional biopsies may be obtained any time 
during the study, if medically feasible. A biopsy may also be obtained  at the first evidence of radiographic or clinical disease 
progression (i.e., not proceeded by meaningful tumor regression). For patients who respond and subsequently progress, an optional 
biopsy may be obtained at the time of disease progression. Patients who are unable to undergo biopsy sample collection but 
otherwise meet criteria outlined in protocol may continue to receive study treatment.  If  the patient is unable to have the biopsy at 
the protocol specified visit (i.e., COVID19 related) then an unscheduled biopsy may be performed. 
t AEs will be collected from the time of informed consent until 30 days after the last dose of study treatment or until initiation of 
another anti-cancer therapy, whichever occurs first. SAEs and AESIs will be collected from the time of informed consent until 90 
days after the last dose of study treatment of until initiation of anti-cancer therapy, whichever occurs first.  
u Pembrolizumab will be given every 6 weeks until confirmed disease progression, unacceptable toxicity, deemed intolerable by 
investigator or up to 24 months in patients without disease progression. After week 9, the pembrolizumab and SNS-301 visits 
will not coincide.  The SNS-301 dosing should not be adjusted. The investigator may choose to give a 3-week dose (i.e., 
pembrolizumab 200 mg) in order for the visits to align.  The investigator should consult the sponsor if there are questions 
regarding aligning the study treatment schedule. The window for each visit is ± 3 days unless otherwise noted. A 60 minute 
observation period is recommended for the first dose and 30 minutes for subsequent doses.  
v SNS-301 is administered Day 0, Week 3, Week 6 and Week 9,  then every 6 weeks for 6 more doses (until week 48). Thereafter 
it will be administered every 12 weeks until confirmed disease progression, unacceptable toxicity, deemed intolerable by 
investigator or up to 24 months in patients without disease progression. The window for each visit is ± 3 days unless otherwise 
noted. A 30-minute observation period is recommended after each study treatment. 
P 
w
P Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinical visits approximately 
every 3 months for up to 3 years, until death, lost to follow-up, withdrawal of consent, or trial termination by Sponsor. All patients 
will be followed for survival and new anticancer therapy information unless the patient requests to be withdrawn from follow-up; 
this request must be documented in the source documents and signed by the investigator. If the patient discontinues study treatment 
without documented clinical disease progression, every effort should be made to follow up regarding survival, progression and new 
anti-cancer therapy. 
 
 


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 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 23 of 132 
 
2. TERMS, ACRONYMS, ABBREVIATIONS  
Term 
Definition 
5-FU 
Fluorouracil 
ß-HCG 
Beta human chorionic gonadotropin 
µl 
Microliter 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Antigen-presenting cells 
aPTT 
Activated partial thromboplastin time 
ASPH 
Aspartate beta-hydroxylase 
ASR 
Administration site reaction 
AST 
Aspartate aminotransferase 
BLA 
Biologics licensing application 
BRPC 
Biochemically Recurrent Prostate Cancer 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
°C 
Celsius 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
CIOMS 
Council for international organizations of medical sciences 
Cl 
Chloride 
CLIA 
Clinical laboratory improvement amendments 
CNS 
Central nervous system 
CO2 
Bicarbonate or carbon dioxide 
COPD 
Chronic obstructive pulmonary disease 
CpG 
5’-c-phosphate-G-3’(a DNA sequence) 
CPI 
Checkpoint inhibitor (anti-PD-1/anti-PD-L1 therapy) 
CPK 
Creatinine phosphokinase 
CR 
Complete response 
CRF 
Case report form 
CT 
Computerized tomography scan 


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Term 
Definition 
CtDNA 
Circulating tumor deoxyribonucleic acid 
CTL 
Cytotoxic CD8+ T-lymphocytes 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
EBV 
Epstein Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
ELI 
Enzyme linked immunospot 
ELISA 
Enzyme-linked immunosorbent assay 
EPO 
Erythropoietin 
FDA 
Food and Drug Administration (U.S.) 
FFPE 
Formalin fixed paraffin embedded 
GCP 
Good clinical practice 
g/dL 
Grams per deciliter 
gpD 
Head DNA stabilization protein of Bacteriophase lambda 
HAAH 
Human aspartyl-asparaginyl-β-hydroxylase 
HBc 
Hepatitis B core antigen 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA-DR 
Human leukocyte antigen – D related 
hMTS 
3M® hollow microstructured transdermal system 
HPV 
Human papillomavirus 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
ID 
Intradermally 
IDE 
Investigational device exemption 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 


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Term 
Definition 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
iRECIST 
Immune response evaluation criteria in solid tumors  
IV 
Intravenous 
K 
Potassium 
kDa 
Kilodalton 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
mg  
Milligrams 
Mg 
Magnesium 
MHC 
Major histocompatibility complex 
MiRNA 
Micro ribosome nucleic acid 
mL 
Milliliters 
mL/min 
Milliliters per minute 
mm 
Millimeter 
mmol/L 
Millimole per liter 
MTD 
Maximum tolerable dose 
MRI 
Magnetic resonance imaging 
NA 
Sodium 
NCI-CTCAE 
V5.0 
National Cancer Institute Common Terminology Criteria for Adverse Events V 5.0 
NDA 
New drug application 
NK 
Natural killer 
ORR 
Objective response rate 
OS 
Overall survival 
P 
Phosphorus 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Programmed death 
PD 
Progressive disease 
PD-L 
Programmed death ligand 


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Term 
Definition 
PI 
Principal investigator 
PR 
Partial response 
PS 
Performance status 
PSA 
Prostate-specific antigen 
PSADT 
Prostate-specific antigen doubling time 
PT 
Prothrombin time 
PTT 
Partial prothrombin time 
R/M 
Relapsed/recurrent and metastatic 
RBC 
Red blood count 
RECIST 
Response evaluation criteria in solid tumors  
RF 
Rheumatoid factor 
RNA 
Ribosome nucleic acid 
SAE 
Serious adverse event 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SEER 
Surveillance, epidemiology and end results 
SNS-301 
HAAH bacteriophage lambda constructs: HAAH-1λ 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
Standard of care 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
T 
Thyroxine 
TCR 
T-cell repertoire 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
TT 
Thrombin time 
UADE 
Unanticipated adverse device effect 
ULN 
Upper limit of normal 
WBC 
White blood count 
WOCBP 
Women of child-bearing potential 


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3. INTRODUCTION 
 Background 
Refer to the Investigator’s Brochure for more details on SNS-301.  For more details on pembrolizumab refer to 
the package insert https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. 
 Pharmaceutical and Therapeutic Background 
Human aspartyl-asparaginyl-β-hydroxylase (HAAH), also known as aspartate-β-hydroxylase (ASPH), is an ~86 
kDa type 2 transmembrane protein that belongs to the α-ketoglutarate-dependent dioxygenase family [1]. It is a 
highly conserved enzyme, which catalyzes the hydroxylation of aspartyl and asparaginyl residues in epidermal 
growth factor-like domains of proteins including Notch and homologs [2]. ASPH was initially identified in a 
novel screen to identify cell surface proteins up-regulated in hepatocellular carcinoma. It has subsequently been 
detected in a diverse array of solid and blood cancers, including: liver, bile duct, brain, breast, colon, prostate, 
ovary, pancreas, and lung cancers as well as various leukemias (Table2). ASPH is not found in significant 
quantities in normal tissue or in proliferative disorders.   
Table 2 
Tumor Type 
ASPH % Positive Expression (Number Tested) 
IHC of Tissue 
Samples 
Serum ELISA 
Flow Cytometry 
Normal Bone Marrow 
0% (130) 
NT 
NT 
Breast 
85% (47) 
94% (181) 
NT 
Cholangiocarcinoma 
100% (27) 
NT 
NT 
Colon Cancer 
75% (41) 
99% (145) 
NT 
Gastric 
80% (51)  
NT 
NT 
Glioblastoma 
98% (15) 
NT 
NT 
Head and Neck 
91% (22) 
75% (12) 
NT 
Hepatocellular Carcinoma 
92% (87) 
NT 
NT 
Lymphoid Leukemia 
49% (80) 
NT 
NT 
MDS 
NT 
50% (10) 
91% (11) 
Mesothelioma 
100% (3) 
100% (12) 
NT 
Myeloid Leukemia 
88% (79) 
NT 
33% (42) 
Lung 
82% (304) 
99% (160) 
NT 
Osteosarcoma 
80% (18) 
NT 
NT 
Pancreatic 
97% (109) 
NT 
NT 
Prostate Cancer 
96% (46) 
95% (233) 
NT 
Renal cancer 
83% (49) 
NT 
NT 
Soft Tissue Sarcoma 
84% (30) 
NT 
NT 
Over-expression of ASPH has been demonstrated to be sufficient to induce cellular transformation, increase 
cellular proliferation and cellular motility while suppression of ASPH expression (small interfering ribonucleic 
acid) or neutralized activity (monoclonal antibodies) returns cancer cells to a normal phenotype. In cancer cells, 
it has been shown to be translocated to the cellular surface where it is not normally located. Because ASPH is an 
embryonic antigen, and as such presents self-antigen tolerance, it is difficult to elicit a robust immune response 
against it and break immune tolerance. Thus, we hypothesized that effective priming of antigen-presenting cells 
(APC) by ASPH antigen is an essential step to overcome immune tolerance. Indeed, in vitro activation of 
dendritic cells with ASPH, prior to re administration to patients with hepatocellular carcinoma has shown 
promising results [3].   


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Bacteriophage offers a simple, inexpensive and practical way of achieving favorable presentation of peptides to 
the immune system. The phage contains deoxyribonucleic acid (DNA) fragments that present the phage CpG 
motifs, which are known to stimulate the innate immune response and activate the major histocompatibility class 
(MHC) class II pathway in APC. Previous findings have revealed that recombinant bacteriophage can prime 
strong CD8+ T-lymphocyte (CTL) responses both in vitro and in vivo against epitopes displayed in multiple 
copies on their surface [4], activate helper T cells [5] and elicit the production of specific antibodies [6, 7] without 
requiring any exogeneous adjuvants. Thus, we have selected bacteriophage as a platform for eliciting anti-ASPH 
immune responses. Bacteriophages are ubiquitous and essentially innocuous to humans, however, as an added 
safety mechanism, they may be neutralized rendering them non-infective to host bacteria while retaining their 
immunostimulant properties. Once neutralized, the bacteriophage effectively becomes a nanoparticle, for 
enhanced delivery of protein fragments to APC.   
We have designed a bacteriophage lambda system to display ASPH peptides fused at the C terminus of the head 
protein gpD of phage lambda. The phages carry 200-300 copies of the gpD protein on their head and thus display 
many copies of an approximately 25 kDa molecular weight fragment of ASPH on their surface. The drug 
substance is one of these HAAH bacteriophage lambda constructs: HAAH-1λ (SNS-301). 
 Pre-Clinical, Clinical Trials and Other Ongoing Trials 
Pre-Clinical  
In non-clinical studies, the SNS-301 vaccine has been evaluated in rodents for immunogenicity and efficacy 
where dose-dependent humoral responses were demonstrated for ID delivery and solid tumor growth was slowed. 
Further, rodent repeat-dose toxicology with SNS-301 had no evident toxicity. 
For additional information on pre-clinical data refer to the Investigators Brochure. 
Current Clinical Data with SNS-301 
In clinical studies, the SNS-301 vaccine has been evaluated in a Phase 1 study (Study SNS0216) in patients with 
biochemically relapsed prostate cancer. The study evaluated 3 dose levels, 2 x 1010, 1 x 1011 and 3 x 1011 particles 
in a 1 mL dose for safety, immunogenicity and preliminary efficacy. Results showed that all dose levels were 
well-tolerated, with the majority of treatment-emergent adverse events (TEAEs) assessed as mild and unrelated 
to SNS-301; further no dose-limiting toxicities (DLTs) were observed and of the 2 reported serious adverse 
events (SAEs), both were assessed as unrelated to study treatment. Further, SNS-301 at all dose levels was 
immunogenic and 58% of patients achieved improvement in prostate specific antigen (PSA) doubling time. 
Based on results from the Phase 1 Study SNS0216, the recommended Phase 2 dose (RP2D) of SNS-301 1 x 1011 
was chosen for further evaluation in Phase 2 clinical studies of SNS-301 in patients with various solid tumors 
and hematologic malignancies.  See the most recent Investigator’s Brochure for additional details. 
The Phase 1/2 Study (SNS-301-2-2) of SNS-301, 1 x 1011 administered ID, added to pembrolizumab is currently 
ongoing. As of the database cutoff (29 October 2020), the study has enrolled 11 patients with locally advanced 
unresectable or metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN). Of the 11 patients 
enrolled 9 (82%) experienced a TEAE, however, majority of the reported TEAEs were mild (Grade 1) and not 
related to study treatment. There were 3 Grade 3 TEAEs related to study treatment experienced by 2 patients:  
rash, electrocardiogram QT prolongation and dehydration. There were 4 SAEs reported for 3 patients:  Grade 3 
dehydration, G3 electrocardiogram QT prolongation,  Grade 2 Systemic Inflammatory Response Syndrome, G2 
hemoptysis, G2 malnutrition/dehydration. There were no DLTs, Grade 4, or fatal events reported to date. 
For additional information clinical data with SNS-301 refer to the Investigators Brochure. 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 29 of 132 
 
 Rationale 
Anti-PD-1 antibodies including nivolumab and pembrolizumab can induce durable remissions <20% of patients 
with recurrent or metastatic SCCHN in first or subsequent line setting  after platinum-containing 
chemotherapy[8], but the majority of patients fail to respond due to inadequate intra-tumoral immune cell 
infiltration. Other checkpoint inhibitors (CPI; defined as anti-PD-1/anti-PD-L1 therapy) currently in clinical trials 
as combination therapy or monotherapy demonstrate limited responses as well, thus underscoring the importance 
of allowing patients who are unresponsive to CPI therapy the option to participate in a clinical trial, such as the 
study sponsored by Sensei Biotherapeutics.  It is hypothesized that these tumors are generally immunologically 
“cold,” or T-cell excluded for various reasons.  Even if there is intra-tumoral T-cell infiltration, these T cells are 
not able to exert a significant anti-tumor effect, likely owing to the suppressive tumor microenvironment.  ASPH 
is frequently expressed in SCCHN, but de-novo responses to this tumor-specific antigen may be limited due to 
immune tolerance acquired during development. Our hypothesis is that SNS-301 will help generate functional T 
cells when added to a CPI can overcome checkpoint refractoriness or lack of checkpoint efficacy. Sensei 
Biotherapeutics plans to develop SNS-301 in addition to pembrolizumab in a study targeting two different patient 
cohorts: patients that did not achieve objective responses after at least 12 weeks of CPI and patients that are CPI 
naïve.  The overall goal is to improve clinical outcomes in patients with locally advanced or metastatic SCCHN 
receiving CPI therapy.   
 Rationale for the Trial and Selected Subject Population 
It is hypothesized that SNS-301, given its biologic properties and unique ASPH target, can impact on 
biologically-relevant (i.e. ASPH-over-expressing) cancer targets in a differentiated and meaningful manner. 
Accordingly, the Sponsor seeks now to generate initial signals of SNS-301 impact in oncologic investigational 
spaces of high unmet medical need including ASPH-expressing squamous cell carcinoma of the head and neck 
(SCCHN). Preliminary expression data prior to the initiation of the current clinical trial demonstrated ASPH 
expression at any level in about 85% or greater of SCCHN patients. In the current trial, 26 out of the 26 patients 
considered potentially eligible for enrollment tested positive for ASPH expression. Given the prevalence seen 
ASPH expression in tumors, the Sponsor proposes foregoing ASPH expression data prior to trial enrollment and 
proposes to enroll and treat patients regardless of ASPH expression. ASPH expression data will continue to be 
obtained and recorded however it is anticipated that the numbers of patients without ASPH expression will be 
low.  
3.2.1.1  
Unmet Medical Need for Patients with SCCHN 
SCCHN are cancers that comprise the oral cavity, pharynx and larynx, and account for >90% of histological 
subtypes and have an annual incidence of about 45,000 patients in the US alone.  According to SEER, less than 
two-thirds of patients remain alive at 5 years [9]. Tobacco use is the most important risk factor, followed by 
human papilloma virus (HPV), which is primarily seen in oropharyngeal cancers (tonsils and base of the tongue). 
Despite an aggressive multidisciplinary approach, up to 30% of patients with locally advanced disease relapse in 
distant sites, and up to 60% have local recurrence [10].  
Until recently, platinum-based combination chemotherapy with or without cetuximab was the standard of care 
(SOC) for relapsed/recurrent and metastatic (R/M) disease based on the cetuximab in first-line treatment of head 
and neck cancer (EXTREME) trial, which showed the addition of cetuximab to platinum/5-fluorouracil (5-FU) 
chemotherapy improved overall survival (OS) from 7.1 to 10.1 months [11]. However, toxicity with this regimen 
is significant, and responses are relatively short. Unfortunately, patients after disease progression have very low 
responses to additional chemotherapy and low median OS, thus highlighting the need for novel therapies.  
Multiple factors support the use of immunotherapy in SCCHN, which have prompted the development of CPI 
therapy in SCCHN leading to approval of nivolumab and pembrolizumab in the second line (2L) or subsequent 
therapies recurrent/metastatic setting.  For example, nivolumab was approved on the basis of a randomized Phase 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 30 of 132 
 
3 trial in platinum-refractory recurrent/metastatic SCCHN [2]. Three hundred sixty-one patients were assigned 
in a 2:1 ratio to either nivolumab (at a dose of 3 mg/kg of body weight once every 2 weeks) or investigator’s 
choice of single agent standard chemotherapy (methotrexate, docetaxel or cetuximab); 54.6% of patients had at 
least two prior lines of systemic therapy.  Median OS was superior in the nivolumab group (7.5 vs 5.1 months 
(HR=0.70, p=0.01) and was more than double at 1 year (36% vs 16.6%).  The objective response rate (ORR) was 
also superior with nivolumab (13.3% vs 5.8%), and increased durability of response (DoR) was also 
demonstrated with nivolumab.  The safety profile of nivolumab was better tolerated than chemotherapy, with 
grade 3 or higher AEs reported in 13.1% vs 35.1%, respectively, with the most common AEs including fatigue 
(14.0%), nausea (8.5%) and rash (7.6%).   
KEYNOTE-048 (NCT02358031) [8], a randomized, multicenter, three-arm, open-label, active-controlled trial 
conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for 
metastatic disease or with recurrent disease who were considered incurable by local therapies was approved by 
the FDA in June 2019. 
Patients were randomized (1:1:1) to receive one of the following treatments: pembrolizumab as a single agent; 
pembrolizumab, carboplatin or cisplatin, and FU; or cetuximab, carboplatin or cisplatin, and FU. Randomization 
was stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] ≥50% or <50%), HPV status 
according to p16 IHC (positive or negative), and ECOG PS (0 vs 1). PD-L1 expression (TPS and CPS) was 
determined using the PD-L1 IHC 22C3 pharmDx kit.  Overall survival (OS), sequentially tested in the subgroup 
of patients with CPS ≥20 HNSCC, the subgroup of patients with CPS ≥1 HNSCC and the overall population, 
was the major efficacy measure. 
The trial demonstrated a statistically significant improvement in OS in the overall population for patients 
randomized to pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy at a pre-
specified interim analysis. The median OS was 13.0 months for the pembrolizumab plus chemotherapy arm and 
10.7 months for the cetuximab plus chemotherapy arm (HR 0.77; 95% CI: 0.63, 0.93; p=0.0067). Results were 
similar in the CPS ≥20 subgroup (HR 0.69; 95% CI: 0.51, 0.94) and CPS ≥1 subgroup (HR 0.71; 95% CI: 0.57, 
0.88). 
The trial also demonstrated statistically significant improvements in OS for the subgroups of patients with PD-L1 
CPS ≥1 HNSCC and PD-L1 CPS ≥20 HNSCC randomized to pembrolizumab as a single agent compared with 
cetuximab plus chemotherapy. In the CPS ≥1 subgroup, the median OS was 12.3 months for the pembrolizumab 
arm and 10.3 months for the cetuximab plus chemotherapy arm (HR 0.78; 95% CI: 0.64, 0.96; p=0.0171). For 
the CPS ≥20 subgroup, the median OS was 14.9 months for the pembrolizumab arm and 10.7 months for the 
cetuximab plus chemotherapy arm (HR 0.61; 95% CI: 0.45, 0.83; p=0.0015). At the time of the interim analysis, 
there was no significant difference in OS between the pembrolizumab as a single agent arm and the cetuximab 
plus chemotherapy arm for the overall population. There were no significant differences in progression-free 
survival for either pembrolizumab-containing arm compared to the cetuximab plus chemotherapy arm in any 
population. 
The most common adverse reactions reported in ≥20% of patients who received pembrolizumab as a single agent 
in KEYNOTE-048 were fatigue, constipation, and rash. The most common adverse reactions reported in ≥20% 
of patients who received pembrolizumab in combination with chemotherapy in KEYNOTE-048 were nausea, 
fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough. 
Over the last several years advancements regarding the therapeutic role of ICIs led to the approval of 
pembrolizumab and nivolumab for SCCHN; however, response rates are fairly low in the first and second line 
metastatic SCCHN population.  There are multiple other ICIs that are in clinical trials (e.g., atezolizumab, 
durvalumab, avelumab, etc.) and these agents as combination therapy or monotherapy demonstrate limited 
responses as well, thus underscoring the importance of allowing these patients to participate in trials that 


SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 31 of 132 
 
potentially can enhance the efficacy of CPI therapy such as the study sponsored by Sensei Biotherapeutics.  In 
order to provide an option to the majority of SCCHN patients who do not respond to  CPI therapy, Sensei will 
allow inclusion of patients who received widely investigated  ICIs  (anti-PD1, anti-PD-L1 agents) as part of 
clinical trials  as long as patients meet all of the outlined eligibility criteria.  All patients enrolled will be switched 
to pembrolizumab treatment regardless of which ICI therapy the patient was receiving previously. Furthermore, 
given the modest response rates to CPI therapy even in patients with PD-L1 positive tumors in the first line 
setting (19%, Keynote-48), Sensei will allow enrollment to a second cohort with patients that are CPI therapy 
naïve. 
3.2.1.2 ASPH Expression Testing in SCCHN 
Tissue samples from 22 patient with squamous cell cancer of the head and neck were evaluated for ASPH 
expression by IHC at a collaborating laboratory. Twenty (91%) of the patients studied showed evidence of ASPH 
expression with 18 (82%) having moderate to high expression levels (Unpublished data, Dr. Jack Wands, Brown 
University).  As of 29 Oct 2020, 30 additional archived tissue samples have been analyzed from this study.  All 
30 samples were found to be ASPH positive as assessed by a CLIA validated IHC assay from Fred Hutchinson 
Cancer Center.   
 
Figure 1. ASPH Expression in patients with SCCHN as expressed by 
immunohistochemistry    
 
 
 Rationale for Companion Diagnostic and Translational Biomarkers 
 The Sponsor has developed an analytical method to screen for ASPH expression. Immunohistochemistry 
staining for ASPH will be performed on biopsy samples.  
All ASPH (+) samples and a random sample of ASPH negative samples (if available) will be banked in the event 
that they may be necessary for future analysis. 
 Rationale for Dose Selection/Regimen 
The pembrolizumab dose of 200 mg dose IV infusion over 30 minutes every three weeks or pembrolizumab dose 
of 400 mg IV infusion over 30 minutes every six weeks has been chosen based on the US package insert for this 
indication. As of April 2020, Merck has extended dosing for all approved indications to allow for three or six 
week dosing.SNS-301 (1 x 1011 particles in 1ml ID injection) is planned to be administered when pembrolizumab 
dosing is every 3 weeks SNS-301 will be given at Day 0, Week 3, Week 6, Week 9, then every 6 weeks for 6 
more doses (45 weeks). Thereafter, SNS-301 is to be administered every 12 weeks until confirmed disease 
progression, unacceptable toxicity, or deemed intolerable by the investigator. When pembrolizumab dosing is 
every 6 weeks SNS-301 dosing will be at Day 0, Week 3, Week 6, Week 12, every 3 weeks for 4 doses (12 


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weeks), and then every 6 weeks for 6 more doses (45 weeks). Thereafter, SNS-301 is to be administered every 
12 weeks until confirmed disease progression, unacceptable toxicity, or deemed intolerable by the investigator. 
The SNS-301 dose was chosen based on the safety, immunogenicity and preliminary efficacy data that were 
available from the Phase 1 dose escalation study (Study SNS0216) conducted in patients with biochemically 
relapsed prostate cancer.  The overall safety profile, SNS-301 was considered to be tolerable with no dose 
limiting toxicities (DLTs) observed and no discernable safety differences.   
The immunogenicity of SNS-301 was evaluated for both antibody and cellular responses.  At all dose levels 
tested, SNS-301 was able to generate specific anti-ASPH responses, however, the mid-dose level (and proposed 
Phase 2 clinical dose) demonstrated the best ASPH-specific antibody and cellular responses. 
The Sponsor evaluated the clinical efficacy of SNS-301 by examining PSA kinetics such as the effect of SNS-
301 on PSA doubling time (PSADT), absolute PSA levels and PSA velocity (PSAV).  A positive effect in 
lengthening the time in months to double the PSA value in the treatment phase compared to the pre-treatment 
phase was observed in 2 of 3 patients in both the low dose (2 x 1010 particles) and the mid dose (1 x 1011 particles) 
treatment groups.  In the high dose (3 x 1011 particles) group, 3 of 6 patients showed a positive treatment effect. 
.  The efficacy analysis showed a disease stabilizing effect of SNS-301 as evidenced by significant improvements 
in PSADT post-therapy for the patients.  We believe that the excellent safety profile of SNS-301 coupled with 
the preliminary efficacy observed in patients with prostate cancer warrants further evaluation of SNS-301 at the 
mid-dose level of 1x1011  in the unmet medical need patient population of patients with SCCHN who have failed 
prior therapy.  The dose of pembrolizumab is based on the US package insert. No overlapping toxicities are 
anticipated.  
 Benefit/Risk 
Any direct benefit for patients from participating in this clinical trial are unknown. . The median OS of patients 
even in the first line metastatic setting who do not respond to CPI is less than 12 months. However, this study 
may likely enroll who have also previously received and progressed on platinum-based chemotherapy, in which 
population the median OS is less than 6 months. Therefore, the study population represents a high unmet medical 
need and overall the clinical benefit potential outweighs the risks associated with SNS-301   The known risks of 
SNS-301 are described in the pre-clinical and clinical background sections, in the SNS-301 Investigators 
Brochure.   
There have been no significant safety findings with no related Grade 3 or Grade 4 adverse events and no related 
serious adverse events with SNS-301.  Of note, no studies assessing the reproductive and developmental toxicity 
of SNS-301 have been conducted to date. It is not known whether SNS-301 can cross the placenta or cause harm 
to the fetus when administered to pregnant women or whether it affects reproductive capacity. However, the 
antigen targeted by SNS-301 is involved in uterine implantation of the embryo. Therefore, SNS-301 should not 
be administered to pregnant women and pregnancy testing will be performed in women of childbearing potential 
(WOCBP) at screening and prior to each dose. WOCBP and male partners of such women should take necessary 
precautions to avoid pregnancy while receiving SNS-301, for the protocol defined period following the last dose 
of investigational product. 
It is not known whether SNS-301 is excreted in human milk. Because of the unknown potential for serious 
adverse drug reactions in nursing infants, investigational product should not be administered to nursing mothers. 
The known risks of pembrolizumab are described in the package insert. 


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4. OBJECTIVES AND ENDPOINTS 
 Study Objectives 
 Primary Objectives 
• 
To determine the safety and tolerability of SNS-301 delivered by intradermal injection (ID) using the 3M®             
hollow microstructured transdermal system (hMTS) device in addition to pembrolizumab among patients with 
locally advanced unresectable or metastatic/recurrent SCCHN. 
• 
To evaluate the anti-tumor activity of SNS-301 delivered by intradermal injection (ID) using the 3M® hollow 
microstructured transdermal system (hMTS) device in addition to pembrolizumab in patients with locally 
advanced unresectable or metastatic/recurrent SCCHN 
 Secondary Objective 
• 
To evaluate preliminary immune response to SNS-301 delivered by intradermal injection (ID) using the 
3M® hollow microstructured transdermal system (hMTS) device in addition to pembrolizumab in 
patients with locally advanced unresectable or metastatic/recurrent SCCHN. 
 Exploratory Objective 
• 
To evaluate tumor and immune biomarkers and their association with treatment outcome (antitumor activity 
and/or safety) in patients with locally advanced unresectable or metastatic/recurrent SCCHN. 
 Study Endpoints 
 Primary 
1. To determine the safety and tolerability of SNS-301 delivered by intradermal injection (ID) using the 
3M® hollow microstructured transdermal system (hMTS) device in addition to pembrolizumab among 
patients with locally advanced unresectable or metastatic/recurrent SCCHN as measured by the 
following parameters: 
 
• 
All adverse events (AEs) by CTCAE v5  such as clinically significant changes in safety laboratory 
parameters from baseline: CBC with Differential; Chemistry Panel; Urinalysis; T3, Free T4 and 
TSH; creatine phosphokinase (CPK ) and including adverse events of special interest (AESI) 
classified by system organ class (SOC), preferred term (PT), severity and relationship to drug 
 
2. To determine anti-tumor activity of SNS-301 delivered by intradermal injection (ID) using the 3M® 
hollow microstructured transdermal system (hMTS) device in addition to pembrolizumab in patients 
with locally advanced unresectable or metastatic/recurrent SCCHN as measured by the following 
parameters: 
• 
Objective response rate (ORR) by immune Response Evaluation Criteria in Solid Tumors 
(iRECIST)Duration of Response (DoR) as assessed by RECIST version 1.1 and iRECIST 
• 
Objective response rate (ORR) by Response Evaluation Criteria (RECIST) version 1.1 by 
investigator review  
• 
Disease control rate (DCR) as assessed by RECIST version 1.1 and iRECIST 
• 
Progression Free Survival (PFS) as assessed by RECIST version 1.1 and iRECIST  
• 
Overall Survival (OS) 
 


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 Secondary 
To determine preliminary immune response to SNS-301 delivered by intradermal injection (ID) using the 
3M® hollow microstructured transdermal system (hMTS) device in addition to with pembrolizumab in 
patients with locally advanced unresectable or metastatic/recurrent SCCHN by the following parameters: 
• 
Antigen-specific cellular immune responses that may be assessed by but not limited to: Interferon-γ 
secreting T lymphocytes in peripheral blood mononuclear cells (PBMCs) by ELI Spot 
• 
Anti-SNS-301 antibody response 
• 
Assessment of pro-inflammatory and immunosuppressive elements in neoplastic and adjacent normal 
tissue, where feasible 
 Exploratory 
To determine tumor and immune biomarkers and their association with treatment outcome (antitumor activity 
and/or safety) in patients with locally advanced unresectable or metastatic/recurrent solid tumors as measured by 
the following parameters: 
• 
Immune related gene expression  
• 
Expression of tumor specific oncoproteins including but not limited to ASPH 
• 
Correlation of serum ASPH level as determined by ELISA with tissue expression using IHC 
• 
miRNA profiling to predict treatment efficacy evaluating pre and post-treatment peripheral blood 
samples as well as urine samples 
• 
Cytokine and chemokine profiles in urine pre- and post-treatment and longitudinally throughout the 
trial 
• 
TCR sequencing of PBMCs for diversity and putative antigen specificity 
• 
CtDNA analysis and tracking for progression 
5. STUDY DESIGN 
 Research Hypotheses 
SNS-301 delivered by intradermal injection (ID) using the 3M® hollow microstructured transdermal system 
(hMTS) device in addition to pembrolizumab, will be generally safe, well tolerated, immunogenic and lead to 
anti-tumor responses in adult patients with locally advanced unresectable or metastatic/recurrent SCCHN.  
 Overall Design 
This is a Phase 1/2, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical 
efficacy of SNS-301 delivered by intradermally in addition to pembrolizumab in patients with locally advanced 
unresectable or metastatic/recurrent SCCHN.  The trial population consists of patients with locally advanced 
unresectable or metastatic/recurrent SCCHN who are currently receiving a CPI therapy (Cohort A) or are naïve 
to CPI therapy (Cohort B).  CPI therapy are considered agents that are anti-PD1 and anti-PD-L1agents.   Patients 
currently receiving CPI therapy must have a best response of stable disease (SD) or first evidence of progressive 
disease (PD) after a minimum of 12 weeks of a CPI therapy.  Patients receiving first-line pembrolizumab 
monotherapy must be PD-L1 positive. Patients receiving another CPI than pembrolizumab will be switched over 
to pembrolizumab at the time of entering this study.  Each cohort will enroll up to approximately 30 patients.  
Approximately 60 patients will be enrolled over two cohorts at up to 15 institutions within the United States.   
 
 


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The cohorts for this study are highlighted below. 
 
After consenting to participate in this clinical trial, participants will be screened for enrollment.  A tissue sample 
is required for entry onto the study with either a fresh biopsy or archival tissue from a previous biopsy.  Ideally, 
a pre-treatment tissue sample obtained after initiation of ongoing CPI therapy and before first dose of SNS-301 
and pembrolizumab on this current clinical trial will be collected. Patients unable to provide pre-treatment biopsy 
while on CPI will be evaluated on a case-by-case basis for enrollment pending Sponsor consultation. Patients are 
requested to provide archival tissue from a prior biopsy or surgery that is treatment -naïve including prior 1) 
chemotherapy, radiation and/or 2) anti PD(L)-1 treatment-naïve, pending availability. An on-treatment biopsy is 
required when medically feasible, after the  third  dose of treatment around treatment week 6.  Additionally, up 
to two optional biopsies may be obtained at any time during the study, if medically feasible. For patients who 
progress as determined per RECIST1.1/iRECIST criteria, an optional biopsy will be obtained at the time of 
disease progression. 
This study will employ a Simon 2-stage design, with 15 evaluable patients (i.e. meeting the definition for the 
efficacy evaluable analysis set;at  Week 12 for both cohorts . The criteria for advancing to Stage 2 is described 
in Section 10.2.  Non-evaluable patients will be replaced.   
The safety run-in will be performed using a modified rolling six design which will enroll up to six patients (safety 
analysis patients). These patients may contribute to the first 15 in stage 1, assuming they meet the definition for 
evaluable for efficacy. 
Once the first three patients of these six patients have completed Week 6 assessments, in the absence of any dose-
limiting toxicity (DLT), enrollment may proceed through stage 1. However, if prior to the first three patients 
completing Week 6, a single patient from the first six experiences a DLT, then enrollment will be limited to six 
patients until all six patients have reached Week 6 and are assessed for DLT. If no additional patients, of these 
six, experience a DLT within the 6-week safety run in period, then enrollment may proceed to completion. 


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If a second of these first six patients experiences a DLT within the first six weeks, enrollment will stop, and the 
Sponsor’s medical monitor, in addition to the PI and Investigator(s) at the patients’ site(s) will discuss the case, 
and a decision will be made whether to modify the trial or to cease further enrollment. If enrollment is ceased, it 
will only be reinitiated after amendment of the protocol and approval of the amended protocol by the IRB. 
Safety run-in patients that withdraw from the study for reasons other than a DLT, prior to the end of the safety 
run-in period, will be replaced. The end of the safety run-in period is defined as the earliest of the following: 
• 
The first three patients have all completed Week 6 with no DLTs experienced by any of the safety run-
in patients in that cohort (up to six); enrollment may then proceed through stage 1; 
• 
All six patients of the safety run-in phase, have completed week six with only one patient having 
experienced a DLT; enrollment may then proceed through stage 1; 
• 
Two or more of the safety run-in patients, have experienced DLTs prior to completing Week 6; 
enrollment will be suspended. 
DLTs are defined in the protocol section 9.3.9. 
Because this trial is treating patients with SNS-301 and pembrolizumab for the first time, there will be a waiting 
period of one week between enrollment of the first patient and the second patient. 
 
Stopping rules for adverse events will be employed for this trial.  The trial will be stopped if any adverse 
experience of any related death, grade 4 autoimmune toxicity or any grade 4 toxicity that is considered to have a 
causal relationship to study drug.  Any related death, grade 4 autoimmune toxicity and any grade 4 toxicity that 
is considered to have a causal relationship to study drug will be submitted to regulatory agencies within the 
expedited safety reporting criteria. 
 
To ensure patient safety during the study, a Safety Committee will be formed to monitor safety on a periodic basis. 
Members of the Safety Committee will include a Safety representative, Principal Investigator(s) and the Sponsor 
Medical Expert.  A charter will outline their roles and responsibilities. The Safety Committee will meet at the 
completion of the safety run-in to review safety data collected from the point of first patient in (FPI) to review safety, 
or as needed.  The safety data will include demographic data, adverse events, serious adverse events, and relevant 
laboratory data.  Following each data review, the Safety Committee will provide recommendations as to whether the 
study should continue or be amended, or whether the study should be stopped on the basis of safety (i.e., evidence of 
harm). The final decision will rest with the Sponsor.  The interim efficacy assessment, for each cohort, will occur after 
15 patients were enrolled and completed the 12-week follow-up period.  A safety review will occur in parallel to the 
efficacy assessment of the first 15 patients.   Any outcomes of these safety reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the Institutional Review boards/Ethics 
Committees (IRBs/ECs).   
 End of Study Definition 
The clinical trial will be considered completed when all patients have had their three-year follow-up visit, death, 
lost to follow-up, withdrawal of consent, or when the Sponsor deems the study completed, whichever comes 
first.  
6. STUDY POPULATION 
Inclusion Criteria 
In order to be eligible for participation in this trial, the patient must: 


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1. Provide signed IRB approved informed consent in accordance with institutional guidelines.  
2. Be 18 years of age or older on the day of signing the informed consent, and able and willing to comply with all trial 
procedures. 
3. Have histologically or cytologically documented locally advanced unresectable or metastatic/recurrent 
SCCHN and meet the criteria of either Cohort A or B. 
Cohort A:  Patients with Ongoing CPI Therapy 
a. Patients currently receiving a checkpoint inhibitor (anti-PD1 and anti-PD-L1 agents).  
b. Patients currently receiving a CPI must be considered by Investigator to have the potential to derive 
clinical benefit from continued treatment with pembrolizumab. 
c. Based on RECIST 1.1/iRECIST criteria on current CPI treatment (prior to initiation of this study), 
patients must have a best response of  stable disease (SD) or first evidence of progressive disease 
(PD) after a minimum of 12 weeks of a CPI. 
d. Patients on other CPI therapy than pembrolizumab must be willing to switch over to pembrolizumab 
therapy. 
Cohort B:  Patients without Previous CPI Therapy 
a. Patients must be checkpoint inhibitor naïve (anti-PD1 and anti-PD-L1 agents)  
b. Patients should receive study treatment as first line (PD-L1 positive) or as second line (PD-L1 
negative) systemic therapy in the advanced/metastatic setting. 
4. Have measurable disease, as defined by RECIST version 1.1 (investigator assessment).  
5. Have a performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Performance Scale. 
6. Have a life expectancy of ≥ 3 months. 
7. Be willing to provide a pre-treatment tissue sample obtained after initiation of ongoing CPI therapy (Cohort 
A, only) and before first dose of SNS-301 and pembrolizumab on this current clinical trial unless clinically 
contra-indicated per treating physician. Patients unable to provide pre-treatment biopsy while on CPI will be 
evaluated on a case-by-case basis for enrollment pending Sponsor consultation (Cohort A, only). Patients 
are requested to provide archival tissue from a prior biopsy or surgery that is treatment –naïve including prior 
1) chemotherapy, radiation and/or 2) anti-PD(L)-1 treatment-naïve, pending availability.   Tissue provided 
pre-treatment (fresh or archival) will be used to determine ASPH expression . Additionally, an on-treatment 
biopsy is required unless clinically contraindicated, after the third   dose of study treatment at week 6. For 
patients who progress as determined per RECIST1.1/iRECIST criteria, an optional biopsy may be obtained 
at the time of disease progression.  
8. Have an ECG with no clinically significant findings such as stage 2b and 3 heart block, any history of 
ventricular arrhythmias or NYHA heart failure within the past 6 months, and QTc prolongation > 500 ms or 
as deemed clinically significant by the investigator and performed within 28 days prior to first dose.   
9. Demonstrate adequate organ function: hematological, renal, hepatic, coagulation parameters as defined below and 
obtained within 28 days prior to the first study treatment. Adequate hematologic and end-organ function: 
 
System 
Laboratory Value 
Hematological 
 
 
Absolute neutrophil count (ANC) 
≥1500/ µL 
Platelets 
≥100,000/ µL 
Hemoglobin 
≥9 g/dL, or ≥5.6 mmol/L without 
transfusion or EPO dependency within 7 
days  


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Renal 
 
Creatinine OR 
Calculated creatinine clearance                           
≤ 1.5 x upper limit of normal (ULN) OR 
≥ 30 mL/min for patient with creatinine level > 
1.5 x institutional ULN 
Note: Creatinine clearance should be calculated 
per Cockcroft-Gault formula 
Hepatic 
 
Total bilirubin 
≤ 
1.5 
x 
ULN 
OR             
Direct bilirubin ≤ ULN for patients with 
total bilirubin levels > 1.5 x ULN 
AST (SGOT) and ALT (SGPT) 
≤ 
2.5 
x 
ULN 
OR 
≤ 5 x ULN for patients with liver 
metastases 
Coagulation 
 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants 
Activated Partial Thromboplastin Time  
(aPTT) 
≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants 
 
10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
two highly effective contraceptive methods that result in a combined failure rate of < 1% per year during the 
treatment period and for at least 180 days after the last dose of study treatment: 
• 
A woman is considered to be of childbearing potential if she has not reached a postmenopausal state (≥ 
12 continuous months of amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus) 
• 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, 
male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices, and copper intrauterine devices 
• 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, sympto-
thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception 
 
For male patients: Agree that during the period specified above, men will not father a child.  Male patients 
must remain abstinent (refrain from heterosexual intercourse with women of childbearing potential),   must 
be surgically sterile (e.g., vasectomy) or use contraceptive methods that result in a failure rate of < 1% per 
year during the treatment period and for at least 180 days after the last dose of study treatment.  
 
 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from trial entry: 
Cancer-specific Exclusion Criteria: 


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1. Any approved anti-cancer therapy including chemotherapy, targeted small molecule therapy or radiation therapy 
within 2 weeks prior to trial Day 0; or if patient has not recovered (i.e., Less than or equal to grade 1 or returned to 
baseline level) from adverse events due to a previously administered agent; the following exceptions are allowed: 
• 
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 days prior to 
baseline imaging 
• 
Hormone-replacement therapy or oral contraceptives 
• 
Patients with grade 2 neuropathy or grade 2 alopecia 
2. Patients with evidence of rapid progression or prior therapy (if applicable) resulting in rapid clinical 
deterioration should be excluded from participation in the trial; 
3. Currently participating and receiving trial therapy or has participated in a trial of an investigational agent and/or 
has used an investigational device within 28 days prior to Day 0; 
Note: Patients who have entered the follow-up phase of an investigational trial may participate as long as it 
has been 28 days since the last dose of the previous investigational agent or device.  
4. Uncontrolled tumor-related pain 
• 
Patients requiring pain medication must be on a stable regimen at trial entry; 
• 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing 
nerve impingement) should complete treatment at least 7 days prior to enrollment 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once 
monthly and more frequently) 
• 
Patients with indwelling catheters (e.g., PluerX) are allowed;  
6. Malignancies other than indications open for enrollment within 3 years prior to Day 0, with the exception of those 
with negligible risk of metastasis or death treated with expected curative outcome, undergoing active surveillance 
or treatment-naïve for indolent tumors.   
General Medical Exclusion Criteria 
7. Pregnant or lactating or intending to become pregnant or father children within the projected duration of the trial 
starting with the screening visit through 180 days after the last dose of pembrolizumab and/or SNS-301. 
8. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or 
fusion proteins.  
9. Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells 
or any component of the PD-1/PD-L1 inhibitor formulation. 
10. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease 
modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.  
11. History or any evidence of interstitial lung disease such as idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug induced or active non-infectious   pneumonitis, idiopathic pneumonitis, or 
evidence of active pneumonitis on screening chest CT scan 
• 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted  
12. History of HIV. HIV antibody testing recommended per investigator’s clinical suspicion.   
13. Active hepatitis B (hepatitis B surface antigen reactive) or active hepatitis C  (HCV qualitative RNA detected); 
testing recommended per investigator’s clinical suspicion. 
14. Severe infections within 4 weeks prior to enrollment, including, but not limited to, hospitalization for complications 
of infection, bacteremia, or the presence of any active infection requiring systemic therapy. 
15. Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 0 
• 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent 
chronic obstructive pulmonary disease exacerbation) are eligible 
16. History or current evidence of any condition, therapy or laboratory abnormality that in the opinion of the treating 
investigator might confound the results of the trial or interfere with the patient’s participation for the full duration 
of the trial.  


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17. Prior allogeneic stem cell or solid organ transplant. 
18. Received a live, attenuated vaccine within 28 days prior to randomization or anticipation that such a live attenuated 
vaccine will be required during the trial. 
Note: Influenza vaccination should be given during influenza season only (approximately October to March). 
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to Day 0, 
during treatment, or within 90 days following the last dose of study treatment.  
19. Known previous or ongoing, active psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.  
20. Prisoner or patient who is compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric 
or physical (i.e. infectious disease) illness. 
21. Treatment with systemic immunomodulating agents (including but not limited to IFNs, IL-2, ipilimumab) within 6 
weeks or five half-lives of the drug, whichever is shorter, prior to first dose, excluding current  CPI therapy.  
22. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to 
initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course 
of the study, with the following exceptions: 
• 
Patients who received acute, low-dose (≤ 10 mg/day) systemic immunosuppressant medication or a one-
time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast 
allergy) are eligible for the study  
• 
Patients who received mineral corticosteroids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) for asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study. 
 Screen Failures 
If a patient fails to meet an eligibility criterion during the screening period, then the Investigator will complete 
the screen failure section in the e-CRF. 
Patients who have signed informed consent, but do not complete screening and who do not receive treatment on 
study with SNS-301 may be replaced for efficacy, toxicity and translational analyses. 
 Strategies for Recruitment and Retention 
It is anticipated that up to 15 sites will be participate in the study in the United States.  Patients will be recruited 
from either standalone outpatient clinics or hospital clinics.   
7. STUDY INTERVENTION 
 Study Intervention(s) Administration 
 Study Treatment Description 
7.1.1.1 SNS-301 Treatment 
The HAAH Nanoparticle Vaccine drug substance is a recombinant bacteriophage lambda construct that is 
engineered to display a fusion protein of phage gpD and a portion of the HAAH protein sequence. The HAAH-
1λ (SNS-301) construct contains 199 amino acids from the N-terminal region (amino acids 113 – 311) of the 
molecule. 
The drug substance is characterized by testing that includes appearance, pH, and identity by dot blot using 
HAAH-specific monoclonal antibody, impurities (bioburden, endotoxin, host cell protein), determination of size 
distribution by particle analysis, quantitation by particle analysis, protein determination and potency by antigen 
enzyme-linked immunosorbent assay (ELISA). The drug product is a sterile, preservative-free solution. 


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7.1.1.2 Pembrolizumab Treatment 
Keytruda® (Pembrolizumab) is an FDA-approved programmed death receptor-1 (PD-1)-blocking antibody that 
is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and 
neck (HNSCC).  humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 
kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. 
KEYTRUDA may be supplied in two different formulations: 
• 
KEYTRUDA for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-
dose vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted 
solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 
mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5. Or 
• 
KEYTRUDA injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly 
yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is 
formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, 
USP. 
For the purpose of this protocol, study treatment is defined as SNS-301 and pembrolizumab. 
 Dosing, Administration and Preparation 
The study treatment will be administered only to patients included in this study following the procedures set out 
in this clinical study protocol. Administration of the study treatment will be supervised by the Investigator or 
sub-Investigator. Details of the exact time of administration of medication (day/month/year, hour:minute) will 
also be documented in the eCRF. 
7.1.2.1 SNS-301 Dosing 
The vaccine will be delivered intra-dermally by a single-use 3M® hollow microstructured transdermal system 
(hMTS) device. Patients will be administered intradermally the SNS-301 dose of 1.0 x 1011 particles in 1 mL per 
administration.  
Patients will receive SNS-301 on a staged schedule starting every three weeks for four doses, every six weeks 
for 6 doses and thereafter every twelve weeks.   
When pembrolizumab and SNS-301 are dosed on the same day,  SNS-301 will be dosed approximately 1 hour 
after IV infusion of pembrolizumab for the first dose. Subsequent doses of SNS-301 and pembrolizumab can be 
dosed in any order.   
A 60 minutes observation period is recommended for the first dose on this study and 30 minutes for subsequent 
doses. 
Additional information on Dosing, Administration and Preparation can be found in the pharmacy manual for 
SNS-301. 
7.1.2.2 Pembrolizumab Dosing 
A fixed dose of 200 mg pembrolizumab as an intravenous infusion over 30 minutes every 3 weeks or a fixed 
dose of 400 mg pembrolizumab, as an intravenous infusion over 30 minutes every 6 weeks will be administered.  


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A sterile, non-pyrogenic, low-protein binding 0.2 micron to micron in-line or add-on filter will be utilized.  Do 
not co-administer other drugs through the same infusion line. 
A 60 minutes observation period is recommended for the first dose on this study and 30 minutes for subsequent 
doses. 
Additional information of Dosing, Administration and Preparation can be found in the package insert for 
Keytruda https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 
7.1.2.3 Study Treatment Administration 
Patients will receive their study treatment as described in Section 7.1.2.1 & 7.1.2.2 until disease progression, 
unacceptable toxicity, deemed intolerable by investigator or up to 24 months in patients without disease 
progression.   
A safety run-in will be performed using a modified rolling six design which will enroll up to six patients (safety 
analysis patients) as per Section 5.2.  Once the safety run-in has been cleared and communicated with 
Investigator’s further enrollment may occur. 
There will be no dose reductions.  See Section 7.5 for Dose Modifications. 
 Preparation/Handling/Storage/Accountability 
 Acquisition and Accountability 
SNS-301, including the 3M® hMTS transdermal system, will be packaged by the Sponsor, and supplied in an 
open-label basis.  The Investigator or designee is responsible for storing, administering and accounting for the 
SNS-301 according to the instructions provided by the Sponsor.  SNS-301 shall be dispensed in accordance with 
the Investigator's prescription and it is the Investigator's responsibility to ensure that an accurate record of SNS-
301 received, issued, returned and destruction is maintained. 
SNS-301, including the 3M® hMTS transdermal system should be placed in a proper disposal container 
following administration . The person responsible for drug dispensing is required to maintain adequate records 
of SNS-301. These records (e.g., product accountability log) include the date the SNS-301 is received from the 
Sponsor and administered to the patient. 
After review by the Sponsor or designee, all used and unused SNS-301 should be discarded at the investigational 
site, in accordance with the site’s institutional SOPs and/or polices, and a destruction certificate obtained. The 
Investigator or designee will submit the copy of Product Accountability Log to the Sponsor.  If the investigational 
site is unable to destroy SNS-301t, the Sponsor will provide alternate instructions for destruction. 
Under no circumstances will the Investigator supply SNS-301 to a third party, allow SNS-301 be used other than 
as directed by this Clinical Trial Protocol, or dispose of SNS-301 in any other manner. 
Any quality issue noticed with the receipt or use of a SNS-301, including 3M® hMTS transdermal system 
(deficiency in condition, appearance, pertaining documentation, labeling, expiry date, etc.) should be promptly 
notified to the Sponsor, who will initiate a complaint procedure.   
A potential defect in the quality of the SNS-301 may be subject to a recall procedure by the Sponsor. In this case, 
the Investigator will be responsible for promptly addressing any request made by the Sponsor, to recall SNS-301 
and eliminate potential hazards. 


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 Formulation, Appearance, Packaging and Labeling for SNS-301 and Pembrolizumab 
The supplies will be labeled with a minimum of the following: 
• 
Sponsor’s name and address 
• 
Content of the cartridge  
• 
Lot/Batch Number 
• 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use." 
Drug supply will be labeled in accordance to local regulations if study is run outside of the United States. 
 
The 3M® hollow microstructured transdermal system (hMTS) device will be labeled with the following: 
• 
Lot number 
• 
Hazard classification 
• 
Date of manufacture 
• 
Storage conditions 
• 
“For human clinical evaluation use” and “Caution - Investigational device. Limited by Federal (or United 
States) law to investigational use.” 
• 
Sponsor’s name and address 
Refer to the SNS-301 Study Pharmacy Manual for a description of the process of preparation for study drug 
administration 
Pembrolizumab will be labeled as per the manufacture’s specification. 
 Product Storage and Stability 
The SNS-301 is stored at 2 – 8 °C. Temperature excursions to <25°C for less than 24 hours are acceptable.  
Storage at <25°C for less than 24 hours is cumulative.  Time spent at this temperature should be recorded in the 
drug accountability records. 
The 3M® hollow microstructured transdermal system (hMTS) device can be maintained at room temperature. 
Pembrolizumab will be maintained as per the manufacture’s specification. 
 Randomization and Blinding 
This is an open-label, single-arm study; there will be no randomization or blinding. 
All patients who sign the informed consent form (ICF) will be assigned a patient study number which will be 
retained for the duration of the study.  
 Concomitant Therapy 
All treatments including any prescription or over the counter medications taken by the patients seven days prior 
to screening and at any time during the study are regarded as concomitant treatments and must be documented 
in the appropriate section of the e-CRF.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded.  Concomitant medications will be collected 
until 30 days after the last dose of study medication or until the start of a new anti-cancer treatment, whichever 
comes first. 


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 Allowed concomitant treatments 
The following concomitant treatments are permitted during this study: 
• 
Supportive treatment will be given as medically indicated. 
• 
Prophylactic antiemetic premedication including corticosteroids (low dose ≤ 10 mg/day prednisone 
equivalent) and 5-hydroxytryptamine 3 antagonists. 
• 
Supportive treatment with cannabis will be allowed, if  medically indicated. 
 Prohibited Medications or Treatments During Study 
Medications such as those listed below are not permitted in the course of the trial: 
• 
Concurrent treatment with other investigational drugs 
• 
Concurrent treatment with any other anticancer therapy including radiotherapy 
• 
Traditional herbal medicines should not be administered because the ingredients of many herbal 
medicines are not fully studied, and their use may result in unanticipated drug-drug interactions that may 
cause or confound assessment of toxicity.  However, if the investigator feels herbal medication is 
warranted the Sponsor should be consulted 
• 
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte colony-
stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or pegfilgrastim) is strongly 
discouraged 
• 
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-α, IFN-
γ, or IL-2, during the entire trial. These agents, in combination with study treatment, could potentially 
increase the risk for autoimmune conditions 
 Rescue Medication 
This is the first time the SNS-301 is given in addition to pembrolizumab to any patients.  Although most immune-
mediated adverse events observed with immunomodulatory agents have been mild and self-limiting, such events 
should be recognized early and treated promptly to avoid potential major complications. Discontinuation of SNS-
301 or pembrolizumab may not have an immediate therapeutic effect due to the long half-life of the drug or 
longer drug effect, and there is no available antidote for the study treatment. In severe cases, immune-mediated 
toxicities may be acutely managed with topical corticosteroids, systemic corticosteroids, mycophenolate, or 
TNF-α inhibitors per investigator’s discretion. 
For instruction on how to handle pembrolizumab immune response adverse events refer to the pembrolizumab 
package insert. 
Patients should receive appropriate medical intervention necessary to treat medical conditions as they arise.   
 Dose Modification and/or Interruption 
For pembrolizumab, follow the package insert for dose modification instructions. 
For SNS-301, there will be no dose reductions allowed for this study.   
In case of non-DLT AE (grade 2 NCI-CTCAE V5.0 drug related AE), the dosing interval can be extended to up 
42 days to allow the recovery from a related toxicity and the patient will resume at the same dose. If the patient 
experiences the same grade or higher toxicity and same grade requiring a dose-delay at the subsequent cycle, the 
patient should be discontinued from study treatment. 


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Should there be a clinically significant AE or SAE recorded relating to a patient receiving anticoagulants, such 
as clinically noted bleeding, administration of SNS-301 will be held until the AE/SAE returns to baseline.  Should 
there be two individual events of SNS-301 interruption for the same patient, then SNS-301 will be discontinued 
after consultation with the Medical Monitor and Study Sponsor. 
If a patient is unable to receive study treatment (e.g., due to COVID19) the dosing interval can be extended up 
to 42 days after consultation with the Sponsor and the rationale to be documented. 
Treatment with SNS-301 may continue if pembrolizumab is discontinued by the Investigator, if prior to 24 
months.  If both study treatments are stopped for >42 days then the patient should be discontinued from study 
treatment and continue to the study follow up phase. 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/ 
WITHDRAWAL 
 Discontinuation of Study Intervention 
Discontinuation for the study treatment does not mean discontinuation from the study and the remaining study 
procedures should be completed as per the Time and Event Schedule. 
 Participant Discontinuation/Withdrawal from the Study 
The patients may withdraw from study treatment if they decide to do so, at any time and irrespective of the 
reason. In addition, the Investigator or the Sponsor has the right to withdraw the patient from the study and/or 
stop the study at any time. All efforts should be made to document the reason for discontinuation, and this should 
be documented in the electronic case report form (eCRF). 
Other criteria for possible discontinuation are: 
• 
Disease progression 
• 
Unacceptable toxicity as judged by the Principal Investigator 
• 
Adverse events which are dose-limiting toxicities 
• 
Withdrawal of consent 
• 
Subject is lost to follow-up 
• 
Subject non-compliance 
• 
Use of another non-protocol anti-cancer treatment 
• 
Pregnancy 
• 
Completed 24 months of study treatment 
Withdrawn patients will be followed according to the study procedures as specified in this protocol. 
The patients may withdraw from the study follow-up period, before study completion if they decide to do so, at 
any time and irrespective of the reason.  The reason for withdrawal from the study treatment or study follow-up 
will be documented in the eCRF.   
A patient who receives at least one study treatment and who discontinues from the trial for any reasons will not 
be replaced except for patients that withdraw for reasons other than toxicity during the safety run-in phase of the 
study. 
 Lost to Follow-Up 
The Investigator should make every effort to re-contact the patient, to identify the reason why he/she failed to 
attend the visit, and to determine his/her health status, including at least his/her vital status. Attempts to contact 


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such patients must be documented in the patient’s records (e.g. times and dates of attempted telephone contact, 
receipt for sending a registered letter).   It is suggested that the Investigator attempts to contact the patient three 
times before considering the patient lost to follow up. 
9. STUDY ASSESSMENTS AND PROCEDURES 
Refer to the Time and Events Schedule Table1 for an outline of the procedures required at each visit along with 
their associated windows.  All patients must sign and date the most current approved ICF before any study 
specific procedures are performed.  Procedures conducted as per standard of care or routine clinical management 
that are obtained before signing of the ICF may be utilized for screening/baseline purposes. All screening 
assessments may be performed within 28 days of Day 0 with the exception of screening labs (hematology and 
chemistry) which may be performed within 10 days of Day 0. Patients who discontinue will be asked to return 
to the clinic within 30 days of the last dose for a discontinuation visit.  Generally, protocol waivers or exemptions 
will not be granted without discussion with the Sponsor. 
 Efficacy Assessments 
  Tumor Assessment 
Initial (screening) tumor assessments must be performed within 28 days prior to the first dose of study treatment.  
The investigator/site radiologist must review pre-trial images to confirm the patient has measurable disease per 
RECIST 1.1 (Appendix B: Tumor Assessment Criteria).  Tumor assessments performed as standard of care prior 
to obtaining informed consent and within 28 days of the first dose of study treatment may be used rather than 
repeating tests Beginning with screening, all imaging assessments will be evaluated using RECIST 1.1. On-study 
imaging assessments will be performed every 6 weeks (Q6W) calculated from the date of therapy initiation and 
independent of treatment delays. RECIST 1.1 will be used by the site for treatment decisions until the first 
radiologic evidence of progressive disease (PD).  The Sponsor may request digitized scans from patients to 
confirm response. 
Following the first radiologic evidence of PD by RECIST 1.1, treatment decisions may be made by using immune 
iRECIST (Appendix B: Tumor Assessment Criteria) to accommodate tumor response patterns seen with CPI 
therapy including pembrolizumab treatment (e.g., tumor flare). This was described by Nishino, et al. 2016 [13] 
and is used in immunotherapy clinical trials. For a clinically stable subject with first radiologic evidence of PD, 
it is at the discretion of the site investigator to continue treating the subject with SNS-301 and pembrolizumab 
until PD is confirmed at least 4 weeks after the date of the first tumor imaging suggesting PD per the site 
investigator. If radiologic PD is confirmed by the subsequent tumor imaging, the subject should be discontinued 
from treatment unless, in the opinion of the investigator, the subject is achieving a clinically meaningful benefit. 
In this case, an exception for continued treatment may be considered following consultation with the Sponsor. 
Additional treatment response evaluation by RECIST v 1.1 and iRECIST may be performed at the Sponsor’s 
discretion. 
Patients will undergo tumor assessments every 6 weeks (±7 days) until approximately 12 months following first 
dose of study treatment, or earlier if clinically indicated.  After 12 months, tumor assessments will be required 
every 12 weeks (±7 days).  Imaging should continue to be performed until disease progression is assessed by the 
Investigator, the start of new anti-cancer treatment, withdrawal of consent, death or the end of the trial, whichever 
occurs first for efficacy follow-up. Patients who start a new anti-cancer therapy will be censored for survival and 
progression analyses at date of last scan prior to the start of new anti-cancer therapy. 
Tumor imaging should be performed by computed tomography (CT), but may be performed by magnetic 
resonance imaging (MRI) if CT is contraindicated, but the same imaging technique should be used in patient 
throughout the trial. CT scans (with oral/IV contrast unless contraindicated) must include chest, abdomen and 
pelvis. The investigator must review before dosing at the next visit. Per RECIST 1.1, response should be 
confirmed by a repeat radiographic assessment. The scan for confirmation of response may be performed no 


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earlier than 4 weeks after the first indication of response, or at the next scheduled scan, whichever is clinically 
indicated. 
Patients who have unconfirmed disease progression may continue on treatment until progression is confirmed. If 
radiologic imaging by local/site assessment shows progressive disease (PD), tumor assessment may be repeated 
4 weeks later in order to confirm PD with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression. If repeat imaging shows SD, PR or CR, treatment may be continued as per treatment 
schedule. If repeat imaging still meets the threshold for PD (≥ 20% increase in tumor burden compared to nadir) 
but shows a reduction in tumor burden compared to the previous time point, treatment may be continued as per 
treatment calendar after consultation with Sponsor. If repeat imaging confirms progressive disease without 
reduction in tumor burden compared to the previous time point, patients will be discontinued from study 
treatment.  
The decision to continue study treatment after the first evidence of disease progression is at the Investigator’s 
discretion based on the clinical status of the patient as described in Table3  below.  Confirmatory imaging may  
be  performed  as  early  as  28  days  later; alternatively, the scan performed at the next scheduled time point 
may be used as confirmation. Patients may receive study treatment while waiting for confirmation of PD if 
they are clinically stable as defined by the following criteria: 
 
• 
Absence of signs and symptoms (including worsening of laboratory values) indicating disease 
progression 
• 
No decline in ECOG performance status from baseline 
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention 
• 
Evidence of clinical benefit (defined as the stabilization or improvement of disease- related 
symptoms) as assessed by the investigator 
 
Table 3: Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of 
PD 
Repeat 
imaging at ≥ 
4 weeks at 
site to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan by site 
Repeat 
imaging at 
≥4 weeks to 
confirm PD 
per physician 
discretion 
only 
Discontinue 
Treatment 
Repeat scan 
confirms PD (no 
reduction in 
tumor burden 
from prior scan) 
No 
additional 
imaging 
required 
Discontinue treatment 
No additional 
imaging required 
N/A 


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Repeat scan 
confirms 
PD 
(reduction 
in tumor 
burden from 
prior scan) 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment after 
consultation 
with Sponsor 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator 
and Sponsor’s 
discretion 
Repeat scan 
shows SD, 
PR or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
 
Patients in whom radiographic disease progression is confirmed at a subsequent tumor assessment may be 
considered for continued study treatment at the discretion of the investigator if they continue to meet the criteria 
above and have evidence of the clinical benefit (see Figure 2). 


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6T 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Conditions for Continuing Study Treatment in the Presence of Increased Radiographic 
Tumor Size 
 
 
Patients who discontinue from treatment for reasons other than disease progression (e.g., toxicity) will continue 
scheduled tumor assessments until disease progression, start of new-anti cancer therapy, withdrawal of consent, or 
death. Investigators may perform additional scans or more frequent assessments if clinically indicated. Patients who 
continue treatment beyond radiographic or clinical disease progression will be monitored with a follow-up scan at the 
next scheduled tumor assessment.  
 
Imaging timing should follow calendar days and should not be adjusted for delays or changes in treatment 
administration dates.
 


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 Safety Assessments 
 Demographics and Medical History 
Demographics will include gender, year of birth, race and ethnicity. 
Medical history will include details regarding the patients overall medical and surgical history as well as detailed 
information regarding the patient’s previous treatment, including systemic treatments, radiation and surgeries, 
pathology, risk stratification, etc.  since their original diagnosis. HPV status, EBV status and progression data 
will also be collected. Reproductive status and smoking/alcohol history will also be captured.   
 Physical Examinations 
A complete physical exam will include, at a minimum head, eyes, ears, nose, throat and cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal and neurological systems. Height (screening only) 
and weight will also be collected.  Additionally, any signs and symptoms, other than those associated with a 
definitive diagnosis, should be collected at baseline and during the study. 
During the study, a targeted, symptom-directed exam, as clinically indicated will be performed within 72 hours 
of each dosing visit 
 Eastern Cooperative Oncology Performance Status 
The health, activity and well-being of the patient will be measured by the ECOG performance status and will be  
assessed on a scale of 0 to 5 with 0 being fully active and 5 being dead. Full details are described in Appendix 
B: ECOG Performance Status.  ECOG performance status will be collected within 72 hours of each dosing visit. 
 Vital Signs 
Vital signs will include temperature, blood pressure, pulse rate and respiratory rate. For first infusion of pembrolizumab, 
the patient’s vital signs should be determined within 60 minutes before the infusion. If clinically indicated, vital signs 
should be recorded  at 15, 30, 45, and 60 minutes (± 5 minutes for all timepoints) after the start of the infusion, and 30 
(± 10) minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 minutes before the 
infusion and at 30 (± 5) minutes after the infusion.   
Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
trial physician if they develop such symptoms. 
 Electrocardiograms  
A 12-lead ECG will be obtained at screening and when clinically indicated.  Patients should be resting in a supine 
position for at least 10 minutes prior to ECG collection. 
 Clinical Safety Laboratory Assessments 
Hematological toxicities will be assessed in term of hemoglobin value, white blood cell, neutrophil, platelet and, 
lymphocyte count according to NCI-CTCAE V5.0 AE grading. 
Laboratory abnormalities (grade 1 and greater that are listed in the NCI-CTCAE V5.0) should be recorded on 
the AE page regardless of their causality.  Laboratory abnormalities associated with a definitive diagnosis will 
not be recorded as and AE unless it has become worse since baseline.  Test analytes are provided in the table 
below. 


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See the Time and Events Schedule for timing and frequency.  Safety labs will be performed within 72 hours of 
each dosing visit. 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count  
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
Other cells, if any 
Thyroid  
TSH, T3 and FT4 
Coagulation 
International normalized ratio/INR  
Activated partial thromboplastin time (PTT) 
Other anticoagulant monitoring (if required) 
HIV screen (at screening, if indicated) 
Hepatitis screen (at screening, if indicated) 
HPV/EBV screen (at screening, if unknown) 
Pregnancy test 
Serum chemistry 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Blood Urea Nitrogen (BUN) or Urea 
Bicarbonate or Carbon dioxide (CO2) 
Creatinine 
Creatine phosphokinase (CPK) 
Electrolytes (Na, K, Mg, Cl, Ca, P) 
Glucose (either fasting or non-fasting) 
Lactate dehydrogenase (LDH)  
Total bilirubin (direct bilirubin if 
elevated) 
Total protein 
Urinalysis 
Specific gravity 
pH 
Glucose 
Protein 
Ketones 
Blood 
Microscopic exam, if abnormalities 
 Hepatitis and HIV Screening 
Patients should be tested for HIV locally prior to the inclusion into the trial only based on investigator’s clinical 
suspicion for HIV infection and HIV-positive patients will be excluded from the clinical trial. Hepatitis B surface 
antigen, anti-HBc antibody, anti-HBs antibody, and Hepatitis C antibody immunoassays should be tested only 
per investigator’s clinical suspicion during screening and tested locally. In patients who have positive serology 
for the anti-HBc antibody, HBV DNA should be tested prior to Day 0. 


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 Pregnancy Test 
A Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) 
must be performed and documented as negative within 72 hours prior to each dose.  
 Urinalysis 
Urinalysis includes specific gravity, pH, glucose, protein, ketones, blood, and a microscopic exam if abnormal 
results are noted. 
 TSH, T3 and FT4 
Thyroid function tests will be performed at screening and every 6 weeks thereafter. 
 Creatine Phosphokinase (CPK) 
CPK will be performed at screening and at the discontinuation visit. 
 HPV/EBV Testing 
If the patient’s HPV/EBV status is unknown, they should be tested prior to receiving SNS-301.  The results do 
not need to be known before the patient receives study treatment. 
 PD-L1 Testing 
If the patient’s PD-L1 status is unknown, they should be tested, preferably by 22C3 IHC.  Patients who are CPI 
naïve must be PD-L1 positive prior to entry onto the study.  For other patients, the results do not need to be 
known before the patient receives study treatment.  If possible, for patients that started study treatment prior to 
Amendment 2/Version 3.0, retrospective testing should be done. 
 Immunogenicity Assessments 
Detailed instructions on the collection and processing of immunogenicity samples will be located in the 
Laboratory Manual.  See the Time and Events Schedule for a collection timeline for each sample. 
9.2.14.1 Blood Assays 
Blood assays include those measured in serum, plasma and whole blood/PBMCs. 
9.2.14.1.1 Serum and plasma 
Serum and plasma are collected for the direct measure of ASPH levels, anti-ASPH antibodies, anti-phage 
antibodies and other tumor biomarkers. 
9.2.14.1.1.1 ASPH 
Subject sera and/or plasma will be tested for the presence of ASPH and/or exosomes that contain ASPH on their 
surface by ELISA using several different monoclonal antibodies that are reactive with the ASPH protein. The 
presence of ASPH in serum or plasma is an indicator of cancer status. Alterations in ASPH levels may be 
indicative of response to treatment. 


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9.2.14.1.1.2 Anti-ASPH antibodies 
Production of anti-ASPH antibodies is a direct result of an active immune response to the vaccine. Levels of anti-
ASPH antibody are expected to rise during an active immune response and should reach a plateau level at 
maximal response. Continued and regular boosting of the vaccine during the course of treatment is expected to 
maintain or restore this level of anti-ASPH antibody in serum. 
9.2.14.1.1.3 Anti-phage antibodies 
Because the vaccine is delivered using a bacteriophage vector, production of anti-phage antibodies is also 
expected and is a direct result of an active immune response to the vaccine. High levels of anti-phage antibody 
may result in neutralization of further doses/boosts of vaccine. During the Phase I clinical study it was found that 
the use of a lower dose of vaccine during initial vaccination attenuate the production of anti-phage antibodies 
and this finding contributed to the selection of the dose for the current trial. Levels of anti-phage antibodies will 
be monitored here to ascertain if any correlation exists between the production of anti-phage antibodies and 
reduced efficacy of the vaccine.  
9.2.14.1.1.4 Other tumor and immune biomarkers   
Levels of other cancer biomarkers and cytokines may also be tested in serum and/or plasma and may also be 
used to monitor cancer status and response to treatment. 
9.2.14.1.1.5 Circulating tumor DNA (ctDNA) 
Blood samples will be collected in Streck tubes for isolation of ctDNA. ctDNA analysis may be used as a tool to 
monitor for treatment efficacy and resistance and for predicting the likelihood of relapse.  
9.2.14.1.2 Whole blood/peripheral blood mononuclear cells (PBMCs) 
PBMCs are collected to monitor overall and specific immune responses. 
9.2.14.1.2.1.1 T-cells Evaluation 
T cell responses will be assessed using antigen-specific IFN-γ ELISpot assay using antigen presenting cells 
loaded with either full-length recombinant ASPH protein or overlapping peptide libraries covering the SNS-301 
antigens. Antigen specific T cell responses may also be assessed via flow cytometry. Flow cytometric assays 
may include an examination of the influence of immunotherapy on the ability of patient T cells to exhibit 
phenotypic markers associated with cytolytic potential, activation or exhaustion after stimulation by peptides 
corresponding to SNS-301 antigens. Markers that may be used for this purpose include CD3, CD4, CD8, CD137, 
CD69, CD38, PD1, Granzyme A, Granzyme B and Perforin. These markers may change relative to new data 
becoming available that is informative for this assessment. Additionally, T-cell responses to general immune 
stimulators may be evaluated in order to track general cellular immune competence during the trial. 
Additionally, ASPH-specific T-cells may be isolated, cloned and expanded ex vivo. For expansion antigen 
presenting cells loaded with either full-length recombinant ASPH protein or overlapping peptide libraries 
covering the SNS-301 antigens would be employed. These T-cells may be characterized by sequencing of their 
T-cell receptors (TCRs) to assess diversity and putative antigen specificity. 


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9.2.14.2 Tissue  
A tissue sample is required at study entry.  Ideally, a pre-treatment tissue sample obtained after initiation of ongoing  
CPI therapy and first dose of SNS-301 and pembrolizumab on this current clinical trial will be collected.   Patients are 
requested to provide archival tissues from a prior biopsy or surgery that is treatment -naïve including prior 1) 
chemotherapy, radiation and 2) anti PD(L)-1 treatment-naïve, pending availability. In patients undergoing a pre-
treatment biopsy, an archival tumor specimen, if available, should also be submitted. After signing of the Informed 
Consent Form, tumor tissue should be submitted to the Sponsor in a timely manner. All patients will undergo a 
mandatory tumor biopsy sample collection, if clinically feasible as determined by the trial investigator in consenting 
patients, at Week 6/3rd dose (+/- 3 days). Additionally, up to two optional biopsies may be obtained any time during the 
study, if medically feasible. A biopsy may also be obtained at the time of first evidence of radiographic or clinical 
disease progression. For patients who respond and subsequently progress, an optional biopsy may be obtained at the 
time of disease progression. Tumor tissue should be of good quality based on total and viable tumor content. Acceptable 
samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-needle aspiration may be acceptable pending sponsor 
approval however, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. For core needle 
biopsy specimens, at least three cores should be submitted for evaluation.   Patients who are unable to undergo biopsy 
sample collection but otherwise meet criteria outlined in protocol may continue to receive study treatment. 
If a tumor biopsy is to be obtained from an intended target lesion during eligibility assessment, the biopsy should 
be performed prior to obtaining the baseline scan. Otherwise, a new baseline scan should be obtained.  
Archival and fresh tumor tissue samples should be representative tumor specimens in formalin-fixed paraffin 
embedded (FFPE) blocks (preferred) or at least 15 unstained slides, with an associated pathology report, should 
be submitted for intra-tumoral immunology assessments.  Tissue slices of 4-5 microns are mounted on positively 
charged glass slides. Slides should be unbaked and stored cold or frozen. 
9.2.14.2.1 Tissue Assays 
Available tumor tissue collected from pre- and post- treatment may be assessed for the presence of immune cells 
using immunohistochemistry or immunofluorescence. The presence of immune signatures may also be analyzed 
through the assessment of various transcripts suggestive of an inflammatory or an immunosuppressive tissue 
microenvironment. 
Tumor tissue will be collected for immunology assessments including but not limited to markers related to 
inflammation, suppression, T cell infiltration, and associated tumor microenvironment characteristics. Tumor 
infiltrating lymphocytes may be isolated and subjected to single cell expression profiling and/or TCR sequencing. 
In addition, exploratory biomarkers may be evaluated. 
9.2.14.2.2 ASPH Immunohistochemistry (IHC) Assay  
ASPH testing will be done by immunohistochemistry on either fresh or archival tumor tissue.    Samples will be 
analyzed at Fred Hutchinson Cancer Center via a CLIA validated assay. 
9.2.14.3 Future Biomedical Research   
The following samples are obtained as part of the study, if any leftover samples remain, they may be used for 
future biomedical research either during the course of the study or after the study has completed. 
• 
Leftover tumor tissue 
• 
Leftover RNA or DNA isolated from biological samples (blood, urine, tumor) 


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• 
Leftover biomarker samples (serum, plasma and PMBCs) 
9.2.14.3.1 Withdrawal from Future Biomedical Research 
Patients may withdraw their consent for Future Biomedical Research and have their samples destroyed.  Patients 
may withdraw consent at any time by contacting the principal investigator in writing. In turn, the Investigator 
will contact the Sponsor in writing.  Subsequently, the patient’s samples will be removed from the biorepository 
and be destroyed. No future data will be collected, but any data already collected from analysis of samples will 
remain with the Sponsor. A letter will be sent from the Sponsor to the investigator confirming the destruction. It 
is the responsibility of the investigator to inform the patient of completion of destruction. Any analyses in 
progress at the time of request for destruction or already performed prior to the request being received by the 
Sponsor will continue to be used as part of the overall research trial data and results. No new analyses would be 
generated after the request is received. 
 
In the event that the medical records for the trial are no longer available (e.g., if the investigator is no longer 
required by regulatory authorities to retain the main trial records) or the samples have been completely 
anonymized, there will no longer be a link between the patient’s personal information and their samples.  In this  
situation, the request for sample destruction cannot be processed. 
request for sample destruction cannot be processed. 
9.2.14.4 Concomitant Medications 
Concomitant medications include any prescription medications or over-the-counter medications. At screening, 
any medications the patient has used within the 7 days prior to the screening visit should be documented. At 
subsequent visits, changes to current medications or medications used since the last documentation of 
medications will be recorded.  See Section Prohibited Medications or Treatments During Study for a list of 
prohibited medications. 
Patients who are receiving anticoagulants will have anticoagulant specific drug level and/or anticoagulant 
specific factor Xα levels obtained at baseline, at each administration of SNS-301, and at the end of study visit to 
ensure that these levels remain within therapeutic range throughout the duration of the trial. In the event of 
clinically noted bleeding, these tests will be obtained at the time of bleeding as well.  Investigators should use 
tests routinely used in clinical practice to monitor patients receiving Warfarin, Heparin and/or Low Molecular 
Weight Heparins, along with the monitoring schedule provided above.  Should there be two individual events of 
SNS-301 interruption for the same patients, then SNS-301 will be discontinued after consultation with the 
Medical Monitor and Study Sponsor.  Clinical management and further workup of the coagulation pathway 
disturbance will be at the discretion of the investigator. 
9.2.14.5 Adverse Events 
AEs will be collected from the time of informed consent until 30 days after the last dose of study treatment or 
until initiation of another anti-cancer therapy, whichever occurs first. SAEs and AESIs will be collected from the 
time of informed consent until 90 days after the last dose of study treatment of until initiation of anti-cancer 
therapy, whichever occurs first. See Section 9.3 for additional details on Adverse Events and Serious Adverse 
Events. 
9.2.14.6 Follow-Up 
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinical visits 
approximately every 3 months for up to 3 years, until death, lost to follow-up, withdrawal of consent, or trial 
termination by Sponsor. All patients will be followed for survival and new anticancer therapy information unless 
the patient requests to be withdrawn from follow-up; this request must be documented in the source documents 


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and signed by the investigator. If the patient discontinues study treatment without documented clinical disease 
progression, every effort should be made to follow up regarding survival, progression (if not already progressed), 
and new anti-cancer therapy. 
 Adverse Events and Serious Adverse Events 
 Definition of Adverse Event (AE) 
Adverse event is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Any AE that occurs prior to the first dose is part of the medical history.  
AEs will be collected from the time of informed consent until 30 days after the last dose of study treatment or 
until initiation of another anti-cancer therapy, whichever occurs first. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part of the clinical 
syndrome that is being reported as an AE unless worsened on study treatment.  It is the responsibility of the 
Investigator to review all laboratory findings in all patients and determine if they constitute an AE.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE.  Any laboratory abnormality (grade 1 and greater that are listed in the NCI-CTCAE V5.0) 
considered to constitute an AE should be reported on the Adverse Event CRF.   
Pre-planned procedures (surgeries or therapies) that were scheduled prior to the start of study drug exposure are 
not considered AEs.  However, if a pre-planned procedure is performed earlier than anticipated (e.g., as an 
emergency) due to a worsening of the pre-existing condition, the worsening of the condition should be captured 
as an AE. 
Progression of the cancer under trial is not considered an adverse event unless it is considered to be drug related by 
the investigator. Patients will be encouraged to spontaneously report any AE.  Patients will be questioned and/or 
examined by the Investigator and his/her medically qualified designee for evidence of AEs.  The questioning of study 
patients with regard to the possible occurrence of AEs will be generalized, such as, “How have you been feeling since 
your last visit?”  Information gathering for AEs should generally not begin with direct solicitation from patients 
regarding the presence or absence of specific AEs.  Study personnel will ask open-ended questions to obtain 
information about AEs at every visit.  Date and time of onset and resolution (if applicable) of the AE will be 
documented in the patient’s clinical notes. 
A suspected adverse reaction means any AE for which there is a “reasonable possibility” that the drug caused 
the AE.  For the purpose of reporting under this protocol, “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the AE .   
An AE is considered unexpected if the AE is not listed in the current IB or is not listed in the IB at the specificity 
or severity observed. 
 Definition of Serious Adverse Event (SAE) 
A serious adverse event (SAE) is an AE that: 
• 
Is fatal 
• 
Is life-threatening, meaning the patient was, in the view of the Investigator, at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious 
form or progressed, might have caused death 
• 
Is a persistent or significant disability or incapacity or substantial disruption of the ability to conduct 
normal life functions 


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• 
Requires or prolongs inpatient hospitalization 
• 
Is a congenital anomaly or birth defect 
• 
Other important medical events may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes as listed above in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse 
The Medical Monitor will advise the Investigator regarding the nature of any further information or 
documentation that is required.  The Investigator should provide the following documentation at the time of 
notification if available: 
• 
SAE Form 
• 
AE (CRF) page 
• 
Concomitant and support medication pages 
• 
Relevant diagnostic reports 
• 
Relevant laboratory reports 
• 
Admission notes  and hospital discharge summary (when available).
 
Clarification of Serious Adverse Events (SAEs) 
• Death in itself is not an AE. Death is an outcome of an AE. 
• Progression of the cancer under trial is not considered an adverse event unless it is 
considered to be drug related by the investigator.  
• The patient may not have been receiving an investigational medicinal product at the 
occurrence of the event. 
• Dosing may have been given as treatment cycles or interrupted temporarily 
before the onset of the SAE but may have contributed to the event. 
• Complications that occur during hospitalizations are AEs. If a complication 
prolongs the hospitalization, it is an SAE. 
• Inpatient hospitalization means that the patient has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency 
department nor does it include full day or overnight stays in observation 
status. 
The following hospitalization scenarios are not considered to meet the criteria 
for a serious adverse events:  
 
Hospitalization for respite care 
 
Hospitalization to perform an efficacy measurement for the trial 


 
 
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 
Hospitalization for an elective surgery for a pre-existing condition. 
The Investigator will attempt to establish a diagnosis of the event on the basis of 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis 
will be documented as the AE and/or SAE and not the individual 
signs/symptoms. 
 
 Classification of an Adverse Event 
9.3.3.1 Severity of Event 
Adverse events will be graded by the Investigator using the NCI-CTCAE 5.0 graded 1-5. 
Grade refers to the severity of the AE. For events not described in the NCI CTCAE, the 
Investigator will assign grades as 1= mild, 2=moderate, 3=severe, 4=life-threatening, and 
5=fatal based on this general guideline: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL* 
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL**.  
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE.  (Grade 5 (Death) may not appropriate for some AEs and 
therefore may not an option.) 
The highest level of severity attained for each AE will be recorded in the CRFs. 
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.  


 
 
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9.3.3.2 Relationship to Study Medication 
The assessment of relationship of AEs to the administration of study drug is a clinical decision 
based on all available information at the time of the completion of the CRF. Investigators must 
systematically assess the causal relationship of AEs to the study drug using the following 
definitions.  Decisive factors for the assessment of causal relationship of an AE to SNS-301 
include, but may not be limited to, temporal relationship between the AE and SNS-301, known 
side effects of SNS-301, medical history, concomitant medication, course of the underlying 
disease, and study procedures.  
Not Related: 
Not reasonably suspected to be related to the study drug.  The AE could not medically 
(pharmacologically/clinically) be attributed to the study drug under investigation in this 
clinical study protocol.  A reasonable alternative explanation must be made available. 
Related: 
Suspected related to the study drug. The AE could medically (pharmacologically/clinically) 
be attributed to the study drug under investigation in this clinical study protocol. 
 Adverse Event Reporting 
 Serious Adverse Event Reporting 
All SAEs occurring during the course of the clinical trial from signing the informed consent 
through the end of the study will be collected and reported (e-mail ) by the Investigator to the 
Pharmacovigilance Team assigned (see contact information below) by completing a Serious 
Adverse Event Report Form within 24 hours or next business day, whichever is shorter, from 
the point in time when the Investigative site becomes aware of the SAE.  All SAEs must be 
reported whether or not considered causally related to the study treatment. The information 
collected will include patient number, a narrative description of the event and an assessment 
by the Investigator as to the severity of the event, and relatedness to study drug.  Include copies 
of relevant source documents. (e.g., progress notes, autopsy reports, laboratory and diagnostic 
test results, discharge summaries) Follow-up information on the SAE may be requested by the 
Sponsor. 
SAEs should be reported to: 
Global Safety and Pharmacovigilance, Advanced Clinical 
Email: drugsafetypv@advancedclinical.com 
The minimum required information for an initial report of an SAE is:  
• 
Reporter name and contact number, 
• 
Protocol number, 
• 
Site and patient ID information, and  
• 
The SAE term with a brief summary of the event including the causality assessment, 
if possible.  


 
 
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Contact the Sponsor-designated Medical Monitor or designee using the contact information 
and instructions provided supplemental to this protocol. 
The Sponsor must notify FDA and all participating Investigators (i.e., all Investigators to whom the 
Sponsor is providing drug under its INDs or under any Investigator's IND) in an IND safety report 
of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
later than 15 calendar days after the Sponsor determines that the information qualifies for reporting 
under paragraph (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of 21CFR 312.32. The Sponsor must 
identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse 
reaction and must analyze the significance of the suspected adverse reaction in light of previous, 
similar reports or any other relevant information. 
In addition, The Sponsor must also notify FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible but in no case later than 7 calendar days after 
the Sponsor's initial receipt of the information. 
 Serious and unexpected suspected adverse reaction  
The Sponsor must report any suspected adverse reaction that is both serious and unexpected. 
The Sponsor must report an adverse event as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse event, such as: 
1. A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome); 
2. One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture); 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group. 
Reports will be made as soon as possible, and in no event later than seven (7) calendar days if 
the event is a death or is life threatening and 15 calendar days for all other reportable events 
after the Sponsor’s initial receipt of the information. Each written notification may be 
submitted on a CIOMS-I form, a FDA Form 3500A, or in a tabular or narrative format in 
accordance with regulatory requirements. In each report, the Sponsor will identify all safety 
reports previously filed concerning a similar suspected adverse reaction and will analyze the 
significance of the suspected adverse reaction in light of the previous, similar reports. 
Follow-up information to a safety report will be submitted as soon as the relevant information 
is available. If the results of a Sponsor’s investigation show that an AE not initially determined 
to be reportable is, in fact, reportable, the Sponsor will report the suspected AE in a written 
safety report as soon as possible, but in no event later than 15 calendar days after the 
determination is made. Results of investigations of other safety information will be submitted, 
as appropriate, in an information amendment or annual report. 


 
 
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If an investigator receives an IND safety report or other specific safety information (e.g., 
SUSAR, summary or listing of SAEs) from the sponsor, the investigator will review and file 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local regulations.  In these instances, the ICF may need to be revised to inform the patient 
of any new safety concern. 
 Unanticipated (Serious) Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), 
or any other unanticipated   serious problem associated with a device that relates to 
the rights, safety, or welfare of patients. 
Per the definition above, a UADE is a type of SAE that requires expedited reporting 
on the part of the Sponsor. As a reminder, all SAEs regardless of relationship to 
device, drug or procedure are to be reported to Sponsor by the trial Investigator 
within 24 hours. Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan. The Sponsor 
may notify a regulatory authority within the time frame specified by local 
requirements but no later than 10 business days for UADE. 
UADE form should be reported to: 
Global Safety and Pharmacovigilance, Advanced Clinical 
Email: drugsafetypv@advancedclinical.com 
 
 Dose-Limiting Toxicities 
DLTs are events [toxicities] specifically identified in this protocol that must be reported in an 
expeditious manner. Information regarding DLTs should be recorded on a DLT Confirmation 
Worksheet and faxed or emailed within 24 hours of site personnel becoming aware of the 
event. DLTs may or may not be serious adverse events as an Unexpected Adverse Event.  
DLTs are assessed up to week 6 for patients enrolled in the Safety Run-In period. 
Any of the following, if judged to be associated with SNS-301 (i.e., possibly related, probably 
related, or related to), will be considered a DLT which are based on the NCI-CTCAE V5.0 
criteria: 
1) Grade 4 non-hematological toxicities (excluding alopecia) of any duration 
2) Grade 3 non-hematologic (non-laboratory) toxicity lasting > 3 days despite optimal 
supportive care  
3) Any Grade 3 or Grade 4 non-hematologic laboratory value if: a). Medical 
intervention is required to treat the patient; b), the abnormality leads to 
hospitalization; c). The abnormality persists for >1 week.  
4) Grade 4 hematologic toxicity, other than those specified in criteria 5 and 6 below, 
lasting > 7 days 
5) Grade 3 or Grade 4 febrile neutropenia of any duration 
6) Grade 3 thrombocytopenia in combination with a grade 3 or greater blood and 
lymphatic system disorder 


 
 
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7) Grade 3 AST or ALT that is associated with a grade 2 rise in bilirubin 
Additional information regarding reporting DLTs may be required by the Sponsor.  
Completed DLT Confirmation Worksheets should be faxed or e-mailed to: 
Global Safety and Pharmacovigilance, Advanced Clinical 
Email: drugsafetypv@advancedclinical.com 
 Stopping Rules 
Stopping rules for adverse events will be employed for this trial.  The trial will be stopped if 
any adverse experience of any related death, grade 4 autoimmune toxicity or any grade 4 
toxicity that is considered to have a causal relationship to study drug.  Any related death, grade 
4 autoimmune toxicity and any grade 4 toxicity that is considered to have a causal relationship  
to study drug will be submitted to regulatory agencies within the expedited safety reporting 
criteria. 
 Adverse Events of Special Interest 
Adverse events that occur during or within 24 hours after study treatment administration and 
are judged to be related to study treatment infusion should be captured as a diagnosis (e.g., 
“infusion-related reaction”) on the Adverse Event eCRF. If possible, avoid ambiguous terms 
such as “systemic reaction.” If a patient experiences both a local and systemic reaction to the 
same dose of study treatment, each reaction should be recorded separately on the Adverse 
Event eCRF. 
Systemic administration site reactions will be considered an AESI. The area around the 
administration site will be assessed by a medically qualified individual for adverse reactions 
at least 30 minutes post study drug administration. The Investigator will grade any ASRs 
according to the NCI-CTCAE V5.0 (excluding the actual expected micro-injection punctures).  
Patients will be required to report any change in the administration site and return to the clinic 
for evaluation by the Investigator. 
Adverse events of special interest (AESI) are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event;   see  Section  
Adverse Event Reporting for  reporting  instructions).    
AESI s should be reported to: 
Global Safety and Pharmacovigilance, Advanced Clinical 
Email: drugsafetypv@advancedclinical.com 
 Guidance for Investigators for Patients on Anti-coagulants 
Based on the preclinical data and the role of ASPH in post-translational modification of proteins 
involved in the clotting and anticoagulant pathways (Factors VII, IX, X , Protein C), there may a 
potential for abnormal coagulation with SNS-301.  Should there be a clinically significant AE or 
SAE recorded, such as clinically noted bleeding, administration of SNS-301 will be held until the 
AE/SAE returns to baseline. Should there be two individual events of SNS-301 interruption for the 


 
 
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same patient, then SNS-301 will be discontinued after consultation with the Medical Monitor and 
Sponsor. Clinical management and further workup of the coagulation pathway disturbance will be 
at the discretion of the treating physician. 
 Reporting of Pregnancy 
If pregnancy occurs in a female patient, or female partner of a male patient while the patient 
is on treatment or until six months after the last dose, the sponsor will be notified within 24 
hours of learning of the pregnancy.  The pregnancy will be followed until birth or termination.  
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillborn, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Pregnancy should be reported to: 
Global Safety and Pharmacovigilance, Advanced Clinical 
Email: drugsafetypv@advancedclinical.com 
 Time Period and Frequency for Event Assessment and Follow-Up 
All AESIs and SAEs, including death due to any cause, that occur during this study and until 
90 days after the last dose of study treatment or until the start of a new anti-cancer treatment, 
whichever comes first, whether or not expected and regardless of causality, must be reported 
to the Medical Monitor immediately upon discovery of the event, using an SAE Form.  
All AEs will be collected from the time of signing the informed consent form until 30 days 
after the last dose after the last dose of study treatment or until the start of a new anti-cancer 
treatment, whichever comes first. 
Any medical condition that begins after obtaining informed consent will be recorded the AE 
section of the CRF.  If the patient’s condition worsens during the study, the event will be 
recorded as an AE. 
All AEs/SAEs will be captured on the appropriate case report form.  Information to be 
collected includes event description, date of onset, severity, relationship to study intervention 
and date of resolution.   
10. Statistical Considerations 
 Statistical Hypotheses 
Cohort A 
Thirty (30) patients will be enrolled in a two-stage design, with 15 patients in the first stage and 
15 patients in the second stage to assess the null hypothesis that the objective response rate per 
iRECIST is 5%, versus the alternative hypothesis that the ORR is 18%, as described in Section 
10.2. 
Cohort B 
Thirty (30) patients will be enrolled in a two-stage design, with 15 patients in the first stage and 
15 patients in the second stage to assess the null hypothesis that the objective response rate per 


 
 
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iRECIST is 13.3%, versus the alternative hypothesis that the ORR is 29%, as described in 
Section 10.2. 
 
 Sample Size Determination 
Adverse events will be continuously monitored. Among the first phase of 15 patients, for 
adverse events that occur at an incidence of 18% the probability of observing at least one event 
is approximately 95%. Among all 60 patients, for adverse events that occur at an incidence of 
5% the probability of observing at least one event is approximately 95%. 
The sample size for each cohort and stage is based on Simon’s two-stage design for tests of 
one proportion.  
Cohort A 
To evaluate the primary endpoint of objective response rate per iRECIST at 12 weeks with a 
null hypothesis of an objective response rate (ORR) of 5% and an alternative hypothesis of an 
ORR of 18%, 30 patients in a two-stage design with 15 patients in the first stage and 15 
patients in the second stage will be enrolled.  At the first stage analysis if at least 1 response 
is observed out of 15 patients, the study will continue through the second stage.  At the second 
stage analysis, if at least 4 responses are observed out of 30 total patients, the null hypothesis 
will be rejected and further research considered warranted.  The overall power for objective 
response rate at 12 weeks is 80%.  The overall type I error, the chance of incorrectly rejecting 
the null hypothesis is 6% (targeted alpha of 0.10).  The probability of stopping at the first stage 
under the null hypothesis is 46%.  The operating characteristics of this design are calculated 
using the exact binomial distribution. 
Cohort B 
To evaluate the primary endpoint of objective response rate per iRECIST at 12 weeks with a 
null hypothesis of an objective response rate (ORR) of 13.3% and an alternative hypothesis of 
an ORR of 29%, 30 patients in a two-stage design will be enrolled, with 15 patients in the first 
stage and 15 patients in the second stage.  At the first stage analysis if at least 2 responses are 
observed out of 15 patients, the study may continue through the second stage.  At the second 
stage analysis,  if at least 7 responses are observed out of 30 total patients, the null hypothesis 
will be rejected and further research considered warranted.  The overall power for objective 
response rate at 12 weeks is 80.1%.  The overall type I error, the chance of incorrectly rejecting 
the null hypothesis is 9.2% (targeted alpha of 0.10).  The probability of stopping at the first 
stage under the null hypothesis is 38.8%.  The operating characteristics of this design are 
calculated using the exact binomial distribution. 
 
 Populations for Analyses 
The following analysis populations will be used for presentation of the data: 
Safety Analysis Set: The safety analysis will be based on the Safety Analysis Set, which 
comprises all patients who receive at least 1 dose of the study treatment or component of the 
study treatment.  


 
 
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Efficacy-Evaluable Analysis Set: All patients who receive at least 1 dose of the study 
treatment or component of the study treatment and have a post baseline response assessment 
per iRECIST at Week 12. Patients who discontinued prior to Week 12 due to disease clinical 
progression will be included. Patients who do not have a post baseline response assessment 
conducted will not be included. 
Safety Run-In Set: All patients who receive at least 1 dose of the study treatment or component 
of the study treatment apart of the safety run-in. 
Immunologic Analysis Set: All patients who receive at least 1 dose of the study treatment or 
component of the study treatment and have at least one valid post-baseline immunologic 
assessment available.   
 Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the patient populations to be included in the analyses, and procedures for accounting 
for missing, unused and spurious data.   
The statistical analysis plan will specify how lost to follow-up patients will be addressed in 
the primary analysis. 
 General Methods 
All summarizations will be presented separately for each cohort, and over all subjects 
combined. 
For continuous variables, descriptive statistics (number (n), mean, median, standard deviation, 
minimum and maximum) will be presented. For categorical variables, frequencies and 
percentages will be presented. For time-to-event variables, percentages of patients 
experiencing that event will be presented and median time-to-event will be estimated using 
the Kaplan-Meier method. As appropriate, a 95% CI will be presented. Graphical displays will 
be presented, as appropriate.  
Patients demographic characteristics including age, gender, and race will be analyzed, with 
categorical variables summarized in frequency tables while continuous variables summarized 
using mean (standard deviation) and median (range).   
All data collected will be presented in by-patient data listings. 
 Efficacy Analyses 
ORR is defined as the proportion of patients with a confirmed best response of iCR or iPR by 
iRECIST. Objective response rate will be estimated, and 90% CI based on the exact binomial 
distribution will be presented by cohort and overall, including number and percent of patients 
in each overall response category.  
The primary analysis will be based on objective response at Week 12. An additional analysis of 
ORR based on best objective response during the study will be performed.  
DOR, DCR, PFS, and OS will also be calculated, defined as follows:  


 
 
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- 
DOR: time from date of first response to date of progression, where patients without 
progression are censored at date of last valid disease assessment 
- 
DCR: proportion of patients with SD or better (PR and CR).  SD for at least six months 
- 
PFS: time from date of start of treatment to date of progression, where patients without 
progression are censored at date of last valid disease assessment 
- 
OS: time from date of start of treatment to date of death or censored at date of last 
contact 
Efficacy analyses will be performed using the efficacy-evaluable analysis set.  
 Safety Analyses 
Safety evaluations will be based on the incidence, severity, attribution and type of AEs, and 
changes in the patient’s vital signs, and clinical laboratory results, analyzed using the safety 
analysis set. 
Summarization of toxicity data will focus on incidence of treatment-emergent adverse events. 
Treatment-emergent adverse events are defined as any AE that occurs during or after 
administration of the first dose of treatment through 30 days after the last dose, any event that 
is considered study drug-related regardless of the start date of the event, or any event that is 
present at baseline but worsens in intensity. The incidence of serious adverse events, adverse 
events, drug-related adverse events, and adverse events leading to discontinuation or death will 
be presented in tabular form by system organ class and preferred term. Adverse events will be 
assessed for severity according to the NCI CTCAE, version 5.0.  
A presentation of dose-limiting toxicities among patients in the safety run-in set will be 
presented. 
Other safety evaluations including vital sign, laboratory and physical exam results will be 
presented over time. 
 Other Analyses 
Antigen-specific cellular immune response assessed by but not limited to Interferon-γ 
secreting T lymphocytes will be summarized by visit. Immune related gene expression will be 
evaluated with pre- and post-treatment tissue biopsies. Cytokine and chemokine profiles will 
be summarized by visit.  
Additional exploratory analyses may be performed, including evaluation of relationship 
between efficacy endpoints and immunology parameters. 
10.4.4.1 Pharmacodynamics 
Exploratory pharmacodynamic (PD) analysis will be performed using dose, vaccine-specific 
antibody response (geometric mean titer), antigen-specific T and B cell indices, and the 
relative expression of ASPH in each patient’s tumor. The PD will be balanced and optimized 
to the degree of antigen-specific immune response and minimized for the production of 
regulatory immune processes. 
 Interim Analyses 
For each cohort, the objective response rate will be assessed at the completion of stage 1 of 
the 2-stage design, after 15 patients complete the 12-week follow-up period or discontinue 
prior due to disease progression.  See Section 10.2 for additional details. 


 
 
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  Safety Committee 
To ensure patient safety during the study, a Safety Committee will be formed to monitor safety 
on a periodic basis. Members of the Safety Committee will include a Safety representative, 
Principal Investigator(s) and the Sponsor Medical Expert.  A charter will outline their roles 
and responsibilities The Safety Committee will meet at the completion of the safety run-in to 
review safety data collected from the point of first patient in (FPI) to review safety, or as 
needed. The safety data will include demographic data, adverse events, serious adverse events, 
and relevant laboratory data.  Following each data review, the Safety Committee will provide 
recommendations as to whether the study should continue or be amended, or whether the study 
should be stopped on the basis of safety (i.e., evidence of harm). The final decision will rest 
with the Sponsor.  For each cohort, the interim efficacy assessment will occur after 15 patients 
were enrolled and completed the 12-week follow-up period.  A safety review will occur in 
parallel to the efficacy assessment of the first 15 patients in each cohort.  Any outcomes of 
these safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the Institutional Review boards/Ethics Committees 
(IRBs/ECs).   
11.  SUPPORTING DOCUMENTATION & OPERATIONAL CONSIDERATIONS 
 Regulatory, Ethical and Study Oversight Considerations 
 Regulatory and Ethical Issues 
The study will be conducted in accordance with the ethical principles of the current version of 
the Declaration of Helsinki.  The Sponsor and Investigator will comply with their 
responsibilities as defined in 21 CFR 312.50-312.70, International Conference on 
Harmonization Guidance for Industry: E6 (R2) Good Clinical Practice (March 2018) and the 
local regulatory/legal regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  Any amendments to the protocol will 
require IRB/IEC approval prior to implementation, except when necessary to eliminate 
immediate hazard to patients. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
• 
While every effort should be made to avoid protocol deviations, should an important deviation 
be discovered, Sponsor must be informed immediately. Any protocol deviation impacting 
patient safety must be reported to the Medical Monitor immediately and to the IRB/IEC, as 
required per institution 


 
 
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 Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
 Informed Consent Process 
The Investigator will obtain informed consent from each patient enrolled in the study, in 
accordance with requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA), Data Protection regulations, where 
applicable, IRB/IEC and any local laws and regulations in which the investigation is being 
conducted.   
The IRB must approve the ICF to be used by the Investigator.  It is the responsibility of the 
Investigator to ensure that informed consent is obtained from the patient or his/her guardian 
or legal representative before any activity or treatment is undertaken which is not part of 
routine care.  This includes, but is not limited to, the performance of diagnostic, screening, or 
therapeutic procedures and the administration of the first dose of study treatment.  The draft 
version of the ICF will be modified by each site and reviewed and approved in writing by 
Sensei prior to submission to the IRB.   
The investigator or his/her representative will explain the nature of the study to the patient or his/her 
legally authorized representative and answer all questions regarding the study.  The medical record 
must include a statement that written informed consent was obtained before the patient was enrolled 
in the study and the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.  A copy of the ICF(s) must be provided to the patient or 
the patient’s legally authorized representative. 
Should a protocol amendment be made, the patient ICF may be revised to reflect the changes 
of the protocol.  If the ICF is revised, it is the responsibility of the Investigator to ensure that 
an amended ICF is reviewed and approved by the IRB and signed by all patients subsequently, 
as applicable to their treatment and/or follow up status in the study. 
 Data Protection 
All local legal requirements regarding data protection will be enforced.  All study findings and 
documents will be regarded as confidential.  The Investigator and members of his/her research 
team must not disclose such information without prior written approval from Sensei.  The 
anonymity of participating patients must be maintained.  Throughout documentation and 
evaluation, the patients will be identified on CRFs and other documents submitted to Sensei 
by an unique identifier.  Documents that are not to be submitted to Sensei, and that identify 
the patient (e.g., the signed ICF), must be maintained in confidence by the Investigator.  The 
patients will be told that all study findings will be stored and handled in strictest confidence, 
according to local requirements. Patients will be informed that authorized research 
Investigators, IRB/IEC, agents of the FDA or other recognized regulatory authorities, and 
authorized representatives of the Sponsor, Sensei, have the right to inspect their medical 
records. 


 
 
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 Committee Structure 
This is a Phase 2 trial involving 20 study centers located in the United States. The 
Investigator(s) responsible for the conduct of the study at their site, in compliance with this 
Protocol, are identified on the Signature of Agreement Page (Appendix D:  Principal 
Investigator Signature of Agreement Page).  
All questions regarding the enrollment of patients, regulatory requirements for the conduct of 
the study, safety reporting, or study conduct should be addressed to the Medical Monitor. 
 Data Quality Assurance 
The following requirements are necessary to ensure quality data from the study: 
• 
All patient data relating to the study will be recorded on electronic CRF unless transmitted 
to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Programmed computer edit checks will be run against the 
database to check for discrepancies and plausibility of the data.  All issues resulting from 
the computer-generated checks will be resolved according to the Sponsor's standard data 
management practices in conjunction with the medical monitor, clinical study personnel, 
and the study Investigators.   
•     The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
•     Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
•     Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the following timeframes: 
• 
for a minimum of two years following the date the marketing application (NDA/BLA) 
is approved for the indication for which the drug was investigated; or, 
• 
for a minimum of two years following the release date of the final report, if no 
marketing application is to be filed by Sensei, or if the marketing application is not 
approved for the indication for which the drug was investigated or is discontinued, and 
the FDA has been notified; or, 
• 
for a minimum of 15 years after the completion or discontinuation of the study to be 
filed in support of the registration in the European Union. 
• 
 No records may be destroyed without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the 
sponsor.   


 
 
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 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
 Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further study intervention development 
Upon terminating the study, the Investigator will submit a final report to the IRB in keeping 
with local IRB regulations.  This report should include any deviations from the protocol, the 
number and types of patients evaluated, the number of patients who discontinued, including 
reasons, results of the study, AEs, and a conclusion summarizing the results. 
If requested by the Investigator, at the completion of the study and following analysis of the 
data, Sensei will supply a tabulated listing of data and a final clinical statistical report.  A copy 
of the final study report and final CRFs, will be provided to each Investigator. 
 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study for 
the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement.  The results of the 
study may appear on public websites, such as www.clinicaltrials.gov, in compliance with 
clinical trial reporting requirements.  Sensei will prepare an Integrated Clinical/Statistical 
Report.  Any publication/presentation of data must include the entire study population.  
Submission of data for publication/presentation will be reviewed, coordinated and approved 
by Sensei in collaboration with the Investigator.  Sensei will determine authorship of any 
publication by enrollment or by contributing to the protocol, in consultation with the principal 
investigator. 


 
 
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12. REFERENCE LIST  
1. Jia, S., W.J. VanDusen, R.E. Diehl, N.E. Kohl, R.A. Dixon, K.O. Elliston, A.M. Stern, 
and P.A. Friedman. 1992. cDNA cloning and expression of bovine aspartyl 
(asparaginyl) beta-hydroxylase. The Journal of Biological Chemistry 267:14322-
14327. 
2. Lavaissiere, L., S. Jia, M. Nishiyama, S. de la Monte, A.M. Stern, J.R. Wands, and 
P.A. Friedman. 1996. Overexpression of human aspartyl(asparaginyl)beta-
hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. The Journal of 
Clinical Investigation 98:1313-1323. 
3. Shimoda, M., Y. Tomimaru, K.P. Charpentier, H. Safran, R.I. Carlson, and J. Wands. 
2012. Tumor progression-related transmembrane protein aspartate-beta-hydroxylase 
is a target for immunotherapy of hepatocellular carcinoma. Journal of Hepatology 
56:1129-1135. 
4. De Berardinis, P., R. Sartorius, C. Fanutti, R.N. Perham, G. Del Pozzo and G. 
Guardiola. 2000. Phage display of peptide epitopes from HIV-1 elicits strong cytolytic 
responses in vitro and in vivo. Nature Biotechnology 18(8):873-876. 
5. De Berardinis, P., L. D’Apice, A. Prisco, M.N. Ombra, P. Barba, G. Del Pozzo, S. 
Petukhov, P. Malik, R.N. Perham, and J. Guardiola. 1999. Recognition of HIV-
derived B and T cell epitopes displayed on filamentous phages. Vaccine 17 (11-
12):1434-1441. 
6. Di Marzo Veronesse, F., A.E. Willis, C. Boyer-Thompson, E. Appella and R.N. 
Perham. 1994. Structural Mimicry and Enhanced Immunogenicity of Peptide 
Epitopes Displayed on Filamentous Bacteriophage: The V3 loop of HIV-1 gp120. 
Journal of Molecular Biology 243(2):167-172. 
7. Perham, R.N., T.D. Terry, A.E. Willis, J. Greenwood, F. di Marzo Veronesse and E. 
Appella. 1995. Engineering a peptide epitope display system on filamentous 
bacteriophage. FEMS Microbiology Reviews 17(1-2):25-31. 
8. Burtness, B., Harrington, K., Greil, R., Soulières, D., et al.  “Pembrolizumab alone or 
with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic 
squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, 
open-label, phase 3 study.”  Lancet.  2019 October 31; 394: 1915–28. 
9. Siegel R, Miller KD, Jemal A. Cancer Statistics, 2017. Cancer J Clin. 2017; 67: 7-30. 
10. Sacco AG, Cohen EE. “Current Treatment Options for Recurrent or Metastatic Head 
and Neck Squamous Cell Carcinoma.” J Clin Oncol. 2015 Oct 10;33(29):3305-13. 
11. Vermorken JB, Mesia R, Rivera F, et al. “Platinum-based chemotherapy plus 
cetuximab in head and neck cancer.” N Engl J Med. 2008 Sep 11;359(11):1116-27. 
doi: 10.1056/NEJMoa0802656. 
12. Ferris RL, Blumenschein G Jr, Fayette J, et al. “Nivolumab for Recurrent Squamous-
Cell Carcinoma of the Head and Neck.” N Engl J Med. 2016 Nov 10;375(19):1856-
1867. 
13. Nishino M.  “Immune-related response evaluations during immune-checkpoint 
inhibitor therapy:  establishing a “common language” for the new arena of cancer 
treatment.”  Journal for ImmunoTherapy of Cancer. 2016 4:30 doi:10.1186/s40425-
016-0134-0. 


 
 
S N S -3 0 1 - 2-2 / V er si o n 4. 0                                                                           C O N FI D E N TI A L                                           P a g e 7 2  of 1 3 2  
 
A P P E N DI X A : T U M O R A S S E S S M E N T C RI T E RI A  
R E CI S T 1. 1  
Defi niti o ns as per Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n 
s oli d t u m ors: Re vise d R E CI S T g ui deli ne ( Versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 – 4 7. 
 
 
At baseli ne, t u m or lesi o ns/l y m p h n o des will be cate g orize d meas ura ble or n o n-meas ura ble as 
f oll o ws: 
 
Me as ur a ble T u m or  Lesi o ns  
T u m or lesi o ns m ust be acc uratel y meas ure d i n at least o ne di me nsi o n  
(l o n gest dia meter i n t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of: 
•  
1 0 m m b y c o m p ute d t o m o gra p h y ( C T) or ma g netic res o na nce i ma gi n g ( M RI) sca n 
( C T/ M RI sca n slice t hic k ness/i nter val n o greater t ha n 5 m m) 
•  
1 0- m m cali per meas ure me nt b y cli nical e xa mi nati o n (lesi o ns t hat ca n n ot be  
acc uratel y meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas ura ble)  
•  
2 0 m m b y c hest X- ra y 
 
M ali g n a nt L y m p h N o des. T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a 
l y m p h n o de m ust be ≥1 5 m m i n t he s h ort a xis w he n assesse d b y C T sca n ( C T sca n  
slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m). At baseli ne a n d i n f oll o w- u p, 
o nl y t he s h ort a xis will be meas ure d a n d f oll o we d. See als o n otes bel o w o n “ Baseli ne 
D oc u me ntati o n of Tar get a n d N o ntar get Lesi o ns” f or i nf or mati o n o n l y m p h n o de 
meas ure me nt.  
 
N o n -Me as ur a ble T u m or Lesi o ns  
N o n -meas ura ble t u m or lesi o ns e nc o m pass s mall lesi o ns (l o n gest dia meter  <1 0 m m  
or pat h ol o gical l y m p h n o des wit h ≥1 0 t o < 1 5 m m s h ort a xis), as well as tr ul y  
n o n- meas ura ble lesi o ns. Lesi o ns c o nsi dere d tr ul y n o n -meas ura ble i ncl u de  
le pt o me ni n geal disease, ascites, ple ural or pericar dial eff usi o n, i nfla m mat or y breast  
disease, l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, perit o neal s prea d, a n d a b d o mi nal 
masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa mi nati o n t hat is n ot 
meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues. 
 
 
S peci al C o nsi der ati o ns Re g ar di n g Lesi o n Me as ur a bilit y  
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire 
partic ular c o m me nt, as o utli ne d bel o w. 
B o ne lesi o ns: 
•  
B o ne sca n, p ositr o n e missi o n t o m o gra p h y ( P E T) sca n, or plai n fil ms are n ot 
c o nsi dere d a de q uate i ma gi n g tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese  
tec h ni q ues ca n be use d t o c o nfir m t he prese nce or disa p peara nce of b o ne lesi o ns. 
•  
L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de n tifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss- secti o nal i ma gi n g tec h ni q ues s uc h as 
C T or M RI ca n be c o nsi dere d meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets  
t he defi niti o n of meas ura bilit y descri be d a b o ve. 
•  
Blastic b o ne lesi o ns are n o n-meas ura ble.  
C ystic lesi o ns:  
•  
Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be 


 
 
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considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions. 
 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
 
SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
 
Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study. 
Imaging-based evaluation should always be done rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
 
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm in diameter as assessed using calipers (e.g., skin nodules). 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested. 
 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
 
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable. 
 
Ultrasound. Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement. 
 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of 
these techniques for objective tumor evaluation is not advised. 
 
 


 
 
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TUMOR RESPONSE EVALUATION 
 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements. Measurable disease is defined by the presence of at least 
one measurable lesion. 
 
BASELINE DOCUMENTATION OF TARGET AND NONTARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two 
organ sites involved, a maximum of two and four lesions, 
respectively, will be recorded).  
 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor. As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these nodes 
will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node that is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered nontarget lesions. Nodes that have a short axis 
<10 mm are considered nonpathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters. If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum. The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as nontarget lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple nontarget lesions involving the same organ as 
a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 


 
 
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nodes” or “multiple liver metastases”). 
 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
Complete response (CR): Disappearance of all target lesions 
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to <10 mm. 
• 
Partial response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
• 
Progressive disease (PD): At least a 20% increase in the sum of diameters of the target 
lesions, taking as reference the smallest sum on study (nadir), including baseline.  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  Note: the appearance of one or more new lesions is also 
considered progression. 
• 
Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 
 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below10 mm on study. This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
<10 mm. 
 
Target Lesions That Become Too Small to Measure.  
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline become so faint on 
the CT scan that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being too small to measure. When this occurs, it is important that a value be recorded on the 
CRF as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). To reiterate, however, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
 
Lesions That Split or Coalesce on Treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 


 
 
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vector of the longest diameter in this instance should be the maximal longest diameter for the 
coalesced lesion. 
 
Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions. While some nontarget lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
 
• 
CR: Disappearance of all nontarget lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
• 
PD: Unequivocal progression of existing nontarget lesions. The appearance of one or more 
new lesions is also considered progression. 
 
Special Notes on Assessment of Progression of Nontarget Disease 
When the Patient Also Has Measurable Disease 
In this setting, to achieve “unequivocal progression” on the basis of the nontarget disease, there 
must be an overall level of substantial worsening in nontarget disease in a magnitude that, even in 
the presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest increase in the size of one or 
more nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in nontarget 
disease in the face of SD or PR of target disease will therefore be extremely rare. 
 
When the Patient Has Only Non-Measurable Disease 
This circumstance arises in some Phase III studies when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above; however, in this 
instance, there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden. Because worsening in nontarget 
disease cannot be easily quantified (by definition: if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression is 
to consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required 
to declare PD for measurable disease, that is, an increase in tumor burden representing 
an additional 73% increase in volume (which is equivalent to a 20% increase in diameter 
in a measurable lesion). Examples include an increase in a pleural effusion from “trace” 
to “large,” an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.” If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, i.e., not attributable to differences in scanning technique, 


 
 
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change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions). This is particularly important when the patient’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not. 
 
A lesion identified on a follow up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
 
EVALUATION OF RESPONSE 
 
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
Table 2 provides a summary of non-measurable (therefore nontarget) disease only 
Table 3 provides the best overall response when confirmation of CR and PR required 
Table 1:  Time point response: patients with target (+/- non-target disease) 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


 
 
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CR = complete response, PR = partial response, SD=stable disease, PD = progressive disease, 
and NE = inevaluable 
 
Table 2 Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Uniequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = inevaluable 
a Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
 
Table 3 Best overall response when confirmation of CR and PR required 
Overall response  
First time point 
Overall response 
Subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum 
criteria for SD duration 
met, otherwise PD 


 
 
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CR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise PD 
CR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum 
criteria for SD duration 
met, otherwise PD 
PR 
NE 
SD provided minimum 
criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD=stable disease, PD = progressive 
disease, and NE = inevaluable 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR at the first time point.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 
 
 


 
 
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iRECIST 
Definitions as per Seymour, L, et al.   iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet 2017; PE143-E152. 
 
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in 
infiltration of immune cells leading to transient increase in the size in malignant lesions, or 
undetectable lesions becoming detectable. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in tumour 
burden, or the appearance of new lesions, does not reflect true tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be recorded 
separately. 
Confirming Disease Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, is 
seen as evidenced by one or more of the following: 
• 
Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in non-target disease with an increase in 
tumor burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
• 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are 
met compared to baseline). As can be seen in table 2, the prior documentation of iUPD does 
not preclude assigning iCR, iPR, or iSD in subsequent time-point assessments or as best 
overall response (BOR) providing that iCPD is not documented at the next assessment after 
iUPD. 
New lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short 


 
 
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axis for nodal lesions) and recorded as New Lesions-Target (NLT) and New Lesion-Non-
Target (NLNT) to allow clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline. Rather, these measurements will be collected on a separate 
table in the case record form. 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at 
least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD 
with either an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase 
(but not necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of 
additional new lesions 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or progressive 
disease is objectively documented, taking as reference the smallest measurements recorded on 
study (including baseline). 
Stable disease duration will be measured from the time of start of treatment until the criteria 
for progression are met, taking as reference the smallest sum on study (including baseline). 
Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy. While on 
study, all lesions recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the 
lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned. For lesions which fragment/split add together the longest diameters 
of the fragmented portions; for lesions which coalesce, measure the maximal longest diameter 
for the “merged lesion”. 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
recommended. If feasible, imaging is preferred. 
Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 


 
 
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the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Other 
specialized imaging or other techniques may also be appropriate for individual case.4 For 
example, while PET scans are not considered adequate to measure lesions, PET-CT scans may 
be used providing that the measures are obtained from the CT scan and the CT scan is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumour Markers. Tumour markers alone cannot be used to assess objective tumour response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain). When effusions are known to be 
a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumour has met criteria for response or 
stable disease is advised to differentiate between response or stable disease and progressive 
disease 
Table 1:  Assigning time point response for iRECIST 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 


 
 
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iUPD with 
no change 
OR 
decrease 
from last 
TP 
iUPD with no 
change 
OR 
decrease from last 
TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified and increase 
in size (≥5 mm in SOM for NLT or any increase for NLNT) or 
number. If no change in NLs (size or number) from last TP, 
remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further increase in 
size of NT disease (need not meet RECIST 1.1 criteria for 
unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, otherwise remains 
iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase 
in: 
o previously identified T lesion iUPD SOM ≥5 mm and / or 
o NT lesion iUPD (prior assessment - need not be unequivocal 
PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase 
in: 
o previously identified T lesion iUPD ≥5 mm and / or 
o previously identified NT lesion iUPD (need not be 
unequivocal) and /or 
o size or number of new lesions previously identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
o increase in size or number of new lesions previously identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would be 
the same. ** in any lesion category. *** previously identified in assessment immediately prior to this TP. 
iCR- immune complete response; iPR – immune partial response; iSD – immune stable disease; iUPD – immune 
unconfirmed progression; iCPD – immune confirmed progression; NL – new lesions; NLNT – new lesion non target; 
T – target; TP – time point; NA – not applicable; NE – not evaluable/evaluated 


 
 
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Table 2: Assigning best overall response for iRECIST 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, 
iPR, 
iUPD, NE 
iCR, iPR, iUPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE 
iCR 
iCR, iPR, iSD, iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, NE, iCPD 
iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomised study where confirmation of CR or PR is not required. 
• 
NE = not evaluable that cycle. 
• 
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR but 
is not shown in the table for ease of presentation. 
iCR- immune complete response; iPR – immune partial response; iSD – immune stable disease; iUPD – immune unconfirmed 
progression; iCPD – immune confirmed progression; iBOR – immune best response; TPR – time point response 
 
 
 
 


 
 
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APPENDIX B: ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS* 
GRADE 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
*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. 
 
 


 
 
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APPENDIX C: SUMMARY OF CHANGES 
 
 
Version Number 
Version Date 
Current 
Approved 
Protocol: 
1.0 
February 6, 2019 
Amended Protocol: 
2.0 
June 27, 2019 
Administrative Letter 
NA 
October 9, 2019 
Administrative Letter 
NA 
April 3, 2020 
Amended Protocol 
3.0 
July 24, 2020 
Amended Protocol 
4.0 
November 6, 2020 
 
 


 
 
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Changes to Amended Protocol Version 4.0 Dated November 6, 2020 
Section #  
Section Title 
Old Text 
New Text 
Rationale for 
Change 
Synopsis, 
4.2.2 
Secondary 
Endpoints 
 
 
 
 
• 
T-cell activation and 
cytolytic cell phenotype 
in PBMCs by Flow 
Cytometry or secretion 
of immune molecules 
• 
B cell activation/ 
secretion 
• 
Assessment of Myeloid 
Derived Suppressor 
Cells (MDSC) 
• 
Immune gene transcript 
profiling of PBMCs 
Deleted  
 
 
 
Deleted to align 
with Sensei’s 
updated 
immunogenicity 
testing. 
Synopsis, 
4.2.3 
Exploratory 
Endpoints 
NA 
• 
TCR sequencing of PBMCs 
for diversity and putative 
antigen specificity 
Moved from 
Secondary 
Endpoints to 
Exploratory 
Endpoints since 
the assay is not 
CLIA certified.  
Synopsis, 5.2 
Trial Population, 
Overall Design 
NA 
Expanded patient population to 
include patient who are naïve to CPI 
therapy. 
Given the 
modest response 
rates to CPI 
therapy even in 
patients with 
PD-L1 positive 
tumors in the 
first line setting, 
Sensei will allow 
enrollment to a 
second cohort 
with patients that 


 
 
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are CPI therapy 
naïve. 
Synopsis, 5.2 
Sample Size,  
Overall Design 
Approximately 30 patients will 
be enrolled in the trial. 
Approximately up to 30 patients will 
be enrolled into each cohort on the 
trial. 
Adjusted to 
include Cohort 
B. 
Synopsis 
 
A minimum accrual rate is 
expected to be 2-3 patients per 
month.  With a minimal accrual 
rate of 2-3 patients per month we 
expect the study enrollment is 
expected to last approximately 
12-15 months. 
The study enrollment is expected to 
last approximately 18-24 months. 
Updated to 
account for new 
cohort. 
Synopsis, 5.2 
Overall Design 
NA 
Additionally, up to two optional 
biopsies may be obtained at any time 
during the study, if medically 
feasible. 
Optional 
biopsies added 
in select cases to 
increase 
scientific 
knowledge of 
the study 
treatment. 
Synopsis, 5.2 
Statistical 
Methods:  
Sample Size 
Justification, 
Overall Design 
Approximately 15 participants 
will be enrolled in Stage 1 and an 
additional approximately 15 
participants will be enrolled in 
Stage 2, if the cohort is expanded.  
 
To evaluate the primary endpoint 
of objective response per 
Each cohort will enroll in two stages.  
Within each cohort, approximately 15 
participants will be enrolled in Stage 1 
and an additional approximately 15 
participants may be enrolled in Stage 
2, if expanded. The sample size for 
each cohort and stage is based on 
Simon’s two-stage design for tests of 
one proportion.  
Updated for 
Cohort B.  
Deleted detailed 
information on 
sample size 
justification in 
the synopsis.  
The reader 
should refer to 


 
 
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iRECIST at 12 weeks with a null 
hypothesis of an objective 
response rate (ORR) of 5% and 
an alternative hypothesis of an 
ORR of 18%, 30 patients in a 
two-stage design with 15 patients 
in the first stage and 15 patients 
in the second stage will be 
enrolled.  Patients with evidence 
of disease progression or deemed 
unevaluable at 12 weeks will not 
be counted towards assessment of 
futility. At the first stage analysis 
if at least 1 response is observed 
out of 15 patients, the study will 
continue through the second 
stage.  At the second stage 
analysis, if at least 4 responses 
are observed out of 30 total 
patients, the null hypothesis will 
be rejected, and further research 
considered warranted.  The 
overall power for objective 
response rate at 12 weeks is 80%.  
The overall type I error, the 
chance of incorrectly rejecting 
the null hypothesis is 6% 
(targeted alpha of 0.10).  The 
probability of stopping at the first 
stage under the null hypothesis is 
46%.  The operating 
characteristics of this design are 
calculated using the exact 
binomial distribution. 
 
the Statistics 
section of the 
protocol. 


 
 
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Synopsis 
General 
Methods 
NA 
All summarizations will be presented 
separately for each cohort, and over all 
subjects combined. 
 
Added 
information 
regarding Cohort 
B. 
Synopsis 
General 
Methods 
Objective response rate (ORR) is 
defined as the proportion of 
patients with a confirmed best 
response of CR or PR by RECIST 
1.1. Objective response rate will 
be estimated, and 95% CI based 
on the exact binomial distribution 
will be presented. 
Objective response rate (ORR) is 
defined as the proportion of patients 
with a confirmed best response of 
CR or PR by iRECIST. 
Sentence 
simplified.  
Statistics section 
includes 
additional 
details. 
Synopsis, 6 
Inclusion 
Criteria 
Have histologically or 
cytologically documented locally 
advanced unresectable or 
metastatic/recurrent SCCHN and 
currently receiving a checkpoint 
inhibitor (anti-PD1 and anti-PD-
L1 agents). 
a. 
Eligible patients 
currently receiving a 
checkpoint inhibitor 
must be considered 
by Investigator to 
have the potential to 
derive clinical 
benefit from 
continued treatment 
with 
pembrolizumab. 
Have histologically or cytologically 
documented locally advanced 
unresectable or metastatic/recurrent 
SCCHN and meet the criteria of 
either Cohort A or B. 
Cohort A:  Patients with 
Ongoing CPI Therapy 
a. 
Patients currently 
receiving a checkpoint 
inhibitor (anti-PD1 and 
anti-PD-L1 agents). 
b. Patients currently 
receiving a CPI must be 
considered by 
Investigator to have the 
potential to derive 
clinical benefit from 
Updated to 
account for new 
cohort. 


 
 
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b. Based on RECIST 
1.1/iRECIST 
criteria on current 
checkpoint inhibitor 
treatment (prior to 
initiation of this 
study), patients must 
have a best response 
of  stable disease 
(SD) or first 
evidence of 
progressive disease 
(PD) after a 
minimum of 12 
weeks of a 
checkpoint 
inhibitor. 
c. 
Patients receiving first-
line pembrolizumab 
monotherapy prior to 
this study must be PD-
L1 positive. 
d. Patients on  other 
checkpoint inhibitor 
therapy than 
pembrolizumab 
must be willing to 
switch over to 
pembrolizumab 
therapy. 
 
continued treatment 
with pembrolizumab. 
c. 
Based on RECIST 
1.1/iRECIST criteria on 
current CPI treatment 
(prior to initiation of 
this study), patients 
must have a best 
response of  stable 
disease (SD) or first 
evidence of progressive 
disease (PD) after a 
minimum of 12 weeks 
of a CPI. 
d. Patients on other CPI 
therapy than 
pembrolizumab must be 
willing to switch over 
to pembrolizumab 
therapy. 
Cohort B:  Patients without 
Previous CPI Therapy 
a. 
Patients must be 
checkpoint inhibitor 
naïve (anti-PD1 and 
anti-PD-L1 agents) 
b. Patients should receive 
study treatment as first 
line (PD-L1 positive) or 
as second line (PD-L1 
negative) systemic 
therapy in the 
advanced/metastatic 
setting. 


 
 
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Synopsis, 6 
Exclusion 
Criteria 
10. 
Active or history of 
autoimmune disease or immune 
deficiency, including but not 
limited to myasthenia gravis, 
myositis, autoimmune hepatitis, 
systemic lupus erythematosus, 
rheumatoid arthritis, 
inflammatory bowel disease, 
vascular thrombosis associated 
with anti-phospholipid syndrome, 
Wegener granulomatosis with 
polyangiitis, Sjögren’s syndrome, 
Guillain-Barrѐ syndrome, 
multiple sclerosis, vasculitis, or 
glomerulonephritis (See protocol 
Appendix A: PREEXISTING 
AUTOIMMUNE DISEASE for a 
more comprehensive list of 
autoimmune diseases and 
immune deficiencies) 
• 
Patients with history of 
autoimmune-related 
hypothyroidism on a stable dose 
of thyroid replacement hormone 
as well as patients with adrenal 
insufficiency may be eligible for 
this trial 
• 
Patients with controlled 
Type I diabetes mellitus on a 
Active autoimmune disease that has 
required systemic treatment in the 
past 2 years (i.e. with use of disease 
modifying agents, corticosteroids or 
immunosuppressive drugs). 
Replacement therapy (e.g., 
thyroxine, insulin, or physiologic 
corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, 
etc.) is not considered a form of 
systemic treatment.   
Simplified 
exclusion 
criteria for 
previous 
autoimmune 
diseases. 


 
 
SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 93 of 132 
 
stable dose of insulin regimen 
may be eligible for this trial 
Synopsis 
Trial Schedule 
of Events 
Pembrolizumab 
Schedule – 
Every 3 & 6 
Weeks 
SNS Dosing Schedule for 
Pembro Q6 weeks 
Day 0, Week 3, Week 6, Week 
12, etc. 
SNS Dosing Schedule for Pembro Q6 
weeks 
Day 0, Week 3, Week 6, Week 9, etc. 
Q6W Pembro 
After week 9, the pembrolizumab 
and SNS-301 visits will not coincide.  
The SNS-301 dosing should not be 
adjusted. The investigator may 
choose to give a 3-week dose (i.e., 
pembrolizumab 200  mg) in order for 
the visits to align.  The investigator 
should consult the sponsor if there 
are questions regarding aligning the 
study treatment schedule 
SNS-301 dosing 
schedule  
updated to 
administer same 
SNS-301 
regimen 
regardless of 
pembrolizumab 
dosing regimen.  
Synopsis 
Trial Schedule 
of Events 
 
Anticoagulants - After week 9, 
Q6 w until week 45, thereafter Q 
12 w 
Q3W Pembro 
Anticoagulants - At week 12 then, 
Q6w until week 45, thereafter Q12w 
Q6W Pembro 
Anticoagulants - At week 12 then, 
Q6w until week 42, thereafter Q12w 
Changed 
schedule to line 
up with SNS-
301 dosing. 
Synopsis, 
9.1.1, 
9.2.14.2 
Trial Schedule 
of Events - 
Pembrolizumab 
Schedule – 
Every 3 & 6 
Weeks, Tumor 
Tumor Imaging 
RECIST/iRECIST - Q6w from 
Day 0 for first 54 weeks (~12 
months), there after Q12w 
PD-L1 – Day 0 
Tumor Imaging RECIST/iRECIST - 
Q6w from Day 0 until~12 months, 
there after Q12w 
PD-L1 – Screening 
Tumor imaging 
should be at 
approximately 
12 months from 
Day 0. 


 
 
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Assessment, 
Tissue 
Blood Samples for immunology 
assessments - At week 12 and 
Q12w thereafter until disease 
progression as well as at disease 
progression 
Tumor specimen - At first 
evidence of disease progression 
Blood Samples for immunology 
assessments - At week 12, then Q6 
weeks until Week 36 and Q12w 
thereafter until disease progression as 
well as at disease progression 
Tumor specimen - Up to 2 optional 
biopsies and at disease progression 
 
PD-L1 should be 
done at 
screening since 
CPI naïve 
patients are 
allowed onto the 
study. 
Increase the 
number of blood 
draws to allow 
further 
evaluations of 
the 
immunogenicity 
of  the phage and 
tumor associated 
antigen (ASPH), 
and the 
dynamics 
thereof. 
Increased 
optional biopsies  
in select cases of 
special interest 
to further 
understand how 
study treatment 
affects the 
patient’s tumor. 
Synopsis 
Trial Schedule 
of Events 
If the first dose of SNS-301 is 
given one week before or one 
week after pembrolizumab vital 
signs will be collected within 60 
Deleted 
This statement 
was included in 
error. 


 
 
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Pembrolizumab 
Schedule – 
Every 3 & 6 
Weeks 
minutes before the injection and 
at 30 (± 5) minutes after the 
injection. 
Synopsis 
Trial Schedule 
of Events 
Pembrolizumab 
Schedule – 
Every 6 Weeks 
 
Anticoagulants -  after week 12, 
Q6w until week 42, thereafter Q12w 
Updated to 
reflect the 6W 
pembrolizumab 
dosing schedule. 
3.1.2 
Pre-Clinical, 
Clinical Trials 
and Other 
Ongoing Trials 
The Phase 2 Study (SNS-301-2-
2) of SNS-301, 1 x 1011 
administered ID, added to 
pembrolizumab is currently 
ongoing. As of the database 
cutoff (23 July 2020), the study 
has enrolled 9 patients with 
ASPH positive locally advanced 
unresectable or 
metastatic/recurrent squamous 
cell carcinoma of the head and 
neck (SCCHN). Of the 9 patients 
enrolled 7 (77.8%) experienced a 
TEAE, however, majority of the 
reported TEAEs were mild 
(Grade 1) and not related to study 
treatment. There were 2 Grade 3 
TEAEs (Dehydration and 
Hypertension) and only Grade 3 
Dehydration was assessed as 
related to study treatment. There 
were 2 SAEs (Grade 3 
Dehydration and Grade 1 
The Phase 1/2 Study (SNS-301-2-2) 
of SNS-301, 1 x 1011 administered 
ID, added to pembrolizumab is 
currently ongoing. As of the database 
cutoff (29 October 2020), the study 
has enrolled 11 patients with locally 
advanced unresectable or 
metastatic/recurrent squamous cell 
carcinoma of the head and neck 
(SCCHN). Of the 11 patients 
enrolled 9 (81.8.8%) experienced a 
TEAE, however, majority of the 
reported TEAEs were mild (Grade 1) 
and not related to study treatment. 
There were 3 Grade 3 TEAEs related 
to study treatment experienced by 2 
patients:  rash, electrocardiogram QT 
prolongation and dehydration. There 
were 4 SAEs reported for 3 patients:  
Grade 3 dehydration, G3 
electrocardiogram QT prolongation,  
Grade 2 Systemic Inflammatory 
Response Syndrome, G2 hemoptysis, 
G2 malnutrition/dehydration. There 
Updated data for 
this clinical trial. 


 
 
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Systemic Inflammatory Response 
Syndrome). There were no DLTs, 
Grade 4, or fatal events reported 
to date. 
were no DLTs, Grade 4, or fatal 
events reported to date. 
 
3.2 
Rationale 
Anti-PD-1 antibodies including 
nivolumab and pembrolizumab 
can induce durable remissions in 
13-18% of patients with SCCHN, 
but the majority of patients fail to 
respond due to inadequate intra-
tumoral immune cell infiltration. 
Other checkpoint inhibitors 
currently in clinical trials as 
combination therapy or 
monotherapy demonstrate limited 
responses as well, thus 
underscoring the importance of 
allowing patients who are 
unresponsive to checkpoint 
inhibitor therapy the option to 
participate in a clinical trial, such 
as the study sponsored by Sensei 
Biotherapeutics.  
 Sensei Biotherapeutics plans to 
develop SNS-301 in addition to 
pembrolizumab in a study 
targeting patients with SCCHN 
that is resistant to CPI which is a 
population with high unmet 
medical need.  The overall goal is 
to improve clinical outcomes in 
patients who have failed to 
respond to CPI therapy. 
Anti-PD-1 antibodies including 
nivolumab and pembrolizumab can 
induce durable remissions <20% of 
patients with recurrent or metastatic 
SCCHN in first or subsequent line 
setting and after platinum-containing 
chemotherapy[8], but the majority of 
patients fail to respond due to 
inadequate intra-tumoral immune 
cell infiltration. Other checkpoint 
inhibitors (CPI; defined as anti-PD-
1/anti-PD-L1 therapy) currently in 
clinical trials as combination therapy 
or monotherapy demonstrate limited 
responses as well, thus underscoring 
the importance of allowing patients 
who are unresponsive to CPI therapy 
the option to participate in a clinical 
trial, such as the study sponsored by 
Sensei Biotherapeutics.   
Sensei Biotherapeutics plans to 
develop SNS-301 in addition to 
pembrolizumab in a study targeting 
two different patient cohorts: 
patients that did not achieve 
objective responses after at least 12 
weeks of CPI and patients that are 
CPI naïve.  The overall goal is to 
improve clinical outcomes in 
patients with locally advanced or 
Updated to 
provide rationale 
to include CPI 
naïve patients. 


 
 
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metastatic SCCHN receiving CPI 
therapy. 
3.2.1.1 
Unmet Medical 
Need for 
Patients with 
SCCHN 
There are multiple other ICIs that 
are in clinical trials (e.g., 
atezolizumab, durvalumab, 
avelumab, etc.) and these agents 
as combination therapy or 
monotherapy demonstrate limited 
responses as well, thus 
underscoring the importance of 
allowing these unresponsive 
checkpoint inhibitor therapy 
patients to participate in trials 
such as the study sponsored by 
Sensei Biotherapeutics.  In order 
to provide an option to the 
majority of SCCHN patients who 
do not respond to  checkpoint 
inhibitors, Sensei will allow 
inclusion of patients who 
received widely investigated  
ICIs  (anti-PD1, anti-PD-L1 
agents) as part of clinical trials  as 
long as patients meet all of the 
outlined eligibility criteria.  All 
patients enrolled will be switched 
to pembrolizumab treatment 
regardless of which ICI therapy 
the patient was receiving 
previously. 
However, patients that do not 
respond to immune checkpoint 
inhibitors continue to represent a 
significant number of the 
There are multiple other ICIs that are 
in clinical trials (e.g., atezolizumab, 
durvalumab, avelumab, etc.) and 
these agents as combination therapy 
or monotherapy demonstrate limited 
responses as well, thus underscoring 
the importance of allowing these 
patients to participate in trials that 
potentially can enhance the efficacy 
of CPI therapy such as the study 
sponsored by Sensei Biotherapeutics.  
In order to provide an option to the 
majority of SCCHN patients who do 
not respond to  CPI therapy, Sensei 
will allow inclusion of patients who 
received widely investigated  ICIs  
(anti-PD1, anti-PD-L1 agents) as 
part of clinical trials  as long as 
patients meet all of the outlined 
eligibility criteria.  All patients 
enrolled will be switched to 
pembrolizumab treatment regardless 
of which ICI therapy the patient was 
receiving previously. Furthermore, 
given the modest response rates to 
CPI therapy even in patients with 
PD-L1 positive tumors in the first 
line setting (19%, Keynote-48), 
Sensei will allow enrollment to a 
second cohort with patients that are 
CPI therapy naïve. 
Updated to 
provide rationale 
to include CPI 
naïve patients. 


 
 
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SCCHN patients and thus remain 
a high unmet medical need 
population with a median OS of 
12 months or less.  Furthermore, 
for patients who have also 
previously received and 
progressed on platinum-based 
chemotherapy, the median OS is 
less than 6 months. The need to 
develop novel clinically 
meaningful therapies for these 
patients remains.  
Sensei Bio plans to evaluate 
SNS-301 in patients with 
SCCHN who have failed to 
respond to CPI therapy, but 
investigators feel that continued 
treatment with a CPI and another 
targeted agent may provide 
clinical benefit for these patients. 
3.2.1.2 
ASPH 
Expression 
Testing in 
SCCHN 
As of 16 July 2020, 26 additional 
archived tissue samples have 
been analyzed from this study.  
All 26 samples were found to be 
ASPH positive as assessed by a 
CLIA validated IHC assay from 
Fred Hutchinson Cancer Center.   
As of 29 Oct 2020, 30 additional 
archived tissue samples have been 
analyzed from this study.  All 30 
samples were found to be ASPH 
positive as assessed by a CLIA 
validated IHC assay from Fred 
Hutchinson Cancer Center.   
Updated with 
current data. 
3.2.3 
Rationale for 
Dose 
Selection/Regim
en 
In summary, SNS-301 was 
considered to be well tolerated at 
all dose levels evaluated with no 
DLTs or grade 4/5 AEs noted. 
Three patients experienced a total 
Deleted 
Deleted text 
from the 
Rationale for 
Dose 
Selection/Regim


 
 
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of five adverse events considered 
by investigators to be at least 
possibly related to study drug and 
all AEs were considered to ≤ 
grade 3.    
One patient experienced an AE in 
the form of migratory arthralgia 
that was attributed as possibly 
related to the study drug given 
that the patient was diagnosed 
with RF+ rheumatoid arthritis 
and the immunization contributed 
to the pain flare.   
One patient 001-004 in the high 
dose cohort experienced mild 
erythema at the injection site 
which resolved within 3 days.   
There was one serious treatment 
related TEAE reported.  The 
patient (004-003), a 72-year-old, 
white male experienced 
positional vertigo that was 
deemed definitely not related by 
the reporting Investigator.   
No other noteworthy AEs have 
been observed..   
en section.  
Safety is 
addressed in 
Section 3.1.2. 
7.1.2.1 
SNS Dosing 
SNS-301 Dosing Schedule when 
pembrolizumab dosing at 3 week 
intervals:  Patients will receive 
SNS-301 on a staged schedule 
starting every three weeks for 
Patients will receive SNS-301 on a 
staged schedule starting every three 
weeks for four doses, every six 
SNS-301 dosing 
schedule  
updated to 
administer same 
SNS-301 


 
 
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four doses, every six weeks for 6 
doses and thereafter every twelve 
weeks.   
SNS-301 Dosing Schedule when 
pembrolizumab dosing at 6 week 
intervals:  Patients will receive 
SNS-301 on Day 0, Week 3, 
Week 6, Week 12 then every six 
weeks for 6 doses and thereafter 
every twelve weeks. 
weeks for 6 doses and thereafter 
every twelve weeks.   
When pembrolizumab and SNS-301 
are dosed on the same day,  SNS-301 
will be dosed approximately 1 hour 
after IV infusion of pembrolizumab 
for the first dose. Subsequent doses 
of SNS-301 and pembrolizumab can 
be dosed in any order.   
regimen 
regardless of 
pembrolizumab 
dosing regimen. 
9.2.1, 9.2.13 
Demographics 
and Medical 
History,  
PD-L1 Testing 
PD-L1 status will also be 
collected, if available. 
 
New 
Deleted 
 
Patients who are CPI naïve must be 
PD-L1 positive prior to entry onto the 
study. 
PD-L1 status 
will be collected 
for all patients 
9.2.14.1.1.4, 
9.2.14.1.2..1, 
9.2.14.1.2.2, 
9.2.14.1.2.2.1 
Other tumor and 
immune 
biomarkers,  
Immunophenoty
ping, T-cells, T-
cell profiling 
miRNA profiling of pre and post-
treatment serum and/or plasma 
samples may also be performed 
to predict treatment efficacy. 
Immunophenotyping 
will 
be 
performed by flow cytometry to 
monitor the levels of all immune 
cells including B-cells, CD4+ T-
cells, CD8+ T-cells, NK cells, 
monocytes, 
neutrophils, 
eosinophils and myeloid derived 
suppressor cells (MDSCs). In 
patients 
mounting 
an 
active 
immune response it is expected for 
Deleted 
Analyses will 
not be done on 
blood samples. 


 
 
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the percentages of certain cell 
types to increase. 
T-cells form the cellular arm of 
the immune response. Vaccination 
with SNS-301 is expected to result 
in maturation and activation of 
ASPH specific T-cells. 
The cellular immune response can 
generally be characterized as 
having to primary arms, CD4+ 
helper T-cell responses and CD8+ 
cytotoxic T-cell responses. In 
preclinical studies as well as the 
phase I clinical trial of SNS-301, 
activation of both T-cell subsets 
was noted. Furthermore, immune 
responses are often hampered by 
the presence of regulatory T-cells 
which may downregulate T-cell 
responses. Multi-parameter flow 
cytometry 
will 
be 
used 
to 
characterize the various subsets of 
T-cells in peripheral blood during 
the entire course of the study. 
Flow cytometric assays will also 
be utilized to assess the presence 
of cells that are known to play a 
role in immune suppression and 
may include an examination of the 
influence of these cells on the 
induction or expansion of an 
immune 
response 
after 
immunotherapy. 
Markers 
that 
may be used for this purpose 
include 
CD3, 
CD16, 
CD19, 


 
 
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CD20, CD56, CD11b, CD14, 
CD15, CD33 and HLA-DR. These 
markers may change relative to 
new data becoming available that 
is informative for this assessment. 
9.3.10 
Adverse Events 
of Special 
Interest 
Administration site reaction will 
be considered an AESI. 
Systemic administration site 
reactions will be considered an 
AESI. 
 
Clarified to 
address systemic 
reactions versus 
mild local 
reactions. 
10.1 
Statistical 
Hypotheses 
New 
Cohort B 
Thirty (30) patients will be enrolled 
in a two-stage design, with 15 
patients in the first stage and 15 
patients in the second stage to assess 
the null hypothesis that the objective 
response rate per iRECIST is 13.3%, 
versus the alternative hypothesis that 
the ORR is 29%, as described in 
Section 10.2. 
Updated to 
include statistics 
for the CPI naïve 
patient 
population. 
10.2 
Sample Size 
Determination 
Among all 30 patients, for 
adverse events that occur at an 
incidence of 9.5% the probability 
of observing at least one event is 
approximately 95%. 
Among all 60 patients, for adverse 
events that occur at an incidence of 
5% the probability of observing at 
least one event is approximately 
95%. 
The sample size for each cohort and 
stage is based on Simon’s two-stage 
design for tests of one proportion. 
Updated to 
include statistics 
for the CPI naïve 
patient 
population. 


 
 
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Cohort A 
At the second stage analysis, if at least 
4 responses are observed out of 30 
total patients, the null hypothesis will 
be rejected and further research 
considered warranted.  The overall 
power for objective response rate at 
12 weeks is 80%.  The overall type I 
error, the chance of incorrectly 
rejecting the null hypothesis is 6% 
(targeted alpha of 0.10).  The 
probability of stopping at the first 
stage under the null hypothesis is 
46%.  The operating characteristics of 
this design are calculated using the 
exact binomial distribution. 
 
Cohort B 
To evaluate the primary endpoint of 
objective response rate per iRECIST 
at 12 weeks with a null hypothesis of 
an objective response rate (ORR) of 
13.3% and an alternative hypothesis 
of an ORR of 29%, 30 patients in a 
two-stage design will be enrolled, 
with 15 patients in the first stage and 
15 patients in the second stage.  At the 
first stage analysis if at least 2 
responses are observed out of 15 
patients, the study may continue 
through the second stage.  At the 


 
 
SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 104 of 132 
 
second stage analysis, if at least 7 
responses are observed out of 30 total 
patients, the null hypothesis will be 
rejected 
and 
further 
research 
considered warranted.  The overall 
power for objective response rate at 
12 weeks is 80.1%.  The overall type 
I error, the chance of incorrectly 
rejecting the null hypothesis is 9.2% 
(targeted alpha of 0.10).  The 
probability of stopping at the first 
stage under the null hypothesis is 
38.8%.  The operating characteristics 
of this design are calculated using the 
exact binomial distribution. 
10.4.1 
General 
Methods 
New 
All summarizations will be presented 
separately for each cohort, and over 
all subjects combined. 
Updated to 
include statistics 
for the CPI naïve 
patient 
population. 
10.4.2 
Efficacy 
Analyses 
ORR is defined as the proportion 
of patients with a confirmed best 
response of iCR or iPR by 
iRECIST. Objective response rate 
will be estimated, and 95% CI 
based on the exact binomial 
distribution will be presented, 
including number and percent of 
patients in each overall response 
category. 
ORR is defined as the proportion of 
patients with a confirmed best 
response of iCR or iPR by iRECIST. 
Objective response rate will be 
estimated, and 90% CI based on the 
exact binomial distribution will be 
presented by cohort and overall, 
including number and percent of 
patients in each overall response 
category. 
Clarified the 
confidence 
interval. 


 
 
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12  
Reference List 
New 
8. 
Burtness, B., Harrington, 
K., Greil, R., Soulières, D., et al.  
“Pembrolizumab alone or with 
chemotherapy versus cetuximab with 
chemotherapy for recurrent or 
metastatic squamous cell carcinoma 
of the head and neck (KEYNOTE-
048): a randomised, open-label, 
phase 3 study.”  Lancet.  2019 
October 31; 394: 1915–28. 
Added reference 
for Keynote-048.  
Appendix A 
Pre-existing 
Autoimmune 
Disease 
 
Deleted 
Simplified 
exclusion 
criteria for 
previous 
autoimmune 
diseases. 
Multiple 
Multiple 
NA 
NA 
Updated typos, 
provided 
additional 
clarification, 
abbreviations  


 
 
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Changes to Amended Protocol Version 3.0 Dated July 24, 2020 includes Administrative Letters (October 9, 2019 & April 3, 2020 
{University of California San Francisco only}) 
Section #  
Section Title 
Old Text 
New Text 
Rationale for Change 
Multiple 
Title, Inclusion 
Criteria,  
Rationale for the 
Trial and 
Selected Subject 
Population, 
Study 
Population, 
Screen Failures 
An Open-Label, Multi-
Center Trial of SNS-301 
Added to Pembrolizumab 
in Patients with ASPH+ 
Locally Advanced 
Unresectable or 
Metastatic/Recurrent 
Squamous Cell Carcinoma 
of the Head and Neck 
An Open-Label, Multi-
Center Trial of SNS-301 
Added to Pembrolizumab 
in Patients with Locally 
Advanced Unresectable or 
Metastatic/Recurrent 
Squamous Cell Carcinoma 
of the Head and Neck 
Given that 26 of 26 
obtained tumor samples 
for pre-screening were 
positive for ASPH per 
IHC,  the requirement for 
ASPH + has been dropped.  
ASPH will still be 
analyzed, but patients can 
be enrolled prior results 
received.  
 
Sponsors 
Protocol 
Signature Page 
Ildiko Csiki 
Marie-Louise Fjaellskog 
Personnel change 
Multiple 
Synopsis, 
Pembrolizumab 
Dosing 
Pembrolizumab 200 mg 
every 3 weeks 
Pembrolizumab 200 mg 
every 3 weeks or 400 mg 
every 6 weeks 
To allow patients more 
flexibility in dosing as per 
Merck’s expanded 
pembrolizumab usage 
(refer to  USPI).  
Multiple 
Trial Population, 
Inclusion 
Criteria, 
Rationale, 
Overall Design 
The trial population 
consists of patients with 
ASPH+ locally advanced 
unresectable or 
metastatic/recurrent 
SCCHN who are currently 
receiving pembrolizumab 
or nivolumab  
The trial population 
consists of patients with 
locally advanced 
unresectable or 
metastatic/recurrent 
SCCHN who are currently 
receiving a checkpoint 
inhibitor therapy 
To expand to all previous 
PD-1/PDL-1inhibitors 


 
 
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Multiple 
Synopsis, 
Rationale for 
Dose Selection/ 
Regimen, SNS-
301 Dosing 
SNS-301 
will 
be 
administered intradermally 
using the 3M micro-needle 
device every 3 weeks (± 3 
days) for 4 doses then 
every 6 weeks (±3 days) for 
6 
additional 
doses, 
thereafter every 12 weeks 
(±3 days) until confirmed 
disease 
progression, 
unacceptable 
toxicity, 
deemed intolerable by the 
investigator or up to 24 
months in patients without 
disease progression. 
 
SNS-301 will be 
administered intradermally 
using the 3M micro-needle 
device.  The dosing 
schedule will be as 
follows: 
a. When pembrolizumab is 
given every three weeks:  
Day 0, Week 3, Week 6, 
Week 9 then every  6 
weeks (±3 days) for 6 
additional doses, thereafter 
every 12 weeks (±3 days) 
until confirmed disease 
progression, unacceptable 
toxicity, deemed 
intolerable by the 
investigator or up to 24 
months in patients without 
disease progression. 
b. When pembrolizumab is 
given every six weeks:   
Day 0, Week 3, Week 6 
and Week 12,  then every 
6 weeks (±3 days) for 6 
additional doses, thereafter 
every 12 weeks (±3 days) 
until confirmed disease 
progression, unacceptable 
toxicity, deemed 
intolerable by the 
SNS-301 dosing updated 
to account for either the 
every 3 or 6 week 
pembrolizumab dosing 
schedule 


 
 
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investigator or up to 24 
months in patients without 
disease progression. 
Synopsis
, 5.2, 
9.3.9 
Stopping Rules, 
Overall Design, 
Stopping Rules 
The trial will be stopped if 
any adverse experience of 
any related death, grade 4 
autoimmune toxicity or 
any grade 4 toxicity that is 
furthermore considered 
possibly, probably or 
definitely related to study 
drug should occur.  Any 
related death, grade 4 
autoimmune toxicity and 
any grade 4 toxicity that is 
furthermore considered to 
be possibly, probably or 
definitely related to study 
drug will be submitted will 
be submitted to regulatory 
agencies within the 
expedited safety reporting 
criteria. 
The trial will be stopped if 
any adverse experience of 
any related death, grade 4 
autoimmune toxicity or 
any grade 4 toxicity that is 
considered to have a 
causal relationship to study 
drug.  Any related death, 
grade 4 autoimmune 
toxicity and any grade 4 
toxicity that is considered 
to have a causal 
relationship to study drug 
will be submitted to 
regulatory agencies within 
the expedited safety 
reporting criteria. 
Clarification 
Synopsis 
Trial Schedule of 
Events 
 
1. Deleted:   Urine 
immunology sample 
2. Added:  PDL-1 testing 
3. Added: The Sponsor 
may request digitized 
1. Sample determined to 
be unnecessary 
2.PDL-1 added to 
understand patient 
characteristics and 
interpret objective 


 
 
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scans from patients during 
the study. 
4. If the patient is unable 
to have samples obtained 
at the protocol specified 
visit (i.e., COVID19 
related) then an 
unscheduled sample may 
be drawn 
5. Added:  Pembrolizumab 
Schedule – Every 6 weeks 
responses to study 
treatment 
3. In order to assess tumor 
responses imaging scans 
may be requested 
4.To allow flexibility for 
missed visit due to 
COVID19 or other reasons 
3.1.2 
Pre-Clinical, 
Clinical Trials 
and Other 
Ongoing Trials 
 
1.Deleted:  Pre-Clinical 
section 
 
2.Added: Data for this 
study 
1.Refer to Investigators 
Brochure for updated 
information 
2. Emerging clinical data 
added. 
3.2.1.1 
Unmet Medical 
Need for Patients 
with SCCHN 
 
Over the last several years 
advancements regarding 
the therapeutic role of ICIs 
led to the approval of 
pembrolizumab and 
nivolumab for SCCHN; 
however, response rates 
are fairly low in the first 
and second line metastatic 
SCCHN population.  
There are multiple other 
ICIs that are in clinical 
Rationale for including all 
PD-1/PD-L1 inhibitors 


 
 
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trials (e.g., atezolizumab, 
durvalumab, avelumab, 
etc.) and these agents as 
combination therapy or 
monotherapy demonstrate 
limited responses as well, 
thus underscoring the 
importance of allowing 
these unresponsive 
checkpoint inhibitor 
therapy patients to 
participate in trials such as 
the study sponsored by 
Sensei Biotherapeutics.  In 
order to provide an option 
to the majority of SCCHN 
patients who do not 
respond to  checkpoint 
inhibitors, Sensei will 
allow inclusion of patients 
who received widely 
investigated  ICIs  (anti-
PD1, anti-PD-L1 agents) 
as part of clinical trials  as 
long as patients meet all of 
the outlined eligibility 
criteria.  All patients 
enrolled will be switched 
to pembrolizumab 
treatment regardless of 
which ICI therapy the 
patient was receiving 
previously. 


 
 
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3.2.1.2 
 ASPH 
Expression 
Testing in 
SCCHN 
 
Added:   As of 16 July 
2020, 26 additional 
archived tissue samples 
have been analyzed from 
this study.  All 26 samples 
were found to be ASPH 
positive as assessed by a 
CLIA validated IHC assay 
from Fred Hutchinson 
Cancer Center.   
Provide update on the 
ASPH testing for this 
study 
7.5 
Dose 
Modification 
and/or 
Interruption 
 
Added: If a patient is 
unable to receive study 
treatment (e.g., due to 
COVID19) the dosing 
interval can be extended 
up to 42 days after 
consultation with the 
Sponsor and the rationale 
to be documented. 
To allow flexibility for 
missed visit due to 
COVID19 or other reasons 
9.1.1 
Tumor 
Assessment 
 
Added:  The Sponsor may 
request digitized scans 
from patients to confirm 
response. 
In order to assess tumor 
responses imaging scans 
may be requested 
9.2.13 
PD-L1 Testing 
 
Added:  If the patient’s 
PD-L1 status is unknown, 
they should be tested, 
preferably by 22C3 IHC.  
The results do not need to 
PDL-1 added to 
understand patient 
characteristics and 
interpret objective 
responses 


 
 
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be known before the 
patient receives study 
treatment.  If possible, for 
patients that started study 
treatment prior to 
Amendment 2/Version 3.0, 
retrospective testing 
should be done. 
10.2.13.1 
Urine 
 
Deleted 
Sample determined to be 
unnecessary 
10.2.13.2
.2.2, 
10.2.13.2
.2.2.1, 
10.2.13.2
.2.2.2 
B-cells, B-cell 
profiling, ASPH 
specific B cells 
 
Deleted 
Assays determined to be 
unnecessary 
9.2.14.22 
ASPH Immuno-
histochemistry 
(IHC) assay 
ASPH testing will be done 
by immunohistochemistry 
on either fresh or archival 
tumor tissue.  Additional 
preparation of the slides 
will be performed at 
Sensei Biotherapeutics or 
designee.  Tissue will be 
deparaffinized and 
rehydrated, quenched with 
hydrogen peroxide and 
blocked with horse serum. 
Slides are stained 
ASPH testing will be done 
by immunohistochemistry 
on either fresh or archival 
tumor tissue.    Samples 
will be analyzed at Fred 
Hutchinson Cancer Center 
via a CLIA validated assay 
Deleted detailed 
instruction on analysis in 
the protocol.  


 
 
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overnight at 4 °C with an 
ASPH-specific murine 
monoclonal or a non-
relevant mouse IgG as a 
negative control. Detection 
employs a secondary anti-
mouse antibody and a 
chromogenic substrate. 
Slides are counterstained 
with hematoxylin and 
cover slipped. 
Semiquantitative analysis 
of staining intensity and 
distribution of ASPH 
levels is evaluated 
according to the following 
scale (0, negative; 1+, 
moderate; 2+, strong; and 
3+, very strong 
immunoreactivity). 
9.3.1 
Definition of 
Adverse Event 
(AE) 
Adverse event is defined as 
any 
untoward 
medical 
occurrence associated with 
the use of a drug in 
humans, whether or not 
considered drug related and 
occurs after the patient is 
given the first dose of study 
drug.  Any AE that occurs 
prior to the first dose is part 
of the medical history.   
Adverse event is defined as 
any 
untoward 
medical 
occurrence associated with 
the use of a drug in 
humans, whether or not 
considered drug related.  
Any AE that occurs prior to 
the first dose is part of the 
medical history.  AEs will 
be collected from the time 
of informed consent until 
30 days after the last dose 
Clarification on when to 
initiate collection of 
adverse events 


 
 
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Changes to Amended Protocol Version 2.0 Dated June 27, 2019 
Section #  
Section Title 
Old Text 
New Text 
Rationale for Change 
1 
Summary of Changes 
New 
Summary of changes from final 
protocol to amendment 1 
To assist sites in identifying 
changes to the protocol. 
2.1, 5.1.1, 
6.1 
-Protocol Title  
-Signature Page 
-Clinical Protocol Synopsis 
-Primary Objectives 
-Research Hypotheses 
An Open-Label, Multi-Center 
Trial of SNS-301 Added to 
Pembrolizumab in Previously 
Treated Patients with ASPH+ 
Locally Advanced Unresectable 
or Metastatic/Recurrent 
Squamous Cell Carcinoma of the 
Head and Neck 
An Open-Label, Multi-Center 
Trial of SNS-301 Added to 
Pembrolizumab in Patients with 
ASPH+ Locally Advanced 
Unresectable or 
Metastatic/Recurrent Squamous 
Cell Carcinoma of the Head and 
Neck 
Removed previously treated 
patient population to allow for 
patients receiving pembrolizumab 
as first line treatment to be 
consistent with the new standard 
of care.   
 
of study treatment or until 
initiation of another anti-
cancer therapy, whichever 
occurs first. 
9.3.2.2 
Relationship to 
Study 
Medication 
Listed categories: of Not 
Related Unlikely Related, 
Possibly Related, Probably 
Related and Related 
Listed categories: 
Not Related and Related 
Streamlined the choices 
for relationship to study 
medication 
10.4.2 
Efficacy 
Analysis 
DCR: proportion of 
patients with SD or better 
(PR and CR 
DCR: proportion of patients 
with SD or better (PR and 
CR).  SD for at least six 
months 
Include timeframe for 
stable disease 
Multiple 
Multiple 
NA 
NA 
Updated typos, provided 
additional clarification  


 
 
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2.1, 6.2 
-Clinical Protocol Synopsis 
-Overall Design 
The trial population consists of 
previously treated patients with 
ASPH+ locally advanced 
unresectable or 
metastatic/recurrent SCCHN 
who are currently receiving 
pembrolizumab and have not had 
evidence of disease progression 
within the first 12 weeks of 
pembrolizumab therapy. Patients 
must have received platinum-
based therapy with evidence of 
disease progression or had 
intolerable toxicity to platinum-
based chemotherapy prior to 
initiation of pembrolizumab. 
The trial population consists of 
patients with ASPH+ locally 
advanced unresectable or 
metastatic/recurrent SCCHN 
who are currently receiving 
pembrolizumab or nivolumab 
therapy.    Patients must have a 
best response of stable disease 
(SD) or first evidence of 
progressive disease (PD) after a 
minimum of 12 weeks of 
pembrolizumab or nivolumab 
therapy. Patients may or may not 
have received platinum-based 
therapy with evidence of disease 
progression prior to initiation of 
pembrolizumab or nivolumab. 
Patients receiving first-line 
pembrolizumab monotherapy 
prior to this study must be PD-
L1 positive. Patients receiving 
nivolumab will be switched over 
to pembrolizumab at the time of 
entering this study.  
Added previous treatment to also 
include nivolumab to be 
consistent with treatment 
paradigms within participating 
institutions.   
 
Dropped the requirement for 
previous platinum-based therapy 
to allow for first line 
pembrolizumab treatment. 
2.1, Table 
1 
-Clinical Protocol Synopsis 
-Time Schedule of Events 
Ideally, a pre-treatment tissue 
sample obtained after initiation 
of ongoing pembrolizumab 
therapy and  first dose of SNS-
301 and pembrolizumab on this 
current clinical trial will be 
collected.   
Ideally, a pre-treatment tissue 
sample obtained after initiation 
of ongoing pembrolizumab or 
nivolumab therapy and  first 
dose of SNS-301 and 
pembrolizumab on this current 
clinical trial will be collected.   
Expanded previous PD-1 therapy 
to include both pembrolizumab 
and nivolumab to allow for 
standard of care paradigms at 
clinical sites. 
2.1, Table 
1 
-Clinical Protocol Synopsis 
-Time Schedule of Events 
An on-treatment biopsy is 
required when medically 
feasible, after the second or third  
An on-treatment biopsy is 
required when medically 
feasible, after the third  dose of 
Clarified the biopsy timeframe. 


 
 
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dose of the study treatment, 
treatment around week 6. 
the study treatment, treatment 
week 6. 
2.1 
Clinical Protocol Synopsis 
New follow up procedure 
A pregnancy test is also required 
for patients of WOCBP every 3 
months. 
To track pregnancy during the 
survival follow up period. 
2.1, 6.2 
-Clinical Protocol Synopsis 
-Overall Design 
If a second of these first six 
patients experiences a DLT 
within the first six weeks, 
enrollment will stop, and the 
Sponsor’s medical monitor, in 
addition to the PI and 
Investigator(s) at the patients’ 
site(s) will discuss the case, and 
a decision will be made whether 
to modify the trial such as 
continue dosing respective 
patient at lower dose of SNS-
301, or to cease further 
enrollment.  
If a second of these first six 
patients experiences a DLT 
within the first six weeks, 
enrollment will stop, and the 
Sponsor’s medical monitor, in 
addition to the PI and 
Investigator(s) at the patients’ 
site(s) will discuss the case, and 
a decision will be made whether 
to modify the trial  or to cease 
further enrollment. 
Delete allowance of lowering 
SNS-301 dose since dose 
modifications are not allowed. 
2.1, 6.2, 
10.3.9 
-Clinical Protocol Synopsis 
-Overall Design 
-Stopping Rules 
 
 
New 
Stopping Rules 
 
The trial will be stopped if any 
adverse experience of any 
related death, grade 4 
autoimmune toxicity or any 
grade 4 toxicity that is 
furthermore considered possibly, 
probably or definitely related to 
study drug should occur.  Any 
related death, grade 4 
autoimmune toxicity and any 
grade 4 toxicity that is 
furthermore considered to be 
possibly, probably or definitely 
To implement stopping rules to 
protect patients. 


 
 
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related to study drug will be 
submitted will be submitted to 
regulatory agencies within the 
expedited safety reporting 
criteria. 
 
2.1, 7.0 
-Clinical Protocol Synopsis 
-Inclusion Criteria 
3. Have histologically or 
cytologically documented locally 
advanced unresectable or 
metastatic/recurrent ASPH+ 
SCCHN and currently receiving 
pembrolizumab. Patients must 
have received platinum-based 
therapy with evidence of disease 
progression or had intolerable 
toxicity to platinum-based 
chemotherapy prior to initiation 
of pembrolizumab.  
a. Eligible patients 
currently receiving 
pembrolizumab must be 
considered by 
Investigator to have the 
potential to derive 
clinical benefit from 
continuing treatment 
with pembrolizumab. 
b. Based on RECIST 
version 1.1 criteria on 
current pembrolizumab 
treatment (prior to 
initiation of this study), 
3.  Have histologically or 
cytologically documented locally 
advanced unresectable or 
metastatic/recurrent ASPH+ 
SCCHN and currently receiving 
pembrolizumab or nivolumab.   
a. Eligible patients currently 
receiving pembrolizumab or 
nivolumab must be considered 
by Investigator to have the 
potential to derive clinical 
benefit from continued treatment 
with pembrolizumab. 
b.  Based on RECIST 
1.1/iRECIST criteria on current 
pembrolizumab or nivolumab 
treatment (prior to initiation of 
this study), patients must have a 
best response of  stable disease 
(SD) or first evidence of 
progressive disease (PD) after a 
minimum of 12 weeks of 
pembrolizumab or nivolumab 
therapy. 
c.  Patients receiving first-line 
pembrolizumab monotherapy 
prior to this study must be PD-
L1 positive. 
Added previous treatment to also 
include nivolumab to be 
consistent with treatment 
paradigms within participating 
institutions.   
 
Dropped the requirement for 
previous platinum-based therapy 
to allow for first line 
pembrolizumab treatment. 


 
 
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patients must have a best 
response of confirmed 
stable disease (SD) or 
progressive disease (PD) 
after a minimum of 12 
weeks of 
pembrolizumab therapy.  
d.  Patients on nivolumab 
therapy must be willing to 
switch over to pembrolizumab 
therapy. 
2.1, 6.2, 
7.0 
 
-Clinical Protocol Synopsis 
-Inclusion Criteria 
-Overall Design 
 
8.  Be willing to provide a pre-
treatment tissue sample obtained 
after initiation of ongoing 
pembrolizumab therapy and first 
dose of SNS-301 and 
pembrolizumab on this current 
clinical trial. Subjects are 
requested to provide archival 
tissue from a prior biopsy or 
surgery that is treatment –naïve 
including prior 1) chemotherapy, 
radiation and 2) anti-PD(L)-1 
treatment-naïve, pending 
availability.   An on-treatment 
biopsy is required when 
medically feasible, after the 
second  dose of the study 
treatment. For patients who 
progress as determined per 
RECIST1.1/iRECIST criteria, an 
optional biopsy will be obtained 
at the time of disease 
progression. 
8.  Be willing to provide a pre-
treatment tissue sample obtained 
after initiation of ongoing 
pembrolizumab or nivolumab 
therapy and first dose of SNS-
301 and pembrolizumab on this 
current clinical trial unless 
clinically contra-indicated per 
treating physician. Patients 
unable to provide pre-treatment 
biopsy while on CPI will be 
evaluated on  a case-by-case 
basis for enrollment pending 
Sponsor consultation. Patients 
are requested to also provide 
archival tissue from a prior 
biopsy or surgery that is 
treatment –naïve including prior 
1) chemotherapy, radiation 
and/or 2) anti-PD(L)-1 
treatment-naïve, pending 
availability.   Tissue provided 
pre-treatment (fresh or archival) 
will be used to determine ASPH 
expression and eligibility for the 
trial. Additionally, an on-
Added previous nivolumab 
treatment. 
Clarified collection of fresh 
versus archived biopsy for 
enrollment purposes and timing 
of on treatment biopsy. 


 
 
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treatment biopsy is required 
unless  clinically 
contraindicated, after the third  
dose of study treatment at week 
6. 
2.1 
Clinical Protocol Synopsis 
 
Albumin ≥ 3.0 g/dL 
Deleted 
Deleted for consistency.  
Albumin is not required for 
eligibility. 
2.1, 7.0 
-Clinical Protocol Synopsis 
-Exclusion Criteria 
21. Treatment with systemic 
immunomodulating agents 
(including but not limited to 
IFNs, IL-2, ipilimumab) within 6 
weeks or five half-lives of the 
drug, whichever is shorter, prior 
to first dose, excluding current 
pembrolizumab therapy.  
 
21. Treatment with systemic 
immunomodulating agents 
(including but not limited to 
IFNs, IL-2, ipilimumab) within 6 
weeks or five half-lives of the 
drug, whichever is shorter, prior 
to first dose, excluding current 
pembrolizumab or nivolumab 
therapy.  
 
Added previous nivolumab 
treatment. 
Table 1 
Trial Schedule of Events 
New 
Anticoagulant specific drug 
and/or anticoagulant factor Xa 
levels obtained at Screening, 
Day 0, Week 3, Week 6, Week 
9, Q6W until Week 45 , 
thereafter Q12W. 
 
For patients on anticoagulants 
only 
To monitor patients on 
anticoagulation therapy.  
Table 1 
Trial Schedule of Events 
New 
Pregnancy test at 
Discontinuation Visit and 
Follow Up 
To track pregnancy at 
discontinuation and during the 
survival follow up period. 
Table 1 
Trial Schedule of Events 
TSH, T3 and T4 
TSH, T3 and  Free T4 
For consistency for on treatment 
thyroid testing. 


 
 
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Table 1 
Trial Schedule of Events 
 
Patients who discontinue early 
from study treatment for 
progression will be asked to 
return to the clinic within 30 
days after the last dose for a 
treatment discontinuation visit. 
Patients who discontinue early 
from study treatment (i.e., 
progression, adverse event, etc.), 
will be asked to return to the 
clinic within 30 days after the 
last dose for a treatment 
discontinuation visit. 
Clarified the treatment 
discontinuation visit for all 
patients. 
Table 1, 
10.2.1 
-Trial Schedule of Events 
-Demographics & Medical 
History 
Demographic information 
includes sex, age, and self-
reported race/ethnicity. HPV, 
EBV, reproductive status and 
smoking history should also be 
captured. 
Demographic information 
includes sex, age, and self-
reported race/ethnicity. HPV, 
EBV, reproductive status and 
smoking/alcohol history should 
also be captured.  PD-L1 status 
will also be collected, if 
available. 
Added alcohol history and PD-L1 
status. 
Table 1 
Trial Schedule of Events 
 
New footnote “i” 
Specific anticoagulant drug 
and/or anticoagulant factor Xa 
levels will be obtained only on 
patients receiving anticoagulant 
therapy.  Drug levels will also be 
obtained at any time of clinical 
bleeding.  Traditional testing 
methods can be used for 
warfarin, heparin (e.g., PT/INR, 
aPTT, TT).  Novel oral 
anticoagulants may require 
anticoagulant factor Xa levels or 
anticoagulant drug specific level 
testing.  See sections  
Concomitant Medications  & 
Guidance for Investigators for 
Patients on Anti-coagulants for 
additional information. 
To monitor patients on 
anticoagulation therapy. 


 
 
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Table 1, 
10.2.4 
-Trial Schedule of Events 
-Vital Signs 
If clinically indicated, vital signs 
should be recorded during the 
infusion at 15, 30, 45, and 60 
minutes (± 5 minutes for all 
timepoints) during the infusion, 
and 30 (± 10) minutes after the 
infusion. For subsequent 
infusions, vital signs will be 
collected within 60 minutes 
before the infusion and at 30 (± 
5) minutes after the infusion. 
If clinically indicated, vital signs 
should be recorded at 15, 30, 45, 
and 60 minutes (± 5 minutes for 
all timepoints) after the start of 
the infusion, and 30 (± 10) 
minutes after the infusion. For 
subsequent infusions, vital signs 
will be collected within 60 
minutes before the infusion and 
at 30 (± 5) minutes after the 
infusion.  
Clarified 45 & 60 minute vitals 
are after the start of the infusion. 
Table 1 
Trial Schedule of Events 
 
Eligibility based on ASPH 
expression will be provided back 
to the sites within 5 calendar 
days. 
Eligibility based on ASPH 
expression will be provided back 
to the sites within 5-8 business 
days. 
Timeline extended to account for 
ASPH testing process. 
2.2 
Schema 
-Stage 1 review 3-6 patients 
-Biopsy at PD 
Biopsy at PD (arrow) 
-Removed Stage 1 review box 
-Removed arrow for Biopsy at 
PD box for clarity. 
3 
Terms, Acronyms, 
Abbreviations 
New 
TT- Thrombin Time 
New definition. 
4.2 
Rationale 
Sensei Biotherapeutics plans to 
develop SNS-301 in addition to 
pembrolizumab in a study 
targeting patients with refractory 
SCCHN,  a population  with 
high unmet medical need. 
Sensei Biotherapeutics plans to 
develop SNS-301 in addition to 
pembrolizumab in a study 
targeting patients with  SCCHN 
that is resistant  to CPI which is 
a population with high unmet 
medical need.   
Changed wording based on 
patient eligibility. 
4.2.1.1 
Unmet Medical Need for 
Patients with SCCHN 
New 
KEYNOTE-048 
(NCT02358031), a randomized, 
multicenter, three-arm, open 
label, active controlled trial 
conducted in 882 patients with 
metastatic HNSCC who had not 
previously received systemic 
To provide additional 
background. 


 
 
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therapy for metastatic disease or 
with recurrent disease who were 
considered incurable by local 
therapies was approved by the 
FDA in June 2019. 
Patients were randomized (1:1:1) 
to receive one of the following 
treatments: pembrolizumab as a 
single agent; pembrolizumab, 
carboplatin or cisplatin, and FU; 
or cetuximab, carboplatin or 
cisplatin, and FU. 
Randomization was stratified by 
tumor PD-L1 expression (Tumor 
Proportion Score [TPS] ≥50% or 
<50%), HPV status according to 
p16 IHC (positive or negative), 
and ECOG PS (0 vs 1). PD-L1 
expression (TPS and CPS) was 
determined using the PD-L1 IHC 
22C3 pharmDx kit.  Overall 
survival (OS), sequentially tested 
in the subgroup of patients with 
CPS ≥20 HNSCC, the subgroup 
of patients with CPS ≥1 HNSCC 
and the overall population, was 
the major efficacy measure. 
The trial demonstrated a 
statistically significant 
improvement in OS in the 
overall population for patients 
randomized to pembrolizumab 
plus chemotherapy compared 
with cetuximab plus 


 
 
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chemotherapy at a pre-specified 
interim analysis. The median OS 
was 13.0 months for the 
pembrolizumab plus 
chemotherapy arm and 10.7 
months for the cetuximab plus 
chemotherapy arm (HR 0.77; 
95% CI: 0.63, 0.93; p=0.0067). 
Results were similar in the CPS 
≥20 subgroup (HR 0.69; 95% 
CI: 0.51, 0.94) and CPS ≥1 
subgroup (HR 0.71; 95% CI: 
0.57, 0.88). 
The trial also demonstrated 
statistically significant 
improvements in OS for the 
subgroups of patients with PD 
L1 CPS ≥1 HNSCC and PD-L1 
CPS ≥20 HNSCC randomized to 
pembrolizumab as a single agent 
compared with cetuximab plus 
chemotherapy. In the CPS ≥1 
subgroup, the median OS was 
12.3 months for the 
pembrolizumab arm and 10.3 
months for the cetuximab plus 
chemotherapy arm (HR 0.78; 
95% CI: 0.64, 0.96; p=0.0171). 
For the CPS ≥20 subgroup, the 
median OS was 14.9 months for 
the pembrolizumab arm and 10.7 
months for the cetuximab plus 
chemotherapy arm (HR 0.61; 
95% CI: 0.45, 0.83; p=0.0015). 


 
 
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At the time of the interim 
analysis, there was no significant 
difference in OS between the 
pembrolizumab as a single agent 
arm and the cetuximab plus 
chemotherapy arm for the 
overall population. There were 
no significant differences in 
progression-free survival for 
either pembrolizumab-
containing arm compared to the 
cetuximab plus chemotherapy 
arm in any population. 
The most common adverse 
reactions reported in ≥20% of 
patients who received 
pembrolizumab as a single agent 
in KEYNOTE-048 were fatigue, 
constipation, and rash. The most 
common adverse reactions 
reported in ≥20% of patients 
who received pembrolizumab in 
combination with chemotherapy 
in KEYNOTE-048 were nausea, 
fatigue, constipation, vomiting, 
mucosal inflammation, diarrhea, 
decreased appetite, stomatitis, 
and cough. 
4.2.1.1 
Unmet Medical Need for 
Patients with SCCHN 
However, patients that do not 
respond to immune checkpoint 
inhibitors represent a high unmet 
medical need with a median OS 
of 6 months or less and there is a 
high unmet medical need to 
However, patients that do not 
respond to immune checkpoint 
inhibitors continue to represent a 
significant number of the 
SCCHN patients and thus remain 
a high unmet medical need 
Updated based on change in 
patient population.  


 
 
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develop novel clinically 
meaningful therapies for these 
patients.  
 
Sensei Bio plans to evaluate 
SNS-301 in patients with 
recurrent/metastatic SCCHN 
who have failed to respond to 
CPI therapy in the post-platinum 
setting. 
population with a median OS of 
12 months or less.  Furthermore, 
for patients who have also 
previously received and 
progressed on platinum-based 
chemotherapy, the median OS is 
less than 6 months. The need to 
develop novel clinically 
meaningful therapies for these 
patients remains.  
 
Sensei Bio plans to evaluate 
SNS-301 in patients with 
SCCHN who have failed to 
respond to CPI therapy, but 
investigators feel that continued 
treatment with a CPI and another 
targeted agent may provide 
clinical benefit for these patients. 
4.3 
Benefit/Risk 
However, the median OS of 
SCCHN post-platinum 
progression and refractory to 
CPI is about 6 months. 
The median OS of patients even 
in the first line metastatic setting 
who do not respond to CPI is 
less than 12 months. However, 
this study may likely enroll who 
have also previously received 
and progressed on platinum-
based chemotherapy, in which 
population the median OS is less 
than 6 months. 
Included OS for first line 
metastatic setting. 
8.2.2 
Formulation, Appearance, 
Packaging & Labeling of 
SNS-301 & Pembrolizumab 
New 
-… “Caution - Investigational 
device. Limited by Federal (or 
United States) law to 
investigational use.” 
-Sponsor’s name and address 
Added additional labeling for 
hMTS device. 


 
 
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8.5 
Dose Modification and/or 
Interruption 
If the subject experiences the 
same toxicity requiring a dose-
delay at the subsequent cycle, 
the subject should be 
discontinued from study 
treatment.   
If the subject experiences the 
same grade or higher toxicity 
requiring a dose-delay at the 
subsequent cycle, the subject 
should be discontinued from 
study treatment.   
Should there be a clinically 
significant AE or SAE recorded 
relating to a patient receiving 
anticoagulants, such as clinically 
noted bleeding, administration of 
SNS-301 will be held until the 
AE/SAE returns to baseline.  
Should there be two individual 
events of SNS-301 interruption 
for the same patient, then SNS-
301 will be discontinued after 
consultation with the Medical 
Monitor and Study Sponsor. 
Provide guidance on dose 
interruptions. 
10.1.1 
Tumor Assessment 
New 
Beginning with screening, all 
imaging assessments will be 
evaluated using RECIST 1.1. 
On-study imaging assessments 
will be performed every 6 weeks 
(Q6W) calculated from the date 
of therapy initiation and 
independent of treatment delays. 
RECIST 1.1 will be used by the 
site for treatment decisions until 
the first radiologic evidence of 
progressive disease (PD). 
Following the first radiologic 
evidence of PD by RECIST 1.1, 
treatment decisions may be made 
Clarified on study assessments 
utilizing iRECIST. 


 
 
SNS-301-2-2 / Version 4.0                                                                           CONFIDENTIAL                                           Page 127 of 132 
 
by using immune iRECIST 
(Appendix B: Tumor 
Assessment Criteria) to 
accommodate tumor response 
patterns seen with checkpoint 
inhibitor therapy including 
pembrolizumab treatment (e.g., 
tumor flare). This was described 
by Nishino, et al. 2016 [12] and 
is used in immunotherapy 
clinical trials. For a clinically 
stable subject with first 
radiologic evidence of PD, it is 
at the discretion of the site 
investigator to continue treating 
the subject with SNS-301 and 
pembrolizumab until PD is 
confirmed at least 4 weeks after 
the date of the first tumor 
imaging suggesting PD per the 
site investigator. If radiologic 
PD is confirmed by the 
subsequent tumor imaging, the 
subject should be discontinued 
from treatment unless, in the 
opinion of the investigator, the 
subject is achieving a clinically 
meaningful benefit. In this case, 
an exception for continued 
treatment may be considered 
following consultation with the 
Sponsor. Additional treatment 
response evaluation by RECIST 
v 1.1 and iRECIST may be 


 
 
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performed at the Sponsor’s 
discretion. 
10.2.6 
Clinical Safety Laboratory 
Assessments 
New 
Other anticoagulant monitoring 
(if required) 
To monitor patients on 
anticoagulation therapy. 
10.2.13.3 
 
 
Tissue 
Moved and modified from 
section 10.2.13.3.2 
Archival and fresh tumor tissue 
samples should be representative 
tumor specimens in formalin-
fixed paraffin embedded (FFPE) 
blocks (preferred) or at least 15 
unstained slides, with an 
associated pathology report, 
should be submitted for intra-
tumoral immunology 
assessments.  Tissue slices of 4-5 
microns are mounted on 
positively charged glass slides. 
Slides should be unbaked and 
stored cold or frozen. 
 
Provide clearer instruction on 
biopsy under broader title of 
Tissue. 
 
10.2.13.3.2 
 
ASPH Immunohisto- 
chemistry (IHC) Assay 
New 
ASPH testing will be done by 
immunohistochemistry on either 
fresh or archival tumor tissue.  
Additional preparation of the 
slides will be performed at 
Sensei Biotherapeutics or 
designee.   
Provide clarification of ASPH 
testing. 
10.2.13.5 
Concomitant Medications 
New 
Patients who are receiving 
anticoagulants will have 
anticoagulant specific drug level 
and/or anticoagulant specific 
factor Xα levels obtained at 
baseline, at each administration 
of SNS-301, and at the end of 
study visit to ensure that these 
Provide guidance on treating 
patients receiving anticoagulation 
therapy.  


 
 
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levels remain within therapeutic 
range throughout the duration of 
the trial. In the event of 
clinically noted bleeding, these 
tests will be obtained at the time 
of bleeding as well.  
Investigators should use tests 
routinely used in clinical practice 
to monitor patients receiving 
Warfarin, Heparin and/or Low 
Molecular Weight Heparins, 
along with the monitoring 
schedule provided above.  
Should there be two individual 
events of SNS-301 interruption 
for the same patients, then SNS-
301 will be discontinued after 
consultation with the Medical 
Monitor and Study Sponsor.  
Clinical management and further 
workup of the coagulation 
pathway disturbance will be at 
the discretion of the investigator. 
10.3.11 
Guidance for Investigators 
for Patients on Anti-
coagulants 
New 
Based on the preclinical data and 
the role of ASPH in post-
translational modification of 
proteins involved in the clotting 
and anticoagulant pathways 
(Factors VII, IX, X , Protein C), 
there may a potential for 
abnormal coagulation with SNS-
301.  Should there be a clinically 
significant AE or SAE recorded, 
such as clinically noted bleeding, 
Provide guidance on treating 
patients receiving anticoagulation 
therapy. 


 
 
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administration of SNS-301 will 
be held until the AE/SAE returns 
to baseline. Should there be two 
individual events of SNS-301 
interruption for the same patient, 
then SNS-301 will be 
discontinued after consultation 
with the Medical Monitor and 
Sponsor. Clinical management 
and further workup of the 
coagulation pathway disturbance 
will be at the discretion of the 
treating physician. 
 
 
13 
References 
Guidance for Industry: 
Estimating the maximum safe 
starting dose in initial clinical 
trials for therapeutics in adult 
healthy volunteers. U.S. 
Department of Health and 
Human Services; Food and Drug 
Administration Center for Drug 
Evaluation and Research 
(CDER); July 2005, 
Pharmacology and Toxicology. 
Deleted 
Obsolete reference. 
13 
References 
Added 
12.  Nishino M.  “Immune-
related response evaluations 
during immune-checkpoint 
inhibitor therapy:  establishing a 
“common language” for the new 
arena of cancer treatment.”  
Journal for ImmunoTherapy of 
Cancer. 2016 4:30 
doi:10.1186/s40425-016-0134-0. 
New reference.  


 
 
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Multiple 
Multiple 
Subjects 
Patients 
Updated for consistency. 
Multiple 
Multiple 
NA 
NA 
Updated typos, provided 
additional clarification for 
Background section (4.2.1.1) 
which do not have an impact on 
study procedures, moved 
paragraph in Background section 
(4.2.1.1). 


 
 
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APPENDIX E: PRINCIPAL INVESTIGATOR SIGNATURE OF AGREEMENT 
PAGE 
 
INVESTIGATORS AGREEMENT 
This document is a confidential communication of Sensei Biotherapeutics, Inc. (Sensei).  The 
recipient agrees that no unpublished information contained herein will be published or 
disclosed without prior written permission of Sensei.  However, this document may be 
disclosed to appropriate Institutional Review Boards, ethics review committees, or authorized 
representatives of the Investigator or regulatory agencies under the condition that they are 
requested to respect the confidentiality of the document. 
 
The signature of the Principal Investigator below constitutes his/her agreement to comply with 
the contents of this Protocol. 
 
 
 
 
Principal Investigator’s Name 
 
 
 
 
 
 
 
 
Principal Investigator’s Institution 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 

SAP_001.pdf: 
 
 
Sensei Biotherapeutics 
 
Statistical Analysis Plan 
 
An Open-Label, Multi-Center Trial of SNS-301 Added to Pembrolizumab in Patients 
with Locally Advanced Unresectable or Metastatic/Recurrent Squamous Cell 
Carcinoma of the Head and Neck 
 
Protocol Number 
SNS301-2-2  V4.0 (November 6, 2020) 
 
SAP Version 
V1.0 (May 05, 2021) 
 
 
 
Prepared By: 
Advanced Clinical 
10 Parkway North, Suite 350 
Deerfield, IL 60015 
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TABLE OF CONTENTS 
Content 
 
 
 
 
 
 
 
 
 
      Page 
1.0 
ACRONYMS.......................................................................................... 4 
1. 
PURPOSE ............................................................................................. 7 
2. 
OVERALL STUDY DESIGN AND OBJECTIVE ......................................... 7 
 
Trial Objectives .................................................................................................... 7 
 
Trial Design and Trial Procedures ....................................................................... 7 
 
Treatments and Assignment to Treatments........................................................ 10 
 
Determination of Sample Size ........................................................................... 11 
3. 
GENERAL ANALYSIS CONVENTION ................................................... 12 
 
General Methods ................................................................................................ 12 
 
Trial Periods ....................................................................................................... 12 
 
Visit Windows ................................................................................................... 13 
4. 
ANALYSIS POPULATIONS.................................................................. 14 
5. 
SUBJECT DISPOSITION ..................................................................... 14 
6. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ......................... 16 
 
Demographics Characteristics ........................................................................... 16 
 
Smoking History and Alcohol Use .................................................................... 16 
 
Medical History ................................................................................................. 17 
 
Cancer History ................................................................................................... 17 
 
Prior Cancer Therapy ......................................................................................... 17 
 
Prior Radiotherapy ............................................................................................. 18 
 
Target, Non-target and New Lessions ............................................................... 18 
 
Prior and Concomitant Medications .................................................................. 19 
 
Serology Testing Results (HIV, Hepatitis and PD-L1 Status) ........................... 20 
 
Virology Testing Results (HPV and EPV) ........................................................ 20 
7. 
EFFICACY ANALYSIS ......................................................................... 20 
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Primary Efficacy Analysis ................................................................................. 20 
 
Secondary Efficacy Analysis ............................................................................. 22 
 
Exploratory Efficacy Analysis ........................................................................... 22 
8. 
SAFETY ANALYSIS ............................................................................. 23 
 
Trial drug Exposure and Compliance ................................................................ 23 
 
Dose-Limiting Toxicities ................................................................................... 24 
 
Adverse Events .................................................................................................. 24 
 
Clinical Safety Laboratory Assessments ........................................................... 27 
 
Urinalysis ........................................................................................................... 29 
 
Thyroid Function ............................................................................................... 29 
 
Coagulation and Anticoagulation Levels ........................................................... 29 
 
Electrocardiograms ............................................................................................ 29 
 
Eastern Cooperative Oncology Performance Status .......................................... 29 
 
Vital Signs and Weight ...................................................................................... 30 
 
Physical Examinations ....................................................................................... 30 
 
Pregnancy Testing .............................................................................................. 30 
 
Immunogenicity Assessments ............................................................................ 30 
 
ASPH Immunohistochemistry (IHC) Assay ...................................................... 30 
9. 
STATISTICAL/ANALYTICAL ISSUES .................................................. 31 
 
Handling of Dropouts or Missing Data .............................................................. 31 
 
Pooling of Centers in Multi-Center Trials ......................................................... 32 
 
Multiple Comparisons/Multiplicity ................................................................... 32 
 
Examination of Subgroups ................................................................................. 32 
 
Interim Analysis and Data Monitoring .............................................................. 32 
10. 
QUALITY CONTROL ........................................................................... 32 
11. 
RECORD RETENTION ......................................................................... 32 
12. 
TABLES AND LISTING CONVENTIONS ............................................... 33 
 
Statistical Table Conventions ............................................................................ 34 
 
Data Listing Conventions .................................................................................. 34 
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13. 
REFERENCES ..................................................................................... 34 
14. 
CHANGE HISTORY ............................................................................. 35 
 
Appendix A: Schedule of Trial Assessments..................................................... 36 
 
Appendix B: Laboratory Cut off Values ............................................................ 40 
 
Appendix C: ECOG Performance Status ........................................................... 41 
 
Appendix D: Overall Status Calculation (Measurable Disease) ........................ 42 
 
Appendix E: Overall Status Calculation (Non_target Disease) ......................... 43 
 
Appendix F: Calculation of Best Overall Response .......................................... 44 
 
 
 
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1.0 ACRONYMS  
Term 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASPH 
Aspartate beta-hydroxylase 
ASR 
Administration site reaction 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
Cl 
 Chloride 
CO2 
 Bicarbonate or carbon dioxide 
CPI 
Checkpoint Inhibitor (anti-PD-1/anti-PD-L1 therapy) 
CPK 
Creatinine phosphokinase 
CR 
Complete response 
CRF 
Case report form 
CT 
Computerized tomography scan 
CtDNA 
Circulating tumor deoxyribonucleic acid 
CTL 
Cytotoxic CD8+ T-lymphocytes 
DCR 
Disease Control Rate DLT Dose-limiting toxicity 
DOR 
Duration of response  
EBV 
Epstein Barr virus  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
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HIV 
Human immunodeficiency virus 
hMTS 
3M® hollow microstructured transdermal system 
HPV 
Human papillomavirus 
ICH 
International conference on harmonization 
ID 
Intradermally 
IFN 
Interferon 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
iRECIST 
Immune response evaluation criteria in solid tumors 
IV 
Intrvenous 
K 
Potassium 
LDH 
Lactate dehydrogenase  
mAb 
Monoclonal antibody 
MDSC 
Myeloid derived suppressor cells  
mg 
Milligrams 
Mg 
Magnesium 
MiRNA 
Micro ribosome nucleic acid  
MRI 
Magnetic resonance imaging  
NA 
Sodium 
NCI-CTCAE 
National Cancer Institute Common 
Terminology Criteria for Adverse 
Events V 5.0 
ORR 
Objective response rate 
OS 
Overall survival 
P 
Phosphorus 
PFS 
Progression free survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PR 
Partial response 
PS 
Performance status 
RBC 
Red blood count 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribosome nucleic acid   
SAE 
Serious adverse event 
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SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SNS-301 
HAAH bacteriophage lambda constructs: HAAH-1λ transaminase 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
TT  
Thrombin Time 
ULN 
Upper limit of normal 
WBC 
White blood count 
 
 
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1. PURPOSE  
This Statistical Analysis Plan (SAP) describes the methods to be used in the analysis of trial data 
from clinical protocol ‘An Open-Label, Multi-Center Trial of SNS-301 Added to Pembrolizumab 
in Patients with Locally Advanced Unresectable or Metastatic/Recurrent Squamous Cell 
Carcinoma of the Head and Neck’ in order to answer the trial objective(s), and is based on the 
trial protocol SNS301-2-2, dated November 6, 2020 (Version 4.0). 
Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are described within this document. The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the CSR for 
this trial. The SAP outlines any differences in data analysis methods relative to those planned in 
the trial protocol.  Any changes to the data analysis methods after the SAP is finalized will be 
described in the CSR. 
2. OVERALL STUDY DESIGN AND OBJECTIVE 
 Trial Objectives 
Primary Objective 
• To determine the safety and tolerability of SNS-301 delivered by intradermal injection 
(ID) using the 3M® hollow microstructured transdermal system (hMTS) device in 
patients with locally advanced unresectable or metastatic/recurrent SCCHN. 
• To evaluate the anti-tumor activity of SNS-301 delivered by intradermal injection (ID) 
using the 3M® hollow microstructured transdermal system (hMTS) device in addition to 
pembrolizumab in patients with locally advanced unresectable or metastatic/recurrent 
SCCHN 
 Secondary Objective 
• To evaluate preliminary immune response to SNS-301 delivered by intradermal injection 
(ID) using the 3M® hollow microstructured transdermal system (hMTS) device in 
addition to pembrolizumab in patients with locally advanced unresectable or 
metastatic/recurrent SCCHN.  
Exploratory Objective  
• To evaluate tumor and immune biomarkers and their association with treatment outcome 
(antitumor activity and/or safety) in patients with locally advanced unresectable or 
metastatic/recurrent SCCHN. 
 Trial Design and Trial Procedures 
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This is a Phase 1/2, open-label, multi-center trial to evaluate the safety, immunogenicity and 
preliminary clinical efficacy of SNS-301 delivered by intradermally in addition to 
pembrolizumab in patients with locally advanced unresectable or metastatic/recurrent SCCHN. 
The trial population consists of patients with locally advanced unresectable or 
metastatic/recurrent SCCHN who are currently receiving a checkpoint inhibitor (CHI) therapy 
(anti-PD1 and anti-PD-L1agents) (Cohort A) or are naïve to CPI therapy (Cohort B). The cohorts 
for this study are highlighted below: 
 
Each cohort will enroll up to approximately 30 patients. Approximately 60 patients will be 
enrolled over two cohorts at up to 15 institutions within the United States. The study enrollment 
is expected to last approximately 18-24 months.   
Patients who are currently receiving CPI therapy must have a best response of stable disease 
(SD) or first evidence of progressive disease (PD) after a minimum of 12 weeks of a CPI 
therapy. Patients receiving first-line pembrolizumab monotherapy must be PD-L1 positive. 
Patients receiving a CPI other than pembrolizumab will be switched over to pembrolizumab at 
the time of entering this study. 
A tissue sample is required for entry onto the study with either a fresh biopsy or archival tissue 
from a previous biopsy. Ideally, a pre-treatment tissue sample obtained after initiation of ongoing 
CPI therapy and before first dose of SNS-301 and pembrolizumab on this current clinical trial 
will be collected. Patients unable to provide pre-treatment biopsy while on CPI will be evaluated on a 
case-by-case basis for enrollment pending Sponsor consultation. 
Patients are requested to  provide archival tissue from a prior biopsy or surgery that is treatment -
naïve including prior 1) chemotherapy, radiation and 2) anti PD(L)-1 treatment-naïve, pending 
availability. An on-treatment biopsy is required when medically feasible, after the second or 
third  dose of treatment around treatment week 6.  Additionally, up to two optional biopsies may 
be obtained at any time during the study, if medically feasible. For patients who progress as 
determined per RECIST1.1/iRECIST criteria, an optional  biopsy will be obtained at the time of 
disease progression. The Sponsor may request digitized scans from patients to confirm response.   
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This study will employ a Simon 2-stage design, with 15 evaluable patients (i.e. meeting the 
definition for the efficacy evaluable analysis set; at Week 12 for both cohorts. Non-evaluable 
patients will be replaced.    
The safety run-in will be performed using a modified rolling six design which will enroll up to 
six patients (safety analysis patients). These patients may contribute to the first 15 in stage 1, 
assuming they meet the definition for evaluable for efficacy. The end of the safety run-in period 
is defined as the earliest of the following: 
• The first three patients have all completed Week 6 with no DLTs experienced by any of 
the safety runin patients in that cohort (up to six); enrollment may then proceed through 
stage 1;  
• All six patients of the safety run-in phase, have completed week six with only one patient 
having experienced a DLT; enrollment may then proceed through stage 1;  
• Two or more of the safety run-in patients, have experienced DLTs prior to completing 
Week 6; enrollment will be suspended.  
If at least one responder (ORR per iRECIST) is observed in the first 15 evaluable patients (i.e. 
meeting the definition for the efficacy evaluable population) by Week 12, then the study will 
continue to Stage 2 and enroll up to 15 additional patients. If at least 4 responders are observed 
overall, further research will be deemed warranted.   
There will be a waiting period of one week between enrollment of the first patient and the second 
patient because this trial is treating patients with SNS-301 and pembrolizumab for the first time. 
The interim efficacy assessment, for each cohort, will occur after 15 patients were enrolled and 
completed the 12-week follow-up period.  A safety review will occur in parallel to the efficacy 
assessment of the first 15 patients 
The trial will be stopped if any adverse experience of any related death, grade 4 autoimmune 
toxicity or any grade 4 toxicity that is considered to have a causal relationship to study drug should 
occur. These events will be submitted to regulatory agencies within the expedited safety reporting 
criteria. 
The clinical trial will be considered completed when all patients have had their three-year follow-up visit, 
death, lost to follow-up, withdrawal of consent, or when the Sponsor deems the study completed, 
whichever comes first. 
The study schema is presented in Figure 1: 
 
 
 
 
 
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Figure 1: Study Schema 
 
 Treatments and Assignment to Treatments 
SNS-301 Dosing 
• SNS-301 (1x1011 dose/1ml) ID is administered using the 3M® hollow microstructured 
transdermal system (hMTS) device.  
• 
Patients will receive SNS-301 on a staged schedule starting every three weeks for four doses, 
every six weeks for 6 doses and thereafter every twelve weeks. 
• 
When pembrolizumab and SNS-301 are dosed on the same day, SNS-301 will be dosed 
approximately 1 hour after IV infusion of pembrolizumab for the first dose. Subsequent doses of 
SNS-301 and pembrolizumab can be dosed in any order.  
• 
A 60 minutes observation period is recommended for the first dose on this study and 30 minutes 
for subsequent doses. 
Pembrolizumab Dosing 
• 
A fixed dose of 200 mg pembrolizumab as an intravenous infusion over 30 minutes every 3 
weeks or a fixed dose of 400 mg pembrolizumab, as an intravenous infusion over 30 minutes 
every 6 weeks will be administered. A sterile, non-pyrogenic, low-protein binding 0.2 micron to 
micron in-line or add-on filter will be utilized. A 60 minutes observation period is recommended 
for the first dose on this study and 30 minutes for subsequent doses. 
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Patients will receive their study treatments until disease progression, unacceptable toxicity, 
deemed intolerable by investigator or up to 24 months in patients without disease progression.  
There will be no SNS-301 dose reductions.   
In case of non-DLT AE (grade 2 NCI-CTCAE V5.0 drug related AE), the dosing interval can 
be extended  up to 42 days to allow the recovery from a related toxicity and the patient will 
resume at the same dose. If the patient experiences the same grade or higher toxicity and same 
grade requiring a dose-delay at the subsequent cycle, the patient should be discontinued from 
study treatment. 
Should there be a clinically significant AE or SAE recorded relating to a patient receiving 
anticoagulants, such as clinically noted bleeding, administration of SNS-301 will be held until the 
AE/SAE returns to baseline. Should there be two individual events of SNS-301 interruption for 
the same patient, then SNS-301 will be discontinued after consultation with the Medical Monitor 
and Study Sponsor. 
If a patient is unable to receive study treatment (e.g., due to COVID19) the dosing interval can be 
extended up to 42 days after consultation with the Sponsor and the rationale to be documented. 
Treatment with SNS-301 may continue if pembrolizumab is discontinued by the Investigator, 
if prior to 24 months.  If both study treatments are stopped for more than 42 days then the 
patient should be discontinued from study treatment and continue to the study follow up phase. 
 Determination of Sample Size  
The sample size for each cohort and stage is based on Simon’s two-stage design for tests of one 
proportion.  
Cohort A 
To evaluate the primary endpoint of objective response per iRECIST at 12 weeks with a null 
hypothesis of an objective response rate (ORR) of 5% and an alternative hypothesis of an ORR 
of 18%, 30 patients in a two-stage design with 15 patients in the first stage and 15 patients in the 
second stage will be enrolled.  
Subjects with evidence of disease progression or deemed unevaluable at 12 weeks will not be 
counted towards assessment of futility. At the first stage analysis if at least 1 response is 
observed out of 15 patients, the study will continue through the second stage.  At the second 
stage analysis,  if at least 4 responses are observed out of 30 total patients, the null hypothesis 
will be rejected, and further research considered warranted.   
The overall power for the objective response rate at 12 weeks is 80%.  The overall type I error, 
the chance of incorrectly rejecting the null hypothesis is 6% (targeted alpha of 0.10).  The 
probability of stopping at the first stage under the null hypothesis is 46%.  The exact binomial 
distribution is used in the operating characteristics of this design.  
 
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Cohort B 
To evaluate the primary endpoint of objective response rate per iRECIST at 12 weeks with a null 
hypothesis of an objective response rate (ORR) of 13.3% and an alternative hypothesis of an 
ORR of 29%, 30 patients in a two-stage design will be enrolled, with 15 patients in the first stage 
and 15 patients in the second stage. At the first stage analysis, if at least 2 responses are observed 
out of 15 patients, the study may continue through the second stage.  At the second stage 
analysis, if at least 7 responses are observed out of the total 30 patients, the null hypothesis will 
be rejected and further research considered warranted.  The overall power for objective response 
rate at 12 weeks is 80.1%.  The overall type I error, the chance of incorrectly rejecting the null 
hypothesis is 9.2% (targeted alpha of 0.10).  The probability of stopping at the first stage under 
the null hypothesis is 38.8%.  The operating characteristics of this design are calculated using the 
exact binomial distribution. 
3. GENERAL ANALYSIS CONVENTION 
 General Methods 
All summaries will be presented separately for each cohort, and overall for all subjects 
combined. 
For continuous variables, descriptive statistics (number (n), mean, median, standard deviation, 
minimum and maximum) will be presented. For categorical variables, frequencies and 
percentages will be presented.  
For time-to-event variables, 25th,  50th (median) and 75th percentile will be estimated using the 
Kaplan-Meier method. Number of patients with event and number of patients censored will be 
presented. As appropriate, a 95% CI will be presented. Graphical displays will also be presented, 
as appropriate. 
All data collected will be presented in by-patient data listings 
 Trial Periods 
The pre screening period is up to 28 days prior to first drug administration. Patients will undergo 
tumor assessments every 6 weeks (±7 days) until approximately 12 months following first 
dose of study  treatment, or earlier if clinically indicated. After 12 months, tumor assessments 
will be required every 12 weeks (±7 days). Survival follow-up information will be collected via 
telephone calls, patient medical records, and/or clinical visits approximately every 3 months for 
up to 3 years, until death, lost to follow-up, withdrawal of consent, or trial termination by 
Sponsor. The Trial Schedule of Events  is presented in Appendix A. 
 
 
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 Visit Windows  
The allowed visit windows are summarized in Table 1 below: 
Parameter 
Visit 
Allowed Window 
Tumor Biopsy 
Week 6 
± 3 days 
SNS-301 Administration ( 
When pembrolizumab is 
given every three weeks) 
 
Day 0, Week 3, 6, 9, 15, 21, 27, 33, 39 
and 45 
± 3 days 
After week 45, every 12 weeks  
until confirmed disease progression, 
unacceptable toxicity, deemed 
intolerable by the investigator or up to 
24 months in patients without disease 
progression. 
± 3 days 
SNS-301 Administration ( 
When pembrolizumab is 
given every six weeks) 
 
Day 0, Week 3, 6, 12, 18, 24, 30, 36, 
42 and 48 
± 3 days 
After Week 48, every 12 weeks until 
confirmed disease progression, 
unacceptable toxicity, deemed intolerable 
by the investigator or up to 24 months in 
patients without disease progression.  
± 3 days 
Pembrolizumab 
Administration 
Every 3 weeks until confirmed disease 
progression, unacceptable toxicity,  
deemed intolerable by investigator or 
up to 24 months in patients without 
disease progression 
± 3 days 
Imaging 
Week 6 
± 7 days 
Every 6 Weeks till Week 54 
± 7 days 
Every 12 Weeks after Week 54 
± 7 days 
Vital Signs  
(Heart rate, respiratory rate, 
blood pressure, and 
temperature) 
15 Min after start of first infusion 
± 5 Min 
30 Min after start of first infusion 
± 5 Min 
45 Min after start of first infusion 
± 5 Min 
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60 Min after start of first infusion 
± 5 Min 
30 Min after first infusion 
± 10 Min 
60 Min before subsequent infusions 
<60 Min to infusion 
30 Min after subsequent infusions 
± 5 Min 
 
4. ANALYSIS POPULATIONS 
Safety Analysis Set 
The Safety Analysis Set comprises all patients who receive at least 1 dose of the study treatment 
or component of the study treatment. 
Efficacy-Evaluable Analysis Set 
The Efficacy-Evaluable Analysis Set comprises all patients who receive at least 1 dose of the 
study treatment or component of the study treatment and have a post baseline response 
assessment per iRECIST at Week 12. Subjects who discontinued prior to Week 12 due to 
radiological disease progression will be included. Subjects who do not have a post baseline 
response assessment conducted will not be included in the analysis of efficacy. 
Safety Run-In Set 
Safety Run-in Set comprises all patients who receive at least 1 dose of the study treatment or 
component of the study treatment as part of the safety run-in. 
Immunologic Analysis Set 
Immunological Analysis Set comprises all patients who receive at least 1 dose of the study 
treatment or component of the study treatment and have at least one valid post-baseline 
immunologic assessment available. 
5. SUBJECT DISPOSITION  
Subject disposition will be summarized overall for all subjects who entered the study in a 
disposition table (i.e., signed the informed consent for the study). In addition, the number of 
subjects in each population (Safety Analysis Set, Safety Run-in Set, Efficacy Evaluable Analysis 
Set and Immunologic Analysis Set) and subjects that were removed from a population will be 
summarized. The number and proportion of subjects who complete the study, as well as those 
who discontinue the study will be summarized along with the reason for discontinuation. 
Primary reason for SNS-301 treatment termination include the following criteria: 
• Adverse Event 
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• Death 
• Progression 
• Lost to Follow-up 
• Non-Compliance with Study Drug 
• Physician Decision 
• Pregnancy 
• Protocol Deviation 
• Site Terminated by Sponsor 
• Study Terminated by Sponsor 
• Withdrawal by Patient 
• Other 
Primary reason for Pembrolizumab treatment termination include the following criteria: 
• Adverse Event 
• Death 
• Progression 
• Lost to Follow-up 
• Non-Compliance with Study Drug 
• Physician Decision 
• Pregnancy 
• Protocol Deviation 
• Site Terminated by Sponsor 
• Study Terminated by Sponsor 
• Withdrawal by Patient 
• Other 
Primary reason for study discontinuation include the following criteria: 
• Death 
• Lost to Follow-up 
• Withdrawal by patient from Study 
• Termination of study by Sponsor 
• Completed 24 months of therapy 
• Other (Disease progression, Unacceptable toxicity as judged by the Principal Investigator, 
Adverse events, which are dose-limiting toxicities, Withdrawal of consent, Subject is lost 
to follow-up, Subject non-compliance, Use of another non-protocol anti-cancer treatment, 
Pregnancy)  
Subject disposition data will also be presented in data listings. 
If study treatment is definitively discontinued, the patient will remain in the study for long term 
follow-up post-treatment to be evaluated for survival, including information on subsequent 
anticancer therapies and progression. In the case where consent for study treatment is withdrawn, 
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the patient will be encouraged to continue study participation for long term follow-up post-
treatment. 
6. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 Demographics Characteristics  
Demographic and baseline characteristics at study entry will be summarized in tables and listings 
by study cohort and overall.  
Number, mean (SD), median, min and max will be provided for these continuous variables:  
• Age (years) at time of consent  
• Weight (kg) 
• Height (cm) 
• Body Mass Index (kg/m2) 
Number and percentage of patients will be provided for the following categorical variables: 
• Sex  
• Child-bearing potential (females) 
• Race 
• Ethnicity 
Patients are allowed to select more than one race to define multiple-race. 
 Smoking History and Alcohol Use 
Smoking  history and alcohol use data will be collected at study entry and will be summarized in 
tables and listings by cohort and overall.  
Number and percentage of patients will be provided for the following categorical variables: 
• Smoking History (Yes/No) 
• Status of Tobacco Use (Current/Former) 
• Type (Cigarette, Cigar, Pipe, Smokeless tobacco, Electronic cigarette, Other) 
• Tobacco use  frequency per day (1- 4, 5-10, 10 - 20, >20, Unknown) 
• Alcohol use (Never/Current/Former) 
• Number of Alcoholic drinks consumed (never, 1 or 2, 3 or 4, 5 or 6, 7 or 8, 10 or more) 
Number, mean (SD), median, min and max will be provided for these continuous variables:  
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 Medical History 
Medical History will be collected at the Screening/Baseline visit. will include details regarding 
the patients overall medical and surgical history as well as detailed information regarding the 
patient’s previous treatment, including systemic treatments, radiation and surgeries, pathology 
and risk stratification. Medical History will be summarized for the Safety Analysis Set. 
The frequency count and percentage of subjects experiencing any medical conditions will be 
tabulated by system organ classifications (SOC) and preferred term (PT). If a preferred term or 
system organ class was reported more than once for a subject, the subject would only be counted 
once in the incidence for that preferred term or system organ class. 
Medical history data will also be listed for Safety Analysis Set by patient. 
 Cancer History 
Cancer History will be collected at the Screening/Baseline visit. The following data will be 
summarized by number and percentage of patients in each category for the Safety Analysis Set.  
• Histologic Diagnosis 
o Differentiattion (Well, Moderate, Poor,  Not Specified) 
o Stage at Screening (Stage II, Stage II, Stage III,  Stage IV, Stage IVA, Stage IVB 
Stage IVC 
• TNM Staging 
o T Stage (T1, T2, T3, T4) 
o N Stage (N0, N1, N2a, N2b, N2c, N3, NX) 
o M Stage (M0, M1, MX) 
• Anatomical Location (Lip, Oral cavity, Oropharynx, Hypopharynx, Nasopharynx, Glottic 
larynx, Supraglottic larynx, Ethmoid sinus , Maxillary sinus, Salivary gland, Other) 
 Prior Cancer Therapy 
Prior cancer therapy data  will be collected at the Screening/Baseline visit. 
The following data will be summarized by number and percentage of patients in each category 
for the Safety Analysis Set.  
• Did the subject have any prior Cancer therapy? (Yes/No) 
• Was the therapy ongoing at the time of consent? (Yes/No) 
• Best Overall Response 
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o Complete response (CR) 
o Partial response (PR) 
o Progressive disease (PD) 
o Stable disease (SD) 
o Unconfirmed Progression (uPD) 
• Duration of Response (Weeks) will be summarized as a continuous variable (N, Mean 
(SD) Median Min Max) 
 Prior Radiotherapy 
Prior radiotherapy data  will be collected at the Screening/Baseline visit. 
The following data will be summarized by number and percentage of patients in each category 
for the Safety Analysis Set.  
• Did the subject have any prior radiotherapy? (Yes/No) 
• Was radiotherapy ongoing at the time of consent? (Yes/No) 
• Type of radiotherapy 
o Intensity-Modulated Radiation 
o Therapy (IMRT) 
o AP-PA Therapy 
o Proton Therapy 
o Other 
The following paramenters will be summarized as continuous variables (N, Mean (SD) Median 
Min Max) 
• Dose per fraction 
• Number of fractions 
 Target, Non-target and New Lessions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions must meet the criterion of a short axis of ≥15 mm by CT scan. All other pathological 
nodes (those with short axis ≥10 mm but <15 mm) should be considered nontarget lesions. Nodes 
that have a short axis <10 mm are considered nonpathological and should not be recorded or 
followed.  
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The following categorical variables for target, non-target and new lesions will be summarized 
using descriptive statistics (number (percent)) 
• Site of lesion (Bone, Brain, Chest Wall, Liver, Lung, Lymph Node, Neck, Oral Cavity, 
Skin; Soft Tissue, Other) 
• Modality (CT with Contrast, CT without Contrast, MRI) 
The following continous variables for target, non-target and new lesions will be summarized 
using descriptive statistics (n mean (SD), median, min, max)) 
• Longest Diameter 
• Sum of the longest diameter (Derived) 
Summaries for target, non-target and new lesions’ data as assessed using iRECIST will also be 
presented. Data listings will also be presented for target, non-target and new lesions’ data. 
 Prior and Concomitant Medications 
Prior medications any prescription medications or over-the-counter medications taken or 
performed within 7 days prior to screening and before the first dose of study drug. At subsequent 
visits, changes to current medications or medications used since the last documentation of 
medications will be recorded. 
Concomitant medications are all medications, other than the study drug, taken on or after the first 
day of study drug dose through 30 days after end of study medication or until the start of a new 
anti-cancer treatment, whichever comes first. Concomitant medications will be categorized into 
the following categories (listed in section 8.4 of the protocol): 
• Allowed concomitant treatments 
• Prohibited medications or treatments during study 
• Rescue medications 
Prior and concomitant medications  and procedures will be coded using the World Health 
Organization Drug Dictionary. 
• Prior and concomitant medications will be summarized by the number and proportion of 
the subjects who took each medication, or had qualifying concomitant procedures and  
will be tabulated by the ATC-2 level and preferred name. A subject will only be counted 
once within each ATC-2 code and within each preferred name. 
Prior and concomitant medications will also be listed for Safety Analysis Set . 
 
 
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 Serology Testing Results (HIV, Hepatitis and PD-L1 Status)  
If the patient’s tumor’s HPV/EBV status is unknown, they will be tested prior to receiving SNS-
301. If the patient’s tumor’s PD-L1 status is unknown, they should be tested, preferably by 22C3 IHC. 
Patients who are CPI naïve must be PD-L1 positive prior to entry onto the study. For other 
patients, the results do not need to be known before the patient receives study treatment. For 
patients that started study treatment prior to Amendment 2/Version 3.0, retrospective PD-
L1testing should be done, whenever possible. 
The results of the following tests will be summarized using descriptive statistics 
(Number (percent)) 
• HIV Testing (Positive, Negative, Unknown) 
• Hepatis B surface Testing Antigen (Positive, Negative, Unknown) 
• Anti-HBc Antibody Testing (Positive, Negative, Unknown) 
• Anti-HBs Antibody Testing (Positive, Negative, Unknown) 
• Hepatitis C Antibody Testing (Positive, Negative, Unknown)  
• PD-L1 Status (Positive, Negative, Unknown)  
 Virology Testing Results (HPV and EPV)   
The results of the following tests will be summarized using descriptive statistics 
(Number (percent)) 
• HPV Status (Positive, Negative, Unknown) 
• EBV Status (Positive, Negative, Unknown) 
7. EFFICACY ANALYSIS  
 Primary Efficacy Analysis 
The primary efficacy analysis will be based on the Efficacy-Evaluable Analysis Set at week 12. 
All efficacy variables will be presented by cohort. The following primary efficacy variables will 
be summarized to determine the anti-tumor activity of SNS-301: 
Objective Response Rate (ORR) 
• ORR is defined as the proportion of patients with a confirmed best response of iCR 
or iPR by iRECIST. 
• 
ORR, and 90% CI at week 12 based on the exact binomial distribution will be presented, 
including number and percent of patients in each overall response category. 
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• 
Best Overall Response ( BOR) will also be presented. 
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with SD or better (PR and CR) as assessed by 
RECIST version 1.1 and iRECIST. SD must be for at least six months.  
• A 95% Confidence Interval based on binomial distribution will be constructed for the 
estimated DCR at 12 weeks. 
• Subjects who drop out prior to meeting the responder criteria for DCR will be considered 
as non-responders. 
Clinical Benefit Rate (CBR) 
• CBR is defined as the proportion of patients with CR, PR or had stable disease for at least 
6 Months as assessed by RECIST version 1.1 and iRECIST. 
• A 95% Confidence Interval based on binomial distribution will be constructed for the 
estimated CBR. 
Progression Free Survival (PFS) 
• PFS is defined as the time from date of start of treatment to date of progression or 
death (whichever comes first) as assessed by RECIST version 1.1 and iRECIST.  
• Subjects who are alive and without documentation of progression at the time of the 
analysis will be censored at the date of last tumor assessment.  
• Subjects with no tumor response assessment will be censored at the start date of the 
treatment.  
• Subjects who discontinued treatment or withdrew from the study for reasons other than 
documented PD or death will be censored at the date of last tumor assessment prior to 
discontinuation or withdrawal. 
• PFS rate at 12 weeks and the corresponding 95% CIs will be calculated based on 
Kaplan-Meier product limit estimates and will be displayed along with the 
corresponding number of subjects at risk. 
• The 25th percentile, Median, and 75th percentile of PFS as well as the corresponding 
95% confidence limits will be estimated using Kaplan-Meier method. Number of 
patients with PD, number of deaths and number censored will be presented. 
• Kaplan-Meier curves of PFS by cohort will be displayed graphically. 
 
Duration of Response (DOR) 
• DOR is defined as time from date of first loss of response as assessed by RECIST 
version 1.1 and iRECIST.   
• DOR in weeks = (Date of PD or death – date of first response + 1) / 7. Patients 
without progression or death are censored at the date of last tumor assessment. 
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• The median DOR with 2-sided 95% confidence intervals will be presented for subjects 
who have a confirmed CR or PR at 12 weeks. 
• The 25th percentile, Median, and 75th percentile of DOR as well as the corresponding 
95% confidence limits will be estimated using Kaplan-Meier method. Number of patients 
who lost response and number censored will be presented. 
• Kaplan-Meier curves of DOR by cohort will be displayed graphically. 
  
Overall Survival (OS) 
• OS is defined as time from date of start of treatment to date of death.   
• OS rate at 12 weeks and the corresponding 95% CIs will be calculated and summarized 
based on Kaplan-Meier product limit estimates and will be displayed along with the 
corresponding number of subjects at risk.  
• Subjects who are still alive will be censored on the date of last contact.  
• The 25th percentile, Median, and 75th percentile of OS as well as the corresponding 
95% confidence limits will be estimated using Kaplan-Meier method. Number of 
patients who died and number censored will be presented. 
• Kaplan-Meier curves of OS by cohort will be displayed graphically. 
 Secondary Efficacy Analysis 
To determine preliminary immune response to SNS-301, the following parameters will be 
assessed: 
• Antigen-specific cellular immune responses that may be assessed by but not limited to: 
Interferon-γ secreting T lymphocytes in peripheral blood mononuclear cells (PBMCs) by 
ELI Spot 
• Anti-SNS-301antibody secretion 
• Assessment of pro-inflammatory and immunosuppressive elements in neoplastic and 
adjacent normal tissue, where feasible 
Categorical results will be summarized using the number (percent) format and continuous results 
will be presented in the n, mean(SD), median, min and max format. 
 
 
 Exploratory Efficacy Analysis 
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To determine tumor and immune biomarkers and their association with treatment outcome 
(antitumor activity and/or safety) in patients with locally advanced unresectable or metastatic/recurrent 
SCCHN,the following parameters will be assessed: 
• Immune related gene expression  
• Expression of tumor specific oncoproteins including but not limited to ASPH 
• Correlation of serum ASPH level as determined by ELISA with tissue expression using 
IHC 
• Cytokine and chemokine profiles in urine pre- and post-treatment and longitudinally 
throughout the trial  
• TCR sequencing of PBMCs for diversity and putative antigen specificity 
• CtDNA analysis and tracking for progression 
Categorical results be summarized using the number (percent) format and continuous results will 
be presented in the n, mean(SD), median, min and max format. 
8. SAFETY ANALYSIS  
Safety evaluations will be based on exposure and compliance to study drugs, the incidence, 
severity, attribution and type of AEs, and changes in the patient’s vital signs, and clinical 
laboratory results.  
 Trial drug Exposure and Compliance 
Extent of treatment exposure to SNS-301, will be assessed for each of the two study stages. 
• Duration of SNS-301 treatment (week), will be calculated as: (Last dose date – first dose 
date + 1) / 7  
• Was full dose of SNS-301 administered?  (Yes/No) 
• Were any injection or device malfunctions noted? (Yes/No) 
• Type of Malfunction (Device failed, User Error) 
• Did the malfunction affect the dose received by thesubject? (Yes/No) 
Pembrolizumab exposure will be summarized by the following parameters:  
• Duration of Pembrolizumab treatment (week), calculated as: (Last dose date – first dose 
date + 1) / 7  
• Was full dose of Pembrolizumab administered?  (Yes/No) 
• Was infusion interrupted?  (Yes/No) 
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• Reason for interruption (AE, IV Issue Other)  
 
 Dose-Limiting Toxicities 
Dose-Limiting Toxicities (DLTs) are events identified below that must be reported in an 
expeditious manner. DLTs may or may not be serious adverse events as an Unexpected Adverse 
Event (SUSAR). DLTs are assessed up to week 6 for patients enrolled in the Safety Run-In 
period. 
1)   Grade 4 non-hematological toxicities (excluding alopecia) of any duration 
2)   Grade 3 non-hematologic (non-laboratory) toxicity lasting > 3 days despite 
optimal supportive care 
3)   Any Grade 3 or Grade 4 non-hematologic laboratory value if: a). 
medical intervention is required to treat the patient; b), the abnormality 
leads to hospitalization; c). The abnormality persists for >1 week. 
4)   Grade 4 hematologic toxicity, other than those specified in criteria 5 and 6 
below, lasting > 7 days 
5)   Grade 3 or Grade 4 febrile neutropenia of any duration 
6)   Grade 3 thrombocytopenia in combination with a grade 3 or greater blood 
and lymphatic system disorder 
7)   Grade 3 AST or ALT that is associated with a grade 2 rise in bilirubin 
Safety analysis will based on  the safety analysis set. 
 Adverse Events 
Adverse event (AE)  
is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. Any AE that occurs prior to the first dose is part of the medical history. AEs 
will be collected from the time of informed consent until 30 days after the last dose of study treatment or 
until initiation of another anti-cancer therapy, whichever occurs first.  
Adverse events (AEs) will be coded using MedDRA v20 or later and will be classified by 
System Organ Class (SOC) and preferred term (PT). 
Treatment-emergent adverse events (TEAEs) are defined as any AE that occurs during or after 
administration of the first dose of treatment through 30 days after the last dose, any event that is 
considered study drug-related regardless of the start date of the event, or any event that is present 
at baseline but worsens in intensity. 
Severity of AEs will be assessed according to CTCAE (v5.0):  
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• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2:  Moderate;  minimal,  local  or  noninvasive  intervention  indicated;  
limiting  age- appropriate instrumental ADL. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. 
• Grade 4: Life-threatening consequences; urgent intervention 
indicated. 
• Grade 5:  Death related to AE. (Grade 5 (Death) may not appropriate for some 
AEs and therefore may not an option.) 
Prior AEs are those occurring after subject sign off the informed consent and before the 
administration of the first dose of study treatment.  
Relationship to study medication is  categorized as follows based on clinical decision using all 
available information at the time of completing the CRF: 
• Related (The AE could medically (pharmacologically/clinically) be attributed to the study drug 
under investigation in this clinical study protocol)  
• Not related (The AE could not medically (pharmacologically/clinically) be attributed to the 
study drug under investigation in this clinical study protocol.) 
Systemic administration site reactions will be considered as Adverse Events of Special Interest 
(AESI). The area around the administration site will be assessed by a medically qualified 
individual for adverse reactions at least 30 minutes post study drug administration. The 
Investigator will grade any ASRs according to the NCI-CTCAE V5.0 (excluding the actual 
expected micro-injection punctures). 
An unanticipated (serious) Adverse Device Effect (UADE) is any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, 
if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of patients. 
An overall AE summary for number of subjects will be presented for the following categories:  
• Any Adverse Event 
• Any Treatment-Emergent Adverse Event (TEAE)  
• Any deaths within the AE reporting period 
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• Any study drug-related adverse event (TRAE) (i.e. related to SNS-301 or  
Pembrolizumab)  
• Any SNS-301-related adverse event (TRAE)  
• Any Pembrolizumab-related adverse event (TRAE)  
• Any AE related to device for injection  
• Any AE related to a Dose-Limiting Toxicity (DLT)  
• Any TEAE ≥ CTCAE Grade 3 
• Any TRAE ≥ CTCAE Grade 3 
• Any treatment-emergent Serious AEs (SAEs) 
• Any Serious TRAEs 
• Any TEAE leading to treatment (SNS-301 or Pembrolizumab) discontinuation 
• Any TEAE leading to SNS-301 treatment discontinuation 
• Any TEAE leading to Pembrolizumab treatment discontinuation 
• AESIs 
• UADEs 
The following events will be tabulated by SOC and PT. Summaries will be sorted by decreasing 
frequency of PT within SOC which is sorted alphabetically.  
• TEAEs by SOC and PT 
• TEAEs by PT frequency only 
• Treatment-emergent SAEs  
• SNS-301 Treatment-related AEs 
• Pembrolizumab Treatment-related AEs 
• SNS-301 Treatment-related SAEs 
• Pembrolizumab Treatment-related SAEs 
• TEAEs leading to SNS-301 treatment discontinuation or death 
• TEAEs leading to Pembrolizumab treatment discontinuation or death 
• DLTs 
• AESIs 
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A summary of TEAEs by SOC, PT and maximum severity, sorted by decreasing frequency of PT 
within SOC which is sorted alphabetically, will also be provided for:  
• All TEAEs 
• TEAEs ≥ CTCAE Grade 3 
• SNS-301 Treatment-related AEs 
• Pembrolizumab Treatment-related AEs 
• TRAEs ≥ CTCAE Grade 3 
In tabulation by severity grade, only the most severe SOC for each subject will be included for a 
given SOC.  For a given PT, only the most severe PT for each subject will be included.  
The following listings will be provided:  
• All AEs   
• DLTs  
• SAEs  
• AESIs 
• TEAEs leading to study treatment discontinuation 
• Deaths in the AE reporting period 
 Clinical Safety Laboratory Assessments 
Hematology, serum chemistry, coagulation and urinalysis  data will be collected as specified in 
the study schedule of Assessments (Apendix A). Hematological toxicities will be assessed 
according to NCI-CTCAE V5.0 AE grading.  
All laboratory results will be presented in the listings.  Abnormal laboratory values with their 
clinical significance status will be presented in a listing. The laboratory tests cut off values are 
presented in Appendix B. 
 
Table 2: Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Platelet count 
Albumin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
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Red blood cell (RBC) count 
White blood cell (WBC) count 
Neutrophils 
Lymphocytes 
Eosinophils 
Monocytes 
Basophils 
Other cells, if any 
Platelets 
Thyroid 
TSH, T3 and FT4 
Coagulation 
International normalized ratio/INR 
Activated partial thromboplastin time (PTT) 
Other anticoagulant monitoring (if required)  
HIV screen (at screening, if indicated) 
 
Hepatitis screen (at screening, if indicated)  
 
HPV/EBV screen (at screening, if unknown)  
 
Pregnancy test 
Blood Urea Nitrogen (BUN) or Urea 
Bicarbonate or Carbon dioxide (CO2) 
Creatinine 
Creatine phosphokinase (CPK) 
Electrolytes (Na, K, Mg, Cl, Ca, P) 
Glucose (either fasting or non-fasting) 
Lactate dehydrogenase (LDH) 
Total   bilirubin   (direct   bilirubin   if 
elevated) 
Total protein 
Urinalysis 
Specific gravity 
pH 
Glucose 
Protein 
Ketones 
Blood 
Microscopic exam, if abnormalities 
 
The following summaries will be presented for Clinical Laboratory tests: 
• Overall values by time point utilizing continuous descriptive statistics for each study 
stage. 
• For categorical parameters, the n and percentage will be displayed for each study stage. 
• The change from baseline to each time point for continuous parameters.   
• Frequencies and percentages for the shifts in these categories (i.e., low to normal, low to 
high, high to low, etc.) from baseline to each post-treatment assessment time point.  For 
each continuous laboratory (hematology and chemistry) parameter, results will be 
categorized as low, normal, or high based on the laboratory normal ranges.  Percentages 
for the shift tables will be calculated based on the number of subjects who had results for 
both baseline and the corresponding post-treatment assessment time point.  
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 Urinalysis 
Urinalysis includes specific gravity, pH, glucose, protein, ketones, blood, RBC, WBC, 
Casts, and a microscopic exam if abnormal results are noted. 
 
Summaries will be presented by cohort. 
• Categorical urinalysis variables (Glucose, Blood, Protein, Ketones, RBC, WBC, Casts) 
will be summarized by number and percentage (n(%)) of subjects. 
• The urine pH and specific gravity will be summarized using descriptive statistics (n, 
mean (SD), median, Min and Max).    
 Thyroid Function 
Thyroid function tests will be performed at screening and every 6 weeks thereafter. 
• TSH, T3 and FT4 data will be summarized using descriptive statistics (n, mean (SD), 
median, Min and Max).    
  Coagulation and Anticoagulation Levels 
Anticoagulant specific drug and/or anticoagulant factor Xa levels will be obtained from patients 
receiving anticoagulation therapy at Screening, Day 0, Week 3, Week 6, Week 9, Q6W until 
Week 45 , thereafter Q12W . 
• aPTT, INR, PT, TT and Xa data will be summarized using descriptive statistics (n, mean 
(SD), median, Min and Max).    
 Electrocardiograms 
12-Lead ECG will be completed at screening/baseline visit. 
• The overall assessment categories (Normal, Abnormal; not clinically significant, 
Abnormal; clinically significant) will be summarized.  
• ECG data will be presented in a data listing. 
 Eastern Cooperative Oncology Performance Status 
ECOG perfomance will be completed at screening/baseline, Cycles 1,2,3,4 and every 3 weeks 
thereafter, and at the discontinuation visit on a 6-point scale from grade 0-5 as presented in 
Appendix C.   
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• ECOG PS assessments will be summarized overall as categorical variables by time point 
utilizing descriptive statistics.  
 Vital Signs and Weight 
Vital signs and Weight will be taken at various timepoints: Baseline/Screening visit, Cycle 1 Day 
0, Cycle 2 Week 3, Cycle 3 Week 6, Cycle 4 Week 9, Every  3 weeks, and at the discontinuation 
visit. Height will only be taken at baseline/screening visit. 
• Descriptive statistics will be presented for each timepoint. 
• Descriptive statistics will also be presented for the changes in vital signs from baseline to 
each post-treatment assessment time point. 
 Physical Examinations 
A full physical examination will be performed at screening/baseline. There will also be targeted  
physical examinations at these timepoints: Cycle 1 Day 0, Cycle 2 Week 3, Cycle 3 Week 6, 
Cycle 4 Week 9, Every 3 weeks afterwards and at discontinuation visit.  
• Physical exams will be presented in data listings 
 Pregnancy Testing 
Pregnancy testing (when applicable) will be  carried out at every visit  except the every 6 weekly 
visits.  
• Pregnancy testing results will be presented in data listings 
 Immunogenicity Assessments 
Processing of immunogenicity samples will be performed at Sensei Biotherapeutics or 
designee. The analyses of these assessments is beyond the scope of this SAP.  
 ASPH Immunohistochemistry (IHC) Assay 
ASPH testing will be done by immunohistochemistry on either fresh or archival tumor 
tissue. Additional preparation of the slides will be performed at Sensei Biotherapeutics or 
designee. Staining intensity and distribution of ASPH levels will be evaluated according 
to the following scale: 
• Negative =0;  
• Moderate =1+ 
• Strong=2+  
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• Very strong immunoreactivity = 3+ 
Preparation of the slides will be performed at Sensei Biotherapeutics or designee. The analyses of 
these assessments is beyond the scope of this SAP.  
9. STATISTICAL/ANALYTICAL ISSUES  
 Handling of Dropouts or Missing Data 
All available data will be presented on the data listings as collected. 
Algorithms for imputing partial or missing dates related to AEs and prior/concomitant 
medications are shown below.  
Table 3 
Imputation Rules for Partially Missing Dates 
Variable 
Missing Day 
Missing Day, Month 
Missing Day, Month, 
Year 
Date of Last 
Therapy/Date of Initial 
Diagnosis 
Assign 1 
Assign January 1 if 
prior to date of 
informed consent, 
otherwise use date of 
informed consent 
Missing (do not 
impute) 
Adverse Event/Medication 
Start 
Date 
Assign first day of month 
unless it is the month of 
first dose of study 
medication. Otherwise, 
assign date of first dose of 
study medication. 
Assign January 1 
unless the year is year 
of first dose of study 
medication Otherwise, 
assign date of first 
dose of study 
medication. 
Assign date first 
dose of study 
medication. 
Adverse Event/Medication 
End Date 
Assign the last day of the 
month or end of study 
date, whichever is 
earlier. 
Assign December 31 
or end of study date, 
whichever is earlier. 
If ongoing, end date 
is missing. 
Otherwise, assign 
end of study date. 
 
Every effort to re-contact the patient lost to follow-up patients will be made, to identify the 
reason why he/she failed to attend the visit, and to determine his/her health status, including at 
least his/her vital status. Data from lost to follow-up subjects to the date of last recorded contact 
will be included in the analyses.  
Non-evaluable patients will be replaced. 
 
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 Pooling of Centers in Multi-Center Trials 
There will be no pooling of centers. 
 Multiple Comparisons/Multiplicity 
No adjustments for multiple comparisons or multiplicity will be made. 
 Examination of Subgroups 
No subgroup analysis will be performed in this study. 
 Interim Analysis and Data Monitoring 
A Safety Committee will be formed to monitor safety on a periodic basis. The Safety Committee 
will meet at the completion of the safety run-in to review safety data collected from the point of 
first patient in (FPI) to review safety, or as needed. The safety data will include demographic 
data, adverse events, serious adverse events, and relevant laboratory data.  
The interim efficacy assessment, for each cohort, will occur after 15 patients were enrolled and 
completed the 12-week follow-up period. The objective response rate, for each cohort, will be 
assessed at the completion of stage 1 of the 2-stage design, after 15 patients complete the 12-week 
follow-up period or discontinue prior due to disease progression. A safety review will occur in 
parallel to the efficacy assessment of the first 15 patients in each cohort. 
10. 
 QUALITY CONTROL  
All data displays and analyses will adhere to the International Conference on Harmonization 
(ICH) Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports. 
All analyses will be performed using SAS® Version 9.4 (or later). Advanced Clinical will follow 
its standard operating procedures in the creation and quality control of all tables, listings, figures, 
and analyses. 
Sensei Biotherapeutics will review all tables, listings, and figures prior to final database lock. 
Final SAS datasets, programs and outputs will be transferred to Sensei biotherapeutics at project 
completion. 
11. 
RECORD RETENTION  
Records related to the activities listed in this plan will be retained according to AC SOP AD-005. 
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12. 
TABLES AND LISTING CONVENTIONS 
Mock-ups for statistical tables and listings will be provided. Final formats for the statistical 
tables and listings may deviate from these mock-ups upon agreement with Sensei. Footnotes will 
be used as needed to clarify the information that is presented in the tables and listings. Unless 
otherwise requested by Sensei, the term ‘patient’ will be used in all tables and listings, in 
accordance with CDISC standards. 
The general layout of tables and listings will be as follows. 
 
 
 
All tables and listings will use landscape orientation. Margins will be at least 2.0 cm at the top 
and bottom and at least 0.8 cm on the left and right, excluding headers and footers, in accordance 
with electronic Common Technical Document (eCTD) guidelines. Font will be Courier New, 
unless otherwise specified, with an 8-point font size in most cases. Page numbering will be 
sequential within each table, listing, and figure. Column headers should be in initial capital 
letters. Units for numeric data will be included when appropriate. 
Tables and data listings will be created from different SAS programs. A single program may 
produce multiple tables or multiple data listings from the same dataset (e.g., all clinical 
chemistry data listings may be generated by a single program). 
 
 
<Sponsor name> 
Page x of y 
Protocol: <protocol identifier>  
Run Date: DDMMMYY-HH:MM 
Clinical/Statistical Report 
 
Listing 16.2_x (or Table 14.x_x) 
<Title> 
<Population> 
 
___________________________________________________________________________________________________
 
                                   
Col 1 
Col 2 
Col 3 
etc 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________________________________ 
 
<Any footnotes> 
 
File Name:   <pathname for SAS program> 
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 Statistical Table Conventions 
Mock-ups for statistical tables will include headers, title numbers, titles, column headers and 
footers, and a proposed layout for the display of data. The final decision on the precision (i.e., 
number of decimal places) for presentation of descriptive statistics will be made by Sensei 
Biotherapeutics after review of draft statistical tables and before database freeze. 
 Data Listing Conventions 
Mock-ups for data listings will include headers, title numbers, titles, column headers, and 
footers. Data listings will provide all data collected on the corresponding eCRF page or provided 
by external vendors, unless otherwise indicated. If there are too many fields to be fit into a single 
page, data should be grouped logically and the listings will be generated as Part I, Part II, etc. 
In general, data listings should include all patients with data. However, if only patients who meet 
a certain condition are listed (e.g., patients with SAEs) and no patients meet the condition, the 
data listing will so indicate. 
The  data presented in data listings will be sorted by patient ID. Within a patient, data will be 
listed in chronological order. Whenever possible, formatted values will be displayed (i.e., 
decoded). Where applicable, calendar date and study day of evaluations/events will be provided 
in the data listings. 
13. 
REFERENCES 
1. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Published: 
November 27, 2017. National Cancer Institute, National Institutes of Health. U.S. 
Department of Health and Human Services. 
2. International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical 
Practice 
3. International Conference on Harmonization (ICH, 1997) E8 Guideline: General 
Considerations for Clinical Trials 
4. Medical Dictionary for Regulatory Activities (MedDRA), Version 20. 
5. World Health Organization (WHO) Drug Dictionary (WhoDrugDDEB2_201703). 
 
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14. 
CHANGE HISTORY  
Version 
Date 
Description of Changes  
0.1 
16JAN2020 
Original Document  
0.2 
27FEB2020 
Internal review, Not reviewed by Sensei 
0.3 
 
01MAY2020 
Internally Revised and resubmitted to reduce overall revew 
cycles. Protocol amendments pending  
0.4 
 
29JUN2020 
Reviewed by Sensei. Protocol amendments still pending 
0.5 
 
24SEP2020 
First version incorporating protocol amendment (protocol V3.0) 
1.0 
20NOV2020 
Revisions following protocol amendment (protocol V4.0) 
2.0 
25JAN2021 
Revisions to Section 1 and Section 2 and section 6 following 
protocol amendment V4.0 
3.0 
15MAR2021 
Final version approved by Sensei Biotherapeutics 
1.0 
05MAY2021 
Version Number Change only. Change history updated. eTMF 
Lead directed that this should revert to V1.0 as it is the first 
version signed by Sensei Biotherapeutics. Previous versions had 
been reviewed but not signed off by sponsor. 
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APPENDICES 
       Appendix A: Schedule of Trial Assessments 
Screeninga 
Cycle 1 
Day 0 
Cycle 2 
Week 3 
Cycle 3 
Week 6 
Cycle 4 
Week 9 
Every 3 
weeks 
Every 6 
weeks 
Discontinuation 
Visitb 
Follow
-up 
Day -28 to 
Day -1 
Signed Informed 
Consent Form(s) 
X 
Medical, surgical, and 
cancer histories, 
including demographic 
X 
Inclusion/Exclusion 
criteria 
X 
X 
Complete Physical 
examd 
X 
Targeted Physical 
exame 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
ECOG performance 
statusf 
X 
X 
X 
X 
X 
X 
X 
HIV, Hep B and Hep C 
serologyg 
X 
Concomitant 
Medicationsh 
X 
X 
X 
X 
X 
X 
X 
Anticoagulant specific 
drug and/or 
anticoagulant factor Xa 
levelsi 
X 
X 
X 
X 
X 
At Week12, then Q6w until 
week 45, thereafter Q12w 
X 
For patients on 
anticoagulants only 
Vital Signs and Weightj 
X
X
X
X
X
X
X
Height 
X
12-lead ECGk 
X
Tumor Imagingl 
X
Q6w from Day 0 until ~12 months, there after Q12w 
RECIST/iRECIST 
X
Q6w from Day 0 until ~12 months, there after Q12w 
Hematologym 
X
Xf
Xf
Xf
Xf
Xf
X
Serum Chemistryn 
X
Xf
Xf
Xf
Xf
Xf
X
Coagulation Panel 
(aPTT, INR) 
X 
Urinalysiso 
X 
X 
X 
X 
Pregnancyp 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, T3 and  Free T4q 
X 
X 
X 
CPK 
X 
X 
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HPV/EBV, if unknown 
X 
Blood samples for 
immunology 
assessmentsr 
X 
X 
X 
X 
At week 12, then Q6 
weeksuntill week 36 
and Q12w 
thereafter as well as at 
disease progression 
Tumor specimens 
X 
X 
Up to 2 optional biopsies 
and at disease 
progression 
Adverse Eventst 
X 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumabu 
X 
X 
X 
X 
X 
SNS-301v 
X 
X 
X 
X 
After week 9, Q6w for 6 
more doses (week 45), 
thereafter Q12w until PD 
or 24 months if no PD 
Survival and new anti- 
cancer therapy follow- 
upw 
X 
Note: Assessments scheduled on the days of study treatment should be performed before the study treatment 
unless otherwise noted. 
a  P Written informed consent can be obtained up to 28 days prior to Day 0 and is required for performing any 
trial-specific tests or procedures. Tumor tissue may be submitted up to 28 days prior to Day 0. Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior 
to Day 0 may be used for screening assessments rather than repeating such tests. Screening labs (CBC and 
chemistry) may be used for Day 0 if they are within 10 days of Day 0. 
b        P          Patients who discontinue early from study treatment (i.e.,  progression, adverse event, etc.), will be asked to 
return to the clinic 
within 30 days after the last dose for a treatment 
discontinuation visit. 
c        P     P Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Previous progression data 
should be collected as well. Demographic information includes sex, age, and self-reported race/ethnicity. HPV, 
EBV, reproductive status and smoking/alcohol history should also be captured. PD-L1 status will also be 
collected, if available. 
d        P             A complete physical exam will include head, eyes, ears, nose, throat and cardiovascular, dermatological, 
musculoskeletal, 
respiratory, gastrointestinal and neurological systems.  Height and weight will also be collected.  Any signs 
and symptoms, other than those associated with a definitive diagnosis, should be collected at baseline and 
during the study. 
e A targeted, symptom-directed exam will be performed, as clinically indicated. 
f ECOG performance status, targeted physical exam, and local laboratory assessments may be obtained ≤ 72 
hours before each dosing visit. 
g      P   P   P Patients should be tested for HIV locally prior to the inclusion into the trial only based on  investigator’s 
clinical suspicion for 
HIV infection and HIV-positive patients will be excluded from the clinical trial. Hepatitis B surface antigen, 
anti-HBc antibody, anti-HBs antibody, and Hepatitis C antibody immunoassays should be tested only per 
investigator’s clinical suspicion during screening and tested locally. In patients who have positive serology for 
the anti-HBc antibody, HBV DNA should be tested prior to Day 0. 
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h
      P         Concomitant medications include any prescription medications or over-the-counter medications. At screening, 
any medications the patient has used within the 7 days prior to the screening visit should be documented. At 
subsequent visits, changes to current medications or medications used since the last documentation of 
medications will be recorded. 
i Specific anticoagulant drug and/or anticoagulant factor Xa levels will be obtained only on patients receiving 
anticoagulant therapy. Drug levels will also be obtained at any time of clinical bleeding.  Traditional testing 
methods can be used for warfarin, heparin (e.g., PT/INR, aPTT, TT).  Novel oral anticoagulants may require 
anticoagulant factor Xa levels or anticoagulant drug specific level testing.  See sections Concomitant 
Medications & Guidance for Investigators for Patients on Anti-coagulants for additional information. 
j Vital signs include heart rate, respiratory rate, blood pressure, and temperature. For first infusion of 
pembrolizumab, the patient’s vital signs should be determined within 60 minutes before the infusion. If clinically 
indicated, vital signs should be at 15, 30, 45, and 60 minutes (± 5 minutes for all timepoints) after the start of the 
infusion, and 30 (± 10) minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 
minutes before the infusion and at 30 (± 5) minutes after the infusion. Patients will be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their trial physician if they develop such 
symptoms. 
k ECG recordings will be obtained during screening and as clinically indicated at other time points. Patients 
should be resting and in a supine position for at least 10 minutes prior to ECG collection. 
l Examinations performed as standard of care prior to obtaining informed consent and within 28 days of first dose 
of study treatment may be used rather than repeating tests. All measurable and evaluable lesions should be 
assessed and documented at the screening 
visit. Tumor imaging should be performed by computed tomography (CT), but may be performed by magnetic 
resonance imaging (MRI) if CT is contraindicated, but the same imaging technique should be used in patient 
throughout the trial. CT scans (with oral/IV contrast unless contraindicated) must include chest, abdomen and 
pelvis. The investigator must review before dosing at the next visit. Patients will undergo tumor assessments 
every 6 weeks (±7 days) for the first 54 weeks (approximately 12 months) following first dose of study 
treatment, or earlier if clinically indicated. After 54 weeks, tumor assessments will be required every 12 weeks 
(±7 days). Patients who discontinue from treatment for reasons other than disease progression (e.g., toxicity) will 
continue scheduled tumor assessments until disease progression, start of new-anti cancer therapy, withdrawal of 
consent, or death. Investigators may perform additional scans or more frequent assessments if clinically 
indicated. Patients who continue treatmentbeyond radiographic or clinical disease progression will be monitored 
with a follow-up scan at the next scheduled tumor assessment. Imaging timing should follow calendar days and 
should not be adjusted for delays or changes in treatment administration dates. The Sponsor may request digitized 
scans from patients during the study. 
m  
P Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated 
differential (absolute counts of neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells (if 
any)), and platelet count. A manual differential can be done if clinically indicated. 
n  Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or 
CO2, calcium, phosphorus, glucose, total bilirubin (direct bilirubin only if total bilirubin is elevated), ALT, 
AST, alkaline phosphatase, lactate dehydrogenase, total protein, and albumin. 
o Urinalysis includes specific gravity, pH, glucose, protein, ketones, blood, and a microscopic exam if abnormal 
results are noted. Urinalysis to be performed every 6 weeks.  
 p Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) 
must be performed and documented as negative within 72 hours prior to each dose. 
q Thyroid function tests will be performed on first dose and every 6 weeks thereafter. 
P 
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r Immunology samples are to be drawn at Day 0, Week 3, Week 6, Week 9, Week 12, then Q6 weeks until Week 
36 and thereafter every 12 weeks until disease progression, as well as at disease progression.  If the patient is 
unable to have samples obtained at the protocol specified visit (i.e., COVID19 related) then an unscheduled 
sample may be drawn. 
s A pre-treatment tumor tissue sample will be analyzed for ASPH expression as part of the screening process. After 
signing of the Informed Consent Form, tumor tissue should be submitted to the Sponsor in a timely manner.  
Samples will be collected and analyzed preferably before other non-SOC procedures.  Eligibility based on ASPH 
expression will be provided back to the sites within 5-8 business days.  A pre-treatment sample is defined as a 
specimen obtained after initiation of ongoing CPI therapy and before first dose of SNS-301 and pembrolizumab on 
this current clinical trial. Patients are requested to provide archival tissue from a prior biopsy or surgery that is 
treatment –naïve including prior 1) chemotherapy, radiation and/or 2) anti- PD(L)-1 treatment-naïve, pending 
availability.  Tumor tissue should be of good quality based on total and viable tumor content. Acceptable samples 
include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-needle aspiration may be acceptable pending 
Sponsor approval however, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. For 
core needle biopsy specimens, at least three cores should be submitted for evaluation. All patients will undergo a 
mandatory tumor biopsy sample collection, if clinically feasible as determined by the trial investigator, at the Week 
6 (at the time of third dose +/- 3 days). Additionally, up to two optionalbiopsies may be obtained at any time during 
the study, if medically feasible. A biopsy may also be obtainedat the first evidence of radiographic or clinical disease 
progression (i.e., not proceeded by meaningful tumor regression). For patients who respond and subsequently 
progress, an optional biopsy may be obtained at the time of disease progression. Patients who are unable to undergo 
biopsy sample collection but otherwise meet criteria outlined in protocol may continue to receive study treatment. 
t   AEs will be collected from the time of informed consent until 30 days after the last dose of study treatment or 
until initiation of another anti-cancer therapy, whichever occurs first. SAEs and AESIs will be collected from the 
time of informed consent until 90 days after the last dose of study treatment of until initiation of anti-cancer therapy, 
whichever occurs first. 
u Pembrolizumab will be given every 3 weeks until confirmed disease progression, unacceptable toxicity,  deemed 
intolerable by investigator or up to 24 months in patients without disease progression. The window for each visit 
is ± 3 days unless otherwise noted. A 60 minutes observation period is recommended for the first dose and 30 
minutes for subsequent doses. 
v  SNS-301 is administered every 3 weeks until week 9 (ie.,4 doses). Then every 6 weeks for 6 more doses 
(until week 45). Thereafter it will be administered every 12 weeks until confirmed disease progression, 
unacceptable toxicity, deemed intolerable by investigator or up to 24 months in patients without disease progression. 
The window for each visit is ± 3 days unless otherwise noted. A 30-minute observation period is recommended after 
each study treatment. 
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinical visits 
approximately every 3 months for up to 3 years, until death, lost to follow-up, withdrawal of consent, or trial 
termination by Sponsor. All patients will be followed for survival and new anticancer therapy information unless 
the patient requests to be withdrawn from follow-up; this request must be documented in the source documents and 
signed by the investigator. If the patient discontinues study treatment without documented clinical disease 
progression, every effort should be made to follow up regarding survival, progression (if not already progressed), 
and new anti-cancer therapy. 
 
 
 
 
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       Appendix B: Laboratory Cut off Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1500/ µL 
Platelets 
≥100,000/ µL 
Hemoglobin 
≥9 g/dL, or ≥5.6 mmol/L without transfusion or EPO 
dependency within 7 days 
Renal 
Creatinine OR 
Calculated creatinine clearance 
≤ 1.5 x upper limit of normal (ULN) OR 
≥ 30 mL/min for patient with creatinine level > 
1.5 x institutional ULN 
Note: Creatinine clearance should be calculated per Cockcroft-
Gault formula 
Hepatic 
Total bilirubin 
≤ 1.5  x ULN  OR Direct bilirubin ≤ ULN for patients 
with total bilirubin levels > 1.5 x ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 x ULN 
OR 
≤ 5  x  ULN  for  patients  with  liver metastases 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
≤1.5 x ULN unless patient is receiving anticoagulant 
therapy as long as PT or 
PTT   is   within   therapeutic   range   of intended use of 
anticoagulants 
Activated Partial Thromboplastin 
Time 
(aPTT) 
≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
 
 
 
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CONFIDENTIAL                                      Statistical Analysis Plan                                 Version 1.0 
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       Appendix C: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
GRADE 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
*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. 
 
 
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CONFIDENTIAL                                      Statistical Analysis Plan                                 Version 1.0 
Page 42 of 45 
 
       Appendix D: Overall Status Calculation (Measurable Disease) 
 
Time point response: patients with target (+/- non-target disease) at baseline 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD=stable disease, PD = 
progressive disease, and NE = inevaluable 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL                                      Statistical Analysis Plan                                 Version 1.0 
Page 43 of 45 
 
       Appendix E: Overall Status Calculation (Non_target Disease) 
Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Uniequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = inevaluable 
aNon-CR/non-PD is preferred over stable disease for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 
 
 
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CONFIDENTIAL                                      Statistical Analysis Plan                                 Version 1.0 
Page 44 of 45 
 
       Appendix F: Calculation of Best Overall Response 
Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD=stable disease, PD = progressive disease, and NE = 
inevaluable 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes CR may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
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