A Phase 1b Safety and Feasibility Study of Personalized Immunotherapy in Adults With Advanced Cancers
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Aaron Miller

A Phase 1b Safety and Feasibility Study of Personalized 
Immunotherapy in Adults with Advanced Cancers 
NCT03568058
Document Date: 2/20/2022

Protocol 180410 PSLP  
Protocol Amendment 7.2 
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Protocol Date  20 February 2022 
A Phase 1b Safety and Feasibility Study of Personalized 
Immunotherapy in Adults with Advanced Cancers 
PROTOCOL 
Study Chair (Principal Investigator) 
Ezra Cohen, M.D. 
Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Phone: 858-534-6161 
Fax: 858-822-5754 
Email: ecohen@ucsd.edu 
Study Site 
UCSD Moores Cancer Center 
3855 Health Sciences Drive #0698 
La Jolla, CA 92093-0698 
Protocol Number 
 180410 
IND Number: 
 18183 
IND Holder Name: 
 Ezra Cohen, MD 
Protocol Date: 
 
20 February 2022 
Protocol 
Date 
Original (v 1.2) 
6/25/2018 
Protocol Amendment 1 (v 3.0) 
8/05/2018 
Protocol Amendment 2  
10/09/2018 
Protocol Amendment 3 
10/26/2018 
Protocol Amendment 3.1 
12/19/2018 
Protocol Amendment 3.2 
1/28/2019 
Protocol Amendment 3.3 
4/25/2019 
Protocol Amendment 4.0 
7/9/2019 
Protocol Amendment 5.0 
12/19/2019 
Protocol Amendment 6.1 
12/17/2020 
Protocol Amendment 7.0 
11/27/2021 
Protocol Amendment 7.2 
02/20/2022 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or consultant for review by you, your staff, and the 
applicable Institutional Review Board. Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from the Sponsor 

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Protocol Date  20 February 2022 
LIST OF INVESTIGATORS 
PRINCIPAL INVESTIGATOR 
Ezra Cohen, M.D.  
Professor of Medicine  
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive  
La Jolla, CA 92093-0658  
Phone: 858-534-6161  
Fax: 858-822-5754  
Email: ecohen@ucsd.edu 
CO-INVESTIGATOR(S) 
Stephen Schoenberger, Ph.D. 
Professor 
Division of Developmental Immunology 
La Jolla Institute for Immunology  
9420 Athena Circle 
La Jolla, CA 92037 
Email: sps@lji.org 
Sandip Patel, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0820 
Email: sandippatel@ucsd.edu 
Aaron Miller, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: ammiller@health.ucsd.edu 
Rebecca Shatsky, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: rshatsky@ucsd.edu 
Rana McKay, M.D. 
Assistant Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: rmckay@ucsd.edu  
Shumei Kato, M.D. 
Associate Professor of Medicine  
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: smkato@ucsd.edu  
BIOSTATISTICIAN 
Karen Messer, Ph.D.  
Professor of Family Medicine & Public Health 
UC San Diego Moores Cancer Center  
3855 Health Sciences Drive #0901  
La Jolla CA, 92093-0901  
Phone: 858-822-6823  
E-mail: kmesser@ucsd.edu
Xinlian Zhang, PhD 
Assistant Professor of Family Medicine & Public 
Health  
UC San Diego Moores Cancer Center  
3855 Health Sciences Drive #0901  
La Jolla CA, 92093-0901  
Phone: (858) 822-4838E-mail:  xizhang@ucsd.edu 

 
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Protocol Date  20 February 2022 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator / Study Chair 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
Participating Site Principal Investigator 
 
 
_____________________________  
_____________________________ 
Printed Name  
 
 
 
Institution 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 

 
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Protocol Date  20 February 2022 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................................... 6 
STUDY SUMMARY .................................................................................................................................................. 9 
1.0 
BACKGROUND AND RATIONALE ...................................................................................................... 19 
1.1 
Immunotherapy in Advanced Cancer Patients ....................................................................................... 19 
1.2 
Summary of Clinical Studies with personalized vaccine-based Immunotherapy ................................... 19 
1.3 
Rationale for Personalized Immunotherapy ........................................................................................... 20 
1.4 
Dose Selection Rationale ....................................................................................................................... 20 
1.5 
Selection and Validation of Neoantigens ............................................................................................... 21 
1.6 
Rationale for Addition of anti-PD1 Antibody ........................................................................................... 23 
1.7 
Study Rationale ...................................................................................................................................... 24 
2.0 
STUDY OBJECTIVES ........................................................................................................................... 25 
2.1 
Primary Objectives ................................................................................................................................. 25 
2.2 
Secondary Objectives (defined in Section 9.0) ...................................................................................... 25 
2.3 
Exploratory Objectives ........................................................................................................................... 25 
3.0 
PATIENT ELIGIBILITY .......................................................................................................................... 26 
3.1 
Inclusion Criteria ..................................................................................................................................... 26 
3.2 
Exclusion Criteria ................................................................................................................................... 28 
4.0 
TREATMENT PLAN .............................................................................................................................. 30 
4.1 
Study Design .......................................................................................................................................... 30 
4.2 
Definition of Dose Limiting Toxicities (DLTs) ......................................................................................... 31 
4.3 
Pembrolizumab ...................................................................................................................................... 33 
4.4 
Treatment Dosage and Administration ................................................................................................... 33 
4.5 
Dosing Eligibility and Delayed Dosing .................................................................................................... 34 
4.6 
Concomitant therapy and procedures .................................................................................................... 35 
4.7 
Prohibited concomitant therapy .............................................................................................................. 35 
4.8 
Rescue Medications & Supportive Care ................................................................................................ 36 
4.9 
Toxicities and Dosing Delays/Dose Modifications ................................................................................. 36 
4.10 
Duration of Study Treatment .................................................................................................................. 43 
4.11 
Discontinuation from Study Participation ............................................................................................... 43 
5.0 
STUDY PROCEDURES ......................................................................................................................... 44 
5.1 
Definitions of Study Assessments .......................................................................................................... 45 
5.2 
Screening/Baseline Procedures ............................................................................................................. 47 
5.3 
Procedures During Treatment ................................................................................................................ 48 
5.4 
Follow-up Procedures ............................................................................................................................ 48 
5.5 
Correlative Studies ................................................................................................................................. 48 
6.0 
MEASUREMENT OF EFFECT .............................................................................................................. 54 
6.1 
Safety/tolerability .................................................................................................................................... 54 
6.2 
Antitumor Effect ...................................................................................................................................... 54 
7.0 
ADVERSE EVENTS ............................................................................................................................... 54 
7.1 
Adverse Event Monitoring ...................................................................................................................... 57 
7.2 
Severity ................................................................................................................................................... 58 
7.3 
Seriousness ............................................................................................................................................ 58 

 
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Protocol Date  20 February 2022 
7.4 
Relationship ............................................................................................................................................ 59 
7.5 
Evaluation of Adverse Events ................................................................................................................ 59 
7.6 
Reporting Requirements for Adverse Events ......................................................................................... 61 
8.0 
AGENT INFORMATION ........................................................................................................................ 64 
8.1 
Personalized vaccine ............................................................................................................................. 64 
8.2 
Pembrolizumab ...................................................................................................................................... 65 
9.0 
STATISTICAL CONSIDERATIONS ...................................................................................................... 66 
10.0 
STUDY MANAGEMENT ........................................................................................................................ 72 
10.1 
Conflict of Interest .................................................................................................................................. 72 
10.2 
Institutional Review Board (IRB) Approval and Consent ....................................................................... 72 
10.3 
Subject Data Protection .......................................................................................................................... 72 
10.4 
Data and Safety Monitoring/Auditing ...................................................................................................... 73 
10.5 
Adherence to the Protocol ...................................................................................................................... 73 
10.6 
Protocol Amendments ............................................................................................................................ 74 
10.7 
Record Retention ................................................................................................................................... 74 
10.8 
Obligations of Investigators .................................................................................................................... 74 
11.0 
REFERENCES ....................................................................................................................................... 75 
12.0 
APPENDICES ........................................................................................................................................ 77 
Appendix A. Performance Status ....................................................................................................................... 77 
Appendix B. Response Evaluation Criteria in Solid Tumors (RECIST) .............................................................. 78 
Appendix C: Contraceptive Guidance and Pregnancy Testing .......................................................................... 84 
 
 
 

 
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Protocol Date  20 February 2022 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CRP 
C-reactive Protein 
CSF 
Cerebrospinal Fluid 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dendritic Cell 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice  
HIV 
Human Immunodeficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HPV 
Human Papillomavirus 
HRPP 
Human Research Protections Program 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry  
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
I.V. 
Intravenous 
LDH 
Lactate Dehydrogenase 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PBMCs 
Peripheral Blood Mononuclear Cells 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 

 
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Protocol Date  20 February 2022 
PT 
Prothrombin Time 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
UPR 
Unanticipated Problems involving Risk to subjects or others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol Date  20 February 2022 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 

 
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Protocol Date 20 February 2022 
STUDY SUMMARY 
 
Title 
A Phase 1b Safety and Feasibility Study of Personalized Immunotherapy in Adults with Advanced 
Cancers 
Short Title 
Personalized Vaccine in Advanced Cancer Patients 
Phase 
1b 
Methodology 
Open label, single arm, unblinded 
Study Duration 
Approximately 4 years  
Study Center(s) 
Single-center  
Objectives 
Demonstrate induction or increase in T cell neoantigen reactivity 
Number of Subjects 
  n=30 
Diagnosis and Main 
Inclusion Criteria 
• 
Advanced Solid Tumor patients who are not candidates for curative therapy 
• 
Measurable disease 
• 
At least one site of disease amenable to core needle biopsy 
Study Product(s), 
Dose, Route, 
Regimen 
Personalized vaccine (encoding tumor-specific neoantigens) at a dose of 100 µg per peptide.  
 
Arm A: Personalized vaccine and anti- PD-1 administered concurrently at the start of study therapy. 
Personalized vaccine will be administered by subcutaneous injection. Vaccine will be administered every 
three weeks for a total of three doses.  Vaccine may continue to be administered at 3 week intervals  for an 
additional 9 doses  if there is no evidence of disease progression. Treatment for up to 9 doses may 
continue past progression if the treating physician feels there is continued benefit.     
 
Arm B: Anti-PD-1 antibody for 6 weeks followed by personalized vaccine therapy. Personalized vaccine will 
be administered by subcutaneous injection. Vaccine will be administered every three weeks for a total of 
three doses.  Vaccine may continue to be administered at 3 week intervals  for an additional 9 doses  if 
there is no evidence of disease progression. Treatment for up to 9 doses may continue past progression if 
the treating physician feels there is continued benefit. 
 
Arm C: Personalized vaccine and anti- PD-1 administered concurrently in a boosted schedule at the start of 
study therapy. Personalized vaccine will be administered by intramuscular injection. Vaccine will be 
administered three weekly priming vaccine doses, followed by six vaccine doses administered every three 
weeks.  Vaccine may continue to be administered at 3 week intervals for an additional 18 doses if there is 
no evidence of disease progression. Treatment for up to 9 doses may continue past progression if the 
treating physician feels there is continued benefit. 
 
Arm D: Personalized vaccine alone, in a boosted schedule at the start of study therapy. Personalized 
vaccine will be administered by intramuscular injection. Vaccine will be administered three weekly priming 
vaccine doses, followed by six vaccine doses administered every three weeks.  Vaccine may continue to 
be administered at 3 week intervals for an additional 18 doses if there is no evidence of disease 
progression. Treatment for up to 9 doses may continue past progression if the treating physician feels there 
is continued benefit. 

 
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Protocol Date 20 February 2022 
 
TABLE 1a: SCHEDULE OF EVENTS: ARM A (CLOSED TO ENROLLMENT) 
Assessmentsr 
Screening 
Treatment Period a 
Treatment 
Continuation 
End of 
Treatmentb 
Follow-up 
Eligibility 
Pre-vaccine 
Week 0 
Week 3 
Week 6 
Week 9 
Q 3 Wks 
4 wks post 
final treatment 
Q 12 Wksc 
Day 
 
Within 14 days of 
Week 0 Day1 
D1 
D8 
D1 a 
D8 
D1 a 
D8 
D1 a 
D8 
D1 
D1 
  
Visit Window 
(days) 
 
±1 
±3 
±1 
±3 
±1 
±3 
±3 
 ±3 
±7 
±7 
Informed consent 
X 
X  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical history, 
heightd 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Virology screene 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Coagulation paneln 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
CT or MRIp 
  
X 
  
  
  
  
  
  
X 
  
Q 9 wks 
±7 daysp 
X 
  
Genome 
sequencing (blood) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy 
Xf 
  
  
  
  
  
  
  
Xf,l 
  
  
Xf,l 
  
Physical examg 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
ECOG status 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Vital signsh 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Pregnancy testi 
 
X 
  
  
  
  
  
  
  
  
  
  
  
Clinical labsj 
Xj 
Xj 
Xj 
  
Xj 
  
Xj 
  
Xj 
  
Xj 
Xj 
  
TSH 
 
X 
 
 
Xq 
 
 
 
Xq 
 
Xq 
X 
 
Con. Meds 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood for Correlative 
Studiesk 
 Xk 
Xk 
  
  
  
  
  
Xk 
 Xk 
  
Xk 
  
  
Vaccine 
administrationo 
  
  
X 
  
X 
  
X 
  
  
  
 Xo 
  
  
Pembrolizumabm 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
Status, cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 
 

 
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Protocol Date 20 February 2022 
 
 
 
FOOTNOTES 
a. 
At visits where dosing is indicated, all assessments should be completed prior to dosing unless stated otherwise. If any doses are delayed, adjust subsequent dosing schedule 
accordingly. The Week 3, Day 1 visit must be ≥ 21 days post the Week 0, Day 1 visit. 
b. EOT Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new therapy. If the EOT visit occurs earlier than 4 weeks, a safety follow-up 
telephone call on Day 28 (-3 days) is required; document contact in the study records.  
c. 
Follow-up begins 12 weeks after final anti-PD1 dose and every 12 weeks thereafter. 
d. Medical history, medication history, and demographics will be recorded, including cancer-related treatments and procedures. 
e. 
Virology screen only if clinically indicated and includes HIV antibody, hepatitis B surface antigen, and hepatitis C antibody. Subjects who are hepatitis C antibody positive 
with confirmed negative viral load are eligible. 
f. 
A core needle biopsy may be obtained at any accessible tumor site (primary or metastatic); CT scan-may be needed to assist during the biopsy procedure.  
g. Complete physical examinations conducted at screening and EOT; symptom-directed physical examinations conducted at all other indicated visits (up to 3 days prior to 
dosing). 
h. Vital signs include blood pressure, pulse, respiratory rate, temperature, pulse oximetry, and weight.  
i. 
Urine or serum pregnancy tests administered to WOCBP only. In case of delayed menstrual period (> 1 month) confirm absence of pregnancy prior to dosing. Pregnancy test 
for screening must be completed within 28 days prior to dosing. 
j. 
Clinical hematology includes complete blood count with differential ANC and platelet count; serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen, creatinine, lactate dehydrogenase, ALT, AST, alkaline phosphatase, bilirubin (total, direct, indirect), total protein, albumin, calcium, magnesium, uric 
acid, and phosphate. Urinalysis includes blood, glucose, ketones, leukocytes, nitrite, pH, protein, and specific gravity; perform using test strip (dipstick) unless full urinalysis 
with microbiology is clinically indicated. All prior to dosing; testing may be done up to 3 days prior to dosing. 
k. Arm A patients will have blood for correlative studies collected at the following time points: 1) Screening, eligibility 2) Screening, Pre-Vaccine (within 14 days prior to Week 
0 Day 1 vaccine administration); 3) Week 6 (within 7 days post-vaccine administration); 4) Within Week 9-12  5) Week 18 (within 12 weeks of last vaccine dose (+/- 3 days) 
and anti-PD1 antibody administration). Please see section 5.5 for details. If additional vaccine doses are administered, additional samples may be collected per investigator, a 
sample should collected within 12 weeks of last vaccine dose (+/-3 days). 
l. 
A tumor biopsy within  Weeks 9-12 and at disease progression is not required, but strongly encouraged. 
m. Pembrolizumab will be administered for a maximum of 35 cycles (approximately 2 years) if there is no evidence of disease progression. 
n.  Coagulation panel includes PT, INR, and APTT. 
o. Vaccine may be administered for an additional 12 doses if there is no evidence of disease progression. Treatment for up to 9 doses may continue past progression if the treating 
physician feels there is continued benefit. 
p. CT or MRI scans will be performed every 9 weeks (+/- 7 days) for the first 6 months of therapy and then can be performed as clinically indicated. 
q. Starting Week 3, TSH will be drawn every other pembrolizumab administration (i.e., Week 9, Week 15, Week 21, etc.) 
r. 
Alternative methods for informed consent and safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) 
may be implemented when necessary (e.g. COVID-19 pandemic) and feasible. 
s. 
Survival contacts via medical record review, telephone call, or review of the Social Security Index. 
 
 
ABBREVIATIONS FOR TABLE 
ALT=alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST=aspartate aminotransferase; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; HIV = human immunodeficiency virus; INR = international normalized ratio of prothrombin time; 
MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; PT = prothrombin time; WOCBP = woman of childbearing potential. 

 
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Protocol Date 20 February 2022 
 
 
 
 
TABLE 1b: SCHEDULE OF EVENTS: ARM B  (CLOSED TO ENROLLMENT) 
Assessmentss 
Screening 
Treatment Period a 
Treatment 
Continuation 
End of Treatmentb 
Follow-up 
Eligibility 
Pre-vaccine 
Week 0 
Week 3 
Week 6 
Week 9 
Q 3 Wks 
4 wks post final 
treatment 
Q 12 Wksc 
Day 
 
Within 14 days of 
Week 0 Day1 
D1 
D8 
D1 a 
D8 
D1 a 
D8 
D1 a 
D8 
D1 
D1 
  
Visit Window (days) 
 
±1 
±3 
±1 
±3 
±1 
±3 
±1 
±3  
±7 
±7 
Informed consent 
X 
 X 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical history, heightd 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Virology screene 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Coagulation panelo 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
CT or MRIq 
  
X 
  
  
  
  
  
  
X 
  
Q 9 wks 
±7 daysq 
X 
  
Genome sequencing 
(blood) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy 
Xf 
  
  
  
  
  
  
  
 
  
Xf,l,p  
Xf,l 
  
Physical examg 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
ECOG status 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Vital signsh 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Pregnancy testi 
 
X 
  
  
  
  
  
  
  
  
  
  
  
Clinical labsj 
Xj 
Xj 
Xj 
  
Xj 
  
Xj 
  
Xj 
  
Xj 
Xj 
  
TSH 
 
X 
 
 
Xr 
 
 
 
Xr 
 
Xr 
X 
 
Con. Meds 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood for Correlative 
Studiesk 
Xk  
Xk 
  
  
  
  
Xk 
  
 Xk 
  
Xk 
  
  
Vaccine 
administrationm 
  
  
  
  
  
  
X 
  
X 
  
Xm 
  
  
Pembrolizumabn 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
Status, cancer 
treatment 
  
  
  
  
  
  
  
  
  
  
  
  
X 

 
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Protocol Date 20 February 2022 
 
 
 
FOOTNOTES 
a. 
At visits where dosing is indicated, all assessments should be completed prior to dosing unless stated otherwise. If any doses are delayed, adjust subsequent dosing schedule 
accordingly. The Week 3, Day 1 visit must be ≥ 21 days post the Week 0, Day 1 visit. 
b. EOT Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new therapy. If the EOT visit occurs earlier than 4 weeks, a safety follow-up 
telephone call on Day 28 (-3 days) is required; document contact in the study records.  
c. 
Follow-up begins 12 weeks after final anti-PD1 dose and every 12 weeks thereafter. 
d. Medical history, medication history, and demographics will be recorded, including cancer-related treatments and procedures. 
e. 
Virology screen only if clinically indicated and includes HIV antibody, hepatitis B surface antigen, and hepatitis C antibody. Subjects who are hepatitis C antibody positive 
with confirmed negative viral load are eligible. 
f. 
A core needle biopsy may be obtained at any accessible tumor site (primary or metastatic); CT scan-may be needed to assist during the biopsy procedure. 
g. Complete physical examinations conducted at screening and EOT; symptom-directed physical examinations conducted at all other indicated visits (up to 3 days prior to 
dosing). 
h. Vital signs include blood pressure, pulse, respiratory rate, temperature, pulse oximetry, and weight.  
i. 
Urine or serum pregnancy tests administered to WOCBP only. In case of delayed menstrual period (> 1 month) confirm absence of pregnancy prior to dosing. Pregnancy test 
for screening must be completed within 28 days prior to dosing.  
 
j. 
Clinical hematology includes complete blood count with differential ANC and platelet count; serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen, creatinine, lactate dehydrogenase, ALT, AST, alkaline phosphatase, bilirubin (total, direct, indirect), total protein, albumin, calcium, magnesium, uric 
acid, and phosphate. Urinalysis includes blood, glucose, ketones, leukocytes, nitrite, pH, protein, and specific gravity; perform using test strip (dipstick) unless full urinalysis 
with microbiology is clinically indicated. All prior to dosing; testing may be done up to 3 days prior to dosing. 
k. Arm B patients will have PBMC Research samples collected at the following time points: 1) Screening, eligibility 2) Screening, Pre-Vaccine (within 14 days prior to Week 0 
Day 1); 3) Week 6 (within 7 days prior to vaccine administration); 4) Week 12 (within 7 days post-3rd vaccine administration); 5) Week 24 (within 12 weeks of last vaccine 
dose (+/- 3 days) and anti-PD1 antibody administration) If additional vaccine doses are administered, additional samples may be collected per investigator, a sample should 
collected within 12 weeks of last vaccine dose (+/-3 days). 
l. 
A tumor biopsy within Week 12-15 and at disease progression is not required, but strongly encouraged. 
m. Vaccine administered on Week 12. Vaccine may continue to be administered  at 3 week intervals  for an additional 12 doses  if there is no evidence of disease progression. 
Treatment for up to 9 doses may continue past progression if the treating physician feels there is continued benefit.     
n. Pembrolizumab will be administered for a maximum of 35 cycles (approximately 2 years) if there is no evidence of disease progression. 
o. Coagulation panel includes PT, INR, and APTT. 
p. 2nd tumor biopsy on arm B should be performed after the 3rd dose of vaccine is administered and is optional 
q. CT or MRI scans will be performed every 9 weeks (+/- 7 days) for the first 6 months of therapy and then can be performed as clinically indicated 
r. 
Starting Week 3, TSH will be drawn every other pembrolizumab administration (i.e., Week 9, Week 15, Week 21, etc.) 
s. 
Alternative methods for informed consent and safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) 
may be implemented when necessary (e.g. COVID-19 pandemic) and feasible. 
t. 
Survival contacts via medical record review, telephone call, or review of the Social Security Index. 
 
 
 
ABBREVIATIONS FOR TABLE 

 
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ALT=alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST=aspartate aminotransferase; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; HIV = human immunodeficiency virus; INR = international normalized ratio of prothrombin time 
MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; PT = prothrombin time WOCBP = woman of childbearing potential. 
 
 
 
TABLE 1c: SCHEDULE OF EVENTS: ARM C 
Assessmentss 
Screening 
Treatment Period a 
Treatment 
Continuation 
End of 
Treatmentb 
Follow-up 
Eligibility 
Pre-vaccine 
 
 
Week -1 
 
 
 
Week 0 
 
 
 
Week 1 
Week 2 
Week 5  
Week 8 
Week 9 
 
Week 11 
Week 14 
Week 17 
 
Week 18 
 
 
Week 20 
Q 3 Wks 
4 wks  
post final 
treatment 
Q 12 Wksc 
Day 
 
Within 
 28 days of 
Week -1  
Day 1 
D1 
D1 
D1  
D1 a 
D8 
D1 a 
D1 a 
D8 
D1 a 
D1 a 
D8 
D1 
D1 
  
Visit Window 
(days) 
 
 
 
±3 
±1 
±7 
±3 
±1 
±7 
±3 
±1 
±3  
±7 
±7 
Informed consent 
Xt  
Xt  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/ 
Exclusion 
X 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history, 
heightd 
X 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Virology screene 
X 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation panelo 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
CT or MRIp 
  
X 
 
  
  
 
  
X 
 
  
X 
 
  
Q 9 wks 
±7 daysp 
X 
  
Genome 
sequencing (blood) 
X 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy 
Xf 
  
 
  
  
 
  
Xf,l 
 
  
 
 
  
 
Xf,l 
  
Physical examg 
X 
X 
Xg 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
ECOG status 
X 
X 
Xr 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
Vital signsh 
X 
X 
Xr 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
Pregnancy testi 
 
X 
 
  
  
  
  
  
  
 
  
  
  
  
  
Clinical labsj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
  
Xj 
  
 
Xj 
  
Xj 
Xj 
  
TSH 
 
X 
 
 
 
Xq 
 
 
Xq 
 
 
 
 
Xq 
X 
 
Con. Meds 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood for 
Correlative 
Studiesk 
Xk  
Xk 
 
  
  
Xk 
  
 
  
  
 
  
  
Xk 
  
  

 
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Page 15 of 85 
Protocol Date 20 February 2022 
 
Vaccine 
administrationm 
  
  
 
X 
X 
X 
  
 
X 
  
 
X 
  
Xm 
  
  
Pembrolizumabn 
  
 
Xn 
  
 
X 
  
X 
  
 
X 
  
X 
  
  
Status, cancer 
treatment 
  
  
 
  
  
  
  
  
  
 
  
  
  
  
X 
 
 
 
 
FOOTNOTES 
a. 
At visits where dosing is indicated, all assessments should be completed prior to dosing unless stated otherwise. If any doses are delayed, adjust subsequent dosing schedule 
accordingly. The Week 5, Day 1 visit must be ≥ 21 days post the Week 2, Day 1 visit. 
b. 
EOT Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new therapy. If the EOT visit occurs earlier than 4 weeks, a safety follow-up telephone 
call on Day 28 (-3 days) is required; document contact in the study records.  
c. 
Follow-up begins 12 weeks after final anti-PD1 dose and every 12 weeks thereafter. 
d. 
Medical history, medication history, and demographics will be recorded, including cancer-related treatments and procedures. 
e. 
Virology screen only if clinically indicated and includes HIV antibody, hepatitis B surface antigen, and hepatitis C antibody. Subjects who are hepatitis C antibody positive with 
confirmed negative viral load are eligible. 
f. 
A core needle biopsy may be obtained at any accessible tumor site (primary or metastatic); CT scan-may be needed to assist during the biopsy procedure. 
g. 
Complete physical examinations conducted at screening and EOT; symptom-directed physical examinations conducted at all other indicated visits (up to 3 days prior to dosing; for 
Week -1, up to 7 days prior to dosing). 
h. 
Vital signs include blood pressure, pulse, respiratory rate, temperature, pulse oximetry, and weight.  
i. 
Urine or serum pregnancy tests administered to WOCBP only. In case of delayed menstrual period (> 1 month) confirm absence of pregnancy prior to dosing. Pregnancy test for 
screening must be completed within 28 days prior to dosing.  
 
j. 
Clinical hematology includes complete blood count with differential ANC and platelet count; serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, lactate dehydrogenase, ALT, AST, alkaline phosphatase, bilirubin (total, direct, indirect), total protein, albumin, calcium, magnesium, uric acid, and phosphate. 
Urinalysis includes blood, glucose, ketones, leukocytes, nitrite, pH, protein, and specific gravity; perform using test strip (dipstick) unless full urinalysis with microbiology is clinically 
indicated. All tests must be performed prior to dosing. For Week 0 Day 1, pre-vaccine screening labs may be used up to 28 days prior to dosing. For subsequent treatment days on 
which laboratory assessments are required, labs must be performed up to 3 days prior to dosing. 
k. 
Arm C patients should have Blood Collection for Correlative Studies samples collected at the following time points: 1) Screening, eligibility 2) Screening, Pre-Vaccine (within 28 days 
prior to Week -1 Day 1);  3) Week 8 (within 7 days after vaccine administration); 4) Week 32 (within 12 weeks of last vaccine dose (+/- 3 days) and anti-PD1 antibody administration). 
If additional vaccine doses are administered, additional samples may be collected per investigator, a sample should collected within 12 weeks of last vaccine dose (+/-3 days). For 
neoantigen identification, an additional 75-100 mL whole blood (eight to ten 10mL heparin tubes) may be collected every 4 weeks. 
l. 
A tumor biopsy within  Weeks 9-12 and at  disease progression is not required, but strongly encouraged. 
m. Vaccine administered on Week 20. Vaccine may continue to be administered at 3 week intervals for an additional 18 doses if there is no evidence of disease progression.  Treatment for 
up to 9 doses may continue past progression if the treating physician feels there is continued benefit.  
n. 
Pembrolizumab will be initiated 1 week prior to the first vaccine dose (week -1). Pembrolizumab will be administered for a maximum of 35 cycles (approximately 2 years) if there is no 
evidence of disease progression. 
o. 
Coagulation panel includes PT, INR, and APTT  
p. 
CT scans will be performed every 9 weeks (+/- 7 days) for the first 6 months of therapy and then can be performed as clinically indicated 
q. 
Starting Week 2, TSH will be drawn every other pembrolizumab administration following (i.e., Week 8, Week 14, Week 20, etc.) 
r. 
ECOG and Vital signs for Week -1 may be performed up to 7 days prior to dosing. 

 
Protocol  180410 PSLP  
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s. 
Alternative methods for informed consent and safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) may be 
implemented when necessary (e.g. COVID-19 pandemic) and feasible. 
t. 
Subjects may sign an initial consent allowing the vaccine to be manufactured. Subsequently, the subject would sign a second consent for treatment when they and the IP are ready to 
proceed. 
u. 
Survival contacts via medical record review, telephone call, or review of the Social Security Index. 
 
ABBREVIATIONS FOR TABLE 
ALT=alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST=aspartate aminotransferase; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; HIV = human immunodeficiency virus; INR = international normalized ratio of prothrombin time 
MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; PT = prothrombin time WOCBP = woman of childbearing potential. 
 
 
TABLE 1d: SCHEDULE OF EVENTS: ARM D 
 
Assessmentsq 
Screening 
Treatment Period a 
Treatment 
Continuation 
End of Treatmentb 
Follow-up 
Eligibility 
Pre-vaccine 
 
 
Week 0 
 
 
 
Week 1 
Week 2 
Week 5  
Week 8 
Week 9 
 
Week 11 
Week 14 
Week 17 
 
Week 18 
 
 
Week 20 
Q 3 Wks 
4 wks  
post final 
treatment 
Q 12 Wksc 
Day 
 
Within  
28 days of 
Week 0  
Day1 
D1 
D1  
D1 a 
D8 
D1 a 
D1 a 
D8 
D1 a 
D1 a 
D8 
D1 
D1 
  
Visit Window 
(days) 
 
 
±3 
±1 
±7 
±3 
±1 
±7 
±3 
±1 
±3  
±7 
±7 
Informed consent 
Xr 
Xr 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/ 
Exclusion 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history, 
heightd 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Virology screene 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Coagulation paneln 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
CT or MRIo 
  
X 
  
  
 
  
X 
 
  
X 
 
  
Q 9 wks 
±7 dayso 
X 
  
Genome 
sequencing (blood) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy 
Xf 
  
  
  
 
  
Xf,l 
 
  
 
 
  
 
Xf,l 
  
Physical examg 
X 
X 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
ECOG status 
X 
X 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
Vital signsh 
X 
X 
X 
X 
X 
  
X 
  
 
X 
  
X 
X 
  
Pregnancy testi 
 
X 
  
  
  
  
  
  
 
  
  
  
  
  
Clinical labsj 
Xj 
Xj 
Xj 
Xj 
Xj 
  
Xj 
  
 
Xj 
  
Xj 
Xj 
  
TSH 
 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol  180410 PSLP  
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Con. Meds 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood for 
Correlative 
Studiesk 
Xk  
Xk 
  
  
Xk 
  
  
  
 
  
  
Xk 
  
  
Vaccine 
administration 
  
  
X 
X 
X 
  
X 
  
 
X 
  
Xm 
  
  
Status, cancer 
treatment 
  
  
  
  
  
  
  
  
 
  
  
  
  
X 
 
FOOTNOTES 
a. 
At visits where dosing is indicated, all assessments should be completed prior to dosing unless stated otherwise. If any doses are delayed, adjust subsequent dosing schedule 
accordingly. The Week 5, Day 1 visit must be ≥ 21 days post the Week 2, Day 1 visit. 
b. EOT Visit will occur within 4 weeks after the last dose of study drug or prior to commencing the new therapy. If the EOT visit occurs earlier than 4 weeks, a safety follow-up 
telephone call on Day 28 (-3 days) is required; document contact in the study records.  
c. 
Follow-up begins 12 weeks after final vaccine dose and every 12 weeks thereafter. 
d. Medical history, medication history, and demographics will be recorded, including cancer-related treatments and procedures. 
e. 
Virology screen only if clinically indicated and includes HIV antibody, hepatitis B surface antigen, and hepatitis C antibody. Subjects who are hepatitis C antibody positive 
with confirmed negative viral load are eligible. 
f. 
A core needle biopsy may be obtained at any accessible tumor site (primary or metastatic); CT scan-may be needed to assist during the biopsy procedure. 
g. Complete physical examinations conducted at screening and EOT; symptom-directed physical examinations conducted at all other indicated visits (up to 3 days prior to 
dosing). 
h. Vital signs include blood pressure, pulse, respiratory rate, temperature, pulse oximetry, and weight.  
i. 
Urine or serum  pregnancy tests administered to WOCBP only. In case of delayed menstrual period (> 1 month) confirm absence of pregnancy prior to dosing. Pregnancy test 
for screening must be completed within 28 days prior to dosing.  
j. 
Clinical hematology includes complete blood count with differential ANC and platelet count; serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen, creatinine, lactate dehydrogenase, ALT, AST, alkaline phosphatase, bilirubin (total, direct, indirect), total protein, albumin, calcium, magnesium, uric 
acid, and phosphate. Urinalysis includes blood, glucose, ketones, leukocytes, nitrite, pH, protein, and specific gravity; perform using test strip (dipstick) unless full urinalysis 
with microbiology is clinically indicated. For Week 0 Day 1, pre-vaccine screening labs may be used up to 28 days prior to dosing. For subsequent treatment days on which 
laboratory assessments are required, labs must be performed up to 3 days prior to dosing. 
k. Arm D patients may have Blood Collection for Correlative Studies samples collected at the following time points: 1) Screening, eligibility 2) Screening, Pre-Vaccine (within 
28 days prior to Week 0 Day 1);  3) Week 8 (within 7 days after vaccine administration); 4) Week 32 (or within 12 weeks of last vaccine dose (+/- 3 days). If additional 
vaccine doses are administered, additional samples may be collected per investigator, a sample should collected within 12 weeks of last vaccine dose (+/-3 days). For 
neoantigen identification, an additional 75-100 mL whole blood (eight to ten 10mL heparin tubes) may be collected every 4 weeks. 
l. 
A tumor biopsy within  Weeks 9-12 and at  disease progression is not required, but strongly encouraged. 
m. Vaccine administered on Week 20. Vaccine may continue to be administered at 3 week intervals for an additional 18 doses if there is no evidence of disease progression. 
Treatment for up to 9 doses may continue past progression if the treating physician feels there is continued benefit.    
n. Coagulation panel includes PT, INR, and APTT.  
o. CT scans will be performed every 9 weeks (+/- 7 days) for the first 6 months of therapy and then can be performed as clinically indicated 
p. TSH performed as clinically indicated, 

 
Protocol  180410 PSLP  
Protocol Amendment 7.2 
 
 
 
 
 
Page 18 of 85 
Protocol Date 20 February 2022 
 
q. Alternative methods for informed consent and safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) 
may be implemented when necessary (e.g. COVID-19 pandemic) and feasible. 
r. 
Subjects may sign an initial consent allowing the vaccine to be manufactured. Subsequently, the subject would sign a second consent for treatment when they and the IP are 
ready to proceed. 
s. 
Survival contacts via medical record review, telephone call, or review of the Social Security Index. 
 
 
ABBREVIATIONS FOR TABLE 
ALT=alanine aminotransferase; ANC = absolute neutrophil count; APTT = activated partial thromboplastin time; AST=aspartate aminotransferase; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; HIV = human immunodeficiency virus; INR = international normalized ratio of prothrombin time 
MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cells; PT = prothrombin time WOCBP = woman of childbearing potential. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Immunotherapy in Advanced Cancer Patients 
 
Incurable advanced cancers will eventually develop resistance to standard systemic therapies. 
Recent data have demonstrated that immunotherapy can be an effective modality in several 
malignancies with regulatory approvals for checkpoint blocking agents in many settings. 
Moreover, the responses observed to these agents in many patients can be deep and durable 
emphasizing the role for immunotherapy in cancer. It is now appreciated that the critical 
determinant of a response to checkpoint blockade and other immunotherapies is the formation 
of a T cell response to cancer neoantigens. In fact, an expansion of specific T cell clones is the 
hallmark of response to checkpoint blockade.  
 
Cancer neoantigens can encompass a variety of different molecules but among the most 
attractive candidates for therapy are ones derived from genomic alterations. Mutation derived 
neoantigens are recognized by the immune system as non-self and can induce powerful T cell 
responses. In theory, a neoantigen cancer vaccine should induce both CD4 and CD8 responses 
and subsequently produce tumor responses. However, several challenges exist in producing an 
effective neoantigen vaccine for cancer patients including determining which neoantigens are 
most relevant to the immune system, finding an effective vaccine platform that induces the 
appropriate immune response, and incorporating the neoantigen sequence into the chosen 
platform. 
 
1.2 
Summary of Clinical Studies with personalized vaccine-based Immunotherapy 
Recent studies have shown that neoantigen vaccine approaches are able to induce robust 
antitumor responses in mice [1-3]. These findings led to phase 1 studies in melanoma patients 
using different vaccine platforms and neoantigen candidates derived from in silico prediction 
models [4-6].  The first report employed neoantigen-pulsed dendritic cells and demonstrated 
neoantigen-specific T-cell responses in three patients. However, clinical responses were not 
reported [6]. 
 
Two additional clinical trials have administered neoantigen vaccines in melanoma patients both 
relying on similar strategies to identify neoantigens based on computational algorithms to 
predict neoantigen to binding MHC class I molecules and prioritize candidates. Both studies 
vaccinated patients without evidence of active disease so clinical responses to the vaccine was 
not available. Ott et al. [4]  vaccinated six patients with synthetic long peptides (SLP; up to 20 
total peptides in 4 pools for each patient) after surgical resection. Sahin et al. [5] used synthetic 
RNA vaccines, each encoding five 27-mer neoantigens and up to 10 mutations targeted in each 
patient’s tumor (two RNA vaccines). Importantly, the studies to date have demonstrated only 
mild treatment-related adverse events consisting of mild flu-like symptoms, injection site 
reactions, rash, and fatigue – all grade 1.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Immune monitoring analyses of patients’ PBMCs (IFN-γ ELISPOT, intracellular cytokine 
staining, multimer staining) in both studies [4, 5] revealed that SLP and RNA vaccines can (i) 
enhance pre-existing but weak neoantigen-specific T-cell responses and (ii) generate de 
novo neoantigen-specific T-cell responses. As noted above, the majority of the ex vivo IFN-γ 
responses were generated by CD4+ T cells. Both studies also found that vaccination resulted in 
an expansion of the neoantigen-specific T-cell repertoire. Taken together, these studies provide 
strong rationale for further clinical development and testing of neoantigen vaccines.  
1.3 
Rationale for Personalized Immunotherapy 
For many patients with advanced solid tumors, no standard therapy is recognized or patients 
have failed or are intolerant to standard-of-care (SOC) treatment. For these patients, there is 
significant unmet medical need in these life-threatening indications. Nonclinical and clinical 
evidence suggests vaccine-based immunotherapy has the potential to induce potent T cell 
immune responses and clinical benefit in multiple advanced tumor types.  
Advances in genome sequencing technology have enabled identification of a new class of 
tumor-specific antigens derived from mutated proteins that are present only in the tumor (i.e. 
neoantigens) [7, 8]. Mounting evidence highlights the critical role of these patient-specific 
neoantigens for the induction of highly specific antitumor immunity. Tumor-infiltrating 
lymphocyte populations in patients benefiting from immunotherapy represent dominant 
neoantigen-specific populations sufficient to induce tumor regression in mice and humans [9-
12].  In addition to widespread detection of neoantigen-specific T cells in the tumor, biochemical 
tools have been used to demonstrate that processing and presentation of multiple neoantigens 
occurs at the tumor site [13, 14]. Moreover, checkpoint blockade and dendritic cell 
immunotherapies have revealed new and amplified neoantigen-specific responses to be central 
to disease control [6, 15]. 
The principal objective for inducing immunity to tumor-specific neoantigens is to generate a 
systemic population of potent T lymphocytes that traffic to advanced, metastatic disease sites 
resulting in a T cell inflamed tumor phenotype, reduction of disease burden, and clinical benefit.  
In both nonclinical and clinical settings, priming of neoantigen-specific CD8+ T cells has been 
shown to result in significant tumor regression, providing proof of concept for this approach. The 
strength of neoantigen-based immunotherapy is therefore dependent on stimulation of a potent 
neoantigen-specific immune response. 
1.4 
Dose Selection Rationale 
Studies involving patients with cervical cancer administering a vaccine of synthetic long 
peptides covering E6 and E7 of HPV16, ISA101, have demonstrated that an optimal T-cell 
immune response is reached at 100 ug per peptide and that increasing to 300 ug does not 
further improve immunogenicity. However, 300 ug/peptide does increase local side effects at 
the injection site which can be dose limiting. The CervISA trial administered increasing doses of 
vaccine in combination with chemotherapy to patients with recurrent or metastatic cervical 
cancer. It was clear from measuring HPV-specific peripheral T cell responses that maximal 
immune responses were generated at 100 ug/peptide while HPV-specific T cell responses were 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
associated with significantly greater overall survival [ASCO-SITC 2017, San Francisco, Abstract 
140, Melief et al]. 
 
1.5 
Selection and Validation of Neoantigens 
 
Neoantigens (NeoAg) are those that are entirely absent from the germline genome. As applied 
to tumors, NeoAg comprise the set of expressed somatic mutations by which a tumor can be 
distinguished from the normal self by host CD4+ and CD8+ T cells [10]. As such, tumor 
NeoAg constitute unique targets of opportunity for directing a patient’s immune responses 
exclusively to the tumor, and thereby sparing normal tissues from the ‘collateral damage’ 
normally attendant to most systemic cancer therapies [16]. Accordingly, significant efforts 
have gone towards the identification of tumor NeoAg in individual patients for a range of 
therapeutic purposes, including personalized vaccines or adoptive immunotherapy, as for 
purposes of diagnosis and immune monitoring [17]. The screening strategy to identify 
immunogenic neo-epitopes in this application (Figure 1) is based on over a decade of 
experience in the Peters lab of designing and carrying out human T cell epitope mapping 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
studies in a number of systems, including infectious diseases [18-20], diabetes [21, 22], and 
allergies [23, 24]. Peptide candidate selection in these studies commonly relied on 
bioinformatic prediction tools for MHC binding, antigen processing and presentation, and 
TCR recognition which the Peters lab has a long-standing interest in [19, 25]as part of 
leading the bioinformatic component of the Immune Epitope Database and Analysis 
Resource [ 2 6 ,  2 7 ] . The approach used in current proposal, and the commitment to the 
functional verification of NeoAg in cancer patients at the level of a T cell response has 
emerged from a long-standing collaborative effort between the Schoenberger and Peters 
labs [ 2 8 ,  2 9 ] that has been recently been informed by findings involving the 
Schoenberger lab that expression data that accompanies genomic sequencing can be used 
to guide discovery of MHC class II-restricted NeoAg [2]. 
 
 
 
Neoantigen discovery and workflow 
 
Biospecimens, briefly a small amount (approximately 2 mg – 50 mg) of fresh tumor tissue is 
obtained via fine-needle aspirate, core biopsy, surgical resection, or as needed, from FFPE 
material, along with 1 ml PBMC to provide DNA for a patient-specific reference genome. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Coincident to tissue collection or at a later date 75-100 ml whole blood is obtained, yielding 3-
5x106 PBMC that can be cryopreserved for use in functional testing of T cell response.  
Sequencing: Paired tumor/control genomic DNA and tumor RNA is isolated and next-
generation sequencing is performed on the Illumina platform. Specifically, whole-exome 
sequencing (WES) is performed to a depth of at least 200x coverage on both tumor and 
reference (PBMC) exome and RNA seq on tumor RNA, obtaining at least 30 million reads per 
sample. 
Bioinformatic analysis of the combined exome and RBA sequence is performed using 
empirically developed algorithm. Selection is primarily based on the confidence that a mutation 
in DNA is specific to the tumor but not healthy tissue in the patient, and the degree of 
expression of the mutation in the tumor at the RNA level. 
Immunological analysis. Synthesis peptides are used to restimulate patient PBMC and TIL 
missense mutations selected for testing are represented as pairs of 20-mer peptides with the 
altered residue at position +6 or +15 in the linear sequence. NeoORFs created by indel 
(frameshift) mutations are represented as overlapping 15-mer peptides with an increment of 5, 
to cover all possible peptides and binding frames. Patient PBMC are stimulated with pools of 
peptides representing 5-10 mutations in 24-well plates for a 14-day expansion culture with 
autologous patient PBMC. Following the expansion, viable cells are collected and tested for 
functional reactivity against individual peptides comparing the stimulating pool using 2-color 
ELISPOT assay that simultaneously detects IFN-gamma and IL-5. Expansion cultures shown to 
contain significant T cell responses by ELISPOT against specific mutant peptides are 
immediately retested 1 day later by cytokine-capture assay to allow phenotyping of the 
responding cells as CD4+ or CD8+ and to allow fluorescence-activated cell sorting of a 
representative population of 100-500 cytokine-positive cells per neoantigen for T cell receptor 
analysis by single-cell transcriptomics and bioinformatics analysis [30, 31]. Our studies to-date 
have indicated that the endogenous response to a given somatic mutation is dominated by 1-5 
clonal TCRs. We therefore expect that sampling 100 cells per antigen on the basis of activation-
induced cytokine production will allow us to identify the clonotype of the responding cells with a 
high degree of confidence. The output of these studies will a) identify which somatic mutations 
are recognized by a patient’s T cells, b) the nature of the responding T cell subset (CD4+ or 
CD8+) and the cytokine polarity (IFN- versus IL-5), and c) the TCR clonotypes expressed in the 
responding cells. This information will be utilized to select which mutated peptides to use in 
each patient’s vaccine formulation, as well as in the post-vaccination immune monitoring. 
 
 
1.6 
Rationale for Addition of anti-PD1 Antibody 
Recently, drug discovery efforts to target the tumor microenvironment and reactivate the 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
antitumor immunity have been demonstrating great potential. One of the most promising 
approaches has been to inhibit immune checkpoints that block anti-tumor immune responses. 
These checkpoint inhibitors can act by blocking interactions between ligands and receptors on 
tumor cells and T cells, such as PD-L1 and PD-1, respectively, and lead to enhanced anti-tumor 
immunity. Five anti-PD-1/PD-L1 antibodies have been approved by the Food and Drug 
Administration (FDA), with others currently in clinical trials. We believe that anti-PD1 therapy will 
augment vaccine stimulation of CD8+ T cells against recognized neoantigens. Hence, we will 
accrue this study in four cohorts: A) vaccine administered concurrently with anti-PD1 and B) 
anti-PD1 antibody alone followed by vaccine and C) vaccine administered concurrently with 
anti-PD1 and D) vaccine administered alone. In all arms the strength of the T cell response to 
predicted and validated neo-epitopes will be measured. This design will allow evaluation of the 
T cell response to anti-PD1 alone versus anti-PD1 with vaccine. In addition, we will measure 
any change in T cell response in Arm B after addition of the vaccine. We hypothesize that the 
combination of anti-PD1 and vaccine will demonstrate the greatest T cell response against the 
desired neo-epitopes.   
 
1.7 
Study Rationale 
This phase 1b study will evaluate the immune response of patients with advanced cancers to 
personalized vaccine with an anti-PD1 antibody in sequential cohorts. The primary endpoint of 
the study will be formation of neoantigen specific T cell responses after 3 doses of personalized 
vaccine administered every 3 weeks.  The primary hypothesis of this study is that administration 
of the vaccine, based on expressed and functionally validated neoantigens, will result in a 
quantifiable increase in T cell specific responses. In addition, we hypothesize that the addition of 
anti-PD1 antibody, either prior to 3 doses of or concurrent with personalized vaccine, will be 
feasible and safe. Furthermore, we hypothesize that the concurrent administration of anti-PD1 
antibody with vaccine therapy will result in a greater neoantigen specific T cell response. 
Ultimately, the demonstration of a neoantigen specific T cell response will provide the rationale 
to conduct larger studies of this approach in patients with advanced cancers. 
 
Cohorts A and B will enroll 5 subjects to receive either: Arm A) personalized vaccine and anti- 
PD-1 administered concurrently at the start of study therapy or Arm B) anti-PD-1 antibody for 6 
weeks followed by personalized vaccine therapy. Arm C will enroll 10 subjects to receive 
personalized vaccine and anti- PD-1 administered concurrently in a boosted schedule at the 
start of study therapy. An additional 5 subjects may be enrolled on to Arm C. Arm D will enroll 
10 subjects to receive personalized vaccine alone, in a boosted schedule at the start of study 
therapy. 
 
Eligible subjects for this study will include all patients with advanced solid tumors who meet the 
eligibility criteria. Patients with hematologic malignancies will not be included in the current 
study due to the relatively low antigen load in many of these cancers, likelihood of bone marrow 
toxicity from prior therapy, and potential difficulty in extracting tumor infiltrating lymphocytes. 
Patients who have been previously treated with an anti-PD1 or anti-PDL1 antibody will be 
eligible to participate if they did not experience severe toxicity to prior immunotherapy and any 
toxicity has resolved.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.0 
STUDY OBJECTIVES 
The purpose of this study is to measure neoantigen specific T cell responses to vaccination with 
a neo-epitope vaccine with anti-PD1 antibody in patients with advanced cancers. 
2.1 
Primary Objectives 
1. To determine the increase in neoantigen specific T cell response to vaccine with an 
anti-PD1 antibody compared to anti-PD1 antibody alone using a TCR clonotype 
assay.  
2. To determine the safety and feasibility of generating a personalized, tumor 
neoantigen-specific therapeutic vaccine and the safety of combining it with 
checkpoint blockade immunotherapy.    
 
 
Primary Safety Endpoint 
Adverse events, reported overall and by grade, body system, attribution, and dose 
received. 
 
 
Primary Pharmacodynamic Endpoint:  
Quantitative frequency of neoantigen specific TCR clonotypes – see Section 5.5.2, 
Assay 3.   
2.2 
Secondary Objectives (defined in Section 9.0) 
1. To describe the efficacy of vaccine with anti-PD1 antibody in patients with advanced 
cancers that includes 
a. Objective response rate using RECIST 1.1 
b. Time to response 
c. Duration of response 
d. Progression free survival 
e. Overall Survival 
2. To determine the safety and feasibility of administering vaccine with anti-PD1 
antibody in patients with advanced cancers 
 
2.3 
Exploratory Objectives 
1. To characterize immune infiltrates in the tumor microenvironment including lymphoid 
and 
myeloid 
cell 
subsets, 
immune 
checkpoint 
expression, 
and 
other 
immunomodulatory molecules  
2. Evaluate genomic changes in the tumor in response to personalized vaccine 
3. Evaluate circulating cellular, protein, and genomic changes in response to 
personalized vaccine  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.0 
PATIENT ELIGIBILITY 
3.1 
Initial Screening Inclusion Criteria 
Subjects must meet all of the following inclusion criteria at initial screening eligibility review to 
participate in this study.  
 
1. Patient has the ability to understand and the willingness to sign a written informed consent. 
2.   Histologically or cytologically documented incurable solid tumor including lymphoma. 
3.   Patients can be enrolled in two categories: 
      a. Measurable disease as defined by RECIST 1.1 that has progressed on or be intolerant to     
therapies that are known to provide clinical benefit Lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions. These 
patients must have at least one tumor site accessible for biopsy. Tumor lesions used for biopsy 
should not be lesions used as RECIST target lesions, unless there are no other lesions suitable 
for biopsy. If a RECIST target lesion is used for biopsy the lesion must be > 2 cm in its longest 
diameter (Arms A, B, and C). 
     b. Non-measurable disease by RECIST 1.1 and high-risk (> 50% over 5 years) of mortality 
(Arm D).  
4.   Patient is ≥ 18 years of age. 
5.   ECOG Performance Status ≤ 1. 
6.   Patient has adequate organ function as defined below: 
• 
Absolute Neutrophil Count 
≥ 1.5 x 109/L 
• 
Platelet count  
 
≥ 90 x 109/L 
• 
Hemoglobin 
 
 
≥ 9.0 g/dL 
• 
AST/SGOT and ALT/SPGT ≤ 2.5 X institutional upper limit of normal  
• 
Total Bilirubin  
 
≤ 1.5 x ULN or ≤3× ULN if due to Gilbert’s disease 
• 
Serum creatinine 
 
≤ 2 x institution’s ULN  
3.2  
Initial Screening Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation at the initial screening eligibility review.  
1.   Patient has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients. 
2.   Known or suspected allergy or hypersensitivity to any component of vaccine. 
3.   Has a known history of Human Immunodeficiency Virus (HIV).   
4.   Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) 
or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: 
no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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(Individuals who are hepatitis C antibody positive may be enrolled if negative viral load 
confirmed). 
5.   History of autoimmune disease including: inflammatory bowel disease (including ulcerative 
colitis and Crohn’s Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), 
systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener’s granulomatosis); central 
nervous system or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré 
syndrome, myasthenia gravis, multiple sclerosis). Individuals with vitiligo, Sjogren’s Syndrome, 
interstitial cystitis, Graves’ or Hashimoto’s Disease, celiac disease, DM1, hypothyroidism stable 
on hormone replacement, or any autoimmune disease without symptoms and not requiring 
active therapy for at least 2 years  will be allowed with Study Medical Monitor’s approval. 
6. Has a known history of active TB   (Bacillus Tuberculosis).   
7. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
8. History of receiving a solid organ transplant or allogeneic bone marrow transplant. 
9. Unable or unwilling to withhold or discontinue any prohibited or restricted 
medications/procedures for the specified windows during the study. 
 
3.3  Pre-Treatment Inclusion Criteria 
Subjects must meet all of the inclusion criteria to continue participation in this study. 
 
1. Patient has the ability to understand and the willingness to sign a written informed consent. 
 
2. Histologically or cytologically documented incurable solid tumor including lymphoma.  
 
3. Patients can be enrolled in two categories:  
 
a. Measurable disease as defined by RECIST 1.1 that has progressed on or be intolerant to 
therapies that are known to provide clinical benefit Lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions. 
These patients must have at least one tumor site accessible for biopsy. Tumor lesions used 
for biopsy should not be lesions used as RECIST target lesions, unless there are no other 
lesions suitable for biopsy. If a RECIST target lesion is used for biopsy the lesion must be > 
2 cm in its longest diameter (Arms A, B, and C). 
 
b. Non-measurable disease by RECIST 1.1 and high-risk (> 50% over 5 years) of mortality 
(Arm D).  
 
4. Patient is ≥ 18 years of age. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. ECOG Performance Status ≤ 1. 
 
6. Patient has adequate organ function as defined below: 
 
• 
Absolute Neutrophil Count 
≥ 1.5 x 109/L 
• 
Platelet count  
 
≥ 90 x 109/L 
• 
PT and PTT 
 
 
< 1.5 × ULN 
• 
Hemoglobin 
 
 
≥ 9.0 g/dL 
• 
AST/SGOT and ALT/SPGT ≤ 2.5 X institutional upper limit of normal  
• 
Total Bilirubin  
 
≤ 1.5 x ULN or ≤3× ULN if due to Gilbert’s disease 
• 
Serum creatinine 
 
≤ 2 x institution’s ULN  
 
7. Women of child-bearing potential and men with partners of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) as detailed in Appendix C prior to study entry, for the duration of study 
participation, and for 180 days following completion of therapy.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. 
• 
A woman of child-bearing potential is any female (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
o Has not undergone a hysterectomy or bilateral oophorectomy; or 
o Has not been naturally postmenopausal for at least 12 consecutive months (i.e., 
has had menses at any time in the preceding 12 consecutive months) 
 
8. Women of child-bearing potential has negative pregnancy test prior to initiating vaccine 
dosing (See Table 1 for pregnancy testing requirements). 
 
3.4  Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Patient is currently receiving or has received another systemic anti-cancer therapy within 4 
weeks prior to first dose of study treatment. 
• 
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
• 
Note: If participant received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting study 
treatment. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Note: Participants who have received prior radiotherapy must have recovered from 
all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis prior to starting study treatment. 
• 
Note: Participants may continue maintenance anti-cancer therapy (e.g. hormone 
ablation or anti-HER) if clinically indicated. 
2. Patient is currently receiving or has received PD1/PDL1 inhibitor immunotherapy within 4 
weeks prior to first dose of study treatment. 
3. Patient is currently receiving or has received anti-PD1 or anti-CTLA4 treatment during the 
vaccine preparation period. 
4. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of 
live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
5. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
6. Patient has not recovered (to CTCAE ≤ Grade 1) from all clinically significant toxicities 
related to prior therapy.  
7. Receiving TNF pathway inhibitors, PI3 kinase inhibitors, systemic steroid therapy or any 
other form of immunosuppressive therapy within 14 days prior to the first dose of study 
medication.  
8. Received an investigational agent within 28 days prior to the first dose of study drug.  
9. Untreated brain metastases; individuals with treated and stable metastases are eligible.  
Eligible subjects should have recovered from the acute effects of radiation therapy or 
surgery prior to study entry, have discontinued corticosteroid treatment for brain metastases 
for at least 4 weeks and are neurologically stable for 8 weeks (confirmed by MRI) prior to 
administration of experimental therapy 
10. Known or suspected allergy or hypersensitivity to any component of vaccine.  
11. Has a known history of Human Immunodeficiency Virus (HIV).   
12. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) 
or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health 
authority. (Individuals who are hepatitis C antibody positive may be enrolled if negative viral 
load confirmed).  
13. History of autoimmune disease including: inflammatory bowel disease (including ulcerative 
colitis and Crohn’s Disease), rheumatoid arthritis, systemic progressive sclerosis 
(scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener’s 
granulomatosis); central nervous system or motor neuropathy considered of autoimmune 
origin (e.g. Guillain-Barré syndrome, myasthenia gravis, multiple sclerosis). Individuals with 
vitiligo, Sjogren’s Syndrome, interstitial cystitis, Graves’ or Hashimoto’s Disease, celiac 
disease, DM1, hypothyroidism stable on hormone replacement, or any autoimmune disease 
without symptoms and not requiring active therapy for at least 2 years  will be allowed with 
Study Medical Monitor’s approval. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
15. Has an active infection requiring systemic therapy. 
16. Has a known history of active TB   (Bacillus Tuberculosis).   
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
18. History of receiving a solid organ transplant or allogeneic bone marrow transplant. 
19. Major surgical procedure within 28 days prior to the first dose of study drug.  
20. Unable 
or 
unwilling 
to 
withhold 
or 
discontinue 
any 
prohibited 
or 
restricted 
medications/procedures for the specified windows during the study.  
21. If female, pregnant or breastfeeding. 
4.0 
TREATMENT PLAN 
4.1 
Study Design 
This is an open-label Phase 1b, sequential cohort, clinical study in adults with incurable solid 
tumors that will enroll subject in four arms.  
Arm A) Subjects on this arm will receive personalized vaccine and anti-PD-1 administered 
concurrently at the start of study therapy. In Arm A, the first vaccine dose will be initiated with 
the anti-PD1 antibody. Vaccine will be administered starting on week 0, day 1 Q3W for 3 doses 
(9 weeks) at a dose 100 µg per peptide. Pembrolizumab will be administered starting on week 
0, day 1 Q3W at a dose of 200 mg IV.  Subjects may receive additional doses administered at 3 
week intervals for an additional 12 doses if there is no evidence of disease progression. 
Treatment for up to 9 doses may continue past progression if the treating physician feels there 
is continued benefit.    See Table 1a for further details. (CLOSED TO ENROLLMENT) 
 
Arm B) Subjects on this arm will receive anti-PD-1 antibody alone for 6 weeks followed by the 
addition of personalized vaccine therapy. In Arm B, anti-PD1 antibody will be initiated for 6 
weeks prior to administration of vaccine. Pembrolizumab will be administered starting on week 
0, day 1 Q3W at a dose of 200 mg IV.  Vaccine will be administered starting on week 6, day 1 
Q3W for 3 doses (9 weeks) at a dose 100 µg per peptide. Subjects may receive additional 
doses administered at 3 week intervals for an additional 12 doses if there is no evidence of 
disease progression. Treatment for up to 9 doses may continue past progression if the treating 
physician feels there is continued benefit.  See Table 1b for further details. (CLOSED TO 
ENROLLMENT) 
Arm C) Subjects on this arm will receive personalized vaccine therapy (PSLP) and anti-PD1 
administered concurrently. In Arm C, a prime-boost vaccine schedule will be used with subjects 
receiving three weekly (Q7day) priming vaccine doses of PSLP followed by 6 boost vaccine 
doses of PSLP administered every 3 weeks. Vaccine will be administered starting on week 0, at 
a dose 100 µg per peptide. Subjects will receive 9 doses including priming. Subjects may 
receive additional doses administered at 3 week intervals for an additional 18 doses if there is 
no evidence of disease progression. Treatment for up to 9 doses may continue past progression 
if the treating physician feels there is continued benefit. Pembrolizumab (anti-PD1) will be 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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initiated one week prior to the first priming dose of PSLP (week -1) and continue Q3W at a dose 
of 200 mg IV. See Table 1c for further details. 
 
Arm D) Subjects on this arm will receive personalized vaccine therapy (PSLP). In Arm D, a 
prime-boost vaccine schedule will be used with subjects receiving three weekly (Q7day) priming 
vaccine doses of PSLP followed by 6 boost vaccine doses of PSLP administered every 3 
weeks. Vaccine will be administered starting on week 0, at a dose 100 µg per peptide. Subjects 
will receive 9 doses including priming. Subjects may receive additional doses administered at 3 
week intervals for an additional 18 doses if there is no evidence of disease progression. 
Treatment for up to 9 doses may continue past progression if the treating physician feels there 
is continued benefit. See Table 1d for further details.  
 
In arm A, B, and C pembrolizumab will be administered for a maximum of 35 cycles 
(approximately 2 years) if there is no evidence of disease progression. 
Toxicities related to the personalized vaccine immunotherapy are expected to be consistent with 
prior clinical and non-clinical experience, based on the platform and unrelated to the expressed 
antigens. However, for additional safety monitoring, subjects on each arm will be staggered to 
enroll a maximum of two subjects at a time and allow at least one week between subject pairs, 
i.e. enrollment of subject 1 and 2, followed by a one week interval, followed by enrollment of 
subjects 3 and 4, followed by a one week interval, etc.  
Potential subjects will initially be screened for eligibility. If eligible, subjects will provide a blood 
sample and undergo tumor biopsy. The tumor specimen will be analyzed by next-generation 
sequencing, and RNAseq to determine expressed neoantigens. Ex-vivo T cell reactivity will be 
determined against prioritized neoantigens in a functional assay. Personalized vaccines will be 
constructed that stably express multiple prioritized candidate neoantigen-derived epitopes. The 
personalized vaccine development and manufacture process is targeted to be optimized to 10 
weeks or less duration. During the development period, subjects may initiate or continue other 
anti-cancer therapies as directed by their treating physician. 
Subjects will return to the clinic within 28 days prior to the first dose to confirm eligibility and 
undergo pre-treatment screening procedures. Subjects will begin the Treatment Period when 
personalized vaccine is available; vaccine will be administered at a dose 100 µg per peptide.  
4.2 
Definition of Dose Limiting Toxicities (DLTs)  
 
A DLT is defined as the following treatment-related adverse events or laboratory abnormalities, 
graded according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 5.0: 
• 
≥ Grade 3 hematologic adverse events attributable to either agent. 
• 
≥ Grade 3 non-hematologic adverse events attributable to either agent.  
• 
≥ Grade 2 allergic reaction attributable to Personalized Synthetic Long Peptide (PSLP) 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DLT exceptions 
 
The following Grade 3 immune adverse events experienced may be acceptable as DLT 
exceptions depending on the duration of the events and treatment response.  
 
- 
Grade 3 hypothyroidism and hypophysitis  
- 
Grade 3 toxicities such as transient arthralgia or myalgia of 72 hours or less, transient 
(≤72h) flu-like syndrome 
- 
Grade 3 fever of up to 48h duration 
- 
Grade 3 injection site reaction that resolves to Grade 2 (or lower) level within 72 hours.  
 
Please refer to pembrolizumab-related toxicities outlined on table 4 of the protocol for additional 
information 
 
In order to be evaluable for DLT assessment, subjects must receive all injections within 1 dose 
of PSLP (a complete dose of PSLP may contain up to 3 injections) or at least 1 dose of 
pembrolizumab (pembrolizumab is only administered on Arms A, B, and C). Subjects who 
experience a DLT within the first 3 weeks of treatment and drop out of the study will be 
considered evaluable for DLT and will not be replaced. Subjects who drop out of the study for 
reasons other than DLT will be considered not evaluable and will be replaced. 
 
If a subject experiences a DLT attributable to the investigational product, no additional doses of 
the investigational product will be given. 
 
If ≥ 6 DLTs are observed, further accrual will be held pending safety analysis of the events, and 
the study will be restarted only with Principal Investigator approval. DLTs will be evaluated by a 
Safety Review Team that includes the Investigators who enrolled subjects in the study, the 
Principal Investigator, and the UCSD DSMC. 
 
If ≥  2 serious adverse events (e.g. death or grade 4 toxicities) related to study treatment are 
observed, further accrual will be held pending safety analysis of the events, and the study will 
be restarted only with Principal Investigator approval. 
 
Safety and tolerability will be assessed by monitoring for AEs. Tumor response assessments 
will be performed by radiologic evaluation (CT or magnetic resonance imaging [MRI]) at 
baseline and every 9 weeks thereafter through the EOT visit. A series of blood samples (serum, 
plasma, and peripheral blood mononuclear cells [PBMC]) and an additional tumor biopsy (if 
clinically feasible) will be obtained during the study to characterize the immune response to the 
vaccine and other prognostic tumor markers. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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All subjects will complete an End of Treatment (EOT) visit no more than four weeks following 
the final dose of study medication or prior to receipt of other cancer-related treatment. 
 
4.3 
Pembrolizumab  
Pembrolizumab (trade name Keytruda®) is a potent and highly selective humanized monoclonal 
antibody (mAb) of the immunoglobin G4 (IgG4) / kappa isotype designed to directly block the 
interaction between Programmed Cell Death 1 (PD-1) receptor and its ligands, Programmed 
Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2). This blockade enhances 
functional activity of the target lymphocytes to facilitate tumor regression and ultimately immune 
rejection. Details of preclinical and clinical studies are provided in the Investigator’s Brochure. 
Clinical studies with pembrolizumab have demonstrated efficacy in participants with advanced 
melanoma, non-small cell lung cancer, head and neck cancer (HNC), bladder cancer, Hodgkin’s 
lymphoma, and microsatellite instability (MSI) high cancers. Pembrolizumab is currently in 
clinical development for a number of advanced malignancies. For more detail on specific 
indications, please refer to the Pembrolizumab US Package Insert. 
 
4.4 
Treatment Dosage and Administration 
 
The investigational product (study treatment) administered in this study is vaccine. The PSLP 
vaccine will be constructed for each subject that stably express multiple candidate tumor-
derived neoantigens. Thirty peptide sequences will be the maximum per site of injection. 
Additional medications will be administered prior to, and following each vaccine dose  as 
needed to manage injection -related reactions. 
 
Arm A and Arm B: A dose of 100 µg per peptide PSLP vaccine will be administered by 
subcutaneous injection in any limb (left upper arm, right upper arm, left upper leg/thigh, or right 
upper leg/thigh) every 3 weeks. The appropriate volume of product to achieve the target dose 
is drawn with a syringe for subcutaneous injection. Additional details for storage and preparation 
of vaccine are provided in the study Pharmacy Manual. 
 
 
Arm C and Arm D: A dose of 100 µg per peptide PSLP vaccine will be administered by 
intramuscular injection (left upper arm, right upper arm, left upper leg/thigh, or right upper 
leg/thigh) using a prime-boost vaccination schedule (see scheme). The appropriate volume of 
product to achieve the target dose is drawn with a syringe for intramuscular injection. 
Additional details for storage and preparation of vaccine are provided in the study Pharmacy 
Manual. 
 
 
Arm A, B, and C: Pembrolizumab is administered on an outpatient basis. 200 mg 
pembrolizumab will be administered as a 30 minute (-5 min/+10 min) intravenous (IV) infusion 
every 3 weeks. Specific instructions for the preparation infusion fluid and administration of 
infusion solution are provided in the Pharmacy Manual.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.5 
Dosing Eligibility and Delayed Dosing 
Prior to the first dose and for each subsequent dose of both the vaccine and pembrolizumab, 
the subject must have adequate organ function as defined by the laboratory values in the Table 
2; laboratory tests may be performed up to 28 days prior to treatment start; laboratory tests may 
be performed up to 3 days prior to dosing for subsequent visits. 
 
If vaccine dosing is delayed due to dosing eligibility, pembrolizumab toxicity, manufacturing 
issues (e.g. sterility), medical / surgical events or logistical reasons not related to study therapy 
(e.g., COVID-19 pandemic, elective surgery, unrelated medical events, patient vacation, and/or 
holidays) the subsequent dosing schedule will be adjusted according to the delayed dose(s).  
 
If possible, the imaging scans and tumor measurement/response assessment should remain 
according to the original schedule of every 9 weeks (+/-7 days) for the first 6 months throughout 
the Treatment and Treatment Continuation Periods. After 6 months of therapy, CT scans will be 
performed when clinically indicated. 
 
 
 
Table 2. Dosing-Eligibility Requirements 
 
During peptide monotherapy and combination therapy 
 
Hematologic 
Renal 
Hepatic 
ANC  1000/µL 
Platelets  90,000/µL 
Hemoglobin   8 g/dL 
PT and PTT < 1.5 × ULN 
(when drawn) 
 
 
Creatinine  2 × ULN    
 
AST/ALT  2.5 × ULN 
Bilirubin  1.5× ULN or ≤3× ULN if 
due to Gilbert’s disease 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; PT = prothrombin time; ULN = upper limit of normal 
 
During pembrolizumab monotherapy 
 
Hematologic 
Platelets  90,000/µL 
Hemoglobin   8 g/dL 
 
 
Please refer to package insert and institutional guidelines regarding non-hematologic dosing 
parameters for pembrolizumab monotherapy.  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.6 
Concomitant therapy and procedures 
Subjects may receive concomitant medications as required, unless specifically restricted or 
prohibited in this study. Subjects are anticipated to continue the use of prescribed medications 
identified during the screening procedures, consistent with study inclusion and exclusion criteria.  
 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. All concomitant medications received within 28 
days before the first dose of trial treatment and 30 days after the last dose of trial treatment 
should be recorded. Concomitant medications administered after 30 days after the last dose of 
trial treatment should be recorded for SAEs and ECIs  
 
4.7 
Prohibited concomitant therapy  
A subject may be discontinued from study treatment for use of prohibited medications. Approval 
must be obtained from the Principal Investigator for a subject to continue dosing if a prohibited 
medication is administered within the specified timeframes. The following therapies are not 
permitted or are restricted following initiation of vaccine: 
• 
Non-study chemotherapy or immunotherapy (approved or investigational) 
• 
TNF pathway inhibitors or PI3 kinase inhibitors 
• 
Any major surgery or surgical procedure; if required must be discussed with the Principal 
Investigator to determine if it is appropriate for the subject to continue study treatment 
• 
Any other investigational product 
In addition, the following medications are only restricted prior to starting treatment as indicated: 
 
 
• 
Systemically active steroids for more than 3 days or use of any systemic steroids within 
14 days before pembrolizumab or vaccine administration, with the exception of inhaled 
steroids. NOTE: Steroids treating immune AEs are allowed. please refer to section 
4.8 for additional information) 
 
In addition, the following medications are only restricted prior to and after vaccine administration 
as indicated: 
• 
Filgrastim (granulocyte colony stimulating factor; G-CSF) or sargramostim (GM-CSF) 
within 14 days prior to or 14 days after vaccine administration  
• 
Prophylactic vaccines (e.g. pneumococcal vaccine, influenza vaccine, COVID-19 
vaccine) within 14 days prior to or after vaccine administration 
• 
Any investigational agent within 28 days of vaccine administration 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants’ primary physician. 
 
4.8 
Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 4.9.  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the Investigator determines the events to be related to 
pembrolizumab or PSLP injection 
 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab or 
PSLP injection, the Investigator does not need to follow the treatment guidance  
4.9 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI Common Toxicity Criteria 
for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity.  
 
4.9.1 Dose modification and toxicity management for immune-related AEs associated 
with vaccine. 
Since the vaccine product administered in this study is unique for each subject, safety data are 
unavailable for the specific vaccine. However, a similar SLP vaccine directed against HPV, 
ISA101, has been administered in clinical trials and safety data are available. Please see 
Section 8.1 for additional information. 
 
Vaccine dose reductions are not permitted. Dosing interruptions are permitted in the case of 
medical / surgical events or logistical reasons not related to study therapy (e.g., elective 
surgery, unrelated medical events, patient vacation, and/or holidays). Dosing interruptions are 
also permitted if corticosteroids are administered due to pembrolizumab toxicity. Patients should 
be placed back on study therapy as soon as possible after the scheduled interruption. The 
reason for interruption should be documented in the patient's study record. Patients should 
receive all doses of vaccine whenever possible.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: PSLP Injection Reaction Dose modification and Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires therapy interruption but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs,  
narcotics, corticosteroids, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs 
Additional appropriate medical therapy may include but 
is not limited to:  
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Corticosteroids 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
No subsequent dosing  
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal impairment, 
pulmonary infiltrates)  
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Additional appropriate medical therapy may include but 
is not limited to:  
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. Hospitalization may be 
indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
4.9.2 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab  
Pembrolizumab dose reductions are not permitted. Dosing interruptions are permitted in the 
case of medical / surgical events or logistical reasons not related to study therapy (e.g., elective 
surgery, unrelated medical events, patient vacation, and/or holidays). Patients should be placed 
back on study therapy within 3 weeks of the scheduled interruption. The reason for interruption 
should be documented in the patient's study record.  
 
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than on body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification and 
toxicity management guidelines for irAEs associated with pembrolizumab are provided in Table 
4. 
 
Table 4 
Dose Modification Guidelines for Pembrolizumab Drug-Related immune 
related Adverse Events 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
 
Immune-
related AEs 
Toxicity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-2 
• 
Monitor participants 
for signs and 
symptoms of 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
mg/kg prednisone 
or equivalent) 
followed by taper 
• Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
pneumonitis 
• 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment 
 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor participants 
for signs and 
symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal 
pain, blood or 
mucus in stool with 
or without fever) 
and of bowel 
perforation 
(i.e., peritoneal 
signs and ileus). 
• 
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis.  
• 
Participants with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids.  If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion. 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is stable 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants 
for hyperglycemia 
or other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.   
 
• 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs 
and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs 
and symptoms of 
thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of 
renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type 
and severity of 
AE administer 
corticosteroids  
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barré Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with 
hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
4.9.3 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 5.  
 
Table 5 
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
None 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to:  
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be 
premedicated 1h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
Diphenhydramine 25-50 
mg PO (or equivalent 
dose of antihistamine). 
Acetaminophen 500 to 
1000 mg PO (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to:  
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.10 
Duration of Study Treatment 
In the absence of treatment delays due to adverse events, treatment may continue until: 
 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
• 
Pembrolizumab will be administered for a maximum of 35 cycles (approximately 2 years) 
if there is no evidence of disease progression. 
• 
Progressive disease; however, treatment for up to 9 doses of vaccine may continue past 
progression if the treating physician feels there is continued benefit. 
 
4.11 
Discontinuation from Study Participation 
Subjects will be encouraged to complete the treatment course and study; however, they may 
voluntarily withdraw from treatment or the study at any time. In the case of a subject who is lost 
to follow-up, attempts to contact the subject must be made and documented in the subject’s 
study records. Sites will attempt to obtain vital status data from public records or other external 
sources where possible if a subject withdraws consent from study (i.e. refuse follow-up for vital 
status) or is lost to follow up.   
 
Participants may discontinue study treatment at any time for any reason or be dropped from the 
study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons.   
 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• 
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment 
• 
 The patient exhibits confirmed radiographic disease progression, unless the patient is 
clinically stable or clinically improved or the investigator believes continued study 
treatment is in the best interest of the patient.  
• 
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• 
Unacceptable adverse experiences which indicates to the Investigator that continued 
participation is not in the best interest of the subject. 
• 
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
continued administration of study treatment. 
• 
The participant has a confirmed positive serum pregnancy test 
• 
Noncompliance with study treatment or procedure requirements 
• 
Recurrent Grade 2 pneumonitis 
• 
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving beyond the date when the initial CR was declared.  
• 
The participant is lost to follow-up 
• 
Completion of 35 treatments (approximately 2 years) with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.   
• 
Administrative reasons 
• 
Termination of the study by the Sponsor, clinical site, or the regulatory authority 
 
 
In addition, a subject will be discontinued from the study if vaccine development is not feasible 
due to a lack of candidate neoantigens or technical constraints.   
 
Subjects who discontinue or withdraw during the screening period will be replaced. 
Subjects in whom the necessary blood samples to measure the primary endpoint are not 
obtained, will also be replaced.  
 
5.0 
STUDY PROCEDURES 
Refer to the study Schedule of Events for procedures. 
 
The Screening Period consists of 2 visits. The first should occur within 6 months of vaccine 
administration and is designed to assess eligibility and collect tissues necessary to prepare the 
product. Potential subjects will be evaluated for entry into the study according to the stated 
inclusion and exclusion criteria. For subjects who meet all inclusion/exclusion criteria, 
enrollment will be completed and reviewed by the Principal Investigator or designee for 
approval. The second screening visit should occur within 28 days of vaccine administration and 
is designed to assess suitability for trial participation.  
 
Individuals deemed ineligible for study enrollment do not need to complete all screening 
procedures. The reason for ineligible status will be documented. A subject who fails screening 
may repeat the screening process once if the Investigator believes there has been a change in 
eligibility status.  
 
The Treatment Period consists of multiple clinic visits for dosing and additional visits/phone calls 
are indicated to assess safety, tumor response, and immune monitoring. During the Treatment 
Continuation Period, dosing and visits occur every 3 weeks, with tumor responses evaluated at 
9-week intervals (+/-7 days). An EOT visit will be conducted approximately 4 weeks following 
the final anti-PD1 antibody infusion.  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
The Follow-up Period begins when subject has discontinued/completed treatment. The subject 
will be contacted by phone every 12 weeks during the Follow-up Period to obtain information on 
any additional cancer treatments and/or survival.  
 
All study visits (and visit windows), assessments, and procedures will be performed as indicated 
in the Schedule of Procedures. 
5.1 
Definitions of Study Assessments 
5.1.1 Medical history 
A complete medical, surgical and oncology history as well as history of infections are 
obtained at screening. Any changes from Screening (e.g. worsening severity or 
abnormal findings) are considered to be adverse events (AEs). 
5.1.2 Demographics 
Demographic profile will include date of birth, gender, race, and ethnicity. 
5.1.3 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for 
study entry. 
5.1.4 Concomitant medications 
All concomitant therapy, including anesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, received by patients from five days prior to the first 
day of study treatment until 28 days after the last study dose (or until the start of a new 
treatment, whichever comes first) will be recorded in the patient’s medical record. If a 
reportable adverse event deemed related to study intervention (see Section 7) occurs 
within 28 days after last study dose and the patient has not started a new treatment, 
recording of concomitant medications related to the treatment of that adverse event 
should continue until resolution of the adverse event. 
5.1.5 Physical exam 
A complete physical examination should include the evaluation of general appearance; 
evaluation of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, 
pulmonary, abdominal, musculoskeletal, skin, lymph nodes, neurological, and 
genitourinary systems. Subsequent exams may be targeted as appropriate. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
clinically significant. 
5.1.6 Vital signs and height  
Vital signs should include blood pressure, pulse, respiratory rate, temperature, and pulse 
oximetry and weight.  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
5.1.7 Performance status 
Performance status is evaluated using the Eastern Cooperative Oncology Group scale. 
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
5.1.9 Hematology 
Hematology includes complete blood count with differential ANC and platelet count. 
  
5.1.10 Serum chemistries 
Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, lactate dehydrogenase, ALT, AST, alkaline phosphatase, bilirubin 
(total, direct, indirect), total protein, albumin, calcium, magnesium, uric acid, and 
phosphate. 
5.1.11 Blood draw for correlative studies 
See Section 5.5 for details. 
5.1.12 Pregnancy test (for females of child bearing potential) 
See section 3.1 for definition of WOCBP. For study eligibility, WOCBP must have 
negative urine or serum pregnancy test within 28 days of first study drug administration. 
If a urine pregnancy test is positive, the results should be confirmed with a serum 
pregnancy test. Pregnancy of a subject or partner must be reported and followed. 
Additional pregnancy tests may be performed if clinically indicated. 
5.1.13 Urine Analysis 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and 
leukocytes) should be performed. This must be supplemented with laboratory 
quantification of any potentially relevant abnormalities. In addition, levels for protein and 
creatinine must be obtained, as a protein: creatinine ratio will be measured. 
5.1.14 Tumor assessment 
Radiographic tumor evaluation consists of a CT scan of all affected sites performed at 
screening (pre-treatment baseline assessment) and at 9-week intervals (+/-7 days) for 
the first 6 months throughout the Treatment and Treatment Continuation Periods. After 6 
months of therapy, CT scans will be performed when clinically indicated. If CT scan is 
contraindicated (e.g. allergy to contrast dye), an MRI should be performed. If there are 
delays in study drug administration, the subject should continue to follow the schedule 
for CT scan/tumor assessments as feasible. 
 
For each scan, tumor measurements should be obtained using RECIST 1.1; assessment 
of response will be determined by the local Investigator. The method of assessment and 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
technique should be consistent throughout the study to enable characterization of each 
identified and reported lesion. 
5.1.15 Tumor tissue collection (See Section 5.5 for details) 
If eligibility criteria are met, the subject will return to provide a blood sample and undergo 
tumor biopsy if necessary. The tumor specimen will be analyzed by next-generation 
sequencing; candidate neoantigens will be identified based on nucleotide sequence 
differences from the individual’s non-malignant cells (blood sample). A core needle 
biopsy using standard techniques will be obtained from accessible tumor site(s) (primary 
and/or metastatic) outside any previous field of radiation. See section 5.5 for details. 
 
Post-vaccine treated biopsies (if available) will be sequenced to evaluate changes in 
neoantigens and other genomic changes. Both pre- and post-vaccine biopsies will 
undergo immune cell subset analysis (e.g. CD4, CD8, 
Treg, myeloid) by 
immunohistochemistry, and gene and protein expression profiling. 
 
5.2 
Screening/Baseline Procedures 
 
Subjects may sign an initial consent allowing the vaccine to be manufactured. Subsequently, the 
subject would sign a second consent for treatment when they and the IP are ready to proceed. 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
The Screening Period consists of 2 visits. The first visit is to assess eligibility and collect tissues 
necessary to prepare the product. Potential subjects will be evaluated for entry into the study 
according to the stated inclusion and exclusion criteria. For subjects who meet all 
inclusion/exclusion criteria, enrollment will be completed and reviewed by the Principal 
Investigator or designee for approval. The second screening visit should occur within 28 days of 
vaccine administration and is designed to assess suitability for trial participation.  
 
The screening procedures include: 
• 
Written informed consent. 
• 
Review of inclusion and exclusion criteria. 
• 
Complete medical/oncology history. 
• 
Demographics. 
• 
Documentation of concomitant medications. 
• 
Complete physical examination, including vital signs and height. 
• 
Performance status assessment. 
• 
Laboratory tests (within 28 days of initial treatment. For subsequent treatment days, labs 
within 3 days of dosing); pregnancy test within 28 days).  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Amendment 7.2 
Protocol Date 20 February 2022 
 
• 
Blood collection for correlative studies. 
• 
Documentation of tumor staging. 
• 
Tumor biopsy tissue collection for correlative studies (if available)  
5.3 
Procedures During Treatment 
Refer to Schedule of Events for procedures and windows during the Treatment Period and 
Treatment Continuation.  
 
5.3.1 Prior to Each Treatment 
• Documentation of concomitant medications and adverse events 
• Physical exam, vital signs 
• Hematology 
• Serum chemistries 
5.3.2 Tumor Assessments 
• CT scan or MRI of all affected sites are performed at 9-week intervals (+/- 7 days) 
for the first 6 months throughout the Treatment and Treatment Continuation 
Periods. After 6 months of therapy, CT scans will be performed when clinically 
indicated.   
5.3.3 End of Treatment Visit 
• Documentation of concomitant medications and adverse events 
• Physical exam, vital signs 
• Hematology 
• Serum chemistries 
5.4 
Follow-up Procedures 
Following the Treatment and Evaluation Period, subjects will be contacted at 12 week (3 month) 
intervals to assess survival and subsequent cancer-related therapies. Follow-up will continue 
until death of the subject, loss to follow-up, or close of study by the Sponsor. For a subject who 
withdraws from the study prior to completion of the Follow-up Period or is documented as lost to 
follow up, sites will attempt to obtain vital status data from public records or other external 
sources where possible. All deaths must be reported on the CRF. 
 
5.5 
Correlative Studies 
Research assessments will be conducted on blood and tumor biopsy samples and will 
characterize the immune responses mediated by vaccine with or without anti-PD1 antibody. 
Blood samples required for exploratory laboratory evaluations will be collected, processed, 
stored, and shipped as outlined below. 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Date 20 February 2022 
 
5.5.1 Sample Collection Guidelines 
A. Tumor tissue: Approximately 2 mg – 50 mg of fresh tumor tissue is obtained via fine-
needle aspirate, core biopsy, surgical resection, or as needed, from FFPE material. 
Three tumor collections are desired: 1) before, during, or after the screening period to 
manufacture the personalized vaccine (this collection is absolutely necessary for 
treatment); 2) within 7 days of 3rd vaccine dose on Arms A and B and within 7 days of 
6th vaccine dose in Arm C and D; and 3) at disease progression.   
B. Peripheral blood mononuclear cells (PBMC):  
o One 10mL heparin tube will be collected at or before screening to provide DNA 
for a patient-specific reference genome. The blood will be given to Dr. 
Schoenberger’s group as fresh whole blood. 
o 75-100 ml whole blood (eight to ten 10mL heparin tubes) to be collected during 
screening period to determine neoantigens. The blood will be given to Dr. 
Schoenberger’s group as fresh whole blood. 
o For neoantigen identification, an additional 75-100 mL whole blood (eight to ten 
10mL heparin tubes) may be collected every 4 weeks.  
o 50-75 ml whole blood (5-8 10 mL heparin tubes) to determine T cell specific 
response to neoantigen. The blood will be given to Dr. Schoenberger’s group as 
fresh whole blood. 
o Arm A and B – samples should be collected during screening, within 28 
days of treatment initiation, within 7 days of last vaccine dose, and within 
7 days of Week 18 
o Arm C – samples should be collected during screening, within 28 days of 
treatment initiation, Week 8 within  7 days after vaccine administration, 
Week 32 (and within 12 weeks of last vaccine dose (+/- 3 days) and anti-
PD1 antibody administration) 
o Arm D – samples should be collected during screening, within 28 days of 
treatment initiation, Week 8 within 7 days after vaccine administration, 
Week 32 (and within 12 weeks of last vaccine dose (+/- 3 days). 
o If additional vaccine doses are administered, additional samples may be 
collected per investigator, a sample should collected within 12 weeks of 
last vaccine dose (+/-3 days). 
o An additional 50-75 mL whole blood (eight to ten 10mL heparin tubes) will be 
collected prior to the first dose of vaccine only in subjects enrolled to Arm B. 
o 10 ml whole blood (cell-free DNA BCT) will be collected at Weeks 9-12. 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Work Flow for Sample Collection: 
 
 
 
 
     

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Blood Collection 
• 
At designated time points, the coordinator will obtain fresh whole blood in the 
appropriate number of heparin tubes. 
• 
Upon start of vaccination period, blood draws should be obtained after the specified 
vaccine dose.   

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Blood will be given to Dr. Schoenberger’s group same day as fresh whole blood. 
 
Tissue Procurement 
• 
Biopsy 
o Patient will undergo biopsy in a clinic setting if needed 
o Coordinator will be present at time of biopsy to collect tissue  
o Tissue will be collected in pre-prepared RPMI provided by Dr. Schoenberger’s 
group 
o Fresh tissue will be given to Dr. Schoenberger’s group same day 
o See lab manual for specific instructions on tissue collection 
• 
Surgery 
o Patient will undergo surgical resection 
o Coordinator will be present at time of surgery to collect tissue 
o Approximately 2 mg – 50 mg of fresh tissue will be collected in pre-prepared 
RPMI provided by Dr. Schoenberger’s group 
o Fresh tissue will be given to Dr. Schoenberger’s group same day 
o See lab manual for specific instructions on tissue collection 
 
Distribution 
• 
Call and/or email Dr. Schoenberger’s group on day of sample collection (blood or tissue) 
@ Aaron Miller - amiller@lji.org/858-249-9097; Milad Bahmanof - milad@lji.org/858-886-
6355;   
• 
De-identified specimen will be released to designated personnel using chain of custody 
form. All personnel in the Schoenberger laboratory will remain blinded regarding subject 
identity or treatment arm allocation. 
• 
If patient consented, additional blood aliquots or frozen solid specimen from 
Biorepository may be requested separately. 
 
5.5.2 Assay Methodology 
Overview:  
 
Our objectives in monitoring the post-vaccination immune responses of trial patients will be 
threefold: 
1) 
To determine whether T cell responses to the original vaccinating antigens have been 
preserved and/or potentiated. 
2) 
To determine whether the treatment protocol results in diversification of immune 
responses to include tumor-expressed somatic mutations not detected as neoantigens in the 
pre-vaccine screen (“epitope spreading”) 
3) 
To determine whether the treatment protocol alters the cytokine polarity or inhibitory 
receptor expression of the responding neoantigen-specific T cells. 
 
Methods:  
 
Assay 1: Functional T cell assay from PBMC: We will perform a variation of the assay used in 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section 1.5 to identify the subset of somatic mutations confirmed as neoantigens by functional T 
cell assay (ELISPOT and CRA) following in vitro expansion to determine whether these 
responses persist in phenotype and magnitude in the treated patients. To do this, PBMC will be 
obtained from vaccinated patients at the time points listed above and an aliquot tested for 
recognition of the vaccinating peptides by ELISPOT (for IFN- and IL-5) either directly ex-vivo or 
after a 3 day co-culture with the individual vaccine peptides, with these time points chosen to 
reflect the presumed higher frequency with which neoantigen-specific T cells will be present in 
the peripheral blood of treated patients. Results will be reported as the frequency of cytokine-
producing cells among total and positive controls will include responses against nominal recall 
antigens (CEF peptides, for CMV, EBV, and Flu).  
 
Assay 2: Response diversification: In addition to measuring responses against the vaccine 
peptides, we will also include peptides comprising the set of tumor-expressed somatic mutations 
that did not elicit a T cell response in the original neoantigen screen in 14-day restimulation 
cultures using PBMC from treated patients to assess whether the antitumor immune response 
we expect to result from vaccination had led to de-novo priming of responses against additional 
neoantigen targets, presumably through enhanced tumor killing and release of tumor antigens in 
a classic ‘abscopal effect’. 
 
Assay 3: T cell clonotype assay from PBMC: The analysis in Section 1.5 will reveal the 
neoantigen targets for each patient’s vaccine formulation on the basis of spontaneous T cell 
responses which are functionally detected on the basis of cytokine production in response to 
specific mutation-encoding peptides. As described, this analysis will also allow us to define the 
specific alpha and beta chains utilized in the TCRs (the ‘clonotype”) of the responding 
neoantigen-specific T cells by bioinformatic analysis of single sorted cells. These data can be 
used as a unique ‘digital fingerprint’ of the relevant clone within a larger population of cells, and 
in fact will be used to longitudinally measure the frequency of the responding neoantigen-
specific T cells in peripheral blood at the time points listed above. To assess the frequency of 
neoantigen-specific clonotypes within the patient’s peripheral lymphocyte pool, we will subject 
an aliquot of the PBMC obtained at each time point to ImmunSEQ analysis which uses highly-
sensitive genomic sequencing and bioinformatics analysis software to give a quantitative 
assessment of the TCR clonotypes within a complex lymphocyte population. As we will know 
which specific paired TCR clonotypes belong to verified neoantigen-reactive T cells, we can 
utilize this approach to monitor the frequency of the specific T cell which we expect to be 
expanded by the vaccine. 
5.5.3 Specimen Banking 
Patient samples collected for this study will be retained at UCSD BTTSR for analysis and future 
cancer research. Specimens will be stored indefinitely or until they are used up. Samples will be 
labeled with the protocol number, subject’s de-identified study number and collection date. The 
link between study number and medical record number will be viewed over a password secured 
encrypted server-client. 
 
The study research coordinator will review their subject's medical record for demographic and 
clinical information pertaining to the subject's general medical history, diagnosis, and outcomes 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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of any treatments received. Samples and data extracted from the subject's medical record will 
be coded with a de-identified study number so that the subject's name and identifying 
information is removed. A log that links the subject's name and identifiers to the study number 
will be maintained in a secure database distinct from the secure database into which the 
subject's clinical information will be entered by study personnel. 
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that there is 
the potential for financial gain by UCSD, the investigator or a collaborating researcher or entity. 
 
6.0 
Measurement of Effect 
6.1 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 5.0 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
adverse events. 
6.2 
Antitumor Effect 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria (see Appendix B). 
6.2.1 Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation. 
6.2.2 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of study 
treatment until objective tumor progression or death. 
6.2.3 Time to Progression 
Time to progression is defined as the duration of time from start of study treatment until 
objective tumor progression. 
6.2.4 Overall Survival 
Overall survival is defined as the duration of time from start of study treatment to death. 
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.   
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
 
Progression of the cancer under study or events which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
 
 
Adverse events may occur during the course of the use of agents in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. 
 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before treatment allocation must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from 
the study, or if the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, or a procedure.  
 
● All AEs from the time of treatment allocation through 30 days following cessation of study 
treatment must be reported by the investigator.  
 
● All pregnancies and exposure during breastfeeding, from the time of treatment allocation 
through 120 days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy  must be reported by the 
investigator.  
 
Serious Adverse Events 
 
● All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if the 
participant initiates new anticancer therapy, whichever is earlier must be reported by the 
investigator.  
 
● SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
 
● Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study treatment or study participation, the investigator must 
promptly notify the Sponsor. 
 
Definition of an Overdose for Pembrolizumab and Reporting of Overdose to the Sponsor 
and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215-661-6229) 
 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229). 
 
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any participant must be reported within 2 working 
days to Merck Global Safety if it causes the participant to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck 
product, must be reported within 2 working days to Merck Global Safety. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Events of clinical interest for this trial include: 
 
1.  An overdose of Merck product, as defined in Section Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
 
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins when the subject signs informed consent and ends 30 days 
following the last administration of study treatment or start of new anti-cancer therapy, 
whichever is earlier. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug will be 
monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
➢ any clinically significant abnormal laboratory values have returned to baseline;  
➢ there is a satisfactory explanation other than the study drug for the changes 
observed; or 
➢ death. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2 
Severity 
 
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse 
Events 
(CTCAE) 
version 
5.0. 
The 
CTCAE 
v5.0 
is 
available 
at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
 
Fatal (grade 5): the event caused death. 
 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. All adverse events regardless of 
CTCAE grade must also be evaluated for seriousness. 
 
7.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
If death results from (progression of) the disease, the disease should be reported as a 
serious adverse event (SAE) itself. 
2. Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization.  
Note: Hospitalization (including hospitalization for an elective procedure) for a pre-
existing condition which has not worsened does not constitute a serious adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose. 
 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.5 
Evaluation of Adverse Events  
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid 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 
or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); 
or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse event.  
A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor 
within 24 hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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event of clinical interest and must be reported within 24 hours to the Sponsor and to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  Did the adverse event cause Merck product or PSLP product to be discontinued? 
Relationship 
to Merck 
Product or 
PSLP 
product 
Did Merck product or PSLP product cause the adverse event? The determination of the likelihood that Merck product or PSLP 
product caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the test drug and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely an investigational  
product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to investigational product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of investigational product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 
to Merck 
Product 
 
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Sponsor’s product; or (3) the trial is a single-dose 
drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or 
(2) the trial is a single-dose drug trial); or (3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician 
according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative 
to the administration of Merck product is reasonable.  The AE is more likely explained by Merck 
product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another 
cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 
 
7.6 
Reporting Requirements for Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
7.6.1 Expedited Reporting 
A. The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the study drug. 
 
B. The Sponsor (or designee) will report all SAEs that are unexpected and considered related 
to the administration of the investigational agent to the appropriate health and regulatory 
authorities and Investigators in the form of an expedited safety report within 15 calendar 
days after receiving information on the SAE. The Investigators will notify their reviewing IRB 
and other committee(s) as required by institutional policies. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The Sponsor will also report to the appropriate health and regulatory authorities by 
facsimile, e-mail, or phone within 7 days of receiving the information, any unexpected 
life-threatening or fatal SAEs that are considered related to the investigational agent. 
C. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, and updated 
sponsor safety report), interim result or other finding that indicates an unexpected 
change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
 
D. The Sponsor (or designee) will report all SAEs that are unexpected and considered related 
to the administration of pembrolizumab to Merck within 2 working days. SAE reports and 
any other relevant safety information are to be forwarded to the Merck Global Safety 
facsimile number:  +1-215-661-6229 
 
 
7.6.2 Pregnancy and Lactation Reporting 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation  must be reported by the investigator if they cause the 
participant to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure.   

 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation through 120 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator.   
If the subject or partner of a subject participating in the study becomes pregnant during the 
study or within 28 days of discontinuing study drug, the Investigator should report the pregnancy 
within 24 hours of being notified. A subject becoming pregnant while on study drug will 
immediately be withdrawn from the study and EOT study procedures will be performed. 
 
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
designated safety personnel. At the completion of the pregnancy, the Investigator will document 
the outcome of the pregnancy. SAE reporting procedures should be followed if the outcome of 
the pregnancy meets the criteria for immediate classification as an SAE (i.e. postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly). 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
 
7.6.3 Routine Reporting Requirements 
A. The IRB must be notified of all adverse events, as required by institutional policies, at the 
time of the annual Continuing Review.  
B. The FDA must be notified of all non-serious adverse events annually at the time of the 
annual report.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.0 
AGENT INFORMATION 
 
8.1 
Personalized vaccine 
Storage and stability: PSLP lyophilized powder is stored in glass vials in the dark (away from 
light) at -20°C or lower. Once product has been fully prepared, it should be administered within a 
2 hour timeframe. If there is a delay in administration, product will be kept at 4°C or colder. 
Product will be protected from light. The product must be administered within 24 hour timeframe. 
See Pharmacy Manual for additional details. 
 
Preparation:  The vaccine will not be prepared until sterility results are returned and the product is 
confirmed to be uncontaminated. Vaccine is prepared by thawing the appropriate quantity of vials of 
drug product at room temperature.  
 
For Arm A and B: PSLP lyophilized powder will be dissolved in dimethylsulfoxide (DMSO) and 
admixed with sterile water for injection (WFI) or phosphate buffered saline (PBS) and adjuvant 
Montanide ISA-51 VG.  
 
For Arm C and D: PSLP lyophilized powder will be dissolved in dimethylsulfoxide (DMSO) and 
admixed with sterile water for injection (WFI) or phosphate buffered saline (PBS). Poly-ICLC 
(Hiltonol®) adjuvant will be prepared in a separate syringe for administration.  
 
The appropriate volume of product to achieve the target dose (100 µg per peptide) is drawn with a 
syringe for injection. See Pharmacy Manual for additional details.  
 
 
Route of administration: 
 
Arm A and Arm B: Subcutaneous injection.   
Arm C and Arm D: Intramuscular injection. Note: The adjuvant should be administered 
in a separate syringe as an intramuscular injection concurrent with the peptide 
vaccine. 
 
A dose of 100 µg per peptide PSLP vaccine will be administered by  injection in any limb (left upper 
arm, right upper arm, left upper leg/thigh, or right upper leg/thigh). Watch patient for  signs of 
allergic responses. Ensure that immediate treatment of severe allergic reactions are available prior 
to investigational drug administration, including staff well-trained in resuscitation, intravenous 
access for administration of fluids, antihistamines and corticosteroids, and epinephrine for 
intramuscular injection. 
 
In case a subject experiences a DLT attributable to the investigational product, no additional doses 
of the investigational product will be given. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Side effects: Since the vaccine product administered in this study is unique for each subject, safety 
data are unavailable for the specific vaccine. However, a similar SLP vaccine directed against HPV, 
ISA101, has been administered in clinical trials and safety data are available. Side effects of the 
personalized vaccine are expected to be similar since the neoantigens, by definition, are not 
present in normal tissue.  
 
Overall, the observations on the safety profile observed to date with ISA101/101b are summarized 
below and detailed in the IB: 
• 
Most of the AEs in the CervISA study were expected toxicities reported to be related to 
chemotherapy or to complications associated with progression of cervical cancer. 
• 
Dose-related injection site reactions (ISRs) to ISA101 were the most frequent AEs reported 
to be related to ISA101 with ISRs occurring in most patients who received ISA101. Most of 
the local ISRs were reported to be grade 1 to 2 in severity. One grade 3 ISR at 
300µg/peptide has been reported. One patient refused additional ISA101 vaccination at 
100µg/peptide due a grade 1 ISR.  
• 
Dose-related systemic allergic reactions were reported particularly at the 300 μg/peptide 
dose. These may, in part, be related to the amount of Montanide administered, which is 
proportional to dose of the peptide vaccine.  
• 
No new or unexpected safety concerns have been identified for ISA101 or ISA101b 
compared to the safety profile of the predecessor vaccine, HPV-16-SLP. 
• 
There do not appear to be any unexpected or overlapping toxicities between ISA101/101b 
when used in combination with chemotherapy (e.g. paclitaxel and carboplatin) or anti-PD-1 
therapy (e.g. Nivolumab). 
• 
No autoimmune complications have been observed in relationship to administration of the 
vaccine. 
• 
The safety profile and immunologic activity of ISA101b appears to be similar to ISA101. 
• 
Based on the assessment of safety data in the initial dose escalation cohorts and the 2 
expansion cohorts, as well as data on the HPV-16 specific T cell responses, the 100 
μg/peptide dose level was selected as the recommended phase 2 dose for further studies in 
patients with advanced cancer. 
 
8.1.1 Return and Retention of Study Drug 
Upon completion or termination of the study, all unopened vials of IP must be returned to the 
Sponsor or Sponsor’s designee, unless authorized by the Sponsor or Sponsor’s designee to be 
destroyed at the study site. All vials of IP returned to the Sponsor or Sponsor’s designee must 
be accompanied by the appropriate documentation and clearly identified by protocol number 
and study site number. 
 
8.2 
Pembrolizumab 
 
When possible, pembrolizumab should be administered IV in a limb on contralateral to the site of 
vaccine administration. 
Details on preparation and administration of IV pembrolizumab are provided in the Package Insert and 
Merck, Inc.’s Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.0 
STATISTICAL CONSIDERATIONS 
Statistical Analysis Plan 
 
Study design 
 
This is an open-label Phase 1b, sequential cohort, clinical study in adults with incurable solid tumors.  
Cohorts A and B will enroll 5 subjects to receive either: Arm A) personalized vaccine and anti- PD-1 
administered concurrently at the start of study therapy or Arm B) anti-PD-1 antibody for 6 weeks 
followed by personalized vaccine therapy. Arm C will enroll 10 subjects to receive personalized vaccine 
and anti- PD-1 administered concurrently in a boosted schedule at the start of study therapy. An 
additional 5 subjects may be enrolled on to Arm C. Arm D will enroll 10 subjects to receive personalized 
vaccine alone, in a boosted schedule at the start of study therapy. Toxicities related to the personalized 
vaccine immunotherapy are expected to be consistent with prior clinical and non-clinical experience, 
based on the platform and unrelated to the expressed antigens. However, for additional safety 
monitoring subjects on each arm will be staggered to enroll a maximum of two subjects at a time and 
allow at least one week between subject pairs, i.e. enrollment of subject 1 and 2, followed by a one 
week interval, followed by enrollment of subjects 3 and 4, followed by a one week interval, etc. 
 
 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Arm C 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Arm D 
 
 
 
Primary safety endpoints 
Adverse events, reported overall and by grade, body system, attribution, and dose received. 
 
Primary pharmacodynamic endpoint: neoantigen-specific T cell response, as measured by the T cell 
clonotype assay (Assay 3 below). 
 
The primary pharmacodynamic outcome will be the change in neoantigen-specific clonotypes within the 
patient’s peripheral lymphocyte pool.  Validated personalized peptides will be injected for each patient. 
To assess the frequency of neoantigen-specific clonotypes within the patient’s peripheral lymphocyte 
pool, we will subject an aliquot of the PBMC obtained at each time point to ImmunSEQ analysis. The 
within-patient change of TCR clonotypes corresponding to the pre-specified injected peptide sequences 
will be the primary outcome. Response to each peptide will be measured and the average value across 
injected peptides reported.  
 
Primary efficacy hypothesis: 
 
Concurrent administration of anti-PD1 antibody with vaccine therapy will result in a greater neoantigen-
specific T cell response, than anti-PD1 therapy alone.   
Hypothesis 1a: Draw #2 within-patient change from baseline for arms A and C (combination therapy) 
will be greater than Draw #2 within-patient change from baseline for arm B (anti-PD1 alone) and the 
corresponding Draw from arm D (anti-PD1 alone).  
Key secondary efficacy hypotheses: 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Administration of the vaccine, after priming with anti-PD1 therapy, will result in a quantifiable increase in 
neoantigen-specific T cell response.  
 
Hypothesis 2:  Arm B: post-sequential therapy (Draw #3) vs post- antiPD1 therapy alone (Draw #2) 
within-patient change will be greater than 0. 
Boosted combination therapy will be better than evenly spaced combination therapy.  
Hypothesis3: Arm C Post-sequential therapy (Draw #3) within-patient change from baseline will be 
greater than Arm A post-sequential therapy (Draw #3) within-patient change from baseline. 
Additional efficacy hypotheses: 
a. Concurrent combination therapy will be associated with increased neoantigen-specific T cell 
response. Hypothesis: Arms A and C: Post-combination therapy (Draw #2) within-patient 
change from baseline will be greater than 0. 
b. Sequential combination therapy will be associated with increased neoantigen-specific T cell 
response. Hypothesis: Arm B: Post-sequential therapy (Draw #3) within-patient change from 
baseline will be greater than 0. 
c. Sequential therapy will differ from combination therapy in neoantigen-specific T cell 
response 
Hypothesis: Arms A and C post-combination-therapy (Draw #3) within-patient change from 
baseline will differ from Arm B Post-sequential therapy (Draw #3) within-patient change from 
baseline. 
d. Anti-PD1 therapy alone will be associated with increase in neoantigen-specific T cell 
response 
Hypothesis: Arm B Post anti-PD1 (Draw #2) within-patient change from baseline will be 
greater than 0. 
Secondary efficacy endpoints 
 
a. Objective response rate using RECIST 1.1. 
b. Progression free survival – measured, in months, from date of enrollment until disease 
progression or death. 
c. Overall Survival – measured, in months, from date of enrollment until disease progression or 
death.  
d. Time to response – measured, in weeks, from date of first study treatment until best 
response assessed by RECIST 1.1. 
e. Duration of response – measured, in weeks, from date of best response to date of 
progression assessed by RECIST 1.1. 
 
 
 
Secondary feasibility endpoints 
 
The proportion subjects with peptides sent for manufacture who receive at least one dose of PSLP 
vaccine 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A consort-like diagram will be presented which displays the disposition of subjects screened for this trial 
according to feasibility outcomes.  The manufacturing step  is expected to be most important for cost 
and thus feasibility for future studies.  Hence the primary feasibility endpoint is  above.  If fewer than 
half of subjects with peptides sent for manufacture are given a dose of vaccine, the feasibility criterion 
will not have been met.  If fewer than 20% of eligible subjects whose tumor is sequenced are treated, 
the feasibility criterion will not have been met. 
 
 
Exploratory Endpoints 
 
• 
Response diversification assay 
• 
Functional T cell assay 
• 
Immune infiltrates in the tumor microenvironment including lymphoid and myeloid cell subsets, 
immune checkpoint expression, and other immunomodulatory molecules 
• 
Genomic changes in the tumor 
 
Analytic strategy 
We will test the primary hypothesis at 0.05 alpha and test the key secondary hypotheses at the same 
familywise level only if the primary hypothesis is significant.  This will control the type I error for both 
sets of hypotheses at 5%.  To control the 2 key secondary hypotheses, we will use a Holm step-down 
test at 5% level. 
The remaining secondary hypotheses will also be tested at familywise 5% level, using a Holm step-
down test at familywise 5% level.  This strategy will control the overall familywise error rate for the 
primary and key secondary outcomes at 5%, and will separately control the familywise error rate for the 
secondary hypotheses at 5%.    
The secondary efficacy endpoints will be summarized by overall study arm, using an intent to treat 
analysis for sequential vs concurrent therapy. Because of the small sample sizes, no formal 
comparison between arms will be made for secondary outcomes. Exploratory outcomes will also be 
summarized by study arm.   Subjects who are treated but have no efficacy evaluation following baseline 
will be considered treatment failures    
Hypothesis tests will be carried out in R.  For continuous endpoints, we will use t-tests on possibly log 
transformed data, with unequal variances if appropriate.   Descriptive statistics will also be presented. 
Categorical variables will be summarized by treatment arm using frequency distributions: the number 
and percentage of non-missing observations will be given. Continuous variables will be summarized 
using standard quantitative statistics: the number of non-missing observations, mean, standard 
deviation, median and range (minimum and maximum observed values).  
 
Sample Size and Power computations, primary and key secondary efficacy analysis  
 
Primary Hypothesis: Hypothesis 1: Draw #2 within-patient change from baseline for Arms A and C 
(antiPD1-vaccine  combination therapy) will be greater than with Draw #2 within-patient change from 
baseline for arm B (anti-PD1 alone). 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Key Secondary Hypotheses: Hypothesis 2:  Arm B: post sequential antiPD1-vaccine therapy (Draw #3) 
vs post- antiPD1-therapy alone (Draw #2) within-patient change in neoantigen specific T cell response 
will be greater than 0. Hypothesis 3:  Arm B: post-sequential therapy (Draw #3) vs post- antiPD1 
therapy alone (Draw #2) within-patient change will be greater than 0. 
Stevanović et al [32] report on 2 subjects with HPV positive cervical cancer, treated with adoptive 
transfer of tumor infiltrating lymphocytes.  Pre- and post- treatment PBMC samples from these 2 
subjects were assayed for prevalence of 14 and 2  predefined neo-antigen specific  T cell clones, 
respectively, using a similar TCR sequencing based assay.  In both cases,  consistent robust increases 
in relative abundance of the specific targeted T Cell clones were observed, of 3 to 4 orders of 
magnitude or more (Figure 3 C and D from the Stenanovic et al). A second study of treatment in 
cervical cancer with neoantigens (ASCO-SITC 2017, San Francisco, Abstract 140, Melief et al) show 
very large increases in antigen specific T Cell clones, with good reproducibility across the highest dose 
cohorts (5, 5b and 6), albeit measured with a different assay. Hence it is reasonable to power for very 
large effect sizes. 
Arms A and B will accrue 5 subjects each; Arm C and D will accrue 10 subjects each. 
We assume an approximately normal distribution for the final outcome measure, although it is likely 
skewed right. Using a two-sample, one-sided t-test with equal variances at 5% significance level to 
approximate power, with n=15 in combined Arms A and C vs 5 in Arm B, we have 80% power to detect 
a mean increase of about 1.33 standard deviations in the change in numer of neo-antigen specific 
clonotypes. As observed effect sizes appear to be much greater than this, we appear to be well-
powered for Hypothesis 1. 
For the two  comparisons of the key secondary hypotheses, we again use a one-sided, one or two 
sample t-test with equal variances to approximate power. Here, at significance level 0.025 (to control 
for the 2 hypotheses) we have 80% power to detect an effect size of 1.7 standard deviations for 
Hypothesis 2 (within subject change for Arm B)  and also  of 1.7 standard deviations for Hypothesis 3 
(Arm C vs Arm A).  While we have no preliminary data on anti-PD1 therapy alone, it is likely that effect 
sizes much greater than this will be needed for clinical significance.  Thus we are powered to detect 
meaningful pharmacodynamic effect sizes in this preliminary Phase 1b study. 
 
Safety Analysis 
 
Safety and tolerability data as well as demographic data will be summarized in tabular and/or graphical 
format for each treatment arm. The incidence of all laboratory test abnormalities and the median 
changes from baseline will be tabulated by treatment regimen and time point.  The safety population 
will be used for these analyses. 
 
Analysis populations 
• The Safety population will include all randomized patients who took at least one dose of the 
study medication. 
• The modified Intent-to-Treat (mITT) population will include all patients originally assigned to a 
study arm who took at least one dose of the study medication and who have at least one 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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efficacy evaluation following baseline.  
• The Per Protocol (PP) population will include all subjects who: 
- took at least 90% of the assigned medication during the treatment period, and 
- did not have any major protocol deviations, and 
- completed efficacy measurements at baseline and at the end-of-study visit. 
 
The primary population for all efficacy analyses is the mITT population, without imputation for missing 
values. Sensitivity analyses will also be performed using the PP populations for efficacy endpoints, 
using the mITT population with multiple imputation.  
Adverse Events 
 
Adverse events (AE) occurring after the start of study drug dosing at baseline (week 0) will be 
summarized descriptively for the safety population. All AEs will be coded according to system organ 
class (SOC) and preferred term (PT) using a Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Summary tables showing the number of patients and percent within each category will be 
generated for each of the following types of adverse events and its relationship to study treatment 
(related to study treatment): 
• 
All events 
• 
Serious events 
• 
Deaths 
• 
Events leading to withdrawal 
• 
Severe events 
 
Laboratory Parameters 
 
Laboratory parameters will be summarized by visit. Frequencies of high and low values with respect to 
the normal range will be displayed, as will shift tables comparing each treatment visit and baseline visit 
by time point and treatment group.  
 
Pharmacodynamic Outcome measures 
 
Assay 1: Functional T cell assay from PBMC:   PBMC will be obtained from vaccinated patients at 
the time points listed above and an aliquot tested for recognition of the vaccinating peptides by 
ELISPOT (for IFN- and IL-5) either directly ex-vivo or after a 3 day co-culture with the individual 
vaccine peptides, with these time points chosen to reflect the presumed higher frequency with which 
neoantigen-specific T cells will be present in the peripheral blood of treated patients. Positive controls 
will include responses against nominal recall antigens (CEF peptides, for CMV, EBV, and Flu).  The 
primary outcome will be the proportion of cytokine-producing cells in response to the individual vaccine 
peptides, among total PBMC.   
 
Assay 2: Response diversification assay: In addition to measuring responses against the vaccine 
peptides, we will also include peptides comprising the set of tumor-expressed somatic mutations that 
did not elicit a T cell response in the original neoantigen screen in 14-day restimulation cultures using 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PBMC from treated patients to assess whether the antitumor immune response we expect to result 
from vaccination had led to de-novo priming of responses against additional neoantigen targets. The 
outcome will be the proportion of cytokine-producing cells in response to any neoantigen, among total 
PBMC 
 
Assay 3: T cell clonotype assay from PBMC: To assess the frequency of neoantigen-specific 
clonotypes within the patient’s peripheral lymphocyte pool, we will subject an aliquot of the PBMC 
obtained at each time point to ImmunSEQ analysis which uses highly-sensitive genomic sequencing to 
give a quantitative assessment of the TCR clonotypes within a complex lymphocyte population. As we 
will know which specific paired TCR clonotypes belong to verified neoantigen-reactive T cells, we can 
utilize this approach to monitor the frequency of the specific T cell clones which we expect to be 
expanded by the vaccine. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed 
according to UCSD conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the patient and the investigator is assured that the 
patient understands the implications of participating in the study, the patient will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
10.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects who 
have provided written informed consent must also sign a subject authorization to release medical 
information to the study and allow a Sponsor (or designee), and authorized regulatory authorities to 
have direct  access to subject’s medical information relevant to the study. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.4 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the Study Chair, site principal 
investigator and co-investigators, quality assurance of the study will be performed by the UCSD Moores 
Cancer Center Clinical Trials Office internal monitor. Monitoring intervals will be dependent upon the 
number of patients enrolled and the complexity of the study.  
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board (DSMB) to 
provide oversight in the event that this treatment approach leads to unforeseen toxicities. Data from this 
study will be reported annually and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study.  
2) 
the number of patients enrolled to date  
3) 
the dates of  patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution   
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study.  
10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, investigators are required to conduct their research 
according to the plans reviewed and approved by the IRB.  
10.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency modification 
implemented must be noted and reported to the IRB along the lines of a protocol deviation or violation, 
depending on the nature of the modification.  
10.5.2 Protocol Violations 
Any unplanned variance from an IRB approved protocol is considered a violation and must be reported 
to the IRB in a timely fashion. 
A. Major violations must be reported to the IRB within 10 working days of awareness of the 
violation. 
Major violations include: 
• 
Instances that have harmed or increased the risk of harm to one or more research 
participants. 
• 
Instances that have damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or University policies. 
B. Minor violations may be reported to the IRB at the time of the continuing review. 
Minor violations have no substantive effect on the risks to participants or on the scientific 
integrity of the research plan or the value of the data collected. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.6 
Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment.. Protocol 
amendments should also receive written IRB approval before implementation, except when necessary 
to eliminate immediate hazards to the patients or when the changes involve only logistical or 
administrative aspects of the trial (e.g., change of study monitor, telephone numbers).  In this case, the 
Sponsor will amend and implement the protocol change and subsequently notify the regulatory 
authorities and/or the IRB, as appropriate.  Note to File may be used for minor clarifications and 
included in future amendments so as long as it does not impact the safety. 
10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, correspondences, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on Harmonization (ICH) region. In 
all other cases, study documents should be kept on file until three years after the completion and final 
study report of this investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The Principal 
Investigator must assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding 
clinical trials both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms. 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.0 
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28. 
Maybeno, M., et al., Polyfunctional CD4+ T cell responses to immunodominant epitopes 
correlate with disease activity of virulent Salmonella. PLoS One, 2012. 7(8): p. e43481. 
29. 
Arens, R., et al., Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell 
response. J Immunol, 2008. 180(10): p. 6472-6. 
30. 
Stubbington, M.J.T., et al., T cell fate and clonality inference from single-cell transcriptomes. Nat 
Methods, 2016. 13(4): p. 329-332. 
31. 
Bolotin, D.A., et al., MiTCR: software for T-cell receptor sequencing data analysis. Nat Methods, 
2013. 10(9): p. 813-4. 
32. 
Stevanovic, S., et al., Landscape of immunogenic tumor antigens in successful immunotherapy 
of virally induced epithelial cancer. Science, 2017. 356(6334): p. 200-205. 
33. 
Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. 
N. Engl. J. Med, 2009. 361, p. 1838–1847. 
34. 
Ressing, Maaike, et al. Detection of T Helper Responses, But Not of Human Papillomavirus-
Specific Cytotoxic T Lymphocyte Responses, After Peptide Vaccination of Patients With 
Cervical Carcinoma. Journal of Immunotherapy, 2000. 23.2, p. 255-266.  
35. 
Ott, P.A., et al., An immunogenic personal neoantigen vaccine for patients with melanoma. 
Nature, 2017. 547(7662): p. 217-221 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.0 
APPENDICES 
 
Appendix A. Performance Status 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, 
able to carry on all pre-
disease performance without 
restriction. 
1 
Symptoms, but ambulatory. 
Restricted 
in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. 
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 
In bed > 50% of the time.  
Capable of only limited self-
care, confined to bed or 
chair more than 50% of 
waking hours 
4 
100% 
bedridden.  
Completely 
disabled.  
Cannot carry on any self-
care.  Totally confined to bed 
or chair 
5 
Dead. 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix B. Response Evaluation Criteria in Solid Tumors (RECIST) 
Tumor assessments will be made according to the schedule of assessments. Response and 
progression will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
guidelines [Eisenhauer et al. 2009]. 
 
1 
Definitions 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
1.1 
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT 
scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If the investigator thinks it appropriate to include them, the conditions under which such 
lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are present in 
the same patient, these are preferred for selection as target lesions. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), 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 
which can be measured reproducibly should be selected.  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 diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
1.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
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. Imaging-based evaluation is preferred to 
evaluation by 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 (e.g., 
skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin 
nodules).  In the case of skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If 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 in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  
As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should 
be optimized for the evaluation of the type and site of disease.  Furthermore, as with CT, the modality 
used at follow-up should be the same as was used at baseline and the lesions should be 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the site can 
document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 
3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are 
needed to determine if there is truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds 
to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported by 
disease-specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
 
1.3 
Response Criteria 
 
1.3.1 Evaluation of target lesions 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of 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 diameters while on study.  
 
1.3.2 Evaluation of non-target lesions 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion status.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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It must be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
1.3.3 Evaluation of best overall response  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
1.3.4 Duration of overall response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent 
or progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 
1.3.5 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever 
occurs first. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix C: Contraceptive Guidance and Pregnancy Testing 
 
Definition 
 
Woman of Childbearing Potential (WOCBP): A woman of child-bearing potential is any female 
(regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) 
who meets the following criteria: 
o Has not undergone a hysterectomy or bilateral oophorectomy; or 
o Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 
menses at any time in the preceding 12 consecutive months) 
 
 
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
  
○ Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Requirements 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree to 
one of the following during the protocol:  
• 
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a 
long term and persistent basis) and agree to remain abstinent 
• 
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per 
year as described in Table 6 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration.Female Participants: 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 6. 
 
Table 6 
Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception  
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception  
○ Oral  
○ Injectable  
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency 
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant  
● Intrauterine hormone-releasing system (IUS)   
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected menstrual 
cycle is missed or when pregnancy is otherwise suspected; at the time points specified in the Schedule 
of Activities, and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected.