Peripheral T Cell Determinants of Response and Resistance to Pembrolizumab in Melanoma
Conditions: Melanoma, Advanced Melanoma
Sponsor: University of California, San Francisco

Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except to the 
extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal and state 
laws.  Persons to whom this information is disclosed should be informed that this information is privileged and confidential 
and that it should not be further disclosed. 
Peripheral T cell determinants of response and resistance 
to pembrolizumab in melanoma
Protocol Number:  CC# 21853
Version Number: 1.6
Version Date: 02/26/2025
 NCT Number: NCT05105100
Principal Investigator (Sponsor-Investigator)
Adil Daud, MD
University of California San Francisco 
t
San Francisco, CA 94158 
 
 
Co-Investigator
Laura Huppert, MD
 
 
Statistician
Jimmy Y. Hwang, Ph.D.
Revision History
Version 1.0
10-12-2020
Version 1.1
12-22-2020
Version 1.2
04-15-2021
Version 1.3
06-07-2021
Version 1.4
Version 1.5
06-09-2022
09-30-2022
Version 1.6
02-26-2025

UCSF Helen Diller Family Comprehensive Cancer Center
Version date:02/26/2025 
Protocol CC#: 21853
Non-therapeutic investigational trial
 Page 2 of 32
Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review and 
Monitoring Committee (PRMC), Institutional Review Board (IRB), and Data and Safety 
Monitoring Committee (DSMC).
2.
I will conduct the study in accordance with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
Good Clinical Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, 
and local regulatory requirements.
3.
I certify that I, and the study staff, have received the required training to conduct 
this research protocol.
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, 
federal, state and local laws and regulations.
UCSF Principal Investigator
Printed Name
Signature
Date

UCSF Helen Diller Family Comprehensive Cancer Center
Version date:02/26/2025 
Protocol CC#: 21853
Non-therapeutic investigational trial
 Page 3 of 32
Abstract
Title
Peripheral T cell determinants of response and resistance to 
pembrolizumab in melanoma
Study Description
This is a non-therapeutic study assessing peripheral T cell 
determinants of response and resistance to immunotherapy in patients 
with advanced melanoma. Patients will be eligible to enroll if they have 
unresectable/metastatic stage III/IV melanoma and are 
immunotherapy naïve with an indication to start anti-PD1 therapy per 
NCCN guidelines. Tumor and peripheral blood mononuclear cells 
(PBMC) will be collected for correlative studies before and during 
treatment with pembrolizumab. A total of 28 subjects will be enrolled in 
this study.
Phase of Study
Non-therapeutic exploratory study
Study population
Patients will be eligible to enroll if they have unresectable/metastatic 
stage III/IV melanoma and are immunotherapy naïve with an indication 
to start anti-PD1 therapy per NCCN guidelines. Participants will be 
recruited from the Melanoma and Cutaneous Oncology Program at the 
University of California San Francisco Comprehensive Cancer Center. 
Patients must have accessible tumor for research biopsy.
Primary Objective
To understand how the systemic immune profile (T cell activation and 
expansion in the tumor microenvironment (TME)) changes in response 
to anti-PD1 therapy in patients with advanced or metastatic melanoma 
on pembrolizumab monotherapy.
Exploratory 
Objectives
1.
To correlate the peripheral T cell profiles with the objective 
response rate (ORR) at 24 weeks in patients with advanced 
melanoma on pembrolizumab monotherapy.
2.
To correlate the peripheral T cell profiles with progression free 
survival (PFS) in patients with advanced melanoma on 
pembrolizumab monotherapy.
3.
To correlate the peripheral T cell profiles with overall survival (OS) 
in patients with advanced melanoma on pembrolizumab 
monotherapy.
4.
To correlate the peripheral T cell profiles with toxicity profile
5.
To determine the transcriptional and phenotypic features of tumor 
directed T cells in blood using a combination of phenotypic 
markers derived from COMET and cite-seq
Sample Size
28 patients
Duration of Study 
Treatment
Patients will be followed for 6 months from time of treatment initiation. 
After 6 months, patients do not need to be followed but standard of 
care scans and survival status can be assessed for up to 5 years.

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Protocol CC#: 21853
Unique Aspects of 
this Study
A key question is whether systemic tumor directed CD8+ T cells can
be identified and relatedly whether they can be used as a biomarker 
for response to immunotherapy. Integrating the local and systemic 
immune component into a model of PD-1 action is vital to a better 
mechanistic understanding of PD-1 response and resistance.

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Protocol CC#: 21853
List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CBC
Complete blood cell (count)
CRF
Case report form
CT
Computerized tomography
CTLA-1
Cytotoxic T lymphocyte-associated protein 4 
CTCAE
Common Terminology Criteria for Adverse Events 
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan 
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group 
FDA
Food and Drug Administration
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HIPAA    
Health Insurance Portability and Accountability Act 
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization 
IgG4
Immunoglobulin G4
irAE
Immune-related adverse event 
IRB
Institutional Review Board
IV
Intravenous
MHC
Major histocompatibility complex 
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Center 
ORR
Overall response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell 
PD-1
Programmed cell death 1
PDL-1 
Programmed cell death ligand 1
PDL-2      
Programmed cell death ligand 2 
PI
     Principal investigator
PFS
     Progression free survival
PRC
     Protocol Review Committee (UCSF)

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List of Abbreviations
PT
Prothrombin time
RANO
Response Assessment in Neuro-oncology 
RR
Response rate
TCR
T-cell receptor
TME
Tumor microenvironment
UCSF
University of California, San Francisco 
WOCBP
Woman of childbearing potential

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Table of Contents
Protocol Signature Page...............................................................................................................2
Abstract.........................................................................................................................................3
List of Abbreviations......................................................................................................................6
Table of Contents..........................................................................................................................7
1
Introduction ............................................................................................................................9
1.1.2  Identification and characterization of peripheral tumor-directed CD8+ T cells ...................9
1.1.3  Preliminary work .................................................................................................................9
1.2
Rationale for the Proposed Study ....................................................................................10
1.3
Rationale for the Dose Selection/Regimen ......................................................................10
1.4
Rationale for Exploratory Biomarker Research ................................................................10
2
Study Objectives ..................................................................................................................11
2.1
Hypothesis........................................................................................................................11
2.2
Primary Objective and Endpoints.....................................................................................11
3
Study Design........................................................................................................................12
3.1
Characteristics..................................................................................................................12
3.2
Trial Schema ....................................................................................................................12
3.3
Sample Size .....................................................................................................................12
3.3.1  Participant Discontinuation Criteria...................................................................................12
3.4
Eligibility Criteria...............................................................................................................13
3.4.1  Inclusion Criteria................................................................................................................13
3.4.2  Exclusion Criteria..............................................................................................................13
3.5
Inclusion of Women and Minorities ..................................................................................13
3.5.1  Eligibility of Women and Minorities....................................................................................13
3.5.2  Recruitment of Minority Groups ........................................................................................13
3.6
Accrual estimates.............................................................................................................14
4
Specimen Collection and Processing...................................................................................14
4.1.1  Fresh Tissue Collection ....................................................................................................14
4.1.2  Blood.................................................................................................................................14
4.2
Specimens Processing.....................................................................................................14
4.2.1
Tissue Processing and Analysis......................................................................................14
4.2.2
Blood Processing and Analysis.......................................................................................14
4.3
Specimen Coding and Labeling .......................................................................................14
4.4
Specimen Transport.........................................................................................................15
5
Study Timeline......................................................................................................................15
5.1
Primary Completion..........................................................................................................15
5.2
Study Completion.............................................................................................................15
5.3
Study Calendar.................................................................................................................16
5.4
Participant Registration ....................................................................................................17
5.5
Schedule of Procedures and Assessments......................................................................17
5.5.1  Screening (prior to standard of care treatment) ................................................................17
5.5.2  Study Procedures during standard of care treatment .......................................................17
5.5.3  Follow-up ..........................................................................................................................18
5.5.4  Safety Follow-Up Visit.......................................................................................................18
5.5.5  Prohibited Medications......................................................................................................18
5.6
Response Criteria.............................................................................................................18
6
Statistical Considerations and Evaluation of Results ...........................................................21
6.1
Sample Size Justification .................................................................................................21
6.2
Statistical Analysis Plan Summary...................................................................................21
6.2.1  Subject Demographic and Baseline Characteristics.........................................................21

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6.2.2  Primary Analysis ...............................................................................................................21
6.2.3  Exploratory Analysis .........................................................................................................22
7
Study Management ..............................................................................................................22
7.1
Pre-study Documentation.................................................................................................22
7.2
Institutional Review Board Approval ................................................................................22
7.3
Informed Consent.............................................................................................................23
7.3.1  General Informed Consent................................................................................................23
7.4
Changes in the Protocol...................................................................................................23
7.5
Case Report Forms (CRFs) .............................................................................................23
7.6
Oversight and Monitoring Plan.........................................................................................24
7.7
Record Keeping and Record Retention............................................................................24
8
Safety Parameters................................................................................................................25
8.1
Definition of Adverse Events ............................................................................................25
8.1.1  Adverse Event (AE) ..........................................................................................................25
8.1.2  Serious Adverse Event (SAE)...........................................................................................25
8.1.3  Unanticipated Problem (UP) .............................................................................................25
8.2
Classification of Adverse Events......................................................................................26
8.2.1  Severity.............................................................................................................................26
8.2.2  Attribution..........................................................................................................................26
8.2.3  Expectedness ...................................................................................................................26
8.3
Recording of Adverse Events...........................................................................................26
8.4
Expedited Reporting.........................................................................................................26
8.4.1  Reporting to the HDFCCC Data and Safety Monitoring Committee .................................26
8.4.2  Reporting to Institutional Review Board............................................................................27
8.5
Follow-up of Adverse Events............................................................................................27
8.6
Adverse Events Monitoring ..............................................................................................27
9
References......................................................................................................................28
Appendix 1: Data and Safety Monitoring Plan for a Non-therapeutic Institutional Trial ..............30

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1
Introduction
1.1
Background on Indication
1.1.1 The local and systemic immune response in checkpoint inhibitor therapy
Cancer immunotherapy has revolutionized the treatment of malignancy, leading to durable 
responses in some patients(1). The effectiveness of checkpoint inhibitor therapy depends on the 
presence of CD8+ T cells in the tumor microenvironment as well as the systemic immune 
response(2). “Exhaustion markers” on tumor infiltrating CD8+ cells such as programmed cell 
death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are required 
for effective PD-1 blockade(3–7). These “exhausted” T cells have a finite lifespan even with PD- 
1 blockade(3, 4) and appear to be replaced by fresh clonal proliferating T cells, a concept 
termed “clonal replacement”(8). Specifically, systemic immune cells undergo priming and 
infiltrate the tumor in response to PD-1 blockade, thus playing an important role in maintaining 
and generating a PD-1 response(9, 10). A key question is whether these systemic tumor 
directed CD8+ T cells can be identified and relatedly whether they can be used as a biomarker 
for response to immunotherapy. Integrating the local and systemic immune component into a 
model of PD-1 action is vital to a better mechanistic understanding of PD-1 response and 
resistance.
1.1.2  Identification and characterization of peripheral tumor-directed CD8+ T 
cells
The vasculature is a major site of CD8+ T cell trafficking between primary tumors, secondary 
lymphoid organs, and metastatic sites(11), making the blood an ideal location to sample to 
investigate peripheral anti-tumor responses. Multiple recent studies have provided 
comprehensive profiling of T cells in the blood of patients with cancer, including patients on 
checkpoint blockade(12–17). However, the ability to identify T cell populations directed against 
tumor epitopes has been more challenging. Historically, it had been difficult to track tumor 
antigen-specific CD8+ T cells using conventional methods like peptide major histocompatibility 
complex (MHC) tetramers due to the limited number of defined tumor antigens and the limited 
number of MHC haplotypes that bind these antigens . Improved methods to identify T cell 
populations directed against tumor epitopes are needed to focus these analyses in order to 
better identify and characterize the minority of circulating T cell populations that have functional 
and prognostic relevance to the anti-tumor immune response.
1.1.3  Preliminary work
Recently, our group demonstrated that T cell receptor (TCR) analysis combined with single cell 
RNA sequencing can be used to detect tumor directed CD8+ T cells in mice with MC38 tumors 
and in humans with melanoma (Figure 1) (20). Tumor matching CD8+ T cells showed increased 
signs of activation compared to non-tumor matching cells in the blood but were less 
dysfunctional than corresponding clones in the tumor. This work provided both a technological 
advance as well as new insight into the biology of the tumor-matching T cells in the blood.
However, a limitation of this work was that only four human subjects were included, and 
longitudinal samples were collected in only two participants. Therefore, there was limited ability 
to assess dynamic changes in peripheral tumor-directed CD8+ T cells and clinical response to 
immunotherapy.

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1.2
Rationale for the Proposed Study
To define the mechanistic basis of PD-1 action with particular interest in studying the peripheral 
T cell component. See background discussion above.
1.3
Rationale for the Dose Selection/Regimen
Pembrolizumab will be administered per standard of care, according to the NCCN guidelines. 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).
1.4
Rationale for Exploratory Biomarker Research
Tumor and blood samples will be processed to isolate T cells using 10X Chromium sequencing 
using standard methods. For each blood sample, in addition to the single-cell assay, we will 
generate bulk RNA-seq and freeze a subset of the sample for downstream validation assays. 
We will characterize the transcriptional landscape and subsequent differentiation state of the 
matching clones in blood and tumor using transcriptional signature analysis of the RNAseq data.
To test whether single-gene markers can be used to identify the CD8+ TM component with flow 
cytometry, we will apply COMET, a computational tool developed in the Singer lab that can help 
predict markers from single-cell RNA-seq data. We can use this program, as well as additional 
tailored code, to derive novel hypotheses (e.g. pathways enriched in clones that expand in 
responders) as well as to test hypotheses of interest (e.g. testing whether recently published cell 
states are enriched or depleted in responders when compared to non-responders).
Figure 1: Identifying T cell clones shared between tumor 
and blood (Pauken et. al. JCI 2021)
This figure depicts the method for peripheral tumor directed 
CD8+ T cell identification. The tumor-specific CD8+ T cells 
are shown in navy blue.

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2
Study Objectives
2.1Hypothesis
We hypothesize that systemic T cells traffic into the tumor microenvironment (TME) and predict 
response and resistance to immunotherapy. These systemic tumor directed T cells can be 
defined by tumor/blood scRNA using TCR as a barcode and can help predict response to PD-1 
therapy.
2.2
Primary Objective and Endpoints
Primary Objective
Endpoints
Time Frame
To understand how the 
systemic immune profile (T cell 
activation and expansion in 
TME) changes in response to 
pembrolizumab therapy in 
patients with advanced 
melanoma on pembrolizumab 
monotherapy.

Tumor and blood T cell TCR + single cell 
RNA profile
o
pre-immunotherapy initiation in 
peripheral blood and tumor
o
post-immunotherapy initiation in 
peripheral blood (and optional post- 
immunotherapy tumor biopsy)
24 weeks
2.3
Exploratory Objectives and Endpoints
Exploratory Objective
Endpoints
Time Frame
To correlate the peripheral T cell profiles with the 
objective response rate (ORR) at 24 weeks in 
patients with advanced melanoma on 
pembrolizumab monotherapy.

ORR at 24 weeks
24 weeks
To correlate the peripheral T cell profiles with 
progression free survival (PFS) in patients with 
advanced melanoma on pembrolizumab 
monotherapy.

PFS
5 years
To correlate the peripheral T cell profiles with 
overall survival (OS) in patients with advanced 
melanoma on pembrolizumab monotherapy.

OS
5 years
To correlate the peripheral T cell profiles with 
toxicity profile

CTCAE v. 5
24 weeks
Transcriptional and phenotypic features of tumor 
directed T cells in blood using a combination of 
phenotypic markers derived from COMET and 
cite-seq

Mean (95% CI) change 
in biomarker levels with 
treatment, by cycle
24 weeks

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3
Study Design
3.1
Characteristics
This is a non-therapeutic exploratory study assessing the peripheral T cell determinants of 
response and resistance to immunotherapy in melanoma. Patients will be enrolled if they have 
unresectable/metastatic stage III/IV melanoma and are immunotherapy naïve with indication to 
start anti-PD1 therapy per NCCN guidelines. Patients will be started on pembrolizumab 
monotherapy per standard of care. Tumor and peripheral blood mononuclear cells (PBMC) will be 
collected for correlative studies before and during treatment. If fresh tissue collection is not 
possible or not safe, archival tissue such as core or incisional biopsy or FNA cell block may be 
used. A total of 28 subjects will be enrolled in this study.
3.2
Trial Schema
Participants will be recruited from the Melanoma and Cutaneous Oncology Program at the 
University of California San Francisco Comprehensive Cancer Center. Patients must have 
accessible tumor for the research biopsy which needs to be a core, punch, excisional or 
incisional biopsy. A clinical research coordinator from our Melanoma and Cutaneous Oncology 
Program will be assigned to manage this trial and will assist with patient screening and consent. 
The trial will be reviewed at the Melanoma research site committee, which occurs twice per 
month. After enrolling in this study, participants will undergo a pre-treatment tumor core biopsy 
and PBMC collection. If fresh biopsy is not possible, archival tissue may be used. Then, 
patients will be started on pembrolizumab per standard of care and PBMCs will be collected 
every cycle (q3wk) (Figure 2).
3.3
Sample Size
Approximately 28 participants will be consented to achieve the target sample size of 28 
evaluable subjects.
3.3.1  Participant Discontinuation Criteria
Participants may discontinue study activities at any time for any reason or be discontinued from 
the study activities at the discretion of the investigator should any untoward effect occur
Pembrolizumab monotherapy
Shown is the study schema. Day 0 is defined as the first day of pembrolizumab monotherapy. “Tumor” 
indicates a research tumor biopsy, which must be a core biopsy (16-18 g needle X2), punch, excisional or 
incisional biopsy. If fresh biopsy is not possible, archival tissue may be used “PBMC” indicates collection 
of peripheral blood mononuclear cells. The baseline tumor/PBMC collection must be done within 28 days
PBMC
PBMC
Tumor/ 
PBMC
Day 84
Day 21
Figure 2: Clinical trial schema
Day -14
Day 0
Study screening 
& enrollment
Treatment response 
assessment per 
RECIST 1.1

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3.4
Eligibility Criteria
3.4.1  Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Patients must have histologically confirmed locally advanced or metastatic melanoma 
and be starting on standard of care pembrolizumab monotherapy. Patients may have 
received any or no prior anti-cancer therapy without limitation.
2.
Must have one or more sites of disease amenable to biopsy (tumor, skin, lymph node, 
pleural fluid, peritoneal fluid, cerebral spinal fluid (CSF)).
3.
Have measurable disease based on RECIST 1.1. Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in 
such lesions.
4. Participants must be age 18 years or older on the day of signing informed consent.
5.
Have the ability to provide written informed consent for the trial.
6.
Be able and willing to comply with study procedures including provision of basic 
demographic information and medical history.
7.
Be willing to receive periodic follow up phone calls to monitor health status and survival 
status.
3.4.2  Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4,
OX-40, CD137).
2.
Has received prior systemic anti-cancer therapy including investigational agents within 
the prior 2 weeks.
3.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.
4.
Has a contraindication to tissue biopsy for minimally-invasive research-procedure
5.
Contraindication to phlebotomy (up to 40 mL per phlebotomy every three weeks).
3.5
Inclusion of Women and Minorities
3.5.1  Eligibility of Women and Minorities
Individuals of any sex/gender, race, or ethnicity are eligible for this study.
3.5.2  Recruitment of Minority Groups
The study recruitment strategy aims to achieve representation of minority groups that reflects 
the demographics of the affected population in the catchment area.

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3.6
Accrual estimates
The study planned to accrue a total of 28 evaluable patients.
4
Specimen Collection and Processing
4.1
Types of specimens
At baseline prior to starting pembrolizumab, blood and tumor tissue will be collected. Repeat 
blood collection will occur every three weeks on study. Two-six weeks after treatment initiation, 
an optional repeat tumor biopsy and/or biopsy of a metastatic site can be performed at the 
discretion of the study provider if the patient is amenable.
4.1.1  Fresh Tissue Collection
Biopsy of the tumor tissue can be done via a core needle biopsy, excisional, or incisional 
biopsy. The baseline tissue biopsy will be collected in conjunction with a standard of care biopsy 
if possible. One to four additional passes of core needle, or FNAs (number determined by safe 
accessibility and size of lesion) will be collected for research purposes. If no standard of care 
biopsy is planned, a research-only biopsy can be performed. This can be done via core biopsy, 
excisional biopsy, or incisional biopsy at the discretion of the study provider. If fresh tissue 
biopsy is not possible, archival tissue may be used.
Two to six weeks after starting immunotherapy, an optional repeat tumor biopsy can be 
performed (research only). This can be done via core biopsy, excisional biopsy, or incisional 
biopsy at the discretion of the study provider with patient consent. In addition, an optional biopsy 
of a metastatic site (skin/subcutaneous tissue, lymph node FNA/core biopsy, tissue FNA/core 
biopsy, pleural fluid collection, peritoneal fluid collection, and/or cerebral spinal fluid collection) 
can also be performed at the discretion of the study provider at baseline and/or after initiation of 
immunotherapy. These will be done in conjunction with standard of care biopsies if possible or 
can be performed as research-only biopsies at the discretion of the study provider with patient 
consent.
4.1.2  Blood
Up to 40 mL of blood will be collected at baseline and every 3 weeks after starting 
pembrolizumab for at least the first eight cycles of pembrolizumab. Thereafter, additional 
research blood specimens can be collected at later timepoints at the discretion of the study PI 
and with patient consent. Blood draws will be performed during standard of care or clinical trial 
phlebotomy collections, whenever possible, to minimize patient risk. The amount of blood drawn 
will not exceed 100 mL in total.
4.2
Specimens Processing
4.2.1 Tissue Processing and Analysis
Tissue will be processed as per standard operating procedure for these sample types by a 
research technician or investigator.
4.2.2 Blood Processing and Analysis
Blood will be processed as per standard operating procedure for these sample types by a 
research technician or investigator.
4.3
Specimen Coding and Labeling
Specimens will be de-identified and assigned a study number for storage purposes. Specimens 
will be collected and managed using encrypted databases stored on the secure UCSF server, 

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using appropriate database software. Principal Investigator, Co-Investigators and lab personnel 
will have access to de-identified specimens.
4.4
Specimen Transport
The transportation, coding and storage systems will be performed under UCSF biohazardous 
specimen guidelines. The transportation of all tissues is handled by specially-trained research 
assistants employed by the Cancer Center or organ-based projects.
5
Study Timeline
5.1
Primary Completion
The study completion date is 60 months after study initiation.
5.2
Study Completion
The study completion date is 60 months after study initiation.

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5.3
Study Calendar
Table 1- Schedule of Activities (SoA)
1 Standard of care Pembrolizumab 200 mg q every 3 weeks
2 Tumor imaging is strongly preferred to be acquired by computed tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be 
used when CT with iodinated contrast is contraindicated, or when local practice mandates it.
3 Core biopsy (16-18 g needle X2) or a punch or excisional or incisional biopsy. Required biopsy prior to starting treatment.
4 Up to 40 mL of whole blood collection for PBMC will be collected at baseline and prior to the first eight cycles of treatment with pembrolizumab. Blood can be collected at later 
timepoints at the discretion of the study PI and with patient consent.
5 An optional repeat tumor biopsy will occur two-six weeks after treatment initiation at the discretion of the study PI and with the consent of the patient. This can be a biopsy of the
primary tumor and/or a metastatic site, at the discretion of the study PI and with patient consent.
6 Imaging will occur every 9-12 weeks per standard of care. Preferred imaging: PET/CT, CT CAP, or MRI at the discretion of the study provider
7 Patients will be followed for 6 months on study, but then standard of care imaging and survival status can be tracked for up to five years
Study Period
Scree 
ning
Treatment cycle
EOT
Efficacy Follow- 
up
Survival 
Follow-Up
Visit Number/Title:
Scree 
ning
1
2
3
4
5
6
7
8
Discontinua 
tion
Scheduling window 
(days):
-28 to
-1
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
+/-3
Every 9 or 126 
Weeks(±7 days)
Every 12 Weeks7
Standard of Care1
Pembrolizumab
X
X
X
X
X
X
X
X
Administrative 
Procedures
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
Medical History
X
Prior/Concomitant 
Medication Review
X
AE assessment
X
X
X
X
X
X
X
X
X
Tumor
biopsy/correlative 
studies
Tumor biopsy3
X
X5
Correlative blood 
collection4
X
X
X
X
X
X
X
X
X
X
Survival Status
================================================================
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5.4
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records.
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system 
is password protected and meets HIPAA requirements.
5.5
Schedule of Procedures and Assessments 
5.5.1  Screening (prior to standard of care treatment)
The Screening procedures and assessments must be completed within 28 of initiating study 
treatment.

Informed Consent

Eligibility (inclusion and exclusion) - All inclusion and exclusion criteria will be reviewed by 
the investigator or qualified designee to ensure that the subject qualifies for the trial.

Demographics: Age, gender, medical comorbidities

Cancer and medical history review - A medical history will be obtained by the investigator 
or qualified designee. Medical history will include all active conditions, and any condition 
diagnosed within the prior 10 years that are considered to be clinically significant by the 
Investigator. Details regarding the disease for the subject enrolled in this study will be 
recorded separately and not listed as medical history.

Medication review - The investigator or qualified designee will review prior and 
concomitant medication that the subject use and will record the medications taken by the 
subject.

Up to 40cc PBMC blood collection

Tumor/tissue collection - Fine needle aspiration (FNA) or core needle biopsy of the tumor, 
portions of excisional biopsies or surgical resections

Stagging imaging: PET/CT, CT chest/abd/pelvis, or MRI abd/pelvis

Optional tissue collection form a metastatic site – Skin/subcutaneous tissue, lymph node 
FNA/core biopsy, tissue FNA/core biopsy, pleural fluid collection, peritoneal fluid 
collection, and/or cerebral spinal fluid collection.
5.5.2  Study Procedures during standard of care treatment
After initiation of pembrolizumab per standard of care, the following will occur each cycle:

Up to 40cc PBMC blood collection every three weeks for the first eight weeks of 
pembrolizumab treatment, with optional PBMC collection during later cycles at the 
discretion of the study PI and with patient consent.

2-6 weeks after study initiation: Optional tumor/tissue collection – Fine needle aspiration 
(FNA) or core needle biopsy of the tumor, portions of excisional biopsies or surgical 
resections.
2-6 weeks after study initiation: Optional tissue collection from a metastatic site - 
Skin/subcutaneous tissue, lymph node FNA/core biopsy, tissue FNA/core biopsy, pleural 
fluid collection, peritoneal fluid collection, and/or cerebral spinal fluid collection.

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
Tumor imaging will be conducted per standard of care, approximately every 8-12 weeks. 
PET/CT, CT scan or MRI of chest, abdomen and pelvis is preferred. It is preferred if 
serial imaging is consistent for each participant.
5.5.3  Follow-up
Given that this is not an interventional trial, the clinical assessment and monitoring should occur 
per standard of care and at the discretion of the provider and are not specified by this trial.
5.5.4  Safety Follow-Up Visit
Given that this is not an interventional trial, the clinical assessment and monitoring should occur 
per standard of care and at the discretion of the provider and are not specified by this trial.
Each individual participant will be followed for up to 5 years post treatment to determine OS. 
They will not be followed beyond 5 years as part of this study.
5.5.5  Prohibited Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy. Radiation therapy to symptomatic lesion(s) or to the brain may be 
allowed at the investigator’s discretion.
Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
The use of steroids up to the equivalent of 10mg prednisone daily is allowed. Doses exceeding 
that is not allowed on this study.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 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.
5.6
Response Criteria 
 Evaluation of Target Lesions 
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart. Any pathological lymph nodes (whether target or non-target) must

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have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes). 
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD. There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the 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 (0.5 cm). (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
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 (< 10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Incomplete Response/Stable Disease (SD)
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.
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 participant’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.

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Table 2.1 Response Criteria for Participants with Measurable 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
CR
Not evaluated
No
PR
PR
Non-CR/Non- 
PD/not evaluated
No
PR
≥4 wks. Confirmation**
SD
Non-CR/Non- 
PD/not evaluated
No
SD
Documented at least once ≥4 wks. 
from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
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: Participants 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.
Table 2.2 Response Criteria for Participants with Non-Measurable 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
‘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
Duration of 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 recurrent 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.
Progression-Free Survival
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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6
Statistical Considerations and Evaluation of Results
6.1
Sample Size Justification
This is a non-therapeutic clinical trial assessing peripheral T cell determinants of response and 
resistance to immunotherapy in melanoma. The proposed sample size of the study is not based 
on the alpha level and the power estimate for hypothesis testing, but rather on the assumed 
measurements of the TCR biomarkers profile under systemic immune environment during the 
PD-1 blockade with pembrolizumab in patients with melanoma. A total of 28 subjects will be 
accrued to develop the systemic immune biomarkers profile and to determine preliminary 
clinical evidence on the progression-free survival and objective response rate.
6.2
Statistical Analysis Plan Summary
6.2.1  Subject Demographic and Baseline Characteristics
Subject disposition (e.g., the number of subjects signing the informed consent, completed, and 
discontinued) along with the number of subjects in the analysis populations will be summarized. 
Descriptive statistics will be used to summarize subject demographics and baseline 
characteristics such as medical and surgical history. Additionally, demographics will also be 
presented for screen failure subjects.
6.2.2  Primary Analysis
We will analyze the bulk RNAseq data as described below:
Step 1: Identify genes predictive of response to anti-PD-1 therapy by testing for significant 
associations across expression rates of each gene and response/resistance, within a hurdle- 
Gaussian mixed-effect framework that accounts for variance across patients and technical noise 
present in single-cell data. The use of single-cell analysis to detect differentially expressed 
genes gives significant statistical power and our anticipated number of patients (n = 28, ≥300K 
total T cells) is sufficient to detect even subtle effects. Following identification of genes indicative 
of response to anti-PD-1 treatment, we will identify gene modules (gene sets that co-vary within 
the single-cell data using hierarchical clustering within the gene-space on batch corrected data). 
We will identify predicted functional attributes and central regulators for each module with 
statistical enrichment tests (e.g. GSEA17 and Enrichr18).
Step 2: Identify changes in subpopulation frequencies associated with response to anti-PD-1 
therapy. We will identify T cell subpopulations in the tumor-directed component in blood whose 
relative frequency is indicative of response to anti-PD-1 therapy, using a negative binomial 
regression model. We will test for predictive differences in relative frequencies before and after 
treatment initiation separately, as well as when combining both timepoints with appropriate 
interaction terms.
Step 3: Identify differences in clonal expansion, distribution, and “transcriptional migration” of T 
cells associated with response to anti-PD-1 therapy. We will build a novel computational 
framework to identify T cell clonal behavior associated with response to anti-PD-1 therapy. We 
will use the profiling of TCR sequences at single-cell resolution to compare various clonal 
attributes (e.g. clonal size and expansion following treatment) in each of the subpopulations 
identified in Step 2 for their association with response to anti-PD-1 therapy. Additionally, we will 
search for “transcriptional migration” events, in which T cell clones change their transcriptional 
profile following treatment and will assess the predictive power of such events to the success of

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anti-PD-1 therapy. Following clonal identification, analyses of clonal size, expansion, and 
change in transcriptional states are conducted using statistical modeling (mixed-effect 
generalized regression models with coefficients for response state while accounting for 
technical affects like batch effects and gene count in cells).Clinical outcomes will be evaluated 
base on the objective response (CR/PR) by RECIST 1.1 by Week 24. Descriptive statistics with 
frequency and proportions will be used to evaluate the ORR rate by Week 24. Descriptive 
statistics with mean, median, STD and 95%CI will be analyzed for the systemic immune 
biomarkers. The association between the systemic immune T cell levels and clinical response to 
anti-PD1 therapy will be analyzed using T-tests for significance.
6.2.3  Exploratory Analysis
Time to event variables (progression-free survival and overall survival) will be summarized using 
the Kaplan-Meier method, including graphical displays and incidence estimates at 12 and 24 
weeks.
For immunologic and genomic correlative tests, the study endpoint will be determining changes 
in the expression with treatment. We will estimate mean (95% CI) changes in biomarker level 
with treatment. To examine trends, we will examine mean biomarker levels by cycle. If patients 
vary by amount of therapies received, we will model mean biomarker levels by dose & cycle.
We will use generalized estimating equation models to determine if changes in immunologic and 
genomic biomarker levels correlate with patient response, for responses evaluated at the end of 
each treatment cycle and biomarkers evaluated at baseline and after cycles 3 and 6.
The exploratory analyses will evaluate systemic TCR matched newly activated effector CD8+ 
cells and intratumoral exhausted T cells as well as intratumoral Treg cells. In this analysis data 
will be summarized using descriptive statistics. For continuous variables, descriptive statistics 
will include the number of non-missing values, mean, standard deviation, median, min and 
maximum. For categorical variables, descriptive statistics will include counts and percentages 
per category. For association between biomarkers, Spearman correlations will be calculated to 
determine the significance of the association between the biomarkers of interest.
7
Study Management
7.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional Review 
Board for the protocol, written informed consent form, subject recruitment materials, and any other 
written information to be provided to participants before any protocol related procedures are 
performed on any participants.
The PI must comply with the applicable regulations in Title 21 of the Code of Federal Regulations 
(21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements. The 
IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
7.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the IRB of record. Prior to obtaining IRB approval, the protocol must be approved

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by the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC). The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.
7.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB -approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document.
The original signed copy of the consent document must be retained in the medical record or 
research file.
7.3.1  General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the participant’s dated signature or by 
the participant’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
If the investigator recommends continuation of study intervention beyond disease progression, 
the participant or his/her legally acceptable representative will be asked to sign consent.
7.4
Changes in the Protocol
Once the protocol has been approved by the IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.
7.5
Case Report Forms (CRFs)
The PI and/or designee will prepare and maintain adequate and accurate participant case 
histories with observations and data pertinent to the study. Study specific Case Report Forms 
(CRFs) will document safety and treatment outcomes for safety monitoring and data analysis. 
All study data will be entered into OnCore® via standardized CRFs in accordance with the

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CTMS study calendar, using single data entry with a secure access account. Study personnel 
will complete the CRFs; the PI will review and approve the completed CRFs.
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the participant’s medical records maintained by 
study personnel. All source documentation should be kept in separate research files for each 
participant.
In accordance with federal regulations, the PI is responsible for the accuracy and authenticity of 
all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to 
attest that the information contained on the CRFs is true and accurate.
The PI will be responsible for ensuring the accurate capture of study data. At study completion, 
when the CRFs have been declared to be complete and accurate, the database will be locked. 
Any changes to the data entered into the CRFs after that time can only be made by joint written 
agreement among the PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
7.6
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring/auditing entity for this study. The UCSF DSMC will monitor or audit the study in 
accordance with the NCI-approved Data and Safety Monitoring Plan (DSMP). The DSMC will 
review study-related activities to ensure that the study is conducted in accordance with the 
protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP). Significant results of the DSMC monitoring/auditing review will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an 
expedited fashion, as applicable (see Appendix 1).
7.7
Record Keeping and Record Retention
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each participant. Case histories 
include the case report forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of the physician, the 
individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant 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.

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8
Safety Parameters
8.1
Definition of Adverse Events
8.1.1  Adverse Event (AE)
Adverse event means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
All Grade 3-5 adverse events (AEs), whether or not considered expected or unexpected and 
whether or not considered associated with the study intervention or procedure, will be entered into 
OnCore®, UCSF’s Clinical Trial Management System. Adverse events are graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE) as developed and revised by the 
Common Therapy Evaluation Program (CTEP) of the National Cancer Institute. See Appendix 1.
8.1.2  Serious Adverse Event (SAE)
An adverse event is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes:

Death

Life-threatening adverse event
o
An adverse event is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the 
participant at immediate risk of death. It does not include an 
adverse event that, had it occurred in a more severe form, might 
have caused death.

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
8.1.3  Unanticipated Problem (UP)
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
1)
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being study;
2)
related or possibly related to participation in the research; and

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3)
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized.
Only a small subset of adverse events occurring in human subjects participating in research will 
meet these three criteria for an unanticipated problem. Furthermore, there are other types of 
incidents, experiences, and outcomes that occur during the conduct of human subjects research 
that represent unanticipated problems but are not considered adverse events. For example, 
some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events. In other cases, unanticipated problems 
place subjects or others at increased risk of harm, but no harm occurs.
8.2
Classification of Adverse Events
8.2.1  Severity
Adverse events are graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse events (CTCAE) version 5.0.
8.2.2  Attribution
Adverse events are given an assignment of attribution or relationship to the investigational 
agent(s) or study procedure. Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure.

Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure.

Possible – The adverse event may be related to the investigational agent(s) or study 
procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure.
8.2.3  Expectedness
An adverse event is considered unexpected if the nature, severity, or frequency of the event is 
not listed in the study protocol, product inserts, investigator brochure or informed consent 
document.
8.3
Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
8.4
Expedited Reporting
8.4.1  Reporting to the HDFCCC Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the UCSF PI or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail.

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8.4.2  Reporting to Institutional Review Board
The UCSF PI must report events to the IRB according to institutional guidelines.

UCSF IRB website for guidance in reporting adverse events:
8.5
Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator. For selected 
adverse events for which administration of the study drug/intervention was stopped, a re- 
challenge of the subject with the study drug/intervention may be conducted if considered both 
safe and ethical by the investigator.
8.6
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 1.

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18. Jenkins MK, Chu HH, McLachlan JB, Moon JJ. On the composition of the preimmune 
repertoire of T cells specific for Peptide-major histocompatibility complex ligands. Annu 
Rev Immunol. 2010;28:275-294.
19. Martinez RJ, Evavold BD. Lower Affinity T Cells are Critical Components and Active 
Participants of the Immune Response. Front Immunol. 2015;6. 
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Appendix 1: Data and Safety Monitoring Plan for a Non-therapeutic Institutional Trial
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and 
Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and 
participant safety for all HDFCCC institutional clinical trials. A summary of DSMC 
activities for this trial includes:
•
Annual auditing
•
Review of serious adverse events
•
Minimum of biennial regulatory auditing
The UCSF HDFCCC Data and Safety Monitoring Committee (DSMC) is responsible for 
participant safety for all HDFCCC institutional clinical trials. Greater than minimal risk 
nontherapeutic studies are characterized as low risk studies due to the trial design, as 
there isn’t administration of drugs or complementary therapy that puts the participants at 
significant risk.
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly 
site committee meetings where the status of each participant is discussed and 
documented in the site committee minutes.
For “greater than minimal risk” nontherapeutic trials, the assigned DSMC Senior 
Monitor/Auditor will audit three of the enrolled participants once per year, with a 
maximum of ten participant charts audited during the entire course of auditing this trial 
until IRB closure.
If blood or tissue banking trials are determined to be “greater than minimal risk”, then 
only Serious Adverse Events (SAEs) recorded in OnCore will be reviewed at each 
DSMC meeting for these trials.
After completion of each auditing visit, the DSMC Monitor/Auditors will send a follow-up 
report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business 
days. An abbreviated regulatory review (i.e., reviewing protocol and consent versions, 
SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each participant monitoring review; 
however, a full regulatory review will occur on a biennially basis by the DSMC for 
regulatory compliance.
Auditing of all enrolled participants in these trials will be complete after 10 enrolled 
participants have been audited. However, regulatory reviews of the trial, safety reviews 
(i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) reviews), and 
audit/inspection preparation (as applicable) will continue until the trial is closed by the 
IRB.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring
All Grade 3-5 adverse events (AEs), whether or not considered expected or unexpected 
and whether or not considered associated with the study intervention or procedure, will 
be entered into OnCore®, UCSF’s Clinical Trial Management System.
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute. Adverse events are further given an 
assignment of attribution or relationship to study intervention or procedure. Attribution 
categories are:

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•
Definite – The adverse event is clearly related to the study intervention or 
procedure.
•
Probable – The adverse event is likely related to study intervention or procedure.
•
Possible – The adverse event may be related to study intervention or procedure.
•
Unrelated – the adverse event is clearly not related to the study intervention or 
procedure.
All clinically significant adverse events entered into OnCore® will be reviewed on a 
monthly basis at the Site Committee meetings
3.2
Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:
•
Death.
•
Life-threatening (i.e., results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization.
•
Permanent or significant disability/incapacity.
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that 
may require medical or surgical intervention to prevent one of the outcomes 
listed above.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.
UCSF IRB website for guidance in reporting serious adverse events: 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB. 
The SAEs are reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis and discussed at DSMC meetings, which take place every six weeks. 
The date the SAE was sent to all required reporting agencies will be documented in 
OnCore®.
If a death occurs during the treatment phase of the study and is determined to be 
possibly, probably, or definitely related either to the study intervention or procedure, the 
Investigator or his/her designee must notify the DSMC Chair or Vice Chair and DSMC 
Director within one business day.
3.3
Review of Adverse Event Rates
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting requirements.