Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination With Intratumoral SD-101 Therapy in Patients With Hormone-Naïve Oligometastatic Prostate Cancer Receiving Stereotactic Body Radiation Therapy and Intermittent Androgen Deprivation Therapy
Phase: PHASE2
Conditions: Prostatic Neoplasms
Sponsor: David Oh

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.  
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TITLE: Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination with Intratumoral SD-
101 Therapy in Patients with Hormone-Naïve Oligometastatic Prostate Cancer Receiving 
Stereotactic Body Radiation Therapy and Intermittent Androgen Deprivation Therapy
CC#: 16703
Version Date:  06/03/2024
Protocol Version: 12
IND NUMBER: 130103
SPONSOR-INVESTIGATOR/PRINCIPAL INVESTIGATOR:
David Oh, MD PhD
University of California, San Francisco
CO-PRINCIPAL INVESTIGATOR:
Anthony C. Wong, MD, PhD
STATISTICIAN:
Li Zhang, Ph.D.  
REVISION HISTORY
Version 3.0
09/10/14
Version 4.0
03/15/16
Version 11.0
04/10/23
Version 5.0
04/26/16
Version 12.0
06/03/24
Version 5.1
05/05/16
Version 5.2
05/19/16
Version 6.0
06/23/16
Version 6.1
10/06/16
Version 6.2
11/10/16
Version 7.0
09/11/17
Version 8.0
11/15/17
Version 9.0
08/07/18
Version 9.1
01/17/19
Version 10.0
12/23/19
Version 10.1
07/07/20
NCT03007732

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Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring 
Committee (DSMC). 
2.
I will conduct the study in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and 
welfare of study participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to 
conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the 
applicable ethical principles, the Statement of Investigator (Form FDA 1572), and 
with local regulatory requirements. In accordance with the FDA Modernization Act, I 
will ensure the registration of the trial on the www.clinicaltrials.gov website.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, state 
and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date

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TRIAL SUMMARY
Abbreviated Abstract
Abbreviated Title
Pembrolizumab +/- SD-101 in Hormone-Sensitive 
Oligometastatic Prostate Ca with RT and iADT
Trial Phase
II
Clinical Indication
Patients with newly diagnosed, hormone-naïve oligometastatic 
prostate cancer who have not previously undergone radical 
prostatectomy or prostatic radiation
Trial Type
Open-label phase II study with safety lead-in
Type of control
Historical control
Route of administration
Pembrolizumab IV and SD-101 intraprostatic injection
Trial Blinding
None
Treatment Groups
Cohort 1 (enrollment complete)
Arm 1: ADT + SBRT to prostate + Pembrolizumab 
Arm 2: ADT + SBRT to prostate + Pembrolizumab + SD-101
Cohort 2
Arm 1: ADT + SBRT to prostate and oligometastatic sites + 
Pembrolizumab 
Arm 2: ADT + SBRT to prostate and oligometastatic sites + 
Pembrolizumab + SD-101
Number of trial subjects
42 patients total
Estimated enrollment 
period
18 months
Estimated duration of trial
54 months
Duration of Participation
9 months on-treatment period

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Full Abstract
Title
Phase 2 Trial of Pembrolizumab or Pembrolizumab in Combination with 
Intratumoral SD-101 in Patients with Newly Diagnosed Hormone-Naïve 
Oligometastatic Prostate Cancer Receiving Stereotactic Body Radiation 
Therapy and Intermittent Androgen Deprivation Therapy
Patient 
population
Patients with newly diagnosed, hormone-naïve oligometastatic prostate 
cancer who have not previously undergone radical prostatectomy or prostatic 
radiation.
Rationale 
for Study
Androgen deprivation therapy (ADT) is the mainstay of therapy for patients 
with hormone-sensitive metastatic prostate cancer. However, treatment is 
palliative, and the duration of response to ADT is variable before the 
development of castration resistant disease.
Immune checkpoint antibodies that target the immune system have the 
potential to induce durable clinical responses in a subset of patients with 
different solid malignancies, including melanoma, NSCLC and RCC. 
However, immune checkpoint blockade in castrate-resistant prostate cancer 
(CRPC) that progressed after chemotherapy has not been very active (Kwon 
ED et al, 2014). Combination immunotherapy has the potential to activate 
multiple cellular components and augment anti-tumor immune responses 
(Larkin J et al, 2015). We hypothesize the combination of checkpoint 
blockade with the anti-PD-1 antibody pembrolizumab, and localized therapies 
that prime and augment an immune response, specifically definitive prostatic 
radiotherapy with or without intratumoral SD-101 (a TLR9 agonist), will 
induce a durable clinical response in a subset of patients with metastatic 
hormone-sensitive prostate cancer reflected by a prolonged period of PSA < 
nadir +2 ng/mL after cessation of all therapies including ADT.
Primary 
Objectives
Cohort 1
1. To assess the safety associated with giving RT and pembrolizumab with 
or without intratumoral SD-101.
Cohort 2
1. To continue to assess the safety associated with giving RT and 
pembrolizumab with or without intratumoral SD-101.
2. To assess if the rate of PSA < nadir + 2 ng/mL at 15 months in patients 
with non-castrate levels of testosterone is greater than the historical 
control in each study arm.

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Secondary 
Objectives
2. To determine the rate of testosterone-PSA uncoupling (section 3.2.3.1) in 
each study arm in cohort 2.  Testosterone-PSA uncoupling is defined as 
PSA < 50% baseline and < 20ng/mL for at least 3 months after 
testosterone recovers to >150 ng/dL. In patients with metastatic hormone-
sensitive prostate cancer off hormonal therapy, >90% patient are expected 
to have PSA increase to > 50% baseline after 3 months of testosterone 
recovery.
3. To estimate time to clinical progression in each study arm in cohort 2.
4. To estimate progression-free survival (PFS) in each study arm in cohort 2.
Exploratory 
Objectives
1. To assess peripheral and tumor-based biomarkers of response and 
resistance in both cohorts.
2. To define the treatment-induced effects on circulating immune cells in 
both cohorts.
3. To explore remodeling of circulating T cell repertoire in both cohorts.
4. To explore the concordance of PSMA-PET scanning with conventional 
imaging in oligometastatic prostate cancer patients in both cohorts.
Study 
Design
This is an open-label Phase 2 clinical trial combining stereotactic body 
radiation therapy (SBRT) and pembrolizumab with or without intratumoral 
SD-101 in patients with newly diagnosed hormone-naive oligometastatic 
prostate cancer.
A safety lead-in for each treatment arm will be performed for the first 3 
participants enrolled into each arm in cohort 1. For cohort 2, SBRT will be 
delivered to the whole prostate and all oligometastatic sites. Five (5) 
treatments will be delivered to the prostate and 3-5 treatments to 
oligometastatic sites every other day within a 10-21 day period. In both arms, 
marker placement and simulation will occur 1-5 weeks prior to start of 
pembrolizumab (C1D1). SBRT will start 1-5 weeks after marker placement 
and simulation. Subjects will start C1D1 and SBRT 1 month after ADT 
initiation at the earliest, and 4 months after ADT initiation at the latest. SD-
101 will be injected into the dominant prostatic lesion at the time of fiducial 
marker placement, and 1-3 weeks after C1D1. SD-101 will be administered 
intratumorally in concert with prostate biopsies. Pembrolizumab will be 
continued for a total of 13 cycles, until disease progression, or unacceptable 
toxicity, whichever occurs first. Patients will receive 3 months of ADT run-
in, followed by GnRH targeting agent (leuprolide preferred), abiraterone, and 
prednisone (or equivalent) for 9 months, then discontinuation of androgen 
deprivation therapy (ADT). Primary outcome is to evaluate the rate of PSA < 
nadir +2 ng/mL at 15 monthsfrom the start of treatment among patients with 
non-castrate levels of testosterone (>150 ng/dL). Serum, archival prostate 
biopsy, optional baseline metastatic tumor biopsy, and optional repeat biopsy 
at time of progression, will be obtained to characterize circulating and 
intratumoral immune responses.

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Number of 
patients
Cohort 1: 10 participants
Cohort 2: 32 participants
Total: 42 participants
Duration of 
Therapy
Patients may continue treatment for 9 months (13 cycles) from the time of 
study entry.
Duration of 
Follow up
Patients will be followed every 12 weeks +/- 2 weeks for up to 3 years (years 
one and two are mandatory; year three is optional) after completion of 
therapy, until disease progression, removal from study, or death, whichever 
occurs first.
Duration of 
study
The study will reach completion 4.5 years from the time the study opens to 
accrual.
Study Drugs 
and 
Therapies
ADT: 3 month ADT run-in followed by leuprolide 22.5 mg every 3 months 
for 3 doses (or another FDA approved GnRH agent for 9 months) + 
abiraterone (e.g. Zytiga, Yonsa) with prednisone (or equivalent medication 
per local standard practice) for 9 months starting on Cycle 1 Day 1 (Arms 1 
and 2).
SD-101: 5 mg will be delivered to the dominant prostatic tumor lesion at time 
of fiducial marker placement (1-5 weeks prior to C1D1) and 1-3 weeks after 
C1D1, Arm 2 only.
Pembrolizumab (Keytruda, MK-3475): 200 mg IV every 21 days for up to 13 
doses (Arms 1 and 2).
Radiotherapy: 7 Gy x 5 fractions (35 Gy total) delivered to the whole prostate 
gland and soft tissue oligometastases, 10 Gy x3 fractions (30 Gy total) to 
osseous metastases via stereotactic body radiation therapy (SBRT).

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LIST OF ABBREVIATIONS
ABC
active-breathing control
ACE
angiotensin-converting enzyme
ADL
activities of daily living
ADT
androgen deprivation therapy
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
anti-KLM
liver kidney microsomal type 1 antibody
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BID
twice a day
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CBCT
Cone-beam CT
CD
cluster of differentiation
CFR
Code of federal regulation
CHR
Committee on Human Research (UCSF IRB)
CNS
central nervous system
CpG
cytidine-phospho-guanosine
CR
complete response
CRC
clinical research coordinator
CRF
case report form
CRPC
castrate-resistant prostate cancer
CSF
cerebral spinal fluid
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTLA4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
CTV
clinical target volume
DFS
disease-free survival
DLT
dose limiting toxicity

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LIST OF ABBREVIATIONS
DNA
Deoxyribonucleic acid
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
EBRT
external beam radiation therapy
ECG
electrocardiogram
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EPO
Erythropoietin
FDA
Food and Drug Administration
FFF
flattening‐filter‐free
FFPE
formalin-fixed paraffin-embedded
FIH
first-in-human
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
GNRH
gonadotropin-releasing hormone
GTV
gross tumor volume
Gy
Gray
HBeAg
hepatitis B “e” antigen
HBV
hepatitis B virus
HCT
hematocrit
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HER2
human epidermal growth factor receptor 2
HGB
hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HTN
hypertension
IB
Investigator’s brochure
IC
immune cells
ICF
Informed consent form
ICH
International Conference on Harmonization
ICRU
International Commission on Radiation Units and Measurements

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LIST OF ABBREVIATIONS
IFN-α
interferon alpha
IgG4
immunoglobulin G4
IGRT
image guided radiation therapy
IHC
immunohistochemistry
IMRT
intensity modulated radiation therapy
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
irAEs
immune-related adverse events
IRB
Institutional Review Board
irRC
immune-related response criteria
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
mAb
monoclonal antibody
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
Na-F
sodium fluoride
NCI
National Cancer Institute
NHL
non-Hodgkin’s lymphoma
NSCLC
non-small cell lung cancer
ODN
Oligodeoxynucleotide
OHRP
Office for Human Research Protections
ORR
overall response rate
OTC
over the counter
PBMC
peripheral blood mononuclear cells
PCWG
Prostate Cancer Working Group
PD
disease progression
PD-1
programmed death 1 (PD-1)
pDC
plasmacytoid dendritic cells
PD-L1
programmed death-ligand 1 (PD-L1)
PD-L2
programmed death-ligand 2 (PD-L2)
PET
positron emission tomography

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LIST OF ABBREVIATIONS
PFS
progression-free survival
PI
Principal Investigator
PK
pharmacokinetics
PO
per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
PS
Phosphorothioate
PSA
prostate specific antigen
PSMA
prostate specific membrane antigen
PTT
partial thromboplastin time
PTV
planning target volume
PVC
polyvinyl chloride
Q2W
Once every 2 weeks
Q3W
Once every 3 weeks
QD
Once every day
RBC
red blood cell (count)
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RT
radiotherapy
SAE
Serious adverse event
SBRT
stereotactic body radiation therapy
SC
subcutaneous
SD
stable disease
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
System Order Classes
SOP
Standard operating procedure
t1/2
half-life
TCR
T cell receptor
TLR9
Toll-like receptor 9
TRUS
transrectal ultrasound
TSH
thyroid-stimulating hormone
ULN
upper limit of normal

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LIST OF ABBREVIATIONS
UTI
urinary tract infection
WBC
white blood cell (count)

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TABLE OF CONTENTS
TRIAL SUMMARY ................................................................................................................2
LIST OF ABBREVIATIONS.................................................................................................6
TABLE OF CONTENTS ......................................................................................................11
1.0
TRIAL DESIGN ........................................................................................................15
1.1
Trial Design .............................................................................................................15
1.2
Trial Diagram ..........................................................................................................15
2.0
OBJECTIVE(S) & HYPOTHESIS(ES) ..................................................................16
2.1
Primary Objective(s) & Hypothesis(es) ..................................................................16
2.2
Secondary Objective(s) & Hypothesis(es) ..............................................................16
2.3
Exploratory Objectives............................................................................................17
3.0
BACKGROUND & RATIONALE ..........................................................................17
3.1
Background..............................................................................................................17
3.1.1
Pharmaceutical and Therapeutic Background .....................................................18
3.1.2
Preclinical and Clinical Trial Data.......................................................................20
3.2
Rationale..................................................................................................................28
3.2.1
Rationale for the Trial and Selected Subject Population .....................................28
3.2.2
Rationale for Dose Selection/Regimen/Modification..........................................29
3.2.3
Rationale for Endpoints .......................................................................................33
4.0
METHODOLOGY ....................................................................................................34
4.1
Entry Criteria ...........................................................................................................34
4.1.1
Diagnosis/Condition for Entry into the Trial.......................................................34
4.1.2
Subject Inclusion Criteria ....................................................................................34
4.1.3
Subject Exclusion Criteria ...................................................................................36
4.2
Trial Treatments ......................................................................................................39
4.2.1
Study drugs – Description, Supply and Storage of Investigational Drugs ..........40
4.2.2
Stereotactic Body Radiation Therapy (SBRT) ....................................................43
4.2.3
Drug Accountability ............................................................................................59
4.2.4
Drug Ordering......................................................................................................59
4.2.5
Packaging and Labeling of Study Drugs .............................................................59

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4.2.6
Dose Selection/Modification ...............................................................................59
4.2.7
Timing of Dose Administration...........................................................................67
4.2.8
Trial Blinding/Masking........................................................................................68
4.3
Randomization or Treatment Allocation .................................................................68
4.4
Stratification ............................................................................................................68
4.5
Concomitant Medications/Vaccinations (allowed & prohibited)............................68
4.5.1
Acceptable Concomitant Medications.................................................................69
4.5.2
Prohibited Concomitant Medications ..................................................................69
4.6
Rescue Medications & Supportive Care..................................................................70
4.6.1
Supportive Care Guidelines.................................................................................70
4.7
Diet/Activity/Other Considerations.........................................................................70
4.7.1
Diet.......................................................................................................................70
4.7.2
Contraception.......................................................................................................70
4.7.3
Use in Pregnancy .................................................................................................71
4.8
Replacement Policy .................................................................................................71
4.9
Safety Lead-In .........................................................................................................71
4.10
Interim Analyses and Stopping Rules .....................................................................72
4.11
Clinical Criteria for Early Trial Termination ..........................................................72
5.0
TRIAL FLOW CHART............................................................................................73
5.1
Study Flow Chart.....................................................................................................73
6.0
TRIAL PROCEDURES ............................................................................................78
6.1
Trial Procedures.......................................................................................................78
6.1.1
Administrative Procedures...................................................................................78
6.1.2
Clinical Procedures/Assessments ........................................................................80
6.1.3
Withdrawal/Discontinuation................................................................................83
6.1.4
End-of-Treatment Study Procedures ...................................................................84
6.1.5
Post-treatment/Follow Up Visits .........................................................................85
6.2
Assessing and Recording Adverse Events...............................................................86
6.2.1
Definitions of Adverse Events.............................................................................86
6.2.2
Recording of an Adverse Event...........................................................................88
6.2.3
Follow-up of Adverse Events ..............................................................................88
6.2.4
Adverse Events Monitoring.................................................................................89

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6.2.5
Expedited Reporting ............................................................................................89
6.2.6
Reporting Events to Merck..................................................................................91
6.2.7
Reporting Events to TriSalus Life Sciences ........................................................93
6.2.8
Evaluating Adverse Events..................................................................................94
6.2.9
Sponsor Responsibility for Reporting Adverse Events .......................................99
7.0
STATISTICAL CONSIDERATION .......................................................................99
7.1
Sample size calculation ...........................................................................................99
7.2
Statistical Analysis Plan ..........................................................................................99
7.2.1
Analysis population .............................................................................................99
7.2.2
Analysis of Primary Endpoint..............................................................................99
7.2.3
Analysis of Secondary Endpoints......................................................................100
7.2.4
Analysis of Exploratory Endpoints....................................................................100
8.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................102
8.1
Investigational Product..........................................................................................102
8.2
Packaging and Labeling Information ....................................................................102
8.3
Clinical Supplies Disclosure..................................................................................102
8.4
Storage and Handling Requirements .....................................................................102
8.5
Returns and Reconciliation....................................................................................102
9.0
ADMINISTRATIVE AND REGULATORY DETAILS .....................................103
9.1
Pre-study Documentation ......................................................................................103
9.2
Institutional Review Board Approval....................................................................103
9.3
Informed Consent ..................................................................................................103
9.4
Changes in the Protocol.........................................................................................104
9.5
Handling and Documentation of Clinical Supplies ...............................................104
9.6
Case Report Forms (CRFs)....................................................................................104
9.7
Oversight and Monitoring Plan .............................................................................105
9.8
Coordinating Center Documentation of Distribution ............................................105
9.9
Regulatory Documentation....................................................................................105
9.10
Protection of Human Subjects ...............................................................................106
9.10.1 Protection from Unnecessary Harm...................................................................106
9.10.2 Protection of Privacy .........................................................................................106

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10.0
REFERENCES ........................................................................................................107
11.0
APPENDICES..........................................................................................................111
Appendix 1...................................................................................Performance Status 
Criteria......................................................................................................................112
Appendix 2 ................Common Terminology Criteria for Adverse Events V5.0 
(CTCAE)...................................................................................................................113
Appendix 3Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors...................................................................114
Appendix 4 .......Data and Safety Monitoring Plan for Phase II Trial with Safety Lead-
In................................................................................................................................115
Appendix 5................................................................................Specimen and blood 
collection ...................................................................................................................118
Appendix 6 ............................................................................................Prohibitive 
Medication................................................................................................................119

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1.0 TRIAL DESIGN
1.1
Trial Design
This is an open-label phase 2 clinical trial combining definitive prostatic radiotherapy (RT) and 
pembrolizumab with or without intratumoral SD-101 in patients with newly diagnosed hormone-
naive oligometastatic prostate cancer. 
A safety lead-in will be performed for the first 3 participants enrolled into each treatment arm in 
cohort 1. SBRT to the whole prostate ± oligometastatic sites will be administered 1-5 weeks after 
fiducial marker placement and SBRT simulation. 7 Gy x 5 fractions will be given via SBRT to 
the whole prostate and soft tissue oligometastatic sites (cohort 2 only) and 10 Gy x 3 fractions to 
osseous metastases (cohort 2 only), over 10-21 days. Fiducial marker placement and SBRT 
simulation will be performed 1-5 weeks prior to C1D1 (start of pembrolizumab). In Arm 2 (for 
both cohorts), SD-101 will be delivered to the dominant prostatic lesion at time of fiducial 
marker placement and 1-3 weeks after C1D1.  Pembrolizumab will be continued for 13 cycles, 
until disease progression, or unacceptable toxicity, whichever occurs first. Patients will receive 3 
months of ADT run-in, followed by GnRH targeting agent (leuprolide preferred), abiraterone, 
and prednisone (or equivalent) for 9 months, then discontinuation of androgen deprivation 
therapy (ADT). The primary outcome for cohort 2 is to evaluate the rate of PSA < nadir + 2 
ng/mL after discontinuation of ADT 15 months from start of treatment among patients with non-
castrate (>150 ng/dL) levels of testosterone.  Serum, archival prostate biopsy, optional baseline 
metastatic tumor biopsy, and optional repeat biopsy at time of progression, will be obtained to 
characterize circulating and intratumoral immune responses.
1.2
Trial Diagram
Cohort 1
[NOTE: As of 08/05/2019, cohort 1 completed enrollment and closed to accrual.]

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Cohort 2
2.0 OBJECTIVE(S) & HYPOTHESIS(ES)
2.1
Primary Objective(s) & Hypothesis(es)
Cohort 1
(1) Objective: To assess the safety associated with giving RT and pembrolizumab with 
intratumoral SD-101.
Cohort 2
(1) Objective: To assess the safety associated with giving RT and pembrolizumab with or 
without intratumoral SD-101.
(2) Objective: To assess if the rate of PSA < nadir + 2 ng/mL at 15 months in patients with 
non-castrate levels of testosterone is greater than the historical control for each arm.
Hypothesis: The combination of PD-1 blockade with pembrolizumab and localized therapies 
that prime and augment an immune response—specifically SBRT with or without 
intratumoral SD-101, a TLR9 agonist—will induce a durable clinical response in a subset of 
patients with metastatic hormone-sensitive prostate cancer, reflected by a prolonged period of 
PSA < nadir + 2 ng/mL after cessation of all therapies including ADT.  With standard of care 
intermittent ADT alone, no patients are expected to experience a PSA < nadir + 2 ng/mL 
after cessation of ADT.
2.2
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To determine the rate of testosterone-PSA uncoupling (section 3.2.3.1) in 
each study arm in cohort 2.
Hypothesis: Combination therapy of pembrolizumab with RT with or without SD-101 leads 
to testosterone-PSA uncoupling in a subset of patients after discontinuation of therapies.

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(2) Objective: To estimate time to clinical progression in each study arm in cohort 2.
Hypothesis: Combination therapy of pembrolizumab with RT with or without SD-101 leads 
to prolonged time to clinical progression in a subset of patients after discontinuation of 
therapies.
(3) Objective: To estimate progression-free survival (PFS) in each study arm in cohort 2.
Hypothesis: Combination therapy of pembrolizumab with RT with or without SD-101 leads 
to improved PFS compared to historical controls in a subset of patients after discontinuation 
of therapies.
2.3
Exploratory Objectives
(1) Objective: To assess peripheral and tumor-based biomarkers of response and resistance 
for both cohorts.
(2) Objective: To define the treatment-induced effects on circulating immune cells for both 
cohorts.
(3) Objective: To explore the remodeling of circulating T cell repertoire for both cohorts.
(4) Objective: To explore the concordance of PSMA-PET scanning with conventional 
imaging in oligometastatic prostate cancer patients for both cohorts.
3.0 BACKGROUND & RATIONALE
3.1
Background
Prostate cancer is the most common malignancy and the second leading cause of cancer-related 
death in men in Western countries. In the United States, 233,000 new cases were diagnosed and 
nearly 30,000 men died from prostate cancer in 2014 (Siegel R et al, 2014). While surgery and 
radiotherapy are potentially curative treatments in patients with localized prostate cancer, 
androgen deprivation therapy (ADT) is the mainstay of therapy for patients with hormone-
sensitive metastatic prostate cancer. The duration of response to ADT is variable, and patients 
eventually develop castration-resistant disease (CRPC). 
The development of novel hormonal agents, including abiraterone acetate and enzalutamide, has 
significantly improved outcomes for patients with metastatic CRPC (de Bono JS et al, 2011; 
Ryan CJ et al, 2013; Scher HI et al, 2012; Beer TM et al, 2014). However, resistance eventually 
develops, and emerging evidence suggest that these novel androgen signaling inhibitors may 
promote the development of more aggressive forms of prostate cancer with neuroendocrine 
features (Small EJ et al, 2015). Immunotherapeutic approaches, which do not target cancer cells 
directly but targets the patient’s immune response to recognize and attack cancer, have the 
potential to lead to durable responses without driving mechanisms of resistance in advanced 
prostate cancer.

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Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on pembrolizumab.
3.1.1
Pharmaceutical and Therapeutic Background
3.1.1.1
Pembrolizumab
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.

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Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  Pembrolizumab has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
Pharmacokinetics and Metabolism of Pembrolizumab 
The PK profile of pembrolizumab investigated in Part A of the ongoing study P001 has obtained 
results following a single dose at 1, 3, and 10 mg/kg pembrolizumab to 17 subjects with solid 
tumors in Cycle 1. The observed PK profile of pembrolizumab was typical of those observed for 
other IgG mAbs with a half-life (t1/2) of approximately 2 to 3 weeks. There was no indication of 
dose dependency of t1/2 in the 3 dose groups. A dose-related increase in exposure was observed 
from 1 to 10 mg/kg. The long t1/2 supports a dosing interval of every 2 weeks or every 3 weeks.
No traditional metabolism studies were conducted with pembrolizumab per current ICH S6 (R1) 
guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals. 
Pembrolizumab has a low potential of eliciting the formation of anti-drug antibodies. 
Toxicity and Safety Pharmacology of Pembrolizumab
The safety of pembrolizumab was characterized in the 1-month repeat-dose toxicity study in 
Cynomolgus monkeys when administered as IV doses of 6, 40, or 200 mg/kg once a week (a 
total of 5 doses) and in the 6-month repeat-dose toxicity study in Cynomolgus monkeys when 
administered as IV doses of 6, 40, or 200 mg/kg every other week (a total of 12 doses). 
Pembrolizumab was well-tolerated in Cynomolgus monkeys with a systemic exposure (AUC) of 
up to approximately 170,000 µg.day/mL over the course of the 1-month study and with a 
systemic exposure (AUC) of up to approximately 67,500 µg.day/mL over the course of the 6-
month study. No findings of toxicological significance were observed in either 1-month or 6-
month toxicity study with pembrolizumab, and the NOAEL was = 200 mg/kg.  In addition, no 
findings of toxicological relevance were observed in the in vitro tissue cross-reactivity study 
using human and Cynomolgus monkey tissues.  There were no nonclinical findings that would 
preclude testing of pembrolizumab in clinical trials.
3.1.1.2
SD-101
SD-101 is an oligodeoxynucleotide (ODN) enriched with cytidine-phospho-guanosine (CpG) 
motifs of Class C-type sequence (CpG-C). The CpG-C type sequences are an agonist for Toll-
like receptor 9 (TLR9) and potent inducers of interferon alpha (IFN-α) production from 
plasmacytoid dendritic cells (pDCs), as well as pDC maturation and B cell proliferation. TLR9 
stimulation by CpG-ODNs may have a significant antitumor effect by several potential 
mechanisms including enhancement of innate and T-cell immunity, stimulation of cytokines with 
direct or indirect antitumor activities (including IFN-α), and production of cytotoxic antibodies 
(Marshall JD et al, 2003; Marshall JD et al, 2005). Preclinical mouse models show that the 
combination of CpG therapy with checkpoint blockade enhances tumor regression and long-term 
survival (Mangsbo SM et al, 2010; Duraiswamy J et al, 2013).

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Pharmacokinetics and Metabolism of SD-101
In the healthy normal volunteer trial, 20 subjects (18 years and older) were given a single fixed 
subcutaneous (SC) dose of SD-101 (0.1, 1.0, 3.0, or 5.0 mg) or placebo, SD-101 levels in the 
plasma peaked 2 to 4 hours after drug administration. The mean maximum plasma concentration 
for 6 subjects injected with SD-101 3.0 mg was approximately 7 ng/mL and was higher than for 
subjects receiving SD-101 1.0 mg. The SD-101 levels in plasma declined after 4 hours. Due to 
limitations in the analytical method such as a lower limit of quantitation of 5 ng/mL and analyte 
stability in matrix, the data provided are for information only. The dataset was insufficient for 
the calculation of parameters such as clearance rate or half-life. 
Toxicity and Safety Pharmacology of SD-101
Three toxicity studies have been performed with SD-101, including a 14 once-weekly dose 
subcutaneous (SC) study in rats, a 14 once-weekly dose SC study in monkeys, and a safety 
pharmacology SC study in monkeys. No significant safety concerns have been identified in any 
of the toxicity studies conducted to date with SD-101. Genotoxicity studies indicated that SD-
101 has no mutagenic or clastogenic activity.
Nearly all of the findings in the toxicity studies conducted with SD-101 were expected and 
consistent with the known properties of immunostimulatory ODNs, or the known class effects of 
PS ODNs. Also the effects of SD-101 were more pronounced in rats than in non-human 
primates. As an immunostimulatory molecule, SD-101 would be expected to induce reactivity of 
lymphoid tissues (i.e. spleen and lymph nodes), as well as immunocompetent cells in other 
organs in the clinical dose range. At higher dose levels, the effects on target tissues are 
exaggerated, well understood, dose-dependent, and reversible.
3.1.2
Preclinical and Clinical Trial Data
3.1.2.1
Pembrolizumab
Refer to the Investigator’s Brochure for pembrolizumab for complete Preclinical and Clinical 
data.
The safety and efficacy of pembrolizumab in subjects with hematologic malignancies and solid 
tumors have been evaluated in 18 ongoing, Merck-sponsored clinical trials: P001, P002, P006, 
P010, P011, P012, P013, P021, P022, P023, P024, P025, P028, P029, P030, P041, P045, and 
P055.
P001: P001 is an open-label, Phase I, first-in-human (FIH) study of IV pembrolizumab in 
subjects with progressive locally advanced or metastatic carcinomas, especially melanoma or 
NSCLC.
Part A of the study involved dose escalation that used a traditional 3+3 design.  Cohorts of 3 to 6 
subjects were enrolled sequentially at escalating doses of 1, 3, or 10 mg/kg administered Q2W.  

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Once the dose escalation was completed, additional subjects were enrolled into Parts A1 and A2 
to further characterize the PK and pharmacodynamics of pembrolizumab.  
In Parts B and D, subjects with metastatic melanoma were enrolled to assess the safety and 
antitumor activity of pembrolizumab.  Additionally, Part B explored 3 different dose regimens in 
subjects with metastatic melanoma: 10 mg/kg Q2W, 10 mg/kg Q3W, and 2 mg/kg Q3W.
In Part C, subjects with NSCLC (with prior systemic therapy) were enrolled at 10 mg/kg
Q3W to assess the tolerability, safety, and antitumor activity of pembrolizumab in NSCLC.  
In Part F, subjects with NSCLC in Cohort F-1 (without prior systemic therapy) and
Cohort F-2 (with prior systemic therapy), whose tumors expressed PD-L1, were enrolled at
10 mg/kg Q2W and 10 mg/kg Q3W to characterize the tolerability, safety, and antitumor activity 
of pembrolizumab.  A small cohort of previously treated subjects with NSCLC and at least 2 
lines of systemic therapy, whose tumors did not express PD-L1, were enrolled and treated at a 
dose of 10 mg/kg Q2W in Cohort F-2.  In Cohort F-3, previously treated subjects with NSCLC 
whose tumors express PD-L1 were enrolled at 2 mg/kg Q3W to better characterize the efficacy, 
safety, and antitumor activity of pembrolizumab.
Each of the 2 disease specific cohorts (melanoma and NSCLC) were enrolled to confirm 
tolerability and evaluate tumor response to pembrolizumab.
P002: P002 is a partially blinded, randomized, Phase II study designed to evaluate 2 doses of 
pembrolizumab versus a chemotherapy control arm in subjects with IPI-refractory metastatic 
melanoma.  Subjects were randomized in a 1:1:1 ratio to receive pembrolizumab 2 mg/kg
Q3W or pembrolizumab 10 mg/kg Q3W, or chemotherapy (according to current clinical 
practice) for the treatment of melanoma.  Subjects assigned to the control chemotherapy arm 
could cross over to the experimental pembrolizumab arm once progression was confirmed 
(approximately = Week 12).
P006: P006 is a multicenter, worldwide, randomized, controlled, open-label, 3-arm pivotal Phase 
III study of 2 dosing regimens of IV pembrolizumab versus IV IPI in subjects with unresectable 
or metastatic melanoma who had not received prior IPI treatment.  Subjects were randomized in 
a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg Q2W, 10 mg/kg Q3W, or IPI at 3 mg/kg 
Q3W for a total of 4 doses.
P010: P010 is a multicenter, worldwide, randomized, adaptively designed Phase II/III trial of
IV pembrolizumab at 2 dosing schedules versus docetaxel in subjects with NSCLC with PD-L1 
positive tumors, who have experienced disease progression after platinum-containing systemic 
therapy.  Subjects were randomized in a 1:1:1 ratio to receive pembrolizumab 10 mg/kg Q3W, 2 
mg/kg Q3W, or docetaxel 75 mg/m2 Q3W.
P011: P011 is an open-label, nonrandomized, multicenter Phase I study of pembrolizumab 
monotherapy in Japanese subjects with advanced solid tumors and in combination with 
cisplatin/pemetrexed and carboplatin/paclitaxel in subjects with advanced NSCLC in Japan.  

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In Part A (monotherapy, 3+3 design), subjects with advanced solid tumors received escalating 
doses of pembrolizumab 2 mg/kg Q2W (dose level 1) or 10 mg/kg Q2W (dose level 2).  In Part 
B (combination, 3+6 design), subjects with advanced NSCLC receive pembrolizumab 10 mg/kg 
Q3W in combination with either cisplatin/pemetrexed (Cohort 1) or carboplatin/paclitaxel 
(Cohort 2) are to be enrolled.
P012: P012 is a multicenter, nonrandomized, multi-cohort Phase Ib trial of pembrolizumab in 
subjects with PD-L1 positive advanced solid tumors. All subjects receive pembrolizumab 10 
mg/kg Q2W.  Cohort A enrolled subjects with triple negative breast cancer; Cohorts B and B2 
enrolled subjects with squamous cell carcinoma of the head and neck; Cohort C enrolled subjects 
with urothelial tract cancer of the renal pelvis, ureter, bladder, or urethra; and Cohort D enrolled 
subjects with adenocarcinoma of the stomach or gastroesophageal junction.
P013: P013 is an open-label, multicenter trial of pembrolizumab in subjects with hematologic 
malignancies. All subjects receive pembrolizumab at 10 mg/kg Q2W. Cohort 1 is enrolling 
subjects with intermediate-1, intermediate-2, or high-risk myelodysplastic syndrome who have 
failed at least 4 cycles of hypomethylating agent treatment. Cohort 2 is enrolling subjects with 
relapsed/refractory multiple myeloma. Cohort 3 is enrolling subjects with relapsed/refractory 
Hodgkin lymphoma who are ineligible for or refused a stem cell transplant and whose disease 
has relapsed after treatment with or failed to respond to brentuximab vedotin. Cohort 4a is 
enrolling subjects with relapsed/refractory mediastinal large B cell lymphoma who are ineligible 
for or refused a stem cell transplant, and Cohort 4b is enrolling subjects with any other positive 
PD-L1 positive relapsed/refractory non-Hodgkin lymphoma who are ineligible for or refused a 
stem cell transplant.
P021: P021 is a multicenter, open-label Phase I/II study of IV pembrolizumab at 2 dosing 
schedules in combination with chemotherapy or immunotherapy in subjects with locally 
advanced or metastatic NSCLC.  The study is composed of 2 parts.
The objective of Part 1 is to determine the recommended Phase II dose (RP2D) for 
pembrolizumab in combination with different chemotherapy and/or immunotherapy regimens:

Cohort A – 1:1 randomization to carboplatin and paclitaxel plus either pembrolizumab 2 
mg/kg or pembrolizumab 10 mg/kg

Cohort B – 1:1 randomization to carboplatin, paclitaxel, and bevacizumab plus either 
pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg

Cohort C – 1:1 randomization to carboplatin and pemetrexed plus either pembrolizumab 
2 mg/kg or pembrolizumab 10 mg/kg

Cohort D – ipilimumab plus pembrolizumab

Cohort E – erlotinib plus pembrolizumab

Cohort F – gefitinib plus pembrolizumab
The objective of Part 2 is to evaluate the antitumor activity of pembrolizumab in combination 
with chemotherapy or immunotherapy.  Part 2 includes a randomized comparison of 
chemotherapy ± pembrolizumab based on the doses defined in Part 1, as well as a cohort 
expanding the ipilimumab cohort from Part 1:

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
Cohort G – 1:1 randomization to carboplatin and pemetrexed with or without 
pembrolizumab 200 mg 

Cohort H – ipilimumab (RP2D from Part 1 Cohort D) plus pembrolizumab, followed by 
pembrolizumab monotherapy
P022: P022 is a multicenter, worldwide, Phase I/II 3-part trial of IV pembrolizumab in 
combination with oral dabrafenib and/or trametinib in subjects with advanced or metastatic 
melanoma. 
Part 1 is a non-randomized, multi-site, open-label portion of the study using a traditional 3+3 
design to evaluate safety, tolerability, and dosing of pembrolizumab (MK) in combination with 
dabrafenib (D) and trametinib (T) in BRAF mutation-positive (V600 E or K) melanoma subjects.  
Additionally in Part 1, dosing of pembrolizumab in combination with trametinib only (MK+T) 
will be explored in BRAF mutation-negative (without V600 E or K) melanoma subjects, to 
evaluate safety, tolerability, and efficacy of MK+T in Part 2 in this population.  Part 2 is a non-
randomized, multisite, open-label portion of the study using an expansion cohort to further 
evaluate safety and confirm dose of MK+D+T.  Also in Part 2, an expansion cohort will be used 
to further evaluate safety and preliminary efficacy in the MK+T combination.  Part 3 is a 
randomized (1:1), active-controlled, multi-site, 2-arm study of the confirmed dose of the triplet 
combination (MK+D+T) versus placebo (PBO) in combination with D+T (PBO+D+T).
P023: P023 is an open-label, Phase I, multicenter, trial of pembrolizumab in combination with
lenalidomide (Len) and dexamethasone (Dex) or pembrolizumab and Len in subjects with 
relapsed/refractory multiple myeloma who have failed at least 2 lines of prior therapy, including 
a proteasome inhibitor (e.g., bortezomib or carfilzomib) and an immunomodulary derivative 
(thalidomide, pomalidomide, lenalidomide). The trial uses a modified 3+3 design for dose 
determination, followed by dose confirmation and expansion, a further evaluation of safety, and 
a preliminary assessment of efficacy.  During dose determination, cohorts of approximately 3 to 
6 subjects are enrolled and receive pembrolizumab 2 mg/kg or 1 mg/kg IV Q2W in each 28-day 
cycle, in combination with Dex 40 mg QW and/or Len 25 mg or 10 mg on Days 1 to 21. After a 
preliminary MTD/maximum administered dose (MAD) is identified, additional subjects are 
enrolled at a fixed dose of pembrolizumab 200 mg or 100 mg in combination with Len/Dex to 
confirm the MTD/MAD.
P024: P024 is a multicenter, international, randomized, open-label trial of IV pembrolizumab 
monotherapy vs the choice of multiple, standard-of-care, platinum-based chemotherapies in 
subjects previously untreated for their Stage IV, PD-L1 strong, NSCLC. All subjects are 
randomized in a 1:1 ratio to receive pembrolizumab at 200 mg IV Q3W or 1 of the 5 following 
platinum doublets:

Pemetrexed at 500 mg/m2 Q3W and carboplatin AUC 5-6 day 1 Q3W for 4 to 6 cycles 
followed by optional pemetrexed 500 mg/m2 Q3W

Pemetrexed 500 mg/m2 Q3W and cisplatin 75 mg/m2 day 1 Q3W for 4 to 6 cycles 
followed by optional pemetrexed 500 mg/m2 Q3W

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
Gemcitabine 1250 mg/m2 days 1 and 8 and cisplatin 75 mg/m2 day 1 Q3W for 4 to 6 
cycles

Gemcitabine 1250 mg/m2 days 1 and 8 and carboplatin AUC 5-6 day 1 Q3W for 4 to 6 
cycles

Paclitaxel 200 mg/m2 Q3W and carboplatin AUC 5-6 day 1 Q3W for 4 to 6 cycles 
followed by optional pemetrexed maintenance
P025: P025 is an open-label, non-randomized, multicenter Phase Ib study of pembrolizumab in 
Japanese subjects with positive PD-L1 advanced NSCLC in Japan.  All subjects received 
pembrolizumab at 10 mg/kg Q3W.
P028: P028 is an open-label, non-randomized, multicenter, multicohort Phase Ib trial of 
pembrolizumab in subjects with PD-L1 positive advanced solid tumors.  Subjects are enrolled 
into 1 of the following 20 solid tumor cohorts:  A1 Colon or Rectal Adenocarcinoma; A2 Anal 
Canal Squamous Cell Carcinoma; A3 Pancreas Adenocarcinoma; A4 Esophageal Squamous Cell 
Carcinoma or Adenocarcinoma (Including GE Junction); A5 Biliary Tract Adenocarcinoma 
(Gallbladder and Biliary Tree but excluding Ampulla of Vater Cancers); A6 Carcinoid Tumors; 
A7 Neuroendocrine Carcinomas (well or moderately differentiated Pancreatic Neuroendocrine 
Tumor); B1 ER Positive HER2 Negative Breast Cancer; B2 Ovarian Epithelial, Fallopian Tube 
or Primary Peritoneal Carcinoma; B3 Endometrial Carcinoma; B4 Cervical Squamous Cell 
Cancer; B5 Vulvar Squamous Cell Carcinoma; C1 Small Cell Lung Cancer; C2 Mesothelioma 
(Malignant Pleural Mesothelioma); D1 Thyroid Cancer (Papillary or Follicular Subtype); D2 
Salivary Gland Carcinoma; D3 Nasopharyngeal Carcinoma; E1 Glioblastoma Multiforme E2 
Leiomyosarcoma; or E3 Prostate Adenocarcinoma.  All subjects receive pembrolizumab 10 
mg/kg Q2W.
 
P029: P029 is a multicenter, open-label, 3-part Phase I/II trial of IV pembrolizumab in 
combination with subcutaneous Pegylated Interferon Alfa-2b (PEG-IFN) or IV IPI in subjects 
with advanced or metastatic melanoma or renal cell carcinoma.  Part 1A, the Phase I portion of 
the trial, will define the preliminary MTD or MAD of pembrolizumab + PEG-IFN (Group A) 
and pembrolizumab + IPI (Group B), and confirm the tolerability of these treatment doublets. 
Part 1B is a single-arm expansion cohort designed to better characterize the safety and 
tolerability, as well as to evaluate preliminary efficacy of the pembrolizumab + IPI combination 
in melanoma subjects.  Part 2, the randomized portion of the trial, will evaluate preliminary 
clinical efficacy in advanced melanoma at the RP2D for pembrolizumab + PEG-IFN and the 
Phase II Dose determined in Part 1A and 1B for pembrolizumab + IPI.  Evaluation of 
pembrolizumab monotherapy may also occur during Part 2.
P030: P030 is a multisite, worldwide, expanded access program for subjects with metastatic 
melanoma who have limited or no treatment options.  Subjects must have progressed after prior 
systemic therapy, including standard-of-care agents which include IPI and a BRAF/MEK 
inhibitor when indicated. Subjects cannot be eligible for an available pembrolizumab clinical 
trial or have participated in a pembrolizumab clinical trial. Subjects are evaluated for safety at 
baseline and before each cycle of treatment with pembrolizumab 2 mg/kg/Q3W.  Subjects are 
treated until progression of disease or until the subject has received up to 2 years of treatment.

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P041: P041 is an open-label, nonrandomized, multicenter Phase Ib study to evaluate the safety, 
tolerability, and antitumor activity of treatment with pembrolizumab 2 mg/kg Q3W in subjects 
with advanced melanoma in Japan.  Treatment with pembrolizumab will continue unless a 
subject meets the discontinuation criteria such as disease progression (evaluated by modified 
Response Evaluation Criteria In Solid Tumors [RECIST] 1.1), unacceptable toxicity, or 
completion of 24 months of treatment with pembrolizumab.
P045: P045 is a randomized, active-controlled, multisite, open-label, Phase III trial to evaluate 
the efficacy of treatment with pembrolizumab versus paclitaxel, docetaxel, or vinflunine in 
subjects with metastatic or locally advanced/unresectable urothelial cancer that has recurred or 
progressed following platinum-containing chemotherapy.  Subjects are randomized in a 1:1 ratio 
to receive pembrolizumab 200 mg Q3W or the Investigators’ choice of paclitaxel 175 mg/m2 
Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W.  The study also evaluates the 
safety and tolerability profile of pembrolizumab in subjects with recurrent/progressive metastatic 
urothelial cancer.
P055: P055 is a multicenter, unblinded, open-label, single-cohort, Phase II trial to determine the 
safety, tolerability, and antitumor activity of a 200 mg Q3W dose of pembrolizumab in subjects 
with recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed 
on platinum and cetuximab therapy.  Antitumor activity is also assessed in the subset of subjects 
for whom a biopsy sample is determined to be PD-L1 positive.
3.1.2.2
SD-101
Refer to the Investigator’s Brochure for SD-101 for complete Preclinical and Clinical data.
TriSalus Life Sciencesclinical trials in healthy normal volunteers and in patients with chronic 
HCV infection have concluded, and results are summarized below. One phase 1 trial in patients 
with low-grade untreated NHL (DV3-LYM-01) is ongoing. In DV3-LYM-01, 3 patients have 
received 5 intratumoral doses of SD-101 1.0 mg, and 3 patients have received 5 intratumoral 
doses of SD-101 2.0 mg without DLT. The most common AEs were transient flu-like illness. In 
the initial dose-escalation study with melanoma, SD-101 will be administered by intratumoral 
injection with doses from 2.0 mg to 8.0 mg, and these doses are at least 67-fold below the 
NOAEL in monkeys. Based on the extensive clinical experience with another CpG-ODN 
administered by intratumoral injection (Brody JD et al, 2010; Kim YH et al, 2012), in addition to 
the tolerability of SD-101 demonstrated to date, no major local reactions are expected with 
intratumoral injections of SD-101. It is expected that intratumoral injection of SD-101 (at 
maximal proposed doses up to 0.12 mg/kg for a 65 kg person) will result in a similar acceptable 
safety profile. Therefore, the dose of 2 mg SD-101 is expected to be safe and effective, and was 
chosen for this study.
Healthy Normal Volunteer Trial (DV3-HNV-01)
Trial DV3-HNV-01, A Phase 1, Randomized, Single-Blind, Placebo-Controlled Study to Assess 
the Safety, Pharmacokinetics, and Pharmacodynamics of SD-101 in Healthy Normal Male 
Volunteers was completed at 1 trial site and enrolled 26 subjects. 

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In this trial, 20 subjects (18 years and older) were given a single fixed SC dose of SD-101 or 
placebo and were evaluated for safety, tolerability, PK, biomarker activation (type I IFN-
inducible gene expression and serum protein levels), blood lymphocytes, and dendritic cells 
(DC) subsets. Fixed escalating doses of SD-101 (0.1, 1.0, 3.0, or 5.0 mg) were administered as 
follows: 2 subjects were treated at a dose level; if no dose-limiting toxicity (DLT; any SD-101-
related SAE, any single Grade 3, 4, or 5 toxicity, or any unexpected Grade 2 toxicity) occurred, 
then 8 additional subjects were randomized in a single-blind fashion: 4 to the dose level being 
tested, 2 to placebo, and 2 to the next higher dose. Six subjects were enrolled at each of the 0.1, 
1.0, and 3.0 mg dose levels, 6 additional subjects received placebo, and 2 subjects were enrolled 
to the 5.0 mg dose level before the trial was halted for DLTs.  
Overall, 24 (92.3%) subjects reported 80 AEs. Of these AEs, 77.5% were assessed by the 
investigator as Grade 1 (mild), 17.5% were assessed as Grade 2 (moderate), and 5% were 
assessed as Grade 3 (severe). There were no Grade >4 AEs and no SAEs in this trial. The most 
frequently reported AEs were classified within the System Organ Classes (SOC) of blood and 
lymphatic system disorders, general disorders, and administration site conditions. One (1) subject 
at the 5.0 mg dose level experienced Grade 3 neck pain, headache, and a 10-cm injection-site 
induration. These 3 events were considered DLTs, and the trial was interrupted and subsequently 
concluded per the protocol’s stopping rule. Additional AEs included influenza-like symptoms 
such as headache, chills, fatigue, and pyrexia, as well as injection site events such as erythema, 
induration, and pain.  
No subject showed evidence of complement activation or autoantibody (anti-dsDNA or anti-
nuclear antibody) formation. Transient lymphopenia was the most common laboratory 
abnormality observed, although transient thrombocytopenia and neutropenia were also reported 
in 2 subjects and 1 subject, respectively.
Trial in Patients with HCV Infection (DV3-HCV-01)
Trial DV3-HCV-01, A Phase 1, Randomized, Single-Blind, Placebo-Controlled Dose-Escalation 
Study of SD-101 to Assess the Safety, Pharmacodynamics, and Preliminary Evidence of Anti-
Viral Effect in Subjects Diagnosed with Chronic Hepatitis C, Genotype 1, was completed at 4 
study sites and enrolled 34 patients.
This was a trial of 4 fixed SC doses (0.1, 1.0, 3.0, and 5.0 mg) of SD-101 in 34 male and female 
patients (age 18-55 years) (28 patients in SD-101 and 6 patients in placebo). The planned 
treatment schedule was as follows:  4 weeks of once-weekly SD-101 alone or placebo, followed 
by 8 weeks of a combined once-weekly fixed dose of SD-101 or placebo and ribavirin, followed 
by 12 weeks of standard-of-care treatment (pegylated IFN--2a and ribavirin). Viral load 
assessment was conducted at specified time points through Week 25. If at Week 25 patients 
compared with Week 13, treatment with standard-of-care (pegylated IFN--2a and ribavirin) was 
provided by TriSalus Life Sciencesto continue for a total of 48 weeks.
Overall, during the combined dosing periods (study drug or placebo monotherapy and with 
ribavirin), 32 (94.1%) patients, including 27 patients treated with SD-101 at any dose and

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5 patients treated with placebo, reported an AE. The most frequently reported AEs by Preferred 
Term were injection site pain, injection site erythema, injection site swelling, and injection site 
pruritus. In general, injection site reactions were noted with high frequency in all dose groups, 
including the placebo group. Influenza-like symptoms, pyrexia, and myalgia were the most 
frequently reported non-injection site reactions overall.
Most AEs were Grade 1 or 2 (mild to moderate) in severity. There were no Grade 4 AEs.
Grade 3 events were reported in the patient with an SAE (hyperthyroidism), who had received 8 
doses of SD-101 0.1 mg. 
 
.  
One additional patient who had received 12 doses of SD-101 1.0 mg (and was receiving 
pegylated IFN- and ribavirin at the time of the AE) was discontinued by the investigator due to a 
reported AE, positive test for anti-dsDNA, not associated with other symptoms or signs of 
complications related to the positive ds-DNA. The patient was negative for anti-dsDNA at the 
Discontinuation Visit. 
  
Trial in Patients with Untreated Low-Grade B-Cell Lymphomas (DV3-LYM-01)
Trial DV3-LYM-01, A Phase 1/2, Non-randomized, Open-label, Multicenter, Dose Escalation 
and Expansion Study of Intratumoral Injections of SD-101 in Combination With Localized
Low-dose Radiation in Patients With Untreated Low-grade B-cell Lymphoma   
This is a phase1/2, non-randomized, open-label, multicenter, dose-escalation, and expansion trial 
designed to evaluate the safety and preliminary efficacy of localized low-dose XRT and 
intratumoral SD-101 injection into a single target lesion (“Lesion A”) in patients with untreated 
low-grade B-cell lymphomas who do not require immediate systemic therapy and are appropriate 
candidates for “watch and wait”. This trial is being conducted in 2 parts. Part 1 (Dose Escalation) 
consists of the evaluation of 4 escalating dose levels, and Part 2 (Expansion) includes enrollment 
of additional patients at the MTD or optimal dose level from Part 1.  
To date, 3 patients have received 5 intratumoral doses of SD-101 1.0 mg, and 3 patients have 
received 5 intratumoral doses of SD-101 2.0 mg. No DLT was observed, and the most common 
AEs were transient flu-like illness in the 2.0 mg cohort. Dosing at 4.0 mg is planned but has not 
yet begun.  
Trial in Patients with Recurrent Lymphoma following Allogeneic Hematopoietic
Cell Transplantation (Investigator-Sponsored Trial at Stanford University
Medical Center)
IND 111985:  Intratumoral Injection of SD-101 Combined with Local Radiation for the
Treatment of Recurrent or Progressive Lymphoma After Allogeneic Hematopoietic Cell
Transplantation.
In this investigator-sponsored dose-escalation trial, up to 18 patients will receive 2 doses of RT 
(4 Gy) over 2 days and then received 3 weekly doses of SD-101 in a standard 3+3 design. SD-
101 is administered intratumorally using the following doses:  0.3 mg, 1.0 mg, and 3.0 mg. To 
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weekly intratumoral doses of SD-101 1.0 mg. One unrelated SAE of Klebsiella bacteremia was 
reported in a patient who received SD-101 1.0 mg. No other AEs have been reported (TriSalus 
Life Sciencespersonal communication with investigator).
SD-101, Radiation, and Ipilimumab Trial in Patients with Relapsed Lymphoma
(Investigator Sponsored Trial at Stanford University Medical Center)
IND 111985: A Phase I/II Study of Intratumoral Injection of SD-101, an Immunostimulatory 
CpG, and intratumoral Injection of Ipilimumab, an anti-CTLA4 Monoclonal Antibody, in 
Combination with Local Radiation in Low-Grade B-cell Lymphomas
In this investigator-sponsored dose-escalation of ipilimumab trial, up to 12 patients will receive 2 
doses of RT (4 Gy) over 2 days and then receive 1 intratumoral dose of ipilimumab (5, 10, or 25 
mg), and 5 weekly doses of 1 mg of SD-101 intratumorally in a standard 3+3 design. This trial is 
ongoing but no patients have been treated as of 1 March 2015.  
3.2
Rationale
3.2.1
Rationale for the Trial and Selected Subject Population
Prostate cancer is a target of the host immune response.  Multiple treatment factors play into this 
immune response, which is a complex, constantly changing equilibrium affected by radiation 
therapy, androgen deprivation therapy, and checkpoint regulation.  With radiation therapy and 
androgen deprivation therapy, increased effector T-cell infiltration is observed within the 
prostate gland and tumor(s).  However, effector T cell infiltration is often transient due, in part, 
to the tumor’s ability to activate immune checkpoints.  New agents targeting checkpoint 
inhibition help to combat the immunosuppression.   Specifically, drugs targeting the PD-L1/PD-1 
checkpoint pathway have generated significant clinical interest in prostate cancer. 
The PD-L1/PD-1 axis is a potent immune regulator through inhibition of effector T cell function.  
The PD-L1 protein is undetectable in most normal tissues, but can be induced by radiation.  
Although at baseline, prostate cancer expresses low levels of PD-L1, the T-cells that infiltrate the 
prostate gland highly express PD-1.1, 2  A phase Ib trial investigated the efficacy of PD-1 
blockade in 236 patients with various solid malignancies, included 17 patients with castration-
resistant prostate cancer (CRPC).  In 2 of the 17 patients, PD-L1 expression in tumor specimens 
were evaluated and were negative.  Response to anti-PD-1 therapy may reflect the level of PD-
L1 expression.3 .  Thus, a greater response may have been seen with induction of PD-L1 
expression.  However, we have assessed PD-L1 expression in a collaboration with the Johns 
Hopkins group, and can detect >5% PD-L1 staining by their scoring in approximately half of the 
prostatectomy specimens assessed from our neoadjuvant SipT trial.  In addition, a recent study 
demonstrated that ionizing radiation increases tumoral expression of PD-L1.  When anti-PD-L1 
therapy was subsequently administered after irradiation (IR), a synergistic effect on tumor 
regression was observed.  The concept of IR-induced PD-L1 expression and subsequent anti-
PDL1/PD-1 blockade was suggested to broaden the application of PD-L1/PD-1 axis inhibitors 
leading to potent antitumor responses when combined with radiotherapy.4 

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Radiation therapy is commonly used to treat primary and metastatic tumors.  As suggested 
above, radiation therapy may improve the therapeutic efficacy of checkpoint inhibition.  Recent 
studies demonstrated that high-dose ablative radiotherapy triggers a rapid, adaptive immune 
response mediating tumor regression. Radiation therapy may be utilized to tip the balance toward 
a more robust anti-tumor response in combination with checkpoint inhibitor therapy than with 
the checkpoint inhibitor alone.  Recent studies suggest that the combination of radiation therapy 
and checkpoint inhibitors may synergistically promote T-cell antitumor immunity and prolonged 
protective immunity.4, 5  Moreover, the effects of combination radiation therapy and checkpoint 
inhibitor blockade have been visualized at secondary sites that did not receive radiotherapy (i.e., 
abscopal effect).  
SD-101 is an oligodeoxynucleotide (ODN) enriched with cytidine-phospho-guanosine (CpG) 
motifs of Class C-type sequence (CpG-C). The CpG-C type sequences are an agonist for Toll-
like receptor 9 (TLR9) and potent inducers of interferon alpha (IFN-α) production from 
plasmacytoid dendritic cells (pDCs), as well as pDC maturation and B cell proliferation. TLR9 
stimulation by CpG-ODNs may have a significant antitumor effect by several potential 
mechanisms including enhancement of innate and T-cell immunity, stimulation of cytokines with 
direct or indirect antitumor activities (including IFN-α), and production of cytotoxic antibodies 
(Marshall JD et al, 2003; Marshall JD et al, 2005). Preclinical mouse models show that the 
combination of CpG therapy with checkpoint blockade enhances tumor regression and long-term 
survival (Mangsbo SM et al, 2010; Duraiswamy J et al, 2013).
The combination approach of radiation therapy, androgen deprivation therapy, SD-101, anti-PD-
L1 therapy has not been well studied in prostate cancer.  We hypothesize that the combination of 
PD-1 blockade (pembrolizumab) and localized therapies that prime and augment an immune 
response (definitive prostatic radiotherapy with or without intratumoral SD-101, an TLR9 
agonist), will induce a durable clinical response in a subset of patients with metastatic hormone-
sensitive prostate cancer, reflected by a prolonged period of PSA < nadir + 2 ng/mL after 
cessation of all therapies including ADT.
The study population of chemotherapy-naïve oligometastatic hormone-sensitive prostate cancer 
is selected based on emerging data that immunotherapy for prostate cancer is most likely to 
benefit patients with lower disease burden (Kwon ED et al, 2014), presumably due to a lower 
level of immunosuppression, both systemically and in the tumor microenvironment.
3.2.2
Rationale for Dose Selection/Regimen/Modification
3.2.2.1
Pembrolizumab
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in 
PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test 

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for initial tumor activity.  Recent data from other clinical studies within the MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.

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3.2.2.2
SD-101
Three toxicity studies have been performed with SD-101, including a 14 once-weekly dose 
subcutaneous (SC) study in rats, a 14 once-weekly dose SC study in monkeys, and a safety 
pharmacology SC study in monkeys. No significant safety concerns have been identified in any 
of the toxicity studies conducted to date with SD-101. Genotoxicity studies indicated that SD-
101 has no mutagenic or clastogenic activity.  
Nearly all of the findings in the toxicity studies conducted with SD-101 were expected and 
consistent with the known properties of immunostimulatory ODNs, or the known class effects of 
PS ODNs. Also the effects of SD-101 were more pronounced in rats than in non-human 
primates. As an immunostimulatory molecule, SD-101 would be expected to induce reactivity of 
lymphoid tissues (i.e. spleen and lymph nodes), as well as immunocompetent cells in other 
organs in the clinical dose range. At higher dose levels, the effects on target tissues are 
exaggerated, well understood, dose-dependent, and reversible.
TriSalus Life Sciencesclinical trials in healthy normal volunteers and in patients with chronic 
HCV infection have concluded, and one phase 1 trial in patients with low-grad untreated NHL is 
ongoing. In the NHL study, 3 patients have received 5 intratumoral doses of SD-101 1.0mg, and 
3 patients have received 5 intratumoral doses of SD-101 2.0mg without DLT. The most common 
AEs were transient flu-like illness. In the initial dose-escalation study with melanoma, SD-101 
will be administered by intratumoral injection with doses form 2.0mg to 8.0mg, and these doses 
are at least 67-fold below the NOAEL in monkeys. Based on the extensive clinical experience 
with another CpG-ODN administered by intratumoral injection (Brody JD et al, 2010; Kim YH 
et al, 2012), in addition to the tolerability of SD-101 demonstrated to date, no major local 
reactions are expected with intratumoral injections of SD-101. It is expected that intratumoral 
injection of SD-101 (at maximal proposed doses up to 0.12 mg/kg for a 65 kg person) will result 
in a similar acceptable safety profile. Therefore, the dose of 5 mg SD-101 is expected to be safe 
and effective, and was chosen for this study. 
3.2.2.3
Radiotherapy
Radiotherapy (RT) has the potential to enhance anti-tumor effects of immune checkpoint 
blockade by multiple mechanisms, including providing antigen presentation, releasing 
proinflammatory signals from dying tumor cells, and enhancing the diversity of TCR repertoire 
of intratumoral T cells (Cha E et al, 2010; Twyman-Saint Victor C et al, 2015). Preclinical 
mouse models have shown that the combination of RT with immunotherapies can enhance anti-
tumor efficacy and improve long-term survival, including in glioma, melanoma and breast cancer 
(Belcaid Z et al, 2014; Twyman-Saint Victor C et al, 2015; Demaria S et al, 2005). There is 
evidence that RT produces more immune-mediated effect when given fractionated compared to 
in a single-dose (Dewan MZ et al, 2009; Vanpouille-Box CI et al, 2015).
In this study, RT to the whole prostate and soft tissue oligometastatic sites will be delivered via 
SBRT at a dose of 7 Gy x 5 fractions to a total of 35 Gy.  RT to osseous metastases will be 
delivered via SBRT at a dose of 10 Gy x 3 fractions to a total of 30 Gy. RT will start 1-5 weeks 
after fiducial marker placement and SBRT simulation, and will be delivered every other day so 
that the last treatment will be 10-21 days after the start of SBRT. Intratumoral 5 mg SD-101 

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injection will be performed at the time of fiducial marker placement, and 1-3 weeks after C1D1.  
This prostate and soft tissue oligometasis-directed SBRT dose and fractionation scheme is 
chosen because it is an option for radiation with definitive intent in localized prostate cancer 
(Kishan AU & King CR, 2017). The dose and fractionation scheme for osseous oligometastases 
is chosen based on its established safety and efficacy in a prior randomized trial of 
oligometastasis-directed SBRT (Ost P et al, 2017). This dose and fractionation is considered 
ablative, and ablative dosing is hypothesized to transform an immunosuppressive tumor 
microenvironment to an immunogenic tumor microenvironment (Lee Y et al, 2009; Filatenkov A 
et al, 2015). 
3.2.2.4
Androgen deprivation therapy
Subjects will receive intermittent androgen deprivation therapy consisting of 3 months of ADT 
run-in, followed by 9 months of GnRH targeting agent (leuprolide preferred), abiraterone, and 
prednisone (or equivalent), then discontinuation of ADT. A large, randomized phase III study did 
not demonstrate a significant difference in overall survival in patients receiving intermittent 
androgen deprivation therapy when compared with continuous androgen deprivation therapy.  Of 
note, there were too few events to rule out non-inferiority of intermittent therapy when compared 
to continuous androgen deprivation therapy.  Intermittent androgen therapy was associated with 
small improvements in quality of life including erectile function and mental health at month 3 
(Hussain M et al, 2014). Furthermore, meta-analyses of randomized control trials have not 
shown a survival difference between intermittent and continuous ADT (Botrel TE et al, 2014, 
Niraula S et al, 2013). Therefore, intermittent androgen therapy has been accepted as a standard 
of care regimen in patients with metastatic prostate cancer.  The withdrawal of androgen 
deprivation therapy with recovery of testosterone levels will allow us to evaluate the effect of the 
treatment regimen on the PSA response.
Subjects who have received less than 2 months of ADT prior to screening are eligible for the 
study. To ensure homogenous treatment among patients and to allow for scheduling of SBRT 
with or without SD-101 therapy (depending on study arm), subjects will have a 3 month period 
of ADT run-in prior to Cycle 1 Day 1. Subjects will start C1D1 and SBRT 1 month after ADT 
initiation at the earliest, and 4 months after ADT initiation at the latest.
Combined androgen blockade with GnRH targeting agent, abiraterone, and prednisone (or 
equivalent) PO daily are preferred and will be started for patients who have not received any 
ADT at time of screening. For subjects who have been started on leuprolide or another GnRH 
agent at time of screening, they will continue the respective GnRH agent for the remainder of 
ADT run-in (3 months total, accounting for duration of ADT prior to screening). They will 
continue this GnRH agent for the subsequent 9 months.
Subjects who were not on an antiandrogen, or were on an antiandrogen other than abiraterone at 
time of screening are required to start or switch to abiraterone (e.g. Zytiga, Yonsa) with 
prednisone (or equivalent) daily, respectively. They will continue abiraterone (e.g. Zytiga, 
Yonsa) daily with prednisone (or equivalent) daily for the remaining duration of ADT run-in and 
for 9 months starting on Cycle 1 Day 1.

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3.2.3
Rationale for Endpoints
The primary endpoint is to determine the percentage of patients in cohort 2 who achieve PSA < 
nadir + 2 ng/mL at 15 months from the start of treatment who have non-castrate testosterone 
levels, where non-castrate testosterone level is defined as testosterone >150 ng/dL. 
This primary endpoint is selected because we anticipate that at least 2 patients in each arm in 
cohort 2 will achieve non-castrate testosterone (>150 ng/dL) at 15 months from the start of 
treatment. PSA rise of 2 ng/mL or more above the nadir PSA is the standard definition for 
biochemical failure after definitive radiation with or without hormonal therapy for patients with 
localized prostate cancer. In patients with metastatic hormone-sensitive prostate cancer who have 
ceased all therapies including ADT with testosterone recovery, PSA will almost certainly rise to 
above nadir + 2 ng/mL, without a significant and durable clinical benefit from immunotherapy. 
Therefore, the primary endpoint serves as a surrogate marker for the clinical activity of 
combination immunotherapy in this study with intermittent ADT.
3.2.3.1
Efficacy Endpoints
The following secondary endpoints were chosen to further assess the clinical activity of 
pembrolizumab combined with RT with or without SD-101 in patients with hormone-sensitive 
oligometastatic prostate cancer receiving intermittent androgen deprivation. Testosterone-PSA 
uncoupling serves as a less stringent assessment of PSA response in comparison to the primary 
endpoint. Time to clinical progression and progression-free survival (PFS) are well established 
efficacy endpoints, but would require a significantly larger sample size to establish statistical 
significance.

To determine the rate of testosterone-PSA uncoupling in patients in cohort 2 treated with RT 
+ Pembrolizumab (Arm 1) and RT + Pembrolizumab + SD-101 (Arm 2), where uncoupling 
is defined as PSA less than 50% baseline for at least 3 months after testosterone recovers to 
>150 ng/dL after discontinuation of ADT.

To estimate time to clinical progression, defined as radiographic progression by RECIST 
v1.1, symptomatic progressive disease, or PSA progression on therapy in participants in each 
study arm in cohort 2.

To estimate progression-free survival (PFS) of participants in each arm in cohort 2, where 
PFS is a composite endpoint based on PSA progression, radiological progression, clinical 
deterioration, or death.
3.2.3.2
Biomarker Research
Intratumoral T-cell infiltration and PD-L1 expression have been shown to correlate with 
improved clinical outcomes after PD-1 and PD-L1 blockade in some clinical studies. 
Furthermore, we have shown that clinical responses to immune checkpoint therapy in patients 
with prostate cancer and melanoma are associated with the amplification of pre-existing immune 
response (Cha E, et al. 2014). Thus, we will explore the following biomarkers as exploratory 
endpoints in this study, and correlate results with clinical response and outcomes.

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
To assess peripheral and tumor-based biomarkers of response and resistance by:
o
Immunohistochemistry of immune cell infiltrates on baseline biopsy tissues and 
optional progression biopsy tissues
o
Assessment of PD-L1 staining on tumor and tumor-infiltrating immune cells (IC) on 
baseline biopsy tissues and optional progression biopsy tissues
o
Exploration of gene signature in pre-treatment tumor biopsies that correlates with 
treatment response

To define the treatment-induced effects on circulating immune cells by flow cytometry.

To explore remodeling of circulating T cell repertoire in the tumor and blood by deep 
sequencing of VDJ regions of TCRs.
4.0 METHODOLOGY
4.1
Entry Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
4.1.1
Diagnosis/Condition for Entry into the Trial
Patients must have histologically proven diagnosis of prostate cancer, with hormone-sensitive 
oligometastatic disease.
4.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be  18 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the ECOG Performance Scale.
4. Histologically documented adenocarcinoma of the prostate
5. Oligometastatic disease. In order to be eligible, the patient must have a total of <4 
metastatic bone and/or metastatic lymph node sites based on bone and/or soft tissue 
lesions as defined by any of the following:

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a.
Bone metastases will be defined by bone imaging. If the patient has technetium 
bone scan, and/or NaF PET performed, either study may be used for documenting 
metastases; both scans do not need to show the number of metastases required for 
study entry. For patients undergoing PSMA PET, only PSMA avid lesions that are 
consistent with metastasis will be counted as a site of metastasis.  
b. Distant metastatic lymph node disease.  A lymph node ≥1 cm in shortest 
dimension will be noted as involved with disease. Distant metastatic lymph nodes 
will be determined as any lymph nodes outside the confines of the true pelvis.  
For patients undergoing PSMA PET, only PSMA avid lesions that are consistent 
with metastasis will be counted as a site of metastasis. 
c.
Any other soft tissue lesion deemed by the physician to be consistent with distant 
metastatic disease. For patients undergoing PSMA PET, only PSMA avid lesions 
that have a CT or MRI correlate consistent with metastasis will be counted as a 
site of metastasis. 
Note: Radiographic imaging performed as standard of care prior to obtaining informed 
consent and within 60 days of initiating study treatment may be used to assess 
oligometastatic disease during screening, rather than repeating scans. For patients who 
have started on ADT, they must have had imaging prior to initiation of hormonal therapy.
6. Treatment naïve, defined as less than 2 months of standard of care ADT (e.g. GnRH 
agonist or antagonist with or without antiandrogen, including abiraterone) for metastatic 
hormone-sensitive prostate cancer prior to enrollment (at time of consent)
7. No prior chemotherapy for prostate cancer
8. Not a candidate for or refuse chemotherapy
9. No prior prostatectomy or prostatic radiation
10. PSA >2 ng/mL at baseline or prior to initiation of hormonal therapy
11. Baseline testosterone >150 ng/dL if patient has not initiated hormonal therapy. For those 
patients who have already initiated hormonal therapy, baseline testosterone is not 
required.
12. Consent to undergo mandatory prostatic core biopsies at the time of fiducial marker 
placement and 1-3 weeks after C1D1 of pembrolizumab.
13. The effects of pembrolizumab on the developing human fetus is unknown. Men treated or 
enrolled on this protocol must agree to use adequate contraception prior to the first dose 
of study therapy, for the duration of the study participation, and for 120 days after the last 
dose of study therapy.
14. Demonstrate adequate organ function as defined in Table 1:.

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Table 1: Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count 
(ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(GFR can also be used in place 
of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 g/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT)
Activated Partial 
Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
15. Subjects should agree to use an adequate method of contraception prior to the first dose 
of study therapy through 120 days after the last dose of study therapy. 
a.
Their partners should also be encouraged to use proper method of contraception.
4.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Patients who are not appropriate candidates for prostate-directed SBRT (cohort 1), or 
prostate and oligometastasis-directed SBRT (cohort 2).
2. Patients with neuroendocrine or small cell features are not eligible.

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3. Patients with evidence of liver metastasis are excluded.
4. GnRH agonists or GnRH antagonists (e.g., leuprorelin, degarelix) for > 2 months  prior to 
consenting
5. Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide) for 
> 2 months prior to consenting.  Patients on 5-alpha reductase inhibitors are allowed on 
study.
6. Estrogen containing compounds for > 2 months prior to enrollment
7. PC-SPES or PC-x products. Other herbal therapies or supplements will be considered by 
the Principle Investigator on a case-by-case basis based on their potential for hormonal or 
anti-cancer therapies.
8. Prior immunotherapy or chemotherapy for prostate cancer
9. Prior radiation therapy to the prostate 
10. Prior prostatectomy
11. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment.
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of systemic immunosuppressive therapy within 7 days prior to the first dose of 
trial treatment, with the exception of steroids for adrenal insufficiency in which case 
prednisone < 10mg/day or its equivalent is allowed.
13. Has a known history of active TB   (Bacillus Tuberculosis).
14. Hypersensitivity to pembrolizumab or any of its excipients.
15. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.
16. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent.
-
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study.
-
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  

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17. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include carcinoid, basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ cervical 
cancer.
18. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroid treatment for at least 14 days prior to the first dose of study treatment. This 
exception does not include carcinomatous meningitis, which is excluded regardless of 
clinical stability.  
19. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
20. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
21. Has an active infection requiring systemic therapy.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
24. Expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 120 days after the last dose of trial treatment.
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
27. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
28. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose 
of study drug.  Administration of killed vaccines is allowed.

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4.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 2.
Table 2: Trial Treatments
Study 
Drugs/Therapies
Premedication; 
precautions
Dose
Route
Schedule
Cycle 
Length
Leuprolide (e.g., 
Lupron, 
Eligard)a
None
22.5 
mgg
Intramuscular
1st dose at the start 
of 3 mo ADT run-
inb. Then 22.5 mg 
every 3 mo x 3 
dosesg starting 
Cycle 1 Day 1 
N/A
Prednisone (or 
equivalent 
medication)c
None
Per local 
standard 
practicef
Oral
Daily for 3 months 
during ADT run-
inc. Then daily for 
9 months, starting 
Cycle 1 Day 1
N/A
Abiraterone (e.g. 
Zytiga, Yonsa)
None
Per local 
standard 
practicef
Oral
Daily for 3 months 
during ADT run-
inc. Then daily for 
9 months, starting 
Cycle 1 Day 1
N/A
Radiotherapy 
(whole prostate 
and soft tissue 
oligometastases)
None
7 Gy x 5 
fractions 
(35 Gy 
total) 
SBRT
1-5 weeks after 
fiducial marker 
placement and 
simulation, over 
10-21 days
N/A
Radiotherapy 
(osseous 
metastases)
None
10 Gy x 
3 
fractions 
(30 Gy 
total) 
SBRT
1-5 weeks after 
fiducial marker 
placement and 
simulation, over 
10-21 days
N/A
SD-101d
None
5 mg
Intraprostatic, 
intratumoral
At time of fiducial 
maker placement 
(1-5 weeks prior to 
C1D1) and 1-3 
weeks after C1D1 
(conjointly prostate 
biopsies)
N/A
Pembrolizumab 
(Keytruda)e
None for the first 
dose
200 mg
Intravenous
Day 1 each cycle
21 days

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aSubjects will receive 3 months of ADT run-in, followed by 9 months of GnRH targeting agent, 
abiraterone, and prednisone (or equivalent) then discontinuation of ADT. Leuprolide is the 
preferred GnRH agent, but patients who were already on another GnRH agent may continue this 
agent. All subjects are required to start or continue abiraterone at enrollment for ADT run-in and 
subsequent 9 months. Patients who are unable to tolerate or experience toxicity from abiraterone 
and/or prednisone (equivalent) may discontinue abiraterone and prednisone (or equivalent) and 
continue on study.  GnRH is standard of care treatment and will not be supplied by the study.
bSubjects who have received less than 2 months of ADT prior to screening are eligible for the 
study. For subjects who have been started on Leuprolide or another GnRH agent at time of 
screening, they will continue the respective GnRH agent for the remainder of ADT run-in (3 
months total, accounting for duration of ADT prior to screening). They will continue this GnRH 
agent for the subsequent 9 months.
cSubjects who were not on an antiandrogen, or were on an antiandrogen other than abiraterone at 
time of screening are required to start or switch to abiraterone (e.g. Zytiga, Yonsa) and 
prednisone (or equivalent) daily, respectively. They will continue abiraterone and prednisone (or 
equivalent) daily for the remaining duration of ADT run-in and for 9 months starting on Cycle 1 
Day 1. Abiraterone and prednisone (or equivalent) are standard of care treatment and will not be 
supplied by the study. Prednisone can be increased to 10mg/day if clinically indicated.
dSD-101 will be delivered to the dominant prostatic tumor lesion in Arm 2 only. All other study 
drugs/therapies will be delivered to both Arm 1 and 2.
eSevere infusion reactions have been reported in 2 (0.1%) of 1562 subjects receiving 
pembrolizumab in KEYNOTE-001 and KEYNOTE-002. For severe infusion reactions, stop 
infusion and permanently discontinue pembrolizumab. Subjects with mild or moderate infusion 
reactions may continue to receive pembrolizumab with close monitoring; premedications with 
antipyretic and antihistamine may be considered.
fThe appropriate dosing of abiraterone and accompanying steroid will be dictated by the 
prescribed formulation. Generic formulations (e.g. Yonsa) are allowed. Steroid dose can start 
with QD or BID dosing (e.g. Prednisone 5mg PO QD with Zytiga) and adjusted as indicated 
clinically.
gEquivalent doses of leuprolide are allowed, e.g., 7.5 mg monthly intramuscular doses or 1 mg 
daily subcutaneous doses, through the 9 month GnRH targeting treatment period. Other GNRH 
agonists/antagonists that are deemed equivalent can be used.
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned.
4.2.1
Study drugs – Description, Supply and Storage of Investigational Drugs
4.2.1.1
Pembrolizumab
Pembrolizumab (KEYTRUDA®, MK-3475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designated to 

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block the interaction between PD-1 and its ligands, programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2).
On September 4, 2014, the United States Food and Drug Administration (FDA) granted 
accelerated approval to pembrolizumab for treatment of subjects with unresectable or metastatic 
melanoma and disease progression following treatment with ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor. The recommended dose of pembrolizumab is 2 mg/kg 
administered as an IV infusion over 30 minutes every 3 weeks until disease progression or 
unacceptable toxicity. This indication was approved based on tumor response rate and durability 
of response. Pembrolizumab is currently being investigated across multiple indications.
Mechanism of Action
Pembrolizumab targets PD-1 on T lymphocytes and prevents interaction with PD-L1 and PD-L2, 
which are inhibitory receptors expressed on tumor cells and antigen presenting cells. The 
blockade of PD-1 with PD-L1 and PD-L2 enhances functional activity of the target lymphocyte 
to facilitate tumor regression and ultimately immune rejection. 
Pharmacokinetics and Metabolism
The PK profile of pembrolizumab investigated in Part A of the ongoing study P001 has obtained 
results following a single dose at 1, 3, and 10 mg/kg pembrolizumab to 17 subjects with solid 
tumors in Cycle 1. The observed PK profile of pembrolizumab was typical of those observed for 
other IgG mAbs with a half-life (t1/2) of approximately 2 to 3 weeks. There was no indication of 
dose dependency of t1/2 in the 3 dose groups. A dose-related increase in exposure was observed 
from 1 to 10 mg/kg. The long t1/2 supports a dosing interval of every 2 weeks or every 3 weeks.
No traditional metabolism studies were conducted with pembrolizumab per current ICH S6 (R1) 
guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals. 
Pembrolizumab has a low potential of eliciting the formation of anti-drug antibodies. 
Contraindications
No specific contraindications has been determined for pembrolizumab. Provisional adverse 
reactions with pembrolizumab are described in the Investigator’s Brochure, and exclusion 
criteria for the study are listed in Section 4.1.3.
Availability
Pembrolizumab will be supplied by Merck Sharp & Dohme Corporation.
Storage and handling
Pembrolizumab is provided as a liquid solution (100 mg/vial) in Type 1 glass vials intended for 
single use only. The drug product is stored under refrigerated conditions (2 to 8oC). Diluted 
pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours. This includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. In addition, IV bags can be stored at 2 to 8oC for up to a cumulative time of 
20 hours.
Preparation for Administration
Pembrolizumab solution  product are a clear to opalescent solutions, essentially free of visible 

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particles. It is intended for IV administration. The drug can be further diluted with normal saline 
or 5% dextrose in the concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. Vials should be immediately used to prepare the infusion 
solution in the IV bag and the infusion solution should be immediately administered. Diluted 
pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours. This includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. In addition, IV bags can be stored at 2 to 8oC for up to a cumulative time of 
20 hours. This recommendation is based on up to 24 hours of room temperature and up to 24 
hours of refrigerated stability data of diluted MK-3475 solutions in the IV bags. Clinical supplies 
are to be stored in accordance with specific instructions on the label.
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert.
4.2.1.2
SD-101
Classification
SD-101 is a 30-mer phosphorothioate (PS) oligodeoxynucleotide (ODN) enriched with cytidine-
phospho-guanosine (CpG) motifs with the following sequence:
5’ – TCG AAC GTT CGA ACG TTC GAA CGT TCG AAT – 3’ 
SD-101 contains juxtaposed CpG motifs with flanking regions, in a self-complimentary 
palindromic sequence that is designated as a Class C-type sequence (CpG-C). SD-101 is being 
developed for an indication in hematologic malignancies, malignant melanoma, and other solid 
malignancies. No structurally similar compound (i.e. CpG-ODN) has been approved as a drug 
substance for any indication.
Mechanism of Action
The CpG-C type sequences in SD-101 are an agonist for Toll-like receptor 9 (TLR9) and potent 
inducers of interferon alpha (IFN-α) production from plasmacytoid dendritic cells (pDCs), as 
well as pDC maturation and B cell proliferation. TLR9 stimulation by CpG-ODNs may have a 
significant antitumor effect by several potential mechanisms including enhancement of innate 
and T-cell immunity, stimulation of cytokines with direct or indirect antitumor activities 
(including IFN-α), and production of cytotoxic antibodies (Marshall JD et al, 2003; Marshall JD 
et al, 2005). Signaling by CpG-ODNs through TLR9 requires active uptake of the ODN as TLR9 
is present only in specific intracellular compartments (Krieg AM, 2002). The TLR9 signaling 
occurs in two distinct intracellular structures, early and late endosomes (Honda K et al, 2005; 
Guiducci C et al, 2006), leading to different outcomes.

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Pharmacokinetics and Metabolism
In the healthy normal volunteer trial, 20 subjects (18 years and older) were given a single fixed 
subcutaneous (SC) dose of SD-101 (0.1, 1.0, 3.0, or 5.0 mg) or placebo, SD-101 levels in the 
plasma peaked 2 to 4 hours after drug administration. The mean maximum plasma concentration 
for 6 subjects injected with SD-101 3.0 mg was approximately 7 ng/mL and was higher than for 
subjects receiving SD-101 1.0 mg. The SD-101 levels in plasma declined after 4 hours. Due to 
limitations in the analytical method such as a lower limit of quantitation of 5 ng/mL and analyte 
stability in matrix, the data provided are for information only. The dataset was insufficient for 
the calculation of parameters such as clearance rate or half-life. 
Contraindications
SD-101 should only be administered by routes specified in the protocol. SD-101 should not be 
administered intravenously. SD-101 is contraindicated for patients who are allergic to any of its 
components.
Availability
SD-101 will be supplied by TriSalus Life Sciences.
Storage and handling
SD-101 contains no preservatives and must be stored under refrigerated conditions (2oC to 8oC). 
SD-101 is not to be frozen. Vials of SD-101 are for single use only.
Stability
Available stability data indicate that SD-101 (16 mg/mL) is stable for at least 36 months when 
stored refrigerated at 2 to 8oC, the recommended storage condition.
Preparation for Administration
SD-101 may only be administered by intratumoral injection according to instructions specified in 
the trial protocol. SD-101 is supplied in single use 2-mL vials containing 0.75 mL of sterile, 
preservative-free drug at a concentration of 16mg/mL to be diluted with sterile Normal Saline to 
a total volume of 1 mL. SD-101 will be administered at doses specified in the protocol. Dilutions 
of SD-101 are to be made at the investigative site using commercially-available sterile Normal 
Saline, and must be administered within 8 hours of removal of the drug product vial from storage 
for preparation of the dilution (dosing solution).
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert.
4.2.2
Stereotactic Body Radiation Therapy (SBRT)
The goal of SBRT is to deliver ablative radiation therapy while minimizing exposure of 
surrounding normal tissues. The dose used to treat a given tumor will be based on its location, 
as normal tissue toxicity is likely to arise from the surrounding organs at risk. The dose level for 
each metastatic location has been selected based on available evidence and expert consensus. 
SBRT should be completed within 3 weeks of the first dose of SBRT. Each site will be treated 
on an every other day schedule. Not all sites need to receive radiation therapy on the same day.

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Radiation therapy will be delivered on specialized linear accelerators with image guidance (e.g., 
Novalis, Trilogy, Synergy, Artiste, TrueBeam). IGRT is required for this study. Either 3DCRT 
or IMRT (including VMAT) are all acceptable planning techniques. Planning techniques may 
differ for each lesion to be treated provided that the tumor motion is properly accounted for with 
each technique when the target or targets are in or near the thorax region.
4.2.2.1
Dose Specifications
Dose Fractionation
Patients will receive 3 or 5 fractions of radiation as determined by the location of the 
target to be irradiated. There should be a minimum of 40 hours between treatments for an 
individual targets. However, a patient may receive radiation for different targets on 
consecutive days. Maximum dose to 0.1cc of the PTV will be 130% of the prescription 
dose. 
Prescription Doses
Tumor Location 
Dose
Primary tumor (prostate, seminal vesicles)
35 Gy
(5 fractions)
Soft tissue metastases
35 Gy
(5 fractions)
Osseous metastases
30 Gy
(3 fractions)
4.2.2.2
Technical Factors
Physical Factors
Only photon (x-ray) beams with photon energies ≥ 6MV will be allowed. For lung 
metastases, 6 MV photon beam energies are required. For patients with implanted cardiac 
devices, 6-10 MV photon beam energies are required. FFF photon beams are allowed.
Dose will be calculated using heterogeneity correction algorithms approved by IROC Houston
independent of the treatment planning technique. All doses should be reported in terms of 
dose- to-water and not in terms of dose-to-medium.
Stereotactic Targeting
For the purposes of this protocol, the term ‘stereotactic’ implies the targeting, planning, and 
directing of radiation beams along any trajectory in 3-D space toward a target of known 3-D 
coordinates. The coordinate system is defined by reliable ‘fiducials.’ A fiducial may be external 
or internal to the patient’s body. External fiducials may relate to a frame or treatment device.
Internal fiducials may be implanted markers OR reliably identifiable anatomy that is clearly 
visible on orthogonal kV imaging including the tumor itself. In all cases, the relationship 
between the fiducial and the actual tumor position in real time should be reliably understood for 
both planning and treatment.
Isocenter Placement

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When using a gantry mounted linear accelerator for this protocol, the isocenter is defined as 
the common point of gantry, collimator, and couch rotation for the treatment unit. When 
treating multiple lesions, it is best to use multiple isocenters, each centered on a separate 
lesion,and to treat different targets on different days in order to decrease treatment time for a 
single day. For widely spaced lesions (over 10 cm apart), localization is improved when the 
isocenter is placed in the center of each target and image guidance is performed individually 
for each target. This is due to the limitation of most IGRT systems which ignore necessary 
rotational corrections when table shift coordinates are derived. The use of a single isocenter to 
treat multiple lesions in proximity (<10 cm) is permitted.
Composite Dose Calculations
Composite plans should be generated to incorporate the dose to surrounding normal tissues from 
each metastasis treated. The composite doses to critical normal tissues will be used to evaluate 
plan compliance. Composite planning refers to dose summation from multiple treatment sites on
a single CT scan that encompasses the relevant anatomy. Composite treatment planning is best 
accomplished by obtaining a planning CT dataset that incorporate all targets and relevant 
critical structures in the imaging study. If this is not possible due to restrictions on the size of 
the imaging study that can be managed by the treatment planning system, CT datasets should 
be divided into two parts and treatment fields should be adjusted so that dose spillage from the 
treatment of targets in one dataset to the next is minimal such that the dose contributions do not 
require summation. The two datasets should be obtained so that they have some amount of 
overlap that can be used to fuse the information using a rigid registration technique. The use of 
deformable registration to sum dose is not allowed. In general, it is best to perform CT 
scanning with the patient in the same position. This implies that, for example, all lesions 
planned on a gated CT scan must be treated with gating. 
4.2.2.3
Localization, Simulation, and Immobilization
Patient Positioning (Immobilization)
Patients will be positioned in a stable position capable of allowing accurate reproducibility of the 
target position throughout treatment. Positions uncomfortable for the patient should be avoided 
so as to prevent uncontrolled movement during treatments. Patient immobilization must be 
reliable enough to ensure that the gross tumor volume (GTV) does not deviate beyond the 
confines of the planning treatment volume (PTV). The degree of bladder fullness should be 
made to duplicate what is anticipated for daily treatment, i.e., if the patient is instructed to 
maintain a full bladder for treatment, he should be simulated as such. Primary tumor treatment 
with a full bladder is strongly recommended. The use of rectal balloons will be allowed but are 
not required in this protocol. The use of a rectal balloon will be documented for each patient for 
future analysis.

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Simulation
All patients will undergo CT-based treatment planning in custom made immobilization devices. 
CT scan range must allow simultaneous view of the patient anatomy and fiducial system for 
stereotactic targeting (if used) and be adequate to ensure contouring of all targeted lesions, as 
well as necessary organs at risk (OAR), defined below. High-resolution CT scans should be 
obtained with uniform slice thickness of ≤ 3mm throughout. If a single CT scan cannot be 
obtained due to a large spatial separation between metastases (i.e., cervical and femoral 
metastases), or planning system slice number limitation, multiple CT scans are allowed 
provided that OAR are entirely encompassed in a single CT scan.  CT imaging should be 
performed so that a composite dose distribution including all treated metastases can be created. 
Ideally all metastases will be treated in one treatment position.  When treating multiple 
metastases such as a lung and extremity, varying the treatment position may be necessary (i.e. 
simulation with arms up and arm to the side). Thus, more treatment positions can be used at the 
discretion of the treating oncologist, but every effort should be made to obtain a composite 
distributions.
The use of IV contrast is required for liver metastases. For other metastases (central & 
peripheral lung, cervical/mediastinal, abdominal-pelvic, and spinal/paraspinal), the use of IV 
contrast is encouraged but will be left to the discretion of the treating physician. The use of other 
contrast agents is left to the discretion of the treating oncologist. Vascular contrast from the 
planning dataset is recommended to be converted to water equivalent density if used for 
planning. Planning datasets without intravenous contrast may be used for dose calculation.
Magnetic Resonance Imaging (MRI)
MRI images are not required for primary tumor SBRT. However, they may be fused for 
assistance with target and/or normal tissue delineation. MRI images are required for spine SBRT. 
In patients with no contraindication to gadolinium, axial MRI T1-weighted post-gadolinium and 
T2-weighted sequences with ≤3 mm cuts, acquired from at least 1 vertebral body above to at 
least 1 vertebral body below the target lesion(s), are required. MRI T2-weighted sequences alone 
are permitted in patients with contraindications to gadolinium.
Respiratory Motion Assessment and Management
All metastases with potential for respiratory motion should be evaluated by appropriate 
means including 4D CT scan, implanted fiducial marker, or flouroscopy at the time of 
simulation.
Respiratory motion management (RMM) including abdominal compression, active breathing 
control, breath hold, end expiratory gating, or fiducial marker tracking, is recommended for any 
metastasis to be treated with motion > 1 cm. A recommended approach would be to use an ITV 
technique for motion < 1cm, but for motion > 1cm (typically too large for a free breathing ITV) 
motion management including but not limited to abdominal compression, active-breathing 
control (ABC), gating, breath hold, etc. should be used.
If a treatment for multiple metastases (i.e., lung and spine) is designed on a CT scan 
employing motion management (i.e., abdominal compression), all metastases should be treated 
with the chosen motion management technique in order to generate an accurate composite 
dose calculation.

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Localization Using Daily IGRT
As an SBRT protocol, this study requires the use of IGRT. IGRT is a computer-assisted 
process that uses imaging devices that generate a series of coordinates for shifting the 
patient support system in three orthogonal directions (sometimes including rotational 
changes) to position the treatment beams relative to target regions. Cone-beam CT 
(CBCT) using a kV imaging head is required for IGRT on this protocol. Use of a 
shortened CT planning scan for registration may be important for IGRT systems that 
cannot handle a large number of CT slices. A subset of the planning CT scan can be 
uploaded to the IGRT system for localization of each targeted lesion. The CT data 
should include the radiation target of interest plus at least 5cm superiorly and inferiorly.
Patient Preparation for Prostate SBRT
Patients will be advised to adhere to a low gas, low motility diet commencing one day prior to 
the treatment. Patients will undergo an enema 1-2 hours before simulation and each treatment. If 
undergoing treatment with a full bladder, patients will drink fluids immediately after the enema 
and refrain from voiding to achieve a comfortably full bladder.
Treatment Planning/Target Volumes
The definition of volumes will be in accordance with the ICRU Reports #50 and #62: 
Prescribing, Recording, and Reporting Photon Beam Therapy.
The Gross Tumor Volume (GTV) is defined by the physician as all known disease as defined by 
the planning CT and MR (when available) along with clinical information. The primary tumor 
GTV (GTVp) for the purposes of this protocol is the whole prostate, or in cases of seminal 
vesicle invasion the whole prostate and the whole involved seminal vesicle(s), and will also 
equal the primary tumor Clinical Target Volume (CTVp). The soft tissue oligometastases GTV 
(GTVstm) is defined as the gross tumor volume of all soft tissue prostate cancer metastases, 
including lymph nodes, and will also equal the soft tissue metastases Clinical Target Volume 
(CTVstm). The osseous metastases GTV (GTVom) is defined as the gross tumor volume of all 
osseous prostate cancer metastases and will also equal the osseous metastases Clinical Target 
Volume (CTVom) in all cases except spine metastases. CTVom delineation for spine metastases 
is sextant-based as specified by the International Spine Radiosurgery Consortium Consensus 
Guidelines (Cox et al, IJROBP 2012).
The Planning Target Volume (PTV) will provide amargin around the CTV to compensate for the 
variability of treatment set up and organ motion. Primary tumor PTV (PTVp) is defined as CTVp 
+3-5mm. Soft tissue oligometastases PTV (PTVstm) is defined as CTVstm +3-5mm. Osseous 
metastases PTV (PTVom) is defined as CTVom +0-2mm. Radiation therapy will be prescribed 
to the PTV using IMRT, prioritizing normal tissue limits.
4.2.2.4
Critical Structures
Contouring of Normal Tissue Structures
In order to verify each of these limits, the organs must be contoured such that appropriate 
volume histograms can be generated. Instructions for the contouring of these organs are as 
follows:

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Spinal Cord
The spinal cord will be contoured based on MRI T2-weighted sequences, ending at L2. The 
spinal cord should be contoured starting at least 10 cm above the superior extent of the PTV 
and continuing on every CT slice to at least 10 below the inferior extent of the PTV.
Cauda Equina
Starting at the conus (end of spinal cord, typically around L1 or L2) include the entire thecal sac 
into the sacrum
Sacral Plexus
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing 
of the nerves at the obturator internus muscle.
Esophagus
The esophagus will be contoured using mediastinal windowing on CT to correspond to 
the mucosal, submucosa, and all muscular layers out to the fatty adventitia. The 
esophagus should be contoured starting at least 10 cm above the superior extent of the 
PTV and continuing on every CT slice to at least 10 cm below the inferior extent of the 
PTV.
Brachial Plexus
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamine on the involved side from around C5 to T2. However, for the purposes of 
this protocol, only the major trunks of the brachial plexus will be contoured using the 
subclavian and axillary vessels as a surrogate for identifying the location of the brachial 
plexus. This neurovascular complex will be contoured starting proximally at the bifurcation 
of the brachiocephalic trunk into the jugular/subclavian veins (or carotid/subclavian 
arteries) and following along the route of the subclavian vein to the axillary vein ending 
after the neurovascular structures cross the second rib. If PTV of all metastases are more 
than 10 cm away from the brachial plexus, this structure need not be contoured.
Heart
The heart will be contoured along with the pericardial sac. The superior aspect (or base) 
for purposes of contouring will begin at the level of the inferior aspect of the aortic arch 
(aortopulmonary window) and extend inferiorly to the apex of the heart.
Trachea and Proximal Bronchial Tree
The trachea and proximal bronchial tree will be contoured as two separate structures using 
mediastinal windows on CT to correspond to the mucosal, submucosa and cartilage rings 
and airway channels associated with these structures. For this purpose, the trachea will be 
divided into two sections: the proximal trachea and the distal 2 cm of trachea. The 
proximal trachea will be contoured as one structure, and the distal 2 cm of trachea will be 
included in the structure identified as proximal bronchial tree.

Proximal Trachea
Contouring of the proximal trachea should begin at least 10 cm superior to the extent of 
the PTV for lung metastases or 5 cm superior to the carina (whichever is more superior) 
and continue inferiorly to the superior aspect of the proximal bronchial tree.

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
Proximal Bronchial Tree
The proximal bronchial tree will include the most inferior 2 cm of distal trachea and the 
proximal airways on both sides as indicated in Figure 6-1. The following airways will be 
included according to standard anatomic relationships: the distal 2 cm of trachea, the 
carina, the right and left mainstem bronchi, the right and left upper lobe bronchi, the 
intermedius bronchus, the right middle lobe bronchus, the lingular bronchus, and the right 
and left lower lobe bronchi. Contouring of the lobar bronchi will end immediately at the 
site of a segmental bifurcation. If there are parts of the proximal bronchial tree that are 
within GTV, they should be contoured separately, as “proximal bronchial tree GTV”, not 
as part of the “proximal bronchial tree”.
Whole Lung
Both the right and left lungs should be contoured as one structure. Contouring should be 
carried out using pulmonary windows. All inflated and collapsed lung should be 
contoured; however, gross tumor (GTV) and trachea/ipsilateral bronchus as defined 
above should not be included in this structure.
Proximal Bronchial Tree Plus 2 cm
As part of determining if lung metastases are central or peripheral, adhering to the eligibility 
the zone of the proximal bronchial tree, the SBRT protocols defined an artificial structure
2 cm larger in all directions from the proximal bronchial tree. If the GTV falls within this 
structure, the patient is eligible for this protocol. Most treatment planning systems have 
automatic contouring features that will generate this structure without prohibitive effort at 
the time of treatment planning. This structure is not required by the protocol, but its 
construction is suggested to facilitate appropriateness of patient selection. Alternately, 
participating sites may use ruler tools in the treatment planning software to ensure protocol 
compliance.
Skin
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of 
uniform thickness (0.5 cm) which envelopes the entire body in the axial planes. The 
cranial and caudal surface of the superior and inferior limits of the planning CT should not 
be contoured as skin unless skin is actually present in these locations (e.g., the scalp on the 
top of the head).
Great Vessels
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be contoured 
using mediastinal windowing on CT to correspond to the vascular wall and all muscular 
layers out to the fatty adventitia. The great vessel should be contoured starting at least 10 
cm above the superior extent of the PTV and continuing on every CT slice to at least 10 
cm below the inferior extent of the PTV. For right sided tumors, the vena cava will be 
contoured, and for left sided tumors, the aorta will be contoured.
Non-adjacent Wall of a Structure
For the esophagus, trachea and proximal bronchial tree, and great vessels, the nonadjacent 
wall corresponds to the half circumference of the tubular structure not immediately 
touching the GTV or PTV, These contours would start and stop superiorly and inferiorly 
just as with the named structure. The half lumen of the structure should be included in this 
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Stomach
The entire stomach and its contents should be contoured as a single structure as a continuation 
of the esophagus and ending at the first part of the duodenum.
Duodenum
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as one 
structure beginning where the stomach ends and finishing as the superior mesenteric artery 
crosses over the third part of the duodenum.
Bowel (Large/Small)
From the ileocecal area to include the ascending, transverse, descending and sigmoid colon as 
one structure.
Rectum
The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus.
Bladder
The whole bladder should be contoured from bladder neck to the dome.
Urethra
The urethra must be visualized and contoured during the treatment planning process.  The 
institutional standard procedure for this will be followed, which may consist of techniques 
including MRI fusion, urethrogram, or placement of a urinary catheter.
Kidney (renal cortex)
Both the right and left kidney, excluding renal pelvis/collecting system, should be contoured 
in their entirety (the renal cortex)
Liver
The entire liver minus the GTV targets.
Bile ducts
May use the portal vein from its juncture with the splenic vein to its right and left birfurcation in 
the liver as a surrogate to identify the bile ducts.
Femoral Heads
The ball of the head and socket joint.
Rib
Ribs within 5 cm of the PTV should be contoured by outlining the bone and marrow. 
Typically, several portions of adjacent ribs will be contoured as one structure. Adjacent ribs, 
however,
should not be contoured in a contiguous fashion (i.e., do not include the inter-costal space as part 
of the ribs).
Other Structures
The constraints tables below contain other structures. These are required if the structure is within
10 cm of the PTV.

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Critical Organ Dose-Volume Limits
This primary purpose of this study is to determine the safety of delivering SBRT to multiple 
targets within one treatment course. To that end composite dose distributions of organs at risk 
are critical to understand toxicity. Composite dose plans including all treated lesions and organs 
at risk must be submitted as well as individual SBRT plans to evaluate protocol compliance. To 
facilitate composite planning, dose to all targets should be calculated on a single CT scan 
simultaneously with in-plane resolution of at least 2 x 2 x 3mm. If this is not possible, composite 
plans should be generated incorporating the dose from each metastasis treated. The composite 
doses to critical normal tissues will be used to evaluate plan compliance.
Dose limits to a point or volume within several critical organs based on the dose fractionation 
schema (three or five fractions) are assigned based on target tumor location. If a given organ 
has > 1 Gy dose contribution from both the three and five fraction plans, then the three 
fraction dose constraints in the table below will be used.
Table 3: OAR Dose Limits for 3 fraction SBRT
Serial Organ
Volume
Volume Dose
(Gy)
Spinal Cord
<0.03 cc
22.5
<1.2 cc
13
Ipsilateral Brachial Plexus
< 0.03 cc
26
<3 cc
22
Cauda Equina
<0.03 cc
25.5
<5 cc
21.9
Sacral Plexus
<0.03 cc
24
<5 cc
22.5
Trachea and Ipsilateral
Bronchus*
<0.03 cc
30
<5cc
25.8
Esophagus*
<0.03 cc
27
<5cc
17.7
Heart/Pericardium
<0.03cc
30

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Serial Organ
Volume
Volume Dose
(Gy)
<15 cc
24
Great vessels*
<0.03cc
45
<10 cc
39
Skin
<0.03cc
33
<10cc
31
Stomach
<0.03cc
30
<10cc
22.5
Duodenum*
<0.03cc
24
<10cc
15
Bowel*
<0.03 cc
34.5
<20cc
24
Rectum*
<0.03 cc
49.5
<3.5 cc
45
< 20 cc
27.5
Bladder
0.03cc
33
<15 cc
16.8
Ureter
<0.03 cc
40
Penile bulb
< 3cc
25
Femoral heads
<10 cc
24
Bile duct
< 0.03 cc
36
Renal hilum/vascular trunk
<15 cc
19.5
Rib
< 0.03 cc
50
<5 cc
40

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Parallel Organ
Volume
Volume Dose
(Gy)
Lung (total)
<15% lung
volume
20
< 37% lung 
volume
11
1500 cc
10.5
1000 cc
11.4
Ipsilateral kidney
<130 cc
12.3
Total Kidney
<200cc
15
Liver
<700 cc
17.1
*NOTE: Avoid circumferential irradiation.
Table 4: OAR Dose Limits for 5 fraction SBRT
Serial Organ
Volume
Volume Dose (Gy)
Spinal Cord
<0.03 cc
28
<0.35 cc
22
<1.2 cc
15.6
Ipsilateral Brachial Plexus
< 0.03 cc
32
<3 cc
30
Cauda Equina
<0.03 cc
32
<5 cc
30
Sacral Plexus
<0.03 cc
32
<5 cc
30
Trachea and Ipsilateral Bronchus*
<0.03cc
40
<5cc
32
Esophagus*
<0.03cc
35
<5 cc
27.5
Heart/Pericardium
<0.03 cc
38

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Serial Organ
Volume
Volume Dose (Gy)
<15 cc
32
Great vessels*
<0.03 cc
53
<10 cc
47
Skin
< 0.03cc
38.5
< 10cc
36.5
Stomach
< 0.5cc
35
< 5cc
26.5
Duodenum*
< 0.5 cc
30
< 5 cc
18.3
Bowel*
< 0.03 cc
40
<20 cc
28.5
Rectum*
<0.03 cc
37.45
<3cc
34.4
D10%
32.63
D20%
29
D50%
18.13
Bladder
< 0.03
37.45
D10%
18.12
Urethra
<0.03cc
37.45
Ureter
< 0.03 cc
45
Penile Bulb
<0.03 cc
35
<3cc
19.25
Femoral head
<10 cc
19.25
1cc
15
Bile Duct
<0.03 cc
41

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Serial Organ
Volume
Volume Dose (Gy)
Renal hilum/Vascular Trunk
<15 cc
23
Rib
<0.03 cc
57
<5 cc
45
Parallel Organ
Volume
Volume Dose (Gy)
Lung (total)
< 37% lung
volume
13.5
< 1500 cc
12.5
< 1000 cc
13.5
Total Kidney
< 200cc
18
Liver
<700 cc
21
*NOTE: Avoid circumferential irradiation.
Rib/Chest wall Dose Constraints
Recent reports have highlighted that the rib and chest wall in proximity to the treated lesion may 
represent an organ at risk for complication. Tumor location, particularly when located 
peripherally, will enhance the potential risk for chest wall toxicity. While target coverage should 
not be compromised to limit dose to the rib/chest wall, every effort should be made to minimize 
dose to this OAR.
4.2.2.5
Organ at Risk Dosimetry Compliance
Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose constraints. Any dose 
to spinal cord, cauda equina, sacral plexus above that is listed in  Table 3 and Table 4 will be 
considered an unacceptable deviation. For all other OAR, when OAR dose criteria provided 
above cannot be accomplished by following planning priorities outlined above, doses to serial 
OAR of more than 105% of the dose prescribed to the PTV will be scored as unacceptable 
deviations. Doses to parallel OAR exceeding 110% of the dose prescribed to the PTV will be 
scored as unacceptable deviations
4.2.2.6
Radiation Therapy Adverse Events
All Radiation Therapy AEs will be scored according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0

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Primary Prostate Tumor:
Clinical discretion may be exercised to treat side effects from radiation therapy. Examples of 
typical medications used in the management of rectal side effects, such as diarrhea, include 
diphenoxylate or loperamide. Bladder or rectal spasms are usually treated with anticholinergic 
agents. Bladder irritation may be managed with phenazopyridine. Erectile dysfunction is often 
treated with medical management or mechanical devices. Proctitis may be treated per standard of 
care, e.g. steroid foam.
Metastases:
Adverse events related to SBRT for the treatment of metastases are dependent on the location of 
the metastases treated as well as from exposure of surrounding normal tissues.
For all treated metastases, fatigue is likely to occur and should be transient lasting < 8 weeks. 
Other adverse events are likely to be related to the specific metastatic location receiving 
SBRT:
Lung (Central and Peripheral), Mediastinal/Cervical Lymph Node Metastases
Cardiac and Pericardial Injury
Although cardiac and pericardial injury is uncommon in the conventionally fractionated course of 
RT, with large doses per fraction of SBRT a number of possible side-effects can be seen.
Gastrointestinal/Esophageal Injury
The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, causing pain 
on swallowing, typically relatively soon after RT course is completed, and typically resolves on 
its own within days to a week or longer), or chronic, typically manifesting with dysphagia due 
to stenosis, or esophageal ulceration, with perforation in the extreme cases.
Central Airway/Bronchial Injury
This bronchial injury with subsequent focal collapse of lung may impair overall pulmonary 
status. It also makes further assessment of tumor response more difficult as the collapsed lung 
approximates the treated tumor. Because atelectatic lung and tumor have similar imaging 
characteristics, radiology reports will often describe the overall process as progressive disease 
while the actual tumor may be stable or shrinking.
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of 
pulmonary function test parameters, pleural effusion or pleuritic pain (associated with 
collapse), should all be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE), v5.0.
Lung Injury
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the end 
bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation injury to the 
irradiated lung. Given the small amount of lung that is typically included in the SBRT portals, 
lung toxicity has not been as dose-limiting as in conventionally fractionated large field RT, but 
it is nevertheless seen, can be symptomatic, and may be confused with other causes of 
respiratory deterioration, including infections, and tumor recurrence.

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Given that larger volumes of lung may be irradiated in this protocol compared to SBRT for 
primary tumors, it is very important that a Radiation Oncologist participate in the care of the 
patient, as the clinical picture may be very similar to acute bacterial pneumonia, with fatigue, 
fever, shortness of breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. The 
infiltrate on chest x-ray should include the area treated to high dose, but may extend outside of 
these regions. The infiltrates may be characteristically “geometric” corresponding to the 
radiation portal, but may also be ill defined.
Patients reporting symptoms as above will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. 
More significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet. Supra- and concurrent infections should be treated with antibiotics. 
Consideration of prophylaxis of opportunistic infections should be considered in 
immunocompromised patients.
Liver/abdominal-pelvic metastases
Very likely (80-90%): Fatigue (which generally goes away after the radiation therapy is 
completed); skin irritation, redness, itchiness, discomfort; temporary changes in blood 
work (decrease in blood counts, increase in liver enzymes), without symptoms
Less likely (30%): Nausea, vomiting (during therapy) – more common if stomach or 
gastrointestinal track irradiated; gastric, esophagus, small bowel or large bowel 
irritation/ulceration, bleeding, fistula, obstruction or changes in motility following therapy (may 
require medications or surgery) (<10% permanent changes); chest wall pain, rib fracture (< 
10%)
Less likely, but serious (<20%): Radiation-induced liver disease (RILD) (<5%). Classic RILD 
is a clinical diagnosis of anicteric ascites, hepatomegaly and elevation of alkaline phosphatase 
relative to other transaminases that may occur 2 weeks to 3 months following radiation to the 
Liver; non-classic RILD includes elevation of liver enzymes and/or any decline in liver 
function within 12 weeks from start of therapy (~20%). RILD can lead to liver failure that 
could lead to death. There is an increased risk of liver toxicity in patients with large tumors and 
in patients with pre-existing liver disease; permanent thrombocytopenia (<1%); this may lead to 
bleeding; kidney injury (<1%); this may lead to changes on imaging and more rarely the need 
for medication.
Spinal metastases
Radiation Myelitis
Given the proximity and position of spinal cord in relation to the radiosurgery target, every 
effort should be made to minimize the radiation dose to the spinal cord. Radiation myelitis is a 
subacute or chronic clinical syndrome after radiation. The symptoms may include 
paresthesia,sensory changes, and motor weakness including paralysis. There is no active 
treatment for radiation myelitis; therefore, it is important to prevent any injury to the spinal cord. 
Corticosteroids are used when clinical symptoms develop.
Radiation Esophagitis

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Patients with thoracic spine treatment will likely develop esophageal mucositis within the first 
2 weeks. These symptoms subside with time; however, adequate symptomatic treatment 
including hydration is advised. There are no long-term adverse events reported with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the normal 
esophagus. The consequences of esophageal toxicity, e.g., swallowing difficulty, dysphagia, 
cough, dehydration, and fistula, should be documented.
Radiation Laryngitis or Pharyngitis
Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis within 
the first 2 weeks. These symptoms subside with time; however, adequate symptomatic 
treatment including hydration is advised. No long-term laryngopharyngeal toxicity has been 
reported with spine radiosurgery. However, it is prudent to minimize the radiation spillage in 
the normal larynx and pharynx. The consequences of toxicity, e.g., swallowing difficulty, 
dysphagia, cough, dysphonia dehydration, and fistula, should be documented.
Tracheal Injury
Although no cases of tracheal injury have been reported with spine radiosurgery, it is prudent to 
minimize the radiation spillage in the normal trachea. The consequences of tracheobronchial 
toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, 
pleural effusion or pleuritic pain (associated with collapse), should be documented.
Radiation Pneumonitis
There have been no reported cases of symptomatic radiation pneumonitis with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the lung tissue. It is 
strongly recommended to use radiation beams directed from posterior to avoid passage of 
radiation through the lungs. Patients with symptoms of pneumonitis will be promptly 
evaluated and treated. Mild radiation pneumonitis may be treated with non-steroidal anti-
inflammatory agents or steroid inhalers. More significant pneumonitis will be treated with 
systemic steroids, bronchodilators, and pulmonary toilet. Supra- and concurrent infections 
should be treated with antibiotics. Consideration of prophylaxis of opportunistic infections 
should be considered in immunocompromised patients.
Compression Fracture of Treated Vertebra
Radiation doses in excess of 19 Gy for a single fraction are associated with higher rates of 
vertebral body compression (Saghal 2013).
In this protocol, doses per fraction this high are not used, so that the estimated rate of vertebral 
body compression fracture following spinal metastases treatment should be approximately 
10%.
Other Adverse Events
Short-term or long-term injury to the kidney or upper airway has not been reported. If other 
severe adverse events occur, details should be documented.
Osseous
Erythema, desquamation and alopecia are common side effects from radiation therapy for 
osseous metastases; other effects are determinate on location of metastasis, and may include pain, 
edema and neuralgia.

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4.2.3
Drug Accountability
The Investigational Pharmacist will manage drug accountability records.
4.2.4
Drug Ordering
UCSF will obtain SD-101 directly from TriSalus Life Sciencesas study supply.
UCSF will obtain pembrolizumab directly from Merck Sharp & Dohme Corporation as study 
supply.
4.2.5
Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws.
4.2.6
Dose Selection/Modification
4.2.6.1
Dose Selection
The rationale for selection of doses for pembrolizumab and SD-101 to be used in this trial is 
provided in Section 3.2.2.
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.  
4.2.6.2
Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab and combination therapy
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of pembrolizumab/ 
combination treatment and may affect more than one 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/combination treatment, 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. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab/combination treatment are provided in Table 5.

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Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event to the combination,  to SD-101 intraprostatic injection alone or to pembrolizumab 
alone, for adverse events listed in Table 5, both interventions must be held according to the 
criteria in Table 5.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 5.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined in Table 5, the 
combination of [SD-101 intraprostatic injection and pembrolizumab] may be restarted at the 
discretion of the investigator. In these cases where the toxicity is attributed to [the combination 
or to SD-101 intraprostatic injection alone], re-initiation of pembrolizumab as a monotherapy 
may be considered at the principal investigator’s discretion .

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Table 5: Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab 
Monotherapy and IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
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 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
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 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 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)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Administer antihyperglycemic in 
participants with hyperglycemia
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Suspected SJS, 
TEN, or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 
10.0 x baseline if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs.

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4.2.6.3
Dose Modification – SD-101
Adverse events (both non-serious and serious) associated with SD-101 exposure may represent 
an immunologic etiology.  These adverse events may occur shortly after the first dose or several 
months after the last dose of treatment.
SD-101 must be withheld for drug-related toxicities and severe or life-threatening AEs as per 
Table 6 below.
Table 6: Toxicity Management Guidelines for AEs Associated with SD-101
Adverse event
Management
Dysuria
Check urinalysis and urine culture to rule out urinary tract infection (UTI). 
Treat UTI with appropriate antibiotics if work-up returns positive. Treat 
dysuria symptomatically (e.g., Pyridium). If symptoms do not improve or 
resolve, consider holding further SD-101 therapy or reducing the dose of 
SD-101 by 50%.
Urinary 
urgency
Grade 1: Monitor closely for clinical worsening.
Grade 2: Withhold subsequent SD-101 therapies until urinary urgency has 
resolved to Grade <2. If urgency is grade 1 at time of second SD-101, then 
SD-101 should be administered at 50% dose. 
Hematuria
Grade 1: Monitor closely for clinical worsening. Consider lowering the 
dose of subsequent SD-101 therapies.
Grade 2: Withhold further SD-101 therapies. Treat symptoms as clinically 
indicated (e.g. urinary catheter, bladder irrigation indicated). Do not restart 
SD-101 until hematuria has resolved to Grade ≤1. Treating physicians 
should discuss with the Medical Monitor prior to any additional SD-101 
therapies. If SD-101 is restarted, lower the dose by 50%. 
Grade 3 or 4: Withhold further SD-101 therapies. Treat symptoms as 
clinically indicated (e.g. transfusion, IV medications, hospitalization, 
elective endoscopic, radiologic or operative interventions). SD-101 therapy 
should not resume until hematuria has resolved to Grade ≤1. Treating 
physicians should discuss with the Medical Monitor prior to any additional 
SD-101 therapies. If SD-101 is restarted, lower the dose by 50%. 
Urinary 
obstruction
Grade 1: Monitor closely for clinical worsening. Consider lowering the 
dose of subsequent SD-101 therapies. The treating physician has the 
discretion to place Foley catheter for remaining localized therapies as 
clinically indicated. 
Grade 2: Withhold further SD-101 therapies. Treat symptoms as clinically 
indicated (e.g. urethral dilation, urinary or suprapubic catheter). Do not 
restart SD-101 until urinary obstruction has resolved to Grade≤1. Treating 

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Adverse event
Management
physicians should discuss with the Medical Monitor prior to any additional 
SD-101 therapies. If SD-101 is restarted, lower the dose by 50%. 
Grade 3 or 4: Withhold further SD-101 therapies. Treat symptoms as 
clinically indicated (e.g. elective radiologic, endoscopic or operative 
intervention). SD-101 therapy should not resume until urinary obstruction 
has resolved to Grade ≤1. Treating physicians should discuss with the 
Medical Monitor prior to any additional SD-101 therapies. If SD-101 is 
restarted, lower the dose by 50%.
Also, the following dose modification guidelines for SD-101 should be followed:
a.
Permanently discontinue SD-101 for treatment-related Grade 4 adverse events of any 
duration.  
b. Hold SD-101 for related Grade 3 adverse events with subsequent dose-reduction of SD-101 
to 50% if adverse events return to Grade ≤1 or baseline within two weeks upon restarting 
SD-101. 
c.
Dose-reduce or discontinue SD-101 before or concurrently with other treatment regimens 
such as pembrolizumab, leuprolide, and/or abiraterone if such adverse event(s) is at least 
possibly related to SD-101.
4.2.6.4
Dose Modification – SBRT
No dose modifications for SBRT are allowed.
4.2.7
Timing of Dose Administration 
4.2.7.1
Pembrolizumab  
Pembrolizumab should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 5.0). Trial treatment may be 
administered up to 7 days after the scheduled Day 1 of each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.

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4.2.7.2
SD-101
SD-101 should be delivered intratumorally to the dominant prostatic lesion at a dose of 5 mg per 
treatment during placement of fiducial marker (1-5 weeks prior to C1D1), and 1-3 weeks after 
C1D1. SD-101 injection will be administered under ultrasound guidance. Intratumoral injection 
of 5 mg SD-101 will be performed by the participating radiation oncologist and/or urologist. The 
second SD-101 injection and prostate core biopsies should be done conjointly, preferably 1-2 
weeks after the completion of SBRT to the prostate. For participants in cohort 2, it is permitted 
to complete the second SD-101 injection and prostate core biopsies while receiving SBRT to 
oligometastatic sites.
The second SD-101 injection may be delayed up to an additional 14 days for treatment-related 
toxicity or other reasons per investigator’s discretion. Consequently, the prostate core biopsy 
may be delayed to allow for conjoint occurrence with the SD-101 injection.
All trial treatments will be administered on an outpatient basis with the option of inpatient 
admission per physician’s discretion.
4.2.8
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
4.3
Randomization or Treatment Allocation
Assignment into Cohort 1 (SBRT to prostate) and Cohort 2 (SBRT to prostate and 
oligometastatic sites) will be determined based on the participant’s planned standard of care.
For both cohorts, eligible patients will be randomized 1:1 into Arm 1 consisting of 
pembrolizumab and RT with intermittent ADT and Arm 2 consisting of pembrolizumab and RT 
as well as SD-101 with intermittent ADT.
4.4
Stratification
There will be no patient stratification.
4.5
Concomitant Medications/Vaccinations (allowed & prohibited)
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 investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.

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4.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’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 as 
defined in Section 6.2.2.
4.5.2
Prohibited Concomitant Medications
Subjects 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

Investigational agents other than pembrolizumab and SD-101

Radiation therapy not specified in this protocol

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 

Systemic glucocorticoids for any purpose other than to ameliorate side effects of the  
abiraterone, or to modulate symptoms from an event of clinical interest of suspected 
immunologic etiology.  The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.

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4.6
Rescue Medications & Supportive Care
4.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined in greater detail in the Pembrolizumab 
Investigator’s Brochure. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the Pembrolizumab ECI Guidance Document v. 3.0).
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the Pembrolizumab ECI Guidance Document v. 3.0, located in Appendix 7.
4.7
Diet/Activity/Other Considerations
4.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
4.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
Subjects should agree to use an adequate method of contraception starting prior to the first dose 
of study therapy through 120 days after the last dose of study therapy, and their partners should 
be encouraged to use adequate method of contraception as well. The following are considered 
adequate barrier methods of contraception: condom, spermicide (by the partner), diaphragm (by 
the partner), copper intrauterine device (by the partner), sponge (by the partner), or spermicide.  
Appropriate hormonal contraceptives (for the partner) will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study by the subject’s partner.  In 
order to participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period defined in section 6.2.6.2. If 
there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study.

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4.7.3
Use in Pregnancy
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor 
 as described here and in 
Section 6.2.6.2. The site will contact the subject at least monthly and document the subject’s 
partner’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the Sponsor 
 without delay and within 24 hours to the 
Sponsor and within 2 working days 
 if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).
4.8
Replacement Policy
All patients who receive any study therapy will be analyzed for safety and efficacy. Subjects who 
discontinue from study participation prior to receiving any study therapy may be replaced after 
discussion with the Sponsor-Investigator. Subjects who have received any dose of study therapy 
will not be replaced. Patients removed from study for unacceptable pembrolizumab or SD-101 
related adverse event(s) will be followed until resolution or stabilization of all treatment related 
AEs to Grade 2 or lower. However, they will not be replaced.
If the treating physician determines that prostate or oligometastatic-directed SBRT can no longer 
be performed for any reason (e.g., safety concerns), then the participant may continue their 
participation in their assigned cohort/arm without undergoing prostate or oligometastatic-
directed SBRT. Data collected from these participants will be included in the data analysis for 
their assigned cohort (see section 7.2); they will not be replaced.
4.9
Safety Lead-In
The first 3 patients enrolled into each arm in cohort 1 will be treated and followed for 6 weeks in 
each arm following initiation of therapy prior to full enrollment onto each arm. If none of the 3 
patients experience a DLT, accrual will continue until a total of 21 patients are accrued in each 
arm.  A DLT will be defined as any unacceptable treatment-related toxicity including any Grade 
4 toxicity, any recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 4 weeks.  
If at most 1 patient experiences a DLT, 3 additional patients will be accrued; if at most 1 patient 
experience a DLT, accrual to the respective study arm will continue.  If more than 1 patient from 
either the initial 3-patient safety cohort or subsequent 3-patient safety cohort experiences a DLT, 
treatment will be halted and the study re-evaluated before continued accrual to the specific arm. 
In Arm 2, if DLT is attributed to SD-101, the dose of SD-101 will be decreased to 1mg for 
subsequent enrollment. If the 1 mg dose of SD-101 in combination with radiation therapy and 
pembrolizumab is not tolerated, the study will be halted and the study re-evaluated before further 
accrual.
A DLT will be deemed as follows:
a.
Any and all adverse events at least possibly related to pembrolizumab, SD-101, 
and/or radiation shall be included in DLT evaluation
b. Most Grade >3 AE excluding electrolytes abnormalities with no clinical adverse 
experiences should be deemed a DLT, except: 

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i.
Grade 3 nausea, vomiting, or diarrhea and grade 4 vomiting or diarrhea in the 
absence of maximal medical therapy that resolves in 72 hrs
ii.
Grade 3 fatigue lasting <5 d
iii.
Grade 3 HTN that can be controlled with medical therapy
c.
AE of episcleritis, uveitis, or iritis of Grade 2 or higher of any duration is a DLT
d. Any toxicity preventing subjects from receiving 75% of abiraterone or 2 doses of 
pembrolizumab, SD-101, or SBRT during the DLT evaluation period is a DLT.  
e.
Any toxicity causing greater than 2 weeks of dose delay is a DLT
NOTE: The safety-lead in component reached completion on 11/19/2018 and 04/05/2019 for 
arms 1 and 2, respectively.
4.10 Interim Analyses and Stopping Rules
A stopping rule for safety will halt accrual to the study and prompt reevaluation of the treatment 
(e.g. dose, site of intratumoral therapy) if unacceptable treatment-related toxicity (defined as any 
Grade 4 toxicity, any recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 4 
weeks) is observed at a frequency of >33%. Because of the known excellent safety profile of 
pembrolizumab, this safety review will occur after 6 patients have been accrued to each arm in 
cohort 2. Should unacceptable treatment-related toxicity be observed at a frequency of 33% or 
greater at any time point attributed to SD-101 in Arm 2, SD-101 dose will be lowered to 2mg for 
subsequent enrollment.
4.11 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.

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5.0 TRIAL FLOW CHART
5.1
Study Flow Chart
Screening
Cycle 1 
(21-Day)
Cycles 2 
to 13 
(21-Day)
Treatment 
Discontinuation
Follow-Up
Assessment Window 
(Days)
D -42a
D1b
Day 1  4 
Days
 30 Days After 
Last Dose of 
Pembrolizumabc
Every 12 wks 
(+/- 2 wks)
Informed consent
x
Informed consent for 
future biomedical 
research
x
Review of eligibility 
criteria
x
Baseline conditions
x
Medical, surgical, and 
cancer histories, 
including demographic 
information
x
Baseline medications 
(taken within 28 days of 
Day 1)
x
Concomitant 
medications
x
x
x
x
Evaluation of clinical 
symptoms or 
deterioration
x
x
x
Review adverse eventsd
x
x
x
x
Prostate tumor tissue 
acquisition or 
15 unstained slidese
x
Metastatic tumor tissue
biopsyf
x
At time of 
progression
Prostate core biopsiesg
At time of 
SBRT 
marker 
placement
1-3 weeks 
after 
C1D1
Treatment administration
Androgen deprivation 
therapy (ADT)h
3 months 
prior to 
C1D1
GnRH targeting agent 
(leuprolide preferred) + 
abiraterone + 
prednisone (or 
equivalent) for 9 
months starting on 

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Screening
Cycle 1 
(21-Day)
Cycles 2 
to 13 
(21-Day)
Treatment 
Discontinuation
Follow-Up
Assessment Window 
(Days)
D -42a
D1b
Day 1  4 
Days
 30 Days After 
Last Dose of 
Pembrolizumabc
Every 12 wks 
(+/- 2 wks)
C1D1
Pembrolizumab (200 
mg)i
x
x
SBRT marker 
placement
1-5 weeks 
prior to 
C1D1
SBRT simulation
1-5 weeks 
prior to 
C1D1
Radiotherapy (SBRT)j
x
Localized therapy with 
SD101 (Arm 2 only)k
At time of 
SBRT 
marker 
placement
1-3 weeks 
after 
C1D1
Clinical procedures
Physical examination
x
x
x
x
x
Performance status 
(ECOG)
x
x
x
x
x
Vital signs including 
Weightl
x
x
x
x
x
Disease/tumor 
assessmentm
x
xw,x,y
xw,x,y
xw,x,y
Survival and anti-cancer 
therapy follow-upn
x
Laboratory procedures
Hematologyo
x
x
x
x
x
Serum chemistryp
x
x
x
x
x
Coagulation panel (PT, 
aPTT, INR)
x
x
Urinalysisq
x
x
x
TSH, free T3, free T4r
x
x
x
x
HIV, HBV, and HCV 
serologys
x
PSA, testosterone
x
x
xt
xt
xt
Immune monitoringu
x
x
x
x
x

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Screening
Cycle 1 
(21-Day)
Cycles 2 
to 13 
(21-Day)
Treatment 
Discontinuation
Follow-Up
Assessment Window 
(Days)
D -42a
D1b
Day 1  4 
Days
 30 Days After 
Last Dose of 
Pembrolizumabc
Every 12 wks 
(+/- 2 wks)
Imaging procedure
ECGv
x
Bone imagingw
x
x
x
x
Abdominal, pelvis, and 
chest imagingx
x
x
x
x
PSMA PET Image 
Collectiony
x
x
anti-HBc  hepatitis B core antigen; HBV  hepatitis B virus, HCV  hepatitis C virus; HIV = human 
immunodeficiency virus; ECG = electrocardiogram; TSH  thyroid-stimulating hormone; PSA = prostate 
specific antigen
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion 
unless otherwise noted.
a. Examinations performed as standard of care prior to obtaining informed consent and within 28 days of fiducial 
marker placement and SBRT simulation may be used rather than repeating tests, and within 60 days of C1D1 for 
radiographic imaging. For patients who have started on ADT, they must have had imaging prior to initiating 
hormonal therapy.
b. Perform procedures on cycle 1 day 1 of pembrolizumab unless indicated otherwise.
c. All patients will return within 30 days for a follow up visit, including those who discontinue study therapy early.
d. After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused 
by a protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be 
reported until 30 days after the last dose of study treatment.  After this period, investigators should report any 
deaths, serious adverse events, or other adverse events of concern that are believed to be related to prior 
treatment with study drug.  The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be 
related to study drug or trial-related procedures until a final outcome can be reported.
e. Prostate tumor tissue from archival TRUS prostate biopsy must be submitted, if available, in the form of 
representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at 
least 15 slides, with an associated pathology report. If archival prostate tissue are unavailable or cannot be 
obtained, a repeat TRUS prostate biopsy is not required. Sample collection, storage and transportation 
instructions for samples to UCSF Cancer Immunotherapy Laboratory will be provided in the Laboratory Manual.
f. Patients will undergo an optional metastatic tumor biopsy, if clinically feasible and safe to perform. Biopsy must 
be collected prior to SD-101 injection and after initiating ADT. Acceptable samples include core needle biopsies 
of bone or lymph node. At least three cores should be obtained. A fine needle aspirate is not acceptable. Repeat 
biopsy at time of progression is optional. Sample collection, storage and transportation instructions for samples 
to UCSF Cancer Immunotherapy Laboratory will be provided in the Laboratory Manual.
g. Mandatory prostatic core biopsies will be obtained 1-5 weeks prior to C1D1 (conjointly with fiducial placement 
[Arm 1] or with fiducial placement and SD-101 therapy [Arm 2]) and 1-3 weeks after C1D1 (conjointly with the 
2nd SD-101 injection for Arm 2). Sample collection, storage and transportation instructions for samples to UCSF 
Cancer Immunotherapy Laboratory will be provided in the Laboratory Manual.

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h. Patients will receive 9 months of GnRH targeting agent, abiraterone, and prednisone (or equivalent) on study 
starting on Cycle 1 Day 1. Patients are required to receive 9 months of abiraterone (e.g., Zytiga, Yonsa) daily, 
prednisone (or equivalent) daily and 9 months of GnRH agonist or antagonist that is FDA approved for prostate 
cancer. Leuprolide 22.5 mg IM every 3 months for 3 doses is preferred, starting on Cycle 1 Day 1. Patients who 
have received less than 2 months of ADT prior to study enrollment are eligible for this study (See Sections 
3.2.2.4 and 4.1). Patients who were on a GnRH agent other than leuprolide may continue the original agent for a 
duration of 9 months starting on Cycle 1 Day 1. Patients who were on an antiandrogen other than abiraterone 
prior to study enrollment must switch to abiraterone for 9 months starting on Cycle 1 Day 1.
i.
The study treatment pembrolizumab will be delivered IV at dose of 200 mg for a total of 13 cycles or until 
disease progression, investigator’s decision to discontinue treatment, or withdrawal of patient consent. Subjects 
will start pembrolizumab (C1D1) 1 month after ADT initiation at the earliest, and 4 months after ADT initiation 
at the latest.
j.
Radiotherapy will begin 1-5 weeks after SBRT marker placement, over 10-21 days. Radiotherapy to the whole 
prostate and soft tissue metastases will be delivered via SBRT at a dose of 7 Gy x 5 fractions (35 Gy total). 
Radiotherapy to osseous metastases will be delivered via SBRT at a dose of 10 Gy x3 fractions (30 Gy total). 
Subjects will start SBRT 1 month after ADT initiation at the earliest, and 4 months after ADT initiation at the 
latest.
k. For Arm 2 only, SD-101 will be delivered to the dominant prostatic lesion at a dose of 5 mg per treatment at the 
time of SBRT marker placement (1-5 weeks prior to C1D1). A second SD-101 injection will be administered 1-3 
weeks after C1D1. See section 4.2.7.2 for details regarding the timing of the SD-101 injections.
l.
Vital signs include heart rate, respiratory rate, blood pressures, temperature, weight, and oxygen saturation. 
Patient should be weighed at the beginning of each cycle. Height should be recorded once during screening or 
prior to cycle 1 day 1. For first infusion of pembrolizumab, the patient’s vital signs should be determined within 
60 minutes before, during (every 15 [ 5] minutes), and 30 ( 10) minutes after the infusion.  For subsequent 
infusions, vital signs will be collected within 60 minutes before infusion and at the end of the infusion.  Patients 
will be informed about the possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms.
m. All measurable and evaluable lesions should be assessed and documented at the screening visit.  The same 
radiographic procedure should be used throughout the study for each patient. Available results must be reviewed 
by the investigator before dosing at the next cycle.  
n. Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 12 weeks (3 months) until death, loss to follow-up, withdrawal of consent, or study 
termination by Sponsor, whichever occurs first.  All patients will be followed for survival and new anti-cancer 
therapy information unless the patient requests to be withdrawn from follow-up; this request must be 
documented in the source documents and signed by the investigator.  If the patient withdraws from study 
treatment but not from follow-up, the study staff may use a public information source (e.g., county records) to 
obtain information about survival status only. Patients will be followed for up to 3 years (years one and two are 
mandatory; year three is optional).
o. Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated 
differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count.  
A manual differential can be done if clinically indicated.  
p. Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, total protein, albumin and LDH.
q. Specific gravity, pH, glucose, protein, ketones, and hemoglobin.
r. Thyroid function tests, specifically thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free 
triiodothyronine (FT3) will be tested during screening, then every 3 cycles after completion of cycle 4 (within 10 
days of starting cycle 5, 8 and 11), at treatment discontinuation, and every 12 weeks during follow-up. Further 
work-up may be needed as clinically indicated.

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s. HIV testing to be performed in accordance with national and/or institutional guidelines.  Hepatitis B surface 
antigen, anti-HBc antibody and anti-HBs antibody should be collected during screening.  In patients who have 
positive serology for the anti-HBc antibody, HBV DNA should be collected prior to Cycle 1, Day 1.
t.
PSA and testosterone levels will be checked every other cycle (at cycle 1, 3, 5, 7, 9 11, 13), at treatment 
discontinuation and at follow-up.
u. Sample collection, storage and transportation instructions for samples to UCSF Cancer Immunotherapy 
Laboratory will be provided in the Laboratory Manual. Screening sample will be collected within 28 days of 
fiducial placement and/or first SD-101 injection.
v. ECG recordings will be obtained during screening and as clinically indicated at other time points. Patients should 
be resting and in a supine position prior to ECG collection.
w. Bone imaging (Technetium, bone scan or Sodium-fluoride PET/CT required at screening) will be obtained every 
3 cycles after completion of Cycle 4 (within 10 days of starting Cycle 5, 8 and 11), at treatment discontinuation, 
and every 12 weeks during follow-up in years 1 and 2.  In year 3, bone imaging will be obtained if clinically 
indicated as determined by the treatment physician. If possible, the same scan that was used at baseline should be 
used for restaging. If both modalities were used at baseline, then the study that demonstrated the highest disease 
burden should be preferred. Results and disease/tumor assessment will be reviewed by the investigator before 
proceeding to the next cycle.
x. CT chest, abdomen, pelvis (or MRI when clinically indicated) with contrast will be obtained every 3 cycles after 
completion of Cycle 4 (within 10 days of starting Cycle 5, 8 and 11), at treatment discontinuation, and every 12 
weeks during follow-up in years 1 and 2.  In year 3,  imaging will be obtained if clinically indicated as 
determined by the treatment physician.  Results and disease/tumor assessment via RECIST v1.1 will be reviewed 
by the investigator before proceeding to the next cycle.
y. PSMA PET images will be collected for those patients who undergo PSMA PET as part of a separate study. If 
available, imaging performed within 6 months of C1D1 and at progression will be obtained. PSMA PET scan is 
not required as part of this study.

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6.0 TRIAL PROCEDURES
6.1
Trial Procedures
The Trial Flow Chart (Section 5.0) summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Screening assessments must be performed within 28 days prior to fiducial marker placement 
(unless otherwise noted).  Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator. All on-study visit procedures are allowed a window of ± 3 days 
unless otherwise noted.  Treatment or visit delays for public holidays or weather conditions do 
not constitute a protocol violation.
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 patients who are consented 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.
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor 
 
for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
6.1.1
Administrative Procedures
6.1.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’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 subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 

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subject’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 subject’s dated signature or by the subject’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 requirements, applicable laws and regulations and 
Sponsor requirements.
6.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
6.1.1.3
Medical History
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 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
6.1.1.4
Prior and Concomitant Medications Review
6.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication. 
6.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 6.2.
6.1.1.5
Disease Details and Treatments
6.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.

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6.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries.
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up. 
6.1.1.6
Assignment of Screening Number
All patients in the screening phase will be assigned a unique screening number for screening log 
that will be filed on OnCore.
6.1.2
Clinical Procedures/Assessments
6.1.2.1
Screening Assessment 
The Screening procedures and assessments must be completed within 28 days of SBRT marker 
placement unless otherwise noted. 

Physical examination

Vital signs including weight

Complete medical history and demographic information

Baseline conditions assessment

Disease/tumor assessment

ECOG performance status 

Baseline medications taken within 28 days of Day 1

Complete blood count (CBC) with differential and platelet count. A manual differential 
can be done if clinically indicated.

Blood chemistry assessment, including sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen (BUN), creatinine, fasting glucose, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, albumin and LDH

Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)

Urinalysis

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4), free 
triiodothyronine (FT3)

HIV testing in accordance with national and/or institutional guidelines 

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
Hepatitis B surface antigen, anti-HBc antibody and anti-HBs antibody. In patients who 
have positive serology for the anti-HBc antibody, HBV DNA should be collected prior to 
Cycle 1, Day 1.

HCV serology (anti-HCV antibody)

PSA

Testosterone

Blood collection for immune monitoring. Screening sample will be collected within 28 
days of fiducial placement and/or first SD-101 injection.

Review of eligibility criteria

Informed consent

Informed consent for future biomedical research 

Prostate tumor tissue acquisition or 15 unstained slides (if archival tissue is available). If 
archival prostate tissue are unavailable or cannot be obtained, a repeat TRUS prostate 
biopsy is not required.

Biopsy of metastatic tumor lesion (if feasible and safe to perform). Acceptable samples 
include core needle biopsies of bone or lymph node. At least three cores should be 
obtained. A fine needle aspirate is not acceptable. Subjects have the option of consenting 
to a repeat biopsy at time of progression. Biopsy must be collected prior to SD-101 
injection and after initiating ADT.

Electrocardiogram (ECG)

CT chest, abdomen, pelvis (or MRI when clinically indicated) with contrast.*

Bone imaging (technetium or sodium-fluoride PET/CT).*

PSMA PET image collection (if available)
o
PSMA PET images will be collected from patients who undergo PSMA PET as 
part of a separate study. If available, imaging performed within 6 months of C1D1 
and at progression will be obtained. PSMA PET is not required as part of this 
study.
*Note: Radiographic imaging performed as standard of care prior to obtaining informed 
consent and within 60 days of initiating study treatment may be used to assess 
oligometastatic disease during screening, rather than repeating scans. For patients who have 
started on ADT, they must have had imaging prior to initiating hormonal therapy.
6.1.2.2
SBRT ± SD-101 injection

SBRT marker placement (1-5 weeks prior to C1D1)

SBRT simulation (1-5 weeks prior to C1D1)

Mandatory prostatic core biopsies (at time of SBRT marker placement).

SD-101 injection (at time of SBRT marker placement, for Arm 2 only).

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
Prostate-directed SBRT (cohort 1), or prostate and oligometastasis-directed SBRT 
(cohort 2): 3-5 treatments to each target over 10-21 days (1-5 weeks after marker 
placement and simulation). Subjects will start SBRT 1 month after ADT initiation at the 
earliest, and 4 months after ADT initiation at the latest.
SBRT and associated procedures (e.g., SBRT marker placement/simulation) will be done 
according to standard of care. See section 4.2.2 for recommended SBRT procedures. Although 
SBRT will be done according to standard of care, adhering to the recommendations in section 
4.2.2 is highly encouraged. The Sponsor-Investigator may need to be notified, as applicable, if 
SBRT cannot be performed as outlined in section 4.2.2.
If the treating physician determines that prostate or oligometastatic-directed SBRT can no longer 
be performed for any reason (e.g., safety concerns) following enrollment, then the participant 
may continue to receive pembrolizumab±SD-101 per their assigned arm without undergoing 
prostate or oligometastatic-directed SBRT. However, the participant must discontinue the trial if 
any of the discontinuation criteria are met (see section 6.1.3).
6.1.2.3
Day 1 of all cycles (+/- 4 days for cycles ≥ 2)

Physical examination

Vital signs including weight

ECOG performance status

Evaluation of adverse events

Evaluation of clinical response or deterioration

Concomitant medications

Complete blood count (CBC) with differential and platelet count. A manual differential 
can be done if clinically indicated.

Blood chemistry assessment, including sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen (BUN), creatinine, fasting glucose, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, albumin and LDH

Urinalysis

Blood collection for immune monitoring

Pembrolizumab infusion. Subjects will start pembrolizumab (C1D1) 1 month after ADT 
initiation at the earliest, and 4 months after ADT initiation at the latest.
6.1.2.4
1-3 weeks after C1D1

SD-101 injection (Arm 2 only). See section 4.2.7.2 for details regarding the timing of the 
SD-101 injection.

Mandatory prostatic core biopsies. For Arm 2, the biopsies should occur conjointly with 
the SD-101 injection.
6.1.2.5
Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, and Cycle 13
These procedures must be completed within 3 days of starting Cycle 1, Cycle 3, Cycle 5, Cycle 
7, Cycle 9, Cycle 11 and Cycle 13.

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
PSA

Testosterone
6.1.2.6
Cycle 5, Cycle 8, Cycle 11
These procedures must be completed within 10 days of starting Cycle 5, 8 and 11.

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4), free 
triiodothyronine (FT3)

CT chest, abdomen, pelvis (or MRI when clinically indicated) with contrast 

Bone imaging (technetium or sodium-fluoride PET/CT). If possible, the same scan that 
was used at baseline should be used for restaging. If both modalities were used at 
baseline, then the study that demonstrated the highest disease burden should be preferred. 

Disease/tumor assessment before starting the next cycle.
6.1.3
Withdrawal/Discontinuation
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator if continued participation is no longer in the patient’s best 
interests. Reasons for withdrawing a patient include, but are not limited to, disease progression, 
the occurrence of an adverse event or a concurrent illness, a patient’s request to end 
participation, a patient’s non-compliance or simply significant uncertainty on the part of the 
Investigator that continued participation is prudent. There may also be administrative reasons to 
terminate participation, such as concern about a patient’s compliance with the prescribed 
treatment regimen.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

Confirmed radiographic disease progression

Unacceptable adverse experiences as described in Section 4.2.6

Intercurrent illness that prevents further administration of pembrolizumab or SD-101

Investigator’s decision to withdraw the subject

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 13 administrations of pembrolizumab.

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
Administrative reasons
Following treatment discontinuation, patients will return to the study site for the End of 
Treatment visit. The End of Treatment procedures are described in Section 6.1.4. Subjects who 
discontinue for reasons other than progressive disease will have additional post-treatment follow-
up visits for disease status. The post-treatment follow-up procedures are described in Section 
6.1.5.
6.1.4
End-of-Treatment Study Procedures
To be completed within 30 days of the last dose of study drug.

Evaluation of clinical response or deterioration

Physical examination

Vital signs including weight

ECOG performance Status

Evaluation of adverse events
Note: serious adverse events will be collected for 90 days after the end of treatment as 
described in Section 6.2.3.

Concomitant medications

Complete blood count (CBC) with differential and platelet count. A manual differential 
can be done if clinically indicated.

Blood chemistry assessment, including sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen (BUN), creatinine, fasting glucose, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, albumin and LDH

Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)

Urinalysis

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4), free 
triiodothyronine (FT3)

PSA

Testosterone

Blood collection for immune monitoring

Biopsy of metastatic site at time of progression, if feasible (optional)

CT chest, abdomen, pelvis (or MRI when clinically indicated) with contrast 

Bone imaging (technetium or sodium-fluoride PET/CT). If possible, the same scan that 
was used at baseline should be used for restaging. If both modalities were used at 
baseline, then the study that demonstrated the highest disease burden should be preferred.

PSMA PET image collection at disease progression (if available)
o
PSMA PET images will be collected from patients who undergo PSMA PET as 
part of a separate study. If available, imaging performed within 6 months of C1D1 
and at progression will be obtained. PSMA PET is not required as part of this 
study. 

Disease/tumor assessment

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6.1.5
Post-treatment/Follow Up Visits
Subjects who complete the treatment period or discontinue early for reasons other than 
progressive disease will have post-treatment follow-up visits every 12 weeks +/- 2 weeks for up 
to 3 years (years one and two are mandatory; year three is optional) after completion of therapy, 
until disease progression, removal from study, or death, whichever occurs first. Subjects will not 
be followed for overall survival. The following procedures will be performed at the Follow Up 
Visit(s):

Record survival and anti-cancer therapy.
Note: May be collected via telephone calls, patient medical records, and/or clinic visits.

Evaluation of clinical response or deterioration

Physical examination

Vital signs including weight

ECOG performance Status

Evaluation of adverse events.
Note: All treatment related adverse events will be followed until resolution or 
stabilization to Grade <2.

Concomitant medications

Complete blood count (CBC) with differential and platelet count. A manual differential 
can be done if clinically indicated.

Blood chemistry assessment, including sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen (BUN), creatinine, fasting glucose, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, albumin and LDH

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4), free 
triiodothyronine (FT3)

PSA

Testosterone

Blood collection for immune monitoring

CT chest, abdomen, pelvis (or MRI when clinically indicated) with contrast 

Bone imaging (technetium or sodium-fluoride PET/CT). If possible, the same scan that 
was used at baseline should be used for restaging. If both modalities were used at 
baseline, then the study that demonstrated the highest disease burden should be preferred.

Disease/tumor assessments
Note: Patients who opt-in to year 3 of follow-up will only require imaging assessments as 
clinically indicated determined by the treating physician.

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6.1.5.1
Blood Collection for correlative studies
Sample collection, storage and transportation instructions for blood samples to UCSF Cancer 
Immunotherapy Laboratory 
 
will be provided in the Laboratory Manual.
The time points for immune-monitoring blood sampling are described in the Trial Flow Chart 
(Section 5.0).
6.2
Assessing and Recording Adverse Events
6.2.1
Definitions of Adverse Events
6.2.1.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality. An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose.
6.2.1.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude that 
the drug caused the event.
6.2.1.3
Suspected
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.
6.2.1.4
Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 

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anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes.
6.2.1.5
Serious
An adverse event or suspected adverse reaction 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

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 patient or subject 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.
6.2.1.6
Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 

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6.2.2
Recording of an Adverse Event
All Grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v5.0.  
If there are specific data plans to this study, such as Grade 1 & 2 AEs are also being entered into 
OnCore, describe that process here.
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
6.2.3
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved or 
stabilization. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  For selected adverse events for which 
administration of the investigational drug was stopped, a re-challenge of the subject with the 
investigational drug may be conducted if considered both safe and ethical by the Investigator.

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6.2.4
Adverse Events Monitoring
All grade 3-5 adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Institutional Review Board (IRB); and, when the study is conducted under an Investigational 
New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria.
[The manufacturer and/or grant sponsor may also need to be notified, as applicable.]
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the administration of the 
study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
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.
For a detailed description of the Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional 
Study at the Helen Diller Comprehensive Cancer Center please refer to Appendix 5.
6.2.5
Expedited Reporting
Reporting to the 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 Investigator 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.
Reporting to UCSF Institutional Review Board (IRB)
The Principal Investigator must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event.
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions:

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
Suspected adverse reaction - A suspected adverse reaction is defined as any adverse event 
for which there is a reasonable possibility that the treatment or procedure caused the 
adverse event. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the treatment or 
procedure and the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction.

Unexpected - An adverse event or suspected adverse reaction is considered unexpected if 
it is not listed in the investigator brochure or package insert(s), or is not listed at the 
specificity or severity that has been observed, or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class 
of treatment or procedure or as anticipated from the pharmacological properties of the 
treatment or procedure, but are not specifically mentioned as occurring with the particular 
treatment or procedure under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in 
the investigator brochure.  For example, a certain number of non-acute deaths in a cancer 
trial would be anticipated as an outcome of the underlying disease, but such deaths would 
generally not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator’s Brochure as occurring with the same 
class of treatment, or as anticipated from the pharmacological properties of the drug, even 
though they have not been observed with the drug under investigation.  Such events 
would be considered unexpected until they have been observed with the drug under 
investigation. For example, although angioedema is anticipated to occur in some patients 
exposed to drugs in the ACE inhibitor class and angioedema would be described in the 
investigator brochure as a class effect, the first case of angioedema observed with the 
drug under investigation should be considered unexpected for reporting purposes.

Serious - An adverse event or suspected adverse reaction 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
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 patient or subject 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.

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If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).
Any relevant additional information that pertains to a previously submitted IND safety report 
will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).
Expedited Reporting to Merck and TriSalus Life Sciences
Refer to sections 6.2.6 and 6.2.7 for details regarding reporting requirements 
 
.
6.2.6
Reporting Events to Merck
6.2.6.1
Pembrolizumab overdose
For purposes of this trial, 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. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject 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. (
 
6.2.6.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 

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cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. 
6.2.6.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
6.2.6.4
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event 
Refer to Table 7 for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 

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regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety;
) at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
6.2.6.5
Events of Clinical Interest
Selected non-serious and serious adverse events (SAEs) are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report forms/worksheets 
and reported within 24 hours to the Sponsor and within 2 working days to the Merck Global 
Safety team. (Attn: Worldwide Product Safety; 
).
ECI (both non-serious and serious adverse events) identified from the date of first dose through 
90 days following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier, need to be reported within 24 hours to the Sponsor and within 2 
working days to the Merck Global Safety team (Attn: Worldwide Product Safety; 
), regardless of attribution to study treatment, consistent with standard SAE reporting 
guidelines.
Events of clinical interest for this trial include:
1.
An overdose of Merck's product, as defined in Section 6.2.6, 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 3 × ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at the same 
time, an ALP lab value that is less than 2 × ULN, 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.
6.2.7
Reporting Events to TriSalus Life Sciences
The Sponsor-Investigator shall notify TriSalus Life Sciencesof any unexpected fatal and/or life 
threatening adverse drug reactions associated with the use of SD-101 as soon as possible and no 
later than seven (7) calendar days after Sponsor's receipt of the information, on an FDA 
MedWatch or narrative form.
The Sponsor-Investigator shall promptly report all other serious adverse events, regardless of 
expectedness or causality, to TriSalus Life Scienceswithin 12 calendar days of receipt, and, 
when necessary, to the FDA and applicable the IRB, according to relevant regulations. The 
Sponsor-Investigator shall promptly make available such records as TriSalus Life Sciencesmay 
deem necessary to investigate and/or report an adverse event associated with the use of SD-101 
during the study.

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E-mail reports to TriSalus Life Sciences at safety.reporting@trisaluslifesci.com
6.2.8
Evaluating Adverse Events
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.

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Table 7: Evaluating 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 subject, 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 [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a 
serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of 
clinical interest and must be reported within 24 hours.
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 subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).

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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 the Merck product to be discontinued?
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck 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 Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck 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 the Merck 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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Dechallenge
Was the 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 Merck product; or (3) the trial is a single-dose 
drug trial); or (4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the 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) Merck 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 THE MERCK PRODUCT, OR IF 
REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED 
IN ADVANCE BY THE U.S. CLINICAL MONITOR 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 the 
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 a Merck product relationship).
Yes, there is a reasonable 
possibility of Merck 
product relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative 
to the administration of the Merck product is reasonable.  The AE is more likely explained by the 
Merck product than by another cause.
No, there is not a 
reasonable possibility 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  
(Also entered for a subject with overdose without an associated AE.)

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Merck product 
relationship

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6.2.9
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
7.0 STATISTICAL CONSIDERATION
7.1
Sample size calculation
The sample size calculation for cohort 2 is based on the hypothesis of the study is combination 
therapy of pembrolizumab with RT with or without SD-101 leads to improved PSA response as 
defined as the proportion of patients achieving a PSA <nadir + 2 ng/mL at 15 months.  
For each arm of cohort 2, the null hypothesis that the true response rate is 0.1% will be tested 
against a one-sided alternative of 12%, with 16 patients in each arm, we would have 82% of 
power at alpha of 0.05.
7.2
Statistical Analysis Plan
7.2.1
Analysis population
All patients who receive any part of a dose of RT, SD-101 or pembrolizumab will be analyzed 
for safety and efficacy. Subjects who discontinue from study participation prior to receiving any 
dose of study therapy may be replaced after discussion with the Sponsor-Investigator. Subjects 
who have received any dose of SD-101 or pembrolizumab will not be replaced. 
Only patients in cohort 2, who achieve testosterone recovery to non-castrate levels (>150 ng/dL) 
at 15 months, will be analyzed for the primary endpoint.
Demographic and baseline characteristics will be summarized by each study arm. In general, 
frequency distribution and percentage will be used to summarize categorical measurements, 
while mean with standard deviation and median with range will be used to describe symmetric 
and skewed continuous measurements, respectively. Univariate analysis among variables will be 
assessed using the two-sample t-test, Wilcoxon-rank-sum test, Chi-square test, as appropriate. 
Missing data will not be imputed.
7.2.2
Analysis of Primary Endpoint
After completion of 9 months of GNRH targeting agent, abiraterone, and prednisone (or 
equivalent), all patients will discontinue ADT to observe for the rate of PSA < nadir + 2 ng/mL 
at 15 months from the start of radiotherapy and cycle 1, day 1 of pembrolizumab, among patients 
whose testosterone recovers to non-castrate levels (>150 ng/dL). In standard of care patients with 
metastatic hormone-sensitive prostate cancer who come off hormonal therapy during intermittent 
ADT, essentially all patients (>99.99%) will have PSA > nadir + 2 ng/mL at 15 months. The 
point estimate of the rate of PSA < nadir + 2 ng/mL will be obtained with its 95% confidence 
interval for participants by arm in cohort 2 and compared to the historical control rate by one-
sample binomial test.

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Safety and tolerability
Adverse events occurring on study will be summarized for all participants that received study 
intervention (including pembrolizumab, SD-101, SBRT to prostate, SBRT to oligometastatic 
sites) by maximum toxicity grade for each study arm. The toxicity grade for laboratory data will 
be calculated using CTCAE v5.0 and the lab data will be summarized according to the subjects’ 
baseline grade and maximum grade for each cycle of therapy. All treatment related adverse 
events will be graded using NCI CTCAE v5.0 and will be recorded and listed.
7.2.3
Analysis of Secondary Endpoints
Testosterone-PSA Uncoupling
Testosterone-PSA uncoupling is defined as PSA < 50% baseline and < 20ng/mL for at least 3 
months after testosterone recovers to >150 ng/dL. In patients with metastatic hormone-sensitive 
prostate cancer off hormonal therapy, >90% patients are expected to have PSA increase to > 
50% baseline after 3 months of testosterone recovery. Therefore, the presence of PSA-
testosterone uncoupling in this study may serve as a surrogate of immunotherapeutic responses 
induced by pembrolizumab combined with RT (arm 1), or RT with SD-101 (arm 2), if a 
prolonged PSA < nadir + 2 ng/mL is not achieved. The point estimate of testosterone-PSA 
uncoupling rate will be obtained with its 95% confidence interval for each arm in cohort 2.
Time to Clinical Progression
The time to clinical progression in each study arm in cohort 2 is defined as the time to 
radiographic progression by PCWG-2 criteria (Scher HI et al, 2008), time to symptomatic 
progressive disease, or PSA progression, whichever comes the first. Kaplan-Meier estimate will 
be obtained for the time to clinical progression in each study arm in cohort 2.
Progression-Free Survival
Progression-free survival (PFS) will be estimated for each study arm on cohort 2 by Kaplan-
Meier estimate, where PFS is a composite endpoint based on PSA progression, radiological 
progression, clinical deterioration, or death.
7.2.4
Analysis of Exploratory Endpoints
Immunohistochemistry (immune cell subsets and PD-L1)
For all subjects, immune cell subsets localization and PD-L1 staining will be assessed by 
immunohistochemistry in tumor biopsies and will be summarized by descriptive statistics 
Immunohistochemistry will be performed in the UCSF Cancer Immunotherapy Laboratory per 
established SOPs. Based on prior experience tissue will be designated into 3 distinct 
compartments: benign epithelium, tumor centers, and tumor interfaces. Tumor interfaces will be 
defined as fields where malignant and benign epithelium are present. Automatic cell counts for 
single- and double-stained cells will be determined for each field with color-specific algorithms. 
The cell count for each compartment will be reported as the mean for each of the five quantitated 
fields.  Cells of interest will include CD3+ T cells, CD3+ Ki67+ proliferative T cells, CD4+ 
FoxP3- helper T cells, CD4+ FoxP3+ regulatory T cells, CD8+ cytotoxic T cells, as well as PD-1 
expression on the different lymphocytes. Tumors will be categorized based on the frequency of 
tumor cells or of immune cells staining positively for PD-L1 as follows: IHC 0: <1%, IHC 1: 1-
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summarize PD-L1 expression by at baseline and at time of progression.  For patients who 
undergo a repeat biopsy of metastatic lesion, changes in immune cell infiltration and PD-L1 
expression will be summarized using descriptive statistics.
Gene signature biomarker
To identify individual genes whose expression levels at baseline are associated with testosterone-
PSA uncoupling, we will apply two-sample Wilcoxon tests to compare patients who achieve 
uncoupling and those who do not for each arm. Adjusted P values controlling for false discovery 
rate (Benjamini and Hochberg method) will be derived. In addition, to assess association of 
baseline immune gene signature with uncoupling, the median expression level of the component 
genes will be used to represent the signature and two-sample Wilcoxon tests will be used. For 
genes or signatures that emerge as significantly associated with response, logistic regression 
models will be used to assess their independent association with response after adjusting for 
known clinical prognostic factors. Association of gene expression levels at baseline and PFS will 
be explored using the Cox proportional hazards regression model. Hierarchical clustering 
superimposed with response status, relevant baseline or prognostic characteristics or 
experimental factors will be performed using Spearman correlation and complete linkage to 
visualize the discriminating power of the immune gene expression and the correlative structure 
among the genes and the samples.
Circulating immune cell subsets
For both cohorts, flow cytometry of circulating immune cell subsets will be performed on 
baseline (before starting any study therapy), on-treatment (while receiving RT with or without 
SD-101 and during cycle 1-13 pembrolizumab), and post-treatment (after completing all cycles 
of pembrolizumab and during follow-up) PBMC. Established flow cytometry panels will 
examine B cell and T cell populations. Immune cell quantification will be summarized by 
changes from baseline, on-, to post-treatment using descriptive statistics.  Furthermore, paired 
Wilcoxon signed-rank test will be applied to test the pre-on, and on-post treatment changes.  
When available, immune cells digested from resected tumor tissues will also be assessed by flow 
cytometry.
TCR repertoire
For both cohorts, the change in circulating and tumor-infiltrating TCR from baseline (before 
starting any study therapy), on-treatment (while receiving RT with or without SD-101 and cycle 
1-13 pembrolizumab), and post-treatment (after completing all cycles of pembrolizumab and 
during follow-up) will be assessed by calculating the number of unique clonotypes, read depth 
and Shannon diversity index. Repertoire overlap and change between sequencing experiments 
will be measured using Baroni-Urbani and Buser overlap index and Morisita’s distance, 
respectively.  TCR repertoire analysis will be performed by the UCSF Cancer Immunotherapy 
Laboratory.

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8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
8.1
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by Merck as summarized in Table 8.
Table 8: Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
SD-101 10 mg/ 2 mL or 100 mg/ 2 mL
Solution for injection
8.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
8.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
8.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
See Section 4.2.1 for details on the storage and handling of pembrolizumab and SD-101.
8.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 

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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
9.0
ADMINISTRATIVE AND REGULATORY DETAILS
9.1
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 Investigator 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 subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator 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.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF Institutional Review Board (IRB).  Prior to obtaining IRB approval, the 
protocol must be approved 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.  
9.3
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.

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9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites.
9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and any participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her 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 CTMS study calendar, using single data entry with a secure access 
account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible 
upon completion of the study visit; the Investigator 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 patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for each 
patient.
In accordance with federal regulations, the Investigator 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. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.

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The Principal Investigator 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 Study Chair, the Trial Statistician, and the Protocol Project 
Manager.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all 
adverse events and suspected adverse reactions considered “serious”.  The DSMC will audit 
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 audit 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 5 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for 
additional information.
9.8
Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
9.9
Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Institutional Review Board (IRB). Prior to implementing this protocol at any 
participating sites, approval for the UCSF IRB approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before any participating site can 
be initiated and begin enrolling participants: 

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
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 

Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.
9.10 Protection of Human Subjects
9.10.1  Protection from Unnecessary Harm
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated risks 
and benefits.
9.10.2  Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) 
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robust type-I interferon induction. Nature. 2005 Apr 21;434(7036):1035-40. PubMed PMID: 
15815647. 
Howard SI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after 
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Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen 
deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data 
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20;24(24):3984-90. PubMed PMID: 16921051. 
Hussain M, Tangen CM, Berry DL, et al.  Intermittent versus continuous androgen deprivation in 
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Kim YH, Gratzinger D, Harrison C, et al. In situ vaccination against mycosis fungoides by 
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Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 
2002;20:709-60. Epub 2001 Oct 4. PubMed PMID: 11861616. 
Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients 
with metastatic castration-resistant prostate cancer that had progressed after docetaxel 
chemotherapy (CA184-043): a multicenter, randomized, double-blind, phase 3 trial. Lancet 
Oncol. 2014 Jun;15(7):700-12. PubMed PMID: 24831977.
Larkin J, Chiarion-Sileni, V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med. 2015 May 31 [Epub ahead of print]. 
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Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require 
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and in vivo across multiple species. DNA Cell Biol. 2005 Feb;24(2):63-72. PubMed PMID: 
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Ost, P, Reynders, D, Decaestecker, K, et al. "Surveillance or metastasis-directed therapy for 
oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II 
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Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. PubMed PMID: 23228172.
Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase 
II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015 
Jun 10;33(17):1889-94. PubMed PMID: 25667295.
Scher HI, Halabi S, Tannock I, et al.  Design and End Points of Clinial Trials for Patietns with 
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Feb;64(1):9-29. PubMed PMID: 24399786.
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11.0 APPENDICES

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Appendix 1
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance without 
restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
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)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
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
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2
Common Terminology Criteria for Adverse Events V5.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm)

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Appendix 3
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.
*As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47.

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Appendix 4
Data and Safety Monitoring Plan for Phase II Trial with Safety Lead-In
1. Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies. A summary of DSMC activities for this study 
includes: 

Review of all participant data in safety lead-in phase

Approval to enroll past safety lead-in phase by DSMC Chair or Vice Chair

Semiannual auditing after safety lead-in phase

Review of serious adverse events

Minimum of biennial regulatory auditing
2. Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.
All institutional Phase II studies with a lead-in are designated with a high-risk assessment during 
the safety lead-in phase and a moderate risk assessment afterwards.  During the safety lead-in 
phase, the DSMC will audit all visits through the first cycle of treatment for all participants 
enrolled in this phase of the trial.
After the completion of enrollment in the safety lead-in phase, the Principal Investigator will 
submit a report to the DSMC Chair outlining all AEs, SAEs, and DLTs (as defined in the 
protocol) with a request to proceed onto the next phase of the study.  Within two business days 
of receipt, the DSMC Chair or designee will review the report and issue written authorization to 
proceed or a request for more information.  The report is then reviewed at the subsequent DSMC 
meeting.
After DSMC authorization to enroll beyond the safety lead-in phase is granted, study data is 
audited semiannually, with a random selection of twenty percent of the participants reviewed (or 
at least three participants if the calculated value is less than three).  The DSMC Monitor/Auditor 
will audit a maximum of 5 cycles of treatment in participants selected for review or until the 
selected participants discontinue study participation or the trial is closed with the IRB. The 
assigned DSMC Monitor/Auditor will review no more than 10 total participant charts during the 
course of auditing this trial. 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.  Additionally, a regulatory audit 
will occur on a biennial basis to review all regulatory documents for the trial.
3. Review and Oversight Requirements
3.1 Adverse Event Monitoring

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All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the investigational 
agent(s) or study 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 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.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Coordinating Center’s Site Committee.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution assignment.
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 occurring in a gene therapy study.

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.

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UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, All SAEs are reviewed and 
monitored by the DSMC 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 an SAE involves death, and occurs during the treatment phase of the study or within 30 
days after the last administration of the study drug(s), and is determined to be possibly, 
probably, or definitely related either to the investigational drug or any research related 
procedure, then the event must be reported to the DSMC Chair (or Vice Chair) and 
DSMC Director within one business day.
3.3 Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator is responsible for notifying the DSMC via report at the time the increased 
rate is identified. The report will indicate if the incidence of adverse events observed in 
the study is above the range stated in the Investigator’s Brochure or package insert.
If at any time the Principal Investigator stops enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and DSMC Director must be notified within one 
business day.
Data and Safety Monitoring Committee Contacts:
Katie Kelley, MD (DSMC Chair)
John McAdams (DSMC Director)

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Appendix 5
Specimen and blood collection
A. For tissue analysis:
Sample collection, storage and transportation instructions for samples to UCSF Cancer 
Immunotherapy Laboratory will be provided in the Laboratory Manual.
B: For blood analyses:
Sample collection, storage and transportation instructions for samples to UCSF Cancer 
Immunotherapy Laboratory will be provided in the Laboratory Manual.

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Appendix 6
Prohibitive Medication
Medications to Avoid
CC# 16703:  Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination with 
Intratumoral SD-101 Therapy in Patients with Hormone-Naïve Oligometastatic Prostate 
Cancer Receiving Definitive Prostatic Radiation and Intermittent Androgen Deprivation 
Therapy
The following is a list of medications to avoid while you are participating in this study. If you go 
to any medical visit, please take this list with you for the doctor’s reference.
Before you begin treatment, Dr. Oh or one of his associates will review all medications you are 
taking. Make sure you talk with Dr. Oh before you start or stop taking any medications. This list 
contains only the most common drugs that are known to interact with the drugs used in this 
study. It is very important to discuss all medications that you are taking with your study doctor. 
This information will be reviewed at each study visit. 
Generic Name
Brand Names ®
Generic Name
Brand Names ®
Eulexin 
Flutamide 
Goserelin
Zoladex
Bicalutamide
Casodex
Nilandron
Nilutamide
Cabazitaxel
Jevtana
Nizoral
Ketoconazole (systemic)
Diethylstilbestrol
PC-SPES (or any 
other PC-X product)
Docetaxel
Taxotere
Radium-223
Xofigo
Enzalutamide
Xtandi
Sipuleucel-T
Provenge