Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab
Phase: PHASE1
Conditions: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IV Prostate Cancer, Stage IVA Prostate Cancer, Stage IVB Prostate Cancer
Sponsor: University of California, San Francisco

Version date: 04/19/2021
Protocol CC#: 185511
Phase I – Lu-PSMA + pembrolizumab
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Immunogenic Priming with PSMA-Targeted Radioligand Therapy in 
Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in 
Combination with Pembrolizumab
Protocol Number: CC# 185511
Study Drugs: 
 177Lu-PSMA-617
Pembrolizumab 
Version Number:  2.0
Version Date:  04/19/2021
IND Number: 139715
Principal Investigator
Rahul Aggarwal, MD
University of California San Francisco
Co-Principal Investigator (Sponsor-Investigator)
Thomas Hope, MD
University of California San Francisco
 
Revision History
Version 1.0 
04/11/2018  
Version 1.1 
05/03/2018
Version 1.2
Version 1.3
Version 1.4
Version 1.5
06/19/2018
09/08/2018
10/01/2018
05/06/2019
Version 1.6 
11/21/2019
Version 1.7
Version 1.8
Version 1.9
01/03/2020
06/01/2020
10/06/2020
Version 2.0
04/19/2021
NCT03805594

Version date: 04/19/2021
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Phase I – Lu-PSMA + pembrolizumab
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Protocol Signature Page
Protocol No.: 185511
Version Date: 04/19/2021
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. 
5.
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

Version date: 04/19/2021
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Phase I – Lu-PSMA + pembrolizumab
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Abstract
Title
Immunogenic Priming with 177Lu-PSMA Targeted Therapy in Advanced 
Prostate Cancer: A Phase 1b Study
Patient 
population
Patients with metastatic castration resistant prostate cancer (mCRPC) will be 
enrolled. All patients must have measurable disease by RECIST 1.1 criteria, 
with at least 3 lesions which are PSMA-avid on 68Ga-PSMA-11 PET imaging. 
Rationale for 
Study
Despite recent advances in the treatment of mCRPC, including the approval of 
novel agents such as sipuleucel-T, abiraterone acetate, enzalutamide, and 
radium-223, patients with mCRPC have a poor prognosis and many eventually 
succumb to their disease. Patients with abiraterone and/or enzalutamide 
refractory mCRPC represents a particularly challenging subgroup of patients 
who have limited effective treatment options other than chemotherapy.
Prostate-Specific Membrane Antigen (PSMA) is a cell surface protein 
overexpressed on most prostate cancer cells, especially in advanced stage 
disease. The safety and efficacy of 177Lu radiolabeled PSMA has been 
reported in several studies, including a recent prospective phase 2 study 
(Hofman et al. 2017). In patients with PSMA-avid metastatic disease, the PSA 
response proportion and objective response rate by RECIST 1.1 range from 
40-60%, in heavily pre-treated patients. However the response duration is 
short, and therefore novel treatment strategies are needed to maintain and 
extend the duration of response achieved. 
We propose to utilize immune checkpoint inhibition with pembrolizumab as a 
means to maintain anti-tumor response. We leverage a robust body of 
literature indicating that radiotherapy induces an immunogenic response, in 
the form of induction of infiltrating T cells, broadening of the T cell repertoire, 
and induction of PD-L1 expression, facilitating subsequent treatment with 
immune checkpoint inhibitor.  
In the current study we will obtain the preliminary safety and efficacy data of 
177Lu-PSMA-617 
radioligand 
therapy 
(RLT) 
in 
combination 
with 
pembrolizumab in patients with metastatic castration resistant prostate cancer. 
Favorable results with respect to toxicity and preliminary evidence of efficacy 
would form the basis for a subsequent definitive randomized study of the 
treatment combination in PSMA-expressing metastatic castration-resistant 
prostate cancer. 
Primary 
Objectives
Part A: To determine the recommended phase 2 dose and schedule of 177Lu-
PSMA-617 in combination with pembrolizumab in patients with mCRPC. 
Part B (Dose Expansion): To determine the objective response rate by 
RECIST 1.1 criteria.  

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Secondary 
Objectives
1.
To characterize the safety profile of the combination
2.
To determine the median duration of response by RECIST 1.1 criteria. 
3.
To determine the proportion of patients who experience ≥ 50% decline 
from baseline in serum PSA. 
4.
To determine the median PSA progression-free survival. 
5.
To determine the median time to symptomatic skeletal related event. 
6.
To determine the 6 month radiographic progression-free survival rate and 
median radiographic progression-free survival.
7.
To determine the median overall survival. 
Correlative
Objectives
1.
To assess the lesion-specific response rate by baseline PSMA avidity on 
68Ga-PSMA-11 PET.
2.
To quantify the change from baseline in T cell repertoire, circulating T cell 
subsets, tumor infiltrating lymphocytes, and tumor PD-L1 expression by 
immunohistochemistry after one priming dose of Lu-PSMA RLT. 
3.
To explore the relationship between timing of the 177Lu-PSMA-617 priming 
dose with initiation of pembrolizumab with respect to immunologic, safety, 
and efficacy outcomes. 
4.
To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 
PET at the time of disease progression. 
5.
To explore relationship between tumor genomic profile with clinical 
outcomes including response rate and progression-free survival. 
6.
To explore the relationship between tumor dosimetry with objective 
response. 

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Study Design
This is a single-center Phase 1b open-label, study of PSMA-targeted 
radionuclide therapy with 177Lu-PSMA-617 in combination with pembrolizumab 
in patients with mCRPC who have previously progressed on at least one prior 
androgen pathway inhibitor (e.g. abiraterone, enzalutamide, apalutamide). 
Patients must have at least three metastatic lesions which are PSMA-avid on 
baseline 68Ga-PSMA-11 PET imaging. 
In Part A of the study, patients will be enrolled sequentially into one of three 
treatment schedules with respect to timing of 177Lu-PSMA-617 in relation to 
first dose of pembrolizumab (N = 6 patients per schedule): 
Schedule 1) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 
followed by pembrolizumab 200 mg IV q 21 days starting Cycle 2 Day 1.
Schedule 2) Priming dose of 177Lu-PSMA-617 administered concurrently with 
initiation of pembrolizumab on Cycle 1 Day 1. 
Schedule 3) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 
following initiation of pembrolizumab on Cycle 1 Day -21. 
The dose-limiting toxicity window will be Cycle 1 + Cycle 2 (i.e. 6 weeks 
following C1D1 administration of Lu-PSMA-617 across) in all three Schedule 
cohorts. 
In Part A of the study, 6 patients will be enrolled to Schedule 1, then 6 patients 
to Schedule 2, and finally 6 patients will be enrolled to Schedule 3.  
The starting dose of 177Lu-PSMA-617 will be 7.4 +/- 15% GBq, which is the 
recommended phase 3 dose of the agent. If the DLT frequency attributable to 
Lu-PSMA exceeds 33% at any point after 6 evaluable patients have been 
enrolled in Part A, Dose Level -1 of 177Lu-PSMA-617 will be investigated (4 
Gbq +/- 15%) for the remainder of patients enrolled on study. 
Using the data obtained in Part A, the recommended phase 2 dose and 
schedule of 177Lu-PSMA-617 will be determined by the Principal Investigator 
using a combination of safety, efficacy, and immunologic effects of treatment 
from the first two cycles (and additional cycles of treatment when available). 
 In Part B of the study, an additional 25 patients will be enrolled at the 
recommended phase 2 dose and schedule to obtain additional safety, efficacy, 
and immunologic data pertaining to the treatment combination. 

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Number of 
patients
Approximately 18 patients will be enrolled during Part A of the study. An 
additional 25 patients will be enrolled in Part B.   
Total sample size: 43
Part A: N ~ 18 patients (6 patients per Schedule; 3 Schedules to be evaluated)
Part B: N ~ 25 patients
Duration of 
Therapy
Patients will be treated until disease progression per PCWG3/RECIST 1.1 
criteria, confirmed by repeat scans performed ≥ 4 weeks later, unacceptable 
toxicity, or patient withdrawal, whichever occurs first.
Duration of 
Follow up
Patients will undergo safety follow up visit approximately 30 days and 90 days 
following end of treatment visit. 
Duration of 
study
The study is anticipated to accrue 2-3 patients per month for an estimated 
accrual period of 21 months. The study is expected to reach completion for 
analysis of primary and secondary endpoints approximately 36 months from 
first patient enrolled. 
Study Drugs
177Lu-PSMA-617 is a PSMA-targeted radioligand that will be produced under 
Current Good Manufacturing Practice (CGMP) regulations. The priming dose 
of 177Lu-PSMA-617 will be 7.4 +/- 15% GBq, which is the recommended phase 
3 dose of the agent. 
The planned dose schedules to be evaluated in Part A of the study include: 
Schedule 1) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 
followed by pembrolizumab 200 mg IV q 21 days starting Cycle 2 Day 1.
Schedule 2) Priming dose of 177Lu-PSMA-617 administered concurrently with 
initiation of pembrolizumab on Cycle 1 Day 1. 
Schedule 3) 177Lu-PSMA-617 administered on Cycle 1 Day 1 following 
initiation of pembrolizumab on Cycle 1 Day -21. 
The cumulative safety data, including safety data beyond Cycle 2 where 
available, 
immunologic 
priming 
effects, 
along 
with 
efficacy 
and 
pharmacodynamic data, will be utilized to determine the recommended 
schedule of 177Lu-PSMA-617 in combination with pembrolizumab. 

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Safety 
Assessments
Safety will be assessed by reviewing adverse events (AEs), laboratory 
evaluations, and by physical examination. The NCI CTCAE v4.0 will be used. 
All AEs and serious AEs (SAEs) that occur on study therapy or within 30 days 
after the last dose of study therapy will be recorded on case report forms 
(CRFs). 
Patients will be assessed for dose-limiting toxicities during Cycle 1 and 2, 
defined as any of the following AEs occurring during Cycle 1 or 2 of the dose-
escalation period: 

Any non-hematologic treatment-related AE ≥ Grade 3, with the 
exceptions of Grade 3 nausea, vomiting, diarrhea, constipation, fever, 
fatigue, skin rash, or non-clinically significant laboratory abnormality 
that resolves to Grade ≤ 2 within 72 hours with optimal medical 
management.

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with Grade > 
1 bleeding or requirement for platelet transfusion.  

Grade 4 neutropenia lasting for > 5 consecutive days 

Grade ≥ 3 febrile neutropenia.
Study Schema
 
 

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Table of Contents
Abstract
3
Study Schema.................................................................................................................7
List of Abbreviations....................................................................................................10
1
Introduction ..........................................................................................................13
1.1
Background...................................................................................................................13
1.2
PSMA and PSMA ligands ............................................................................................13
1.7
Study Rationale.............................................................................................................16
2
Objectives and Endpoints of the Study .............................................................19
2.1
Objectives .....................................................................................................................19
Primary Objectives........................................................................................................19
Secondary Objectives....................................................................................................19
Correlative Objectives ..................................................................................................19
2.2
Endpoints ......................................................................................................................20
2.2.1
Primary Endpoint .............................................................................................20
2.2.2
Secondary Endpoints........................................................................................20
3
Study Design ........................................................................................................20
3.1
Characteristics...............................................................................................................20
3.2
Randomization..............................................................................................................21
3.3
Eligibility Criteria.........................................................................................................21
3.4
Duration of Study Treatment ........................................................................................25
3.5
Subject Replacement.....................................................................................................25
3.6
Study Timeline..............................................................................................................25
3.6.1
Primary Completion .........................................................................................25
4
Study Treatment...................................................................................................26
4.1
177Lu-PSMA-617...........................................................................................................26
4.1.1
Chemical and physical characteristics..............................................................26
4.1.2
Drug preparation...............................................................................................27
4.1.3
Patient preparation............................................................................................28
4.1.4
Concomitant hydration (renal protection) ........................................................28
4.1.5
Method of administration .................................................................................28
4.1.6
Dose Limiting Toxicities and Criteria for Dose De-Escalation .......................29
4.1.7
Contraindications to 177Lu-PSMA-617 ............................................................29
4.1.8
Adverse reactions to 177Lu-PSMA-617 ............................................................29
4.1.9
Drug interactions ..............................................................................................30
4.1.10
Warnings and precautions...............................................................................30
4.1.11
Overdosage .....................................................................................................31
4.1.12
Packaging and Labeling..................................................................................31
4.1.13
Handling of Medication..................................................................................31
4.2
Pembrolizumab .............................................................................................................31
4.3
Packaging and Labeling Information............................................................................32
4.4
Clinical Supplies Disclosure.........................................................................................32
4.5
Storage and Handling Requirements ............................................................................32
4.6
Returns and Reconciliation...........................................................................................32

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4.7
Administration ..............................................................................................................32
4.8
Dose modification for Pembrolizumab.........................................................................32
5
Study Procedures.................................................................................................42
5.1
Discontinuation of Therapy ..........................................................................................43
5.2
Study Calendar: Schedule 1 (177Lu-PSMA-617 prior to Pembrolizumab) ...................45
5.3
Study Calendar – Schedule 2 (Concurrent Dosing)......................................................47
5.4
Study Calendar – Schedule 3 (177Lu-PSMA-617 following Pembrolizumab)..............49
6
Reporting and Documentation of Results .........................................................51
6.1
Evaluation of efficacy (or Activity)..............................................................................51
6.1.1
Definitions........................................................................................................51
6.2
Evaluation of Safety......................................................................................................51
6.3
Definition of Adverse Events........................................................................................51
6.3.1
Adverse Event ..................................................................................................51
6.3.2
Adverse Reaction .............................................................................................51
6.4
Recording of an Adverse Event ....................................................................................54
6.5
Follow-up of Adverse Events .......................................................................................54
6.6
Expedited Reporting .....................................................................................................54
7
Measurement of Response..................................................................................57
8
Statistical Considerations ...................................................................................61
8.1
Sample Size Justification..............................................................................................61
8.2
Accrual..........................................................................................................................61
8.3
Interim Analyses...........................................................................................................61
8.4
Analytic Plan.................................................................................................................61
8.4.1
Analytic Plan for Primary Endpoints ...............................................................61
8.4.2
Analytic Plan for Secondary Endpoints ...........................................................62
9
Study Management ..............................................................................................64
9.1
Pre-study Documentation..............................................................................................64
9.2
Institutional Review Board Approval...........................................................................64
9.3
Informed Consent..........................................................................................................64
9.4
Changes in the Protocol ................................................................................................65
10
Protection of Human Subjects............................................................................65
10.1 Protection from Unnecessary Harm..............................................................................65
10.2 Protection of Privacy.....................................................................................................65
References
66
Appendix 1
Performance Status Criteria ................................................................70
Appendix 2
Data and Safety Monitoring Plan for a Phase 1 Study ......................71
Appendix 3
UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND) ...................................................................................73
Appendix 4
Radioprotection Precautions for Patients Treated with 177Lu-PSMA
75
Appendix 5
Recommended Precautions for Patients Treated with 177Lu-PSMA 76
Appendix 6
 National Cancer Institute Common Terminology Criteria for 

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Adverse Events.............................................................................................................79
List of Abbreviations
5-HT3
Serotonin type-3
ADT
androgen deprivation therapy
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
androgen receptor
AST
aspartate aminotransferase
BS
bone scan
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CGMP
Current Good Manufacturing Practice
CMP
comprehensive metabolic panel
CR
complete response
CRC
Clinical Research Coordinator
CrCl
creatinine clearance
CRF
case report form
CT
computerized tomography
CTC
circulating tumor cell
CTCEA
Common Terminology Criteria for Adverse Events

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List of Abbreviations
CTMS
Clinical Trial Management System
DKFZ
German Cancer Research Center of Heidelberg
DLT
DMT
Dose-limiting toxicity
dose-modifying toxicity
DOTA
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
DTPA
diethylene triamine pentaacetic acid
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
Gbq
Gigabecquerel
Glu-urea
Glutamate-urea
F-18
Fluorine-18
68Ga
Galium-68
GCP
Good Clinical Practice
Gy
Gray
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act (HIPAA)
ICF
informed consent form
ICH
International Conference on Harmonization
IND
investigational new drug application
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous
LHRH
luteinizing hormone-releasing hormone
177Lu
Lutetium-177
mCRPC
metastatic castration resistant prostate cancer
MR
magnetic resonance
MRI
magnetic resonance imaging
NCI
National Cancer Institute
PAP
prostatic acid phosphatase
PCWG3
Prostate Cancer Working Group 3

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List of Abbreviations
PD-L1
PET
Programmed death receptor ligand - 1
positron emission tomography
PFS
progression free survival
PR
partial response
PRC
Protocol Review Committee
PSA
prostate specific antigen
PSMA
RECIST
Prostate specific membrane antigen
Response Evaluation Criteria in Solid Tumors
RLT
SAE
Radioligand therapy
serious adverse event
SUV
standardized uptake values
TCR
ULN
T cell receptor
upper limit of normal

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1
Introduction
1.1
Background
Prostate cancer is the second leading cause of cancer death in men in the Western World 
(Siegel et al. 2015).  While most men with localized prostate cancer are cured with treatment, 
men with recurrent or newly diagnosed metastatic disease have significant morbidity and 
mortality. In these patients, there is generally a rapid and favorable response to androgen 
deprivation therapy (ADT); however, in time, most men eventually develop hormone refractory 
disease, termed castration resistant prostate cancer (mCRPC).
Prior to 2010, docetaxel-based chemotherapy was the only treatment that demonstrated overall 
survival benefit in randomized trials for patients with mCRPC (Tannock et al. 2004, Petrylak et 
al. 2004, Berthold et al. 2008). In 2010, cabazitaxel, a novel taxane, gained FDA approval in 
mCRPC patients previously treated with docetaxel (Bahl et al. 2013). More recently, treatment 
options for mCRPC expanded to sipuleucel-T, an autologous cellular immunotherapy targeting 
PAP (Kantoff et al. 2010); abiraterone acetate and enzalutamide, novel androgen receptor (AR)-
targeting agents which more completely ablate androgen signaling (de Bono et al. 2011, Fizazi 
et al. 2012, Ryan et al. 2013, Scher et al. 2012, Beer et al. 2014); and radium-223, a bone-
targeting alpha emitter (Parker et al. 2013). 
Despite these therapeutic advances, most men with mCRPC develop progressive disease, and 
many eventually succumb to their disease. Men with abiraterone and/or enzalutamide refractory 
mCRPC represents a particularly challenging subgroup who have limited effective treatment 
options outside of chemotherapy, which carries with it a significant risk of side effects. 
Therefore, there is a clinical need to develop novel therapeutics which is not only clinically 
efficacious, but also well tolerated in this often elderly, heavily pretreated patient population.
1.2
PSMA and PSMA ligands 
Prostate-Specific Membrane Antigen (PSMA), also known as folate hydrolase I or glutamate 
carboxypeptidase II, is a cell surface protein that is expressed by normal prostate cells, and 
significantly overexpressed on most prostate cancer cells. Other normal tissues express low 
levels of PSMA, including the kidney, salivary glands, and small intestine (Afshar-Oromieh et al. 
2013, Ahkhtar dt al 2012). In prostate cancer, PSMA expression has been correlated with 
disease grade and disease progression, with the highest expression levels seen in metastatic 
and castration resistant disease (Israeli et al. 1994, Wright et al. 1995, Wright et al. 1996).
Because PSMA is a type II transmembrane protein with glutamate-carboxypeptidase activity, 
efforts have been made to develop small-molecule ligands targeting its proteolytic domain for 
diagnostic and radiopharmaceutical purposes. 177Lu-J591, a radiolabeled monoclonal antibody 
targeting the extracellular domain of PSMA, has shown moderate antitumor activity. However, 
the slow diffusion of antibodies and their long circulation time are associated with significant 
hematotoxicity (Tagawa et al. 2013). Small molecules—in contrast to antibodies—have 
relatively fast blood clearance resulting in a low background activity. Furthermore, after binding 
to PSMA, internalization of the small molecular ligand occurs via clathrin-coated pits and 
endocytosis (Rajasekaran et al. 2003). This leads to enhanced tumor uptake and retention, 
resulting in high image quality for diagnostic procedures and a high local dose for therapeutic 
applications.

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1.3
RLT targeting PSMA is a promising treatment for mCRPC: 
PSMA is also an optimal target for therapy because after binding to PSMA the ligand is 
internalized through clathrin-coated pits and endocytosis. The first attempt at PSMA-targeted 
RLT used an antibody (J591). Clinical results were limited with a PSMA fall of 50% seen in only 
10% of patients while 47% of patients developed grade 4 thrombocytopenia.  This initial stumble 
was subsequently followed by stunning results using small molecule urea-based agents.  Using 
small molecules significantly reduced the associated marrow toxicity seen with antibodies due to 
the rapid clearance of blood pool activity, which allows for a marked improvement in the 
therapeutic window and therefore much higher doses can be safely administered. In 2015, a 
PSMA targeted radioligand (177Lu-PSMA-617) was first reported as having the ability to target 
prostate cancer metastases for therapeutic intent. Like other theranostic agents, this compound 
can also be used to image metastatic lesions. 
Subsequently numerous publications demonstrated efficacy of this treatment in CRPC. PSA 
declines of ≥ 50% are typically seen in >50% of heavily pretreated patients (Figure above) 
(Hofman et al. ESMO 2017). Additionally near complete responses (radiographic and PSA) 
have been observed. It should be noted that 177Lu-PSMA-617 is not the only urea-based small 
molecule that is in development for treating prostate cancer, but the approaches being studied 
in this application are broadly applicable to any RLT that targets PSMA. Importantly, tumor 
responses are rapid and frequently observed after just one dose of Lu-PSMA RLT. 
Despite the significant anti-tumor activity with Lu-PSMA RLT, there are several significant 
limitations of this approach as monotherapy: 1) There is significant heterogeneity of PSMA 
expression, both in analysis of individual circulating tumor cells as well as diagnostic PSMA 
PET imaging of metastatic lesions across individual patients, and 2) Within PSMA-avid lesions, 
there is a limited duration of response. In a recently presented prospective phase 2 study of 
Lu-PSMA, despite enriching for patients with more homogenous level of PSMA uptake on 
baseline PET imaging, the median PSA progression-free survival by PCWG criteria was only 
6.3 months (95% CI 4.8 – 8.3), and median overall survival only 12.7 months. Nearly half of the 
30 patients enrolled received less than the pre-specified 4 doses of Lu-PSMA treatment, for 
both toxicity-related reasons (hematologic, salivary gland) as well as rapid disease progression 
following initial response. The reasons for rapid disease progression include baseline 
heterogeneity of PSMA expression among disseminated tumor cells, leading to diffuse bone 
marrow involvement in a subset of patients. There is a clear and unmet medical need to merge 
the rapid anti-tumor responses achieved by Lu-PSMA RLT with a treatment that can both 
sustain and spread response to PSMA-negative lesions without excess cumulative toxicity. 

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Immune checkpoint inhibition, by virtue of antigen spread induced by immunogenic cell death 
induced by antecedent radioligand treatment, may accomplish this goal. 
1.4
Immune Checkpoint Inhibition Leads to Durable Responses in a Minority of 
mCRPC Patients
Single agent immune checkpoint inhibitor treatment, including therapies blocking PD-L1/PD-1 
as well as CTLA-4 mediated signaling, have demonstrated that durable anti-tumor responses 
can be achieved in mCRPC. Immune checkpoint inhibitors including ipilimumab and 
pembrolizumab have led to durable tumor responses in a limited number of cases in mCRPC, 
but increasing the proportion of patients who respond to single agent checkpoint blockade has 
been challenging. Dr. Fong at UCSF led the first in human study of ipilimumab in mCRPC. 
Overall, the tumor immunogenicity, as reflected by mutational burden, tumor infiltrating 
lymphocytes, and tumor PD-L1 expression, are low in prostate tumors relative to other tumor 
types such as melanoma. In the KEYNOTE-028 study of pembrolizumab in mCRPC patients, 
the tissue screen positivity rate for PD-L1 expression in archival tumor tissue was less than 
10%, and even in PD-L1 positive tumors, the objective response rate by RECIST 1.1 criteria 
was only 17%. However, in those patients who experienced a tumor response, there was 
durable regression of disease with median duration of response of over 15 months. For the 
majority of mCRPC patients who do not benefit from single agent immune checkpoint inhibitors, 
there is an unmet medical need to enhance tumor immunogenicity with priming therapy to 
enhance TILs, induce PD-L1 expression, and expand the T cell repertoire, thereby translating 
into a significant improvement in proportion of patients achieving durable tumor response.
1.5
Immunogenic Priming Effect of Radiation Treatment 
Radiation treatment has long been recognized as a means to induce an anti-tumor response by 
the host immune system. The so-called ‘abscopal effect’, well described in prostate and other 
malignancies, is reflective of the ability of radiation treatment to induce antigen spread, thereby 
stimulating the host immune system to generate an anti-tumor response against distant sites of 
disease. More contemporary data provided a mechanistic link between radiation and 
immunogenic priming. Radiotherapy 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. 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. 
Collectively, these data provide a strong link between radiotherapy-mediated induction of host 
anti-tumor immune response. The logical extension of these findings is that with greater the 
magnitude of immunogenic cell death, the greater the host immune response against the tumor, 
with the potential for spreading of host immune response. PSMA-targeted radiotherapy, 
therefore, is predicted to have a significantly higher immunogenic priming effect than focal 
radiation to a solitary metastasis, as well as greater effect than bone-only radioligands such as 
radium-223, which do not lead to cytoreduction in soft tissue metastases (node and/or visceral). 
These hypotheses will be clinically investigated in our proposed proof-of-concept phase 1b 
study. 
1.6
Measures of Immunogenicity Predictive of Outcomes with Immune 
Checkpoint Inhibitors

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Dr. Lawrence Fong (Co-Investigator) has pioneered methods to quantify the immunogenicity of 
systemic anti-cancer therapies and develop biomarkers predictive of long-term response to 
immune checkpoint inhibitors in mCRPC and other tumor types. Dr. Fong has pioneered efforts 
to develop biomarkers to predict for responsiveness to checkpoint blockade with ipilimumab. 
Use of these biomarkers prior to and early in the course of checkpoint inhibitor treatment may 
serve as a key biomarker to predict the immunogenicity of novel checkpoint inhibitor 
combinations applied in the mCRPC setting.  The Fong laboratory used next-generation 
sequencing to measure the frequency of individual rearranged T cell receptor ß (TCRß) genes 
in mCRPC patients, characterizing their clonotypic diversity upon treatment with the anti-CTLA-
4 antibody ipilimumab. Dr. Fong demonstrated that ipilimumab treatment increased TCR 
diversity and the repertoire of clonotypes continued to evolve over subsequent months of 
treatment (Figure 4, above).  Notably, improved overall survival was associated with 
maintenance of high-frequency clones at baseline, as opposed to expansion of clonotypic 
diversity, suggesting that pre-existing activated T cells are important in achieving prolonged 
response and improved survival with immune checkpoint blockade46.  The logical extension of 
these findings, therefore, is to develop novel therapies that first prime the immune system, via 
generation of activated T cells with high TCR avidity, which may increase the proportion of 
durable response in mCRPC with the subsequent application of immune checkpoint inhibition.
1.7
Study Rationale
Despite encouraging data of 177Lu-PSMA in men with advanced prostate cancer, the responses 
are limited in duration. Rather than attempt to continue men on treatment that may become 
ineffective or lead to excessive toxicity, we will utilize Lu-PSMA RLT in a novel way, via 
immunologic priming with subsequent pembrolizumab to maintain response in a durable 
fashion. In this Phase 1b dose escalation/expansion study we will garner the necessary safety 
and preliminary efficacy data to enable a decision whether to proceed to phase 2/3 study with 
this treatment combination. 
1.7.1
Rationale for the Starting Dose and Proposed Dose Schedules of 177Lu-PSMA-617 
in Combination with Pembrolizumab
The proposed starting dose of 177Lu-PSMA-617 will be 7.4 Gbq (+/- 10%), which is the 
recommended phase 2/3 dose of the compound as monotherapy. In the aforementioned 
prospective single arm phase 2 study of 177Lu-PSMA-617 in 30 patients with mCRPC, the dose 
utilized was 8 Gbq (+/- 10%), which yielded acceptable safety and dosimetry results as outlined 
below:

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For the current study, we will investigate a single planned priming dose of 177Lu-PSMA-617 at a 
starting dose of 7.4 GBq (+/- 10%), in combination with the FDA-approved dose and schedule of 
pembrolizumab of 200 mg IV every 21 days. Given the non-overlapping toxicities between these 
two agents, the safety profile of repeated 177Lu-PSMA-617 dosing demonstrated in the prior 
phase 2 study, and the fact that we are planning a single dose of 177Lu-PSMA-617, this is an 
acceptable starting dose level. 
If the DLT frequency exceeds 33% during Cycles 1 and 2 for the first 6 patients enrolled on Part 
A of the study, a lower dose level (Dose Level -1) of 177Lu-PSMA-617 (4 GBq +/- 10%) will be 
investigated for subsequent patients enrolled in Part A. 
With respect to dose schedule, the majority of trials combining radiation-based treatment with 
immune checkpoint inhibition have utilized schedules in which the priming dose of radiation is 
given prior to or concurrently with initiation of immune checkpoint inhibition. However the 
optimal timing of radiation priming is not well established in prospective clinical trials, and 
rationale arguments support giving priming radiation before or after the first dose of immune 
checkpoint inhibition. In the current study, three schedules will be explored in Part A, with 
priming 177Lu-PSMA-617 delivered prior to, concurrently, or following the first dose of 
pembrolizumab, respectively. The aggregate safety, efficacy, and immunologic parameters 
observed in Part A will be utilized to determine the optimal dose/schedule of 177Lu-PSMA-617 in 
conjunction with pembrolizumab to be further evaluated in Part B of the study. 
As of June 1, 2020, 14 patients have been enrolled in Part A of the study. There has been one 
dose-limiting toxicity (Grade 3 inflammatory arthritis in Schedule 2) observed to date. There 
have not been any other Grade ≥ 3 immune related adverse events outside of this DLT, nor any 
Grade ≥ 3 hematologic toxicities attributable to the priming dose of 
177Lu-PSMA-617. 
Encouraging preliminary evidence of efficacy has been observed with objective response rate 
by RECIST 1.1 criteria of 3/6 patients (50%), and the median duration of response has not been 
reached. Below shows a PSA plot of the two of the patients with ongoing objective + PSA90 
responses to treatment. 

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Given the encouraging preliminary efficacy and safety data, as well as to obtain additional 
correlative samples including paired tumor biopsies that may help to further identify patients 
more likely to respond to treatment, we will increase the pre-specified Dose Expansion sample 
size 
from 
12 
to 
25 
patients.   

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2
Objectives and Endpoints of the Study
2.1
Objectives
Primary Objectives
Part A: To determine the recommended phase 2 dose and schedule of 177Lu-PSMA-617 in 
combination with pembrolizumab in patients with mCRPC. 
Part B (Dose Expansion): To determine the objective response rate by RECIST 1.1 criteria.   
Secondary Objectives
1.
To characterize the safety profile of the combination. 
2.
To determine the median duration of response by RECIST 1.1 criteria. 
3.
To determine the proportion of patients who experience ≥ 50% decline from baseline in 
serum PSA. 
4.
To determine the median PSA progression-free survival. 
5.
To determine the median time to symptomatic skeletal related event. 
6.
To determine the 6 month radiographic progression-free survival rate and median 
radiographic progression-free survival. 
7.
To determine the median overall survival. 
Correlative Objectives
1.
To assess the lesion-specific response rate by baseline PSMA avidity on 68Ga-PSMA-11 
PET.
2.
To quantify the change from baseline in T cell repertoire, circulating T cell subsets, tumor 
infiltrating lymphocytes, and tumor PD-L1 expression by immunohistochemistry after one 
priming dose of Lu-PSMA RLT. 
3.
To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with 
initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes. 
4.
To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of 
disease progression.
5.
To explore relationship between tumor genomic profile with clinical outcomes including 
response rate and progression-free survival.
6.
To explore the relationship between tumor dosimetry with objective response.

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2.2
Endpoints
2.2.1
Primary Endpoint
Part A: Safety profile of 177Lu-PSMA-617 in combination with pembrolizumab as graded by 
CTCAE criteria. 
Part B: Objective response rate by RECIST 1.1 criteria
2.2.2
Secondary Endpoints
1.
Frequency and severity of adverse events as defined by CTCAE criteria.
2.
Median duration of response by RECIST 1.1
3.   PSA response rate
4. Radiographic progression-free survival rate at 6 months and median radiographic 
progression-free survival. 
5.  Overall survival
3
Study Design
3.1
Characteristics
This is a single-center Phase 1b open-label, study of PSMA-targeted radionuclide therapy with 
177Lu-PSMA-617 in combination with pembrolizumab in patients with mCRPC who have 
previously progressed on at least one prior androgen pathway inhibitor (e.g. abiraterone, 
enzalutamide, apalutamide). Patients must have at least three metastatic lesions which are 
PSMA-avid on baseline 68Ga-PSMA-11 PET imaging. 
In Part A of the study, patients will be enrolled in sequential fashion to one of treatment 
schedules with respect to timing of 177Lu-PSMA-617 in relation to first dose of pembrolizumab (N 
= 6 evaluable patients per schedule): 
Schedule 1) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 followed by 
pembrolizumab 200 mg IV q 21 days starting Cycle 2 Day 1.
Schedule 2) Priming dose of 177Lu-PSMA-617 administered concurrently with initiation of 
pembrolizumab on Cycle 1 Day 1. 
Schedule 3) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 following initiation 
of pembrolizumab on Cycle 1 Day -21. 
The priming dose of 177Lu-PSMA-617 will be 7.4 +/- 15% GBq, which is the recommended 
phase 3 dose of the agent. If the DLT frequency exceeds 33% including patients across the 
three schedules, Dose Level -1 of 177Lu-PSMA-617 will be investigated (4 Gbq +/- 15%). 
6 evaluable patients will be enrolled in each of the three cohorts in sequential fashion in Part A 
of the study. The DLT window will be Cycle 1 + Cycle 2. If the DLT frequency is ≥ 33% for a 

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particular cohort, that dosing schedule will be determined to be non-tolerable and the next 
schedule will be evaluated. In addition, if the DLT frequency attributable specifically to Lu-
PSMA-617 is ≥ 33% after 6 or more evaluable patients are enrolled in Part A of the study, the 
dose of Lu-PSMA-617 will be reduced to Dose Level -1 (4 GBq +/- 15%) for the remainder of 
patients enrolled on study. If the DLT frequency attributable to Lu-PSMA-617 at Dose Level -1 is 
≥ 33% after 6 or more patients are treated at Dose Level -1, study accrual will be halted. 
Using the data obtained in Part A, the recommended phase 2 dose and schedule of 177Lu-
PSMA-617 will be determined by the DSMC and Principal Investigator using a combination of 
safety, efficacy, and immunologic effects of treatment from the first two cycles (and additional 
cycles of treatment when available). 
In Part B of the study, an additional 25 patients will be enrolled at the recommended phase 2 
dose and schedule to obtain additional safety, efficacy, and immunologic data pertaining to the 
treatment combination.
Number of Subjects
Approximately 43 patients will be enrolled over an accrual period of approximately 18 months (N 
~ 18 patients in Part A; 25 patients in Part B). 
3.2
Randomization
There is no randomization for the study. 
During Part A of the study, patients will be enrolled in sequential fashion to one of three dosing 
schedules of 177Lu-PSMA-617 as outlined above. 6 patients will be enrolled to Schedule 1, 
followed by 6 patients enrolled on Schedule 2, and then 6 patients will be enrolled on Schedule 
3. 
During Part B of the study, all patients enrolled will receive the recommended phase 2 dose and 
schedule of 177Lu-PSMA-617 plus pembrolizumab.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to Cycle 1 Day 1 of treatment and 
must meet all inclusion and none of the 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.
Inclusion Criteria
Part A:
(1)
The subject is able and willing to comply with study procedures and provide signed 
and dated informed consent.
(2)
Male participants who are at least 18 years of age on the day of signing informed 
consent. 

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(3)
Histologically confirmed prostate adenocarcinoma. De novo small cell 
neuroendocrine prostate cancer will not be allowed due to putative lower PSMA 
expression in this tumor subtype. Treatment-emergent small cell neuroendocrine 
prostate cancer detected in metastatic tumor biopsy is not an exclusion.
(4)
A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with 
positive lesions defined as those with SUVmax values greater than liver.  
(5)
Progressive metastatic castration-resistant prostate cancer by PCWG3 criteria at the 
time of study entry. 
(6)
Castrate level of serum testosterone at study entry (< 50 ng/dL). Patients without 
prior bilateral orchiectomy are required to remain on LHRH analogue treatment for 
duration of study
(7)
Prior progression on at least one second generation androgen signaling inhibitor 
including abiraterone, apalutamide, darolutamide, and/or enzalutamide. 
(8)
Adequate hematologic, renal, and liver function, defined as:
•
Absolute neutrophil count > 1.5 x 109/L
•
Hemoglobin > 9.0 g/dL
•
Platelet count > 100,000/microliter
•
Serum creatinine ≤ 1.5 x ULN or estimated GFR > 50 ml/min by Cockroft-
Gault or 24 hour urine collection. 
•
Total bilirubin ≤ 1.5 x ULN. In patients with known or suspected Gilbert’s 
disease, direct bilirubin ≤ ULN. 
•
Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN 
(≤ 5 x ULN in patients with liver metastases). 
(9)
No other systemic anti-cancer therapies administered other than LHRH analogue 
within 14 days, or 5 half-lives, whichever is shorter, prior to initiation of study 
treatment. Adverse events related to prior anti-cancer treatment other than LHRH 
analog treatment must have recovered to Grade ≤ 1 with the exception of any grade 
alopecia and grade ≤ 2 neuropathy. 
(10) Patients must have an ECOG performance status of 0 or 1.
(11) Patients must use appropriate methods of contraception during study treatment and 
for at least 60 days after last study treatment. 
•
Patients who are sexually active should consider their female partner to 
be of childbearing potential if she has experienced menarche and is not 
postmenopausal (defined as amenorrhea > 24 consecutive months) or 
has not undergone successful surgical sterilization. Even women who 

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use contraceptive hormones (oral, implanted, or injected), an intrauterine 
device, or barrier methods (diaphragms, condoms, spermicide) should 
be considered to be of childbearing potential.
•
Patients who have undergone vasectomy themselves should also be 
considered to be of childbearing potential. 
•
Acceptable methods of contraception include continuous total abstinence, 
or double-barrier method of birth control (e.g. condoms used with 
spermicide, or condoms used with oral contraceptives). Periodic 
abstinence and withdrawal are not acceptable methods of contraception.
(12) Patients must provide consent to comply to recommended radioprotection 
precautions during study 
(13) Patients willing to undergo  tumor biopsy and have at least one lesion safely 
accessible to tumor biopsy. Bone or soft tissue lesion is allowed. 
(14) Measurable disease by RECIST 1.1 criteria 
Exclusion Criteria
(1)
Untreated brain metastases at study entry. Patients with previously treated brain 
metastases are eligible provided the following criteria are all met:
•
Last treatment was > 28 days prior to C1D1
•
No evidence of new/progressive brain metastases is observed on MRI 
obtained during Screening window
•
Patient is clinically stable without requirement of steroid treatment for at 
least 14 days prior to first dose of study treatment. 
(2)
Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or 
antibody-drug conjugate).
(3)
Prior enrollment on clinical study investigating Lu-PSMA-based radioligand therapy 
(4)
Prior treatment with radium-223 or other radioisotope for the treatment of prostate 
cancer. 
(5)
Has received prior radiotherapy within 2 weeks of start of study treatment.  
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
(6)
Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. 
nivolumab, ipilimumab). 

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(7)
Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note:  Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
(8)
Receipt of taxane chemotherapy applied in the castration-resistant setting. Prior 
receipt of taxane chemotherapy in the hormone-sensitive setting is allowed.   
(9)
Grade > 2 peripheral neuropathy at the time of study entry
(10)
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.
(11)
Has an 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) 
or treatment with drugs (e.g. neomercazol, carbamazole, etc.) that function to 
decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g 
in Graves’ disease) is not considered a form of systemic treatment of an 
autoimmune disease.
(12)
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a 
prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive 
therapy within 7 days prior to first dose of study drug. 
(13)
Has a history of (non-infectious) ≥ grade 2 pneumonitis/interstitial lung disease that 
required steroids within past 2 years or has current ≥ grade 1 pneumonitis/ 
interstitial lung disease at the time of study enrollment.
(14)
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of study drug.  Administration of killed is allowed.
(15)
Patients who because of age, general medical or psychiatric condition, or 
physiologic status cannot give valid informed consent.
(16)
Has clinically significant cardiovascular disease including, but not limited to:
•
Uncontrolled or any New York Heart Association Class 3 or 4 congestive 
heart failure.
•
Uncontrolled angina, history of myocardial infarction, unstable angina or 
stroke within 6 months before study entry.
•
Clinically significant arrhythmias not controlled by medication. Chronic 
rate controlled or paroxysmal atrial fibrillation/flutter is not an exclusion to 
study participation. 

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(17)
Prior external beam radiation involving ≥ 25% of bone marrow or within 14 days of 
start of protocol therapy.  
(18)
Major surgery within 28 days of study treatment. Note: If participant received major 
surgery, they must have recovered adequately from the toxicity and/or complications 
from the intervention prior to starting study treatment.
(19)
Has an active infection requiring systemic therapy 
(20)
Has a known history of HIV (screening not required). 
(21)
Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection (screening not required)
(22)
Has a known history of active TB (Bacillus Tuberculosis).  
(23)
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
(24)
Any condition that, in the opinion of the Principal Investigator, would impair the 
patient’s ability to comply with study procedures
(25)
History of bleeding diathesis and not currently on anti-coagulation therapy that 
cannot be safely discontinued for the tumor biopsy procedure.
3.4
Duration of Study Treatment
Patients will be treated until disease progression per PCWG3/RECIST 1.1 criteria, confirmed by 
repeat scans performed ≥ 4 weeks later, unacceptable toxicity, or patient withdrawal, whichever 
occurs first.
Patients with PSA-only progression in absence of radiographic or unequivocal clinical 
progression should remain on study treatment. 
3.5
Subject Replacement 
All subjects who receive the priming dose of 177Lu-PSMA treatment will be analyzed for study 
outcomes.  
Subjects who withdraw from study participation prior to receiving dose of 177Lu-PSMA-617 will 
be not be evaluable and will be replaced. 
3.6
Study Timeline
3.6.1
Primary Completion
The study is anticipated to accrue 2-3 patients per month for an estimated accrual period of 21 
months. The study is expected to reach completion for analysis of primary and secondary 
endpoints approximately 36 months from first patient enrolled. 

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4
Study Treatment
Treatment regimen
177Lu-labeled PSMA is a PSMA-targeted radioligand that will be produced under Current Good 
Manufacturing Practice (CGMP) regulations. 
In Part A of the study, patients will be enrolled in sequential fashion to one of three treatment 
schedules with respect to timing of 177Lu-PSMA-617 in relation to first dose of pembrolizumab (6 
evaluable patients per schedule): 
Schedule 1) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 followed by 
pembrolizumab on Cycle 2 Day 1.
Schedule 2) Priming dose of 177Lu-PSMA-617 administered concurrently with initiation of 
pembrolizumab on Cycle 1 Day 1. 
Schedule 3) Priming dose of 177Lu-PSMA-617 administered on Cycle 1 Day 1 following initiation 
of pembrolizumab on Cycle 1 Day -21. 
Pembrolizumab will be given at the FDA approved dose of 200 mg via IV every 3 weeks. 
Dose-limiting toxicity data, additional safety data beyond Cycle 2 where available, 
along with efficacy and pharmacodynamic data, will be utilized to determine the 
recommended phase 2 dose and schedule of 177Lu-PSMA-617 in combination with 
pembrolizumab to be utilized in Part B of the study.  
4.1
177Lu-PSMA-617
4.1.1
Chemical and physical characteristics
177Lu-PSMA-617 contains a radionuclide (177Lu) chelated to PSMA, a PSMA ligand consisting of 
a Glu-urea motif and DOTA chelator connected by a lipophilic linker. 
Lutetium (177Lu) decays to stable hafnium (177Hf) with a half-life of 6.7 days, by emitting β- 
radiation with a maximum energy of 0.498 MeV and photonic radiations (γ) of 0.208 MeV 
(11.0%) and 0.113 MeV (6.4%). The main radiations are detailed in Table 1, and physical decay 
summarized in Table 2.
Radiation
Energy (keV)
Iβ%
Iγ%
β-
176.5
12.2
-
β-
248.1
0.05
-
β-
384.9
9.1
-
β-
497.8
78.6
-
γ
71.6
-
0.15

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γ
112.9
-
6.40
γ
136.7
-
0.05
γ
208.4
-
11.0
γ
249.7
-
0.21
γ
321.3
-
0.22
Table 1. 177Lu main radiation.
Hours
Fraction Remaining
Hours
Fraction Remaining
0
1.000
48 (2 days)
0.813
1
0.996
72 (3 days)
0.733
2
0.991
168 (7 days)
0.485
5
0.979
336 (14 days)
0.235
10
0.958
720 (30 days)
0.045
24 (1 day)
0.902
1080 (45 days)
0.010
Table 2. Physical decay chart for 177Lu.
4.1.2
Drug preparation
Administration procedures should be carried out in a way to minimize risk of contamination from 
the medicinal product and accidental irradiation of the operators. It is necessary to wear 
waterproof gloves and suitable effective protection when handling 177Lu-PSMA-617. 
Flow valves should be manipulated aseptically when connecting them to the infusion system. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
and federal laws. 
The solution should be inspected visually prior to use, and only clear colorless to yellowish 
solutions free of visible particles should be used. The visual inspection of the solution should be 
performed under a shielded screen for radioprotection purposes. 
The amount of radioactivity in the radiopharmaceutical vial must be measured with an 
appropriate and calibrated device prior to infusion in order to confirm that the actual amount of 
radioactivity to be administered is equal to the planned amount at the infusion time. 

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4.1.3
Patient preparation
Patient should be encouraged to drink a sufficient amount of water necessary to urinate every 
hour on the day of infusion and the day after. Patient should be encouraged to defecate every 
day and to use laxative if needed.
The doctor will explain to the patient the general recommendations and precautions that should 
be followed to limit radiation exposure to third parties.
To avoid treatment-related nausea and vomiting, it is recommended to inject an intravenous 
bolus of 5-HT3 receptor antagonist (e.g. ondansetron 8mg) 30 minutes before the start of 177Lu-
PSMA infusion.
4.1.4
Concomitant hydration (renal protection)
Concomitant infusion of intravenous fluids is required for renal protection. This infusion should 
start 30 minutes before the start of 177Lu-PSMA-617. 500 – 1000 mL of normal saline should be 
administered between 250-500 mLs per hour. During the administration of IV fluids, the patient 
should be encouraged to urinate as frequently as possible. 
 
4.1.5
Method of administration
177Lu-PSMA is a ready to use single dose vial.
177Lu-PSMA must be administered by slow intravenous infusion, over a 20 to 30-minute time 
span (see Appendix 4 for administration method examples).
177Lu-PSMA must not be injected as a bolus.
The following table summarizes the required procedure.
Table 5. 177Lu-PSMA administration procedure
Product to inject
Start time 
(hr)
(+/- 30 min)
Infusion rate* 
(mL/h)
Duration
5-HT3 receptor antagonist (e.g. ondansetron 
8mg)**
0
Bolus
-
Hydration (normal saline)
0
250—550
- 
177Lu-PSMA
0.5
-
20-30 minutes
* Infusion rates may be reduced at the discretion of the physician.
** Additional prophylactic antiemetic regimen may be given at the discretion of the treating physician as clinically 
indicated (e.g. Prochlorperazine, Aprepitant, Lorazepam).

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After the administration is completed, the infusion line and 177Lu-PSMA vial must be immediately 
flushed with at least 25 mL of sodium chloride 9 mg/mL solution for injection, unless the infusion 
method used already requires NaCl to flow through the vial and the line.
4.1.6
Dose Limiting Toxicities and Criteria for Dose De-Escalation
The starting dose level of 177Lu-PSMA-617 is 7.4 GBq (+/- 15%). 
Patients will be assessed for dose-limiting toxicities during Cycle 1 and 2 for patients enrolled in 
Part A of the study, defined as any of the following AEs occurring during Cycle 1 or 2: 

Any non-hematologic treatment-related AE ≥ Grade 3, with the exceptions of Grade 3 
nausea, vomiting, diarrhea, constipation, fever, fatigue, skin rash, or non-clinically 
significant laboratory abnormality that resolves to Grade ≤ 2 within 72 hours with optimal 
medical management.

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with Grade > 1 bleeding or 
requirement for platelet transfusion.  

Grade 4 neutropenia lasting for > 5 consecutive days 

Grade ≥ 3 febrile neutropenia.
6 evaluable patients will be enrolled in each of the three cohorts in sequential fashion in Part A 
of the study. If the DLT frequency is ≥ 33% for a particular cohort, that dosing schedule will be 
determined to be non-tolerable and the next schedule will be evaluated. In addition, if the DLT 
frequency attributable specifically to Lu-PSMA-617 is ≥ 33% after 6 or more evaluable patients 
are enrolled in Part A of the study, accrual will be temporarily halted and the dose of Lu-PSMA-
617 will be reduced to Dose Level -1 (4 GBq +/- 15%) for the remainder of patients enrolled on 
study. If the DLT frequency attributable to Lu-PSMA-617 at Dose Level -1 is ≥ 33% after 6 or 
more patients are treated at Dose Level -1, study accrual will be halted. 
Patients who discontinue study for reasons other than treatment related toxicity during prior to 
the completion of two cycles of therapy, or those who discontinue study prior to receiving 
priming dose of 177Lu-PSMA-617, will be considered inevaluable for purposes of DLT 
determination. 
4.1.7
Contraindications to 177Lu-PSMA-617
Hypersensitivity to the active substance or to any of the excipients.
4.1.8
Adverse reactions to 177Lu-PSMA-617

Nausea 

Fatigue 

Xerostomia 

Hypogeusia 

Anorexia

Bone pain

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
Dry eyes

Thrombocytopenia

Neutropenia

Anemia
4.1.9
Drug interactions
There are no known drug interactions with 177Lu-PSMA-617. 
4.1.10 Warnings and precautions
General warnings and precautions
Given the tolerance profile of 177Lu-PSMA, it is not recommended to start a treatment in the 
following cases:

Previous external beam radiotherapy involving more than 25% of the bone marrow

Renal failure with serum creatinine > 1.5 mg/dL or estimated creatinine clearance < 50 
mL/min

Impaired hematological function with either Hb < 9 g/dL, platelets < 100 x 109/L, or ANC 
< 1.5 x 109/L
Radiation exposure 
See Appendix 4 and 5 for full details regarding protection from radiation exposure. 
It is recommended that the patient urinate as much as possible during this period. Urine and 
feces should be disposed according to the regulation. The patient can leave the controlled area 
or the hospital only when radiation exposure to third parties does not exceed regulatory 
thresholds. 
As long as there is no accidental contamination, such as from the leakage of the infusion 
system or because of urinary incontinence, radioactivity contamination is not expected on the 
patient’s skin. However, it is recommended that when conducting standard care or exams with 
medical devices or other instruments which contact the skin (e.g. ECG), basic protection 
measures be observed such as wearing gloves, installing the material/electrode before the start 
of radiopharmaceutical infusion, changing the material/electrode after measurement, and 
eventually monitoring the radioactivity of equipment after use.
At the time of release, patients are given written instructions (Appendix 5) which outline the 
precautions the patient must take to minimize radiation exposure to people around them. 
Men of childbearing potential 
Ionizing radiations of 177Lu-PSMA-617 may potentially have temporary toxic effects on male 
gonads. Due to the presence of the radionuclide in the product, men of childbearing potential 
must refrain from childbearing by using effective contraception methods during treatment with 
177Lu-PSMA and for 2 months after last dose.  
Fertility 

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Fertility can be temporarily affected in men due to radiation damage to Sertoli cells, as 
evidenced by a decrease of inhibin-B and a concomitant increase of FSH (Teunissen et al., 
2009). Fertility is usually restored 12 to 18 months after treatment. Cryopreservation of sperm 
might be offered to male patients before treatment.
4.1.11 Overdosage
Overdose is unlikely with 177Lu-PSMA-617 as this medicinal product is supplied as a “single 
dose” and “ready to use” product containing a predefined amount of radioactivity.
In the event of administration of a radiation overdose with 177Lu-PSMA:

If not clinically contraindicated, hydration should be reinforced during the first 48 hours 
after infusion. Frequent bladder voiding must also be suggested to the patient. This will 
contribute to reducing the radiation dose to the patient by increasing the elimination of 
the radionuclide from the body

If possible, an estimate of the radiation dose given to the patient should be performed

Forced diuresis might also be considered

For the next 10 weeks, the following should be carried out every week:
o
Hematologic monitoring: white blood cells, platelets, and hemoglobin
o
Blood chemistry monitoring: serum creatinine and liver functions.
4.1.12 Packaging and Labeling
177Lu-PSMA-617 will be prepared, packaged, labeled, and released under Good Manufacturing 
Practice (GMP) guidelines, ICH Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations. 
4.1.13 Handling of Medication
177Lu-PSMA-617 must be administered at the investigational site.
The medication must be handled and administered only by qualified/authorized personnel and 
must be prepared in accordance with pharmaceutical quality requirements, and radiation safety 
regulations for 177Lu-PSMA-617.
4.2
Pembrolizumab
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.
Pembrolizumab will be provided by Merck as summarized in the Table below:

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Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
4.3
Packaging and Labeling Information
Supplies will be labeled in accordance with regulatory requirements.
4.4
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, 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.
4.5
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.
4.6
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 participants and the 
amount remaining at the conclusion of the trial. 
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.
4.7
Administration 
See manufacturer’s guidelines as described in the package insert.
4.8
Dose modification for Pembrolizumab

No dose reductions of pembrolizumab will be permitted. Immune related adverse events 
requiring more than a 12 week interruption of pembrolizumab should discontinue study 
treatment (as outlined below in Table 5.3) but remain in follow up until the time of 
disease progression by RECIST 1.1 criteria or receipt of non-protocol therapy. 

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
Adverse events other than those listed below in the Table below should be attributed to 
the specific study medication whenever possible (Please see Section 6.3.2.5 Attribution 
of Adverse Events for more information).  

Pembrolizumab-related Grade 4 AEs requires permanent discontinuation of study 
treatment. 

For intolerable treatment-related Grade 2 AEs, pembrolizumab may be held per 
investigator discretion. 

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The following dose modification rules will be used with respect to potential toxicity. Toxicity will be assessed according to the NCI 
Common Terminology Criteria for Adverse Events. 
Dose Interruptions/Discontinuation for Specific Adverse Events Related to Pembrolizumab
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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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
Hypophysitis
Grade 2
Withhold
  Administer corticosteroids and initiate 
  Monitor for signs and symptoms of hypophysitis 

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Grade 3 or 4
Withhold or 
permanently 
discontinue d
hormonal replacements as clinically 
indicated
(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
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or 
DRESS
Withhold
  Based on severity of AE administer 
  Ensure adequate evaluation to confirm etiology 

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Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
corticosteroids
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 (e.g. vasculitis and schlerosing cholangitis).

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Supportive Care Measures and Concomitant Medications
Patients who have not had prior bilateral orchiectomy must continue LHRH analogue treatment 
to maintain castrate level of testosterone during the course of study treatment. 
The use of bone-modifying agents (e.g. zoledronic acid, denosumab) is permitted as clinically 
indicated. 
The use of growth factors (e.g. G-CSF) is allowed as clinically indicated for the treatment of 
Grade ≥ 3 cytopenias. 
The use of any other systemic anti-cancer therapies other than outlined in the protocol is 
prohibited during the course of study treatment. 
Focal radiation treatment to symptomatic metastases following C1D1 of study will require 
discontinuation from study. 
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each AE, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the events to 
be related to pembrolizumab.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event.
Pneumonitis:
o For Grade 2 events, treat with systemic corticosteroids (e.g. oral prednisone 1 
mg/kg or equivalent). When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.
o For Grade 3-4 events, immediately treat with IV steroids (e.g. solumedrol 1-2 
mg/kg every 6-8 hours). Administer additional anti-inflammatory measures, as 
needed. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).

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o All subjects who experience 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 administered via IV infusion. For Grade 2 or higher 
diarrhea, consider gastroenterology consultation and endoscopy to confirm or 
rule out colitis.
o For Grade 2 diarrhea/colitis, administer oral corticosteroids (e.g. oral 
prednisone 1 mg/kg or equivalent). When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks.
o For Grade 3 or 4 diarrhea/colitis, treat with IV steroids (e.g. solumedrol 1-2 
mg/kg every 6-8 hours) followed by high dose oral steroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o For T1DM or Grade 3-4 Hyperglycemia
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.
Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.
Hypophysitis:
o For Grade 2 events, treat with corticosteroids (e.g oral prednisone 1 mg/kg/day). 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids (e.g 
solumedrol 1-2 mg/kg every 6-8 hours) for 24-48 hours, followed by high dose 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o Grade 2 hyperthyroidism events and Grade 2-4 hypothyroidism:

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In hyperthyroidism, non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy.
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per SOC.
o Grade 3-4 hyperthyroidism
Treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
Hepatic:
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
Treat with IV or oral corticosteroids (e.g. prednisone 1 mg/kg/day or 
equivalent).
o For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 hours (e.g. 
solumedrol 1-2 mg/kg every 6-8 hours), followed by transition to oral high dose 
steroids (e.g. prednisone 1 mg/kg/day or equivalent).
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.
Renal Failure or Nephritis:
o For Grade 2 events, treat with oral corticosteroids (e.g. prednisone 1 mg/kg/day).
o For Grade 3-4 events, treat with IV corticosteroids (e.g. solumedrol 1-2 mg/kg 
every 6-8 hours) for 24-48 hours followed by transition to oral high dose steroid 
(e.g. prednisone 1 mg/kg/day or equivalent).
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.

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The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion  
interruption not indicated; 
intervention
not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
None
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs
Stop Infusion and monitor 
symptoms. Additional appropriate 
medical therapy may include but is not 
limited to:
IV fluids Antihistamines NSAIDS
Acetaminophen Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing 
will be held until symptoms resolve 
and the subject should be 
premedicated for the next scheduled 
dose.
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with:
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic).

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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grades 3 or 4 
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication  and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids Antihistamines NSAIDS
Acetaminophen Narcotics Oxygen 
Pressors Corticosteroids Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently 
discontinued from further trial 
treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
5
Study Procedures 
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.
The Study Calendar summarizes the trial procedures to be performed at each visit according to 
the assigned Treatment Schedule (Schedule 1, Schedule 2, or Schedule 3, respectively). 
Screening assessments must be performed within 28 days prior to the initiation of protocol 
therapy. Any results falling outside of the reference ranges may be repeated at the discretion of 
the investigator. All on-study 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.
Individual trial procedures are described in the study schedule below. It may be necessary to 
perform these trial procedures at unscheduled time points if deemed clinically necessary by the 
investigator.

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Furthermore, additional evaluations/testing may be deemed necessary by the investigator for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g. HIV, hepatitis C), 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.
5.1
Discontinuation of Therapy
Study treatment will be discontinued at the first occurrence of one of the following:

Radiographic progression by RECIST 1.1/PCWG3 criteria, confirmed by repeat scans 
performed at least 4 weeks following first scans showing progression. 

Unequivocal clinical progression
Note: Patients without clinical or radiographic evidence of disease progression, 
with PSA-only progression, should continue to receive protocol therapy.

Unacceptable toxicity (as described in section 4.8)

Recurrent Grade 2 pneumonitis

Patient withdrawal from study

Investigator withdrawal of patient due to concerns for patient compliance with study 
protocol procedures

Receipt of non-protocol systemic anti-prostate cancer therapy

Death

Completion of 35 treatments (approximately 2 years) with pembrolizumab
Note: The number of treatments is calculated starting with the first dose.  Participants 
who stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed below. Participants may be retreated in the Second Course Phase 
(Retreatment) for up to an additional 17 cycles (approximately 1 year).
Second Course of Pembrolizumab *
All participants who stop study treatment with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress 
after stopping study treatment from the initial treatment phase.  This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains 
open and the participant meets the following conditions:
Either

Stopped initial treatment with study treatment after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of study treatment before discontinuing treatment, and
o
Received at least 2 treatments with pembrolizumab beyond the date when the initial CR 
was declared
OR

Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability

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AND

Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and
o
No new anticancer treatment was administered after the last dose of study treatment, 
and
o
The participant meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria, and
o
The study is ongoing
An objective response or disease progression that occurs during the Second Course 
Phase for a participant will not be counted as an event for the primary analysis of either 
endpoint in this study.
*Note: patients must have measurable disease at the start of protocol treatment to be 
eligible for this provision.

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5.2
Study Calendar: Schedule 1 (177Lu-PSMA-617 prior to Pembrolizumab)
Treatment
End of Treatment
Safety Follow up
Cycle 1
Cycle 2+
(+/- 3 days unless 
otherwise noted)
30 Days (+/- 7 
days) post-last 
dose
90 Days (+/- 14 
days) post last 
dose
Screening
(Day -28 
to -1 
unless 
otherwise 
noted)
D1
(-3 
days)
D2
D8
(+/- 1 
day)
D15
(+/- 1 
day)
D1 (+/- 3 days)
+ 21 days
Informed consent
x
Medical history
x
Baseline conditions
x
Concurrent medications
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
ECOG Performance status 
x
x
x
x
x
x
x
x
Physical exam and vital 
signs
x
x
x
x
x
x
x
x
CBC and Serum Chemistry 
Panel1,2
x
x
x
x
x3
x
x
x
Thyroid function tests2,4
x
x
x
x
x
PSA2
x
x
x
x
x
x
Testosterone
x
68Ga-PSMA-11 PET/CT or 
PET/MR
x5
x
Disease assessment 
x
x
x
1 Chemistry panel to include: sodium, potassium, chloride, bicarbonate, BUN/creatinine, glucose, calcium, total bilirubin, AST, ALT, alkaline phosphatase
2 Labs may be collected within a window of up to 3 days prior to each dose of pembrolizumab.
3 CBC + differential will be measured on C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, Day 1 of C3+, and additionally as clinically indicated.
4 TSH (with reflex free T3/T4) testing to be performed during Screening, Cycle 2 Day 1, and Day 1 of every other cycle thereafter.
5 Allow for a 12-week window for the screening PSMA PET scan. PSMA PET at End of Treatment is optional. 

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Treatment
End of Treatment
Safety Follow up
Cycle 1
Cycle 2+
(+/- 3 days unless 
otherwise noted)
30 Days (+/- 7 
days) post-last 
dose
90 Days (+/- 14 
days) post last 
dose
Screening
(Day -28 
to -1 
unless 
otherwise 
noted)
D1
(-3 
days)
D2
D8
(+/- 1 
day)
D15
(+/- 1 
day)
D1 (+/- 3 days)
+ 21 days
(CT/MR, BS)6
Tumor Biopsy7
x
x
Whole blood for immune 
correlatives8
x
x
x
177Lu-PSMA-617 infusion 
x
SPECT/CT Dosimetry9
X
Normal Saline
x
Anti-emetic pre-medication
x
Pembrolizumab infusion
x
AE assessment
x
x
x
x
x
x
x
6 Tumor assessment will be performed with CT chest/and/pelvis + whole body bone scan during Screening, C4D1 (-14d), C7D1 (-14d), and Day 1 (-14d) of every 4 cycles thereafter. If 
disease progression by RECIST 1.1/PCWG3, confirmatory scans are required ≥ 4 weeks following first scan showing progression.
7 Tumor biopsy will be performed during Screening and within 7 days preceding C2D1 visit. Screening biopsy must be performed prior to initiation of study treatment but is not subject 
to 28-day screening window. Bone biopsies are acceptable if no soft tissue lesion is amenable for biopsy. The same lesion should be selected for the follow up biopsy whenever 
feasible.
8 Whole blood (40 mL in Na-Heparin green top tube) will be collected on C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-dose), on Day 1 of every 3 cycles thereafter (e.g. C6D1, 
C9D1, etc), and at the time of disease progression
9 SPECT/CT dosimetry scan is optional. 

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5.3
Study Calendar – Schedule 2 (Concurrent Dosing)
Treatment
End of Treatment
Safety Follow up
Cycle 1
Cycle 2+
(+/- 3 days unless otherwise 
noted)
30 Days (+/- 7 
days) post-last 
dose
90 Days (+/- 14 
days) post last 
dose
Screening
(Day -28 
to -1 
unless 
otherwise 
noted)
D1
(-3 
days)
D2
D8
(+/- 1 
day)
D15
(+/- 1 
day)
D1
(+/- 3 days)
+ 21 days
Informed consent
x
Medical history
x
Baseline conditions
x
Concurrent medications
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
ECOG Performance status 
x
x
x
x
x
x
x
x
Physical exam and vital signs
x
x
x
x
x
x
x
x
CBC and Serum Chemistry 
Panel1,2
x
x
x
x
x3
x
x
x
Thyroid function tests2,4
x
x
x
x
x
PSA2
x
x
x
x
x
x
Testosterone
x
68Ga-PSMA-11 PET/CT or 
PET/MR
x5
x
Disease assessment (CT/MR, 
x
x
x
1 Chemistry panel to include: sodium, potassium, chloride, bicarbonate, BUN/creatinine, glucose, calcium, total bilirubin, AST, ALT, alkaline phosphatase
2 Labs may be collected within a window of up to 3 days prior to each dosing of pembrolizumab.
3 CBC + differential will be measured on C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, Day 1 of C3+, and additionally as clinically indicated.
4 TSH (with reflex free T3/T4) testing to be performed during Screening, Cycle 1 Day 1, Cycle 2 Day 1, and Day 1 of every other cycle thereafter. 
5 Allow for a 12-week window for the screening PSMA PET scan. PSMA PET scan at End of Treatment is optional. 

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Treatment
End of Treatment
Safety Follow up
Cycle 1
Cycle 2+
(+/- 3 days unless otherwise 
noted)
30 Days (+/- 7 
days) post-last 
dose
90 Days (+/- 14 
days) post last 
dose
Screening
(Day -28 
to -1 
unless 
otherwise 
noted)
D1
(-3 
days)
D2
D8
(+/- 1 
day)
D15
(+/- 1 
day)
D1
(+/- 3 days)
+ 21 days
BS)6
Tumor Biopsy7
x
x
Whole blood for immune 
correlatives,8
x 
x
x
177Lu-PSMA-617 infusion 
x
SPECT/CT Dosimetry9
X
Normal Saline
x
Anti-emetic pre-medication
x
Pembrolizumab infusion
x
x
AE assessment
x
x
x
x
x
x
x
6 Tumor assessment will be performed with CT chest/and/pelvis + whole body bone scan during Screening, C4D1 (-14d), C7D1 (-14d), and Day 1 (-14d) of every 4 cycles thereafter. If 
disease progression by RECIST 1.1/PCWG3, confirmatory scans are required ≥ 4 weeks following first scan showing progression.
7 Tumor biopsy will be performed during Screening and within 7 days preceding C2D1 visit. Screening biopsy must be performed prior to initiation of study treatment but is not subject 
to 28-day screening window. Bone biopsies are acceptable if no soft tissue lesion is amenable for biopsy. The same lesion should be selected for the follow up biopsy whenever 
feasible.
8 Whole blood (40 mL in Na-Heparin green top tube) will be collected on C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-dose), on Day 1 of every 3 cycles thereafter (e.g. C6D1, 
C9D1, etc), and at the time of disease progression. 
9 SPECT/CT dosimetry scan is optional. 

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5.4
Study Calendar – Schedule 3 (177Lu-PSMA-617 following Pembrolizumab)
Treatment
End of Treatment
Safety Follow up
Cycle 1
Cycle 2+
(+/- 3 days unless 
otherwise noted)
30 Days (+/- 7 
days) post-last 
dose
90 Days (+/- 14 
days) post last 
dose
Screening
(Day -49 
to -21 
unless 
otherwise 
noted)
D-21 (-3 
days)
D1
(- 3 days)
D2
D8
(+/- 1 
day)
D15
(+/- 1 
day)
D1
(+/- 3 days)
+ 21 days
Informed consent
x
Medical history
x
Baseline conditions
x
Concurrent medications
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
x
x
x
x
x
ECOG Performance 
status 
x
x
x
x
x
x
x
x
x
Physical exam and vital 
signs
x
x
x
x
x
x
x
x
x
CBC and Serum 
Chemistry Panel1,2
x
x
x
x
x
x3
x
x
x
Thyroid function tests2,4
x
x
x
x
x
x
PSA2
x
x
x
x
x
x
x
Testosterone
x
68Ga-PSMA-11 PET/CT or 
PET/MR5
x5
x
1 Chemistry panel to include: sodium, potassium, chloride, bicarbonate, BUN/creatinine, glucose, calcium, total bilirubin, AST, ALT, alkaline phosphatase
2 Labs may be collected within a window of up to 3 days prior to each dosing of pembrolizumab.
3 CBC + differential will be measured on C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, Day 1 of C3+, and additionally as clinically indicated.
4 TSH (with reflex free T3/T4) testing to be performed during Screening, Cycle 1 Day 1, Cycle 2 Day 1, and Day 1 of every other cycle thereafter.
5 Allow for a 12-week window for the screening PSMA PET scan. PSMA PET scan at End of Treatment is optional. 

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Disease assessment 
(CT/MR, BS)6
x
x
x
Tumor Biopsy7
x
x
Whole blood for immune 
correlatives8 
x
x
x
x
177Lu-PSMA-617 infusion 
x
SPECT/CT Dosimetry9
X
Normal Saline
x
Anti-emetic pre-
medication
x
Pembrolizumab infusion
x
x
x
AE assessment
x
x
x
x
x
x
x
x
6 Tumor assessment will be performed with CT chest/and/pelvis + whole body bone scan during Screening, C4D1 (-14d), C7D1 (-14d), and Day 1 (-14d) of every 4 cycles thereafter. If 
disease progression by RECIST 1.1/PCWG3, confirmatory scans are required ≥ 4 weeks following first scan showing progression.
7 Tumor biopsy will be performed during Screening and within 14 days preceding C3D1 visit. Screening biopsy must be performed prior to initiation of study treatment but is not 
subject to 28-day screening window. Bone biopsies are acceptable if no soft tissue lesion is amenable for biopsy. The same lesion should be selected for the follow up biopsy 
whenever feasible. PSMA-avid lesion should be prioritized for biopsy; non-PSMA avid lesion may be used if no PSMA-avid lesion is accessible.
8 Whole blood (40 mL in Na-Heparin green top tube) will be collected on C1D-21 (pre-dose), C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-dose), on Day 1 of every 3 cycles 
thereafter (e.g. C6D1, C9D1, etc), and at the time of disease progression.
9 SPECT/CT dosimetry scan is optional. 

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6
Reporting and Documentation of Results
6.1
Evaluation of efficacy (or Activity)
6.1.1
Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of the first study drug administration.
6.2
Evaluation of Safety
Analyses will be performed for all patients receiving the radiotracer.  The study will use the 
CTCAE v4.0 for reporting of adverse events.
Any patient with Grade >3 hematologic toxicity will be followed with weekly CBC with differential 
until resolved to Grade 2 or lower.
6.3
Definition of Adverse Events
6.3.1
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. 
6.3.2
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.
6.3.2.1 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.
6.3.2.2 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. 

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“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 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.
6.3.2.3 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

Is a new cancer

Is associated with an overdose
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.
6.3.2.4 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. 
6.3.2.5 Attribution of Adverse Events
The toxicity profiles of the two investigational agents are largely non-overlapping, which should 
facilitate adverse event attribution to the specific agent. Hematologic toxicity will be attributed to 
Lu-PSMA-617 unless there is clear evidence of autoimmune cytopenia. Xerostomia will be 
attributed to Lu-PSMA-617 unless clear evidence of other autoimmune sequelae. Conversely, 
immune-related AEs such as colitis, pneumonitis, transaminitis will be attributed to 
pembrolizumab. In cases where attribution to a specific agent is not possible, the timing of onset 
in relation to timing of initiation of Lu-PSMA and pembrolizumab will be utilized. In cases where 
adverse event attribution to a single agent is not possible, attribution will be to study regimen 

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and dose modification criteria for both agents will be utilized. The PI will have the final 
determination of adverse event attribution that is reported.
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 AE Table.
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 177Lu-PSMA-617  alone or to pembrolizumab alone, for adverse 
events listed in AE Table 6, both interventions must be held according to the criteria in AE Table  
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab.
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 AE Table.

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 AE Table, the 
combination of 177Lu-PSMA-617  and pembrolizumab may be restarted at the discretion of 
the investigator. In these cases where the toxicity is attributed to the combination or to 177Lu-
PSMA-617 alone, re-initiation of pembrolizumab as a monotherapy may be considered at 
the principal investigator’s discretion .

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6.4
Recording of an Adverse Event
All grade 3 and above adverse events will be recorded using the NCI CTCAE v4.0.   The 
Investigator will assign attribution of the possible association of the event with use of the 
investigational drug. 
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
6.5
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  
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.
6.6
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

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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 (Section 7.3): 

Suspected adverse reaction

Unexpected 

Serious 
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
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 2 working days to Merck 
.
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 following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck 
.
All participants with serious adverse events must be followed up for outcome.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA. 
Investigators will cross reference this submission according to local regulations to the Merck 

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Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. 
 
 the time of submission to FDA.
Expedited Reporting to PrimeVigilance
All AEs, SAEs, and SUSARs, related to 177Lu-PSMA-617 will be reported to:
PrimeVigilance 
 
SAEs and SUSARs must be reported to PrimeVigilance within 2 working days. 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck 
 
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck 
 
.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must be 
reported within 2 working days to Merck 
 if it causes the participant to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.

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For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck 
.
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined above, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
7
Measurement of Response
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, with use of 
PCWG criteria for assessment of new/pre-existing bone lesions. Changes in only the longest 
diameter (unidimensional measurement- LD) of the tumor lesions are used in the RECIST 
criteria.
Note: lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. All measurements should be taken and recorded in metric 
notation using a ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 30 days before the beginning of the 
treatment. The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment.
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols.

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7.1
Measurable disease/ Target lesions
All measurable lesions (lesions that can be accurately measured in at least one dimension 
[longest diameter to be recorded] as ≥10mm with spiral CT) up to a maximum of 2 lesions per 
organ and 5 lesions total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the basis 
of their size (lesions with the longest diameter) and the suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum 
LD will be used as a reference by which to characterize the objective tumor response.
Lymph node metastases must measure 1.5 cm or greater in short axis diameter to be 
considered target lesions, while other target lesions must measure 1 cm or greater (with spiral 
CT scans).17
Complete Response (CR):
Disappearance of all target lesions
Partial Response (PR):
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the 
baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started (including baseline 
LD), or the appearance of one or more new lesions
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started (including 
7.2
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level
Incomplete Response/ Stable 
Disease (SD):
Persistence of one or more non-target lesion(s), and/or 
maintenance of tumor marker level above the normal limits
Progressive Disease (PD):
Appearance of one or more new lesions, and/or 
unequivocal progression of existing non-target lesions
Although a clear progression of non-target lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail and the progression status should be 
confirmed later on by the study chair.

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7.3
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started, including baseline; see table below). The 
patient's best response assignment will depend on the achievement of both measurement and 
confirmation criteria.
7.4
Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies no less than 4 weeks after the criteria for response are first met. In the case of 
SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum of 12 weeks after study entry.
7.5
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The duration of overall complete response 
is measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented.
Target Lesions
Non-Target Lesions
New Lesions
Response
CR
CR
No
CR
CR
Incomplete response/SD No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
7.6
Evaluation of non-measurable bone disease per PCWG Criteria
Bone scans obtained after the baseline evaluation will be used to evaluate post-treatment 
changes. Bone scans obtained will be evaluated as either “no new lesions” or “new lesions” on 
the tumor measurement forms.
a. For the first scheduled reassessment: New lesions at the first scheduled evaluation (9 
weeks) will require a confirmatory bone scan 6 or more weeks later. If no new lesions 
are observed on the confirmatory bone scan, study therapy is continued. If additional 
new lesions are observed, then the patient has experienced progression. Progression 
in this situation is dated as the time of the first reassessment scan.

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b. For subsequent scheduled reassessments: If no new lesions are observed, study 
therapy will continue. If new lesions are observed, this is evidence of disease 
progression. Date of progression is the date at which the scan was obtained.
7.7
Post-treatment PSA Changes
All patients will be evaluated for PSA decline. Patients with disease that is not measurable will 
be eligible for this study and will be assessed for response based on changes in PSA and serial 
bone scans (if appropriate). The baseline serum PSA must be at least 2 ng/mL. Patients who 
show PSA increases will not be evaluated for PSA progression prior to 12 weeks of study 
therapy.
a. 30% and 50% PSA Decline: PSA decline of at least 30% and 50%, respectively, from 
baseline confirmed by a second measurement at least 3 weeks later. The reference for 
these declines should be a PSA measured within 2 weeks prior to starting therapy.
b. PSA Progression: Prostate Cancer Working Group 2 (PCWG2) Criteria will be reported. 
PSA progression occurs when the PSA has increased 25% or greater above nadir and 
an absolute increase of 2 ng/mL or more from the nadir is documented. Where no 
decline is observed, PSA progression similarly occurs when a 25% increase from 
baseline value along with an increase in absolute value of 2 ng/mL or more. Patients 
will receive a minimum of 12 weeks of therapy prior to being evaluable for this 
endpoint. PSA progression (without evidence of progression on scans) will not be 
criteria for discontinuation of study therapy.
c. PSA Response Duration: The PSA response duration commences on the date of the 
first 50% decline in PSA. The response duration ends when the PSA value increases 
by 25% above the nadir, provided that the increase in the absolute-value PSA level is 
at least 5 ng/mL or back to baseline, whichever is lower.
d. Progressive Disease by PSA (as defined by PSA Progression, above)
e. Time to PSA Progression: The start of the time to PSA progression is the day treatment 
is initiated. The end date is the date of the first PSA rise over the determined PSA PD 
value.
7.8
Progressive disease (PD)
Progressive disease will be defined by any one of the following:
1. Appearance of new metastatic lesions outside the bone
2. New metastatic lesions on bone scan confirmed as described above
3. Development of an indication for radiotherapy while on treatment
4. Unequivocal progression of non-target lesions
5. Global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression

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Note that PSA progression (as defined above) alone does not meet the criteria for progressive 
disease.
8
Statistical Considerations 
8.1
Sample Size Justification
The sample size determination is based on the primary endpoints of the study, to determine the 
maximally tolerated and recommended phase 2 dose and schedule of the combination. 6 
patients will be enrolled at each of the three planned cohorts in Part A of the study. Therefore, 
up to 18 evaluable patients total will be enrolled in Part A.  
In Part B, the primary efficacy endpoint is objective response rate by RECIST 1.1 criteria. A 
sample size of N = 25 patients is chosen to provide a preliminary estimate of the response rate 
with the recommended phase 2 dose and schedule of 177Lu-PSMA-617 in combination with 
pembrolizumab. Using a historical control objective response rate with pembrolizumab 
monotherapy in mCRPC of 10% (e.g. KEYNOTE-028 study, in press Annals of Oncology), and 
an alternative hypothesis of ORR = 40%, a sample size of 25 patients provides 93% power to 
detect a difference of this magnitude in ORR with a bi-directional level of significance of 0.05. 
8.2
Accrual
The estimated accrual period is 21 months, and total study duration (first patient enrolled to last 
patient off study) is 36 months. 
8.3
Interim Analyses
Patients in Part A will be evaluated for dose-limiting toxicities during the first two cycles of 
treatment as outlined above in Section 7.1. 
In Part B, an interim safety analysis will be performed after 6 patients are enrolled. If the DLT 
frequency exceeds 33%, study accrual will be halted and alternative dose and schedule of Lu-
PSMA-617 may be evaluated based on the prior results of Part A of the study.  
8.4
Analytic Plan
8.4.1
Analytic Plan for Primary Endpoints
Part A:
The recommended phase 2 dose and schedule of 177Lu-PSMA-617 will be determined from the 
aggregate of the safety and efficacy data observed. 
Part B:
Objective response is defined as the best response (complete response or partial response) 
defined by RECIST v1.1, from the start of treatment until disease progression or recurrence, 
where the reference for progressive disease is the smallest measurements recorded from start 
of treatment. To be assigned a status of objective response (CR or PR), changes in tumor 
measurements must be confirmed by repeat scans no less than 4 weeks after the criteria for 

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response are first met. The proportion of patients with objective response will be descriptively 
reported with 95% confidence interval.
8.4.2
Analytic Plan for Secondary Endpoints
Median duration of response
Median duration of response will be estimated using Kaplan-Meier product limit method, starting 
with the date of first scan indicating response until loss of response or progression, or death, 
whichever occurs first. 
PSA response rate
The proportion of patients who achieve a greater than 50% decline from baseline PSA drawn on 
C1D1, at any point in the treatment course, will be descriptively reported along with 95% 
confidence interval. 
PSA progression free survival
PSA progression will be defined using PCWG3 criteria. Median PSA progression free survival 
will be estimated using the Kaplan-Meier method. Duration will be measured from date of first 
treatment to date of first PSA meeting criteria for PSA progression. 
Time to symptomatic skeletal related event
Symptomatic skeletal related event is defined as the first occurrence of one or more of the 
following: symptomatic fracture, surgery or radiation to bone, or spinal cord compression. The 
median time to symptomatic skeletal related event will be determined using Kaplan-Meier 
method. 
Safety
The incidence and severity of adverse events related to study treatment will be descriptively 
reported using CTCAE v4.0.
Radiographic progression free survival and 6-month rPFS rate:
Radiographic progression of disease will be defined by RECIST v1.1 and PCWG3 criteria. For 
the first scheduled reassessment by bone scan (at Cycle 2), new bone lesions will require a 
confirmatory bone scan 6 or more weeks later. Median PFS will be estimated using the Kaplan-
Meier method. Durations will be measured from the first day of study treatment (Cycle 1) to the 
first date of radiographic progression or death, whichever occurs first. Patients who discontinue 
study treatment for toxicity, withdraw from the study, or have PSA-only progression will be 
censored at the date of the last radiographic tumor assessment. Patients who discontinue 
treatment for clinical progression or deterioration will be included in the analysis.
Overall survival
Median overall survival and 95% confidence interval will be estimated using the Kaplan-Meier 
method. Duration will be measured from first date of study therapy to date of death from any 
cause. 

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8.4.3
Analytic Plan for Correlative Endpoints
Lesion-specific response rate by baseline PSMA avidity on 68Ga-PSMA-11 PET:
All target lesions on baseline cross-sectional imaging will be assessed for response (e.g. > 30% 
reduction in longest diameter) on subsequent imaging during the course of study. The median 
baseline uptake on Ga-PSMA-11 PET between responding versus non-responding lesions will 
be compared using Mann-Whitney test. In addition, Spearman’s rank correlation will be used to 
compare baseline lesion uptake on Ga-PSMA-11 PET with percent change from baseline in 
longest tumor diameter on subsequent cross-sectional imaging on study. 
Percent change from baseline in T cell repertoire, circulating T cell subsets, tumor infiltrating 
lymphocytes, and tumor PD-L1 expression by immunohistochemistry after one priming dose of 
Lu-PSMA RLT:
T cell repertoire will be estimated using Morasita’s distance as previously described. 
Quantification of circulating T cell subsets and TILs will be performed using flow cytometry and 
immunohistochemical analysis of tumor tissue and whole blood, respectively. PD-L1 expression 
will be analyzed as the percentage of tumor cells with positive surface expression. Correlative 
testing may be performed at outside laboratory facilities (i.e. Strata Oncology).  The percent 
change from baseline in these parameters will be reported using descriptive statistics (e.g. 
median, range, standard deviation). In an exploratory fashion, the study cohort will be 
dichotomized by those with percent change from baseline above and below median and efficacy 
outcomes will be compared between dichotomized subgroups using log-rank test for time-to-
event endpoints (e.g. rPFS, duration of response) and Fisher’s exact test for categorical 
variables (e.g. objective response rate, 6-month rPFS rate, PSA50 response rate). 
Genomic Sequencing
We will utilize only CLIA-certified laboratories (e.g. Strata Oncology) to identify genetic 
mutations within mCRPC tumors to provide genetic information that can be returned to patient 
to potentially inform treatment decisions. Certain genomic sequencing will be performed by 
Strata Oncology.  Strata Oncology is a precision oncology company that utilizes the 
StrataNGS assay, which is a 90-gene targeted assay that detects actionable genetic 
alterations (standard of care markers and clinical trial eligibility markers). The assay 
sequences DNA and RNA from FFPE slides or blocks for specific single nucleotide variants, 
multi-nucleotide variants, small insertions and deletions, gene fusions, exon skipping 
mutations, copy number changes, and de novo deleterious mutations in tumor suppressor 
genes. The StrataNGS assay will also measure expression levels for some immuno-oncology 
biomarkers that are not yet reported clinically, this data will be available to Strata for 
correlative analyses and future test expansion.
Tests are ordered online by physicians through a secure Physician Portal, and the patient's 
leftover tumor material is shipped to the laboratory (e.g. Strata Oncology) for testing. Positive 
and negative genomic alterations are reported and associated FDA-approved therapies and 
clinical trials are noted. The UCSF treating physician will discuss the results with the patient 
(including matched drug trials and approved therapies). Participant information (name, DOB, 
MRN, subject ID) will be provided to the testing laboratory to ensure that patients continue to 
have access to their genetic sequencing data should they decide to seek care elsewhere 
besides UCSF. Laboratories performing testing will not contact patients at any point during or 

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after study participation. Sample blocks sent to the testing laboratories will be returned to 
UCSF and will not be stored at these laboratories for future testing. Consenting to participate 
in this study does not enroll the participant in Strata’s separate observational study – The 
Strata Trial (NCT03061305). Participants would need to sign a separate consent form for 
Strata Oncology to use the data for any other purpose other than what is specified in this 
protocol. 
Association Between Tumor Dosimetry with Response 
Patients will undergo optional SPECT/CT dosimetry scan on C1D2, approximately 24 hours 
after completion of priming dose of 177Lu-PSMA-617. The median tumor dosimetry on 
SPECT/CT between responding versus non-responding lesions will be compared using 
Mann-Whitney test. In addition, Spearman’s rank correlation will be used to compare tumor 
dosimetry on SPECT/CT with percent change from baseline in longest tumor diameter on 
subsequent cross-sectional imaging on study. 
9
Study Management
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.  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 

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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. 
9.4
Changes in the Protocol
Once the protocol has been approved by the IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the 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.
10
Protection of Human Subjects
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. 
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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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 Data and Safety Monitoring Plan for a Phase 1 Study
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study include: 

Review of subject data

Review of suspected adverse reactions considered “serious”

Monitoring every six months (depending on study accrual)

Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and subject safety and discuss each 
subject’s treatment at monthly Site Committee meetings. These discussions are documented in 
the Site Committee meeting minutes. The discussion will include the number of subjects, 
significant toxicities in accordance with the protocol, and observed responses.
All institutional Phase 2 or 3 studies are designated with a moderate risk assessment. The data 
is monitored twice per year with twenty percent of the subjects monitored (or at least three 
subjects if the calculated value is less than three).
Adverse Event Review and Monitoring
All grade(s) 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®, UCSF’s Clinical 
Trial Management System.
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.
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 within 
1 business day of knowledge of this event. The contact may be by phone or e-mail.
Increase in 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, a report should be submitted to 
the DSMC 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 Brochure or 
package insert.
If at any time the Investigator stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC 
must receive a formal letter within 10 business days and the IRB must be notified.
The decision to proceed to Part B of the study must be approved by DSMC. 

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Data and Safety Monitoring Committee Contacts:
DSMC Chair: 
Robin Kate Kelley, MD
DSMC Monitors 
Phone: 
Email:
Address: 
UCSF
UCSF Helen Diller Family 
Comprehensive Cancer Center

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Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:

IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals

Current and prior approved protocol versions with signed protocol signature page(s)

IRB approval letters and Informed Consent Form(s) (ICF)

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event Reporting

Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting 
fax documentation
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial) or Investigator Brochure

Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)

Patient handouts

Screening/enrollment log

Data and Safety Monitoring Committee (DSMC) monitoring reports

OnCore® Case Report Form (CRF) completion manual

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Documents Filed in Regulatory Binder:

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)

Site Initiation Visit (SIV) minutes and correspondence with participating site(s).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center

Serious Adverse Event (SAE) reports to IRB and sponsor.

MedWatch reporting to FDA and sponsor

Delegation of Authority Form

Drug Destruction Standard Operating Procedure (SOP)

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges

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Appendix 4 Radioprotection Precautions for Patients Treated with 177Lu-PSMA
TECHNICAL DATA
The principle characteristics of lutetium-177 (177Lu) are specified in Table 1 (from Les 
principales caractéristiques du 177 lutetium (177Lu) and Guide Pratique Radionucléides & 
Radioprotection, D. Delacroix, J.P. Guerre, P. Leblanc, EDP Sciences, 2004).
Table 1. Characteristics of 177Lu.
177Lu is generally produced using enriched 176Lu placed in a reactor, following a reaction of the 
type [176Lu n,γ 177Lu]. This reaction results in the production of a small amount of 177Lu meta-
stable (177mLu) which varies according to sources between 10-5 and 4 x 10-4 per MBq of 177Lu 
produced. The characteristics of this radionuclide are given in Table 2.
Table 2. Characteristics of 177mLu.
RECOMMENDATIONS
Based on radiation exposure calculations employing whole body clearance data (Wehrmann C 
et al, 2007) and exposure rates at one meter at 24 h (7.5 ± 3.6 μSv/h, Dpt. of Nucl. Med. 
Erasmus MC Rotterdam), patients may be treated on an outpatient basis for an administration 
of 177Lu-PSMA. As a precaution, it is recommended that patients be kept in radiation isolation for 
a period of 4–5 hours following administration, and be allowed to urinate during that time, and 
before release. This precaution is deemed prudent because this is the primary method of 
elimination. At the time of release, the patient is given written instructions which summarize the 
precautions to take, in order to keep the exposure to others below regulatory limits.

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Appendix 5 Recommended Precautions for Patients Treated with 177Lu-PSMA
Below are recommendations for radiation safety when administered 177Lu-PSMA-617.  The 
local radiation safety officer will meet with each patient and develop a plan to minimize the 
potential exposure.  In accordance with the medical staff, you have agreed to receive a 
treatment using a radioactive medicine. The efficacy of this medicine in treating your tumor is 
due to the radioactivity; but this is also the reason why it is necessary to follow certain 
precautions in order to limit the exposure of the people around you.
Considering current knowledge and experience in the field and the physical and 
radiopharmaceutical properties of the radiopharmaceutical, it is estimated that the health risks to 
your family members and the general public are low. However, you must adhere to the following 
rules to maximize the safety of other persons. These rules are the result of many years of 
experience in the use of radioactivity in medicine, and they include recommendations issued by 
international organizations.
1.
General rule
You must avoid close contact with people who live with you, and should try to keep a distance of 
at least one meter for 2 to 3 days after you receive each treatment.
2.
Use of toilets
Toilets must be used in a seated position, even for men. It is absolutely necessary to use toilet 
paper each time. It is also important to wash your hands to avoid contaminating the door 
handles. It is strongly recommended to move your bowels every day and use a laxative if 
necessary. Furthermore, drink frequently and try to urinate every hour on the day you received 
treatment and on the two following days. Follow your doctor’s advice on how much fluid to drink.
3.
Contact with children less than 10 years old
It is strongly recommended to limit contact with children who are less than 10 years old for 7 
days after the administration.
4.
The spouse and people in the family circle
It is strongly advised to sleep in separate beds at a distance of at least 1 meter. Sexual activity 
is not advised for 7 days after each treatment.
Potential consequences do not justify additional particular recommendation concerning elderly 
persons.
Contact with pregnant women should follow the same restrictions as recommended for children 
less than 10 years old.
5.
Contraception and pregnancy
Due to the radionuclide part of this radiopharmaceutical, men of child-bearing potential must 
refrain from procreation by using effective contraceptive methods during the treatment and for 2 
months after. 

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6.
People who need extra assistance
People who are confined to the bed or have reduced mobility will preferably receive assistance 
by a care provider. It is recommended that when providing assistance in the bathroom, the care 
provider wear disposable gloves for 2-3 days after each administration. In the case of the use of 
special medical equipment such as catheters, colostomy bags bedpan, water nozzle, or 
anything that could be contaminated by your body fluids, they must be emptied immediately in 
the toilet and then cleaned. If anyone helps you clean up vomit, blood, urine, or stool they 
should wear plastic gloves; the gloves should then be put in the specified trash plastic bag 
(according to the recommendation stated in Section 8 below).
7.
Dishes and bathroom accessories
For the first two days after your treatment wipes and/or toilet paper must be flushed down the 
toilet. Always wash your hands well after using the toilet.
It is strongly recommended to shower every day for at least the first 7 days after your treatment.
Try to flush any tissues or any other items that contain anything from your body, such as blood, 
urine and feces down the toilet (at least for two days after administration). Items that cannot be 
flushed, such as menstrual pads and bandages, must be placed in specified plastic trash bags 
(according to the recommendation stated in Section 8).
Wash your underwear, pajamas, sheets and any clothes that contain sweat, blood or urine 
separately from the laundry of others in your household. Wash your items two or three times; 
use a standard washing machine; you do not need to use bleach and do not need extra rinses.
8.
Trash recommendations
Keep the specified plastic trash bags separate from other trash. Keep the bags away from 
children and animals.
A member of the medical staff will tell you how and when to get rid of the specified plastic trash 
bag. You may be asked to bring the bag back to your treatment facility, or, after 70 days, the 
bag may be removed as other household waste.
9.
Professional activities
Impact of the treatment on the ability to conduct professional activities has not been studied. 
Your general condition and the possible adverse reactions to treatment will be taken into 
account by your doctor to assess this ability.
10. Hospitalization
In the case that an unplanned hospitalization occurs, it is important to notify your doctor.
11. Emergency care
Carry your discharge letter with you at all times for at least 3 months after treatment with 177Lu-
PSMA.

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If for any reason you require emergency medical assistance during the first week after your 
treatment, you should inform the medical providers about the nature, the date and the dose of 
your radioactive treatment.
12. Travel
Keep the discharge letter with you whenever you are travelling for at least 3 months after 
treatment.
13. Summary of the most important recommended precautions after each 177Lu-PSMA 
administration
Restriction to be followed after each administration of 
177Lu-PSMA
Number of days
You may return to work after
2 to 3 days
Avoid close contract (less than 1 meter) with children (less 
than 10 years old) and pregnant woman for
7 days
Day-time 
restrictions
Avoid extended time in public places for 
2 to 3 days
Sleep in a separate bed (separated by at least 1 meter) for 
2 to 3 days
Sleep in a separate bed from infants or children for
7 days
Night-time 
restrictions
Sleep in a separate bedroom from pregnant partners for
15 days

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Appendix 6  National Cancer Institute Common Terminology Criteria for Adverse 
Events
Refer to the following website for complete CTCAE guide, version 4.0.3.
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf