A Phase 2 Study of 68Ga-PSMA-11 PET in Patients With Metastatic Castration Resistant Prostate Cancer
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Sponsor: Thomas Hope

A Phase 2 Study of 68Ga-PSMA-11 PET in Patients with 
Metastatic Castration Resistant Prostate Cancer
Protocol Number:  CC # 209211
Investigational Product(s):  68Ga-PSMA-11
Version Number:  1.6
Version Date:  11/08/2022
IND Number:  127621
NCT Number: NCT04716725
Principal Investigator
Ivan de Kouchkovsky, MD
University of California San Francisco
E-mail: 
Co-Principal Investigator (IND Holder)
Thomas Hope, MD
Assistant Professor
UCSF Comprehensive Cancer Center
Nuclear Medicine and Abdominal Imaging
Statistician
Li Zhang, PhD 
Revision History
Version 1.0 
04/05/2020
Version 1.1
04/17/2020
Version 1.2
06/04/2020
Version 1.3
Version 1.4
08/12/2020
09/21/2021
Version 1.5
01/25/2022
Version 1.6
11/08/2022

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Version date: 11/08/2022
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PSMA PET in Advanced Prostate Cancer
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Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review and 
Monitoring Committee (PRMC), Institutional Review Board (IRB), and Data and Safety 
Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices 
(GCP) and the applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date

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PSMA PET in Advanced Prostate Cancer
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Abstract
Title
A Phase 2 Study of 68Ga-PSMA-11 PET in Patients with Metastatic 
Castration Resistant Prostate Cancer
Study Description
This is a phase 2 study investigating the utility of Ga-PSMA-11 PET in 
patients with metastatic castration resistant prostate cancer.   
Phase of Study
Phase 2
Investigational 
Products
68Ga-PSMA-11 at a dose of 3-7 mCi will be administered at up to three 
time points per patient, including baseline, after 16 weeks (+/- 8 
weeks) of systemic treatment, and at the time of disease progression. 
Study population
Approximately 100 patients with metastatic castration-resistant 
prostate cancer planning to receive, or currently receiving systemic 
therapy will be enrolled. 
Primary Objective
To determine whether the percent change from baseline to 16 weeks 
(+/- 8 weeks) in SUVmax averaged across up to a maximum of 16 
lesions per patient (SUVmax-ave) is associated with ≥ 50% decline from 
baseline in serum Prostate specific antigen (PSA50) response.
Secondary 
Objectives

To determine whether the percent change from baseline in 
SUVmax-ave on PSMA PET is associated with time-to-event 
endpoints including Prostate specific antigen (PSA) 
progression-free survival and overall survival.

To determine whether the percent change from baseline in 
SUVmax on PSMA PET is associated with objective response 
by RECIST 1.1 on a per-lesion basis among measurable soft 
tissue lesions present at baseline.

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Exploratory 
Objectives

To descriptively characterize the histologic, transcriptional, 
and genomic features of PSMA low/negative lesions among 
patients who undergo paired optional metastatic tumor 
biopsy.

To descriptively characterize the relationship between 
SUVmax-ave on baseline Ga-PSMA PET with optional baseline 
FDG-PET. 

To determine whether heterogeneity of PSMA expression on 
baseline Ga-PSMA PET is associated with overall survival. 

To descriptively characterize the patterns of PSMA 
expression at the time of disease progression among patients 
who undergo optional PSMA PET.  

To determine whether the percent change from baseline in 
PSMA PET is associated with PSA50 response among 
subgroups of patients defined by treatment modality received, 
including AR targeting treatment, PSMA-targeting radioligand 
therapy, cytotoxic chemotherapy, and immunotherapy.
Sample Size
Approximately 100 evaluable patients with metastatic castration-
resistant prostate cancer will be enrolled.  
Duration of Study 
Participation
Participants will receive Ga-PSMA-11 PET imaging at baseline, 16 
weeks (+/- 8 weeks) after initiating therapy, and optional imaging at 
time of progression, as defined by Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) criteria. After progression, survival follow-
up will be performed every 3 months. 
Study Schema
3

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List of Abbreviations
AE
adverse event
CBC
complete blood cell (count)
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
GCP
Good Clinical Practice
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IND
investigational new drug application
IRB
Institutional Review Board
IV
intravenous
LDH
lactate dehydrogenase
MRI
magnetic resonance imaging
NCI
National Cancer Institute
PR
partial response
PRC
Protocol Review Committee (UCSF)
PSA
Prostate specific antigen
PSA50
≥ 50% decline from baseline in serum PSA 

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Table of Contents
Protocol Signature Page ............................................................................................................2
Abstract
3
List of Abbreviations...................................................................................................................5
Table of Contents.......................................................................................................................6
1
Introduction.....................................................................................................................8
1.1
Background on mCRPC, Shortcomings of Conventional Imaging to 
Monitor Treatment Response in mCRPC..................................................8
1.2
Ga-PSMA PET in Newly Diagnosed and Biochemically Recurrent 
Prostate Cancer ..........................................................................................8
1.3
Preliminary Data with Ga-PSMA PET in Metastatic Castration Resistant 
Prostate Cancer ..........................................................................................8
1.4
Rationale for Inclusion of Optional Paired Tumor Biopsy and FDG-PET9
1.5
Overall Study Rationale.............................................................................9
2
Study Objectives and Hypotheses .................................................................................9
2.1
Hypothesis .................................................................................................9
2.2
Primary Objective and Endpoint(s) .........................................................10
2.3
Secondary Objective(s) and Endpoint(s).................................................11
2.4
Exploratory (Correlative) Objectives.......................................................11
3
Study Design................................................................................................................12
3.1
Characteristics..........................................................................................12
3.2
Sample Size..............................................................................................12
3.3
Eligibility Criteria....................................................................................12
3.3.1
Inclusion Criteria ..........................................................................................12
3.3.2
Exclusion Criteria .........................................................................................13
3.4
Inclusion and Recruitment of Minorities.................................................13
3.5
Duration of Study Participation...............................................................13
3.6
Primary Completion.................................................................................14
3.7
Study Completion ....................................................................................14
3.8
Study Termination ...................................................................................14
4
Investigational Product: 68Ga-PSMA-11.......................................................................14
4.1
Dosage and Administration .....................................................................14
4.2
Description, Supply and Storage .............................................................14
4.3
Accountability Records for Investigational Product................................14
4.4
Ordering Investigational Product.............................................................15
5
Study Procedures and Schedule of Events..................................................................15
5.1
Study Calendar.........................................................................................16
5.2
Participant Registration............................................................................19
5.3
Schedule of Procedures and Assessments ...............................................19
5.3.1
Screening Assessments .................................................................................19
5.3.2
Baseline 68Ga-PSMA-11 PET/MRI or PET/CT ...........................................20
5.3.3
Baseline Tumor Biopsy and Circulating Tumor Nucleic Acid Collection 
(Optional – Within 12 weeks of Baseline PSMA PET) ............................................20

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Table of Contents
5.3.4
Baseline FDG PET (Optional – within 12 weeks of Baseline PSMA PET).20
5.3.5
Initiation of Systemic Therapy......................................................................21
5.3.6
Follow up 68Ga-PSMA-11 PET (16 weeks +/- 8 weeks from date of 
systemic treatment initiation) ....................................................................................21
5.3.7
Time of Disease Progression by PCWG3 Criteria (Optional)......................21
5.3.8
Long Term Survival Follow Up....................................................................21
5.4
Dietary Restrictions .................................................................................22
5.5
Prohibited Medications............................................................................22
6
Reporting and Documentation of Results ....................................................................22
6.1
Evaluation of Safety.................................................................................22
6.2
Definitions of Adverse Events.................................................................22
6.2.1
Adverse Event...............................................................................................22
6.2.2
Adverse Reaction..........................................................................................22
6.2.3
Suspected Adverse Reaction.........................................................................22
6.2.4
Recording of Adverse Events .......................................................................24
6.2.5
Follow-up of Adverse Events .......................................................................24
6.2.6
Adverse Events Monitoring ..........................................................................24
6.2.7
Expedited Reporting .....................................................................................24
7
Statistical Considerations and Evaluation of Results ...................................................25
7.1
Imaging Analysis.....................................................................................25
7.2
Sample Size Considerations.....................................................................25
7.2.1
Sample Size and Power Estimate..................................................................25
7.2.2
Accrual Estimates .........................................................................................25
7.3
Interim Analyses......................................................................................25
7.4
Analyses Plans.........................................................................................26
7.4.1
Analysis Population ......................................................................................26
7.4.2
Primary Analysis (or Analysis of Primary Endpoints) .................................26
7.4.3
Secondary Analysis (or Analysis of Secondary Endpoints) .........................26
8
Study Management ......................................................................................................27
8.1
Pre-study Documentation ........................................................................27
8.2
Institutional Review Board Approval......................................................27
8.3
Informed Consent ....................................................................................27
8.4
Changes in the Protocol...........................................................................27
8.5
Handling and Documentation of Clinical Supplies .................................28
8.6
Case Report Forms (CRFs)......................................................................28
8.7
Oversight and Monitoring Plan................................................................28
8.8
Record Keeping and Record Retention ...................................................29
9
References...................................................................................................................30
Appendix 1
Performance Status Criteria............................................................................33
Appendix 2
Data and Safety Monitoring Plan ....................................................................34

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1
Introduction
1.1
Background on mCRPC, Shortcomings of Conventional Imaging to Monitor 
Treatment Response in mCRPC
Prostate cancer is the most common cancer in men in the US, with over 170,000 estimated new 
cases and 31,000 deaths in 2019.1 Androgen deprivation therapy is the cornerstone of 
treatment for all patients with metastatic disease, or for those who have failed definitive therapy. 
Although most patients respond to ADT at first, resistance invariably develops, and metastatic 
castration resistant prostate cancer remains an incurable disease. Accurate assessment of 
disease burden is often needed to select optimal therapy in patients with metastatic disease.2–4 
Early recognition of resistance can help to avoid unnecessary treatment and prevent cancer-
related morbidity and mortality. Assessment of treatment response in mCRPC is currently 
performed through serial measurements of serum (Prostate specific antigen) PSA and cross-
sectional imaging with computerized tomography (CT), magnetic resonance imaging (MRI) and 
bone scintigraphy. Yet these conventional imaging modalities have several limitations in the 
monitoring of treatment response in mCRPC.5–7 Morphological imaging (such as CT scan and 
MRI) relies on size and anatomical changes to assess treatment response. It may fail to detect 
non-enlarged nodal metastases or early bone marrow involvement, and cannot measure 
skeletal metastases in the absence of a soft tissue component.7 By visualizing secondary 
osteoblastic changes rather than underlying tumor, bone scintigraphy lacks specificity and may 
lag behind treatment changes.6 Novel and more accurate markers of disease burden and 
treatment response are needed for patients with mCRPC.
1.2
Ga-PSMA PET in Newly Diagnosed and Biochemically Recurrent Prostate 
Cancer
Ga-PSMA PET is one of several novel molecular imaging modalities that have recently emerged 
in the field of prostate cancer.6 Using radiolabeled small molecules targeted at PSMA on the 
surface of prostate cancer cells, Ga-PSMA PET demonstrates excellent tumor-to-background 
ratio with little physiological uptake in normal tissue. It is not limited by morphologic size criteria, 
and unlike bone scintigraphy can directly visualize bony metastasis.6 Ga-PSMA PET imaging 
has had a significant impact on the management of early state prostate cancer. In a recently 
published multicenter randomized trial of 302 men with high-risk, clinically localized disease, 
Ga-PSMA PET was more accurate than conventional imaging with CT and bone scanning for 
identifying pelvic nodal or distant metastases.8 Other studies have also shown increased 
sensitivity and specificity over conventional imaging for the localization of recurrent disease in 
patients with rising PSA after definitive therapy.9,10 Although its impact on patient outcomes 
remains to be determined, Ga-PSMA PET is quickly emerging as an alternative to conventional 
imaging for the staging of men with early prostate cancer.
1.3
Preliminary Data with Ga-PSMA PET in Metastatic Castration Resistant 
Prostate Cancer
By comparison, the role of Ga-PSMA PET in patients with mCRPC is less established. Ga-
PSMA PET imaging has been used to select patients for PSMA-targeted radioligand therapy, 
and pre-treatment PSMA uptake appears to predict PSA response to such therapies.11–13 
Prospective studies of serial Ga-PSMA PET imaging in men with mCRPC starting novel 
hormone therapies (e.g. abiraterone or enzalutamide) have reported heterogeneous initial 
increases in PSMA uptake despite PSA responses, suggestive of an early flare 
phenomenon.14,15 Yet these studies are limited by their small sample sizes and short follow-up 
intervals; the clinical significance of these early changes in PSMA uptake is unclear. On the 

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other hand, several retrospectives studies using longer imaging intervals have shown an 
association between changes in Ga-PSMA PET parameters and treatment response.16–18 In one 
such analysis of PSMA-targeted imaging in mCRPC, radiological response at 3 to 6 months was 
concordant with biochemical response in 56 of 68 patients started on abiraterone therapy.19 
Changes in PSMA uptake were also associated with progression free survival. These data 
suggest that Ga-PSMA PET imaging may have a role in monitoring treatment response in 
patients with mCRPC, with key theoretical advantages over conventional imaging for the 
assessment of bony metastases and early nodal metastases. Whether treatment mechanism of 
action,20 or other baseline characteristics modulate PSMA response to therapy remains to be 
determined.
1.4
Rationale for Inclusion of Optional Paired Tumor Biopsy and FDG-PET
Whereas PSMA is uniformly expressed in the early prostate cancer, variable levels of PSMA 
expression have been reported in patients with castration-resistant disease.21 PSMA expression 
is inversely related to neuroendocrine biomarker genes,21 and treatment-emergent small-cell 
neuroendocrine prostate cancer (SCNC) may present as a low-uptake lesion on PSMA-based 
imaging.22 Additionally, up to 25% of patients screened for enrollment in PSMA-targeted 
radioligand therapy fail to meet inclusion criteria due to low- or heterogeneous-PSMA 
expression.11,12,23 “Discordant” metastases on serial Ga-PSMA- and FDG-PET imaging, with low 
PSMA and high Fluorodeoxyglucose (FDG) uptake, have also been described. Limited existing 
data on this subset of patients suggests a particularly aggressive cancer phenotype,23 however 
the histologic and genomic features of this disease entity have yet to be defined. Furthermore, 
heterogeneous treatment effect and/or prior localized therapy may also contribute to intra-
patient variations in PSMA expression. To address this and to better differentiate treatment-
related PSMA suppression from discordant disease, we will offer an optional FDG-PET scan to 
patients with low- or heterogeneous PSMA uptake.24 Additionally, we will offer optional paired 
tumor biopsies in selected patients with low PSMA expression, or heterogeneous PSMA uptake 
on Ga-PSMA PET imaging. As the use of Ga-PSMA PET imaging in mCRPC increases, there is 
an urgent need to better characterize these different patterns of PSMA expression. By 
quantifying variations in PSMA expression levels in patients with mCRPC, Ga-PSMA PET may 
offer non-invasive molecular insight into the underlying biology of advanced prostate cancer.
1.5
Overall Study Rationale
68Ga-PSMA-PET has been shown to have significant utility and clinical impact in the detection of 
prostate cancer in newly diagnosed and biochemically recurrent patients. Preliminary 
retrospective evidence suggests that in patients with metastatic castration resistant prostate 
cancer, decline from baseline in PSMA PET upon application of systemic therapies in mCRPC 
may be associated with subsequent response, however this link has not been definitively 
established. A subset of patients with mCRPC may also present with low or heterogeneous 
PSMA expression, which may be associated with a poor prognosis. We aim to prospectively 
investigate the association between response on PSMA PET with subsequent treatment 
outcomes. We also hope to describe the clinical histologic, genomic features of patients with low 
or heterogeneous PSMA expression.
2
Study Objectives and Hypotheses
2.1
Hypothesis
We hypothesize that decline from baseline in uptake on Ga-PSMA-PET will be associated with 
PSA response. 

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2.2
Primary Objective and Endpoint(s)
Primary Objective
Endpoint(s)
Time Frame
1.
To determine whether the percent change 
from baseline to 16 weeks (+/- 8 weeks) in 
SUVmax averaged across up to 16 lesions 
per patient (SUVmax-ave) is associated with 
PSA50 response

Association 
between 
percent 
change from 
baseline to 
16 weeks 
(+/- 8 weeks) 
in SUVmax 
averaged 
across up to 
16 lesions 
per patient 
(SUVmax-ave) 
with PSA50 
response, 
defined by 
≥ 50% 
decline from 
baseline in 
serum PSA. 
Baseline to 16 
weeks (+/- 8 
weeks) after 
initiation of 
therapy

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2.3
Secondary Objective(s) and Endpoint(s)
Secondary Objective
Endpoint(s)
Time Frame
1.
To determine whether the percent change 
from baseline in SUVmax-ave on PSMA PET is 
associated with time-to-event endpoints 
including PSA progression-free survival by 
Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3)26 criteria and overall 
survival.
Association between 
percent change from 
baseline in SUVmax-ave 
on PSMA PET with 
time-to-event 
endpoints including 
PSA progression-free 
survival by PCWG3 
criteria and overall 
survival.
Baseline to 
time of 
progression 
Baseline to 
time of death
2.
To determine whether the percent change 
from baseline in SUVmax on PSMA PET is 
associated with objective response by 
Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.127 on a per-
lesion basis among measurable soft tissue 
lesions present at baseline
Association between 
percent change from 
baseline in SUVmax 
on PSMA PET with 
objective response 
by RECIST 1.1 on a 
per-lesion basis 
among measurable 
soft tissue lesions 
present at baseline.
Baseline to 
time of 
objective 
response
2.4
Exploratory (Correlative) Objectives
Exploratory Objective
1.
To descriptively characterize the histologic, transcriptional, and genomic features 
of PSMA low/negative lesions among patients who undergo paired optional 
metastatic tumor biopsy.
2.
To descriptively characterize the relationship between SUVmax-ave on baseline Ga-
PSMA PET with optional baseline FDG-PET.
3.
To determine whether heterogeneity of PSMA expression on baseline Ga-PSMA 
PET is associated with overall survival.
4.
To descriptively characterize the patterns of PSMA expression at the time of 
disease progression among patients who undergo optional PSMA PET.  
5.
To determine whether the percent change from baseline in PSMA PET is 
associated with PSA50 response among subgroups of patients defined by 
treatment modality received, including AR targeting treatment, PSMA-targeting 
radioligand therapy, cytotoxic chemotherapy, and immunotherapy.

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3
Study Design
3.1
Characteristics
This is a single site phase 2 prospective imaging study evaluating the utility of Ga-PSMA PET to 
detect treatment response in patients with metastatic castration resistant prostate cancer. There 
are two sub-cohorts:

Sub-cohort A1: Patients with castration-resistant prostate cancer planning to start a new 
line of systemic therapy will be enrolled and undergo a baseline pre-treatment 68Ga-
PSMA-11 PET scan. Patients will then be monitored for treatment response and 
undergo a repeat 68Ga-PSMA-11 PET scan 16 weeks (+/- 8 weeks) after the start of 
systemic therapy. (Note: Patients in sub-cohort A1 who initiate systemic therapy during 
the screening period/prior to study enrollment may be re-consented to transition to sub-
cohort A2.)

Sub-cohort A2: Patients with castration-resistant prostate cancer currently on systemic 
therapy will be enrolled if a baseline pre-treatment 68Ga-PSMA-11 PET scan was 
performed within 12 weeks prior to the start of systemic therapy, and the on-treatment 
PSMA PET can be performed within 16 weeks (+/- 8 weeks) after the start of systemic 
therapy. Patients will then be monitored for treatment response and undergo a repeat 
68Ga-PSMA-11 PET scan 16 weeks (+/- 8 weeks) after the start of systemic therapy.  
3.2
Sample Size
Approximately 110 patients will be consented to achieve the target number of 100 evaluable 
participants (this includes both sub-cohorts A1 & A2). 
Participants who did not complete paired PSMA PET imaging, those with negative baseline 
PSMA PET, or those who did not subsequently start a new systemic therapy for treatment of 
mCRPC following baseline PSMA PET will be considered unevaluable for the primary analysis 
and will be replaced.
3.3
Eligibility Criteria
Patients must meet all inclusion and exclusion criteria. In addition, the patient must be 
thoroughly informed about all aspects of the study, including the study visit schedule and 
required evaluations and all regulatory requirements for informed consent. The written informed 
consent must be obtained from the patient prior to enrollment. Once it has been ascertained that 
subjects are eligible for the study, their authorization to use personal health information for this 
study and their informed consent will be obtained. Each subject will be assigned a unique study 
identification number at the time of study enrollment in order to ensure confidentiality of study 
data.
3.3.1 Inclusion Criteria
1.
Sub-cohort A1: Patients must have baseline evaluations performed within 12 weeks prior 
to the start of systemic therapy. (Note: Patients in sub-cohort A1 who initiate systemic 
therapy during the screening period/prior to study enrollment may be re-consented to 
transition to sub-cohort A2.)
2.
Sub-cohort A2: Patients must meet all the following requirements:

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
Have had a baseline pre-treatment 68Ga-PSMA-11 PET scan and PSA 
measurement performed within 12 weeks prior to the start of current systemic 
therapy. 

Able to have an on-treatment 68Ga-PSMA-11 PET and a PSA measurement within 
16 weeks (+/- 8 weeks) after the start of current systemic therapy.
Note: The screening period for sub-cohort A2 is within 24 weeks after the patient started 
their current systemic therapy.
3.
Patients must have progressive castration resistant prostate cancer, according to 
PCWG3 criteria. 
4.
Patients must have planned initiation of systemic treatment (sub-cohort A1), or ongoing 
systemic treatment (sub-cohort A2) for castration resistant prostate cancer within 12 
weeks of baseline Ga-PSMA PET. 
5.
Patients must have at least one metastatic lesion with PSMA uptake at or above the 
blood pool on their baseline PSMA PET scan.
6.
The patient must be able and willing to comply with study procedures and provide signed 
and dated informed consent.
7.
Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0 or 1.
8.
Patient must be Aged 18 years or older at the time of study entry
9.
Patients  who undergo optional metastatic tumor biopsy following completion of baseline 
Ga-PSMA PET (sub-cohort A1) must additionally meet all of the following criteria: 

Presence of one or more metastases by standard radiographic scans that is safely 
accessible to tumor biopsy in the judgment of treating clinician and/or Interventional 
Radiology.

No history of radiation therapy to the target metastatic lesion selected for tumor 
biopsy 

No contra-indication to biopsy including uncontrolled bleeding diathesis. 

Platelets >75,000/μL and PT or INR and a PTT < 1.5 times the institutional ULN 
within 14 days prior to biopsy
3.3.2
Exclusion Criteria
1.
Patients who because of age, general medical or psychiatric condition, or physiologic 
status cannot give valid informed consent.
2.
Patients with any condition that, in the opinion of the Principal Investigator, would impair 
the patient’s ability to comply with study procedures.
3.
Patients with any contra-indication to MRI (e.g. pacemaker placement, severe 
claustrophobia) 
Note: The exclusion criteria above (3) is only applicable for patients scheduled for a 
PET/MRI.
3.4
Inclusion and Recruitment of Minorities
Participants must have a diagnosis of progressive castration resistant prostate cancer to be 
eligible for this study. Individuals of any race or ethnicity may participate. The inclusion of 
women is not appropriate for the trial design given this is a study of prostate cancer.  

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3.5
Duration of Study Participation
Participants will receive Ga-PSMA-11 PET imaging at baseline, 16 weeks (+/- 8 weeks) after 
initiating therapy, and optional imaging at time of disease progression, as defined by PCWG3 
criteria. After progression, survival follow-up will be performed every 3 months. 
3.6
Primary Completion 
The expected primary completion date is 36 months from the date of first patient enrolled.
3.7
Study Completion
The expected study completion date is 48 months after the study opens to accrual.
3.8
Study Termination
The principal investigator reserves the right to terminate the study at any time.
Termination of the study will be considered in the event of any safety concerns arising at any 
time during the performance of the study.
If it becomes necessary to consider termination of the study after dosing has begun, dosing may 
be suspended pending discussion between the investigators and the Data and Safety 
Monitoring Committee (DSMC).
4
Investigational Product: 68Ga-PSMA-11
68Ga-PSMA-11 is a radiopharmaceutical that is produced under Current Good Manufacturing 
Practice in the Department of Radiology and Biomedical Imaging Radiopharmaceutical Facility. 
The radiopharmaceutical is prepared in the same facility in which the injection and imaging take 
place, the China Basin Imaging Center at UCSF.
4.1
Dosage and Administration
8Ga-PSMA-11 imaging agent will be administered on an outpatient basis.  The injected dose will 
be 3 to 7 mCi of 68Ga-PSMA-11. It will be administered a single time intravenously prior to the 
PET imaging.  
4.2
Description, Supply and Storage 
Formulation and Appearance
PSMA-11 Ga 68 Injection is a positron emitting radiopharmaceutical containing radioactive 
68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-11), which is used for diagnostic 
purposes in conjunction with Positron Emission Tomography (PET). PSMA-11 Ga 68 Injection is 
a sterile, pyrogen free, clear, colorless aqueous solution presented in a multi-dose vial. 
The final drug product volume is 12 mL and contains 10 mL Sodium Chloride 0.9% Injection, 1 
mL of ethanol and 1 mL of Water for Injection. The solution has a pH between 4.0 and 7.0 and 
each mL of PSMA-11 Ga 68 Injection contains between 0.5 - 5 mCi (18.5 – 185 MBq) 68Ga-
PSMA-11 at the end of synthesis (EOS).
Storage and handling

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The investigational product is stored at 20-25°C, excursion permitted to 15-30°C. The stability of 
the investigational product is validated for 3 hours after EOS. Discard after expiration time.
4.3
Accountability Records for Investigational Product
68Ga-PSMA-11 will be provided by the Department of Radiology and Biomedical Imaging 
Radiopharmaceutical Facility. Upon receiving the investigational product, a certified Nuclear 
Medicine technologist will perform dose calibration and complete the radio pharmacy log. Any 
unused investigational products will be disposed of according to local radiation safety 
guidelines.
4.4
Ordering Investigational Product
68Ga-PSMA-11 will be obtained directly from the UCSF Department of Radiology and 
Biomedical Imaging Radiopharmaceutical Facility.
5
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the 
Study Calendar – Section 5.1.  
On-study procedure or visit delays for public holidays, public emergencies, or weather 
conditions do not constitute a protocol violation.

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5.1
Study Calendar
5.1.1 Study Calendar for Sub-Cohort A1
Period / 
Procedure
Screening 
(Within 12 
weeks prior to 
C1D1)
Cycle 1 Day 1
(Start of 
systemic 
therapy) 10
Follow up 
Response 
Monitoring 8 weeks 
(+/-4 weeks)
Follow up PET
16 weeks (+/- 8 
weeks) 
Following 
Treatment 
Initiation9
Disease 
Progression
by PCWG3
Informed consent
X
Baseline conditions
X
Concomitant 
medications
X
Demographics
X
Serum PSA1
X
X
X
X
Performance status
X
LDH, CBC + diff, 
Liver function tests
X
Disease 
assessment by 
cross sectional 
imaging
X2
X3
X4
X4
68Ga-PSMA-11 
PET/CT or PET/MRI
X8
X
X
(Optional)
Tumor biopsy5 
(optional)
X
Circulating tumor 
nucleic acid 
collection6
(optional)
X
X
X
FDG PET/CT7
(optional)
X
1 Response monitoring with respect to serum PSA will occur per standard of care and provider discretion. A minimum 
of three serum PSA values are required including: at baseline prior to initiation of systemic treatment (+/- 12 weeks), 
at 8 weeks (+/- 4 weeks), and at 16 weeks (+/- 8) weeks).
2 Cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI; with IV contrast if medically permissible), including 
paired CT or MRI obtained with baseline PET scan.
3 Response monitoring with respect to conventional imaging will occur per standard of care and provider discretion. 
4 Cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI; with IV contrast if medically permissible), including 
paired CT or MRI obtained with PET scan. Patients who underwent PET/CT at baseline should have same imaging 
modality performed during follow-up, and likewise patients who underwent PET/MR at baseline should have same 
imaging modality performed for follow up PSMA PET imaging.

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5 Metastatic tumor biopsy is optional for eligible participants. Tumor biopsy should be performed within 12 weeks 
following baseline PET. Soft tissue, PET-avid lesions should be prioritized for biopsy whenever feasible. Biopsy will 
be performed under companion protocol CC# 155518. 
6 Circulating tumor nucleic acid collection via peripheral blood collection is optional. Collection will be performed under 
companion protocol CC # 155518. 
7 FDG PET/CT is optional. FDG PET will be performed at baseline (+/ 12 weeks from date of baseline Ga-PSMA 
PET). 
8 At least one metastatic lesion with PSMA uptake at or above that of the blood pool will be required for study entry. A 
68Ga-PSMA-11 PET/CT or PET/MRI obtained prior to study entry may serve as the patient’s baseline PSMA PET 
scan if within 12 weeks of C1D1 (start of systemic therapy).
9 Specific timing of follow up PET to be determined based on modality of therapy (see Section 5.3.6). 
10 Patients started on systemic therapy during the screening period/prior to study enrollment will be transitioned to 
sub-cohort A2.

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5.1.2 Study Calendar for Sub-Cohort A2
Period / 
Procedure
Screening 
(Within 24 
weeks after the 
start of current 
systemic 
therapy)
Follow up 
Response 
Monitoring 8 weeks 
(+/-4 weeks)
Follow up PET
16 weeks (+/- 8 
weeks) 
Following 
Treatment 
Initiation7
Disease 
Progression
by PCWG3
Informed consent
X
Baseline conditions
X
Concomitant 
medications
X
Demographics
X
Serum PSA1
X
X
X
X
Performance status
X
LDH, CBC + diff, 
Liver function tests
X
Disease 
assessment by 
cross sectional 
imaging
              (X)2
X3
X4
X3
68Ga-PSMA-11 
PET/CT or PET/MRI
(X)5,6
X
X
(Optional)
1 Response monitoring with respect to serum PSA will occur per standard of care and provider discretion. A minimum 
of two serum PSA values are required including: at baseline prior to initiation of systemic treatment (+/- 12 weeks), 
and at 16 weeks (+/- 8) weeks).
2 Prior cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI) performed within 12 weeks of the baseline 
68Ga-PSMA-11 PET scan (including paired CT or MRI obtained with baseline PET scan) may serve as a baseline 
and does not need to be repeated.
3 Response monitoring with respect to conventional imaging will occur per standard of care and provider discretion. 
4 Cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI; with IV contrast if medically permissible), including 
paired CT or MRI obtained with PET scan. Patients who underwent PET/CT at baseline should have same imaging 
modality performed during follow-up, and likewise patients who underwent PET/MR at baseline should have same 
imaging modality performed for follow up PSMA PET imaging.
5 A 68Ga-PSMA-11 PET scan performed prior to study enrollment may serve as a baseline PSMA PET if performed 
within 12 weeks prior to the start of current systemic therapy. This scan is required within window as part of eligibility 
requirements (See Section 3.3.1). Patients must also have an on-treatment PSMA PET within 16 weeks (+/-8 weeks) 
after starting treatment.
6 At least one metastatic lesion with PSMA uptake at or above that of the blood pool will be required for study entry. 
7 Specific timing of follow up PET to be determined based on modality of therapy (see Section 5.3.6). 

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5.2
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system 
is password protected and meets HIPAA requirements.
A list of study subjects will be completed, and will include each subject's study number and 
initials. The investigator must also maintain a separate log of all the subjects screened for 
participation in the study but who will not participate, the reasons for their exclusion or non- 
participation, their initials, and the date on which the subject was excluded. 
5.3
Schedule of Procedures and Assessments
5.3.1 Screening Assessments 
The screening procedures and assessments must be completed within 12 weeks prior to the 
start of planned systemic therapy (sub-cohort A1) or within 24 weeks after the start of current 
systemic therapy (sub-cohort A2). (Note: Patients in sub-cohort A1 who initiate systemic therapy 
during the screening period/prior to study enrollment may be re-consented to transition to sub-
cohort A2.)

Baseline conditions

Concomitant medications

Demographic information (e.g. age, race, height, weight, and body mass index)

ECOG or Karnofsky Performance status

Laboratory procedures
o
Prostate-specific antigen 
o
Complete blood count + differential
o
Lactate dehydrogenase
o
Liver function tests including AST, ALT, total bilirubin, and alkaline 
phosphatase
Additional screening assessments for sub-cohort A1:

Baseline 68Ga-PSMA-11 PET scan will performed and reviewed to confirm the 
presence of at least one metastatic lesion with PSMA uptake at or above that of the 
blood pool. A 68Ga-PSMA-11 PET scan performed prior to study entry may serve as 
the baseline PSMA PET scan if within 12 weeks of the start of systemic therapy.

Cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI; with IV contrast if 
medically permissible) within 12 weeks of baseline 68Ga-PSMA-11 PET scan 
(including the same day as baseline PET). Cross-sectional imaging performed prior 
to study entry may serve as baseline imaging if within 12 weeks of the start of 
systemic therapy.
Additional screening assessments for sub-cohort A2:

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
Baseline 68Ga-PSMA-11 PET scan performed within 12 weeks prior to start of 
current systemic therapy will be reviewed to confirm the presence of at least one 
metastatic lesion with PSMA uptake at or above that of the blood pool

Cross-sectional imaging of the chest/abdomen/pelvis (CT or MRI; with IV contrast if 
medically permissible) performed within 12 weeks of baseline 68Ga-PSMA-11 PET 
scan (including the same day as baseline PET) will be reviewed 
5.3.2 Baseline 68Ga-PSMA-11 PET/MRI or PET/CT 

68Ga-PSMA-11 PET/CT or PET/MRI
o
Participants will begin PET imaging between 55 and 70 minutes after the 
injection of Ga-PSMA-11 at a dose of at a dose of 3-7 mCi. 
o
A dose of 20 mg of furosemide (Lasix) is recommended to be injected 
intravenously together with, shortly before, or after, administration of the 
radiotracer in order to minimize PET scatter artifacts from excreted 
radiotracer accumulation in the kidney and urinary bladder that can occur with 
the gallium-68 radionuclide. Furosemide should not be administered in 
patients with medical contraindications to Furosemide. 
o
Contrast agent for MRI or CT will be administered as clinically indicated. 
o
Participants will be monitored for adverse events for two hours after Ga-
PSMA-11 administration.
o
A formal radiology report from the imaging scan will be generated by the 
Nuclear Medicine department. If any unexpected findings are visualized, 
these will be reported to the treating health care provider, who will then 
contact the patient if additional work-up needs to be performed. 
o
If the patient has received a 68Ga-PSMA-11 PET scan prior to study 
enrollment and within 12 weeks prior to the start of current systemic therapy 
(sub-cohort A2), the PET scan may serve as the baseline PET scan and does 
not need to be repeated at screening.
5.3.3 Baseline Tumor Biopsy and Circulating Tumor Nucleic Acid Collection 
(Optional – Within 12 weeks of Baseline PSMA PET)
Patients in sub-cohort A1 will undergo optional metastatic tumor biopsy and circulating tumor 
nucleic acid collection within 12 weeks of baseline PSMA PET scan. Biopsy and/or circulating 
nucleic acid collection will be performed under protocol CC # 155518. Soft tissue lesions with 
low/negative PSMA uptake will be prioritized for tissue acquisition. However, either bone or soft 
tissue lesions that are deemed safely accessible per Interventional Radiology assessment will 
be potentially considered for imaging. 
Optional circulating tumor nucleic acid collection under companion protocol CC# 155518 will 
also be performed at the following times:

Initiation of systemic treatment

Disease progression

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5.3.4 Baseline FDG PET (Optional for sub-cohort A1 only – within 12 weeks of 
Baseline PSMA PET)
Patients in sub-cohort A1 may undergo optional FDG PET/CT scan (within 12 weeks after date 
of baseline Ga-PSMA PET) per standard imaging procedures.  
5.3.5 Initiation of Systemic Therapy

Sub-cohort A1: Patients will subsequently initiate systemic treatment for castration 
resistant prostate cancer. Choice of therapy will be per discretion of the treating 
physician. Response monitoring with respect to serum PSA and conventional imaging 
will occur per standard of care and provider discretion. A minimum of three serum PSA 
values are required including at baseline within 12 weeks prior to initiation of systemic 
treatment, at 8 weeks (+/- 4 weeks), and at 16 weeks (+/- 8) weeks) from start of 
systemic therapy.  

Sub-cohort A2: Patients must be currently receiving systemic treatment for castration 
resistant prostate cancer, initiated within 12 weeks after their baseline 68Ga-PSMA -11 
PET scan. Choice of therapy will be per discretion of the treating physician. Response 
monitoring with respect to serum PSA and conventional imaging will occur per standard 
of care and provider discretion. A minimum of two serum PSA values are required 
including at baseline within 12 weeks prior to initiation of systemic treatment and at 16 
weeks (+/- 8) weeks)) from start of systemic therapy.  
5.3.6 Follow up 68Ga-PSMA-11 PET (16 weeks +/- 8 weeks from date of systemic 
treatment initiation)
Patients will undergo repeat 68Ga-PSMA-11 PET after 16 weeks (+/- 8 weeks) from date of 
initiation of systemic treatment.
The specific time frame for imaging will depend on the treatment modality administered, and will 
be standardized as follows:

Androgen Receptor (AR) targeted therapy (20 weeks +/- 4 weeks)

PSMA-targeting radioligand therapy (12 weeks +/- 4 weeks)

Cytotoxic chemotherapy (12 weeks +/- 4 weeks)

Immunotherapy (12 weeks +/- 4 weeks)
Patients with a negative baseline PSMA PET scan (i.e. no metastatic lesion with PSMA uptake 
at or above that of the blood pool) will not be eligible for the follow up PSMA PET. 
Patients who underwent PET/CT at baseline should have same imaging modality performed 
during follow-up, and likewise patients who underwent PET/MR at baseline should have same 
imaging modality performed for follow up PSMA PET imaging.
5.3.7 Time of Disease Progression by PCWG3 Criteria (Optional)
Patients will undergo an optional third 68Ga-PSMA-11 PET at the time of progression by 
PCWG3 criteria. Patients who underwent PET/CT at baseline should have same imaging 
modality performed during follow-up, and likewise patients who underwent PET/MR at baseline 
should have same imaging modality performed during follow up.

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5.3.8 Long Term Survival Follow Up 
Participants will be followed by telephone call and/or chart review every 3 months to record 
survival status until death, study withdrawal, or study closure, whichever occurs first.
5.4
Dietary Restrictions
None. No fasting is required for PSMA PET imaging.
5.5
Prohibited Medications
None. There are no prohibited medications.
6
Reporting and Documentation of Results
6.1
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of IMP. The study 
will use the Common Terminology Criteria for Adverse Events (CTCAE v5.0) criteria for 
reporting of non-hematologic adverse events and modified criteria for hematologic adverse 
events.
6.2
Definitions of Adverse Events 
6.2.1 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. 
Laboratory test value abnormalities will not be recorded as AEs unless they are designated as 
clinically significant, defined as any one of the following: symptomatic, requiring treatment, 
resulting in dose modification or delay or premature study withdrawal, or placing the subject at 
risk for other toxicity in the judgment of the treating investigator.
6.2.2 Adverse Reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
6.2.3 Suspected Adverse Reaction
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 investigational new drug 
(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.

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6.2.3.1
Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed 
in the investigator brochure or package insert(s), or is not listed at the specificity or severity 
that has been observed, or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would 
generally not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same 
class of drugs, or as anticipated from the pharmacological properties of the drug, even 
though they have not been observed with the drug under investigation.  Such events would 
be considered unexpected until they have been observed with the drug under investigation. 
For example, although angioedema is anticipated to occur in some participants exposed to 
drugs in the angiotensin-converting enzyme inhibitor class and angioedema would be 
described in the investigator brochure as a class effect, the first case of angioedema 
observed with the drug under investigation should be considered unexpected for reporting 
purposes.
6.2.3.2
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
6.2.3.3
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 participant at immediate risk 

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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. 
6.2.4 Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
6.2.5 Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator.  For selected 
adverse events for which administration of the investigational product was stopped, a re-
challenge of the subject with the investigational drug may be conducted if considered both safe 
and ethical by the investigator.
6.2.6 Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
6.2.7 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 Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
Expedited Reporting to the Food and Drug Administration (FDA)
 
If the study is being conducted under an IND, the Sponsor (or 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 needs to ensure that the event meets all three 
definitions: 

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)). 

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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)). 
7
Statistical Considerations and Evaluation of Results
7.1
Imaging Analysis
A trained nuclear medicine physician will evaluate the reconstructed PET, CT or MRI, and fused 
PET/CT or PET/MR images using a PET volume computer-assisted reading software package. 
A positive lesion on PET will be defined as a focus of activity with higher SUV compared with 
mediastinal blood pool that is not attributable to other etiologies of tracer distribution (e.g. 
inflammation, excretion). A volume of interest (VOI) will be semi-automatically placed around 
each lesion, and the calculated maximum standard uptake value (SUVmax) will be recorded for 
each lesion, including lesions that are detected on standard scans but are not positive on PET. 
Adjusted SUVmax data will then be averaged the primary tumor and 5 largest lesions in each of 
three metastatic site (nodal, visceral, and osseous) within a given patient, up to a maximum of 
16 lesions per patient (SUVmax-avg). Irradiated lesions will be excluded from this analysis. 
7.2
Sample Size Considerations
7.2.1 Sample Size and Power Estimate
The sample size of 100 evaluable patients is based on the primary study endpoint. Based on 
the available standard of care and investigational therapies available in mCRPC, it is estimated 
that 40% of patients will experience a PSA50 response on the systemic treatment chosen by 
investigator. Based on prior data from retrospective studies evaluating PSMA PET as an 
indicator of clinical response, patients with clinical response have an approximate 50% 
reduction from baseline in SUVmax-ave on serial PSMA PET. A sample size of 100 patients 
(estimated 40 PSA50 responders, 60 non-responders) provides 89% power to detect an effect 
size of 0.67 with respect to the percent change from baseline in SUVmax-ave on PSMA PET in 
PSA50 responders vs. non-responders, using the Mann-Whitney test and bi-directional alpha = 
0.05. This translates into an absolute mean difference in the percent change from baseline on 
PSMA PET between responders vs. non-responders of 20% (within group SD 30%).
7.2.2 Accrual Estimates
The estimated accrual period is 18-24 months. 
7.3
Interim Analyses 
An interim analysis for feasibility will be performed after 30 patients are enrolled. Baseline and 
on-treatment PSMA PET images will be qualitatively reviewed and preliminary data with respect 
to the mean percent change from baseline in SUVmax-ave will be determined. If it is determined 
that insufficient change is detected, adjustment of on-treatment PSMA PET scan time point may 
be instituted along with specification of the type of systemic therapy allowed post –baseline 
PSMA PET.

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7.4
Analyses Plans
7.4.1 Analysis Population
All data from all subjects dosed in the study will be included in all listings, plots, summary tables, 
and statistical analyses when appropriate. Missing values will not be substituted by estimated 
values, but treated as missing in the statistical evaluation.
7.4.2 Primary Analysis (or Analysis of Primary Endpoints)
The mean (SUVmax,ave), median, and range of SUVmax across the primary tumor and the 5 largest 
lesions in each of three metastatic sites (nodal, visceral and osseous; for a maximum of 16 
lesions per patient) will be descriptively reported. The study cohort will be divided into 
subgroups based on whether or not patient experienced a ≥ 50% decline from baseline in serum 
PSA (PSA50 responder) or not (PSA50 non-responder). The mean percent change from 
baseline in SUVmax-ave on PSMA PET between PSA50 responders vs. non-responders will be 
compared using the Mann-Whitney test. 
7.4.3 Secondary Analysis (or Analysis of Secondary Endpoints)
The study cohort will be dichotomized by the median with respect to percent change from 
baseline in SUVmax-ave on PSMA PET. The time-to-event variables including PSA progression-
free defined by PCWG3, and overall survival will be compared between dichotomized 
subgroups using the log-rank test. Kaplan-Meier product limit method will be used to estimate 
median survival in each subgroup. 
Amongst the subset of measurable soft tissue lesions by RECIST 1.1 criteria, on a per-lesion 
basis, the mean percent change from baseline in SUVmax on PSMA PET will be compared 
between responding lesions by RECIST 1.1 criteria vs. those without response, using Mann-
Whitney test.  
PSMA negative lesions will be defined as those with SUV values below the mediastinal blood 
pool. Low positive lesions will be defined as those with SUVmax values above the blood pool, but 
below background liver uptake. Intermediate positive lesions are those defined by SUVmax 
values above background liver, but below parotid gland uptake. High positive lesions are those 
with SUVmax values above that of parotid gland. The histologic, genomic and transcriptional 
features of each subgroup of PSMA lesion category that has matching tumor tissue will be 
descriptively reported with particular emphasis on the low and negative PSMA lesions that have 
paired tumor tissue available. 
The median and range for inter-tumoral SUVmax across metastatic lesions within individual 
patients will be descriptively reported, to assess for heterogeneity of PSMA uptake. The cohort 
will be dichotomized above and below median range of SUVmax values to define low and high 
heterogeneity subgroups. Overall survival from date of onset of mCRPC will be compared 
between high vs. low heterogeneity subgroups. 
Analysis of the correlation between SUVmax PSMA and FDG PET will be performed on a per-
lesion basis amongst the subset of patients who have paired evaluable imaging using Pearson r 
correlation coefficient.  
Patterns of PSMA expression at the time of progression by PCWG3 criteria will be descriptively 
characterized.
Comparison of mean percent change from baseline in SUVmax-ave in PSA50 responders vs. non-
responders will be performed in pre-specified subgroups based on modality of systemic 

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treatment, including AR targeted therapy, PSMA-directed radioligand therapy, cytotoxic 
chemotherapy, and immunotherapy. 
No adjustment will be made for multiple comparisons for the analysis of the secondary and 
exploratory endpoints.
8
Study Management
8.1
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 Good Clinical 
Practice (GCP) and all applicable regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to participants before any protocol related 
procedures are performed on any participants.  
The PI must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH (International Conference on 
Harmonization) guidelines, and all applicable regulatory requirements.  The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements.
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 FDA has determined that the 
study is exempt from IND requirements. 
8.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB.  Prior to obtaining IRB approval, the protocol must be approved by 
the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC).  The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.  
8.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB -approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
8.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.  

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If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.  
8.5
Handling and Documentation of Clinical Supplies
The Principal Investigator will maintain complete records showing the receipt, dispensation, 
return, or other disposition of all investigational drugs at the site.  The date, quantity and batch 
or code number of the drug, and the identification of participants to whom the investigational 
product has been dispensed by participant number and initials will be included.  
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study participants.  Furthermore, the Principal Investigator will not allow 
the investigational product to be used in any manner other than that specified in this protocol.
8.6
Case Report Forms (CRFs)
The Principal Investigator and/or designee will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and 
data analysis.  All study data will be entered into OnCore® via standardized CRFs in accordance 
with the CTMS study calendar, using single data entry with a secure access account.  Study 
personnel will complete the CRFs; the Principal Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the participant’s medical records maintained by 
study personnel. All source documentation should be kept in separate research files for each 
participant. 
In accordance with federal regulations, the Principal Investigator is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
8.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the National 
Cancer Institute-approved (NCI) Data and Safety Monitoring Plan (DSMP).  The DSMC will 
routinely review all adverse events and suspected adverse reactions considered “serious”.  The 
DSMC will audit study-related activities to ensure that the study is conducted in accordance with 
the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP).  Significant results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
applicable.  See Appendix 2 - Data and Safety Monitoring Plan.

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8.8
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant consent 
forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the Principal Investigator shall retain records for a period of 
2 years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA is 
notified.

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9
References
1.
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA. Cancer J. Clin. 69, 
7–34 (2019).
2.
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. 
N. Engl. J. Med. 363, 411–422 (2010).
3.
Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. 
Engl. J. Med. 369, 213–223 (2013).
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Parker, C. C. et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic 
prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet Lond. Engl. 392, 
2353–2366 (2018).
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Trabulsi, E. J. et al. Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO 
Guideline. J. Clin. Oncol. JCO.19.02757 (2020) doi:10.1200/JCO.19.02757.
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Dorff, T. B. et al. The Evolving Role of Prostate-Specific Membrane Antigen–Based 
Diagnostics and Therapeutics in Prostate Cancer. Am. Soc. Clin. Oncol. Educ. Book 321–330 
(2019) doi:10.1200/EDBK_239187.
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Scher, H. I. et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J. Clin. 
Oncol. Off. J. Am. Soc. Clin. Oncol. 34, 1402–1418 (2016).
8.
Hofman, M. S. et al. Prostate-specific membrane antigen PET-CT in patients with high-
risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, 
randomised, multi-centre study. The Lancet 0, (2020).
9.
Perera, M. et al. Gallium-68 Prostate-specific Membrane Antigen Positron Emission 
Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, 
and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and 
Meta-analysis. Eur. Urol. 77, 403–417 (2020).
10.
Afshar-Oromieh, A. et al. The diagnostic value of PET/CT imaging with the (68)Ga-
labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur. J. Nucl. 
Med. Mol. Imaging 42, 197–209 (2015).
11.
Emmett, L. et al. Results of a Prospective Phase 2 Pilot Trial of 177Lu-PSMA-617 
Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of 
Treatment Response and Patterns of Progression. Clin. Genitourin. Cancer 17, 15–22 (2019).
12.
Hofman, M. S. et al. [177Lu]-PSMA-617 radionuclide treatment in patients with 
metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 
2 study. Lancet Oncol. 19, 825–833 (2018).

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13.
Grubmüller, B. et al. Response assessment using 68Ga-PSMA ligand PET in patients 
undergoing 177Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer. 
Eur. J. Nucl. Med. Mol. Imaging 46, 1063–1072 (2019).
14.
Aggarwal, R. et al. Heterogeneous Flare in Prostate-specific Membrane Antigen Positron 
Emission Tomography Tracer Uptake with Initiation of Androgen Pathway Blockade in 
Metastatic Prostate Cancer. Eur. Urol. Oncol. 1, 78–82 (2018).
15.
Emmett, L. et al. Rapid Modulation of PSMA Expression by Androgen Deprivation: 
Serial 68Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate 
Cancer Commencing Androgen Blockade. J. Nucl. Med. Off. Publ. Soc. Nucl. Med. 60, 950–954 
(2019).
16.
Grubmüller, B. et al. Response assessment using [68 Ga]Ga-PSMA ligand PET in 
patients undergoing systemic therapy for metastatic castration-resistant prostate cancer. The 
Prostate 80, 74–82 (2020).
17.
Seitz, A. K. et al. Preliminary results on response assessment using 68Ga-HBED-CC-
PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy. 
Eur. J. Nucl. Med. Mol. Imaging 45, 602–612 (2018).
18.
Plouznikoff, N. et al. Evaluation of PSMA expression changes on PET/CT before and 
after initiation of novel antiandrogen drugs (enzalutamide or abiraterone) in metastatic 
castration-resistant prostate cancer patients. Ann. Nucl. Med. 33, 945–954 (2019).
19.
Liu, C. et al. Preliminary results of targeted prostate-specific membrane antigen imaging 
in evaluating the efficacy of a novel hormone agent in metastatic castration-resistant prostate 
cancer. Cancer Med. (2020) doi:10.1002/cam4.2964.
20.
Rosar, F. et al. New insights in the paradigm of upregulation of tumoral PSMA 
expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in 
castration-resistant prostate cancer even in patients having previously progressed on 
enzalutamide. Eur. J. Nucl. Med. Mol. Imaging 47, 687–694 (2020).
21.
Bakht, M. K. et al. Neuroendocrine differentiation of prostate cancer leads to PSMA 
suppression. Endocr. Relat. Cancer 26, 131–146 (2019).
22.
Tosoian, J. J. et al. Correlation of PSMA-Targeted 18F-DCFPyL PET/CT Findings With 
Immunohistochemical and Genomic Data in a Patient With Metastatic Neuroendocrine Prostate 
Cancer. Clin. Genitourin. Cancer 15, e65–e68 (2017).
23.
Thang, S. P. et al. Poor Outcomes for Patients with Metastatic Castration-resistant 
Prostate Cancer with Low Prostate-specific Membrane Antigen (PSMA) Expression Deemed 
Ineligible for 177Lu-labelled PSMA Radioligand Therapy. Eur. Urol. Oncol. 2, 670–676 (2019).
24.
Bakht, M. K. et al. Differential expression of glucose transporters and hexokinases in 
prostate cancer with a neuroendocrine gene signature: a mechanistic perspective for FDG 

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imaging of PSMA-suppressed tumors. J. Nucl. Med. Off. Publ. Soc. Nucl. Med. (2019) 
doi:10.2967/jnumed.119.231068.
25.
Scher HI, Morris MJ, Stadler WM, et al: Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3, J Clin Oncol, 1402-18 (2016)
26.
Eisenhauer, Elizabeth A., et al. "New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1)." European journal of cancer 45.2 (2009): 228-247.

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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 
Data and Safety Monitoring Plan for a Phase II or III Institutional Study
1.         Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study 
includes: 

Semiannual auditing (depending on study accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.  
All institutional Phase II and III studies are designated with a moderate risk assessment.  The 
data is audited semiannually with a random selection of twenty percent of the participants 
audited (or at least three participants if the calculated value is less than three).  The DSMC 
Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants selected for 
the review, or until the selected participants discontinue study participation or the trial is closed 
with the IRB.  Additionally, the assigned DSMC Monitor/Auditor will review no more than a 
total of 10 participant charts during the course of auditing this trial. DSMC Monitor/Auditors 
will send a follow-up report to the study team within 20 business days after the auditing visit is 
complete for the PI and the study team to resolve all action items from this report within 20 
business days.  Additionally, a regulatory audit will occur on a biennial basis to review all 
regulatory documents for the trial.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 
investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  

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Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse events are further given an assignment 
of attribution or relationship to investigational agent or study procedure.  Attribution 
categories are:
•
Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.
•
Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.
•
Possible – The adverse event may be related to the investigational agent(s) or 
study procedure.
•
Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and attribution assignment.
3.2
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:
•
Death.
•
Life-threatening (i.e. results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Permanent or significant disability/incapacity
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed 
above. 
•
Event occurring in a gene therapy study.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:

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www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per 
IRB guidelines).  The SAEs are reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE is sent to all required reporting agencies 
will be documented in OnCore®. 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one 
business day.  
1.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC via report at the time the increased rate is identified.  
The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert.
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
  Katie Kelley, MD (DSMC Chair)
  
  
  
  UCSF HDFCCC
  San Francisco, CA 94158
John McAdams (DSMC Director) 
UCSF HDFCCC
San Francisco, CA 94143