Clinical trial NCT03353740
Conditions: Prostate Cancer
Sponsor: Thomas Hope
Start date: 2017-09-20; Completion date: 2020-09-01
Enrollment: 346 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators are imaging patients with prostate cancer using a new PET imaging agent (Ga-68-PSMA-11) in order to evaluate its ability to detection prostate cancer in patients with biochemical recurrence after prostatectomy and radiation therapy.

Detailed description:

Arms: arm 1: PSMA PET imaging: Patients will receive Ga-68 labeled PSMA-11 PET and then undergo PET/CT or PET/MRI approximately 55-70 minutes later.
Interventions: intervention 1: Ga-68 labeled PSMA-11 PET
Intervention descriptions: intervention 1: Patients will be imaged using Ga-68 labeled PSMA-11 PET to determine if the presence of metastatic disease. Prostate Specific Membrane Antigen (PSMA) is a protein expressed on prostate cancer cells that can be imaged using small molecules that target this protocol.

Protocol documents:
Prot_SAP_000.pdf: 
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Gallium-68 PSMA-11 PET in patients with biochemical 
recurrence
Study Drug:  Gallium-68 PSMA-11
Version Date:  08/27/2017
NCT# 03353740


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Abstract
Title
Gallium-68 PSMA-11 PET in patients with biochemical recurrence
Patient 
population

Rising PSA after definitive therapy with prostatectomy or radiation therapy
(external beam or brachytherapy):
o
Post radical prostatectomy (RP) – AUA recommendation

PSA greater than or equal to 0.2 ng/mL measured more than 6
weeks after RP.
o
Post-radiation therapy – ASTRO-Phoenix consensus definition

Nadir + greater than or equal to 2 ng/mL rise in PSA
Rationale for 
Study
Gallium-68 PSMA-11 has been shown to have a higher sensitivity for the 
detection of metastatic prostate cancer compared to choline based imaging.
Primary 
Objective

Sensitivity on a per-patient and per-region-basis of 68Ga-PSMA-11 PET for
detection of tumor location confirmed by histopathology/biopsy, clinical and
conventional imaging follow-up.
Secondary 
Objectives

PPV on a per-patient and per-region-basis of 68Ga-PSMA-11 PET for
detection of tumor location confirmed by histopathology/biopsy, clinical and
conventional imaging follow-up.

Sensitivity and positive predictive value (PPV) on a per-patient and per-
region basis of 68Ga-PSMA-11 PET for detection of tumor location
confirmed by histopathology/biopsy.

Detection rates on a per-patient basis of 68Ga-PSMA-11 PET stratified by
PSA value (0.2 - <0.5, 0.5 - <1.0, 1.0 - <2.0, 2.0 - <5.0, ≥5.0).  Detection
rate will be stratified by history of prostatectomy, radiation or both; as well
as by whether the patient is on androgen deprivation therapy (ADT).

Impact of 68Ga-PSMA-11 PET on clinical management in BCR patients.

Inter-reader reproducibility.

Safety of 68Ga-PSMA-11 administration as categorized by CTCAE 4.03.
Study Design
This is a phase 3 multi-center open label study. 
Number of 
patients
Total population of patients will be 1,500 patients across all institutions.


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Duration of 
Therapy
The study will involve a single imaging study.
Duration of 
Follow up
The patients will be followed-up by phone one day after the study completion, 
and clinical and imaging follow-up will last for up to 12 months after the 
PSMA-11 PET study..
Duration of 
study
The study will reach completion three years from the time the study opens to 
accrual.
Study Drugs
Gallium-68 labeled PSMA-11 (PSMA-HBED-CC)
Safety 
Assessments
Patient vital signs will be taken immediately before and after the 
administration of the radiopharmaceutical.  The patients will also be asked to 
report adverse events.


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List of Abbreviations
AE
adverse event
CHR
Committee on Human Research (UCSF IRB)
CRC
Clinical Research Coordinator
CRF
case report form
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
Ga-68
Gallium 68
HDFCCC
Helen Diller Family Comprehensive Cancer Center
ICH
International Conference on Harmonization
IND
investigational new drug application
IRB
Institutional Review Board
IV
intravenous
MRI
magnetic resonance imaging
NCI
National Cancer Institute
PET
PK
Positron Emission Tomography
pharmacokinetics
PRC
PSA
PSMA
Protocol Review Committee (UCSF)
Prostate specific antigen
Prostate specific membrane antigen
SD
standard deviation


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Table of Contents
Abstract
2
List of Abbreviations ......................................................................................................................4
Table of Contents ..........................................................................................................................5
1
Introduction...........................................................................................................................7
1.1
Overview................................................................................................................7
1.2
Background ............................................................................................................7
1.3
Patient Population ..................................................................................................8
2
Objectives of the Study ........................................................................................................8
2.1
Primary...................................................................................................................8
2.2
Secondary...............................................................................................................9
3
Study Design........................................................................................................................9
3.1
Characteristics ........................................................................................................9
3.2
Number of Subjects................................................................................................9
3.3
Eligibility Criteria ..................................................................................................9
3.3.1
Inclusion Criteria................................................................................................9
3.3.2
Exclusion Criteria.............................................................................................10
3.4
Duration of Follow Up.........................................................................................10
3.5
Study Timeline.....................................................................................................10
3.5.1
Primary Completion .........................................................................................10
3.5.2
Study Completion.............................................................................................10
4
Study Drugs........................................................................................................................10
4.1
Description, Supply and Storage of Investigational Drugs..................................10
4.1.1
Investigational Drug #1....................................................................................10
5
Treatment Plan...................................................................................................................10
5.1
Dosage and Administration..................................................................................10
5.1.1
Other Modality(ies) or Procedures...................................................................11
5.2
Monitoring and Toxicity Management ................................................................11
6
Study Procedures and Observations (Appendix 2) ............................................................12
6.1
Schedule of Procedures and Observations ...........................................................12
6.1.2
Treatment Period ..............................................................................................12
6.1.3
Post-treatment Follow Up Visits ......................................................................12
6.2
Prohibited Medications ........................................................................................13
7
Reporting and Documentation of Results ..........................................................................13
7.1
Evaluation of Side Effects....................................................................................13
7.2
Evaluation of Safety.............................................................................................13
7.3
Definitions of Adverse Events .............................................................................13
7.3.1
Adverse Event ..................................................................................................13
7.3.2
Adverse reaction...............................................................................................13
7.4
Recording of an Adverse Event ...........................................................................14
7.5
Follow-up of Adverse Events...............................................................................15
7.6
Expedited Reporting.............................................................................................15


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Table of Contents
8
Statistical Considerations and Evaluation of Results .........................................................16
8.1
Study Endpoints ...................................................................................................16
8.1.1
Randomization..................................................................................................16
8.1.2
Blinding............................................................................................................16
8.2
Determination of Sample Size and Accrual Rate.................................................17
8.2.1
Sample Size and Power Estimate .....................................................................17
8.2.2
Accrual estimates .............................................................................................18
8.3
Analyses Plans......................................................................................................18
8.3.1
Analysis Population..........................................................................................18
8.3.2
Analysis of Primary Endpoints.........................................................................18
8.3.3
Analysis of Secondary Endpoints.....................................................................26
9
Study Management ............................................................................................................26
9.1
Pre-study Documentation.....................................................................................26
9.2
Institutional Review Board Approval ..................................................................27
9.3
Informed Consent.................................................................................................27
9.4
Changes in the Protocol........................................................................................27
10
Protection of Human Subjects............................................................................................27
10.1
Protection of Privacy............................................................................................27
References
28
Appendices
30
Appendix 1
Performance Status Criteria...............................................................................30
Appendix 2
Schedule of Study Procedures and Assessments .............................................31
Appendix 3 (pre- and post-surveys) ............................................................................................32
List of Tables
Table 1 .............................................................................................................................................5
Table 2 .............................................................................................................................................6
Table 3.1
Schedule of Study Procedures and Assessments........................................................11


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1
Introduction
1.1
Overview
Imaging and staging of prostate cancer is critical for surgical and treatment planning.  We aim to 
image patients with suspected metastatic prostate cancer using Gallium-68 labeled HBED-CC 
PSMA (more commonly called 68Ga-PSMA-11) in order to demonstrate its utility.   We plan to 
utilize this data to obtain further approvals of the 68Ga-PSMA-11 compound, so that this agent 
will become available for clinical imaging in prostate cancer patients.  
This compound has been shown to be superior to choline based PET agents for the staging of 
prostate cancer, both Carbon-11 and Fluorine-18 compounds.  But this compound was not 
patented and therefore no company or private entity will make the investment required to bring 
PSMA-11 to market.  In the vacuum of availability, academic groups must take the lead in order 
to collect the necessary data for future FDA approval.  This protocol was developed in 
collaboration with the Clinical Trials Network of the Society of Nuclear Medicine and Molecular 
Imaging.  The inclusion criteria and study endpoints have been aligned so that inter-institutional 
sharing of data can be performed in order to pool data for final NDA submission.
1.2
Background
Prostate cancer is the most commonly diagnosed cancer and second leading cause of cancer 
death in American men (1).   Existing conventional imaging (CT, MRI and bone scans) has a 
low sensitivity in detecting local recurrence or metastatic disease (2).  The one exception being 
NaF PET/CT for the detection of osseous metastasis.  Due to this limitation, numerous 
approaches to stage patients have been evaluated.
Choline imaging has been frequently used, as prostate cancer exhibits increase choline uptake 
that has been associated with the presence of choline kinase (3).  Choline uptake is increased 
in comparison to FDG in both androgen dependent and independent prostate cancer patients 
(4).  Choline has also been shown to be sensitive for the detection of recurrent tumor in patients 
with PSA (prostate specific antigen) values of less than 1.0 ng/ml (5).  There are two forms of 
choline that are used in imaging prostate cancer, C-11 and F-18 choline.  C-11 choline has a 
short half-life of 20 minutes, which limits its detection for metastatic disease but results in 
improved local detection due to decreased urinary activity at the time of imaging.  F-18 choline 
has significant urinary excretion that limits evaluation of the prostate but, but has been shown to 
have better detection rates for distant metastatic disease (6).  C-11 choline has limited 
sensitivity for osseous metastasis, possibly due to the decreased uptake time (7).  Additionally, 
the sensitivity of C-11 choline is limited in patients with PSA values < 1.0 ng/ml (8-10).  Although 
choline PET may be limited in sensitivity, it clearly delineates more lesions than cross section 
imaging or bone scan in patients with known disease (11).   In 2012, the Mayo Clinic obtained 
NDA (new drug application) approval from the FDA for the use of C-11 choline.  
A separate approach is to image the prostate specific membrane antigen (PSMA).  PSMA is 
expressed on the majority of prostate cancer cells, and so would be an ideal cell membrane 
protein to image.  The initial imaging approach to PSMA imaging target the intracellular domain 
using Indium-111-capromab (Prostascint), a murine monoclonal antibody (12,13).  Although 
there was early promise for the detection of nodal metastasis (14), the agent was never able to 
adequately visualize osseous metastasis (15).  Although combination with SPECT/CT does 
improve lesion detection (16).  One main limitation to In-111-capromab is that it takes a 
prolonged time to localize to the target tissue, which likely relates to both the size of the 
monoclonal antibody and the fact that agent targets the intracellular domain of the PSMA 
protein. Additionally, Prostascint also recognizes an intracellular epitope so the antibody must 


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cross the membrane to be effective. This likely only occurs in permeable dead or dying tumor 
cells. 
Because of the limitations of In-111 capromab, there has been continued effort to develop 
agents that target the extracellular domain of the PSMA protein. The Ga-68 labeled PSMA-11 
compound has become of particular interest because in the last year there have been two 
important articles. The first demonstrates that PSMA-11 has a higher sensitivity for the detection 
of disease than F-18 choline in a head-to-head intra-patient comparison that included 37 
patients (17).  The second paper looked at the sensitivity of PSMA-11 in the detection of 
metastatic lesions in patients with recurrent prostate cancer (18).  Their results demonstrated a 
detection rate of 50% for patients with a PSA less than 1 ng/ml, and detection rate above 85% 
for patients with a PSA greater than 2 ng/ml.  These detection rates are significantly higher than 
that reported by groups using choline (5).
Because of the improved resolution and image quality with PET, ability to quantitate uptake, 
increased sensitivity compared to choline, we intend to evaluate the utility of Ga-68 PSMA-11 
for the imaging of prostate cancer. We expect that the data from this study will support 
applications for clinical approval of this imaging agent, leading to wider availability within the 
United States. 
1.3
Patient Population
Patients with biochemical recurrence after prostatectomy or radiation therapy:
(a) Post radical prostatectomy (RP) – AUA recommendation  

PSA greater than or equal to 0.2 ng/mL measured more than 6 weeks 
after RP.
(b) Post-radiation therapy –ASTRO-Phoenix consensus definition 

Nadir + greater than or equal to 2 ng/mL rise in PSA
2
Objectives of the Study
2.1
Primary

Sensitivity on a per-patient and per-region-basis (Table 1) of 68Ga-PSMA-11 PET for 
detection of tumor location confirmed by histopathology/biopsy, clinical and conventional 
imaging follow-up.
Region
Description
1
Prostate Bed
2
Pelvis outside of prostate bed including lymph nodes
3
Extrapelvic soft tissue, lymph nodes and organ metastases (non-bone)
4
Bone metastases


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2.2
Secondary

PPV on a per-patient and per-region-basis (Table 1) of 68Ga-PSMA-11 PET for detection 
of tumor location confirmed by histopathology/biopsy, clinical and conventional imaging 
follow-up.

Sensitivity and positive predictive value (PPV) on a per-patient and per-region-basis 
(Table 1) of 68Ga-PSMA-11 PET for detection of tumor location confirmed by 
histopathology/biopsy.

Detection rates on a per-patient basis of 68Ga-PSMA-11 PET stratified by PSA value (0.2 
- <0.5, 0.5 - <1.0, 1.0 - <2.0, 2.0 - <5.0, ≥ 5.0).  Detection rate will also be stratified by 
history of prostatectomy, radiation or both; as well as by whether the patient is on 
androgen deprivation therapy (ADT).

Impact of 68Ga-PSMA-11 PET on clinical management in BCR patients.

Inter-reader reproducibility.

Safety, as characterized by CTCAE 4.03.
3
Study Design
3.1
Characteristics
This is a prospective, Phase 3, multi-center, open-label study in patients with prostate cancer. 
Eligible participants will undergo baseline assessments at enrollment. Study participants will 
receive a one-time administration of Ga-68 PSMA-11 and undergo a PET/CT or PET/MRI 
imaging study.
3.2
Number of Subjects
It is anticipated that 1,500 patients will be enrolled in this study. 
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the administration of the 
radiopharmaceutical and must meet all inclusion and exclusion criteria. In addition, the patient 
must be thoroughly informed about all aspects of the study, including the study visit schedule 
and required evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient prior to enrollment. The following criteria 
apply to all patients enrolled onto the study:
3.3.1
Inclusion Criteria
1.
Histopathologically proven prostate adenocarcinoma.
2.
Rising PSA (at least two consecutive rising PSAs) after definitive therapy with 
prostatectomy or radiation therapy (external beam or brachytherapy). 
a.
Post radical prostatectomy (RP) – AUA recommendation for biochemical 
recurrence after radical prostatectomy 
i.
PSA greater than or equal to 0.2 ng/mL measured more than 6 weeks 
after RP.


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b.
Post-radiation therapy –ASTRO-Phoenix consensus definition of biochemical 
recurrence after radiation therapy
i.
Nadir + greater than or equal to 2 ng/mL rise in PSA
3.
Karnofsky performance status of 50 (or ECOG/WHO equivalent).
4.
Age > 18.
5.
Ability to understand a written informed consent document, and the willingness to sign it.
3.3.2
Exclusion Criteria
1.
Unable to lie flat, still or tolerate a PET scan.
2.
Concomitant investigational therapy.
3.
Patient undergoing active treatment for non-prostate malignancy, other than skin basal 
cell or cutaneous superficial squamous cell carcinoma that has not metastasized and 
superficial bladder cancer.
4.
Contraindication to furosemide administration including prior allergy or adverse reaction 
to furosemide or sulfa drugs.  (Note: This exclusion criteria can be removed if 
Furosemide is omitted as part of the PET imaging protocol if a second-generation scatter 
correction is available for the used PET device).
3.4
Duration of Follow Up
Patients will be followed for one day after the administration of the radiopharmaceutical.
3.5
Study Timeline
3.5.1
Primary Completion
The study will reach primary completion 36 months from the time the study opens to accrual.
3.5.2
Study Completion
The study will reach study completion 48 months from the time the study opens to accrual.
4
Study Drugs
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1
Investigational Drug #1
Ga-68 labeled PSMA-11 (or PSMA-HBED-CC) is a radiopharmaceutical that will be produced 
under cGMP.
5
Treatment Plan
5.1
Dosage and Administration
The imaging agent (Ga-68 PSMA-11 or PSMA-HBED-CC) will be administered on an outpatient 
basis.  It will be administered a single time intravenously prior to the PET imaging.  The injected 
dose will be 3 to 7 mCi of 68Ga-PSMA-11.


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5.1.1
Other Modality(ies) or Procedures
5.1.1.1 Change in management surveys
Referring clinicians will be required to fill out a pre-imaging survey prior to imaging. Please see 
Appendix 3.  Additionally within 30 days of the completion of imaging, the referring physician will 
be requested to fill out a post-imaging survey, and finally three to six months after imaging, a 
third survey will be filled out.
5.1.1.2 PET imaging
a)
68Ga-PSMA-11 PET preparation and injection:  
The intravenously injected dose will be 111-259 MBq (3-7 mCi) of 68Ga-PSMA-11 PET.  
A dose of 20 mg of furosemide (Lasix) is recommended to be injected i.v. 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.  Oral hydration is recommended on the day 
of the scan. Voiding is recommended immediately before start of the scan.  Furosemide 
should not be administered in patients with medical contraindications to Furosemide 
administration including allergies and adverse reactions including sulfa allergies.  (Note: 
Application of Furosemide can be omitted as part of the PET imaging protocol if a 
second-generation scatter correction algorithm is available for the PET scanner used in 
this protocol).    PET imaging will begin 50-100 minutes after injection.  Scan time per 
bed position will be determined based on each sites PET scanner capabilities. 
b) Patient preparation: no fasting is required.
c)
PET protocol: Scan coverage will extend from mid thigh to the base of the skull, starting 
from the mid-thighs to prevent urinary bladder radiotracer accumulation at the start of 
PET imaging.  Bed position scan time will be dependent on each sites scanner 
capabilities.  At a minimum, 3 minutes per bed position will be used.  In certain 
circumstances, coverage may be extended to the toes.  Contrast may be administered if 
requested by the referring clinician and is decided site dependent.
d) Patient monitoring: Vital signs will be assessed immediately before and after injection of 
68Ga-PSMA-11 (HR and supine BP).  Patients will be monitored for adverse events 
during injection and for two hours after radiotracer administration.   Additionally, patient’s 
vitals (HR and supine BP) will be checked at the completion of the imaging study prior to 
leaving the imaging center.
e) Patient follow-up: Patients will be contacted one to three days after 68Ga-PSMA-11 PET 
to assess for the development of delayed adverse events.  Patients will be seen in the 
clinic if there are any concerning study related adverse events requiring further 
evaluation.  Patients will also be followed up clinically and using conventional imaging for 
up to 12 months after 68Ga-PSMA-11 PET.  Follow-up imaging will be performed as 
allowed under standard of care.  
5.2
Monitoring and Toxicity Management
Each patient receiving Ga-68 PSMA-11 will be evaluable for safety.  The safety parameters 
include physical findings and spontaneous reports of adverse events reported to the investigator 
by patients.


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6
Study Procedures and Observations (Appendix 2)
6.1
Schedule of Procedures and Observations
Screening assessments must be performed within 30 days prior to the first dose of 
investigational product.  Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator.  Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation.
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
6.1.1.1 Screening Assessments 
The Screening procedures and assessments must be completed within 30 days of the day 1 
Visit. 

Laboratory values: all patients must have a recent PSA (within 30 days prior to study 
enrollment) consistent with BCR
o
If only one PSA greater than or equal to 0.2 ng/dL post radical prostatectomy is 
available, then a second confirmatory PSA must be checked prior to the 68Ga-
PSMA-11 PET study.

Pathology: all patients must have histopathology/biopsy of the prostate with a 
documented Gleason score 

Performance status: all patients must have their Karnofsky performance status (or 
ECOG/WHO equivalent) evaluated (Appendix 1).

Change in management: A pre-imaging survey of planned clinical management will be 
performed prior to 68Ga PSMA-11 PET/CT imaging.
6.1.2
Treatment Period
6.1.2.1 Study Procedures, Imaging Day 1

Vital signs

Evaluation of adverse events
6.1.3
Post-treatment Follow Up Visits
Patients will be followed for 1-3 days after enrollment, by phone.  The following procedure will 
be performed:

Evaluation of adverse events
Additionally, the following post-treatment follow up will be performed:

Change in management: A post-imaging survey of clinical management using PSMA-11 
PET/CT information will be performed ≤ 30 days of PSMA-11 PET/CT imaging for 
assessment of change in clinical management.


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
Change in management 6 months post imaging: A survey of clinical management will be 
performed approximately 6 month after the PSMA-11 PET/CT imaging for assessment of 
change in clinical management.

Conventional imaging follow-up 3-12 months post imaging: Conventional imaging follow-
up shall be performed as per institutional standard of care. DICOM images /or 
associated report should be collected for analysis.
6.2
Prohibited Medications
There are no prohibited medications.
7
Reporting and Documentation of Results
7.1
Evaluation of Side Effects
7.1.1.1 Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of 68Ga-PSMA-11.
7.2
Evaluation of Safety
Analyses will be performed for all patients receiving 68Ga-PSMA-11.  The study will use the 
CTCAE v4.0 for reporting of adverse events.
7.3
Definitions of Adverse Events
7.3.1
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. 
7.3.2
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.
7.3.2.1 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.


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7.3.2.2 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. 
“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.
7.3.2.3 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
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.
7.3.2.4 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. 
7.4
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. 


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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
7.5
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.
7.6
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 Committee on Human Research (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) and the San Francisco VA Medical Center within 5 business days 
of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration


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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: 

Suspected adverse reaction (as defined in 6.1.30)

Unexpected (as defined in 0)

Serious (as defined in 6.1.5)
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)). 
8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
Per patient and per region 68Ga-PSMA-11 sensitivity for the detection of prostate cancer 
recurrence .
8.1.1
Randomization
There will be no randomization performed.  
8.1.2 Blinding

For primary endpoint analysis of 68Ga-PSMA-11 PET imaging studies central readers will 
be fully blinded to clinical information and any conventional imaging results. Central 
readers will have access to the concomitant CT or MRI used for attenuation purposes.

For local interpretation of 68Ga-PSMA-11 PET imaging studies, local readers will be 
unblinded to both clinical information and other conventional imaging data.

For local interpretation of conventional imaging follow-up images 3-12 months post 68Ga-
PSMA-11 PET scan, local readers will be unblinded to all results and will be specifically 
informed of the location of 68Ga-PSMA-11 PET positive lesions so that follow-up 
measurements may be performed on these lesions.


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8.2
Determination of Sample Size and Accrual Rate
8.2.1
Sample Size and Power Estimate
The primary endpoint is to evaluate the sensitivity on a (1) per-patient and (2) per-region-basis 
(prostate bed, pelvis, extrapelvic soft tissue, and bone metastases) of 68Ga-PSMA-11 PET for 
detection of tumor location confirmed by histopathology/biopsy. Based on our first protocol in 
biochemical recurrent patients, we have updated the distribution of disease that we expect the 
find:
a) Prostate bed: 15%
b) Pelvis: 27%
c)
Extrapelvic soft tissue: 24%
d) Bone metastases: 11%
e) No evidence of disease on PSMA PET: 24%
Of our first cohort of patients, 19% of patients underwent biopsy after a positive PSMA PET 
imaging.  Based on biopsy results there was 100% sensitivity and 87% specificity.  There were 
no True Negatives or False Negatives on biopsy.  Imaging follow-up is not complete for our first 
study so we cannot estimate the percent of patients that will have imaging follow-up, but it 
appears that roughly 15 to 20% of patients will have imaging follow-up.  Consistent with our 
second protocol, we anticipated that the sensitivity for the four regions and for all regions 
combined using conventional imaging ranges from 30-60%. An overall sensitivity for 68Ga-
PSMA-11 PET of at most 50% will be considered as unacceptably low. Hence, the null 
hypothesis that the sensitivity is at most 50% will be tested against the alternative hypothesis 
that the sensitivity is greater than 50%. It is hypothesized that 68Ga-PSMA-11 PET imaging on 
the per-region and per-patient basis will substantially increase the sensitivity for the four regions 
to at least 70%. A sample size of 75 true positives is required for rejecting the null hypothesis 
that the sensitivity is at most 50% with 90% power at the one-sided 0.01 (=0.05/5 – a Bonferroni 
adjustment for evaluating the sensitivity for the four regions and for all regions combined) 
significance level, assuming an average regions specific prevalence of 20%.  Although 19% of 
patients underwent biopsy and 15% of patients have imaging follow-up, we anticipate that the 
biopsy rate will fall in this study as referring clinicians become more comfortable with the 
imaging results.  Therefore, we will combine imaging and biopsy follow-up in the primary aim, 
and will require 375 with both imaging and/or biopsy follow-up in order to power the analysis at 
a per region level. Assuming a prevalence rate of 20% for disease in each individual region, a 
total sample size of 1,500 patients is required.  In summary, the proposed target accrual of 
1,500 patients (375 with biopsies or imaging follow-up) will provide adequate power for 
detecting the anticipated improvement in the sensitivity for both the per-patient and per-region 
based 68Ga-PSMA-11 PET imaging.  However, a sample size of 107 patients with 
biopsies/follow-up in total is sufficient for detecting the anticipated improvement in sensitivity 
when evaluating per-patient based sensitivity.  
Our current biochemical recurrence protocol has not completed analysis or enrollment.  
Therefore we will perform an analysis of our first protocol and based on those results we may 
adjust the sample size of this protocol using updated assumptions based on the interim analysis 
of our existing protocol.


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8.2.2
Accrual estimates
We estimate that roughly 250 patients with prostate cancer will be enrolled in this trial per year.  
Over a two-year period this will result in up to 500 patients being enrolled in the study.
8.3
Analyses Plans
8.3.1
Analysis Population
Patients with histopathology correlates will be analyzed for the Primary Aim.  All remaining 
patients will be analyzed for the secondary endpoints.
8.3.2
Analysis of Primary Endpoints
Sensitivity on a per-patient and per-region-basis of 68Ga-PSMA-11 PET for detection of tumor 
location confirmed by histopathology/biopsy, clinical and conventional imaging follow-up will be 
calculated and reported along with the corresponding two-sided 95% confidence intervals. The 
confidence intervals will be constructed using the Wilson score method. For successful 
completion of the primary endpoint, two of the three readers will need to have an 70% sensitivity 
for the detection of disease on a per patient level for the cases that have a) imaging follow-up, 
b) pathology correlation or c) combination of pathology and imaging follow-up and/or pathology 
correlation. 
68Ga-PSMA-11 PET Results Definition
a) Imaging interpretation 68Ga-PSMA-11 PET:
Local Interpretations:  PET images will initially be interpreted by a board certified nuclear 
medicine physician or a board-certified radiologist experienced in reading PET at the 
time of the imaging study at the institution that the study is being performed. These 
interpretations will not be used for final evaluation, and will not be reported as part of the 
primary or secondary endpoints.  
Central Read Logistics: Imaging data will be anonymized and collected at a central site. 
PET data will be interpreted by three different readers in a random order at separate 
reading sessions. Cross sectional imaging (CT or MRI) from the 68Ga-PSMA-11 PET will 
be available for anatomic correlate.  The Central readers will be blinded to all other 
imaging results and all other clinical data.
Reader Positivity and Negativity Definition: Regions defined in Table 1 will be graded for 
the presence of suspected disease on a two-point scale by each reader (0=Negative or 
1=Positive). A region will be judged as positive if at least one lesion in this region is 
visually positive.
Reader Training: 68Ga-PSMA-11 PET/CT reading training set and guides will be 
provided and completion of this training will be required for all central review readers.  
Common pitfalls will be reviewed as part of the reader training.
Criteria for visual interpretation: 
Regions of suspected disease will be graded on a two-point scale by each blinded 
reader (0=Negative or 1= Positive). A region will be judged as positive if at least one 
lesion in this region is visually positive.


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i)
Lymph nodes will be considered positive if the 68Ga-PSMA-11 uptake is focal and 
greater than blood pool (adjacent or mediastinal blood pool). 
(1) Lymph nodes will be classified further by region: pelvic, retroperitoneal, 
thoracic, other.  Additionally, pelvic lymph nodes will be subclassified 
according to their localization as follows: R/L obturator, R/L external iliac, 
R/L internal iliac and other (total of 7 subgroups).  These regions will not be 
used for evaluation of the primary or secondary endpoints, but for 
exploratory analysis.
ii)
Visceral lesions will be considered positive if the 68Ga-PSMA-11 uptake is focal 
and greater than physiologic background activity of the involvement organ or 
anatomic site.
(1) Visceral lesions will be classified further by major organ: lung, liver, other 
tissue.  These regions will not be used for evaluation of the primary or 
secondary endpoints, but for exploratory analysis.
iii) Bone lesions will be considered positive if the 68Ga-PSMA-11 uptake is focal and 
greater than physiologic bone marrow.
(1) Bone lesions will be classified by further by region: spine, ribs, pelvis, 
extremities, skull, sternum, clavicle.  These regions will not be used for 
evaluation of the primary or secondary endpoints, but for exploratory 
analysis. 
iv) Prostate bed and prostate lesions will be considered positive if the 68Ga-PSMA-
11 uptake is focal and greater than physiologic background activity of the 
involvement organ or anatomic site.
Reference Standard Definition
b) Follow-up Imaging:
All patients will be followed up 3-12 months with conventional imaging (dedicated CT, 
MRI and/or bone scan).  Interpretation of follow-up imaging will be performed by local 
read. For lesions that are reported in the blinded reads but not reported in the local 
evaluation of follow-up imaging, the local readers will be informed of the location of the 
lesions and follow-up will be performed for these additional lesions.  Preferably, the 
follow-up conventional imaging should be the same modality/modalities as the initial 
staging work-up to allow for reproducible and accurate comparisons.  
68Ga-PSMA-11 PET validation based on follow-up imaging:
i)
Lymph nodes will be assessed by change in size. 68Ga-PSMA-11 positive lymph 
nodes will be considered:
(1) True positive: 
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 
months, lymph nodes seen on CT or MRI decrease by more than 30% in 
short axis diameter and PSA declines by more than 50%.


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o
If PSA increases by more than 50% on systemic therapy, then a 
increase in the size of lesion by more than 20% will be considered 
a true positive lesion.
- In subjects with localized suspected lymph node(s) receiving targeted 
treatment without concomitant systemic treatment there are two ways to meet 
true positive disease:
o
If the subject shows a decrease of PSA by greater than 50% after 
targeted treatment and the lymph node does not enlarge (change 
in size less than 20% or less than 3 mm increase in short axis 
diameter) [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lymph 
nodes seen on CT or MRI decrease by more than 30% in short 
axis diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lymph 
nodes seen on CT or MRI increase by more than 20% in short axis diameter 
(with a minimum of 3 mm in change in size).
(2) False positive: 
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 
months, lymph nodes seen on CT or MRI increase by more than 20% in short 
axis diameter and PSA decreases by more than 50%.
- In subjects with localized suspected lymph node(s) receiving targeted 
treatment without concomitant systemic treatment there are two ways to meet 
false positive disease:
o
If the subject does not demonstrate a decrease of PSA by greater 
than 50% after targeted treatment [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lymph 
nodes seen on CT or MRI increase by more than 20% in short 
axis diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lymph 
nodes seen on CT or MRI decrease by more than 30% in short axis diameter 
(with a minimum of 3 mm in change in size).
(3) If all regions in a patient/region do not meet criteria for either True positive or 
False positive disease, then the patient/region will be considered inevaluable 
for primary endpoint.
ii)
Visceral lesions (non-lymph node soft tissue or organ) will be assessed by 
change in size. 68Ga-PSMA-11 positive visceral lesions will be considered:
(1) True positive: 
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 


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months, lesions seen on CT or MRI decrease by more than 30% in long axis 
diameter and PSA declines by more than 50%.
o
If PSA increases by more than 50% on systemic therapy, then a 
increase in the size of lesion by more than 20% will be considered 
a true positive lesion.
- In subjects with localized suspected lesions(s) receiving targeted treatment 
without concomitant systemic treatment there are two ways to meet true 
positive disease:
o
If the subject demonstrates a decrease of PSA by greater than 
50% after targeted treatment [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lesions 
seen on CT or MRI decrease by more than 30% in long axis 
diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lesions 
seen on CT or MRI increase by more than 20% in long axis diameter (with a 
minimum of 3 mm in change in size).
(2) False positive: 
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 
months, lesions seen on CT or MRI increase by more than 20% in long axis 
diameter and PSA decreases by more than 50%.
- In subjects with localized suspected lesions(s) receiving targeted treatment 
without concomitant systemic treatment there are two ways to meet false 
positive disease:
o
If the subject does not demonstrate a decrease of PSA by greater 
than 50% after targeted treatment [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lesions 
seen on CT or MRI increase by more than 20% in long axis 
diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lesions 
seen on CT or MRI decrease by more than 30% in long axis diameter (with a 
minimum of 3 mm in change in size).
(3) If all regions in a patient/region do not meet criteria for either True positive or 
False positive disease, then the patient/region will be considered inevaluable 
for primary endpoint.
iii)
68Ga-PSMA-11 positive bone lesions will be considered:
(1) True positive:


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- If there was a corresponding positive sclerotic lesion on the CT portion of 
the 68Ga-PSMA-11 PET or on a separate CT obtained  30 days before or 
after the PET/CT in the same location as the PSMA uptake.
- If there is focal uptake seen in the same location as the PSMA uptake on 
the baseline bone scan performed within one month of 68Ga-PSMA-11 PET.
- If there is a lesion noted in the same location as the PSMA uptake on the 
initial MRI performed within one month of 68Ga-PSMA-11 PET.
- If within 12 months follow-up CT demonstrates development of sclerosis in 
the same location as the PSMA uptake.
- If within 12 months follow-up MRI demonstrates a new bone lesion in the 
same location as the PSMA uptake.
- If within 12 months follow-up bone scan demonstrates new focal uptake in 
the same location as the PSMA uptake.
- In subjects with localized suspected bone lesion(s) receiving targeted 
treatment without concomitant systemic treatment:
o
If the subject demonstrates a decrease of PSA by greater than 
50% after targeted treatment.
(2) False positive:
- In subjects with localized suspected bone lesion(s) receiving targeted 
treatment without concomitant systemic treatment:
o
If the subject does not demonstrate a decrease of PSA by greater 
than 50% after targeted treatment with curative intent (ie non-
palliative radiation).
- If 68Ga-PSMA-11 positive bone lesions do not meet the criteria for true 
positive findings, and appropriate correlative and follow-up imaging was 
acquired.
(3) If bone lesions do not meet criteria for either true positive or false positive 
disease listed above, then the patient/region will be considered inevaluable 
for primary endpoint.
iv)
68Ga-PSMA-11 positive prostate bed and prostate lesions will be considered:
(1) True positive:
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 
months, lesions seen on CT or MRI decrease by more than 30% in long axis 
diameter 
- In subjects with localized suspected lesions(s) receiving targeted treatment 
without concomitant systemic treatment there are two ways to meet true 
positive disease:


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o
If the subject demonstrates a decrease of PSA by greater than 
50% after targeted treatment [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lesions 
seen on CT or MRI decrease by more than 30% in long axis 
diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lesions 
seen on CT or MRI increase by more than 20% in long axis diameter (with a 
minimum of 3 mm in change in size).
(2) False positive: 
- For patients undergoing systemic treatment (alone or in combination with 
targeted treatment): If on post-treatment follow-up imaging within 3-12 
months, lesions seen on CT or MRI increase by more than 20% in long axis 
diameter  and PSA decreases by more than 50%.
- In subjects with localized suspected lesions(s) receiving targeted treatment 
without concomitant systemic treatment there are two ways to meet false 
positive disease:
o
If the subject does not demonstrate a decrease of PSA by greater 
than 50% after targeted treatment [OR]
o
If on post-treatment follow-up imaging within 3-12 months, lesions 
seen on CT or MRI increase by more than 20% in long axis 
diameter (with a minimum of 3 mm in change in size)
- For untreated patients: If on follow-up imaging within 3-12 months, lesions 
seen on CT or MRI decrease by more than 30% in long axis diameter (with a 
minimum of 3 mm in change in size).
(3) If the lesion does not meet criteria for either True positive or False positive 
disease, then the lesion will be considered inevaluable for primary endpoint.
c)
Histopathology/Biopsy:
i)
68Ga-PSMA-11 positive findings are aimed to be confirmed by histopathology/biopsy 
if clinically feasible.  Pathology performed 60 days before the PSMA PET will be 
available for correlation.
ii)
Histopathological procedures and biopsies will be performed as clinically indicated 
and as per institutional protocol.
(1) Positive Histopathology/Biopsy: Confirmed sites of metastatic or tumor 
involvement by histopathology/biopsy will be discussed with the responsible 
physician/surgeon.  
(a) True Positive: lesion is positive on targeted biopsy/surgical sampling and is 
read as positive on PSMA PET.
(b) False Negative: lesion is positive on targeted biopsy/surgical sampling and is 
read as negative on PSMA PET.


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(2) Negative Biopsy: Patients with suspected tumor recurrence on 68Ga-PSMA-11 
PET with negative histopathology/biopsy will be handled as outlined below:
(a) Lymph nodes:

For patients undergoing nodal dissection: Patients will be rescanned with 
dedicated CT, MRI or a repeat 68Ga-PSMA-11 PET to determine if the 
suspicious 68Ga-PSMA-11 positive node was removed.  
1.
If 68Ga-PSMA-11 positive lymph node is still present, a repeat biopsy 
can be pursued if clinically feasible and applicable, or follow-up using 
imaging as described above will be performed.
2.
If the corresponding node was removed, then this will be considered a 
False Positive.

For patients undergoing needle biopsy: Images of the procedure will be 
reviewed to determine if the correct node was biopsied.  
1.
If the correct node was biopsied, then a negative biopsy will be 
considered a False Positive.
2.
If the incorrect node was biopsied, then follow-up imaging as 
described above will be performed.
(b) Bone lesions:  Given the high rate of false negative biopsies for osseous 
metastases in patients with prostate cancer, patients with negative bone 
biopsies of PSMA PET positive lesions will be further evaluated:

If pathology demonstrates an alternative diagnoses that is known to be 
PSMA positive (eg Renal Cell Carcinoma metastases, Paget’s disease), 
then this will be considered a False Positive.

If pathology is indeterminate, then follow-up imaging as described above 
will be performed.
(3) Although not routinely performed during standard practice, immunohistochemical 
staining for PSMA of tumor specimens (primary and lymph node metastases) 
may be performed, although not required.
d) Definitions of True Positive, False Positive, True Negative, and False Negative patients 
and regions: Pathology will be considered superior to imaging and clinical follow-up 
when available as described below. Patient and region level classification will be 
performed for each blinded reader, and be reported separately. The following criteria 
serve as a guide for interpretation. However not all findings on a lesions, region and 
patient level can be detailed here and investigators may deviate from these criteria in 
individual patients.  These will be recorded for each interpretation that is not described in 
this protocol for the definition of a region or patient.
i)
Patient level evaluation: 
(1) True positive patient: A single region in a patient contains a true positive node 
either by pathology or imaging/clinical follow-up.


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(a) For a patient to be considered a True Positive, only one region is required to 
have a true positive lesion as described above, unless one region is 
categorized as a false positive based on pathology.  This means that a single 
pathology false positive region outweighs regions with imaging/clinical follow-
up true positive disease.
(b) A patient will be considered a True Positive if one region contains a lesion 
that is True Positive, even if other regions are categorized as inevaluable or 
false positive based on imaging or clinical follow-up.
(2) True negative patient: in the absence of True Positive or False Positive lesions, a 
patient will be considered a True Negative if there is pathology that is negative 
for disease and corresponding lesion is negative by PSMA PET.
(3) False positive patient: 
(a) Pathology confirms a false positive lesion that is read as positive on PSMA 
PET.
(b) In the absence of pathology: there are no true positive regions, and there is a 
region that is categorized as false positive based on imaging or clinical follow-
up.
(4) False negative patient: in the absence of True Positive or False Positive lesions, 
a patient will be considered a False Negative if there is pathology that is positive 
for disease and corresponding lesion is negative by PSMA PET.  Additionally, 
patients without evidence of disease on PSMA PET but with biochemical 
evidence of disease will be considered a False Negative.
ii)
Region level evaluation: Each patient will have four evaluable regions (Table 1: 
prostate bed, pelvis, extrapelvic soft tissue, and bone metastases).  Each region will 
be categorized as true positive or false positive as described above.  Regions 
without evidence of PSMA positive disease or deemed inevaluable will not be 
included in the analysis.
(1) True positive region: 
(a) Pathology confirms a PSMA avid lesion as a true positive in the region.
(b) In the absence of pathology, clinical or imaging follow-up demonstrates a true 
positive lesion within the region independent of the presence of an 
inevaluable lesion or a false positive lesion 

ie true positive disease will supersede a false positive lesion in the region 
based analysis if based on imaging/clinical follow-up
(2) True negative region: in the absence of True Positive or False Positive lesions 
within a region, the region will be considered a True Negative if there is 
pathology that is negative for disease in the region and corresponding lesion is 
negative by PSMA PET.
(3) False positive region:
(a) Pathology confirms a PSMA avid lesion as a false positive in the region


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(b) In the absence of pathology, there are no true positive lesions in the region, 
and there is a false positive lesion by clinical or imaging follow-up.
(4) False negative region: in the absence of True Positive or False Positive lesions in 
a region, the region will be considered a False Negative if there is pathology that 
is positive for disease in the region and corresponding lesion is negative by 
PSMA PET.
8.3.3
Analysis of Secondary Endpoints
1.
PPVs on a per-patient and per-region-basis of 68Ga-PSMA-11 PET for detection of tumor 
location confirmed by histopathology/biopsy, clinical and conventional imaging follow-up 
will be calculated and reported along with the corresponding two-sided 95% confidence 
intervals. The confidence intervals will be constructed using the Wilson score method. 
PPV will be reported for each of the three blinded readers independently.
2.
Sensitivity and PPVs on a per-patient and per-region basis of 68Ga-PSMA-11 PET for 
detection of tumor location confirmed by histopathology/biopsy will be summarized in 
tabular format. Ninety-five percent confidence intervals of sensitivity, specificity, NPV and 
PPV will be calculated using the Wilson score method.  These will be reported for each of 
the three blinded readers.
3.
Detection rates on a per-patient basis of 68Ga-PSMA-11 PET stratified by PSA value (0.2 
- <0.5, 0.5 - <1.0, 1.0 - <2.0, 2.0 - <5.0, ≥5.0) will be summarized in tabular format and 
compared between PSA strata using chi-square analysis.  Detection rate will also be 
stratified by history of prostatectomy, radiation or both; as well as by whether the patient 
is on androgen deprivation therapy (ADT).  We will use local interpretations for this 
analysis.  
a.
Detection rate is defined as number of patients with PSMA positive disease, 
independent of pathology, imaging or clinical follow-up.  A detection rate will be 
reported for each reader independently stratified by PSA.
4.
The impact of 68Ga-PSMA-11 PET on clinical management in BCR patients will be 
evaluated using descriptive statistics. 
5.
Inter-reader reproducibility for positivity at the patient level and region level will be 
reported using the Fleiss’ Kappa test for multiple readers.  We will use the three blinded 
reads for this analysis.
6.
Safety will be reported descriptively as rates of patient reported adverse events.  
Additionally, adverse events will be characterized and quantified by CTCAE 4.03.
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 


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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.
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 CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
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 CHR-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. 
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF CHR, 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 CHR 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 CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR 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 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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References
1.
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cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among 
persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120:1290–1314.
2.
Oyen RH, Van Poppel HP, Ameye FE, Van de Voorde WA, Baert AL, Baert LV. Lymph 
node staging of localized prostatic carcinoma with CT and CT-guided fine-needle 
aspiration biopsy: prospective study of 285 patients. 1994;190:315–322.
3.
Contractor K, Challapalli A, Barwick T, et al. Use of [11C]choline PET-CT as a 
noninvasive method for detecting pelvic lymph node status from prostate cancer and 
relationship with choline kinase expression. Clin Cancer Res. 2011;17:7673–7683.
4.
Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison 
of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of 
androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273–
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5.
Castellucci P, Ceci F, Graziani T, et al. Early biochemical relapse after radical 
prostatectomy: which prostate cancer patients may benefit from a restaging 11C-Choline 
PET/CT scan before salvage radiation therapy? J Nucl Med. 2014;55:1424–1429.
6.
Brogsitter C, Zöphel K, Kotzerke J. 18F-Choline, 11C-choline and 11C-acetate PET/CT: 
comparative analysis for imaging prostate cancer patients. Eur J Nucl Med Mol Imaging. 
2013;40 Suppl 1:S18–S27.
7.
Picchio M, Spinapolice EG, Fallanca F, et al. [11C]Choline PET/CT detection of bone 
metastases in patients with PSA progression after primary treatment for prostate cancer: 
comparison with bone scintigraphy. Eur J Nucl Med Mol Imaging. 2011;39:13–26.
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Souvatzoglou M, Krause BJ, Pürschel A, et al. Influence of (11)C-choline PET/CT on the 
treatment planning for salvage radiation therapy in patients with biochemical recurrence 
of prostate cancer. Radiother Oncol. 2011;99:193–200.
9.
Castellucci P, Fuccio C, Rubello D, et al. Is there a role for ¹¹C-choline PET/CT in the 
early detection of metastatic disease in surgically treated prostate cancer patients with a 
mild PSA increase. Eur J Nucl Med Mol Imaging. 2011;38:55–63.
10.
Giovacchini G, Picchio M, Scattoni V, et al. PSA doubling time for prediction of 
[(11)C]choline PET/CT findings in prostate cancer patients with biochemical failure after 
radical prostatectomy. Eur J Nucl Med Mol Imaging. 2010;37:1106–1116.
11.
Fuccio C, Castellucci P, Schiavina R, et al. Role of 11C-choline PET/CT in the restaging 
of prostate cancer patients showing a single lesion on bone scintigraphy. Ann Nucl Med. 
2010;24:485–492.
12.
Seltzer MA, Barbaric Z, Belldegrun A, et al. Comparison of helical computerized 
tomography, positron emission tomography and monoclonal antibody scans for 


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evaluation of lymph node metastases in patients with prostate specific antigen relapse 
after treatment for localized prostate cancer. J Urol. 2005;162:1322–1328.
13.
Kahn D, Williams RD, Manyak MJ, et al. 111Indium-capromab pendetide in the 
evaluation of patients with residual or recurrent prostate cancer after radical 
prostatectomy. The ProstaScint Study Group. J Urol. 1998;159:2041–6–discussion2046–
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14.
Manyak MJ, Hinkle GH, Olsen JO, et al. Immunoscintigraphy with indium-111-capromab 
pendetide: evaluation before definitive therapy in patients with prostate cancer. Urology. 
1999;54:1058–1063.
15.
Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide 
immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical 
prostatectomy. Cancer. 2002;94:987–996.
16.
Aparici CM, Carlson D, Nguyen N, Hawkins RA, Seo Y. Combined SPECT and 
Multidetector CT for Prostate Cancer Evaluations. Am J Nucl Med Mol Imaging. 
2012;2:48–54.
17.
Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a 
(68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of 
recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.
18.
Afshar-Oromieh A, Avtzi E, Giesel FL, 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. 2015;42:197–209.
19.
Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid ⁶⁸Ga-PSMA Ligand 
PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl 
Med. Society of Nuclear Medicine. 2015;56:668–674.
20.
Ceci F, Uprimny C, Nilica B, et al. (68)Ga-PSMA PET/CT for restaging recurrent prostate 
cancer: which factors are associated with PET/CT detection rate? Eur J Nucl Med Mol 
Imaging. 2015;42:1284–1294.
21.
van Leeuwen PJ, Stricker P, Hruby G, et al. (68) Ga-PSMA has a high detection rate of 
prostate cancer recurrence outside the prostatic fossa in patients being considered for 
salvage radiation treatment. BJU Int. 2016;117:732–739.


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Appendices
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 Schedule of Study Procedures and Assessments
 * in patients who do not have biopsy proof or other criteria to qualify disease, repeat imaging 3-12 months after initiation of 
treatment or imaging will be performed 
Schedule of Study Procedures and Assessments
Period/
Procedure
Screening
Imaging day 1
1-3 day post 
imaging
Follow-up 
survey 1
Follow-up 
survey 2
Clinical/imaging 
follow-up
Study day / Visit day
-30 to 1
1
2-4
2 – 30 days
Six months
3-12 months
Informed consent
X
Laboratory values, 
history from medical 
record
X
Pre-survey
X
Performance status
X
Blood pressure, HR
X
Imaging Procedure
68Ga-PSMA-11
X
PET/CT or PET/MRI
X
Follow-up
Adverse event reporting
X
Post-survey
X
X
Clinical follow-up
X
Follow-up imaging
X*


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Appendix 3 (pre- and post-surveys)