Conditions: Prostate Cancer Metastatic
Keywords: Prostatic Neoplasms Cancer of Prostate Cancer of the Prostate Neoplasms, Prostate Prostate Cancer Prostatic Cancer Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Neoplasms Genital Diseases, Male Prostatic Diseases PSMA Prostate-specific membrane antigen Gallium radioisotope 68 68Ga-PSMA-R2 68Ga-PSMA ligand
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This was an open-label, multicenter, single dose, Phase I/II study to evaluate the safety and tolerability of a single administration of 3 mega Becquerel (MBq)/kg, but not less than 150 MBq and not more than 250 MBq, of 68\^Ga-PSMA-R2 in adult male patients with biochemical relapse (BR) and metastatic prostate cancer (mPCa).

Detailed description:
This study consisted of 2 parts.

* During the first part (Phase I) of the study, 6 subjects with biochemically recurrent prostate cancer (PCa) received the investigational product (IP) and remained at the site for approximately 6 hours post-administration in order to assess the PK, biodistribution versus time, and dosimetry for critical organs. Subjects received a single dose of 3 MBq/kg, (\>=150 and =\<250 MBq), of 68\^Ga-PSMA-R2 intravenously. Serial blood and urine samples were collected for PK characterization and dosimetry and whole-body PET/CT were acquired at selected time points (0 to 4 hours) to determine organ and tumor absorbed doses. Safety assessments were conducted after IP administration on Day 1, and during follow-up on Days 7 and 28.
* In the second part of the study (Phase II), 2 groups of 12 subjects were enrolled (subjects with PCa in biochemical recurrence \[PCa-BR\], and subjects with prostate cancer in the metastatic stage \[mPCa\]). Based on the preliminary data analysis from the Phase I part of the study provided sufficient dosimetry data, all subjects underwent the whole body PET/CT imaging optimized for time (up to 2 time points) according to the data analysis from the Phase I part of the study.

This study was comprised of 4 clinical visits and conducted in 3 study periods: screening, administration/imaging, and safety follow-up period.

Arms:
arm 1: All eligible participants received recommended dose of \[68Ga\]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) \[but not more than 250 and not less than 150 MBq\]. arm 2: All eligible participants received recommended dose of \[68Ga\]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) \[but not more than 250 and not less than 150 MBq\]. arm 3: All eligible participants received recommended dose of \[68Ga\]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) \[but not more than 250 and not less than 150 MBq\].

Interventions: intervention 1: [68Ga]-PSMA-R2
Intervention descriptions: intervention 1: radio-labelled PSMA ligand

Protocol document:
Prot_001.pdf: 
Page 1 of 57 
 
 
 
 
 
 
 
Clinical Study Protocol 
 
STUDY TITLE 
A Phase 1/2 open-label, multi-center, safety and tolerability study of a 
single dose of 68Ga-PSMA-R2 in patients with biochemical relapse (BR) 
and metastatic prostate cancer (mPCa). 
SHORT TITLE 
PROfind 
INVESTIGATIONAL PRODUCT 
Kit for the preparation of 68Ga-PSMA-R2 for injection 
STUDY 
Safety and Tolerability Study (Phase 1/2) 
OBJECTIVES 
 
 
 
 
 
SPONSOR 
 
 
 
 
IND NO. 
PROTOCOL NUMBER 
PROTOCOL VERSION/DATE 
Assessment of the safety and tolerability of a single administration of 
3 mega Becquerel (MBq)/kg, but not less than 150 MBq and not more 
than 250 MBq, of 68Ga-PSMA-R2, to assess the pharmacokinetics (PK), 
biodistribution, and dosimetry of 68Ga-PSMA-R2, and to establish the 
optimal imaging method for determining location and burden of positive 
lesions in adult male patients with biochemical relapse (BR) and 
metastatic prostate cancer (mPCa). 
Advanced Accelerator Applications International SA 
4 rue de la tour de l’ile 
1204 Geneva, Switzerland 
Tel: +41 (0)22 519 0700 
www.adacap.com / info@adacap.com 
135350 
A206D-A01-001 / NCT03490032 
Version 2.2, 22 February, 2018 
 
 
 
 
 
Property of Advanced Accelerator Applications International SA 
Confidential 
May not be used, divulged, published or otherwise disclosed without the 
consent of Advanced Accelerator Applications International SA 


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Protocol # A206D-A01-001 
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Tel: 
E-mail: 
Tel: 
E-mail: 
This trial will be conducted in compliance with the protocol, the principles of Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
This confidential document is property of the Sponsor. No information contained in this 
document may be disclosed without prior written approval of the Sponsor. 
, MD 
Advanced Accelerator Applications International SA 
 USA Inc. 
 
 
 
 
 
Advanced Accelerator Applications USA Inc. 
 
SCIENTIFIC ADVISOR CHAIRS 
 
 
 
 
 
 
CONTACTS FOR SAFETY 
REPORTING 
Advanced Accelerator Applications SA 
20 rue Diesel 
01630 Saint Genis Pouilly 
Tel: +33 4 50 99 30 70 
www.adacap.com / info@adacap.com 
 
 
 
GOOD CLINICAL PRACTICE AND CONFIDENTIALITY STATEMENT 
Tel: 
E-mail: 
Advanced Accelerator Applications
Tel: 
E mail: 
, MD, PhD. 
Tel: 
E-mail: 


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Protocol # A206D-A01-001 
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SYNOPSIS 
 
Version Date 
Version 2.2, 22 February, 2018 
Protocol Number 
A206D-A01-001 
Phase of Development 
Safety and Tolerability Study (Phase 1/2) 
IND Number 
135350 
Investigational Product 
68Ga-PSMA-R2 
Protocol Titles 
A Phase 1/2 open-label, multi-center, safety and tolerability study of a single dose of 
68Ga-PSMA-R2 in patients with biochemical relapse (BR) and metastatic prostate 
cancer (mPCa) 
Short Title 
PROfind 
Number of Study Sites 
Approximately 4 clinical sites in the US 
Sponsor 
Advanced Accelerator Applications International SA 
Co-Principal 
Investigators 
and 
, MD, PhD 
Investigational Product 
Kit for the preparation of 68Ga-PSMA-R2 for injection 
Objectives 
Primary objective: 
To assess safety and tolerability of a single administration of 3 mega Becquerel 
(MBq)/kg, but not less than 150 MBq and not more than 250 MBq, of 68Ga-PSMA- 
R2 
Secondary Objectives 
• To assess the pharmacokinetics (PK), biodistribution, and dosimetry of 68Ga- 
PSMA-R2. 
• To establish the optimal imaging method for determining location and burden of 
positive lesions on 68Ga-PSMA-R2 positron emission tomography (PET) imaging 
in patients in comparison with lesions identified with conventional imaging scans 
(computed tomography (CT)/magnetic resonance imaging (MRI) and bone scan), 
and to calculate the agreement of 68Ga-PSMA-R2 PET with conventional 
anatomical/functional imaging on a per patient basis. 
Endpoints 
Primary Endpoints: 
• Adverse events (AEs) and serious adverse events (SAEs) 
• Absolute changes and changes from baseline in clinical laboratory parameters, vital 
signs, electrocardiogram (ECG) 
Secondary Endpoints: 
• Generation of decay corrected tissue time-activity curves (TACs) from 68Ga- 
PSMA-R2 PET/CT images in normal organs and tumor lesions. 
• Urinary excretion of 68Ga-PSMA-R2 
• Calculation of half-life of 68Ga-PSMA-R2 in blood 


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• Generation of non-decay-corrected time activity curves from 68Ga-PSMA-R2 
PET/CT images in normal organs and tumor lesions 
• Calculation of residence times in organs and tumor lesions of 68Ga-PSMA-R2 
• Calculation of absorbed doses and effective whole-body dose of 68Ga-PSMA-R2 
• To establish optimal threshold, expressed as standard uptake value (SUV) to 
discriminate positive PET imaging results from negative ones. 
• Burden and location of tumor lesions detected by 68Ga-PSMA-R2 in comparison 
with standard imaging modalities such as CT/MRI and/or bone scan and/or biopsy. 
• Calculation of patient level agreement of 68Ga-PSMA-R2 PET imaging relative to 
conventional techniques in prostate cancer patients 
Study Design 
This study will consist of 2 parts. 
• During the first part (Phase 1), approximately 6 patients with biochemically 
recurrent PCa will receive the investigational product (IP) and will remain at the 
site for approximately 6 hours post-injection in order to assess the PK, 
biodistribution vs. time, and dosimetry for critical organs. Patients will receive a 
single dose of 3 MBq/kg, (≥ 150 and ≤ 250 MBq), of 68Ga-PSMA-R2 
intravenously. Serial blood and urine samples will be collected for PK 
characterization and dosimetry and whole-body PET/CT will be acquired at 
selected time points (0-4 hours) to determine organ and tumor absorbed doses. 
Safety assessments will be conducted after IP administration on Day 1, and during 
follow-up on Days 7 and 28. 
• In the second part of the study (Phase 2), two groups of approximately 12 patients 
will be enrolled (patients with PCa in biochemical recurrence (PCa-BR), and 
patients with prostate cancer in the metastatic stage (mPCa)). Enrollment will be 
capped at 12 patients in each group to ensure an even distribution of patient 
conditions. If preliminary data analysis from the Phase 1 part of the study provides 
sufficient dosimetry data, all patients will undergo whole body PET/CT imaging 
optimized for time (up to 2 time points) according to the data analysis from the 
Phase 1 component of the study. 
Study Population 
Patients with histologically confirmed adenocarcinoma of prostate staged as PCa-BR 
or mPCa 
Study Duration 
Approximately 6 weeks: up to 2 weeks of screening assessment, a 1-Day IP 
administration and imaging period, and three safety follow-up visits, at least one hour 
after the administration, then 7 Days and 28 Days after the administration. End of the 
study is defined as the date the last patient enrolled completes the 28 Days safety 
follow-up. 
Treatment Duration 
One Day/single IP administration 
Number of Patients 
Planned 
Approximately 30 patients will be enrolled in this trial. 
Phase 1 will include approximately 6 patients with adenocarcinoma of prostate origin 
staged as PCa-BR. 
Phase 2 will be comprised of 2 groups: one of approximately 12 patients with PCa- 
BR and another of approximately 12 patients with mPCa. 
Inclusion Criteria 
1. Male patients, 18 years of age or older. 
2. Signed and dated written informed consent by the patient prior to any study- 
specific procedures. 
3. Histologically confirmed adenocarcinoma of the prostate. 
a. Biochemical recurrence: defined as prostate specific antigen (PSA) level of 
≥ 0.2 ng/mL after radical prostatectomy or PSA nadir plus 2 ng/mL after radiation 
therapy with corresponding CT/MRI or bone scan revealing absence of local 
recurrence or metastatic lesions. 


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OR 
b. Metastatic disease: defined as both, castration-sensitive or castration-resistant 
mPCa (presence of at least one metastatic lymph-node, visceral metastasis and/or 
bone metastasis). 
c. At least 2 weeks must have elapsed between last anti-cancer treatment 
administration and the administration of the imaging product, 68Ga-PSMA-R2. 
4. Prior major surgery must be at least 12 weeks prior to study entry. 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2, with a life 
expectancy ≥ 6 months. 
6. Adequate bone marrow reserve and organ function as demonstrated by complete 
blood count, and biochemistry in blood and urine at Screening: 
o Hemoglobin (Hb): > 8.0 g/dL 
o Platelet count of > 50.000/mm3 
7. Serum creatinine < 1.5 ´ upper limit normal (ULN) or estimated glomerular 
filtration rate (eGFR) > 50 mL/min based upon The Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation [34]. 
8. For male patients with partners of childbearing potential, agreement to use barrier 
contraceptive method (condom) and to continue its use for 28 days after IP 
administration. 
Exclusion Criteria 
1. Pathological finding consistent with small cell, neuroendocrine carcinoma of the 
prostate or any other histologies different than adenocarcinoma. 
2. Administered a radioisotope ≤ 10 physical half-lives prior to the day of PET/CT. 
3. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, 
or need of indwelling/condom catheters. 
4. Uncontrolled pain or incompatibility that results in patient’s lack of compliance 
with imaging procedures 
5. Other known co-existing malignancies except non-melanoma skin or low grade 
superficial bladder cancer unless definitively treated and proven no evidence of 
recurrence for at least 5 years. 
6. Patient with known incompatibility to CT scans. 
7. Any evidence of severe or uncontrolled systemic or psychiatric diseases, including 
uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s 
opinion makes it undesirable for the patient to participate in the trial or which 
would jeopardize compliance with the protocol, or active infection including human 
immunodeficiency virus (HIV) and untreated hepatitis B, hepatitis C. Screening for 
chronic conditions is not required. 
8. Patients who have received any investigational agent within the last 28 days are 
excluded from participation in this trial. 
9. Any acute toxicity due to prior chemotherapy and/or radiotherapy that has not 
resolved according to the Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
10. Known allergy, hypersensitivity, or intolerance to the investigational product or 
its excipients. 
11. Patient unlikely to comply with study procedures, restrictions and requirements 
and judged by the Investigator to be unsuitable for study participation. 
Investigational 
Product, Dosage, and 
Mode of 
Administration 
68Ga-PSMA-R2 will be prepared on the day of the administration using a reaction 
vial containing a lyophilized labelling formulation of 30 µg of PSMA-R2 to be 
reconstituted with the addition of 68GaCl3 solution coming from a GMP 68Ge/68Ga 
generator and reaction buffer. After 7 minutes at 95°C, the final labelled 68Ga- 
PSMA-R2 product is ready for injection. The reconstituted product is stable for at 
least 4 hours after labelling. 


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Before administration, quality control (QC) testing will be performed and the exact 
volume to be injected will be determined (based on the weight of the patient, the 
estimated time of injection, and the physical decay of the radionuclide). The final 
volume and activity of the reconstituted product provides enough solution for QC 
testing and for the subsequent administration. 
Imaging 
Dosimetry assessments will be conducted based on time activity curves (TAC), time 
integrated activity coefficients (TIAC), absorbed doses and effective dose. Maximum 
standardized uptake values (SUVmax) will be used to determine the tumor lesions, 
defined as focal areas of abnormal uptake showing a higher SUVmax than surrounding 
tissue. Identification of the time points post-injection with the highest observed 
number of lesions and the highest SUVmax, SUVmean values and the tumor to 
background ratios for each SUV will be determined. The later will be conducted 
separately for each imaging time point (approximately at 20-30 minutes, 1, 2, 
3-4 hours) post-injection. For Phase 2, all patients will undergo whole body PET/CT 
imaging optimized for time (up to 2 time points) according to the data analysis from 
the Phase 1 component of the study. Qualitative visual analysis of total number of 
lesions identified by PET, and semi-quantitative analysis by means of SUVmax and 
SUVmean values per dose and time points will be conducted. 
Distribution and 
Dosimetry 
Dosimetry data will be issued from serial imaging data. Organ radiation absorbed 
doses will be calculated. 
Blood and Urine 
Collection for PK and 
Dosimetry 
Serial samples (blood and urine) will be collected from approximately 6 patients on 
Day 1 visit for PK, biodistribution and dosimetry analysis as outlined below. 
• Blood: Immediately prior to IP administration, approximately 5, 10, 20, 40 minutes, 
1, 2, 4 and 6 hours post injection. 
• Urine: Pre-injection, approximately 0-20 minutes after IP administration, 
approximately 0-1 hour, 1-2 hours, 2-4 hours, 4-6 hours post-injection 
Discontinuation from 
Study Treatment 
Patients may withdraw from this study if: 
• It is in the patient’s best interest as determined by the study Investigator 
• Withdrawal of consent 
• Any manifestation of unacceptable toxicity defined as any major adverse event 
(AE) related to treatment procedures 
• Lost to follow-up 
• Early study termination by the Sponsor 
Safety and Tolerability 
All patients will be evaluated for safety and tolerability based on results of vital signs 
recorded at each visit, ECG after IP administration on Day 1, and laboratory 
assessments (including hematology, blood chemistry, urinalysis) at each study visit. 
Adverse events will be recorded using the Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
Adverse events will be recorded and monitored from the time the patient signs the 
informed consent form (ICF) until 28 Days end of study visit. Serious adverse events 
(SAEs) will be submitted to the Advanced Accelerator Applications (AAA) 
pharmacovigilance department and will be followed until stabilization or resolution. 
Sample Size 
Calculations 
The number of patients in this study is not based on statistical power considerations. 
It is anticipated that data for up to 30 evaluable patients distributed in the two study 
phases will provide sufficient data to assess the safety and tolerability of the 
intravenous administration of 68Ga-PSMA-R2. 
Statistical Analysis 
All statistical analyses will be primarily descriptive in nature and will include 
summaries and graphical presentations of the data. Data presentations will group the 
PCa-BC and mPCa populations and also include an overall total patients column. 


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The safety assessments will be performed after a single administration of 68Ga- 
PSMA-R2. Safety and tolerability will be primarily evaluated by the incidence of 
AEs, changes in clinical laboratory values (hematology, blood chemistry, and 
urinalysis), vital signs (temperature, blood pressure, heart rate, and respiratory rate), 
and ECGs. All adverse events will be listed on an individual basis. They will be 
summarized by System Organ Class and preferred term including relationship and 
severity on a patient basis. Clinical laboratory parameters, vital signs and ECG 
parameters will be summarized and presented graphically as observed values and 
changes from baseline at each measuring time. Clinical laboratory parameters will 
also be analyzed in terms of tabulations to within, below or above normal ranges 
provided by the laboratory of each site. 
Descriptive statistics and graphical presentation will be produced for bio-distribution, 
radiation dosimetry and PK data as appropriate. 
The number and location of lesions identified by 68Ga-PSMA-R2 PET imaging will 
be summarized and compared with those identified with conventional imaging 
techniques. Tumor uptake will be evaluated by SUV. SUVmean and SUVmax will be 
determined along with tumor to background ratio and these will be summarized 
descriptively. Positive and negative lesions by the two imaging techniques will be 
cross tabulated overall and by localization area on a lesion level and a patient level. 
Agreement calculations will be performed on a patient level and tests of association 
may be performed where appropriate. 
Preliminary explorations of 68Ga-PSMA-R2 imaging performance relative to 
cytology and/or histopathology findings from archival and/or recent biopsy 
specimens will be performed for patients with biopsy data available. 


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STUDY PROCEDURES AND ASSESSMENTS 
 
Table 1 
Schedule of Procedures and Assessments 
Screening 
(Day -14 to Day -1 
(+1 day) 
Imaging 
Day 1 (+1 day) 
Safety Follow-up 
Day 7 (+1 day) 
Safety Follow-up 
Day 28 (+1 day) 
Informed consent 
X 
Inclusion/Exclusion Criteria Assessment 
X 
Medical History & Demographics 
X 
ECOG Performance Status 
X 
X 
X 
X 
Standard 12-lead ECG 
X 
Xa 
Disease Assessment: Imaging (CT/MRI or Bone Scan) 
Xb 
Vital Signs: Temperature (Temp), Blood Pressure (BP), 
Heart Rate (HR), and Respiratory Rate (RR) c 
X 
X 
X 
X 
PSA 
X 
Lab Analysis: Hematology, Blood Chemistryd 
X 
X 
X 
X 
Urine Analysis (Dipstick)e 
X 
X 
X 
X 
68Ga-PSMA-R2 Administration 
X 
68Ga-PSMA-R2 PET/CT (Dosimetry)f 
X 
PK and Dosimetry Sample Collection (Blood)g 
X 
PK and Dosimetry Sample Collection (Urine)h 
X 
Adverse Event Collection 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 


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a On Day 1, 12-Lead ECG will be collected after dosage administration. 
bAll patients are required to undergo a CT/MRI and bone scan if indicated (can be performed ≤ 2 months prior to study entry). 
c On Day 1 vital signs (temp, BP, HR, and RR) will be performed before and after to 68Ga-PSMA-R2 injection and also at the end of 68Ga-PSMA-R2 PET/CT 
scan. 
d Peripheral venous blood samples will be collected at each visit. On Day 1, blood samples will be collected after administration of 68Ga-PSMA-R2. 
e A urine sample will be collected at each visit and analyzed at the clinical site if dipstick results are abnormal. Sample collection on Day 1 will be performed 
after the administration of IP 
f Patients in Phase 1 only: PET/CT scans will be performed at approximately 20-30 min and at 1, 2, 3-4 hours post-injection. For patients in Phase 2 only, PET/CT 
scan will be performed at up to 2 optimal time points as determined in the Phase 1 portion of the study. 
g Patients in Phase 1 only: PK and dosimetry blood samples will be collected immediately prior to injection, approximately 5, 10, 20, 40 minutes, 1, 2, 4, and 
6 hours post injection. 
h Patients in Phase 1 only: Urine sample for PK will be collected pre-injection, approximately 0-20 minutes after IP administration, and approximately 0- 
1 hours,1-2 hours, 2-4 hours, and 4-6 hours post-injection. 
BP = blood pressure; CT = computerized tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HR = heart rate; MRI = 
magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; PSA = prostate specific antigen; PSMA = prostate specific membrane 
antigen 


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INVESTIGATOR’S STATEMENT 
I agree to conduct the study as outlined in the protocol entitled “A Phase 1/2 open-label, multi- 
center, safety and tolerability study of a single dose of 68Ga-PSMA-R2 in patients in biochemical 
relapse (BR) and metastatic prostate cancer (mPCa).” in accordance with the guidelines and all 
applicable government regulations. These guidelines and regulations include, but are not limited 
to: 
1. The right for the Sponsor and the Regulatory Agencies to inspect study facilities and 
pertinent records any time they may consider appropriate and in a reasonable manner that 
ensures patient confidentiality. If this study is to be inspected by a Regulatory Agency, the 
Sponsor should be notified as soon as possible; 
2. When required, submission of the proposed clinical investigation, including the protocol and 
the consent form to a duly constituted Institutional Review Board (IRB) or Ethics Committee 
(EC) for approval and acquisition of written approval for each, prior to the use of the 
experimental study drug; 
3. Obtaining the written informed consent prior to administration of study drug or any protocol- 
specified procedures or intervention that involve risk, and that contains all the elements of 
consent as specified in any applicable regulation and has been previously approved by the 
Sponsor and the IRB/EC; 
4. Submission of any proposed change in or deviation from the protocol to the IRB/EC using a 
signed formal amendment document approved by the Sponsor. Any proposed changes or 
amendment in the protocol require that the informed consent also reflect such changes or 
amendment and that the revised informed consent be approved by the IRB/EC; 
5. Documentation and detailed explanation of individual protocol deviations on the appropriate 
case report form page or in letters to the Sponsor; 
6. Reports of Serious Adverse Events (SAE) to the Sponsor or designee (e.g. CRO) within 24 
hours by email/fax and a written report of the serious adverse event within 24 hours after the 
Investigator’s initial receipt of the information; 
7. After the 28-Day safety follow-up period, all SAEs possibly related to 68Ga-PSMA-R2 or to 
the study procedures must be reported to the Sponsor 
8. Documentation of SAEs, as outlined in the protocol, to the IRB/EC within 15 calendar Days 
of their disclosure and 7 Days for death and life threatening; 
9. Submission of timely progress reports to the IRB/EC as determined by the IRB/EC, and/or 
Sponsor, at appropriate intervals or upon request if applicable; 
Regulations require an Investigator to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data (such as study drug accountability) pertinent to 
the investigation on each individual enrolled in the study. These records must be maintained by 
the Investigator for a period established in the current regulation in place or a period of time 
determined by the Sponsor following the date a marketing application is approved 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 or a period of time determined by 


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Name: 
Date: 
Signature: 
Name: 
Date: 
Signature 
the Sponsor after the investigation is discontinued and the appropriate regulatory authorities are 
notified. 
In addition, I agree to provide all the information requested in the case report form in a manner 
to assure legibility and accuracy. To this end, I shall carefully follow the instructions for 
completing case report forms. 
I also agree that all information provided to me by the Sponsor, including protocols, case report 
forms, and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study. It is recognized that this information may be 
disclosed in confidence with the IRB/EC overseeing the study conduct. I also understand that 
reports of information about the study or its progress will not be provided to anyone who is not 
involved in the study other than to the Principal Investigator, or in confidence to the IRB/EC or 
to the legally constituted regulatory authorities. 
Principal Investigator(s): 
 
 
 
 


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Tel: 
Tel: 
Tel: 
Tel: 
Mobile:
E-mail: 
, MSc Pharm 
Advanced Accelerator Applications SA 
20 rue Diesel 01630 Saint Genis Pouilly, France 
E mail: 
Advanced Accelerator Applications USA Inc. 
350 Fifth Avenue, Suite 6902 
New York, NY 10118, USA 
E mail: 
, MD 
Advanced Accelerator Applications USA Inc. 
350 Fifth Avenue, Suite 6902 
New York, NY 10118, USA 
E mail: 
, MD 
Advanced Accelerator Applications 
International SA 
4 rue de la tour de l’ile 
1204 Geneva, Switzerland 
Signature and Date 
Name and contact details 
Role 
SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: 
Safety and tolerability study of 68Ga-PSMA-R2 in patients with 
prostate cancer (PCa). 
PROTOCOL NUMBER: 
Protocol A206D-A01-001 
Signatures on this page denote approval of the study protocol outline by the respective Sponsor 
Department 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AAA 
Advanced Accelerator Applications 
AE(s) 
Adverse Event(s) 
ALAT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
ASAT 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BR 
Biochemical Relapse 
BUN 
Blood Urea Nitrogen 
Cast(s)/lpf 
Cast per low power field 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
eCRF 
Electronic Case Report Form 
CRO 
Clinical Research Organization 
CT 
Computed Tomography 
CTA 
Clinical Trial Agreement 
CV 
Curriculum vitae 
DOTA 
1,4,7,10-Tetraazacyclododecane-N,N’,N”,N’’’-tetraacetic acid 
68Ga 
Gallium radioisotope 68 
68Ga-PSMA-R2 
68Ga-PSMA ligand 
68Ge 
Germanium radioisotope 68 
GGT 
Gamma-Glutamyl Transpeptidase 
EANM 
European Association of Nuclear Medicine 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EEC 
European Economic Community 
EMA 
European Medicines Agency 
E.U. 
Endotoxin Units 
EU 
European Union 
EURATOM 
European Atomic Energy Community 
EuQPPV 
European Qualified Person for Pharmacovigilance 
GBq 
Giga Becquerel 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-Glutamyl Transpeptidase 
GMP 
Good Manufacturing Practices 
Hb 
Hemoglobin 
H 
Hour 


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HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
I.V. 
Intravenous 
kVp 
peak kilovoltage 
LDH 
Lactate Dehydrogenase 
MBq 
Mega Bequerel 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minute(s) 
mPCa 
Metastatic Prostate Cancer 
mCRPC 
MRI 
Metastatic Castration-resistant Prostate Cancer 
Magnetic Resonance Imaging 
PCa 
Prostate Cancer 
PCa-BR 
Prostate Cancer in Biochemical Relapse 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRLT 
PSA 
Peptide Radio-Ligand Therapy 
Prostate Specific Antigen 
PSMA 
Prostate Specific Membrane Antigen 
PT 
Preferred Term 
QC 
Quality Control 
RBC 
Red Blood Cell 
ROI 
RR 
Region Of Interest 
Respiratory Rate 
SAE 
Serious Adverse Events 
SOC 
System Organ Class 
SOP 
Standard Operation Procedures 
SPECT 
Single Photon Computed Tomography 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardized Uptake Value 
TAC 
Time Activity Curves 
TIAC 
TRUS 
Temp 
ULN 
Time Integrated Activity Coefficient 
Trans Rectal Ultrasound 
Temperature 
Upper Limit Normal 
VOI 
Volume Of Interest 


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VCT 
WBC 
WHO 
WMA 
Volume Computed Tomography 
White Blood Cell 
World Health Organization 
World Medical Association 


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TABLE CONTENTS 
Synopsis .......................................................................................................................................... 3 
Study Procedures and Assessments ............................................................................................. 8 
Investigator’s Statement ............................................................................................................. 10 
Sponsor Signature Page .............................................................................................................. 12 
List of Abbreviations and Definitions of Terms ....................................................................... 13 
Table Contents ............................................................................................................................ 16 
List of Tables ............................................................................................................................... 18 
1. Introduction ........................................................................................................................... 19 
1.1. Prostate Specific Membrane Antigen ............................................................................ 19 
1.2. 
68Ga-PSMA-R2 (Investigational Product for PET Imaging) ........................................ 20 
1.3. Study Rationale ............................................................................................................. 21 
2. Study Objectives and Endpoints .......................................................................................... 21 
2.1. Objectives ...................................................................................................................... 21 
2.1.1. 
Primary Objective ............................................................................................ 21 
2.1.2. 
Secondary Objectives ....................................................................................... 21 
2.2. Endpoints ....................................................................................................................... 21 
2.2.1. 
Primary Endpoints ............................................................................................ 21 
2.2.2. 
Secondary Endpoints ........................................................................................ 22 
3. Study Design and Patient Population .................................................................................. 22 
3.1. Study Design ................................................................................................................. 22 
4. Study Population ................................................................................................................... 23 
4.1. Inclusion Criteria ........................................................................................................... 23 
4.2. Exclusion Criteria .......................................................................................................... 24 
4.3. Screen Failures .............................................................................................................. 24 
4.4. End-of-Study ................................................................................................................. 25 
5. Study Medication .................................................................................................................. 25 
5.1. Investigational Product for PSMA Imaging: 68Ga-PSMA-R2 ...................................... 25 
5.2. Investigational Product Packaging, Labeling, and Handling ........................................ 25 
5.3. Investigational Product Administration and Accountability ......................................... 26 
5.4. Patient Release and Radioprotection Precautions ......................................................... 26 
5.5. Concomitant Medications ............................................................................................. 27 
5.6. Prohibited Concomitant Medications and Procedures .................................................. 27 
6. Study Procedures and Assessments ..................................................................................... 27 
6.1. Informed Consent .......................................................................................................... 27 
6.2. Screening Visit (Day -14 to Day -1) ............................................................................. 28 
6.3. Administration/ Imaging Period (Day 1) .......................................................................... 28 
6.4. Safety Follow-up Visits (Day 7 ± 2 Days and Day 28 ± 3 Days) ................................. 29 
6.5. Special Study Assessments ........................................................................................... 29 
6.5.1. 
Histological / Immunohistochemical Assessment ........................................... 29 


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6.5.2. 
CT/MRI/Bone Scan .......................................................................................... 29 
6.5.3. 
Clinical Laboratory Assessments ..................................................................... 30 
6.5.4. 
Imaging assessments ........................................................................................ 31 
6.5.5. 
Other Safety Assessments ................................................................................ 33 
6.5.6. 
Concomitant Medications and Other Restrictions ........................................... 33 
6.6. Reasons for Withdrawal ................................................................................................ 33 
6.7. Handling of Withdrawals .............................................................................................. 34 
6.8. Sponsor’s Termination of Study .................................................................................... 34 
6.9. Close-out of a Site ......................................................................................................... 34 
6.9.1. 
Investigator’s Decision..................................................................................... 34 
6.9.2. 
Sponsor’s Decision........................................................................................... 34 
6.10. Replacement Policy ....................................................................................................... 35 
7. Safety Definitions, Reporting, and Monitoring .................................................................. 35 
7.1. Adverse Events and Serious Adverse Events ................................................................ 35 
7.1.1. 
Adverse Events................................................................................................. 35 
7.2. Abnormal Laboratory Findings and Other Objective Measurements ........................... 36 
7.3. Baseline Medical Conditions ........................................................................................ 36 
7.4. Baseline Medications .................................................................................................... 36 
7.5. Clinical Condition Impairment ...................................................................................... 36 
7.6. Procedures for Obtaining, Recording and Reporting Adverse Events .......................... 36 
7.6.1. 
Obtaining Adverse Events ............................................................................... 36 
7.6.2. 
Recording of Adverse Events in the eCRF ...................................................... 37 
7.6.3. 
Serious Adverse Events Requiring Expedited Reporting ................................ 37 
7.6.4. 
Pregnancy ......................................................................................................... 38 
7.6.5. 
Expedited Reporting Procedure ....................................................................... 38 
7.6.6. 
Reporting to the Competent Authorities and IRB/IEC .................................... 39 
7.7. Reporting Period ........................................................................................................... 39 
8. Statistical Methods and Analysis ......................................................................................... 40 
8.1. Sample Size Calculation ................................................................................................ 40 
8.2. Analysis Methods .......................................................................................................... 41 
8.2.1. 
Safety and Tolerability Analyses ..................................................................... 41 
8.2.2. 
Analysis of Biodistribution, Pharmacokinetic and Dosimetry Data ................ 42 
8.2.3. 
Preliminary Targeting Properties of 68Ga-PSMA-R2 PET Imaging ................ 42 
8.3. Data Management ......................................................................................................... 43 
8.3.1. 
Data/Documents ............................................................................................... 43 
8.4. Monitoring, Auditing and Inspection ............................................................................ 43 
8.5. Monitoring Case Report Forms ..................................................................................... 43 
8.6. Audits and Inspections .................................................................................................. 44 
9. Operational, Ethical, and Administrative Considerations ................................................ 44 
9.1. Data Quality Control ..................................................................................................... 44 
9.1.1. 
Documentation Required Prior to Initiation ..................................................... 44 
9.1.2. 
Documentation Required During the Trial ...................................................... 45 
9.1.3. 
Assignment of Patient Numbers and Dose allocation ...................................... 45 
9.1.4. 
Certification of Accuracy of Data .................................................................... 45 


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9.2. Ethical and Regulatory Considerations ......................................................................... 46 
9.2.1. 
Study Conduct .................................................................................................. 46 
9.2.2. 
Informed Consent ............................................................................................. 46 
9.2.3. 
Confidentiality ................................................................................................. 46 
9.2.4. 
Institutional Review Board/ Independent Ethics Committee Approval ........... 47 
9.3. Administration ............................................................................................................... 47 
9.3.1. 
Trial Record Retention ..................................................................................... 47 
9.3.2. 
Protocol Deviations and Amendments ............................................................. 48 
9.3.3. 
Clinical Data Reporting.................................................................................... 48 
9.3.4. 
Emergency Sponsor Contact ............................................................................ 49 
9.4. Financing and Insurance ................................................................................................ 49 
9.4.1. 
Financial Disclosure ......................................................................................... 49 
9.4.2. 
Insurance .......................................................................................................... 49 
10. References .............................................................................................................................. 50 
11. Appendices ............................................................................................................................. 53 
11.1. ECOG Performance Status ............................................................................................ 53 
11.2. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials ................................................................................ 54 
 
LIST OF TABLES 
Table 1 
Schedule of Procedures and Assessments ..................................................................1 
Table 2 
Summary of Laboratory Assessments ......................................................................31 


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1. 
INTRODUCTION 
Prostate cancer (PCa) is the second most common type of cancer in men worldwide leading to 
substantial morbidity and mortality [1]. It represents the second most common cause of cancer 
death in men in the USA and the third most common cause of death in developed countries [2-3]. 
Most cases of PCa are curable if diagnosed at an early stage. Nevertheless, a number of patients 
will progress to metastatic PCa or metastatic castration-resistant PCa (mCRPC). Despite the 
effectiveness of hormone therapy in the treatment of metastatic PCa, patients who live long 
enough will ultimately succumb to mCRPC. 
Up to 40% of the patients with PCa develop biochemical recurrence within 10 years after initial 
local treatment with curative intent [4]. Usually an increase of the PSA-level precedes a 
clinically detectable recurrence by months to years [5]. However, it cannot differentiate between 
local, regional or systemic disease with the necessary precision that is essential for further 
disease management [6]. Morphological imaging methods exhibit considerable limitations: 
sensitivity ranges between 25% and 54% for the detection of local recurrence by trans rectal 
ultrasound (TRUS) or contrast-enhanced CT and is moderately improved by using functional 
MRI techniques [6-8]. The sensitivity for detection of lymph node metastases of CT or MRI is 
reported to be 30-80% [9]. Early detection of bone metastasis is also critical in the management 
of patients with high risk prostate cancer [10]. Currently available bone scan or CT scan imaging 
techniques rely on non-specific osteoblastic activity and mineralization changes, respectively, 
rather than detection of actual tumor cells. 
1.1. 
Prostate Specific Membrane Antigen 
Prostate Specific Membrane Antigen (PSMA) is a type II integral membrane glycoprotein 
identified on human prostatic carcinoma cell lines. The PSMA protein has a unique 3-part 
structure consisting in a 19-amino-acid internal portion, a 24-amino-acid transmembrane portion, 
and a 707-amino-acid external portion. The PSMA gene is located on the short arm of 
chromosome 11 in a region that is not commonly deleted in prostate cancer. PSMA triggers a 
signal that allows internalization of the protein on the cell surface into an endosomal 
compartment. This characteristic seems to be useful for diagnostic and therapeutic (theragnostic) 
approach in which PSMA could be used as an antigenic target or as a specific docking-station for 
tailored small molecules [11]. 
Increased PSMA expression has been detected most notably in prostate cancer; though, it was 
also detected in the peritumoral and endotumoral capillaries of a variety of malignancies 
including renal cell carcinomas, transitional cell carcinomas, and colon carcinomas [12]. Nearly 
all adenocarcinomas of the prostate demonstrate PSMA expression in most primary and 
metastatic lesions [13-14]. Immuno-histochemical studies have shown that PSMA expression 
increases in cases of de-differentiated, metastatic, or hormone-refractory disease [15] and its 
expression level is a significant prognosticator for disease outcome [16]. Since internalization 
occurs much easily after binding of small-molecule ligands to PSMA, these molecules may be 
the ideal candidates for peptide-radio-ligand therapy [17]. 


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In addition to the promising emerging data on the use of PSMA-radioligands for the treatment of 
mPCa [18-20], PSMA is also expressed in normal tissues with relatively high density to 
potentially induce off-target effects, as in the red bone marrow, the salivary and lacrimal glands 
[21], or the kidneys [22]. The unwanted radio-ligand uptake can reach elevated absorbed doses in 
normal tissues [23-24] due to the variable tissue-binding site density and blood flow perfusion 
rate, which may lead to toxic effects. 
For some forms of peptide-radio-ligand therapy, the assessment of tumor uptake by means of 
pre-therapeutic imaging is considered predictive of the therapeutic success if associated with 
high tumor-absorbed dose [25], where the SUV may serve as indicator [26-28]. For an 
appropriate patient selection, based on the specific expression of PSMA in the tumor, the 
correlation between pre-therapeutic SUV and the calculated absorbed tumor dose are considered 
critical. Image-based absorbed dose calculations are needed as a means to achieve the optimal 
therapeutic effect of therapy while minimizing the possibility of side effects. 
The treatment of a localized PCa can vary considerably depending on several factors, options 
may include active surveillance, radical prostatectomy, or radiotherapy. Definitive treatment of 
PCa using prostatectomy or radiation therapy often results in cure. About 70% of patients who 
undergo definitive treatment with a radical prostatectomy remain biochemical progression-free at 
10 years. External beam radiation therapy or brachytherapy, can also be utilized for definitive 
therapy with curative intent of clinically localized prostate cancer, with a 10-year biochemical 
progression-free survival of 50–70% [29]. Unfortunately, despite high cure rates after definitive 
therapy, approximately 30-35% of patients will still experience a biochemical progression within 
10 years of initial treatment, and about one third of those will later develop radiographic 
evidence of disease progression [30]. At the time of biochemical recurrence, localization of 
disease is pivotal as it helps deciding the appropriate clinical management, which may include 
salvage therapy for local recurrence and/or systemic therapy for metastatic disease [31]. 
The positron emitter 68Ga is gaining great interest in nuclear medicine because of its suitable 
physical characteristics such as the high positron yield (89%), and the short half-life (68 
minutes). The clinical use of 68Ga-labelled compounds hails from the 1960s, applying initially to 
central nervous system processes [32-33]. Despite the availability of 68Ga for more than 30 years, 
recognition of its uses for clinical PET is relatively recent and only in the last decade is being 
applied to pre-clinical models of human disease and to clinical studies. 
The 68Ga-labeling procedures currently implemented in clinical practice vary among the clinical 
centers and involve a complex sequence of operations that are still largely based on the use of 
automatic synthesis modules. This is because the synthesis procedures are still not robust and 
standardized enough to avoid the processing of generator eluate and the purification of the final 
product before administration. 
1.2. 
68Ga-PSMA-R2 (Investigational Product for PET Imaging) 
The proposed investigational product (IP), a 2 vial- kit for the preparation of 68Ga-PSMA-R2, 
allows a simple 68Ga-labeling procedure based on direct reconstitution of a pre-formulated good 
manufacturing practices (GMP) kit with the eluate provided by commercially available GMP 


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68Ge/68Ga generators. This method does not require any processing of the eluate or any 
additional filtration or purification step. 
In support of its potential use for the diagnosis of PCa in biochemical recurrence and metastatic 
disease, a Phase 1/2 study with a novel diagnostic radio-labelled PSMA-ligand is proposed. The 
purpose of this study is to assess the safety and tolerability, and to evaluate the preliminary 
diagnostic value of 68Ga-PSMA-R2 in patients with PCa in biochemical relapse, and a 
comparison to conventional morphological imaging for cancer lesions in patients with mPCa. 
1.3. 
Study Rationale 
PSMA is an ideal target to develop radiopharmaceuticals for peptide radio-ligand therapy 
(PRLT) based on small molecule PSMA inhibitors. Studies based on PET and SPECT imaging 
using 68Ga, 18F, 123I, and 99mTc labeled small molecule glutamate urea heterodimers have clearly 
documented the specific localization of these agents in PCa lesions of the prostate gland, and in 
the distant metastatic lesions. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
• 
To evaluate the safety and tolerability of 3 MBq/Kg, but not less than 150 MBq and no more 
than 250 MBq, of a single i.v. administration of 68Ga-PSMA-R2. 
2.1.2. 
Secondary Objectives 
• 
To assess PK, biodistribution, and dosimetry of 68Ga-PSMA-R2. 
• 
To establish the optimal imaging method for determining location and burden of positive 
lesions on 68Ga-PSMA-R2 PET imaging in comparison with lesions identified with 
conventional anatomical imaging scans (CT/MRI and bone scan), and to calculate the 
agreement of 68Ga-PSMA-R2 PET with conventional anatomical imaging on a per patient 
basis. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
• 
Incidence and severity of AEs, and SAEs 
• 
Absolute changes and changes from baseline in clinical laboratory parameters (hematology, 
blood chemistry and urine values), including assessment of shifts from baseline to abnormal 
values 
• 
Absolute changes and changes from baseline in vital signs & ECG parameters 


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2.2.2. 
Secondary Endpoints 
• 
Generation of decay corrected TACs from 68Ga-PSMA-R2 PET/CT images in normal organs 
and tumor lesions. 
• 
Urinary excretion of 68Ga-PSMA-R2 
• 
Calculation of half-life of 68Ga-PSMA-R2 in blood 
• 
Generation of non-decay-corrected time activity curves from 68Ga-PSMA-R2 PET/CT 
images in normal organs and tumor lesions 
• 
Calculation of residence times in organs and tumor lesions of 68Ga-PSMA-R2 
• 
Calculation of absorbed doses and effective whole-body dose of 68Ga-PSMA-R2 
• 
To establish optimal threshold, expressed as SUV to discriminate positive PET imaging 
results from negative ones. 
• 
Burden and location of tumor lesions detected by 68Ga-PSMA-R2 in comparison with 
standard imaging modalities such as CT/MRI and/or bone scan and/or biopsy. 
• 
Calculation of patient level agreement of 68Ga-PSMA-R2 PET imaging in prostate cancer 
patients 
 
3. 
STUDY DESIGN AND PATIENT POPULATION 
3.1. 
Study Design 
This is an open label, multi-center, single dose, Phase 1/2 study to evaluate the safety and 
tolerability of 3 MBq/Kg, but not less than 150 and no more than 250 MBq, of 68Ga-PSMA-R2 
in adult patients with PCa expressing PSMA receptors. 
This study will consist of 2 phases. 
Phase 1: 
During the Phase 1 portion of the study, approximately 6 patients with biochemically recurrent 
PCa will receive the IP and will remain at the site for approximately 6 hours post-injection in 
order to assess PK, biodistribution, and dosimetry for critical organs. Patients will receive a 
single dose of 3 MBq/kg, (≥ 150 MBq and ≤ 250 MBq), of 68Ga-PSMA-R2. The product will be 
prepared prior to administration and injected intravenously and each patient will undergo a 
whole-body PET/CT scan following IP administration. Serial blood and urine samples will be 
collected for PK characterization and dosimetry. Safety assessments will be conducted after IP 
administration on Day 1, and during follow-up on Days 7 and 28. 
Dosimetry will be assessed in 6 patients, they will undergo static whole-body PET/CT images at 
0-4 hours to determine absorbed doses by the normal organs and target tumor lesions. 


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Phase 2: 
Two groups of approximately 12 patients will be enrolled in the Phase 2 portion of the study 
(patients with PCa-BR, and mPCa). Enrollment will be capped at 12 patients in each group to 
ensure an even distribution of patient condition. If preliminary data analysis from the Phase 1 
portion of the study provides sufficient dosimetry data, all patients will undergo whole body 
PET/CT imaging optimized for time according to the data analysis from the Phase 1 component 
of the study. 
Patients who have signed the informed consent and are eligible for study participation according 
to the inclusion and exclusion criteria will receive a single intravenous bolus of 68Ga-PSMA-R2 
on Day 1. 
This study is comprised of 4 clinical visits and will be conducted in 3 study periods including: 
Screening, administration/ imaging, and safety follow-up period (final/early termination). 
4. 
STUDY POPULATION 
Up to 30 evaluable patients with histologically confirmed PCa (staged as PCa-BR or mPCa) will 
be enrolled. 
4.1. 
Inclusion Criteria 
1. Males, 18 years or older 
2. Signed and dated written informed consent by the patient prior to any study-specific 
procedures. 
3. Histologically confirmed adenocarcinoma of the prostate. 
a. biochemical recurrence: defined as PSA is ≥ 0.2 ng/mL after radical prostatectomy or 
PSA nadir plus 2 ng/mL after radiation therapy with corresponding CT/MRI or bone scan 
revealing absence of local recurrence or metastatic lesions. 
OR 
b. metastatic disease: defined as both, castration-sensitive or castration-resistant mPCa 
(presence of at least one metastatic lymph-node, visceral metastasis and/or bone 
metastasis). 
c. At least 2 weeks must have elapsed between last anti-cancer treatment administration and 
the administration of the imaging product, 68Ga-PSMA-R2. 
4. Prior major surgery must be at least 12 weeks prior to study entry. 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2, with a life expectancy 
≥ 6 months. 
6. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, 
and biochemistry in blood and urine at Screening: 
○ Hemoglobin (Hb): >8.0g/dL 


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○ Platelet count of > 50.000/mm3 
7. Serum creatinine < 1.5 ´ upper limit normal (ULN) or estimated glomerular filtration rate 
(eGFR) > 50 mL/min based upon The Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation. 
8. For male patients with partners of childbearing potential, agreement to use barrier 
contraceptive method (condom) and to continue its use for 28 days after IP administration. 
4.2. 
Exclusion Criteria 
1. Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or 
any other histologies different than adenocarcinoma. 
2. Administered a radioisotope ≤ 10 physical half-lives prior to the day of PET/CT. 
3. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, or need of 
indwelling/condom catheters. 
4. Uncontrolled pain or incompatibility that results in patient’s lack of compliance with imaging 
procedures 
5. Other known co-existing malignancies except non-melanoma skin or low grade superficial 
bladder cancer unless definitively treated and proven no evidence of recurrence for 5 years. 
6. Patient with known incompatibility to CT scans. 
7. Any evidence of severe or uncontrolled systemic or psychiatric diseases, including 
uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion 
makes it undesirable for the patient to participate in the trial or which would jeopardize 
compliance with the protocol, or active infection including human immunodeficiency virus 
(HIV) and untreated hepatitis B, hepatitis C. Screening for chronic conditions is not 
required. 
8. Patients who have received any investigational agent within the last 28 days are excluded 
from participation in this trial. 
9. Any acute toxicity due to prior chemotherapy and/or radiotherapy that has not resolved 
according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (Section 11.2). 
10. Known allergy, hypersensitivity, or intolerance to the investigational product or its 
excipients. 
11. Patient unlikely to comply with study procedures, restrictions and requirements and judged 
by the Investigator to be unsuitable for study participation. 
4.3. 
Screen Failures 
A “screen failure” is a patient who consented to participate but was not eligible to participate in 
the study. 
For patients not considered eligible after the screening period, the reason for not being eligible 
must be documented. No additional assessments are needed. 


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4.4. 
End-of-Study 
End of study will be achieved by a patient after all study procedures and the follow up visit are 
completed and no further study related activities are required, or when a patient withdraws 
consent at any time. 
Study will be terminated when all patients have completed their end of study activities or at any 
time due to sponsor decision. 
5. 
STUDY MEDICATION 
5.1. 
Investigational Product for PSMA Imaging: 68Ga-PSMA-R2 
The full name of the Investigational Product (IP) is “68Ga-PSMA-R2 kit for radiopharmaceutical 
preparation”. 
The IP is a sterile 2-vial kit which consists of: 
• 
Vial 1: PSMA-R2, 30 µg, powder for solution for injection, to be reconstituted with a 
solution of gallium-68 chloride (68GaCl3) in HCl eluted from a GMP 68Ge/68Ga generator; 
• 
Vial 2: Reaction buffer. Vial 2 is to be added to the reconstituted Vial 1. 
The kit has to be used in combination with a solution of 68Ga in HCl provided by a GMP 
68Ge/68Ga generator to obtain 68Ga- PSMA-R2 solution for injection, being the radiolabeled 
imaging product, which can be directly injected to the patient. 
After reconstitution with the eluate from a GMP 68Ge/68Ga generator and addition of kit reaction 
buffer (vial 2), the reconstituted solution must be used within 4 hours. 
The volume of 68Ga- PSMA-R2 solution for injection, corresponding to the radioactive dose to 
be administered, is calculated according to the estimated time of injection, on the basis of the 
current activity provided by the generator and of physical decay of the radionuclide (half-life, 
68 minutes). 
This is a mono-dose product. 
Vial 1 is a powder for solution for injection containing PSMA-R2 as active ingredient. The 
powder is packed in 10 mL Ultra-inert Type I Plus glass vials. Vial 2 Reaction buffer contains 
no active ingredient. Reaction buffer solution is contained in a 10-mL cyclic olefin polymer vial 
The kit will be prepared, packaged and released according to Sponsor Standard Operating 
Procedures (SOPs), GMP guidelines, International conference on harmonization (ICH) GCP 
guidelines, and applicable local laws/regulations. 
5.2. 
Investigational Product Packaging, Labeling, and Handling 
The investigational product will be supplied by the Sponsor as a sterile, two-vial kit for 
reconstitution with 68Ga solution eluted from approved commercial GMP 68Ge/68Ga generator. 


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Labeling will be handled per the Sponsor’s SOP. The site personnel will maintain shipping, 
dispensing, and collection logs provided in Investigator file by the Sponsor or designee (e.g. 
CRO). The IP will be inventoried according to the protocol instructions and applicable 
regulations and will be stored in a secure, locked place with limited authorized access at the 
investigational site. 
After reconstitution with 68Ga solution eluted from approved commercial GMP 68Ge/68Ga 
generator, the investigational product is a radioactive substance, and it must be handled and 
administered by qualified/authorized personnel only, and must be prepared in accordance with 
pharmaceutical quality requirements and radiation safety regulations. 
5.3. 
Investigational Product Administration and Accountability 
When investigational product is received at the site, the Investigator, Pharmacist or authorized 
designee shall check for accurate delivery and acknowledge receipt by signing and dating the 
shipping documentation, and returning the reception form to the Sponsor or designee. A copy of 
this documentation shall be retained for the Investigator file. 
Any use or manipulation of the IP shall be carefully recorded on the IP accountability form 
provided by the Sponsor, and an accurate accounting must be available for verification by the 
clinical research associate (CRA) at each monitoring visit. 
IP accountability records shall include: 
• 
confirmation of the IP delivery to the study site; 
• 
inventory at the study site; 
• 
use of IP by each patient; and 
• 
it should include delivery dates, quantities, lot/batch numbers and manufacture/expiration 
dates for the IP. Investigators should maintain records to document adequately that: 
○ the patients were administered the doses specified by the protocol and any amendment(s); 
and 
○ all IP provided by the Sponsor were fully reconciled. 
Unused investigational product must be destroyed per local practice. 
The administration volume (containing the planned dose) is determined according to the 
estimated time of injection, on the basis of the physical decay of the radionuclide (half-life, 68 
minutes). 
5.4. 
Patient Release and Radioprotection Precautions 
Following administration of 68Ga-PSMA-R2, patients should remain at the clinical site for an 
additional 6 hours in an area with suitable radiation shielding to protect others from unnecessary 
exposure. At the time of release, patients are given written instructions which outline the 
precautions the patient must take to minimize radiation exposure to people around them. 


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Excessive release of hormones or bioactive substances are not expected to occur following 
treatment, therefore, observation of patients by overnight hospitalization is not required. 
5.5. 
Concomitant Medications 
Previous and concomitant medications will be coded using World Health Organization (WHO) 
dictionary. Type and incidence of previous and concomitant medications will be tabulated 
(generic terms). 
All medications taken at the start of Screening until the end of the study, or early termination, are 
to be recorded. This includes prescription and over-the-counter medications taken during this 
time frame. 
5.6. 
Prohibited Concomitant Medications and Procedures 
While participating in this study cancer targeted therapy including but not limited to 
chemotherapy, hormonal therapy (except for LHRH or GnRH), or external beam radiation is not 
permitted within four weeks prior to 68Ga-PSMA-R2 PET/CT scan. 
Any medications which are considered necessary for the patient’s welfare, may be given at the 
discretion of the Investigator; however, if it belongs to the list above the patient will have to be 
withdrawn from the study treatment. 
6. 
STUDY PROCEDURES AND ASSESSMENTS 
A schedule for all procedures and evaluations to be conducted in this study is outlined in the 
visits schedule presented in 
of this protocol. 
6.1. 
Informed Consent 
Each potentially eligible patient will be informed of the study objectives and overall 
requirements. Before conducting any of the screening tests, the Investigator or an authorized 
delegate will explain the study fully to the patient using the patient information leaflet/ICF. If the 
patient is willing to participate in the study, written informed consent will be requested after the 
patient has been given sufficient time to consider participation and the opportunity to ask for 
further details. The ICF will be signed and personally dated by both the patient and the 
Investigator or an authorized delegate. A copy of the signed consent form will be provided to the 
patient, and the original will be retained with the source documents. 
A screening log will be completed for all patients who sign the ICF. These patients will be 
identified with their identification (ID) number; in addition, eventual reasons for exclusion from 
the study will be recorded. 


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6.2. 
Screening Visit (Day -14 to Day -1) 
Each patient will be allocated a unique patient ID number, which will identify the patient 
throughout the study. 
During the Screening visit, the following activities will be performed: 
• 
Written informed consent will be obtained prior to performing any study related activities 
• 
Inclusion/exclusion criteria will be checked. 
• 
Each patient’s demography: date of birth, gender, ethnicity, weight, height, medical history, 
and relevant baseline characteristics will be recorded. 
• 
Historic and current prostate cancer related biopsies (prostate and metastatic sites) should be 
performed per local practice. All data related to date of biopsy, site of lesion, and pathology 
results will be collected in the database. 
• 
ECOG performance status must be assessed (Section 11.1). The medical history will be 
recorded as well as all concomitant medications taken including therapies for PCa. 
• 
All patients will have undergone histological/immunohistochemical exam at the time of the 
original PCa diagnosis and CT/MRI exam, within two months before enrollment. 
• 
Vital signs will be assessed. 
• 
ECG (12-lead) will be recorded. 
• 
Blood samples for PSA, hematology, blood chemistry and urinalysis will be obtained. 
• 
All concomitant medications including PCa therapies taken 2 weeks prior to the IP 
administration date through the end of study will be recorded. 
• 
Any AEs occurring after the ICF signature will be recorded and followed until resolution. 
6.3. 
Administration/ Imaging Period (Day 1) 
Eligible patients who have met all inclusion criteria and none of the exclusion criteria will 
receive an injection of 3 MBq/Kg, but not less than 150 MBq and no more than 250 MBq of 
68Ga-PSMA-R2. Patient will enter the trial unit on the morning of the exam. Each subject will be 
allocated one single imaging kit. 
• 
All concomitant medications including PCa therapies taken 2 weeks prior to the IP 
administration date through the end of study will be recorded. 
• 
Any AEs occurring after the ICF signature will be recorded and followed until resolution. 
• 
Vital signs will be assessed before and after the 68Ga-PSMA-R2 injection and at the end of 
the PET/CT exam. 
• 
ECOG performance status will be assessed. 
• 
Patient will be injected intravenously one single bolus dose of 68Ga-PSMA-R2. 
• 
ECG (12-lead) will be recorded immediately after IP administration. 


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• 
For patients entering in Phase 1: PET/CT scans will be performed at approximately 20-30 
minutes and at 1, 2, 3-4 hours post-injection. 
• 
Patients in the Phase 1 portion of the study will undergo distribution/ dosimetry analysis 
• 
For patients entering Phase 2, patients will have PET/CT imaging reduced to up to 2 whole 
body scans within the optimal time frame, to confirm the high tumor to background ratio, and 
agreement compared to standard conventional method. 
• 
Samples for hematology, biochemistry and urinalysis will be collected after the 
administration of IP. 
• 
Patients entering Phase 1 only: PK and dosimetry blood samples will be collected 
immediately prior to IP administration, approximately 5, 10, 20, 40 minutes, as well as 
immediately after, 1, 2, 4, and 6 hours post IP administration. 
• 
Patients entering Phase 1 only: Urine sample for PK will be collected Pre-injection, 
approximately 0-20 minutes after IP administration , 0-1 hour, 1-2 hours, 2-4 hours, 4-6 
hours post-injection. 
6.4. 
Safety Follow-up Visits (Day 7 ± 2 Days and Day 28 ± 3 Days) 
After IP administration, two safety follow-up visits will be performed on Day 7 (± 2 Days) and 
Day 28 (± 3 Days). 
• 
All concomitant medications including PCa therapies taken 2 weeks prior to IP 
administration date through the end of study will be recorded. 
• 
Any AEs occurring after the ICF signature will be recorded and followed until resolution. 
• 
ECOG performance status is assessed. 
• 
Vital signs will be assessed. 
• 
Blood samples for hematology, biochemistry and urinalysis will be obtained. 
6.5. 
Special Study Assessments 
6.5.1. 
Histological / Immunohistochemical Assessment 
All patients are required to have histological confirmation of adenocarcinoma of the prostate 
based on surgery/biopsy specimens of the primary tumor or the metastatic disease. Most recent 
biopsy sample collected should be used. All data related to date of biopsy, site of lesion, and 
pathology results will be collected in the database. No new biopsy is required for the purposes of 
this study. 
6.5.2. 
CT/MRI/Bone Scan 
All patients are required to undergo a CT/MRI within 2 months prior to enrollment. If a CT is 
performed, this should be a standard diagnostic thoracic and abdominopelvic CT scan, with a 
slice thickness of ≤ 5 mm; if MRI is performed, the injection of a contrast medium is 
recommended. Standard imaging modality for patients with PCa in biochemical relapse or with 


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metastatic disease, as applicable, will be performed as per routine institutional practice. Per 
RECIST v1.1 the imaging modality must be consistent throughout the study. Tumor assessment 
imaging procedures will be performed per local practice. CT scan is the preferred method and 
MRI will be done per local standard-of-care. Patients with either previous history of metastatic 
disease to the bone or any symptoms indicative of metastatic bone disease will require a bone 
scan. 
All patients with metastatic prostate cancer enrolled in Phase 2 portion of the study will have 
their imaging procedures assessed locally for clinical management and centrally for comparison 
with 68Ga-PSMA-R2 PET imaging. 
6.5.3. 
Clinical Laboratory Assessments 
Clinical laboratory assessments for safety monitoring will be performed by an accredited local 
laboratory. Blood and urine samples for hematology, serum chemistry and urinalysis, will be 
prepared using standard procedures. 
PSA sample will be collected at Screening (unless performed within one month of enrollment 
and results are available), and results will be entered into the eCRF. 
The following laboratory tests will be performed at Screening, Day 1 (after the administration of 
the IP), Day 7, and Day 28: 
• 
Hematology: White blood cell (WBC) count with differential, red blood cell (RBC) count, 
Hb, hematocrit, platelet count, mean corpuscular volume (MCV). 
• 
Blood chemistry profile: albumin, alkaline phosphatase (AP), alanine transaminase (ALAT), 
aspartate transaminase (ASAT), blood urea nitrogen (BUN), corrected calcium, chloride, 
creatinine, eGFR (preferably CKD-EPI), glucose, uric acid, gamma-glutamyl transpeptidase 
(GGT), lactate dehydrogenase (LDH), potassium, sodium, total bilirubin and total protein. 
• 
Urinalysis: (dipstick), appearance, color, pH, specific gravity, protein, glucose and occult 
blood, RBC and WBC counts, Casts per low power field (Casts/lpf), Protein (dipstick test 
accepted). 
Table 2 summarizes general laboratory assessments to be performed. 


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Table 2 
Summary of Laboratory Assessments 
Hematology 
Blood Chemistry 
Urinalysis* 
• WBC with differential 
• RBC 
• Platelets 
• Hb 
• MCV 
• Hematocrit 
• PSA (Screening visit only) 
• BUN 
• Serum creatinine 
• eGFR 
• Albumin 
• Total bilirubin 
• AP 
• AST/ASAT 
• ALT/ALAT 
• Gamma-GT 
• Sodium 
• Potassium 
• Chloride 
• LDH 
• Corrected Calcium 
• Glucose 
• Total protein 
• Uric acid 
• Appearance 
• Color 
• pH 
• Specific gravity 
• Glucose 
• Occult blood 
• RBC/hpf 
• WBC/hpf 
• Casts/lpf 
• Protein (dipstick test accepted) 
*A urine sample will be collected at each visit and analyzed at the clinical site if dipstick results are abnormal. 
WBC = white blood cell; RBC = red blood cell; Hb = hemoglobin; MCV = mean corpuscular volume; PSA = prostate specific 
antigen; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; AST/ASAT = aspartate aminotransferase; 
ALT/ALAT = alanine aminotransferase; gamma-GT = gamma glutamyl transferase; LDH = lactate dehydrogenase; pH = 
potential of hydrogen; hpf = high power field; lpf = low power field. 
 
The total volume of blood required per patient for clinical laboratory assessment will be 
approximately 70 mL (approximately 15 mL on each sampling at Screening, Day 7, and Day 28), 
and approximately 25 mL on Day 1. Blood and urine samples will be analyzed in an accredited 
local laboratory. 
6.5.4. 
Imaging assessments 
6.5.4.1. 
Imaging Procedure During the Phase 1 Portion of the Study 
68Ga-PSMA-R2 PET/CT imaging (four scans) will be performed using a standard integrated 
PET/CT system. Patients will be placed on the scanner table to allow a vertex to mid-thigh low- 
dose CT scan without contrast (used for anatomic localization and attenuation correction), 
followed immediately by emission scan after 68Ga-PSMA-R2 injection. PET scans will be 
performed from vertex to mid-thigh in 3D (3-dimentional acquisition) mode. Please refer to 
Section 6.5.4.2 for more details. 
Maximum standardized uptake values (SUVmax) will be used to determine the tumor lesions, 
defined as focal areas of abnormal uptake showing a higher SUVmax than surrounding tissue. 


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Identification of the time points post-injection with the highest observed number of lesions and 
the highest SUVmax, SUV mean values and the tumor to background ratios for each SUV will be 
determined. The later will be conducted separately for each imaging time point (20-30 minutes, 
1, 2, 3-4 h) post-injection through qualitative visual analysis of total number of lesions identified 
by PET, and semi-quantitative analysis by means of SUVmax and SUVmean values and time point 
will be conducted. 
Lesions suggestive of PCa will be counted and analyzed for radioactive uptake (expressed as 
SUVmean and SUVmax) and localization. Any PCa lesion will be counted and analyzed. Tumor 
contrast will be measured by dividing the SUVmean of tumor lesions by the SUVmean of the 
background (e.g. gluteal musculature) and by dividing the SUVmax of tumor lesions by the 
SUVmean of the background. 
6.5.4.2. 
Biodistribution and Dosimetry Phase 1 Portion of the Study 
Patients enrolled in the biodistribution and dosimetry set will undergo for a series of static 
whole-body PET/CT images at 20-30 minutes and at 1, 2 and 3-4h to determine absorbed doses 
to normal organs and to target tumor lesions. A low dose non-contrast-enhanced CT will be 
performed at 20-30 minutes, 1, 2, and 3-4 hours post injection. Immediately after CT scanning, 
PET scan will be performed from vertex to mid thighs in 3D (3-dimensional acquisition) mode at 
20-30 minutes, 1, 2, and 3-4 hours imaging. The emission data will be corrected for dead-time, 
scatter, and decay, and resulting voxels were stored in units of Bq/mL. Reconstruction will be 
conducted with an ordered subset expectation maximization algorithm. Attenuation correction 
will be performed using low-dose non-enhanced CT data acquired at each time point. 
Regions of Interest (ROIs)/ volume of interests (VOIs) will be drawn on the static whole-body 
PET images over the critical organs and tumor lesions to generate time-activity curves, and 
assess the time integrated activity coefficients (TIAC) (35). Up to 10 lesions which have the 
highest tumor to background ratio will be selected for dosimetry analysis for each patient. 
Dosimetry calculations will be issued from the analyses of organs receiving the highest dose, 
identified visually. ROIs/VOIs will be placed over these organs to determine relative radiotracer 
uptake calculated as a percentage of the activity (%IA). 
Tissue activity curves will be generated and fitted to mono- and bi-exponential curves to yield 
TIAC values. To assess pharmacokinetics and red marrow dosimetry, serial venous blood 
sampling withdrawn at immediately prior to IP administration, 5, 10, 20, 40 minutes, as well as 
immediately after, 1, 2, 4 and 6 hours post IP administration will be analyzed. Urine samples 
pre-injection, approximately 0-20 minutes after IP administration, 0 to 1 hour, 1 to 2 hours, 2 to 
4 hours, and 4 to 6 hours post-injection will be collected to complete biodistribution and 
dosimetry assessments. The absorbed doses (µGy/MBq) for critical organs will be evaluated, as 
well as the effective dose (µSv/MBq). 
6.5.4.3. 
Whole Body PET/CT Imaging for Phase 2 Portion of the Study 
Preliminary data analysis from the Phase 1 portion of the study will provide sufficient dosimetry 
data, therefore all Phase 2 patients will have PET/CT imaging reduced to up to 2 whole body 


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scans within the optimal time frame, to confirm the high tumor to background ratio, and 
agreement compared to standard conventional method. 
68Ga PSMA-R2 PET/CT imaging will be performed using a standard integrated PET/CT system. 
Patients will be placed on the scanner table to allow a vertex to mid-thigh low-dose CT scan 
without contrast (used for anatomic localization and attenuation correction), followed 
immediately by emission imaging after 68Ga-PSMA-R2 injection. A non-contrast-enhanced CT 
will be performed using routine investigational site imaging parameters. Immediately after CT 
scanning, PET scan will be performed from vertex to mid thighs in 3D (3-dimensional 
acquisition) mode. The scan duration will be 3 min for each bed position. The emission data will 
be corrected for dead-time, scatter, and decay, and resulting voxels were stored in units of 
Bq/mL. Attenuation correction will be performed using low-dose non-enhanced CT data 
acquired at each time point. 
6.5.5. 
Other Safety Assessments 
Results of the ECGs, and vital sign assessment will be evaluated by the Investigator for evidence 
of immediate safety concerns or for changes in values that indicate a potential danger for the 
patient to continue in the study. The Investigator should contact the medical monitor from 
Sponsor or designee (e.g. CRO) with questions regarding vital sign values. 
6.5.5.1. 
Standard 12-Lead ECG 
ECGs will be recorded at the screening visit and at Day 1 (after the administration of the IP) to 
measure the different ECG intervals (RR, PR, QRS, and a more extended QT evaluation 
according to ICH E14, and heart rate, HR). A single ECG will be taken supine, after 5 minutes 
rest, and not immediately after a meal. The parameters will be measured as a mean value of 
minimally 3 beats. The Investigator will note in the electronic CRF (eCRF) whether the ECG is 
normal or abnormal, as well as the clinical relevance of abnormal ECGs. Clinically relevant 
abnormalities will be recorded on the AE page of the eCRF. 
6.5.6. 
Concomitant Medications and Other Restrictions 
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that details regarding the medication are recorded in full in the case report 
form, including any changes that have occurred during the study. 
6.6. 
Reasons for Withdrawal 
A patient may withdraw from the study at any time for any reason (see section 6.7). 
The Investigator may discontinue the patient from the study if he experiences a serious or 
intolerable adverse event(s) or discontinue from study if the patient is in violation of the 
protocol. 
Protocol can be terminated by the sponsor prematurely. 


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If a patient is discontinued due to an AE, the event will be followed until it is resolved. 
6.7. 
Handling of Withdrawals 
When a patient withdraws from the study, the reason(s) for withdrawal must be recorded by the 
Investigator in the patient’s source document and the relevant page of the eCRF. For patients 
who remain in the study but fail to return for final assessments, every effort should be made to 
collect the information specified in the protocol. 
It is vital to obtain follow-up data for any patient withdrawn as consequence of an AE. Every 
patient who discontinues prematurely must be contacted 15 Days (± 3 Days) after 
discontinuation to obtain adverse event information. 
6.8. 
Sponsor’s Termination of Study 
The Sponsor reserves the right to discontinue the study at any time for clinical or administrative 
reasons. In that event, the Sponsor will immediately notify and instruct investigational sites, who 
in turn must promptly notify their patients and respective Institutional Review Board / Ethics 
Committee (IRB/EC) and or regulatory authorities. 
6.9. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
6.9.1. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice. The final decision should be made through mutual agreement with the 
sponsor. Both parties will arrange the close-out procedures after review and consultation. 
6.9.2. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others: 
• 
The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
• 
The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
• 
The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 


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6.10. 
Replacement Policy 
Patients who discontinued for any reason during the study will not be replaced. 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1. 
Adverse Events and Serious Adverse Events 
The safety of the radiolabeled imaging final product 68Ga-PSMA-R2 will be assessed through 
recording, reporting and analyzing medical conditions, infections, vital signs (temperature, blood 
pressure, heart rate, and respiratory rate), ECGs, and safety laboratory tests (blood chemistry, 
hematology, urinalysis). 
Adverse events encountered from the time of ICF signature through the follow-up period (until 
Day 28 after administration of 68Ga-PSMA-R2) will be recorded by the Investigator on the 
appropriate AE pages of the eCRF as defined in the following sections. Adverse events will be 
recorded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (Section 11.2). 
Only adverse events with start date on or after the IP administration date will be considered 
treatment emergent. 
After the follow-up period, the Investigator must report to the Sponsor only SAEs possibly 
related to 68Ga-PSMA-R2 or to the study procedures (see SAE definition in Section 7.6.3). 
7.1.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical 
study with an investigational product, regardless of causal relationship and even if no 
investigational product has been administered. 
In this study, the term “investigational product” refers to the radiolabeled imaging final product 
68Ga-PSMA-R2. 
Unchanged/stable pre-existing, chronic medical conditions present at baseline, or those medical 
conditions related to the underlying disease should not be recorded on AE pages of the eCRF. 
However, in case of worsening of a pre-existing condition, this should be considered and 
reported as AEs. 
• 
Relationship to IP, 
○ based on temporal association: temporal relationship between administration of the IP 
and AEs occurrence is compatible, 
○ based on AEs presentation and IP characteristics 
○ If no alternative explanations (patient’s medical history, patient’s concomitant treatment, 
circumstance of AEs occurrence) are identified 


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• 
Not related to IP: 
○ In case an alternative explanation regarding the AEs occurrence had been identified. 
7.2. 
Abnormal Laboratory Findings and Other Objective Measurements 
All clinically relevant abnormal laboratory findings must be captured and reported as AEs. 
Abnormal laboratory findings and other objective measurements that meet the criteria for SAE, 
result in discontinuation of the Investigational Product, or require medical intervention, should 
be captured and reported on the SAE/AE pages of the eCRF. 
If reporting an abnormal laboratory finding on the AE pages of the eCRF, a clinical description 
or diagnosis should be recorded rather than the abnormal value itself, if this is available (for 
example “anemia” rather than “decreased red blood cell count” or “hemoglobin = 10.5 g/dL”). 
In the event of unexplained clinically abnormal laboratory values, the tests should be repeated 
immediately and followed up until returns to normal range and/or an adequate explanation of the 
abnormality is found. If a clear explanation is established, this must be recorded on the eCRF. 
7.3. 
Baseline Medical Conditions 
Medical conditions present at the screening visit, that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not adverse events. These 
medical conditions should be adequately documented on the appropriate page of the eCRF, i.e. 
medical history page. 
However, worsening of medical conditions present at the initial study visit, either severity or 
frequency during the study should be recorded and reported as AEs. 
7.4. 
Baseline Medications 
Any medication taken prior to investigational product administration will be considered baseline 
medications. Any medications taken from the Day of administration (Day 1) to the end of the 
trial will be considered concomitant medications and captured on the appropriate eCRF page. 
7.5. 
Clinical Condition Impairment 
Exacerbation or worsening of symptoms will be recorded on the AE page of the eCRF. 
7.6. 
Procedures for Obtaining, Recording and Reporting Adverse Events 
7.6.1. 
Obtaining Adverse Events 
Adverse event data will be obtained by the Investigator at scheduled study visits, based on 
information spontaneously provided by the patient and/or through questioning. The patient will 
be instructed upon signing the ICF to contact the Investigator if any adverse or unusual event 
occurs during his participation in the study. 


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To obtain adverse events, simple questions with minimal connotations should be used as the 
initial questions at all evaluation points during the study. For example: 
• 
How did you feel since your last visit? 
• 
Have you had any health problems since you were visited? 
In the case that a patient was seen by a different health care professional (e.g. at a different 
institution), in relation with an adverse event, every effort should be made by the Investigator to 
contact the treating physician in a timely manner to obtain all necessary information and report 
the event appropriately in the eCRF. 
7.6.2. 
Recording of Adverse Events in the eCRF 
Adverse events will be recorded in the patient’s medical records (source document) and eCRF, 
whether observed by the Investigator, the investigational staff, or spontaneously reported by the 
patient. 
As quality and precision of acquired AE data is of key importance, Investigators should use the 
adverse event definitions provided in the sections above and observe the following guidelines 
when completing the AE pages of the eCRF: 
• 
Whenever possible, recognized medical terms should be used to describe AEs rather than 
colloquialisms (e.g. ‘influenza’ rather than ‘flu’), and abbreviations should be avoided. 
• 
Adverse events should be described using a specific clinical descriptions or diagnosis rather 
than component signs or symptoms (e.g. ‘congestive heart failure’ rather than ‘dyspnea, rales 
and cyanosis’). However, signs and symptoms that are considered unrelated to an identified 
disease or syndrome might be reported as individual AEs on the eCRF if no clearer diagnosis 
can be drawn. 
• 
Adverse events occurring secondary to other events (e.g. sequelae or complications) should 
be identified by the primary cause. A primary AE, if clearly identifiable, generally represents 
the most accurate clinical term to record on AE pages of the eCRF. 
It is important that each AE report includes a description of the event, seriousness status and 
criteria, duration, severity, and causality, other causality factors (if any), any concomitant 
medications dispensed, concomitant procedure prescribed or other action taken, including dose 
modification and/or discontinuation of the investigational product and its outcome as per the end 
of the reporting period. 
7.6.3. 
Serious Adverse Events Requiring Expedited Reporting 
Any SAE requires expedited reporting to the Sponsor or designee, regardless of relationship to 
the Investigational Product. 
An SAE is defined as an AE that at any dose: 
• 
Resulted in death: i.e. the AE causes or contributes to the death. 


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• 
Was life threatening: i.e. the AE places the patient at immediate risk of death; the definition 
does not apply to an AE that hypothetically might cause death if it was more severe. 
• 
Required or prolonged hospitalization: i.e. the AE requires at least a 24-hour in-patient 
hospitalization or prolongs a hospitalization beyond the expected length of stay. Hospital 
admissions for surgery planned before trial entry, for social reasons or for normal disease 
management (including treatment adjustment) are not to be considered as SAE according to 
this criterion. 
• 
Is a congenital anomaly or birth defect: i.e. an adverse outcome in a child or fetus of a 
patient’s partner exposed to the investigational product, before conception or during 
pregnancy. 
• 
Resulted in persistent or significant disability or incapacity: i.e. the AE resulted in a 
substantial disruption of the patient’s ability to conduct normal life functions. 
• 
Was a medically important condition: Such an event may not be immediately life- 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the above definition should also 
usually be considered as serious. 
Investigators must indicate the possible cause(s) of the SAE in the appropriate section of the 
SAE reporting form (e.g. underlying disease, study treatment, other treatment[s], study 
procedures, or other cause[s]). 
7.6.4. 
Pregnancy 
The occurrence of a pregnancy of a partner of a trial patient discovered within 1 week after last 
administration of the IP and up to the end of follow-up period, is to be communicated to the 
Sponsor in an expedited manner with the same procedure and timelines as for SAEs (see 
paragraph 7.6.5), independently from the occurrence of an AE. 
7.6.5. 
Expedited Reporting Procedure 
Besides AEs and SAEs entry in the eCRF, investigators must notify the Sponsor or designee 
within 24 hours of awareness of a new SAE/pregnancy case or of new information on a 
previously reported SAE/pregnancy case (follow-up), regardless of relationship to the 
investigational product. 
The Investigator/Reporter must complete an SAE form and the following minimum information 
is required as initial notification: 
• 
Clear identification of the Investigator/Reporter with full contact information, 
• 
A unique clinical trial identification 
• 
Patient identification details (trial number, site number, identification code number, date of 
birth), 
• 
Investigational Product administration details (product name, dose and dates), 


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• 
Reported event as a diagnosis term with its description (or a brief description of 
signs/symptoms/clinical course if the diagnosis is not available) 
• 
Date of onset of the event, 
• 
Reason(s) for considering the event serious, 
• 
Investigator causality assessment 
The opinion of the Investigator about the causal relationship between the event and the IP is 
required. Even if not all the facts are known, an initial report should be sent to the Sponsor. 
The initial report must be followed by a detailed report as soon as possible. 
Any additional information received on an initial SAE report must be sent to the Sponsor 
following the same timelines. 
If considered necessary by the Sponsor and in order to allow a sound medical assessment of the 
reported SAEs, the Sponsor may request additional documentation such as technical 
investigation reports, histology findings, hospital discharge documents. All these additional 
documents must be blinded with respect to the patient’s name and provided to the Sponsor in due 
time by email (pharmacovigilance@adacap.com). 
When the Investigator determines that no additional information is likely to be available, a final 
report should be provided. 
7.6.6. 
Reporting to the Competent Authorities and IRB/IEC 
The Sponsor or designee will assume responsibility for appropriate reporting of Suspected 
Unexpected Serious Adverse Reaction (SUSAR) to the Competent Authorities and Independent 
Ethics Committee(s)/Institutional Review Board(s) (IEC/IRB) according to local laws and 
regulations. 
The Sponsor will inform Competent Authorities, IRB/IEC, and Investigators of “findings that 
could adversely affect the safety of patient and impact the conduct of the study or alter the 
IRB/IEC’s approval/favorable opinion to continue the study”. 
Copies of safety reports should be kept in the Investigator file as well as inserted into the 
relevant Investigator Brochure. In addition, all correspondence relating to their notification to the 
Competent Authorities and IRB/IEC should be maintained in the Investigator file. 
Development safety update report (DSUR)/IND report will be sent to inform competent 
authorities, IRB/IEC, and Investigators. 
7.7. 
Reporting Period 
Adverse Events are collected on an ongoing basis from signing of Informed Consent until the 
last follow up visit. 


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All SAEs, including deaths, independently of causality, that occur from informed consent until 
the last scheduled follow-up visit will be recorded on an SAE form, in addition to the eCRF data 
entry. After the last follow-up visit, the Investigator must report to the Sponsor only SAEs 
possibly related to 68Ga-PSMA-R2 or to the study procedures. 
All SAEs must be followed-up by the Investigator until resolution or stabilization, and follow-up 
information must be reported to the Sponsor according to the reporting procedure. 
All pregnancy cases occurring one week after IP administration and until the last follow-up 
(Day 28) will be reported according to the SAE reporting procedures. All pregnancy reports will 
be followed-up until delivery. 
A last batch of queries will be sent after Last Patient Last Visit for all AEs with 
ongoing/unknown outcomes. After the last batch of queries with all collected data have been 
fully processed, eCRFs and database will no longer be updated. Only SAEs and medically 
relevant ongoing/unknown outcome AEs will be followed-up until resolution or stabilization. 
Beyond this defined reporting period, any new unsolicited serious AE spontaneously reported to 
CRO/Sponsor by the Investigator would however be collected and processed by 
pharmacovigilance. 
Any patient who received a partial or full dose of the investigational product and who withdraws 
prematurely or is withdrawn by the Investigator from the trial, should have a follow-up safety 
visit 28 (± 3) Days after the investigational product administration. 
If a patient is documented as lost-to follow-up or consent withdrawal, ongoing/unknown 
outcome AEs will not be followed-up. 
For screen failure patients, new AEs and updates must be recorded in eCRFs until the date the 
patient was determined to be a screen failure. Beyond that date, only SAEs possibly related to the 
investigational product or to the study procedures will be reported to the CRO/Sponsor. 
8. 
STATISTICAL METHODS AND ANALYSIS 
8.1. 
Sample Size Calculation 
The primary objective of the trial is to assess the safety and tolerability of 68Ga-PSMA-R2. Data 
for this objective will be reported descriptively. No formal statistical sample size calculation was 
done. The planned sample size includes a total of up to 30 patients which is believed to provide 
sufficient data to assess the safety and tolerability of 68Ga-PSMA-R2, and to reliably estimate 
distribution and dosimetry parameters. In addition, an overall sample size of 30 patients should 
provide reasonable precision around estimations of preliminary targeting properties of the 68Ga- 
PSMA-R2 imaging. For example, if patient level agreement of 83.3% if observed (for e.g. if 
25 patients had lesions detected by 68Ga-PSMA-R2 imaging out of 30 patients in the trial), then 
the 95% CI around this would be 66.4% to 92.7%. 


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8.2. 
Analysis Methods 
Statistical analysis will be described in detail in the statistical analysis plan prior to database 
lock. 
Due to the single arm design of the study, the primary focus of the statistical analysis will be on 
descriptive statistics and graphical presentations of data. Continuous variables will be presented 
as number of non-missing values, mean, standard deviation, median, minimum, maximum and 
quartiles. For categorical variables, descriptive statistics will include counts and percentages per 
category. Confidence intervals will be computed when appropriate, usually as 95% intervals, but 
80% intervals may also be produced in some instances due to the early phase nature of this trial. 
Continuous variables will be compared where relevant using the most appropriate test such as 
paired analysis Mann-Whitney-Wilcoxon U test. Proportions will be compared using the 
appropriate test among Fisher’s exact test or McNemar test. Pearson’s or Spearman linear 
regression analysis will be used to explore potential relationships between two continuous 
variables as appropriate. Any hypothesis testing that is performed will be interpreted as 
exploratory and no emphasis will be placed on nominal significance levels. No adjustment for 
multiplicity will be applied and missing data will not be replaced. 
Data presentations will group the PCa-BC and mPCa populations and also include an overall 
total column. 
For analysis purposes, baseline for a given assessment will be defined as the last non-missing 
value prior to the administration of 68Ga-PSMA-R2. 
The Full Analysis Set will consist of all patients who enter the study and receive at least one dose 
of 68Ga-PSMA-R2. The safety set in this case is identical to the full analysis set and so will not 
be de-fined as a separate set. The Per Protocol set consists of all patients in the full analysis set 
who complete the study according to the protocol with no major protocol violations. All analyses 
will primarily be performed on the full analysis set, select analyses may be repeated on the per 
protocol set if there are sufficient violations to warrant it and deviation of results by using the per 
protocol set will be discussed. 
8.2.1. 
Safety and Tolerability Analyses 
Safety evaluations on the full analysis set will be based on the incidence, type, severity and 
consequences (e.g. study discontinuation) of an AE as well as on clinically significant changes in 
the patient's ECGs, vital signs, and clinical laboratory results. ECG parameters will include heart 
rate (HR), RR interval, PR interval, QRS width and QTc interval. Statistical analysis includes 
descriptive tabulation using measures which are absolute and relative frequencies for categorical 
data and means, standard deviations, medians and interquartile ranges for continuous data for 
observed values as well as for changes from baseline in continuous parameters at each measuring 
time. Clinical laboratory data, ECGs and vital signs will also be presented graphically in terms of 
box plots of absolute values over time and changes from baseline over time. Clinical laboratory 
data will be summarized with respect to the normal ranges of values provided by the laboratory 
and with respect to pre-defined levels of change in these values. 


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All original AE/SAE terms will be coded using the current Medical Dictionary for Regulatory 
Activities (MedDRA) version. All Adverse events will be listed on an individual basis. AEs will 
be summarized by System organ classes and preferred terms on a patient basis. Patients with 
more than one adverse event within a particular SOC and PT will be counted only once for that 
SOC and PT. The type and incidence of AEs/SAEs, as well as severity and causality will be 
tabulated on a patient basis using the worst severity/causality for patients with several AES 
within the same particular SOC and PT. 
Only treatment emergent events will be included in summaries of AEs, but all adverse events 
will be presented in listings. Summaries of adverse drug reactions will also be produced, which 
are defined as treatment emergent adverse events at least possibly related to treatment. 
8.2.2. 
Analysis of Biodistribution, Pharmacokinetic and Dosimetry Data 
The analysis of biodistribution, pharmacokinetic and dosimetry endpoints will consist of 
descriptive summaries and graphical presentations of the derived parameters on the sub- 
population of the full analysis set who underwent dosimetry assessments. The 68Ga-PSMA-R2 
biodistribution, and absorbed dose in critical organs will be determined and stability will be 
analyzed using HPLC measurements. Regions of interest (ROI) for critical organs and tumor 
lesions will be drawn using the acquired images resulting in time-activity curves with 
quantitative fractions of administered activity. Dosimetry calculations will be issued from the 
analyses of organs receiving the highest dose, identified visually. ROI will be placed over these 
organs to determine relative radiotracer up-take calculated as a percentage of the injected dose. 
Time activity curves (TACs) will be fitted to mono- and bi-exponential curves to yield 
cumulative activities. Urine samples approximately 0-2 hours and 4 hours post-injection will be 
collected to complete dosimetry and biodistribution assessments. The absorbed dose (µGy/MBq) 
for critical organs will be evaluated, as well as the effective dose (µSv/MBq). The effective dose 
represents a radiation protection quantity that provides an estimation of detriment to the whole 
organism. According to the National Institutes of Health, for effective doses under 3 mSv, the 
risk is considered to be "minimal". Effective radiation dose will be summarized descriptively as 
related and to the equivalent number of days of exposure to natural background. 
8.2.3. 
Preliminary Targeting Properties of 68Ga-PSMA-R2 PET Imaging 
The number and location of lesions identified by 68Ga-PSMA-R2 PET imaging will be 
summarized and compared with those identified with conventional imaging techniques. Tumor 
uptake will be evaluated by SUV. SUVmean and SUVmax will be determined along with tumor to 
background ratio and these will be summarized descriptively. Positive and negative lesions by 
the two imaging techniques will be cross tabulated overall and by localization area on a lesion 
level and a patient level. Agreement calculations for 68Ga-PSMA-R2 imaging relative to 
conventional techniques will be performed on a patient level and summarized descriptively. 
Tests of association may be performed where appropriate. 
Preliminary explorations of 68Ga-PSMA-R2 imaging results relative to cytology and/or 
histopathology findings from archival and/or recent biopsy specimens will be performed for 
patients with biopsy data available. 


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8.3. 
Data Management 
8.3.1. 
Data/Documents 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained. Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM. 
It is the responsibility of the Investigator to maintain adequate and accurate Case Record Forms 
(according to the technology used Paper or Electronic) to record all observations and other data 
pertinent to the clinical investigation. 
The computerized handling of the data may generate additional requests to which the 
investigator is obliged to respond by confirming or modifying the data questioned. Should a 
correction be made, an audit trail will allow identification and tracking of the modification. 
8.4. 
Monitoring, Auditing and Inspection 
The study monitor and/or designee (e.g. contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study. In accordance 
with International Conference on Harmonisation (ICH) guidelines, the monitor will compare the 
CRF entries with the appropriate source documents. Additional review may include, but is not 
limited to, patient ICFs, documentation of patient recruitment and follow-up, AEs, SAEs, and 
concomitant therapy; as well as records of investigational product dispensing, compliance, and 
accountability. A copy of the IP dispensing log must be provided to the sponsor upon request. 
Before trial initiation, the Investigator will be informed of the anticipated frequency of 
monitoring visits. The Investigator will also receive notification before each monitoring visit 
during the course of the trial. It is expected that the Investigator and/or co-investigator(s) and 
other appropriate staff will be available on the Day of each visit in case questions arise. 
The trial site may be audited either by the Sponsor or designee. The Investigator will be 
informed in advance of such an audit. The trial site may also be inspected by a regulatory 
agency, possibly more than once. 
8.5. 
Monitoring Case Report Forms 
The Investigator shall be responsible for the accuracy of the data entered on the eCRFs and 
medically validated for any SAE. All entries must be written in English. All deletions, additions 
or changes will be recorded and tracked (i.e. owner, date, original entry, etc.), including 
additional information if needed. The relevant pages of each eCRF must be fully completed 
within 5 working Days of the patient’s visit to allow the CRAs to review and verify the forms 
promptly. Sufficient resources must be available to facilitate prompt eCRF completion and 


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collection. Request for data clarifications (queries) must be addressed within 5 working Days of 
receipt. 
The Investigator will grant the Sponsor or designee, IRB/IEC, and regulatory bodies, direct 
access to the source documents to verify the data reported in the eCRFs and data queries (source 
documents are the originals documents used by the Investigator or hospital/institution that allow 
verification of the existence of the patient and substantiate the integrity of the data collected 
during the trial). Source documents should be available to support all the data recorded in the 
eCRF. 
8.6. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• 
Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received, and authorizing the sponsor’s participation in the inspection 
• 
Providing access to all necessary facilities, study data, and documents for the inspection or 
audit 
• 
Communicating any information arising from inspection by the regulatory authorities to the 
sponsor immediately 
• 
Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to 
inspection. In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. In all instances, the confidentiality of the data must be respected. 
9. 
Operational, Ethical, and Administrative Considerations 
9.1. 
Data Quality Control 
9.1.1. 
Documentation Required Prior to Initiation 
The following documents will be required from the Investigator before the Initiation Visit: 
• 
current signed and dated curricula vitae (CV) and license of the Investigator and any sub- 
Investigators and site personnel directly involved in the trial; 
• 
normal ranges for all laboratory tests to be performed at the investigational site and a recent 
certification or accreditation of established quality control (or other documentation of 
established quality control or external quality assessment or other validation) and CV of the 
laboratory director; 


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• 
approved final protocol and informed consent; 
• 
signed originals of the trial protocol and any amendments; 
• 
completed and signed financial disclosure forms; 
• 
signed originals of the clinical trial letter of agreement with the Sponsor; and 
• 
local Regulatory Authorities’ forms where required and/or delegation of authority log 
(Delegation of Responsibilities Form). 
The Sponsor undertakes the obligation to obtain all the necessary approval from the competent 
regulatory authority prior to initiation of the trial. 
9.1.2. 
Documentation Required During the Trial 
The following will be required of the Investigator during the trial: 
• 
current signed and dated curricula vitae and license of the Principal Investigator and Sub- 
investigators or site personnel who are delegated protocol-related responsibilities after trial 
initiation; 
• 
documentation supporting any changes to clinical site staff, laboratory, and site locations; 
• 
financial disclosure forms for any new staff directly involved in the trial; 
• 
updates of normal ranges for all laboratory tests to be performed at the trial site and updates 
in certification or accreditation of established quality control (or other documentation of 
established quality control or external quality assessment or other validation); 
• 
signed originals of any protocol amendments and signature pages; 
• 
copies of any approvals from or other correspondence with the IRB/IEC; and 
• 
updated Local Regulatory Authorities’ forms and/or lists of delegated responsibilities. 
9.1.3. 
Assignment of Patient Numbers and Dose allocation 
A unique patient identification number will be assigned at the start of the screening period to 
each patient who signs the informed consent form. This number will identify the patient 
throughout the study. Patient identification number will include the protocol code 206D, a 4-digit 
country/site code, and a 3-digit patient number (ex: 
for the first patient to be 
recruited). 
Imaging kits will be allocated for single patient use. 
9.1.4. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator. This certification form accompanies each set of CRFs. The signed form will 
be provided to the sponsor with the final set of CRFs for each patient 


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9.2. 
Ethical and Regulatory Considerations 
9.2.1. 
Study Conduct 
This study will be conducted according to the principles of the ICH E6 Guideline on GCPs and 
the principles of the World Medical Association (WMA) Declaration of Helsinki and its most 
recent amendment WMA General Assembly, Seoul, October 2008. The Investigator will conduct 
all aspects of this study in accordance with all national, state and local laws of the pertinent 
regulatory authorities. 
Patient Selection: Up to 30 evaluable patients (for safety: patients who have received the study 
medication; for imaging: patients that have completed the imaging protocol) will be enrolled at 
up to 4 study sites. All patients will receive study imaging product only if they meet all the 
inclusion criteria and none of the exclusion criteria. 
9.2.2. 
Informed Consent 
A properly executed, written informed consent shall be obtained from each patient prior to 
entering the trial or performing any study-related procedure that involves a risk to the patient. A 
copy of the informed consent document to be used will be submitted by the Investigator to the 
IRB/IEC for review and approval prior to the start of the trial. The Investigator shall provide a 
copy of the signed informed consent to the patient, and the original shall be maintained in the 
patient's medical record. Additional elements of informed consent, if appropriate, must be 
provided to the patient. The patient must have signed and been given a copy of the informed 
consent document. 
 
 
9.2.3. 
Confidentiality 
All information provided to the Investigator by the Sponsor or designee including pre-clinical 
data, protocols, case report forms, and verbal and written information, will be kept strictly 
confidential and confined to the clinical personnel involved in conducting the trial. It is 
recognized that this information may be provided in confidence to the IRB/IEC. In addition, no 
report or information about the trial or its progress will be provided to anyone not involved in the 
trial other than to the Sponsor or designee, regulatory authorities and IRB/IEC; except if required 
by law. The Investigator must ensure that the patients’ anonymity is maintained. In the eCRFs or 
other documents submitted to the Sponsor/CRO, patients should not be identified by their names, 
but by their assigned patient ID numbers and initials. 
The Investigator must maintain a separate log (Master Patient List) of patients’ codes, names, 
addresses, telephone numbers and hospital numbers (if applicable). Documents not for 
submission to the Sponsor/CRO, such as signed Informed Consent Forms, should be maintained 
in strict confidence by the Investigator. 


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9.2.4. 
Institutional Review Board/ Independent Ethics Committee Approval 
Before initiation of the trial, the Investigator will submit the following to an IRB or IEC for 
approval: 
• 
trial protocol and any amendments, 
• 
patient information leaflets/ICFs and any other written materials to be provided to the 
patients, 
• 
investigator brochure, 
• 
details of any compensation to the patients, if applicable, and 
• 
any other requested documents. 
Copies of the approval and of all other correspondence with the IRB/IEC will be sent to the 
Sponsor or designee. The letter of approval must be dated, and the protocol number and the date 
of the protocol or amendment that was reviewed and approved must be specified. Likewise, the 
version and date of the patient information leaflet/ICF that was reviewed and approved must be 
specified. 
A dated membership list of the voting members of the IRB/IEC who were present when the 
protocol was reviewed and approved, including their titles or occupations and their institutional 
affiliations, must be provided to the Sponsor or designee, before trial initiation. 
The Investigator will submit a study report at least annually to the IRB/IEC that approved the 
protocol to comply with ICH GCP. 
The Investigator will make all attempts to ensure that the IRB/IEC is constituted and operates in 
accordance with ICH GCP and with relevant local regulations. 
9.3. 
Administration 
9.3.1. 
Trial Record Retention 
The Investigator will retain copies of all the essential documents (as defined by ICH GCP) for at 
least 2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the Investigational Product. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements (for example, European Economic Community (EEC) Directive 91/507 
requires retention of patient codes for at least 15 years after the completion or discontinuation of 
a trial, and retention of hospital records and other source data for the maximum time permitted 
by the institution where the trial takes place). The Investigator should take measures to prevent 
accidental or premature destruction of these documents. 
The essential documents include: 
• 
signed protocol, 


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• 
copies of the completed eCRFs, 
• 
signed Informed Consent Forms from all patients who consented, 
• 
hospital records and other source documents, 
• 
IRB/IEC approvals, 
• 
drug accountability records and trial correspondence. 
The Investigator will inform the Sponsor or designee of the storage location of these essential 
documents, and must contact the Sponsor or designee before disposing of any of these 
documents. 
The Sponsor or designee will inform the Investigator in writing when these documents no longer 
need to be retained. 
9.3.2. 
Protocol Deviations and Amendments 
The sponsor will not implement a change in the design or operation of the protocol or ICF 
without an IRB-approved amendment. Local amendments are highly discouraged unless strictly 
necessary due to regulatory purposes. 
In the event of any medical emergency, the Investigator is free to perform any medical 
intervention or procedure deemed appropriate. Such events and procedures must be reported 
promptly to the Sponsor or designee. 
9.3.3. 
Clinical Data Reporting 
Sponsor or designee Notification: The Investigator will provide the Sponsor or designee with 
all completed patient case report form materials, adverse event reports, and evaluations of patient 
laboratory parameters. 
Clinical Study Report: The Sponsor or designee will prepare a final report of the trial results 
after receiving, reviewing, and verifying the clinical data of the trial from the investigational site. 
For a multi-center trial, copies of this report may be supplied to each Investigator upon request. 
Publication/Presentations: Any publication derived from this study’s data will need to follow 
the publication charter which will be set up and agreed upon by the study co-chairs and the 
sponsor. The results of this study may be published in a medical publication, journal, or may be 
used for teaching purposes. The results of the Phase 1 portion of the study may be published 
prior to the completion of Phase 2. Publication of study findings will be led by sponsor. 
Additionally, this study and its results may be submitted for inclusion in all appropriate health 
authority study registries, as well as publication on health authority study registry websites, as 
required by local health authority regulations. Selection of first authorship will be based on 
several considerations, including, but not limited to study participation, contribution to the 
protocol development, and analysis and input into the manuscript, related abstracts, and 
presentations. 


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9.3.4. 
Emergency Sponsor Contact 
In emergency situations, the Investigator should contact the Sponsor or designee by telephone at 
the number listed on the title page of the protocol. Details of the methodology for identifying 
and reporting all AEs are in the Adverse Events Section (Section 7) of the protocol. 
9.4. 
Financing and Insurance 
9.4.1. 
Financial Disclosure 
In accordance with the ICH E6 GCP Guideline, Part 54 Financial Disclosure by Clinical 
Investigators, addresses the laws requiring financial disclosure by clinical investigators involved 
in (directly or indirectly) the course of a clinical trial diagnostics, reads, and/or interpretations of 
clinical data or results. The Sponsor is required to obtain either: 
• 
certification of the absence of certain financial interests or arrangements of clinical 
Investigators, or 
• 
disclosure of certain financial interests or arrangements of clinical Investigators. 
The Sponsor will request a statement attesting to any such financial arrangements. 
Disclosure is required for those financial interests other than those entered under the Clinical 
Trial Agreement (CTA) for this trial. 
9.4.2. 
Insurance 
The sponsor has covered this study by means of insurance for the patient according to national 
requirements. The name and the address of the relevant insurance company, the certificate of 
insurance, the policy number, and the sum insured are provided in the Investigator’s File. 


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10. 
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15. Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its 
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des metastasierten Prostatakarzinoms mittels Lu-177 PSMA-Liganden in Kombination mit 
Ga-68 PSMA PET/CT. Der Nuklearmediziner. 2015; 38(02):145–52. 
21. Troyer JK, Beckett ML, Wright GL Jr. Detection and characterization of the prostate-specific 
membrane antigen (PSMA) in tissue extracts and body fluids. Int J Cancer. 1995; 62(5):552- 
8. 
22. O'Keefe DS, Bacich DJ, Heston WD. Comparative analysis of prostate-specific membrane 
antigen (PSMA) versus a prostate-specific membrane antigen-like gene. Prostate. 2004; 
58(2):200-10. 
23. Kabasakal L, AbuQbeitah M, Aygun A, Yeyin N, Ocak M, Demirci E, et al. Pre-therapeutic 
dosimetry of normal organs and tissues of 177Lu-PSMA-617 prostate-specific membrane 
antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl 
Med Mol Imaging. 2015; 42(13):1976-83. 
24. Delker A, Fendler WP, Kratochwil C, BrunegrafA, Gosewisch A, Gildehaus FJ, et al. 
Dosimetry for 177Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of 
metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2016; 43:42-51. 
25. Waser B, Tamma M-L, Cescato R, Maecke HR, Reubi JC. Highly efficient in vivo agonist- 
induced internalization of sst2 receptors in somatostatin target tissues. J Nucl Med. 2009; 
50(6):936-41. 
26. Cremonesi M, Botta F, Di Dia A, et al. Dosimetry for treatment with radiolabelled 
somatostatin analogues: a review. Q J Nucl Med Mol Imaging. 2010;54(1):37-51. 
27. Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog 
[177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J 
Clin Oncol. 2005; 23:2754-2762. 


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28. Ezziddin S, Lohmar J, Yong-Hing CJ, et al. Does the pretherapeutic tumor SUV in 68Ga 
DOTATOC PET predict the absorbed dose of 177Lu octreotate? Clin Nucl Med. 2012; 
37(6):e141-7. 
29. Paller CJ, Antonarakis ES. Management of biochemically recurrent prostate cancer after 
local therapy: Evolving standards of care and new directions. Clin Adv Hematol Oncol. 
2013; 11(1): 14–23. 
30. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history 
of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591- 
1597. 
31. Jadvar H. Positron emission tomography in imaging evaluation of staging, restaging, 
treatment response, and prognosis in prostate cancer. Abdom Radiol. 2016; 41(5):889–898. 
32. Anger, H. O. and Gottschalk, A. Localization of brain tumors with the positron scintillation 
camera. J Nucl Med. 1963; 4:326-30. 
33. Schaer, L. R., Anger, H. O. and Gottschalk, A. Gallium edetate 68Ga experiences in brain- 
lesion detection with the positron camera. JAMA. 1966; 21;198(8):811-3. 
34. Levey, A. S., Stevens, L. A., Schmidt, C. H., et al. A New Equation to Estimate Glomerular 
Filtration Rate. Ann. Intern. Med. 2009; 150(9): 604-612. 
35. Bolch WE, Eckerman KF, Sgouros G, Thomas SR. MIRD pamphlet No. 21: a generalized 
schema for radiopharmaceutical dosimetry--standardization of nomenclature. J Nucl Med. 
2009;50(3):477-84 


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11. 
APPENDICES 
11.1. 
ECOG Performance Status 
 
ECOG Performance Status* 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 
50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria 
Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
All rights reserved. 
Revised: July 27, 2006 


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11.2. 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials 
Tables extracted from the FDA’s September 2007 Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials are 
included below for reference. The full text of the guidance is available at the following URL: 
https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidanc 
es/vaccines/ucm074775.htm 
 
 


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SAP_000.pdf: 
Official Title: 
A Phase 1/2 open-label, multi-center, safety and tolerability study of a 
single dose of 68Ga-PSMA-R2 in patients with biochemical relapse (BR) 
and metastatic prostate cancer (mPCa). 
NCT Number: 
Document Date: 
NCT03490032 
SAP Version 2.0: 29 June 2020 


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Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN 
A206O-A01-001 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 1 of 48 
A 
PHASE 
1/11 
OPEN-LABEL, 
MULTI-CENTER, 
SAFETY 
AND 
TOLERABILITY STUDY OF A SINGLE DOSE OF 68GA-PSMA-R2 IN 
PATIENTS WITH BIOCHEMICAL RELAPSE (BR) AND METASTATIC 
PROSTATE CANCER (MPCA) 
A UTHOR: 
 
 
 
 
 
 
V ERSION N UMBER AND D ATE: V2.0, 29illN2020 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V2.0 (Dated 29JUN2020) for Protocol A206D-AOI-OOI. 
Name 
Signature 
Date 
Author : 
 
DDMMMYYYY 
Position: 
 
Company: 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
Name 
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STATISTICAL A NALYSIS PLAN REVIEWED BY 
AAA 
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MODIFICATION HISTORY 
Unique 
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Identifier 
Document 
for this 
Version 
Version 
1.0 
23NOV2018 
 
 
2.0 
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Significant Changes from 
Previous Authorized Version 
Not Applicable - First Version 
. Section 6.1 - The PCa-BR 
population group will be presented 
separately for Phase I and Phase II 
patients. 
. Section I 5.2 - details of data 
presentations updated. 
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TABLE OF CONTE TS 
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A206D-A01-001 ....................................................................................................................................................... l 
A Phase 1/11 open-label, multi-center, safety and tolerability study of a single close of 68Ga-PSMA-R2 in 
patients with biochemical relapse (BR) and metastatic prostate cancer (mPCa) ................................................. 1 
Table of Contents ................................................................................................................................................... 6 
List of Abbreviations ........................................................................................................................................... 11 
I. 
Introduction ................................................................................................................................................. 13 
2. 
Study Objectives .......................................................................................................................................... 13 
2.1. 
Primary Objective ...................................................................................................................................... 13 
2.2. 
Secondary Objectives ................................................................................................................................ 13 
3. 
Study Design ................................................................................................................................................. 13 
3.1. 
Gene ral Description ................................................................................................................................... 13 
3.2. 
Schedule of Events ..................................................................................................................................... 14 
4. 
Planned Analyses ......................................................................................................................................... 14 
4.1. 
PK Analysis .....................................................................................................•.......................................... 14 
4.2. 
Biodistribution, Dosimetry and Imaging Analysis .................•..........................•..........................•............... 14 
4.3. 
Final Analysis ............................................................................................................................................. 15 
S. 
Analysis Sets ................................................................................................................................................. 15 
5.1. 
All Patients Enrolled Set [ENR] ................................................................................................................... 15 
5.2. 
Full Analysis Set [FAS] ................................................................................................................................ 15 
5.3. 
Per Protocol Set [PPS] ................................................................................................................................ 15 
6. 
General Considerations ............................................................................................................................... 15 
6.1. 
Population Summarization ........................................................................................................................ 15 
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6.2. 
Refere nce Sta rt Date a nd Study Day .......................................................................................................... 16 
6.3. 
Base line ..................................................................................................................................................... 16 
6.4. 
Retests, Unscheduled Visits a nd Early Te rmination Data ........................................................................... 16 
6.5. 
Windowing Conventions ............................................................................................................................ 17 
6.6. 
Statistical Tests .......................................................................................................................................... 17 
6.7. 
Common Calculations ................................................................................................................................ 17 
6.8. 
Softwa re Ve rsion ....................................................................................................................................... 17 
7. 
Statistic.al Considerations ............................................................................................................................. 17 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 17 
7.2. 
Multicenter Studies ................................................................................................................................... 17 
7.3. 
Missing data .............................................................................................................................................. 18 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 18 
7.5. 
Examination of Subgroups ......................................................................................................................... 18 
8. 
Output Presentations ................................................................................................................................... 18 
9. 
Disposition and Wit.hdrawals ....................................................................................................................... 18 
10. 
Demographic and Other Baseline Characterist.ics ................................................................................... 19 
11. 
Medical and Prosta te Cancer History ...................................................................................................... 19 
11.1. 
Medical History ...........................................................................................•..........................•............... 20 
11.2. 
Prostate Cancer History ......................................................................................................................... 20 
11.2.1. 
De rivations ............................................................................................................................................ 21 
12. 
Cancer therapies, Medications, Procedures and Radiotherapy .............................................................. 21 
12.1. 
Prior a nd Concomitant Cancer Thera pies ............................................................................................... 21 
12.2. 
Prior a nd Concomitant non-cancer medications .................................................................................... 21 
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12.3. 
Prior a nd Concomitant Procedures ........................................................................................................ 22 
12.4. 
Prior a nd Concomitant Radiotherapy ..................................................................................................... 22 
13. 
Study Medication Exposure ..................................................................................................................... 22 
14. 
Safety Outcomes ....................................................................................................................................... 23 
14.1. 
Adverse Events ...................................................................................................................................... 23 
14.1.1. 
All TEAEs ................................................................................................................................................ 24 
14.1.1.1. 
Severity ...................................................................................................•..........................•............... 24 
14.1.1.2. 
Relationship to Study Medication ...................................................................................................... 24 
14.1.1.3. 
Relationship to Study Procedure ........................................................................................................ 24 
14.1.2. 
TEAEs Leading to Discontinuation of Study ............................................................................................ 24 
14.1.3. 
Serious Adverse Events .......................................................................................................................... 24 
14.1.4. 
Adverse Events Leading to Death ........................................................................................................... 25 
14.2. 
Laboratory Evaluations .......................................................................................................................... 25 
14.2.1. 
Laboratory Reference Ranges ................................................................................................................ 25 
14.2.2. 
Severity Grading for Laboratory Data .................................................................................................... 26 
14.3. 
ECG Evaluations ..................................................................................................................................... 26 
14.3.1. 
ECG Markedly Abnormal Criteria ........................................................................................................... 26 
14.4. 
Vital Signs .............................................................................................................................................. 27 
14.5. 
ECOG ...................................................................................................................................................... 27 
15. 
Biodistribution, Dosimetry a nd Imaging of 68Ga-PSMA-R2 ......................................................................... 27 
15.1. 
Analyses of Biodistribution and Dosimetry ............................................................................................ 28 
15.2. 
Analyses of Imaging ............................................................................................................................... 28 
15.2.1. 
Laboratory Optimal threshold ................................................................................................................ 28 
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15.2.2. 
Lesions detected by PET and/or conventional scan, by TBR ................................................................... 29 
15.2.3. 
Burden and location of tumor lesions det ected by 68Ga-PSMA-R2 in comparison w ith conventional 
imaging modalit ies such as CT/MRI and/or bone scan .......................................................................................... 29 
15.2.4. 
Calculation of patient level agreement of 68Ga-PSMA·R2 PET imaging with conventional imaging in 
prostate cancer patients ....................................................................................................................................... 29 
APPENDIX I. 
Programming Conventions for Outputs .................................................................................. 31 
Output File Naming Convent ions .......................................................................................................................... 31 
Paper Size, Orientation and M argins ..................................................................................................................... 31 
Fonts ..•....•...••..••••...•••.•..•....•...••..•••••..•••.•..•....•...••..•..•...•••.•..•....•...•••.•..•...•••.•..•....•...•••....•...•••.•..•....•.....•....•...•••••..• 31 
Header Information ••.•..•....•...••..•..•...•••.•..•....•...•••.••.•...•••.•..•....•...•••.••.•...•••.•..•....•...•••....•...•••••..•....•.••..•....•...•••••..• 32 
Table and Listing Output Convent ions .........•............•............•...................................................•.......................... 32 
Figure Output Conventions ................................................................................................................................... 34 
Footnote Information .................•................•............•............•...................................................•............•............. 34 
Dat es & Times ..............................................•.............................................................................•.......................... 35 
Spelling Format •••...•••.•..•....•...••..•..•...•••.•..•....•...••..•..•...•••.•..•....•...•••....•...•••.•..•....•...•••....•...•••••..•....•...•••....•...•••••..• 35 
Presentation of Population Groups ....................................................................................................................... 35 
Presentation of Visits ............................................................................................................................................ 35 
Listings •...•...••..••••...•••.•..••...•...•••.•••••..•••.•..••...•...•••••..•...•••.•..••...•...•••....•...•••.•..••...•...••••...•...•••.•..••...•...•••....•...•••.•..• 36 
APPENDIX 2. Partial Date Conventions ......................................................................................................... 37 
Algorithm for Prostate Cancer History .................................................................................................................. 37 
Algorithm for Prior/ Active Procedures, Radiotherapies, Cancer Therapies and M edications .............................. 37 
Algorithm for Treatment Emergent of Adverse Events .......................................................................................... 38 
Algorithm for Prior/ Concom itant M edicatio ns .................................................................................................... 40 
APPENDIX 3. 
Laboratory Assessments .......................................................................................................... 41 
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APPENDIX 4. 
Vital Signs measurements ........................................................................................................ 45 
APPENDIX 5. Dosimetry measurements ......................................................................................................... 47 
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Statistical Analysis Plan 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
BLQ 
Below the Lower Limit of Quantification 
BUN 
Blood Urea Nitrogen 
cs 
Clinically Significant 
CT 
Computed Tomography 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EG 
Enterprise Guide 
eGFR 
Estimated Glomerular Filtration Rate 
ENR 
All Patients Enrolled 
FAS 
Full Analysis Set 
68Ga 
Gallium radioisotope 68 
68Ga-PSMA-R2 
68Ga-PSMA ligand 
g-GT 
Gamma-glutamvl transpeotidase 
Hb 
Hemoglobin 
LDH 
Lactic acid dehydrogenase 
MBq 
Megabecquerel 
MCV 
Mean corpuscular volume 
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MedDRA 
Medical Dictionary for Regulatory Activities 
mPCa 
Metastatic Stage Prostate Cancer 
MRI 
Magnetic Resonance Imaging 
NCS 
Not Clinically Significant 
ODS 
Output Delivery System 
PCa 
Prostate Cancer 
PCa-BR 
Biochemical Recurrence Prostate Cancer 
PET 
Positron Emission Tomography 
PK 
Pharmacokinetic(s) 
PPS 
Per Protocol Set 
PR 
PR interval of the electrocardiogram; time duration between the P and R 
waves 
PSA 
Prostate specific antigen 
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Statistical Analysis Plan 
PSMA 
Prostate Specific Membrane Antigen 
PT 
Preferred Term 
QRS 
QRS interval of the electrocardiogram; duration of the QRS complex 
QT 
QT interval of ECG, duration between the Q and T waves 
OTcB 
QT interval of ECG corrected for heart rate using Bazett's formula 
QTcF 
QT interval of ECG corrected for heart rate using Fridericia's formula 
QI 
First Quartile 
03 
Third Quartile 
RBC 
Red blood cell 
RR 
Time duration between two consecutive R waves of the electrocardiogram 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
soc 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
ULQ 
Upper Limit of Quantification 
WBC 
White blood cell 
WHO-DD 
Who Drug Dictionary 
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Statistical Analysis Plan 
1. INTRODUCTION 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 13 of 48 
This document describes the rules and conventions to be used in the presentation and analysis of safety data, for 
Protocol A206D-A0I -00I. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed. 
This statistical analysis plan (SAP) is based on protocol version 2.2, dated 22 February 2018. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective is to assess safety and tolerability of a single administration of3 mega Becquerel (MBq)/kg, 
but not less than 150 MBq and not more than 250 MBq, of 68Ga-PSMA-R2. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives are: 
• 
To assess the pharmacokinetics (PK) of 68Ga-PSMA-R2. 
• 
To assess biodistribution and dosimetry of 68Ga-PSMA-R2. 
• 
To establish the optimal imaging method for determining location and burden of positive lesions on 68Ga-
PSMA-R2 positron emission tomography (PET) imaging in patients in comparison with lesions identified 
with conventional imaging scans (computed tomography (en/magnetic resonance imaging (MRI) and 
bone scan), and to calculate the agreement of 68Ga-PSMA-R2 PET with conventional 
anatomical/functional imaging on a per patient basis. 
3. STUDY D ESIGN 
3.1. 
GENERAL DESCRIPTION 
This is an open label, multi-center, single dose, Phase 1/11 study to evaluate the safety and tolerability of 3 
MBq/ Kg, but not less than 150 and no more than 250 MBq, of 68Ga-PSMA-R2 in adult patients with PCa 
expressing PSMA receptors. 
This study will consist of 2 parts. 
• 
During the fi rst part (Phase f), approximately 6 patients with biochemically recurrent PCa will receive the 
investigational product (IP) and will remain at the site for approximately 6 hours post-administration in 
order to assess the PK, biodistribution vs. time, and dosimetry for critical organs. Patients will receive a 
sin!de dose of3 MB9/k2, (> 150 and< 250 MBg), of 68Ga-PSMA-R2 intravenously. Serial blood and 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 14 of 48 
urine samples will be collected for PK characterization and dosimetry and whole body PET/CT will be 
acquired at selected time points (0-4 hours) to determine organ and tumor absorbed doses. Safety 
assessments will be conducted after IP administration on Day I, and during follow-up on Days 7 and 28. 
• 
In the second part of the study (Phase 11), two groups of approximately I 2 patients will be enrolled 
(patients with PCa in biochemical recurrence (PCa-BR), and patients with prostate cancer in the 
metastatic stage (mPCa)). Enrollment will be capped at I 2 patients in each group to ensure an even 
distribution of patient conditions. If preliminary data analysis from the Phase I part of the study provides 
sufficient dosimetry data, all patients will undergo whole body PET/CT imaging optimized for time (up 
to 2 timepoints) according to the data analysis from the Phase I component of the study. 
This study is comprised of 4 clinical visits and will be conducted in 3 study periods includ ing: Screening, 
administration/ imaging, and safety follow-up period (final/early termination). 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Section "STUDY PROCEDURES AND ASSESSl'vlENTS" of the protocol. 
4. PLAN ED ANALYSES 
The following analysis will be performed for this study: 
• 
Phase I Analysis assessing PK, Biodistribution, Dosimetry and Imaging 
• 
Final Analysis (combining Phase I and Phase II data) 
This document will provide details for Phase I Biodistribution, Dosimetry and Imaging Analysis and Final 
Analysis. All planned analyses identified in this SAP will be performed by 
 Biostatistics following 
Database Lock. 
4.1. 
PK ANALYSIS 
Phase I PK Analysis will be described in a separate SAP written by the PK specialist from a third-party clinical 
pharmacokinetics vendor. 
Derivation of the PK parameters and the PK summary tables, listings and figures, will be the responsibility of 
th ird-party clinical pharmacokinetics vendor. 
4.2. 
BIODISTRIBUTION, DOSIMETRY AND IMAGING A NALYSIS 
The biodistribution, dosimetry and imaging analysis will be split in two: 
• 
The analysis using data from the principal scientist from a third-party radiation dosimetry vendor will be 
performed only for Phase I. 
• 
T he analysis using data from a third-party medical imaging vendor will be performed for both Phase I and 
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Statistical Analysis Plan 
Phase II. 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 15 of 48 
Summary tables, listings and figures needed for the biodistribution, dosimetry and imaging are described in 
section 15. 
4.3. 
FINAL ANALYSIS 
The final analysis will be conducted at the end of the study and will include the analyses of safety endpoints. This 
analysis will be based on the full analysis set (FAS) and may be repeated o n the per protocol set (PPS). 
5. ANALYSIS SETS 
Agreement and authorization of patients included/ excluded from each analysis set will be conducted prior to the 
final database lock. PK analysis set will be described in the SAP written by a third party clinical pharmacokinetics 
vendor. 
5.1. 
ALL PATIENTS ENROLLED SET [ENR] 
The all patients enrolled (ENR) set will contain all patients who provide informed consent for this study. 
5.2. 
FULL ANALYSIS SET [FAS) 
The full analysis set (FAS) will contain all patients who receive at least one dose of study medication. The safety 
set in this case is identical to the full analysis set and so will not be defined as a separate set. 
5.3. 
PER PROTOCOL SET [PPS] 
The per-protocol set (PPS) will contain all patients in the FAS who complete the study according to the protocol 
with no critical or major protocol deviations. The decisions regarding critical and major protocol deviations, and 
the definition of the analysis population, will be finalized prior to database lock. 
6. GENERAL CONSIDERATIONS 
6.1. 
POPULATION SUMMARIZATION 
In general, data will be presented by population. 
• 
T he following populations will be used in the analyses: 
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Statistical Analysis Plan 
o 
PCa-BR 
o 
mPCa 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 16 of 48 
• 
T he PCa-BR population group will also be presented separately for Phase I and Phase II patients. 
6.2. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/ stop day of assessments 
and events. 
Reference start date is defined as the day of the first and single administration of study medication, (Day I is the 
day of the first and single dose of study medication). 
If the date of the event is on or after the reference date, then: 
• 
Study Day = ( date of event - reference date) + I . 
If the date of the event is prior to the reference date, then: 
• 
Study Day = (date of event - reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will appear 
missing in the listings. 
6.3. 
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference start 
date (including unscheduled assessments). In the case where the last non-missing measurement and the reference 
start date and time coincide, that measurement will be considered pre-baseline, but Adverse Events (AEs) and 
medications commencing on the reference start date will be considered post-baseline. 
6.4. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries but will contribute to the best/worst case 
value where required (e.g. shift tables). 
Treatment Early termination data will not be included in by-visit summaries. 
In the case of a retest (same visit number assigned), the earliest available measurement for that visit will be used 
for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
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Statistical Analysis Plan 
6.5. 
WINDOWING CONVENTIONS 
No visit windowing will be performed for this study. 
6.6. 
STATISTICAL TESTS 
There will be no formal statistical testing of data. 
6.7. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
• 
Test Value at Visit X - Baseline Value 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 17 of 48 
For quantitative measurements, percentage of change from baseline will be calculated as: 
(
Test Value at Visit X -
Baseline Value) 
Baseline Value 
X l OO 
6.8. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher. 
7. STATISTICAL CONSIDERATIO S 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
There will be no statistical testing for safety data, and no covariate adjustment. 
7.2. 
MULTICENTER STUDIES 
The study will be conducted at approximately 4 sites in the US. All data will be pooled for summaries of safety 
with no summaries presented by center. 
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Statistical Analysis Plan 
7.3. 
MISSING DATA 
Missing safety data will not be imputed. 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 18 of 48 
Missing severity and relatedness of AEs will be handled as described in sections 14. 1.1.1 and 14.1.1.2 of this 
analysis plan. 
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
Not applicable. 
7.5. 
EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
8. O UTPUT PRESENTATIONS 
APPENDIX I shows conventions for presentation of data in outputs. 
The templates provided with this SAP describe the presentations for this study and therefore the format and 
content of the summary tables, figures and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study. 
The counts of the analysis sets will be presented: 
• 
All Patients Enrolled Set (ENR) 
• 
Full Analysis Set (FAS) 
• 
Per Protocol Set (PPS) 
The following patient disposition and withdrawals will be presented for the ENR set: 
• 
Screened 
• 
Screen failures 
• 
Phase I 
• 
Phase II 
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Statistical Analysis Plan 
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PROTOCOL A206D-A01-001 
Page 19 of 48 
• 
Number of patients receiving study medication 
• 
Completed study imaging assessments (assessed at Day 1) 
• 
Discontinued from study, reason for premature discontinuation from study 
Duration of follow-up will be presented for the ENR set. Duration of follow-up (day) is defined as date of 
completion/discontinuation - date of first administration + I. 
Critical and major protocol deviations (as defined in section 5.3) will be presented for the ENR set. 
10. 
D EMOGRAPHIC A D OTHER B ASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the FAS and PPS. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic characteristics will be reported: 
• 
Age (years) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islanders, W hite, Other) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• 
Weight (kg) 
• 
Height (cm) 
The following baseline characteristics will be reported: 
• 
ECOG perfonnance status at baseline (0, 2:1) 
• 
PSA test (ng/mL) 
11. 
MEDICAL AND PROSTATE CA CER HISTORY 
Medical and prostate cancer history information will be presented for the FAS and PPS and will be coded using 
MedDRA version 21.0 or higher. 
All reported medical and prostate cancer history will be listed. 
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Statistical Analysis Plan 
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PROTOCOL A206D-A01-001 
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11.1. 
MEDICAL HISTORY 
Medical history will be presented by System Organ Class (SOC) and (Preferred Term (PT). 
They will be sorted by decreasing frequency for SOC and for PT within SOC, based on total count. 
See APPENDIX 2 for handling of partial dates for medical history. 
11.2. 
PROSTATE CANCER HISTORY 
The following prostate cancer history information, as reported in the eCRF, will be summarized: 
• 
T ime since first prostate cancer diagnosis (months) 
• 
T ime since first metastasis (months) 
• 
T ime since disease progression (months) 
• 
Number of PSMA positive patients 
• 
Number of patients by initial diagnostic stage (IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV, unknown) 
• 
Number of patients by current diagnostic stage (IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV, unknown) 
• 
Number of patients by castration type (surgery, pharmacological, not applicable) 
• 
Number of patients by primary and secondary Gleason score: 
o 
Primary Gleason score=3 and Secondary Gleason scor=3 
o 
Primary Gleason score=3 and Secondary Gleason scor=4 
o 
Primary Gleason score=4 and Secondary Gleason scor=3 
o 
Primary Gleason score=4 and Secondary Gleason score=4 
o 
Primary Gleason score=4 and Secondary Gleason score=S 
o 
Primary Gleason score=S and Secondary Gleason score=4 
o 
Primary Gleason score=S and Secondary Gleason score=S 
Number of patients by Total Gleason score >=6 (6, 7, 8, 9, 10) 
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Statistical Analysis Plan 
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PROTOCOL A206D-A01-001 
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11.2.1. DERIVATIONS 
• 
T ime since first prostate cancer diagnosis (months) = (date of screening - date of first prostate cancer 
diagnosis+ I)/ 30.4375 
• 
T ime since first metastasis (months) = (date of screening - date of first metastasis+ I)/ 30.4375 
• 
T ime since disease progression (months) = (date of screening - date of disease progression+ 1)/ 
30.4375 
See APPENDIX 2 for handling of partial dates for prostate cancer history. 
12. 
CA CER THERAPIES, MEDICATIONS, PROCEDURES AND 
RADIOTHERAPY 
12.1. 
PRIOR AND CONCOMITANT CANCER THERAPIES 
Prior and concomitant cancer therapies, as reported in the "Prior and Concomitant Cancer Therapy/M:edications" 
eCRF page, will be presented for the FAS and PPS using WHO-DD Preferred Names. 
• 
Prior cancer therapies are those which started prior to the day of first and single dose of study medication. 
• 
Concomitant cancer therapies are those which: 
o 
started prior to, on or after the first and single dose of study medication, 
AND 
O 
ended on or after the date of first and single dose of study medication or were ongoing at the end of 
the study. 
Number of patients with at least one Line of therapy (Neoadjuvant, Adjuvant, Therapeutic for Metastatic Disease, 
Unknown), number of patients with at least one Therapy type (Chemotherapy, Hormonal, Biological, 
Immunotherapy, Other), number of patients with at least one Treatment intent (Curative, Palliative, Diagnostic, 
Salvage, Other) will be presented as well as the medication and the best response of the latest therapy the patient 
received (Complete response, partial response, stable disease, progressive disease, not evaluable). 
12.2. 
PRIOR AND CONCOMITANT NON-CANCER MEDICATIONS 
Medications will be presented for the FAS and PPS and coded using WHO Drug Dictionary version MAR2018 or 
higher if available at the time of the Database Lock. The medications will be summarized by WHO-DD Preferred 
Names, sorted by decreasing frequency based on total count. 
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Advanced Accelerator Applications 
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Statistical Analysis Plan 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior or concomitant, the medication will be classified by the worst case; i.e. concomitant. 
• 
Prior medications are those which started prior to the day of first and single dose of study medication. 
• 
Concomitant medications are those which: 
o 
started prior to, on or after the first and single dose of study medication, 
AND 
O 
ended on or after the date of first and single dose of study medication or were ongoing at the end of 
the study. 
All prior and concomitant prohibited/restricted medications outlined in protocol section 5.6, as determined by the 
medical advisor, will be listed. 
12.3. 
PRIOR AND CONCOMITANT PROCEDURES 
Prior and Concomitant Procedures (procedure, surgery or no n-drug therapy) will be presented by SOC and PT. 
They will be sorted by decreasing frequency for SOC and for PT within SOC based on total count. 
See APPENDIX 2 for handling of partial dates for prior and concomitant procedures. In the case where it will not be 
possible to define a procedure as previous or active/concomitant. 
• 
Prior procedures are defined as those which started prior to the first and single dose of study medicatio n. 
• 
Concomitant procedures are defined as those which: 
12.4. 
o 
started prior to the first and single dose of study medication and are ongoing or active at the 
date of the first and single dose of study medication 
OR 
o 
started on or after the first and single dose of study medication. 
PRIOR AND CONCOMITANT RADIOTHERAPY 
Prior and concomitant radiotherapy, using radiation type as reported in the eCRF, will be presented by radiation type 
and treatment intent. The total dose received (Gray) will also be summarized. 
See APPENDIX 2 for handling of partial dates for prior and concomitant radiotherapies. In the case where it will not 
be possible to define a radiotherapy as previous or active/concomitant. 
• 
Prior radiotherapies are defined as those which started prior to the first and single dose of study medication. 
• 
Concomitant radiotherapies are defined as those which: 
o 
started prior to the first and single dose of study medication and are ongoing or active at the 
date of the first and single dose of study medication 
OR 
o 
started on or after the first and single dose of study medication. 
13. 
STUDY MEDICATION EXPOSURE 
The following exposure information, as reported in the "68Ga-PSMA-R2 Injection" page of the eCRF, will be 
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Statistical Analysis Plan 
summarized for the FAS and PPS: 
• 
pH 
• 
Radiochemical Purity(%) 
• 
Pre-injection total dose in syringe (MBq) 
• 
Post-injection residual dose in syringe (MBq) 
• 
Total dose injected (MBq) 
• 
Pre-injection volume of solution (mL) 
• 
Post-injection volume of solution (mL) 
• 
Volume of solution administrated (mL) 
• 
Gamma counter calibration factor 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 23 of 48 
• 
Appearance (Clear and Colourless/ Not Clear and Colourless) 
• 
Number of patients with injection interrupted 
• 
Reason for injection interruption 
14. 
SAFETY O UTCOMES 
All outputs for safety outcomes will be based on the FAS. Safety will be assessed as the primary objective in this 
study. 
The primary endpoints are defined as: 
• 
Adverse events and serious adverse events (SAEs) 
• 
Absolute changes and changes from baseline in clinical laboratory parameters, vital signs and 
electrocardiogram (ECG) 
14.1. 
ADVERSE EVENTS 
Adverse Events will be coded using the MedDRA central coding dictionary, Version 21.0 or higher. 
They will be sorted by decreasing frequency for SOC and for PT within SOC, based on total count. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the 
first and single dose of study medication and until the last actual follow up visit. 
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See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment emergent or not, the AE wi II be classified by the worst case; i.e. treatment emergent. 
An overall summary of number of patients within each of the categories described in the sub-sections below, will 
be provided as specified in the templates. 
Listings will include TEAEs and Non-TEAEs. 
14.1.1. ALL TEAEs 
Incidence ofTEAEs, and number of events, will be presented by SOC and PT and broken down further by 
maximum severity and relationship to study medication and study procedure. 
14.1.1.1. Severity 
Severity is classed as mild, moderate, severe, life threatening/disabling or death. TEAEs starting after the first dose 
of study medication with a missing severity will be classified as severe. If a patient reports a TEAE more than 
once within that SOC/ PT , the AE with the worst-case severity will be used in the corresponding severity 
sun1maries. 
14.1.1.2. Relationship to Study Medication 
A related TEAE is defined as a TEAE with a relationship to study medication as "Reasonable possibility" 
according to the investigator. TEAEs with a missing relationship to study medication will be regarded as related to 
study medication. If a patient reports the same AE more than once within that SOC/ PT, the AE with the worst-
case relationship to study medication will be used in the corresponding relationship summaries. 
14.1.1.3. Relationship to Study Procedure 
A related TEAE is defined as a TEAE with a relationship to study procedure as "Reasonable possibility" according 
to the investigator. TEAEs with a missing relationship to study procedure will be regarded as related to study 
procedure. If a patient reports the same AE more than once within that SOC/ PT, the AE with the worst-case 
relationship to study procedure will be used in the corresponding relationship summaries. 
14.1.2. TEAEs LEADING TO D ISCONTINUATION OF STUDY 
TEAEs leading to study d iscontinuation will be identified by using the "Caused Study Discontinuation" category 
on the AE page of the eCRF. 
For TEAEs leading to study discontinuation, a summary by SOC and PT will be prepared. 
AEs leading to study discontinuation will be listed. 
14.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as "Serious" on the Adverse Events page of the (e)CRF. 
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Statistical Analysis Plan 
A summary of serious TEAEs by SOC and PT will be prepared. 
Serious AEs will be listed. 
14.1.4. ADVERSE EVENTS LEADING TO DEATH 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 25 of 48 
TEAEs leading to Death are those events which are recorded as "Fatal" on the Adverse Events page of the (e)CRF. 
A summary ofTEAEs leading to death by SOC and PT will be prepared. 
AEs leading to Death will be listed. 
14.2. 
LABORATORY EVALUATIONS 
Results from the local laboratory will be inc luded in the reporting of this study for Hematology, Blood Chemistry 
and Urinalysis. A list of laboratory assessments to be included in the outputs, and a severity grading system is 
included in APPENDIX 3. 
Presentations will use SI Units. 
Quantitative laborato1y measurements reported as"< X", i.e. below the lower limit of quantification (BLQ), or 
"> X", i.e. above the upper limit of quantification (ULQ), wi ll be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded,. i.e. as "< X" or "> X" in the listings. 
The following summaries will be provided for laboratory data: 
• 
Observed values and change from baseline by visit (for quantitative measurements) 
• 
Summary of qualitative clinical laboratory evaluations by visit 
• 
Incidence of abnormal values at any time post-baseline according to normal range criteria 
• 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 
measurements), by visit 
• 
Shift from baseline to worst post-baseline value, according to severity grading system 
• 
Summary of markedly abnormal post-baseline values 
• 
Listing of patients with Grade 3 or above severity grades 
• 
Box plots of absolute values over time and changes from baseline over time 
14.2.1. LABORATORY REFERENCE RANGES 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges and 
categorized as: 
• 
Low: Below the lower limit of the laboratory reference range. 
• 
Normal: Within the lower and upper limits of the laboratory reference range. 
• 
High: Above the upper limit of the laboratory reference range. 
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Statistical Analysis Plan 
14.2.2. SEVERITY GRADING FOR LABORATORY DATA 
Laboratory results will be classified according to 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 26 of 48 
• 
The Toxicity Grading Scale for Healthy Adult and Adolescem Volunteers Enrolled in Preventive Vaccine 
Clinical Study. 
• 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
• 
The University of Delaware Criteria 
The "Grade O" will be introduced to indicate that a certain laboratory value can be seen as "normal" and does not 
fulfill the criteria of severity grading either within the reference range or elevated in the other direction than defined 
in the APPENDIX 3. 
Parameters flagged as "Medical Advisor Input Needed" in APPENDIX 3, will be graded as per medical advisor 
identification based on listings provided 
. 
14.3. 
ECG EVALUATIONS 
Results from the ECG (Electrocardiogram) will be included in the reporting of this study. 
The following ECG parameters will be reported for this study: 
• 
RR Interval (msec) 
• 
PR Interval (msec) 
• 
QRS Interval (msec) 
• 
QT Interval (msec) 
• 
QTcF Interval (msec) 
• 
QTcB Interval (msec) 
• 
Overall interpretations of ECG (Investigator's judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant 
o 
Abnormal, Clinically Significant 
The following summaries will be provided for ECG data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Incidence of markedly abnormal post-baseline values at any time post-baseline. 
• 
Shift from baseline according to worst overall interpretation 
• 
Box plots of absolute values over time and changes from baseline over time 
• 
Listing of patients meeting markedly abnormal criteria 
The handling of retests, unscheduled and end of study measurements is described in Section 6.4. 
14.3.1. ECG M ARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following 
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Statistical Analysis Plan 
predefined markedly abnormal criteria: 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 27 of 48 
• 
Absolute values for QT interval, QTcB interval and QTcF will be classified as: 
o 
> 450 msec 
o 
> 480 msec 
o 
> 500 msec 
• 
Change from Baseline for QT interval, QTcB interval and QTcF will be classified as: 
o 
>30 msec increase from baseline 
o 
>60 msec increase from baseline 
14.4. 
VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Weight (kg) 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Temperature (0C), considering that °C = (°F - 32) / 1,8 
• 
Heart Rate (bpm) 
• 
Respiratory Rate (resp/min) 
The following summaries will be provided for vital signs data: 
• 
Actual and change from baseline by visit 
• 
Incidence of markedly abnormal values at any time post-baseline 
• 
Shift from baseline according to markedly abnormal criteria by visit 
• 
Box plots of absolute values over time and changes from baseline over time 
• 
Listing of patients meeting markedly abnormal criteria 
The handling of retests, unscheduled and end of study measurements is described in Section 6.4. 
A list of Vital Signs measurements to be included in the outputs, and a severity grading system is included in 
APPENDIX 4. 
14.5. 
ECOG 
ECOG performance status at baseline and post-baseline visits will be listed on the FAS. 
15. 
BIODISTRIBUTION, DOSIMETRY AND IMAGING OF 68GA-PSMA-R2 
Biodistribution is defined as the activity in various organs over time quantified by imaging. Dosimetry is the 
assessment of radiation dose per unit administered activity. 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 28 of 48 
Biodistribution, dosimetry and imaging data are not collected in the CRF. Biodistribution and dosimetry data will 
be received from the principal scientist of a third-party radiation dosimetry vendor while imaging data will directly 
be sent from a third-party medical imaging vendor. Results from the radiation dosimetry vendor will be included 
in the reporting of Phase I of this study. Results from the medical imaging vendor will be included in the reporting 
of Phase I and II of this study. The analysis of imaging data will also be performed on patients from Phase I. 
The terminology, conventional scans and standard imaging, both relate to CT, MRJ and/or bone scans. 
A list of tests and organs to be included in the outputs is included in APPENDIX 5. 
15.1. 
A NALYSES OF BIODISTRIBUTION AND DOSIMETRY 
For phase I, PET and conventional scans will be performed on Day I at 20-30 minutes, and I, 2, and 3 - 4 hours 
post-injection. For Phase II, all patients will undergo whole body PET and conventional scans optimized for time 
(up to 2 time points) according to the data analysis from the Phase I component of the study. Further details about 
imaging assessments can be found in the section 6.5.4 of the protocol. 
Data from the radiation dosimetry vendor will be presented using SI Units and the following statistical summaries 
will be provided: 
• 
Decay corrected tissue activity in normal organs by timepoint 
• 
Non-decay corrected tissue activity in normal organs by timepoint 
• 
Residence times in normal organs 
• 
Absorbed doses, whole body dose and effective dose of 68Ga-PSMA-R2 in normal organs 
Time Activity Curve (TAC) will be produced as graphical representation of Decay corrected tissue activity and 
Non-decay corrected tissue activity. 
15.2. 
A NALYSES OF IMAGING 
15.2.1. LABORATORY OPTIMAL THRESHOLD 
Standard uptake value (SUV) will only be available in PET scans. 
Descriptive analysis will be performed on SUV and the following summaries will be produced: 
• 
SUV max, SUV mean and TBR with positive lesio n status in PET scan 
• 
SUV max, SUV mean and TBR with positive lesion status in PET scan and correlated with conventional scan 
• 
SUV max, SUV mean and TBR with positive lesion status in PET scan and not correlated with conventional 
scan 
Lesion Tumor to Background Ratio (TBR) is defined as SUVmaX(1es;on) / SUVmean<g1u1ea1 orlh;ghJ and will be 
summarized in the same way as SUV max and SUV mean. 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 29 of 48 
15.2.2. LESIONS DETECTED BY PET SCAN A ND/OR CONVENTIONAL SCAN, BY TBR 
The number of positive lesions detected by PET scan, correlated or not with conventional scan, will be presented 
by TBR category. 
15.2.3. BURDEN AND LOCATION OF TUMOR LESIONS DETECTED BY 68GA-PSMA-R2 IN COMPARISON 
W ITH CONVENTIONAL IMAGING MODALITIES SUCH AS CT /MRI AND/OR BONE SCAN. 
• 
T he difference of number of lesions detected by 68Ga-PSMA-R2 PET scan and by conventional scan 
modalities such as CT/MRI and/or bone scan, will be displayed by location. The number of lesions 
detected on the PET scan, correlated and not correlated with conventional scan lesions, will be presented. 
T he number of lesions detected on the conventional scan, not correlated with lesions detected on the PET 
scan, will be presented. 
• 
T he difference in the number of positive patients detected by 68Ga-PSMA-R2 PET and by conventional 
scan modalities such as CT/MRI and/or bone scan, will be displayed by location. The number of positive 
patients detected on the PET scan, with at least 1 lesion correlated, and at least 1 lesion not correlated 
with a lesion detected on the conventional scan, will be presented. The number of positive patients 
detected on the conventional scan, with no lesio ns correlated with any lesion detected on the PET scan, 
will be presented. Note: A positive patient has at least 1 lesion detected. 
15.2.4. CALCULATION OF PATIENT LEVEL AGREEMENT OF 68GA-PSMA-R2 PET IMAGING WITH 
CONVENTIONAL IMAGING IN PROSTATE CANCER PATIENTS 
The patient level agreement is commonly used to characterize the agreement of a new test with the non-reference 
standard. Here 68GA-PSMA-R2 PET scan is the new test and conventional scan is the non-reference Standard. 
68GA-PSMA-R2 
PET Scan 
Total 
+ 
Conventional Scan 
+ 
a 
C 
a+c 
b 
d 
b+d 
The patient-level positive percent agreement, negative percent agreement and overall percent agreeme nt will be 
calculated based on the number of patients with at least one positive lesion detected by conventional scan and/or at 
least one positive lesion detect.ed by PET scan. 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 30 of 48 
These percent agreements will be calculated as follows with their two-sided 95% score confidence intervals: 
• 
Positive percent agreement: a/(a+c) * 100 
• 
Negative percent agreement: d/(b+d) * I 00 
• 
Overall percent agreement: (a+d)/(a+b+c+d) * I 00 
Where 
• 
a is the number of patients with al least one positive lesion detected by conventional scan and at least one 
positive lesion detected by PET scan 
• 
bis the number of patients with at least one positive lesion detected by PET scan that is not correlated 
with conventional scan 
• 
c is the number of patients with at least one positive lesion detected by conventional scan that is not 
correlated with PET scan 
• 
d is the number of patients with no lesions detected by conventional scan or PET scan 
These 3 coefficients and their 95% Clopper Pearson Exact confidence intervals will be calculated using SAS PROC 
FREQ as follow: 
PROC FREQ data=temp; 
tables resp/binomial (exact level=']'); 
RUN; 
The lesion-level positive percent agreement and overall percent agreement will be calculated based on the number of 
lesions detected as positive by conventional scan and/or by PET scan. 
These percent agreements will be calculated as followes with their two-sided 95% score confidence intervals: 
• 
Positive percent agreement: a/(a+c) * I 00 
• 
Overall percent agreement: (a)/(a+b+c) * I 00 
Where 
• 
a is the number of lesions detected as positive in both PET and conventional scan 
• 
bis the number of lesions detected as positive in PET scan but not correlated with conventional scan 
• 
c is the number of lesions detected as positive in conventional scan but not correlated with PET scan 
These 2 coefficients and their 95% Clopper Pearson Exact confidence intervals will be calculated using SAS PROC 
FREQ as above. 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 31 of 48 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT FILE NAMING CONVENTIONS 
File names should only consist of lowercase letters, digits (0 to 9) and hyphens. A period should only be used to 
indicate a separator between the file name and the extension. No spaces, other special characters or punctuation marks 
are permitted. 
The program, program log and output file name should reflect the type of the statistical output. The output files will 
contain the output number in addition. If this is not possible, then the output name should be at least as descriptive as 
possible. A prefix can be used to distinguish between a Table, Listing and Figure document ('t' for table, '1' for listing 
and 'P for figure). If there is only I digit in the number of the table, listing or figure in the place where 2 digits are 
possible, a leading zero should be added in the file name to make sorting consistent with the sequence (e.g. t-14-3-01 -
1.RTF) 
As far as possible, output files should be in RTF and PDF format. 
The outputs will be provided in pdf format. 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter. 
The page orientation should preferably be landscape, but portrait is also permitted. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the paper 
size. 
The number of columns per page (linesize) should be 134 for Letter. 
The number of rows per page (pagesize) should be 40 for Letter. 
FONTS 
The font type 'Cout~er New' should be used as a default for tables and listings, with a font size of 8. The font color 
should be black. No bolding, underlining italics or subscripting should be permitted. Try to avoid using super-scripts, 
unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of "Times Roman", "Helvetica", or "Courier New". 
This can be achieved by using the following options in SAS: 
goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 
ftext = "I imesRoman" 
htext = 2.5; 
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Statistical Analysis Plan 
HEADER INFORMATION 
Headers should be defined as follows: 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 32 of 48 
• 
T he header should be placed at the top of the page (same place on each page) regardless of the size or 
orientation of the table or listing 
• 
The customer name and protocol number should appear in row I, left-aligned 
• 
T he output identification number should appear in row 2, left-aligned 
• 
The output title should start in row 2 after output identification number separated by a double dot, left-aligned 
• 
T he output population should appear in row 2 after output title separated by a dash, left-aligned. The 
population should not be spelled out in full, e.g. FAS in preference to Full analysis set. 
• 
Row 3 should be a continuous row of underscores ('_')(the number of underscores should equal the linesize) 
• 
Row 4 should be a blank line 
• 
Mixed case should be used for titles 
• 
The output titles should be designed so that they are arranged consistently through all outputs. For example, 
content (e.g. Vital Signs) followed by metric (e.g. Change from Baseline) e.g. Vital Signs - Change from 
Baseline. 
• 
T itles should not contain quotation marks or footnote references 
• 
The column headings should be underlined with a row of underscores ('_') 
• 
Column headings spanning more than one column should be underlined and have underscores on either side 
of the title and should be centered 
• 
Column headings containing numbers should be centered 
• 
Column headings should be in sentence case 
• 
In general, the population count should appear in the column header in the form "(N=XXX)" 
• 
"Statistic" should be the column header over n, Mean, SE, n (%) etc. 
• 
As a rule, all columns should have column headings. 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• 
T he first row in the body of the table or listing should be blank 
• 
T he left-hand column should start in column I. No indenting or centering of the output should occur. 
• 
Rounding should be done with the SAS function ROUND, if no further specification. 
• 
Numbers in tables should be rounded, not truncated, if no further specification. 
• 
Alphanumeric output should be left aligned. 
• 
Numbers should be decimal point aligned. 
• 
Whole numbers should be right aligned. 
• 
Text values should be left aligned. 
• 
The first letter of a text entry should be capitalized 
• 
Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological 
order, with earliest adverse event, medication or history coming first. 
• 
The study drug should appear first in tables with treatments as columns 
• 
In general, only present totals (across treatment groups) at baseline/randomization, and do not present them 
post randomization. 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 33 of 48 
• 
If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for 
percentage calculations. 
• 
All listing outputs should be sorted (preferably by Treatment, Site Number and Patient Number). 
• 
Do not use superscripts and subscripts 
• 
The width of the entire output should match the linesize 
Univariate Statistics: 
• 
Statistics should be presented in the same order across tables (i.e., n, Mean, Std Dev, Median, QI, Q3, 
Minimum, Maximum or n, gMean, gCV, Mean, CV, Std Dev, Median, Minimum, Maximum) 
• 
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should 
line up. If the minimum and maximum are output on one line as Minimum, Maximum then the comma should 
line up with the decimal point. 
• 
If the original data has N decimal places, then the summary statistics should have the following decimal 
places: 
o 
Minimum and maximum: N 
o 
Mean, gMean, QI, Q3, median, gCVo/o and CV%: N + I 
o 
Std Dev: N + 2 
Frequencies and percentages (n and %): 
• 
Percent values should be reported inside parentheses, with one space between the count and the left 
parenthesis of the percentage. Parentheses should be j ustified to accept a maximum of I 00.0 as a value and 
padded with blank space if the percent is less than I 00.0. An example is given below: 
77 (100.0%) 
50 (64.9%) 
0 (0.0%) 
• 
Percentages will be reported to one decimal place, except percentages < I 00.0% but >99. 9% wi II be presented 
as '>99.9%' (e.g., 99.99% is presented as >99.9%); and percentages< 0.1% will be presented as '<0.1%' 
(e.g., 0.08% is presented as <0. I%). Rounding will be applied after the <0.1 % and >99.9% rule. 
E.g. ( <0. I%) 
(6.8%) 
(>99.9%) 
• 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is 
relatively small). 
• 
Where counts are zero, percentages of 0.0% should appear in the output. 
Confidence Intervals: 
• 
As a rule, confidence intervals are output to one place more than the raw data (except for the primary analysis 
where we compare against a margin with 3 decimal places), and standard deviations and standard errors to 
two places more than the raw data 
• 
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table "line 
up". 
• 
Boundary values of confidence intervals should be separated by a semi-colon. 
• 
Boundary values should be padded as necessary to accept negative values and to allow alignment of the 
decimal place. 
• 
An example is given below: 
(-0.12; -0.10) 
(9.54; 12.91) 
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Statistical Analysis Plan 
P-values: 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 34 of 48 
• 
P-values should be reported to four decimal places, Rounding will be applied after the <0.0001 and >0.9999 
rule 
Ratios: 
• 
Ratios should be reported to one more decimal place than the original data. 
Spacing: 
• 
T here must be a minimum of I blank space between columns (preferably 2) 
Denominators: 
• 
If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number "n". 
• 
Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
Missing values 
• 
A "0" should be used to indicate a zero frequency. 
• 
A blank will be used to indicate missing data in an end-of-text table or patient listing. 
FIGURE OUTPUT CONVENTIONS 
• 
Figures will be provided in RTF and PDF files using the SAS Output Delivery System (ODS) as generated 
by SAS. 
• 
T he image should be clear and of high quality when viewed in the Word document, and when printed. 
• 
In general, boxes around the figures should be used. 
• 
Boxplots will display whiskers extending from PlO to first quartile and from 3rd quartile to P90. 
FOOTNOTE INFORMATION 
Footers shou Id be defined as follows: 
• 
A continuous line of underscores ('_') will follow the body of the table or listing prior to any footnotes at the 
bottom of the page 
• 
Table footnotes should be defined using compute statements in the proc report, and should appear directly 
after the body of the table 
• 
T he program path and name and version number (if applicable) should appear as footnote 1 at the bottom of 
the page 
• 
T he date/time stamp should appear as footnote 2 at the bottom of the page 
• 
Footnotes should be left-aligned. 
• 
Footnotes should be in sentence case. 
• 
Only "typewTiter" symbols are permitted - e.g."*","$","#","@","&" and "+". 
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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 35 of 48 
• 
The choice of footnote symbols should be consistent. E.g. if you have the footnote "# indicates last 
observation can-ied forward" for one table, the same symbol and footnote should indicate LOCF for all tables. 
• 
If text wraps across more than one line (for a note), the first letter for all lines of text after the first one will 
be indented to align beneath the first letter of the text in the first line. 
• 
T he page identification in the format Page X of Y (where Y is the total number of pages for the output) should 
appear in the footer, right aligned. 
Ordering of footnotes shou Id be as follows: 
I.) Source data listing reference, if necessary 
2.) Abbreviations and definitions 
3.) Formulae 
4.) P-value significance footnote 
5.) Symbols 
6.) Specific notes 
• 
Common notes from table to table should appear in the same order. 
The symbols should appear in the same order as what they are defined in the table or listing, from left to right. 
D ATES & T IMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF POPULATION GROUPS 
For outputs, population groups will be represented as follows and in that order: 
Population Group 
For Tables, Listings and Graphs 
PCa-BR 
PCa-BR 
mPCa 
mPCa 
PCa-BR + mPCa 
Overall 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Version Date: 
29JUN2020 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
Long Name (default) 
Screening 
Baseline (Day I) 
Day7 
Day28 
LISTINGS 
Short.Name 
Screening 
D I 
D7 
D28 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 36 of 48 
All listings wi ll be ordered by the following (unless otherwise indicated in the template): 
o 
Population group 
o 
center-patient ID, 
o 
date (where applicable) 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Version Date: 
29JUN2020 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 37 of 48 
APPENDIX 2. 
PARTIAL D A TE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR PROSTATE CANCER HISTORY 
P 
. Id 
art1a 
ate to e ,mout 
b . 
ed as: 
Start date 
Earliest possible date 
first day of month if day unknown 
or I st January if day and month are 
unknown 
Stop date 
Latest possible date 
last day of month if day unknown 
or 3 I st December if day and month 
are unknown 
ALGORITHM FOR PRIOR/ ACTIVE PROCEDURES, RADIOTHERAPIES, CANCER THERAPIES AND 
MEDICATIONS 
P 
. Id 
artia ate to b 
ed 
e JmPUt 
as: 
Start date 
Earliest possible date 
first day of month if day unknown 
or I st January if day and month are 
unknown 
Stop date 
Latest possible date 
last day of month if day unknown 
or 3 I st December if day and month 
are unknown 
General rules: 
If start date <= study med start date, assign as prior 
If stop date>= study med start date, assign as concomitant 
If Missing Stop date: (Rules 2) 
If stop date is missing, assign as prior and concomitant 
If Missing Start date: (Rules 3) 
If stop date < study med start date, assign as prior 
If stop date>= study med start date, assign as prior and concomitant 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Version Date: 
29JUN2020 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
START 
STOP 
DATE 
DATE 
Known 
Known 
Partial 
Missing 
Partial 
Known 
Partial 
Missing 
Missing 
Known 
Partial 
Missing 
ACTION 
General rules 
General rules 
General rules 
General rules 
General rules 
Rules 2 
Rules 3 
Rules 3 
Rules 2 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 38 of 48 
ALGORITHM FOR TREATMENT EMERGENT OF ADVERSE EVENTS 
START DATE 
STOP 
ACTION 
DATE 
Known 
Known 
If start date < study med start date or start date> actual date of 
Partial 
last follow up visit, then not TEAE 
Missing 
If start date>= study med start date and start date <= actual 
date of last follow up visit, then TEAE 
Partial, but known 
Known 
Not TEAE 
components show that it 
Partial 
cannot be on or after study 
med start date 
Missing 
Partial, could be on or after 
Known 
Impute start date as earliest possible date, (i.e. first day of 
study med start date 
month if day unknown or I st January if day and month are 
unknown), except if only day is missing and month and year 
of start date are the same as for study med start date or if day 
and month are missing and year of start date is the same as for 
study med start date. In the latter cases, the study med start 
date will be used for the imputation. 
If start date <= stop date, then: 
If stop date < study med start date, then not TEAE 
If start date> actual date of last follow up visit, then not 
TEAE 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Version Date: 
29JUN2020 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
START DATE 
STOP 
DATE 
Partial 
Missing 
Missing 
Known 
Partial 
Missing 
ACTION 
Advanced Accelerator Applications 
PROTOCOL A206D-A01 -001 
Page 39 of 48 
If stop date>= study med start date and start date <= 
actual date of last follow up visit, then TEAE 
If start date > stop date, then: 
Consider the start date as Missing and apply the algorithms 
for missing start date 
Impute start date as above. 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), if not resulting in a date later than the date of 
patient's death. In the later case the date of death will be used 
for imputation. 
If start date <= stop date, then: 
If stop date < study med start date, then not TEAE 
If start date> actual date of last follow up visit, then not 
TEAE 
If stop date>= study med start date and start date <= 
actual date of last follow up visit, then TEAE 
If start date > stop date, then: 
Consider the start and stop dates as Missing and apply the 
algorithms for missing start date 
Assumed TEAE 
If stop date < study med start date, then not TEAE 
If stop date>= study med start date, then TEAE 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), if not resulting in a date later than the date of 
patient's death. In the later case the date of death will be 
used for imputation: 
If stop date < study med start date, then not TEAE 
If stop date>= study med start date, then TEAE 
Assumed TEAE 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Version Date: 
29JUN2020 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
ALGORITHM FOR PRIOR/ CONCOMITANT MEDICATIONS 
P 
. Id 
art1a 
ate to e 1mput 
b . 
ed as: 
Start date 
Earliest possible date 
Stop date 
Latest possible date 
General rules: 
If start date <= study med start date, assign as prior 
If stop date>= study med start date, assign as concomitant 
If Missing Stop date: (Rule 2) 
If stop date is missing, assign as prior and concomitant 
If Missing Start date: (Rule 3) 
If stop date < study med start date, assign as prior 
Advanced Accelerator Applications 
PROTOCOL A206D-A01-001 
Page 40 of 48 
first day of month if day unknown 
or I'' January if day and month are 
unknown 
last day of month if day unknown 
or 31" December if day and month 
are unknown 
If stop date >= study med start date, assign as prior and concomitant 
ST ART 
STOP 
ACTION 
DATE 
DATE 
Known 
Known 
General ru Jes 
Partial 
General rules 
Missing 
Rule2 
Partial 
Known 
General rules 
Partial 
General rules 
Missing 
Rule2 
Missing 
Known 
Rule3 
Partial 
Rule 3 
Missing 
Rule2 
Document: 
K:\AM\Ga-PSMA-R2\VYA27826\ Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP _v2.0 
Author: 
 
Version Number: 
2.0 
 
Version Date: 
29JUN2020 
Template No.: CS_TP _8S016 Revision 5 
Effective Date: 01Apr2018 
Reference: CS_WI_BS005 
 
 


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Statistical Analysis Plan 
APPENDIX 3. 
LABORATORY ASSESSMENTS 
a) 
Graclable with Toxicity Grading Scale for Healthy Adult and Aclol, 
Volunteers Enrolled in Preventive Vaccine Clinical Study 
b) 
Graclable with Common Terminology Criteria for Adverse Events 
Version 4.03 
Laboratory parameter 
Grading 
c) 
Graclable with University of Delaware Criteria 
Scale 
(htti:1://wwwl .udel.edu/mls/mclane/KMS3RR.html) 
cl) 
Not Graclable 
Markedly Abnor 
Grade l 
Grade 2 
Grade 3 
Blood chemistry 
I 
ALT/ ALAT 
a 
>=I. 1 x ULN - <2.5 
>=2.5 x ULN -
>=5.0x ULN -
>= 10x 
X ULN 
< 5.0x ULN 
<10 x ULN 
AST/ ASAT 
a 
>=I. I x ULN - <2.5 
>=2.5 x ULN -
>=5.0x ULN -
>= 10x 
X ULN 
< 5.0x ULN 
<10 x ULN 
Gamma glutamyl transpeptidase (g-GT) 
b 
>= 1 X ULN -
>=2.5 x ULN -
>=5.0 x ULN -
>=20.0 
<2.5 x ULN 
<5.0 x ULN 
<20.0 x ULN 
(Liver Function test normal*) 
a 
>=l.lxULN-
>=1.25 x ULN - <1.5 
>=1.5 x ULN -
>= 1.75 
<1.25 x ULN 
X ULN 
<1.75 x ULN 
Total bilirubin 
(Liver Function test 
a 
>= I. 1 x ULN - < 1.5 
>=1.5 x ULN -
>=2.0 x ULN -
>= 3.0: 
increase*) 
X ULN 
<2.0 x ULN 
<3.0 x ULN 
AP (ALP) 
a 
>=I. 1 x ULN - <2.0 
>=2.0 x ULN -
>=3.0x ULN -
>= 10x 
X ULN 
<3.0 x ULN 
<10 x ULN 
BUN 
a 
>=8.21 1 - <9.75 
>=9.75 - <11.625 
>= 11.625 mmol/L 
Require 
mmol/L 
mmol/L 
Total protein 
a 
>55 - <=60 g/L 
>50 - <=55 g/L 
<= 50 g/L 
NA 
Albumin 
a 
>27 - <=31 g/L 
>25 - <=27 g/L 
<= 25 g/L 
NA 
Hyperglycemia 
a 
>=5.55 - <6.1 05 
>=6.105 - <6.9375 
>=6.9375 mmol/L 
Insulin 
Glucose 
mmol/L 
mmol/L 
hyperm 
Hypoglycemia 
a 
>=3.6075 - <3.8295 
>=3.0525 - <3.6075 
>=2.4975 - <3.0525 
<2.497'. 
mmol/L 
mmol/L 
11111101/L 
eGFR (Any eGFR value >90 will be classified as 
b 
<=90 - >60 ml/min/ 
<=60 - >30 ml/min/ 
<=30 - > 15 ml/min/ 
<= 15 ff 
Grade 0) 
1.73 m2 
1.73 1112 
1.73 m2 
LDH 
d 
NA 
NA 
NA 
NA 
Document: 
Author: 
K:\AAA\Ga-PSMA-R2\VYA27826\Biostatistics\Documentation\SAP\v2.0\Ga-PSMA-R2-SAP 
 
\ 
Template No.: CS_TP _B8016 Revision 5 
Effective Date: 01 Apr201 8 
\ 
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Statistical Analysis Plan 
a) 
Graclable with Toxicity Grading Scale for Healthy Adult and Aclol, 
Volunteers Enrolled in Preventive Vaccine Clinical Study 
b) 
Graclable with Common Terminology Criteria for Adverse Events 
Version 4.03 
Laboratory parameter 
Grading 
c) 
Graclable with University of Delaware Criteria 
Scale 
(ht111://wwwl .udel.edu/mls/mclane/KMS3RR.html) 
cl) 
Not Graclable 
Markecllv Abnor 
Gracie l 
Gracie 2 
Gracie 3 
Hypercalcemia 
a 
>=2.625 - <2.75 
>=2.75 - <2.875 
>=2.875 - <3 
>= 3 l1l 
Corrected 
mmol/L 
mmol/L 
mmol/L 
Calcium 
Hypocalcemia 
a 
>=2 - <2.1 mmol/L 
>=1.875 - <2 mmol/L 
>=1.75 - <l.875 
<1 .75 11 
mmol/L 
Serum creatinine 
a 
>= 132.6 - < 150.28 
>=150.28 - <176.8 
>=176.8 - <221 
>= 221 
umol/L 
umol/L 
umol/L 
require: 
Hypernatremia 
a 
>=144 - <145 
>=145 - <147 mmol/L 
>=147 - <150 
>= )50 I 
Sodium 
mmol/L 
mmol/L 
Hyponatremia 
a 
>=132 - <134 
>=130 - <132 
>=125 - <130 
<125 Ill 
mmol/L 
mmol/L 
mmol/L 
Hyperkalemia 
a 
>=5.1 - <5.2 
>=5.2 - <5.4 mmol/L 
>=5.4 - <5.6 
>= 5.6 1 
Potassium 
mmol/L 
mmol/L 
Hypokalemia 
a 
>=3.5 - <3.6 
>=3.3 - <3.5 mmol/L 
>=3.1 - <3.3 
< 3.1 m 
mmol/L 
mmol/L 
>ULN - 10 mg/dL 
>ULN - 10 mg/dL 
Uric acid 
b 
(0.59 mmol/L) 
NA 
(0.59 mmol/L) with 
>10 mg 
without physiologic 
physiologic 
mmol/1 
consequences 
consequences 
Chloride 
d 
NA 
NA 
NA 
NA 
Hematology 
I 
RBC 
d 
NA 
NA 
NA 
NA 
Increased 
a 
>=10.8 - <15 
>= 15 - <20 10"9/L 
>=20- <25 10"9/L 
>= 251 
WBC 
10"9/L 
White blood 
Decreased 
a 
>2.5 - <=3.5 10"9/L 
> 1.5 - <=2.5 I 0"9/L 
> I - <=1.5 10"9/L 
<= I IC 
cells with 
differential 
Monocytes 
d 
NA 
NA 
NA 
NA 
Eosinophils 
a 
>=0.65 - <1.5 
>=1.5 - <5 10"9/L 
>=5 10"9/L 
Hypere 
10"9/L 
Document: 
Author: 
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\ 
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Effective Date: 01 Apr201 8 
\ 
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Statistical Analysis Plan 
a) 
Graclable with Toxicity Grading Scale for Healthy Adult and Aclol, 
Volunteers Enrolled in Preventive Vaccine Clinical Study 
b) 
Graclable with Common Terminology Criteria for Adverse Events 
Version 4.03 
Laboratory parameter 
Gradi ng 
c) 
Graclable with University of Delaware Criteria 
Scale 
(ht111://wwwl .udel.edu/mls/mclane/KMS3RR.html) 
cl) 
Not Graclable 
Markecllv Abnor 
Gracie l 
Gracie 2 
Gracie 3 
Basophils 
d 
NA 
NA 
NA 
NA 
Lymphocytes 
a 
>0.75 - <=1 10"9/L 
>0.5 - <=0.75 10"9/L 
>0.25 - <=0.5 
<= 0.25 
10"9/L 
Neutrophils 
a 
> 1.5 - <=2 10"9/L 
> 1 - <= 1.5 10"9/L 
>0.5 - <= 1 10"9/L 
<= 0.5 
Platelets 
a 
>125 - <=140 
10"9/L 
> 100 - <=125 10"9/L 
>25 - <=100 10"9/L 
<= 25 1 
(Male) - gm/dl 
a 
> 12.5 - <=13.5 
> 10.5 - <=12.5 
>8.5 - <=10.5 
<= 8.5 
Hb 
(Male) change from 
baseline value - gm/dl 
a 
Any decrease - > 1.5 
>=1.5 - >2.0 
>=2.0 - <5.0 
>= 5.0 
MCV 
d 
NA 
NA 
NA 
NA 
Hematocrit 
d 
NA 
NA 
NA 
NA 
PSA 
d 
NA 
NA 
NA 
NA 
Urinalysis 
I 
Appearance 
d 
NA 
NA 
NA 
Color 
b 
Discoloration 
NA 
NA 
pH 
d 
NA 
NA 
NA 
Specific gravity 
d 
NA 
NA 
NA 
Glucose 
a 
Trace 
1+ 
2+ 
Hospita 
hypergl 
Occult blood 
d 
NA 
NA 
NA 
RBC/hpf 
WBC/hpf 
Casts/I pf 
>= 50 and/or gross 
Hospita 
a 
>=l - <10 
>=10 - <50 
packed 
blood 
(PRBC) 
C 
NA 
NA 
NA 
NA 
C 
NA 
NA 
NA 
NA 
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Effective Date: 01 Apr2018 
\ 
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Statistical Analysis Plan 
a) 
Graclable with Toxicity Grading Scale for Healthy Adult and Aclol, 
Volunteers Enrolled in Preventive Vaccine Clinical Study 
b) 
Graclable with Common Terminology Criteria for Adverse Events 
Version 4.03 
Laboratory parameter 
Grading 
c) 
Graclable with University of Delaware Criteria 
Scale 
(ht111://wwwl .udel.edu/mls/mclane/KMS3RR.html) 
cl) 
Not Graclable 
Markecllv Abnor 
Gracie l 
Gracie 2 
Gracie 3 
Protein (dipstick test accepted) 
a 
Trace 
I+ 
2+ 
Hospita 
dialysis 
* This is not specified in FDA guidance. Therefore, we take as reference to the Hy's Law criteria for potential 
Function parameters to be taken in to account are Aspartate transaminase (AST) and Alanine transaminase (Al 
Document: 
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Statistical Analysis Plan 
APPENDIX 4. VITAL SIGNS MEASUREMENTS 
Gradable with Toxicity Grading Scale for Healthy Adult and Adolescent \ 
Grading 
Preventive Vaccine Clinical Study 
Vital Sign parameter 
Gradable with Common Terminology Criteria for Adverse Events (CTCAE 
Scale 
Markedly Abnormal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
>=38.0 - <38.S 
>=38.5 - <39 °C 
Temperature (0C), considering 
oc 
>=101.1- <102.0 
>=39.0 - <40 °( 
>= 40 °( 
that °C = (°F - 32) / 1,8 
a 
>=100.4-
>=102.0 - <104 °F 
>= 104 °F 
<101.1 °F 
OF 
Respiratory Rate (resp/min) 
a 
>=17-<20 
>=20- <25 
>= 25 
Intubation 
Weight gain 
b 
>=5 - <10% 
>=10 - <20% 
>=20% from 
from baseline 
from baseline 
baseline 
NA 
Weight 
>=5 to <10% 
>=10 to <20% 
>=20% from 
baseline; tube 
(kg) 
Weight loss 
b 
from baseline; 
from baseline; 
feeding or total 
NA 
intervention 
nutritional 
not indicated 
support indicated 
parenteral nutrition 
(TPN) indicated 
Emergency 
Heart 
Tachycardia 
a 
>=101-<115 
>=115- <130 
>= 130 
visit or hos 
Rate 
for arrhyth 
(bpm) 
Emergency 
Bradycardia 
a 
>50-<=55 
>45 -<=50 
<= 45 
visit or hos 
for arrhyth 
Systolic 
Emergency 
Blood 
Hypertension 
>=141-<150 
>=150-<155 
>= 155 
visit or hos 
Pressure 
a 
for malignc 
(mmHg) 
hypertensi, 
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Effective Date: 01 Apr2018 
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Statistical Analysis Plan 
Gradable with Toxicity Grading Scale for Healthy Adult and Adolescent \ 
Grading 
Preventive Vaccine Clinical Study 
Vital Sign parameter 
Gradable with Common Terminology Criteria for Adverse Events (CTCAE 
Scale 
Markedly Abnormal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Emergency 
Hypotension 
a 
>85 -<=89 
>80-<=85 
<= 80 
visit or hos 
for hypote1 
Diastolic 
Emergency 
Blood 
Hypertension 
>=91- <95 
>=95-<100 
>= 100 
visit or hos 
Pressure 
a 
for maligm 
(mmHg) 
hypertensi, 
Document: 
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Statistical Analysis Plan 
APPENDIX 5. 
DOSIMETRY MEASUREMENTS 
TEST 
Organs / Lesions 
Decay corrected tissue activity 
Brain 
Heart Wall 
Kidneys 
Lacrimal Glands 
Liver 
Lungs 
Red Marrow 
Salivary Glands 
Spleen 
Thyroid 
Urinary Bladder 
Lesion 1 
... 
Lesion 10 
Percent GI excretion 
Non-decay corrected tissue activity 
Brain 
Heart Wall 
Kidneys 
Lacrimal Glands 
Liver 
Lungs 
Red Marrow 
Salivary Glands 
Spleen 
Thyroid 
Urinary Bladder 
Lesion 1 
... 
Lesion 10 
Absorbed doses 
Brain 
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Author: 
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Statistical Analysis Plan 
Heart 
Kidneys 
Lacrimal glands 
Liver 
Lungs 
Red Marrow 
Salivary glands 
Spleen 
Urinary Bladder 
Whole body dose 
Effective dose 
Lesion doses 
Lesion 1 
... 
Lesion 10 
Residence times 
Brain 
Heart 
Kidneys 
Lacrimal glands 
Liver 
Lungs 
Red marrow 
Salivary glands 
Spleen 
Thyroid 
Urinary bladder 
Remainder 
Lesion 1 
... 
Lesion 10 
Document: 
Author: 
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Statistical Analysis Plan - V2.0 - 30-Jun-2020 
Electronic Signature Manifestation 
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education, training and experience to perform 
this task) 
 
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education, training and experience to perform 
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Page 49 - Object 1000551A000000001C2C04F6 


 
Official Title: 
 
A Phase 1/2 open-label, multi-center, safety and tolerability study of a 
single dose of 68Ga-PSMA-R2 in patients with biochemical relapse (BR) 
and metastatic prostate cancer (mPCa) 
 
NCT Number: 
NCT03490032 
 
Document Date: 
 
SAP Amendment 1: 03 August 2018 
 
 
 
 
 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 1 
PK ANALYSIS 
 
Advanced Accelerator Applications International SA Study Number:  A206D-A01-001 
Protocol Version:  Version 2.2 
Protocol Date: 22 February 2018 
 
 
 Phase Plan Number:  00144186  01129004 
 
 
A Phase 1/2 open-label, multi-center, safety and tolerability study of a single 
dose of 68Ga-PSMA-R2 in patients with biochemical relapse (BR) and 
metastatic prostate cancer (mPCa) 
 
SPONSOR: 
Advanced Accelerator Applications International SA 
4 rue de la Tour de l’île 
1204 Geneva, Switzerland 
TESTING FACILITY: 
 
 
 
United States 
Page 1 of 11 


 
 Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 2 
SUMMARY OF CHANGES AND JUSTIFICATIONS 
 
SAP effective date:   03 AUG 2018 
Note:  When applicable, additions are indicated in bold underlined text and deletions are 
indicated in bold strikethrough text in the affected sections of the document. 
Item or Section(s) 
Justification 
Amendment 1 
Date: 02 OCT 2018 
Throughout Protocol 
Updated 
 study number; the wrong study number was inadvertently 
used in the original protocol. 
5.2 Corrected terminology regarding 
Phase I analysis. 
Clarified wording. 
5.2 Clarified parameter names to 
match SDTM ver. 3.2 controlled 
terminology. 
Clarified wording. 
6 Table added for reporting of 
compartmental PK parameters 
Addition of reporting of compartmental parameters. 
9.  Amendment Approval 
Changed the pharmacokineticist responsible for the phase plan and sample 
analysis. 


 
 Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 3 
TABLE OF CONTENTS 
SUMMARY OF CHANGES AND JUSTIFICATIONS .................................................................2 
1. 
INTRODUCTION ...................................................................................................................4 
2. 
OBJECTIVES ..........................................................................................................................4 
3. 
EXPERIMENTAL DESIGN ...................................................................................................4 
3.1. 
Overall Study Design and Plan ......................................................................................4 
3.2. 
Planned Pharmacokinetics Sampling Schedule .............................................................5 
4. 
GENERAL REPORTING SPECIFICATION: .......................................................................5 
4.1. 
Analyses to be Performed ..............................................................................................5 
4.2. 
Template and Guidelines to be Followed ......................................................................5 
4.3. 
Statistical Methods Planned ...........................................................................................5 
4.4. 
Software Description .....................................................................................................6 
5. 
EVALUATIONS: ....................................................................................................................6 
6. 
TABLES AND FIGURES .......................................................................................................9 
7. 
QUALITY ASSURANCE .....................................................................................................10 
8. 
REPORTS ..............................................................................................................................10 
9. 
AMENDMENT APPROVAL ...............................................................................................11 
 
 


 
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AAA Study No.:  A206D-A01-001 
 
Page 4 
1.   INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting of pharmacokinetic (PK) data collected under Advanced Accelerator Applications 
International SA (AAA) protocol Number:  A206D-A01-001.   
This SAP should be read in conjunction with the study protocol and all applicable Statistical 
Analysis Plans and/or Workplans for the study. This version of the plan has been developed 
using the protocol document Version 2.2 dated 22 February 2018. Any further changes to the 
protocol may require updates to the SAP.  Any deviation from this analysis plan will be 
described in detail in the clinical report. An overall final report of pharmacokinetic data will be 
prepared and provided by 
.  
2.   OBJECTIVES 
The objectives of this study are as follows: 
Primary Objective: 
 To assess safety and tolerability of a single administration of 3 mega Becquerel 
(MBq)/kg, but not less than 150 MBq and not more than 250 MBq, of 68Ga-PSMA-R2. 
 
Secondary Objective: 
 To assess the pharmacokinetics (PK), biodistribution, and dosimetry of 68Ga-PSMA-R2. 
 To establish the optimal imaging method for determining location and burden of positive 
lesions on 68Ga-PSMA-R2 positron emission tomography (PET) imaging in patients in 
comparison with lesions identified with conventional imaging scans (computed tomography 
(CT)/magnetic resonance imaging (MRI) and bone scan), and to calculate the agreement of 
68Ga-PSMA-R2 PET with conventional anatomical/functional imaging on a per patient basis. 
3.   EXPERIMENTAL DESIGN 
3.1.   Overall Study Design and Plan  
This study is an open label, multi-center, single dose, safety and tolerability study of a diagnostic 
radio-pharmaceutical, in subjects with prostate cancer in biochemical relapse and metastatic 
prostate cancer (mPCa). During Phase 1, approximately 6 subjects will enter the trial unit on the 
morning of dosing and will remain there for approximately 6 hours post-injection in order to 
assess the pharmacokinetics (PK), biodistribution vs. time, and dosimetry for critical organs. 
Serial blood and urine samples will be collected for PK characterization. 
Two groups of up to 12 subjects will be enrolled in the second Phase. One group will consist of 
subjects with prostate cancer in biochemical relapse (PC-BR), while the other will consist of 
patients with prostate cancer in the metastatic stage (MPs). If preliminary data analysis from the 
Phase-1 portion of the study returns sufficient data for dosimetry, all Phase-II subjects will have 


 
Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 5 
PET-imaging reduced to 2 whole body scans within the optimal time frame, and blood and urine 
sampling will be omitted. 
Subjects enrolled in the dosimetry set of Phase 1, will enter the trial unit on the morning of the 
exam. Patients will receive a single dose of 3 MBq/kg, (≥ 150 and ≤ 250 MBq), of 68Ga-PSMA-
R2. The product will be prepared prior to administration and injected intravenously and each 
patient will undergo a dosimetry study based on a series of PET/CT images.  
3.2.   Planned Pharmacokinetics Sampling Schedule  
 
Whole blood samples (1 mL in heparinized tubes) will be collected from each of 6 
patients during Phase 1 immediately before administration of 68Ga-PSMA-R2 from the 
opposite arm of drug injection and then at the following approximate time-points 
following injection: 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, and 6 h 
 
Total urine excreted from each of 6 patients during Phase 1 will be collected pre-injection 
and as follows post-injection: 0-20 min, 20 min – 1 h, 1 h – 2 h, 2 h -4 h and 4 h – 6 h. 
4.   GENERAL REPORTING SPECIFICATION:  
4.1.   Analyses to be Performed 
Listings, tables, and graphs that summarize 68Ga-PSMA-R2 whole blood concentrations and 
pharmacokinetic parameters (as applicable) and 68Ga-PSMA-R2 urine recovery will be created 
by 
.  The data will be compiled into a final pharmacokinetic (PK) report.     
4.2.   Template and Guidelines to be Followed 
Reporting methods generally follow FDA guidelines for clinical data analysis and reporting. 
4.3.   Statistical Methods Planned 
No formal statistical analysis beyond descriptive statistics is planned.  Descriptive statistics will 
include number of observations (N), mean, standard error, geometric mean, %CV geometric 
mean (coefficient of variation of the geometric mean) calculation, median, min, and max for 
each parameter, where appropriate. 
Blood radioactivity data will be converted into mass concentration data (e.g. ng/mL), considering 
the specific radioactivity of the product and its radioactive decay.  Individual whole blood 
concentrations will be sorted by dose and subject number and summarized with descriptive 
statistics using protocol-specified sampling times.  Individual pharmacokinetic parameters will 
be listed by subject number and summarized with descriptive statistics.  Both individual and 
geometric mean profiles of whole blood concentrations of 68Ga-PSMA-R2 will be presented 
graphically using protocol-specified sampling times.  For all analyses, actual blood sampling 
times will be used in the in the calculation of individual pharmacokinetic parameters.   


 
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AAA Study No.:  A206D-A01-001 
 
Page 6 
Missing data will not be imputed except for: 
 Tabulation of whole blood concentration data, where concentrations that are below the limit 
of quantification (BLQ) will be treated as zero. 
 Calculation of PK parameters, where BLQ concentrations will be treated as zero.  
 Embedded (i.e., BLQ concentrations bracketed by quantifiable data, in a series of 
concentration measurements constituting a reasonable profile) and/or terminal (after the last 
measureable concentration) BLQ concentrations will be treated as ’missing’.  
Unscheduled measurements will be listed in the individual data listings. Unscheduled 
measurements will be excluded from the descriptive statistical analysis. 
4.4.   Software Description 
The following software maintained at 
 will be used for the analysis: 
 Phoenix® WinNonlin® 6.4 for descriptive statistics calculations and non-compartmental analysis 
and generation of resulting tables.  Phoenix WinNonlin 6.4 has been fully validated in the 
operational environment at 
. 
 Graphical presentations may be performed using Prism® for Windows, version 5.04. 
 Microsoft Excel spreadsheets may be utilized for reporting of interim summary results. 
 Final parameter results will be provided in Microsoft Excel spreadsheets and/or SAS transport 
files.  Specification documents will be provided as appropriate. 
5.   EVALUATIONS: 
5.1.   General Considerations (Controls, Data Rounding, etc.): 
Summary statistics will be presented with the same precision as the original data.  Percentages 
will be presented with one decimal place.  Concentrations reported as below the lower limit of 
quantitation (BLQ) will be set equal to zero for the purpose of analysis.  All data will be included 
in the analysis with the exceptions noted earlier, unless instructions are provided by the Principal 
Investigator or Bioanalyst to exclude certain data points for cause, e.g. problems during sampling 
or analysis or some other protocol deviation. 
5.2.   Non-compartmental Pharmacokinetic Endpoints and Method of Calculation: 
Data for individual subjects will be analyzed using non-compartmental methods. The whole 
blood PK parameters will be estimated from the whole blood concentration-time profiles for all 
subjects included in the PK analysis set using Phoenix WinNonlin Version 6.4. Actual blood 
sampling times will be used in the final analyses.  Protocol-specified times may be used for 
interim PHASE I analyses and actual times will be used for Final Analysis.  


 
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AAA Study No.:  A206D-A01-001 
 
Page 7 
In the pharmacokinetic parameter calculations, BLQ concentrations will be treated as zero except 
for embedded (i.e., BLQ concentrations bracketed by quantifiable data, in a series of 
concentration measurements constituting a reasonable profile) and/or terminal (after the last 
measureable concentration) which will be treated as “missing”. No attempt will be made to 
estimate missing PK data.  
The percentage of AUC0-inf extrapolated (%AUCextra) AUCPEO will be computed. For values 
larger than 20%, AUC0-inf AUCIFO values will be flagged, but not excluded from the 
descriptive statistics. 
The elimination rate constant (kelLAMZ) will be calculated by least squares linear regression of 
the terminal portion of the log-transformed whole blood concentration. This terminal range will 
be determined by visual inspection of the log concentration – time plots. Cmax CMAX will not be 
used for kel LAMZ determination. If adjusted R2 is lower than 0.80, the elimination rate 
constant and derived parameters will be flagged but not excluded from the descriptive statistics.  
For each PK parameter, summary statistics (including number of subjects, arithmetic mean, 
geometric mean (for Tmax TMAX no geometric mean will be calculated), SD, CV, median, Min 
and Max) will be presented. 
The following parameters for whole blood will be reported as data permits: 
CDISC coded variable names (PPTESTCD) CDISC variable names (PPTEST) CDISC definition 
AUCLST 
AUC to Last Nonzero Conc 
The area under the curve 
(AUC) from the time of 
dosing to the last 
measurable concentration. 
AUCLSTD 
AUC to Last Nonzero Conc 
Norm by Dose 
The area under the curve 
(AUC) from the time of 
dosing to the last 
measurable concentration 
divided by the dose. 
AUCIFO 
AUC Infinity Obs 
The area under the curve 
(AUC) extrapolated to 
infinity, calculated using 
the observed value of the 
last non-zero 
concentration. 
AUCPEO 
AUC %Extrapolation Obs 
The area under the curve 
(AUC) from the last 
observed non-zero 
concentration value to 
infinity as a percentage of 
the area under the curve 
extrapolated to infinity. 
CMAX 
Max Conc 
The maximum 
concentration occurring at 
Tmax. 


 
 Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 8 
TMAX 
Time of CMAX 
The time of maximum 
observed concentration 
sampled during a dosing 
interval. 
CLO 
Total CL Obs 
The total body clearance 
for intravascular 
administration, calculated 
using the observed value 
of the last non-zero 
concentration. 
RENALCL 
Renal CL 
The clearance of a 
substance from the blood 
by the kidneys. 
VSSO 
Vol Dist Steady State Obs 
The volume of distribution 
at steady state based on 
the observed CLST for a 
substance administered 
by intravascular dosing. 
VZO 
Vz Obs 
The volume of distribution 
associated with the 
terminal slope following 
intravascular 
administration, calculated 
using the observed value 
of the last non-zero 
concentration. 
LAMZHL 
Half-Life Lambda z 
Terminal half-life. 
MRTIVIFO 
MRT Intravasc Infinity Obs 
The mean residence time 
(MRT) extrapolated to 
infinity for a substance 
administered by 
intravascular dosing, 
calculated using the 
observed value of the last 
non-zero concentration. 
LAMZ 
Lambda z 
The first order rate 
constant associated with 
the terminal (log-linear) 
portion of the curve. 
 
 Cmax:  maximum whole blood concentration observed 
 Tmax:  Observed time of Cmax 
 AUC(0-t):  area under the concentration-time curve between the time of dose and the last 
measurable time point. 
 AUC(0-t)/D:  area under the concentration-time curve between the time of dose and the last 
measurable time point divided by the dose. 


 
 Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 9 
 λz (Kel):  terminal elimination rate constant, determined by linear regression of the terminal 
points of the log-linear whole blood concentration-time curve 
 T1/2:  elimination half-life, defined as 0.693/λz 
 AUCinf:  total AUC up to the last measurable concentration plus the AUC extrapolated from 
the last measurable concentration (Clast at tlast) to infinity:  AUC(0-t) +Clast/λz 
 %AUCextrap:  the percentage of AUC0-inf that is extrapolated beyond the last measurable 
concentration: (AUC0-inf – AUC0-t)/AUC0-inf *100% 
 MRT: the mean residence time of 68Ga-PSMA-R2 
 CL:  clearance; calculated as 68Ga-PSMA-R2 Dose/AUC0-inf  
 Vd:  volume of distribution at steady-state; calculated as Mean Residence Time*CL 
 Vz : volume of distribution during the terminal phase  
 
Total recovery of 68Ga-PSMA-R2 in urine will be calculated as well as percent of dose excreted.  
Renal Cl RENAL CL of 68Ga-PSMA-R2 will be estimated as data permit. 
Additional parameters will be calculated automatically by Phoenix WinNonlin 6.4 and 
maintained in the raw data.  These additional parameters may be reported at the discretion of the 
Sponsor and the pharmacokineticist. 
5.3.   Compartmental Pharmacokinetic Endpoints and Method of Calculation: 
For compartmental analysis, an appropriate compartmental model (e.g. a 1 or 2 compartment 
model) will be fit to the whole blood-concentration time profile using appropriate weighting. 
The final compartmental model used to fit the data will be determined as the model that fits the 
data best.  Criteria used to assess the data fit criteria such as visual interrogation of predicted 
verses observed profiles, correlation coefficient closest to 1.00, and residual Y versus X plots 
that show residual closest to 0 with no obvious positive or negative bias.  Comparisons of 
different models and weighting schemes may also be evaluated using the Akaike Information 
criterion (AIC) with the model with the lowest AIC chosen as the best fit.  The parameters to be 
reported based on the compartmental fit will be determined by the actual model used for the fit. 
In the event that the data is not sufficient for fitting of a model, only parameters from the non-
compartmental analysis will be reported.   
6.   TABLES AND FIGURES 
 Table 1:  Summary PK parameters (NCA) 
 Table 2:  Individual and Mean 68Ga-PSMA-R2 Whole Blood Concentration Versus Time 
 Table 3:  Individual PK Parameters (NCA) 
 Table 4:  Individual and Mean PK Parameters (Compartmental) 
 Table 45:  Individual PK Parameters (Compartmental) 


 
 Phase Plan No.: 00144186 01129004  
 
 
AAA Study No.:  A206D-A01-001 
 
Page 10 
 Table 56:  Individual and Mean Concentrations of 68Ga-PSMA-R2 in Urine and Urine 
Volumes 
 Table 67:  Individual and Mean Recovery of 68Ga-PSMA-R2 in Urine and Dose Recovered at 
Each Interval and Cumulative  
 Figure 1:  Individual 68Ga-PSMA-R2 Whole Blood Concentration Versus Time Profiles 
Following IP Injection (linear and semi-logarithmic scale) 
 Figure 2:  Geometric Mean 68Ga-PSMA-R2 Whole Blood Concentration Versus Time 
Profiles Following IP Injection (linear and semi-logarithmic scale) 
 Figure 3:  Individual and Geometric Mean Cmax CMAX Versus 68Ga-PSMA-R2 Dose 
 Figure 4:  Individual and Geometric Mean AUC(0-t) AUCLST Versus 68Ga-PSMA-R2 Dose 
 
Other Tables and Figures may be added at the discretion of the Sponsor and pharmacokineticist 
7.   QUALITY ASSURANCE 
The study will be audited by 
 Quality Assurance (QA) in accordance with SOP 
QA-001 while in progress to assure compliance with applicable Good Laboratory Practice 
regulations, adherence to the protocol and amendments, if any, and to 
 SOPs.   
8.   REPORTS 
There will be a final report generated for this study.  


9. AMENDMENT APPROVAL
Sponsor approval received via e-mail on 26 Sep 2018.
AJ^^^y O^OUTUl'Y
^r Thomas, PhD^ Date
haA ^{ _DM^US)^
 Maho
ey, BS l ^ Date
ver Phase Plan No.: 00144186 01129004 AAA Study No.: A206D-AO 1-001
Page 11