Clinical trial NCT03042312
Conditions: Metastatic Castration Resistant Prostate Cancer
Sponsor: Endocyte
Start date: 2017-07-12; Completion date: 2020-01-15
Enrollment: 71 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer.

Detailed description:
Upon inclusion patients were randomized in a 1:1 ratio into two treatment doses. Radioligand therapy (RLT) were performed by repeated intravenous (i.v.) injection of 6.0 gigabecquerel (GBq) (+/- 10%) or 7.4 GBq (+/- 10%) 177Lu-PSMA-617 every 8+/- 1 weeks until reaching four cycles or threshold maximum dose to the kidneys of 23 Gray (Gy). All doses after labeling were presented in buffered solution for i.v. injection.

In the initial plan for the study design a total of 200 patients with histologically proven prostate cancer and metastatic castration-resistant prostate cancer (mCRPC) were to be enrolled, however due to early stopping of enrollment only 71 patients were enrolled at time of data base lock. Each patient underwent a screening visit within 14 days prior to receiving study drug. Treatment was continued until either of the following conditions applied:

* Prostate-specific antigen (PSA)/radiographic progression at \>= 12 weeks
* Completion of four RLT cycles
* 23 Gy kidney dose would be exceeded by the next cycle as estimated by dosimetry
* Patient withdrawal (e.g. appearance of intolerable adverse events).

Arms: arm 1: Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry arm 2: Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Interventions: intervention 1: 177Lu-PSMA-617
Intervention descriptions: intervention 1: Lutetium (177Lu) -DOTA (1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid )-PSMA has three components: PSMA is the targeting vector , DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid) is a radiometal chelator and a linking group, and 177Lu is the beta emitter that upon internalization delivers radiation to the nucleus of tumor cells to cause DNA damage. The targeting vector utilizes glu-urea-lys sequence which is an inhibitor capable of binding to the domain of PSMA. These components have been previously used in human subjects and in medical research.

Protocol documents:
Prot_000.pdf: 
e' 
END:QCYTE 
PROTOCOL NO. PSMA-617-02: 
PSMA-DIRECTED ENDORADIOTHERAPY OF CASTRATION-RESISTANT PROSTATE 
CANCER (RESIST-PC). A PHASE II CLINICAL TRIAL 
Approval: 
Clinical Protocol No.: PSMA-617-02 
CT.gov Study Number NCT03042312 
IND No.: 133661 
Phase of Study: Phase II 
Investigational Products: 
171,u- PSMA-617 
Sponsor: Endocyte, Inc. 
3000 Kent Avenue - Suite Al-100 
West Lafayette, Indiana 47906-1075 
(765) 463-7175
Medical Monitor: 
, M.D., M.H.S., M.Sc. 
Endocyte, Inc. 
8910 Purdue Road, Suite 250 
Indianapolis, Indiana 46268 
Version 1.0 28 December 2016 
Version 2.0 07 June 2017 
Version 3.0 29 June 2017 
Version 4.0 18 September 2017 
Version 5.0 01 June 2018 
[signed electronically in MasterControl] 
Medical, Monitor Sign.ature 
Date 
Confidentiality Statement 
By accepting receipt of this document, you (recipient) agree not to disclose the contents (in whole or in part), directly or indirectly, by any 
means except as authorized in writing by the owner, Endocyte, Inc. This document contains commercial and proprietary, or privileged, 
information and trade secrets that may not be disclosed by recipient unless such disclosure is required by federal or state law, and then only to 
the extent required by law, or allowed by Endocyte. Recipient will restrict access to this protected information only to those employees of 
recipient who are required to consider this information for purposes of your interactions with Endocyte. Recipient will talce all steps necessary 
to ensure that these employees protect the information contained herein and do not disclose it to others. Recipient will ensure that each of its 
employees to whom this information is disclosed is told of its protected status and that all St!Ch employees agree not to disclose the information 
to any unauthorized person or entity. These disclosure restrictions apply equally to all related future information supplied to you, which Endocyte 
indicates as privileged or confidential. 
.------. 
t 


SYNOPSIS 
Sponsor: 
Endocyte, Inc. 
3QO0 Kent Avenue - Suite Al-100 
West Lafayette, Indiana 4 7906-10758 
(765) 463-7175 
Name of Finished Product: 
177Lu-PSMA-617 
PSMA-617-02 
Name of Active Ingredient: 
2-[3-(1-Carboxy-5-{3-naphthalen-2-yl-2-[(4-{[2-(4,7,10-tris-carboxymethyl-l,4,7,10-
tetraaza-cyclododec-1-yl)-acetylamino ]-methyl}-cyclohexanecarbonyl)-amino ]-
propionylamino }-pentyl)-ureido ]-pentanedioic acid 
Study Title: 
PSMA-directed endoRadiothErapy of castration-reSISTant Prostate Cancer 
(RESIST-PC). A phase II clinical trial. 
Study Number: 
NCT03042312 
Study Phase: 
Phase TI 
Primary Objective: 
To assess safety and efficacy defined as >50% decline in PSA after 177Lu-PSMA-617 
in patients with metastatic castration resistant prostate cancer 
______ 
_,_,Cnriffelential 
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Secondary Objectives for each Treatment Dose: 
1. To determine maximum PSA decline. 
2. To determine PSA progression-free survival (PFS), measured from start of 
therapy until death or PSA progression. 
3. To determine radiographic PFS, measured from start of therapy until 
death or radiographic progression using RECIST 1.1/PCWG criteria. 
4. To determine disease control rate (DCR) defined as the proportion of 
patients achieving RECIST stable disease (SD), partial response (PR) or 
complete response (CR). 
5. To determine impact on bone pain level 
6. To determine impact on quality oflife 
7. To determine impact on performance status (ECOG) 
Study Design: 
. Open-label, prospective, multicenter clinical trial. 
Study Population: 
Patients with metastatic castration resistant prostate cancer 
Inclusion Criteria: 
1. Prostate cancer proven by histopathology 
2. Unresectable metastases 
3. Progressive disease, both docetaxel naive and docetaxel treated. 
4. Castration resistant disease vvith confirmed testosterone level ~50 ng/ml 
under prior androgen deprlvation therapy (ADT) 
5. Positive 68Ga-PSMA-11 PET/CT or diagnostic 177Lu-PSMA-617 scintigraphy 
or any equivalent PSMA-directed imaging 
6. ECOG0-2 
7. Sufficient bone _marrow capacity as defined by WBC 2:2500/µl, PLT 
count2:100.000/µl, Hb2:9.9 g/dl and ANC2:1500 mm3 for the first cycle 
and 
WBC 2:2.000/µ1, PLT count 2:75.000/µ1, Hb2:8.9 g/dl and 
ANC2:1000 mm3 for the subsequent cycles· 
8. Signing of the Informed Consent Form 
9. Patients enrolling 
in this 
trial should have received either 
Enzalutamide or Abiraterone 
Exclusion Criteria: 
1. Less than 6 weeks since last myelosuppressive therapy (including 
Cpnfider.rtial 
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PSMA-617-02 
Doceta:x.el, Cabazitaxel, 223Ra, 153Sm) or other radionuclide therapy. 
2. Glomerular Filtration Rate (GFR) <40 ml/min 
----------,., Serum creatirune > I.SxULN 
4. AST and ALT> SxULN 
5. Urinary tract obstruction or marked hydronephrosis 
6. Diffuse bone marrow involvement con.finned by super-scans 
*super-scan is defmed by kidney uptake equal or below background due to diffuse 
bone involvement on staging PET/CT or scintigraphy 
Test Product; Dose; and Mode of Administration: 
Randomization into two treatment doses; radioligand therapy (RLT) by 
repeated i.v. application of 6.0 GBq (±10%, arm 1) or 7.4 GBq (±10%, arm 2) 
177Lu-PSMA-617 every 8±1 weeks; RLT until reaching four cycles. 
' 
Study Duration: 
Patients will be followed until either of the following conditions occur: 
1. 24 month after the first treatment. 
2. Progression by RECIST 1.1/PCWG criteria. 
3. Death. 
Safety Assessments: 
AE and safety assessments will be performed through the following mechanisms, also listed 
in Appendix II: 
a. Fallowing laboratory tests will be performed at baseline (within 72 hours of first treatment 
dose) and then every 2 weeks(+/- 3 days) after first dose, continued until 12 weeks after the 
last dose and then every 3 months (+/- 1 week) thereafter until the end of follow-up visits 
(24 months from 1st therapy date) or upon disease progression. The CBC and Cl\1P within 2 
weeks of each subsequent treatment cycle will be used to assess eligibility of the 
corresponding treatment cycle. 
1. Complete metabolic panel and eGFR 
2.CBC 
b. Telephone Follow-up: 7(±3) days after each treatment cycle and for follow-up phase every 
3 (±1 month) until the end of follow-up visits (24 months). 
Following conditions if in view point of investigators deemed study related, will result in 
permanent discontinuation: 
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i. Grade 3-4 non-hematologic toxicities with select exceptions for: 
1. Grade 3 fatigue < 10 days 
PSMA.-617-02 
2. Grade 3 nausea, vomiting, and diarrhea and grade 4 vomiting and diarrhea that persist 
for< 72 hours in the absence of maximum medical therapy. 
3. Asymptomatic grade 3 non-hematological laboratory abnormalities that resolve in 72 
hours. 
4. Grade 3 infections that resolve under medical treatment within 10 days 
ii. AST/ALT> 3x ULN and bilirubin > 2x ULN 
iii. Grade 4 Hematological toxicities persisting >3 weeks. 
iv. Grade 3 Hematological abnormalities that do not return to baseline for> 12 weeks. 
Data Safety Monitoring Board (DSMB) and Data Safety Monitoring Plan (DSMP): 
A Data Safety Monitoring Board (DSMB) has established and will evaluate safety 
throughout the study. The DSMB will advise the Sponsor, Investigators and investigational 
sites regarding the continuing safety of study patients and the patients yet to be recruited to 
the study as well as maintaming validity and scientific merit of the study. The DSMB will 
review ongoing examinations of safety data and promptly give recommendations to continue, 
continue with modification, or terminate the study. 
The Excel Diagnostics DSMB will serve as the lead site DSMB. At UCLA, DSMB oversight 
will be provided by JCCC Data Safety Monitoring Board (DSMB). The monitor:ing board 
will meet quarterly to review safety records including compliance with follow up visits. 
Interim safety analyses: 4 interim safety analyses will be conducted by DSMB that will be 
initiated at the time when 25%, 50%, 75% and 100% of the total 177Lu-PSMA-617 treatments 
in the trial have been completed. The DSMB will meet and assess up-to-date safety 
information within two weeks of a treatment exposure rate being achieved (i.e., the- point 
when 25%, 50%, 75% andl 00% of treatments have occurred). Further patients may only be 
- randomized two weeks after the treatment exposure rate has been reached and after a positive 
opinion from the DSMB. 
Efficacy Assessment for each treatment arm: 
Primary objective: 
12 week PSA response: Proportion of patients with PSA-decline of::::50% at 12 (±1) week 
after the first RL T [1 ]. 
Secondary objectives: 
1. Maximum PSA response: Maximal baseline to follow-up PSA decline at any time during 
or after therapy [1] 
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PSMA-617-02 
2. Time to PSA progression, for each treatment ann. [1] 
_______ a...fo.r..Fati.en:ts with PSA decline: Tune from baseline to time the PSA increases to 25% and 
,,....,....... 
2 ng/ml above nadir which is confirmed by a second value 2::3 weeks later 
b. for patients without PSA decline: Time from baseline to time the PSA increases to 25% 
and 2 ng/ml above baseline which is confirmed by a second value 2::3 weeks later 
3. Radiographic progression free survival (rPFS), for each treatment arm. 
4. Change in Pain, Quality of Life and ECOG performance score: Questionnaires will be 
completed at baseline and at 3, 6, 9, 12, 18 and 24 month, for each treatment ann 
Number of patients enrolled: 
As per statistical evaluation, total of 200 patients will be required to have statistical power 
to achieve the primary endpoints of the study. 
Date of Original Protocol: December 28th, 2016 
Date of Most Recent Protocol Amendment (if applicable): 09/18/2017 
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Table of Contents 
SYNOPSIS .....•........•.........•...........................•................•..•.•.••........•...................... : ............................•.... 2 
LIST OF APPENDICES .....................•..•.......••.......•.•........•.•..........•..........•................•.•........•..•......•........... 11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................•....•......••..•................•........ 12 
1. Introduction ...•.•..•..............•................•.....................•.......•.........•.....•.•.•.••................•...•..............•.... 15 
1.1 Background •............•.•.••.....••.••..•.........•........•.............•..•..........................................•..............•.... 15 
1.1.1. Current treatment options for metastatic castration-resistant prostate cancer: before 
docetaxel .•.............••...............••.•••....•..............•........••.........................•..•..•.....•.•.•......................... 16 
1.1.2. After docetaxel treatment ....•.....•.......•...... : ...................................••.••............•....•................ 18 
1.1.3. New and emerging developments ...•.•.•..•.••.....••.........••........••.................•................... , ....••.• 22 
1.1.4 Targeted therapies ...........•••.......•....•..••...••..•.......................................•............................•.•.. 23 
1.2 Characteristics of 177 Lu-DOTA-PSMA (177Lu-PSMA-617}., .......................................................... 25 
1.3 Background of Drug Development .•....•.•..•.....•..........•..•...•.....•................•....•.....•.•..........•........•.•. 25 
1.3.1 Preclinical Studies ................................................................................................................. 26 
1.3.2 Clinical Studies ••.•..•...............•.•.............................•••...••.........•.••.••..••••.........•....•.....•............. 28 
1.3.3 Sponsors Experiences ............................................................................................................ 34 
2. Study Objectives ...•.•.....•.•.•.•.....•••................•.........•.........•••••••...•••.•........•....•..............•.•..•................. 39 
3. lnvestigational Plan ........................................................................................................................... 40 
3.1 Overall Study Design and Dosing of Targeted PSMA Radio ligand Therapy (RLT) ............................ 40 
3.2 Rationale for Study Design .........................•...••......•..................•..•............................................... 42 
3.2.1 Rationale for a regimen with multiple therapy cycles ............................................................ 42 
3.2.2 Rationale for eight weeks interval ......................................................................................... 42 
3.2.3 Rationale for dose regimen ................................................................................................... 43 
3.2.4 Deterrnination of Sample Size ............................................................................................... 44 
3.3 Study Duration and Dates ............................................................................................................ 45 
3.4 Randomization protocol ......•................•.•..•.....................................•........•.••...........................•.... 45 
3.5 Dose modification ........................................................................................................................ 45 
4. Study Population Selection ................................................................................................................ 48 
4.1 Study Population ......................................................................................................................... 48 
4.2 Inclusion Criteria .......................................................................................................................... 49 
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4.3 Exclusion Criteria .......................•.................•....................•...... .' ••..••.....•....•........•.•...•...••.•.....•...... 49 
------;15,...., Study-T-r..eatmer:it(,_,_,_ ___________ ~~·-··-·~·"····················--··············--·········--···----
49 
5.1 Description ofTreatments{s) .....•..............•......•..................•...........••...........•..•...•.••...................... 49 
5.1.1 Study drug ...................•.....••...•......•••....•.•..••••.....•........••.•••......•..................•..............•.......... 49 
5.1.2 Pharmaceutical Properties of 177Lu-PSMA-617 ....................................................................... 51 
5.2. Treatment(s) administered ...........•.......................... : .....•...............••.•...........••.....••..................... 51 
5.3 Restrictions .................................................................................................................................. 52 
5.3.l Fluid and Food Intake ...•••..•.... : •......................................•••.•.....................•....................•....... 52 
5.3.2 Subject Activity Restriction ........•••..................•...•....................................•..•..........••..........•••. 52 
5.4 Dosing Compliance .............................•...........•...............•........................•.............................•..... 52 
5.5 Packaging and Labeling ..............•..................•...•....•..........•..•....•.•••.......................•.........•.....•...•.. 52 
5.6 Storage and Accountability ••....•••••........•••..........•.......•..................•••........•.•....•..•.........••.............. 53 
5.6.1 Storage ...........•.................•••..........••.•..................•......•..........•.•......•..................................... 53 
5.6.2 Accountability .....••..•..••••............•....•••......•....•........•.......•.........•............•••.......•.•.........•..•...... 53 
5.7 lnvestigational Product Retention at Study Site ..........................••.................•...........•.•................ 54 
6. Study Procedures ...............•.......•.•..........•..............•.•...•....••......•...•••........... .' ...................................... 54 
6.1 Informed Consent ........................................................................................................................ 54 
6.2 Mediqil History •••.......•...•....•.•...•.....•..............•......•.••.....•.••......••.•...................••..........................• 55 
6.3 Vital Signs .•.•.......•..•.•..........................•........................•.•..............•...........•...••.•..•..•..................... 55 
6.4 Dispensing Study Drug •..•••.••.....•.•......................... , ...................................................................... 55 
6.5 Clinical Laboratory Tests •........................•...•..........•..........•.••.................••.............••.........•..•......•. 55 
6.6 Sample Collection, Storage and Shipping ...................................................................................... 56 
6.7 Electrocardiogram •.•....•...•...•.•...•..•..........••.......•.•.............•................•.........••.....................•.•...... 56 
6.8 Adverse Events •.....•••••.....................................•.............•..........•......•.•..................•.••••................. 56 
6.9 Removal of Subjects from the Trial or Study Drug .............................•••...............•........................ 57 
7. Reporting Safety Information ......•.....................•......................•.............••••...•............................•....... 58 
7 .1 Adverse Events ...•••...•••.•...•..•.........•............•...............•..............•.•........•.......•....••......•...........••.... 58 
7.1.1 Definitions .....•....••.............•..........................••..•.......•.•...........•..........................................•.. 58 
7.1.2 Reporting S_erious Adverse Events ......................................................................................... 59 
7 .2 Adverse Event Data Collection .........•..................................•.•.......••..•.....•..............•.......••.••......... 61 
7.3 Clinical Significance ...•..............•.........................................•....•.........•........••...........•..........•••....... 64 
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7 .3.1 Reporting and Evaluation of Clinical Laboratory Test Results ....•.....•.••.......••.............•....•....... 64 
_______ 
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7 .3.3 Vital Signs •...............•......•...•••.•....•.••.......•.••.......•.•...•..••••.........................•...••.........•.........•... 64 
8. Study Activities ......................•••.••..........•.....••........••....•..•••.......•....•...•..•..•......•.................................. 65 
8.1 Screening Visit .•.........•..•......••......•••.......•••••.....•.•.•••.•.....•.•.•............•.•..•.................................•..... 65 
8.2 Within 2 Weeks of Screening ..........•.•.•.•... _. ...•....................•..............•.••.•.••...••..•.....•••............••.... 65 
8.3.1 Pre-dose and Dosing Procedures •••........•..............•......•.................•..••......•.......•....•............... 65 
8.3.2 Post-Dose Procedures •......•..................••...•.......•.......•.•.......••...•.....•...........•...................•...... 66 
8.3.3 ECG Procedures .•.••...••••.•.••.•••.•......•.........•..••......•.•.•..•.•...•......•.............•.....•••••.....•......•......••. 66 
8.4 Follow-up ................•....••.....•.•....••......•......................•....•....•.........•....•....•.•........•..................•...... 66 
8.4.1 PSA Measurements •.......•................•..••.....•...........•..•..•.•••.........•.••..•...•..•.............•...•....•....... 66 
8.4.2 Imaging Studies .......•....••..•.....•...•.....•.•••.•......•.•.......•..•....•..............•.....••..••....•...•.................. 66 
8.4.3 Dosimetry .••.........•.....................•.......•..•.•.••.....•.•.................•.•••..•...•........•......••.................... 67 
8.4.4 Follow-up Labs for Hematological and Kidney Toxicities .....••.••••............................................ 68 
8.4.5 Telephone Follow ups .•...........................•....................•...........••.............•..•..•..........•............ 69 
8.4.6 Longterm Follow ups .•••.••.•...••.........•..•..•....•.•............. : .•••••.......•.....•..•..•.........•..........••.......... 69 
9. Quality Control and Assurance ...•......•..............................•.....••.• .' ••••.......•......•••..•.•.........•................... 70 
10. Planned statistical methods ...••...•........•......•..........•.•................•.•••.•.•....•..•.......••...................•....•.... 71 
10.1 Primary endpoints ...............••............•............................•......•......•••........................•..•..........•.... 71 
10.2. Secondary endpoints ...........•..............................•..........•..................•....................................... 71 
11. Administrative Considerations .................•.........•...•.•.....•...•...•.•..•...••............................................... 73 
11.1 Investigators and Study Administrative Structure ....•........................................•.......•...••.•.......... 73 
11.2 Institutional Review Board ((RB) or Independent Ethics Committee (IEC) Approval... .....••••.......•. 73 
11.3 Ethical Conduct of the Study .•......•..•...•................•...••........•.............................................•••....•.. 74 
11.4 Subject Information and Consent .....•.......••.•..................••....................•.....................•.......•....... 74 
11.5 Subject Confidentiality .........•...•..•..•.•.•.................•...........•........••...........•...............••.................. 74 
11.6 Study Monitoring •.....•..•••.....•.............••........•................•.....................••..•.....•...•......•..•.............. 75 
11.6.1 Data and Safety Monitoring Plan {DSMP) ................•............••............................................. 75 
11.6.2 Monitoring ·Procedures ...•.••••..•......•......•.•.•.•...•.......•....•.•.•.......•...........•...•.••.•••...•............•.. 76 
11.6.3 Auditing ..............................•.........•..•.......••....•................•......••.•......................................... 78 
11.7 Case Report Forms and Study Records ..•.•.•••................•.......•...................•................................. 78 
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11.8 Protocol Violations/Deviations ................................................................................................... 78 
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79 
11.10 Data Generation and Analysis .................................................................................................. 79 
11.11 Retention of Data ..................................................................................................................... 79 
11.12 Financial Disclosure .................................................................................................................. 80 
11.13 Publication and Disclosure Policy .................... : ........................................................................ 80 
12. References ............................................................................................................. · ......................... 81 
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LIST OF APPENDICES 
Appendix I: Preclinical Toxicity Studies 
Appendix II: Visit Specific Schedule 
Appendix ID: Principal Investigator Signature 
Appendix VI: Dosimetry Protocol *Not applicable to previous versions 
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PSMA-617-02 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AB 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
BUN 
Blood urea nitrogen 
,,,--,,, 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
DCR 
Disease Control Rate 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GH 
Growth hormone 
,,--.... 
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-~--~ 
Hct 
Hgb 
IDPAA 
ICH 
IEC 
IND 
!RB 
ITT 
LDH 
MBq 
mCi 
mo 
GBq 
MR 
:MRI 
NIA 
NDA 
PCa 
PET/CT 
PFS 
PSA 
PR 
RBC 
G0n.ji,def.ltia 
PSMA-617-02 
Hematocrit 
Hemoglooinr-----------------------------
Health Information Portability and Accountability Act 
International Conference on Harmonisation 
Independent Ethics Committee 
Investigational New Drug 
Institutional Review Board 
Intent-to-treat 
Lactic dehydrogenase 
MegaBequerel 
milliCurie 
months 
gigabecquerel 
Magp.etic resonance 
Magnetic resonance imaging 
Not applicable 
New Drug Application 
Prostate cancer 
Positron Emission Tomography/Computed Tomography 
Progression-free survival 
Prostate-specific antigen 
Partial response 
Red blood cell 
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PSMA-617-02 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RLT 
Radioligand therapy 
.,, 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAER 
Serious adverse event report 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SE 
Standard error 
SPECT 
Single-photon emission computerized tomography 
PSMA 
Prostate-specific membrane antigen 
us 
United States 
_..--... 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
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PSMA.-617-02 
1. Introduction 
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According to the American Cancer Society more than 1 million people in the United 
States are diagnosed with cancer each year. For American males, prostate cancer is the second 
most common cause of cancer related death [2]. A recent publication [3] estimated the 
prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and 
incidence of metastatic Castration Resistant Prostate Cancer (mCRPC) as 36,100 and 42,970, 
respectively. Various therapies have been developed to improve survival of patients with 
advanced prostate cancer. However, despite such efforts currently all-cause mortality in 
prostate cancer has been estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 
19.5% of these deaths, respectively, occurring in men with mCRPC. 
Patients with metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis, 
and those patients with metastases are expected to survive :519 mo [3] . As patient disease 
progresses, quality of life deteriorates, and until recently, few treatment options were available. 
Several new therapies have shown an improvement in overall survi,val for patients with 
mCRPC who have already received chemotherapy with docetaxel (Fie:. 1) [4] [5] [6, 7] [8]. 
The impact of these new data on clinical practice, treatment sequencing, and best care for 
individu.al patients is not yet fully established. 
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Figure 1: Current, ongoing, and future landscape in the management of castration-resistant prostate cancer. 
Color key: green = US Food and Drug Administmion/European Medicines Agency (FDA/EMA) approved; light green= trial 
results in high-risk patients positive, but not approved; orange = prospective, randomized, phase 3 clinical trial completed, 
results positive, FDA/EMA approval awaited; blue = prospective, randomized, phase 3 clinical trial completed. results 
awaited; pmple = promising agent, phase 3 clinical trials ongoing. * Trial results for denusomab in high risk patients positive, 
but not approved. AA/P = abiraterone acetate with prednisone; ENZ = enzalutamide; Doc/P = docetaxel plus prednisone; 
CBZ/P = cabazitaxel plus prednisone. 
1.1.1. Current treatment options for metastatic castration-resistant prostate cancer: before 
docetaxel 
Sipuleucel-T 
Sipuleucel-T is an autologous vaccine consisting of individually collected antigen-presenting 
cells that are exposed to the fusion protein prostatic acid phosphatase and granulocyte colony-
stimulating factor (GCSF), and then reinfused in the patient at weeks 0, 2, and 4. In the 
Immunotherapy for Prostate Adenocarcinoma Treatment (IMP ACT) study, median survival 
with sipuleucel-T was 25 .8 mo compared with 21. 7 mo with placebo [9]. It has to be 
considered, however, that only patients with a good Eastern Cooperative Oncology Group 
performance status of 0-1, asymptomatic or mildly symptomatic osseous metastases, and 
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absence of visceral metastases were included in the trial. 
Abiraterone acetate 
The COU-AA-302 (Cougar 302) trial randomized 1088 men with mCRPC to receive 
abiraterone acetate with prednisone (AA/P) or placebo [4] with the primary end points of 
overall and radiographic progression-free survival (rPFS) by central review. Median overall 
survival was 35.3 mo and 27.2 mo in the AA/P group and in the placebo group, respectively 
(p = 0.01) [10]. Also, the co-primary end point ofrPFS was significantly improved in the AA/P 
group, at 16.5 mo, as compared to 8.3 mo in the placebo aim (p < 0.001). On all secondary end 
points, AA/P treatment resulted in significantly improved effects. 
Doceta:xel/prednisone 
In 2004, cytotoxic treatment with docetaxel plus prednisone (Doc/P) was the main option for 
treatment ofmCRPC based on the TAX 327 trial [11]. The median survival was 18.9 mo versus 
16.4 mo in the group of patients who received mitoxantrone/prednisone (p = 0.009), the 3-yr 
overall survival rate was 18.6% versus 13.5%, and pain response was 35% versus 22%. It has 
been shown recently that Doc/P is active in men with symptomatic mCRPC and especially in 
patients with poorly differentiated prostate cancer (PCa) (Gleason score: 8-10) [12]. 
Subsequent studies using combinations with docetaxel have not further improved the oncologic 
outcome [3]. The results of the Randomized Study Comparing Docetaxel Plus Dasatinib to 
Docetaxel Plus Placebo in Castration-Resistant Prostate Cancer (READY) and the Aflibercept 
in Combination with Docetaxel in Metastatic Androgen-Independent Prostate Cancer 
(VENICE) trial were disappointing [13] [11]. The median survival after docetaxel and 
docetaxeVdasantinib was 21.2 mo versus 21.5 mo, respectively, and the median survival after 
docetaxel versus docetaxel plus afilbercept was 21.1 mo versus 22.1 mo, respectively. 
The differences in the patient cohorts of the Cougar 302, IMPACT, and TAX 327 trials make 
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it evident that AA/P will be used for asymptomatic or mildly symptomatic mCRPC with a low 
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mCRPC and/or a high metastatic burden as well as an undifferentiated PCa. 
1.1.2. After docetaxel treatment 
Docetaxel rechallenge 
The scientific evidence of this approach results from large, retrospective series that identified 
patients who might be good candidates for re-exposure [14] [15] [16]. Patients who responded 
with a 2:30% decrease in prostate-specific antigen (PSA) level, maintained for at least 8 wk 
after first exposure to docetaxel, demonstrated a positive PSA response in about 55% to 60% 
of the cases during re-exposure without increasing treatment related toxicity. 
Abiraterone acetate plus prednisone 
AA/P versus placebo was evaluated in the Cougar 301 trial, which randomized 1195 patients 
with progressive mCRPC who failed docetaxel-based chemotherapy fil The median follow-
up in the overall study population was 12.8 mo. Overall survival was significantly improved 
from 10.9 mo in the placebo arm to 14.8 mo in the AA/Parm (p < 0.001). All secondary end 
points were met and all end points demonstrated a significantly improved benefit for the AA/P 
group. Adverse events with regard to the CYP 17 blockade were observed significantly more 
often in the AA/Parm (55% vs 43%;p < 0.001). 
Recently, Goodman et al. [17] demonstrated that AA/P is effective even in patients with liver 
or lung metastases, although to a lesser degree. The overall survival times were 12.9 mo versus 
8.3 mo in the placebo group (p = 0.022). Albiges et al. [18] described an AA withdrawal 
syndrome that developed in 32% of 66 patients who had been treate~ for a mean period of 5. 7 
mo. Clayton et aL [19] presented data from a population-based study that included 187 mCRPC 
patients with a mean PSA serum concentration of 138 ng/ml who were treated with AA/P. The 
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median overall survival was only 9 .3 mo and might reflect the oncologic efficacy of AA/P in 
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Enzalutamide (formerly MDV3100) 
Enzalutamide (ENZ) acts as an androgen receptor (AR)-signaling inhibitor, and it was 
evaluated in the Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled, 
Efficacy and Safety Study of Oral MDV3100 in Patients with Progressive Castration-Resistant 
Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial, 
which randomized 1199 mCRPC patients to receive ENZ or placebo [8]. The median follow-
up was 14.4 mo and the median overall survival was 18.4 mo and 13.6 mo (p < 0.0001) in the 
ENZ group and in the placebo group, respectively, with a 37% reduction in relative risk for 
death. All secondary end points were met with a statistically significant benefit in the ENZ 
arm. With regard to safety, the ENZ group experienced fewer grade 3/4 toxicities than the 
placebo group (53% vs 45%). The risk of seizures was slightly elevated in the ENZ group, 
with a :frequency of0.6% versus 0% in the placebo group. 
Recently, Scher et al. [20] demonstrated that the use of corticosteroids in parallel to ENZ not 
only increased grade 3/4 side effects from 34.4% to 63.3%, but it also decreased overall 
survival to a median 11.5 mo. These data suggest that one of the other second-line therapies, 
such as AAfP or cabazitaxel plus prednisone (CBZ/P), might be the drug of choice, rather than 
ENZ, in patients who need corticosteroids for the management of associated comorbidities . 
. Sternberg et al. [21] reported that ENZ is equally effective in patients aged >7 5 yr, with a 
median survival time of 18.2 mo as compared to the placebo group with 13.3 mo (p = 0.0044). 
Fleming et al. [22) identified a longer disease history (7.9 yr vs 5.9 yr), a better PSA response 
(87% vs 52%), and a lower metastatic burden associated with long-term response of 35% and 
22% after 12 mo and>l8 mo, respectively. These data seem to be important for the decision-
' 
making process about the most appropriate therapy for mCRPC patients following docetaxel 
chemotherapy. 
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Cabazitaxel plus prednisone 
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Re:fractory Metastatic Prostate Cancer (TROPIC) trial, 755 patients with mCRPC who progressed 
during or after docetaxel-based chemotherapy were prospectively randomized to 
receive CBZ/P or mitox.antrone/prednisone (MP) at 21-d intervals for 10 cycles [5]. The 
primary end point was achieved and CBZ/P treatment resulted in a median overall survival of 
15.1 mo in the CBZ/P compared to 12.7 mo in the mitox.antrone/prednisone group (hazard ratio 
[HR]: 0. 70; 95% confidence interval [CI], 0.59:--Q.83; p < 0.0001). All secondary end points of 
the trials were reached and they were in favor of CBZ. The most common side effects were 
neutropenia (CBZ/P group: 82% vs MP group: 58%), leukopenia (CBZ/P group: 68% vs MP 
group: 42%), and anemia (CBZ/P group: 11 % vs MP group: 5%). Diarrhea was the most 
common non-hematologic side effect and occurred in 6% of the CBZ/P group and <1 % of the 
MP group. 
· On ~e other hand, the German compassionate use program (CUP) included 111 patients with 
mCRPC who met the inclusion criteria of the TROPIC trial; the frequency ofneutropenia, 
leukopenia, and anemia decreased to 7.2%, 9.0%, and 4.5%, respectively [23]. Grade 3/4 
gastrointestinal toxicity was observed in only 0.9% of the patients. The most likely reason for 
the improved toxicity profile is the experience of the investigators, guideline-compliant 
application of GCSF even at cycle 1, and preventive measures with regard to the treatment of 
diarrhea. 
Recently, Heidenreich et al. [24] analyzed the European CUP, including 746 mCRPC patients, 
with regard to the frequency and management of adverse events in senior adults. In that study, 
325 (43.5%) patients were aged ?:.70 yr and 145 (19.4%) men were ?:.75 yr. The type and the 
frequency of grade 3/4 side effects did not differ significantly between the younger and the 
older patients except that the frequency of grade 3/4 neutropenia was slightly higher in the 
group of men aged ?:.75 yr (19.7% vs 15%). Furthermore, GCSF was used more often at cycle 
I (58.5% vs 47%) and throughout CBZ/P treatment (66.8% vs 58%) in the ?:.75 age group 
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versus the <70 age group. In their analysis, Heidenreich et al. [24] developed a risk model to 
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analysis. Age ?:.75 yr, cycle 1, and neutrophil count <4000/mm3 before CBZ injection were 
associated with neutropenic complications. It has to be mentioned that even in the presence of 
these risk factors, prophylactic application of GCSF significantly reduced 
neutropenic complications by 30% (odds ratio: 0.70; 95% CI, 0.50-0.99; p = 0.04). 
Bone-targeting agents 
More than 90% of patients with CRPC have bone metastases,.which are a major cause of death, 
d~ability, and decreased quality oflife, as well as increased cost of treatment [25]. Zoledronic 
acid and the receptor activator of nuclear factor KB (RANK) ligand inhibitor denosumab are 
the two US Food and Drug Administration-approved bone-targeting agents in the management 
ofCRPC [3]. 
In a phase 3 study, the median time to first on-study, skeletal-related event was 20.7 mo with 
denosumab compared with 17.1 mo with zoledronic acid (HR: 0.82; 95% CI, 0.71-0.95;p = 
0.0002 for noninferiority;p = 0.008 for superiority) [26]. In a recent, prospective, randomized, 
double-blind, placebo-controlled trial, Smith et al. [27] evaluated the therapeutic efficacy of 
denosumab 120mg every week versus placebo in• 1423 men with nonmetastatic CRPC and 
aggressive PSA kinetics (PSA level >8.0 ng/ml and/or PSA doubling time <10 mo). The 
median time to first bone metastases was significantly prolonged by 4.3 mo (29 .5 mo vs 25 .2 
mo;p = 0.028). Bone metastases-free survival was significantly improved by 16%, 23%, and 
29% in patients with a PSA doubling time of <10 mo, <6 mo, and <4 mo, respectively. 
Radium-223 
Radium-223 is a radiopharmaceutical that acts as a calcium mimic and targets new bone 
growth in and around bone metastases via heavy alpha particles that have an ultrashort range 
of <1 OOµm. A Phase 3 Study of Radium-223 Dichloride in Patients with Symptomatic 
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Hormone Refractory Prostate Cancer with Skeletal Metastases (ALSYMPCA), which included 
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223 _ compared with 11.3 mo in the placebo group (HR: 0.695; 95% CI, 0.581-0.8732;p < 
0.0001) [7]. 
1.1.3. New and emerging developments 
Agents targeting steroidogenesis 
Orteronel (I'AK.-700) selectively blocks 17,20-lyase, resulting in fewer mineralocorticoid 
· effects than AA [28]. In the phase 2 portion of a dose-finding study, Orteronel (TAK-700) 
400mg twice daily with prednisone 5mg twice daily resulted in a reduction in PSA level 2:50% 
in 52% of the 96 chemotherapy-naive mCRPC patients at 12 wk. There are two ongoing phase 
3 clinical trials in the prechemotherapy (n = 1454) and postchemotherapy (n = 1083) landscape 
of mCRPC that are evaluating the oncologic activity of orteroneL Both trials have completed 
recruitment. 
Galeterone (I'OK.-001) has combined activity: It inlnbits the human CYPl 7 enzyme, it has 
pure antagonistic activity toward the AR, and it inhibits the binding of androgens to both 
mutant and wild-type AR [29]. In the Androgen Receptor Modulation Optimized for Response 
(AMORI) trial, 49% of chemotherapy-naive mCRPC patients experienced a PSA-level 
reduction of2'.:30%, and a 2:50% reduction was ~chieved by 22% [30]. Despite the absence of 
steroid co-treatment, no adrenal mineralocorticoid excess was observed and a phase 2 trial is 
underway. 
Androgen-receptor blocking agents 
ARN-509 is a full antagonist to AR overexpression: It inhibits androgen-dependent gene 
description, and it impairs nuclear translocalization and DNA binding of AR [31 ]. Currently, 
three prospective randomized phase 3 clinical trials are underway including (1) patients with 
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high-risk and nonmetastatic CRPC, (2) treatment-naive patients with mCRPC, and (3) patients 
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frrst two groups and a 2:50% decline in PSA level was achieved in 91 % of patients with high-
risk and nonmetastatic CRPC and in 88% of treatment-naive patients with mCRPC. The most 
common side effects were tolerable fatigue and gastrointestinal events. 
ODM-201 is another antiandrogen with similar mechanisms of actions as described for ENZ 
and ARN-509 [31]. The potential advantage of ODM-201 is that it does not cross the blood-brain 
barrier and so might prevent the development of seizures. ENZ-417 6 is a novel, nucleic 
acid-based antisense oligonucleotide against AR, which results in selective and specific 
downregulation of AR m.RNA and protein. 
Heat shock proteins 
Heat shock proteins (HSPs) have been identified as AR coactivator~ and chaperone proteins 
that are increased in PCa cell lines after castration [32]. Quite recently, antisense 
oligonucleotides targeting HSP27 were evaluated in a phase 2 clinical trial including 72 
patients chemotherapy-naive mCRPC patients who received OGX-427 plus prednisone versus 
prednisone alone. At 12 wk, 71 % and 40% of the patients were progression-free after OGX-
427 or prednisone, respectively. A decline of:::50% in PSA level was observed in 50% and 
20% in the OGX-427 group and in the prednisone group, respectively. Furthermore,. 
measurable disease response occurred in 44% and 0% of the OGX-427 group and the 
prednisone group, respectively. 
1.1.4 Targeted therapies 
Cabozantinib 
Cabozantinib is another promising bone-targeting agent that inhibits both vascular endothelial 
growth factor and met proto-oncogene (hepatocyte growth factor receptor; ME'l). In a 
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prospective, randomized, placebo-controlled, phase 2 clinical trial, 171 mCRPC patients were 
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early based on the observed activity of cabozantinib. Respectively 5% and 75% of patients 
treated with cabozantimo had a confirmed partial response and stable disease. The median 
progression-free survival was 29.7 wk, 23.9 wk, and 5.9 wk for patients who were docetaxel 
naive, docetaxel pretreated, and on placebo treatment (p < 0.001), respectively. Interestingly, 
PSA changes did not correlate with the antitumor effects in bone metastases and soft-tissue 
lesions. However, patients with complete resolution (n = 14; 12%) or partial resolution (n =65; 
56%) of bone scans experienced significantly better response rates to soft-tissue metastases 
as compared to men with stable or progressing bone scans (81 % vs 61 %), and they also 
experienced longer progression-free survival rates at 6 mo (56% vs 48%, respectively). 
Cabozantinib has significant antitumor activity and a well-tolerated toxicity profile, so it might 
be well integrated into the therapeutic armamentarium to treat mCRPC. 
Targeted radionuclide Therapy 
Over the past several decades, numerous combined diagnostic and therapeutic radio ligands 
(Theranostics) were designed to target receptors on the cancer cell surface. Antibodies (whole 
or small fragments), small molecules, peptides with affinities to receptors (agonist or 
antagonist) have demonstrated in vivo efficacy for targeting cancers based on up-regulated 
antigens or receptor populations. This approach, also called radio ligand therapy (RL T), 
presents several advantages over conv~ntional chemotherapy. The expression of the antigens 
or special receptors can be identified by a diagnostic probe before exposing patients to 
therapeutic doses of these agents allowing identification of suitable subjects for therapeutic 
procedures and preventing unnecessary exposure of the patients to radiation without significant 
benefit. This approach allows the physician to select only those patients with high expression 
of the target prior to treatment. Since the unused radioactive materials are excreted from the 
body, RL Ts are generally well tolerated with no significant or generally reversible or 
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manageable side effects as has been demonstrated for 177Lu-DOTATAIB treatment in patients 
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Prostate cancer demonstrates high expression levels of prostate-specific membrane antigen 
(PSMA) on its cell surface. Thus PSMA has become a biomarker for prostate cancer [35] [36] 
and has attracted significant interest as a target for the imaging [37] [38] and therapy [39, 40]. 
In particular, development of small urea-based PSMA ligands have received significant 
interest due to their high affinity for PSMA [41] [42]. The urea-based PSMA ligands were 
modified to deliver a variety of radio-imaging nuclides for both PET and SPECT. Gallium 
(68Ga) labeled urea-based PSMA ligands have been developed as diagnostic agents and studied 
by several groups [43] [44]. More recently a Lutetium (177Lu) labeled urea based PSMA ligand 
(DOTA PSMA or PSMA 617) were evaluated in preclinical and clinical phase. Characteristics 
.-... 
of 177Lu labeled PSMA are described below. 
1.2 Characteristics of 177 Lu-DOTA-PSMA (l 77Lu-PSMA-617) 
Lutetium (177Lu)-DOTA PSMA has three components: PSMA is the targeting vector, DOTA 
(1, 4, 7, 1 O-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid) is a radiometal chelator and a 
linking group, and 177Lu is the beta emitter that upon internalization delivers radiation to the 
nucleus of tumor cells to cause DNA damage [43] [44, 45]. The targeting vector utilizes glu-
urea-lys sequence which is an inhibitor capable of binding to the domain of PSMA. These 
components have been previously used in human subjects and in medical research. 
1.3 Background of Drug Development 
There is substantial previous pre-clinical and clinical experience with 177Lu-PSMA-617 
published in peer reviewed medical literature from multiple medical centers throughout the 
world. Sponsors are relying on studies published in the peer viewed medical journals for 
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preclinical and preliminary clinical information. Summary of such reports is given below. 
1.3.1 Preclinical Studies. 
Martina Benesova et al. [46] performed a preclinical evaluation of radio labeled PSMA-617. 
PSMA-617 was synthesized by solid phase peptide synthesis. PSMA-617 can be labeled with 
177Lu and Ga-6"8. Both in vivo and vitro studies were performed using LNCaP cell lines 
expressing PSMA, PSMA-617 showed highest inhibition potency Ki= 6.91±1.32 for Lu 
complex; 6.40 ± 1.02nM for Ga complex. PSMA-617 showed higher specific internalization 
in LNCaP cells. 
Figure 2: Structure of PSMA 617. Chemical Name 2-[3-(l-Carboxy-5-{3-naphtb.alen-2-yl-2-[( 4-{[2-
(4, 7,10-tris-carboxymethyl-1,4, 7,10-tetraaza-cyclododec-1-yl)-acetylamino]-methyl}-cyclohexanecarbonyl)-
amino]-propionylamino }-pentyl.)-ureido]-pentanedioic acid. 
The i.v. administered Lu-PSMA-617 effectively cleared the blood by 1 hr. Clearance of 
radioactiviry' occurred largely through the renal system. As a result of this, the kidneys exhibited 
significant uptake 137. 2 ± 77.8% ID/g; this could be effectively blocked (0.85 ± 0.22 ¾ID/g) 
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by co-injection of P:rvIP A [2 mg/kg], a high affinity inhibitor of PSMA. At 24 hr 177Lu-PSMA-
61 9'-shows-rapid--clearance-frem--t-he-lcidae~-d-3-±-I-;J-6-%ID/-g-highli-ghting-its-PotentiaLuse..as, ____ _ 
theranostic agent. At 1 hr time point 177Lu-PSMA-617 displayed good in vivo tumor targeting 
with 11.20 ± 4.17 %ID/g. Accumulation in tumor was PSMA specific with reduction to 0.64 
±0.07 %ID lg by co injection of 2-P:rvIP A. At 24 h post injection 10.58 ± 4.50 %ID/ uptake was 
retained in the tumor tissue. For all other non-target tissues, 177Lu- PSMA-617 demonstrated 
rapid clearance. The ratio of tumor to blood was 1058; tumor to muscle was 529 at 24 hr post 
injection. These favorable pharmacokinetics are crucial for imaging and therapy. The detailed 
biodistribution results are summarized in Figure 3. 68Ga-PSMA 617 showed similar uptake in 
the LnCaP tumors (11.20::l:: 4.17 %ID/g). It also shows similar pharmacok.inetic clearance 
·profile compared with 177Lu- PSMA-617. 
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In summary authors concl~ded the present radiotracer is suitable for theranostic application in 
human prostate cancer. 
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1.3.2 Clinical Studies 
Current literature is available to evaluate 
management of patients with prostate cancers. The studies presented in this section were 
chosen based on novelty of the approach (initial report of application, variables for analys.es) 
and/or the number of patients included. 
Clemens Kratochwil et aL [177Lu]Lutetium-labelled PSMA ligand-induced remission in . 
a patient with metastatic prostate cancer. Eur J Nucl Med Mol Imaging 2015; 42:6 ;987-
988. [47] 
Study Design: First reported application of 177Lu-PSMA-617 for treatment of a patient with 
mCRPC. Patient had proven PSMA expression and PSA of 38.0 ng/ml prior to treatment and 
has received 7.4 GBq of 177Lu-DKFZ-617 in 2 cycles 3 months apart. 
Toxicity: No potential side effects were reported in this study. 
Results: After the radiotherapy 177Lu-PSMA-617, PSA level of patient decreased to 4.6 ng 
/ml. PET/CT images showed no signs of metastases lesions either shrunk or were 
undetectable. 
Conclusion: Authors are planning to conduct multicenter a clinical trial as soon as possible to 
examine clinical potential of 177Lu-PSMA-617. 
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PSMA-617-02 
Figure 4: Above Image has recently awarded as image ofYear Award and the Berson-YalowAward at the 2015 Annual 
Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) in Baltimore, USA. 
Hojjat Ahmadzadehfar et al Early side effects and first results of radioligand therapy 
with 177Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-
center study. EJNMMI Research 2015; 5:36. [48] 
Study Design: A total of 10 consecutive hormone and / or chemo refractory PCa patients with 
distant metastases and progressive disease with rising PSA levels were rec~ted in this study. 
All patients had prior history or were under therapy with enzalutamide and/or abiraterone. Four 
patients had received 223Ra-dichtochloride (1-4 cycles). All 10 patients underwent with 68Ga-
PSMA HBED-CC {68Ga-PSMA) PET /CT prior to therapy to evaluate PSMA expression. Ten 
patients were treated with range of 4.1-6.1 GBq dose of 177Lu-DKFZ-617 PSMA. All patients 
were treated with single dose of 177Lu-PSMA-617. The mean and median PSA levels prior to 
therapy were 339 .4 and 298.5 ng/ml. Complete blood chemistry, renal and liver function tests 
were performed a day before and 2 after the radiotherapy. Patients were followed via telephone . 
every week for safety assessment. 
Conjiaerrtfnl 
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Toxicity: No patient experienced any side effects immediately after injection of 177Lu-DKFZ-
6i-'7-PS-MA-:-Retevant-hematotox:icifyigrade-3-or·4j-<:>eCUITecl-1-weel6-aft-er-the-aem.mistratie ...... -----
in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a 
disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 
1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any 
hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 
3 or 4). 
Results: Eight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of 
which six experienced more than 30 % and five more than 50 %. Three patients showed a 
progressive disease according to the PSA increase. 
Conclusions: 177Lu-DKFZ-617 PSMA radiotherapy with single dose for the treatment of 
metastatic prostate cancer patients without any other therapy option is safe and seems to have 
a low early side-effect profile with evidence of positive response to the therapy according to 
PSA decline in 70 % of patients. The authors also stated 177Lu-DKFZ-617 PSMA has potential 
to exhibit suitable agent for radionuclide radiotherapy. 
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Clemens Kratochwil, et al. PSMA-targeted radionuclide therapy of metastatic 
castration-resistant prostate cancer with Lu-177 labeled PSMA-617 J Nucl Med 
March 16, 2016 [491 
Study Design: Radionuclide therapy with 177Lu-PSMA-617 was performed on 30 patients 
with PSMA positive tumors were enrolled in this study. 30 patients were treated with 1-3 
cycles of 177Lu-PSMA-617. Pharmacokinetic and radiation dosimetry was also evaluated 
during course of the study. 
Results: 21 of 30 patients showed response to therapy; for 13/30 the PSA decreased >50%. 
After 3 cycles 8/11 patients achieved a sustained PSA response (>50%) for over 24 
weeks. 177Lu-PSMA-617 showed fast renal wash out within 48 hours of injection. 
Patients showed mild nausea, fatigue and Xerostomia (<10%) over a period of time. No 
acute hematotoxicity was observed during the study. Dosimetry results revealed that 
177Lu-PSMA-617 has an exposure of 0.75 Gy/GBq for kidney 0.03 Gy/GBq red-marrow, 
1.4 Gy/GBq salivary glands and 6-22 Gy/GBq for tumour lesions. 
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PSMA-617-02 
Conclusion: Based on the results authors concluded that targeted radioligand therapy with 
_____ ...__TIL_.u..::J>SMA-617 is safe and promising therapy option for metastasized castrate 
resistant prostate cancer. 
Ahmadzadehfar H, et al. Therapeutic response and side effects of repeated radioligand 
therapy with 177Lu-SMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. 
Oncotarget. 2016 Feb 8. doi: 10.18632/oncotarget. 7245. [50] 
Study Design: Radionuclide therapy with 177Lu-PSMA-617 was performed in 24 
hormone and/or chemo-re:fractory PC patients. Forty-six cycles of 177Lu-PSMA-617 were 
performed. Side effects and response rate was assessed. 
Results: Eight weeks after the first cycle of 177Lu-PSMA-617 therapy 79.1 % experienced 
A decline in PSA-level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% 
experienced a decline in PSA relative to the baseline value. Apart from two cases of 
grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). 
Conclusion: 177Lu-PSMA-617 is a safe trea1ment option for metastatic PC patients and 
has a low toxicity profile. A positive response to therapy in terms of decline in PSA 
occurs in about 70% of patients. 
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Madhav Prasad Yadav, et al. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration 
-· 
resistant prostate cancer: safety, efficacy, and quality of life assessment. Eur J Nucl 
·Med Mol Imaging. 2016 Aug 10. [51] 
Study Design: Radionuclide therapy with 177Lu-PSMA-617 was performed in 31 patients with 
progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy. 
Patients underwent 1 to 4 cycles after a 68Ga-PS:MA-HBED-CCP ET/CT for inclusion (mean 
activity 5069 ± 1845 MBq). Hematological, kidney function, liver function tests, and serum 
PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. 
Biochemical response was assessed with trend in serum PSA levels. Metabolic response was 
assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score 
01 ASmax) analgesic score (AS), K.aranofsk:y performance status (KPS), and toxicity and 
-
response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. 
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PSMA-617-02 
----uResults:-B-iochemiea:l-resp0nse-in-terms-0f.eemplete-respoo.se-{GRJ,partial-response(E.R~, 
stable disease (SD), and progressive disease (PD) was observed in 2/31, 20/31, 3/31, and 6/31 
had, respectively. Mean VASmax and mean analgesic scores decreased from 7.5 to 3 and 2.5 
to 1.8 after therapy, respectively Mean KPS and mean ECOG performance status score 
improved from 50.32 to 65.42 after therapies, respectively. Two patients experienced grade I 
and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or 
hepatotoxicity. 
Conclusion: 177Lu-DKFZ-PSMA-617 radionuclide therapy is a safe and effective approach in 
the treatment of mCRPC patients. 
1.3.3 Sponsors Experiences 
Confoientia/ 
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l.3.3.1 Preclinical. Toxicity Studi,es 
Toe aim of study was to evaluate toxicity of PSMA-617. PSMA-617 applied once weekly by 
intravenous administration to male rats over 22 days. The animals were treated with 40, 160 
or 400 µg of PSMA-617/k.g b.w. by tail vein intravenous bolus injection on test days 1, 8, 15 
and 22. The control group was treated with physiological saline. No deaths were noted. No 
signs oflocal or systemic intolerance reactions were observed. Body weight and body weight 
gain, food intake, and drinking water consumption were not influenced. No test item-related 
changes were noted for the hematological and biochemical parameters, the urinary status, the 
eyes and optic region, the auditory acuity, the relative and absolute organ weights, and the 
myeloid: erythraid ratio. No test item-related abnormalities were noted during macroscopic 
inspection at necropsy and at histopathological examination. 
Under the test conditions of this study, the no-observ~d-adverse-effect-level (NOAEL) was 
400 µg PSMA-617 I kg b.w. administered once weekly by intravenous bolus injection. Th.is 
dose was the highest dose tested. Detailed description of this study is attached in appendix I. 
1.3.3.2 Summary of Human Studies -GermanMul.ticenter Experience 
Rahbar K, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand 
therapy in advanced prostate cancer patients. J Nucl Med. 2016 [52} 
Study design: Retrospective acquisition and pooling of data for toxicity and PSA response in 
patients after 177Lu-PSMA-617 RLT performed in Germany until July 2015 was initiated by 
the German Society ofNuclear Medicine for research purpose. The following contains a 
summary of the collected data.145 patients with metastatic castration-resistant prostate cancer 
received a median of two cycles (range 1 to 4) of 177Lu-PSMA RL T at twelve German Nuclear 
Medicine Clinics. Data on safety and efficacy were reported. Table 1 lists the administered 
177Lu-PSMA-617 activity for this study cohort. 
Table 1. Administered 177Lu-PSMA-617 activity (n = 248 RL T cycles) 
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Administered activity (GBq) 
Cycle 1 
Cycle2 
Cycle3 
Cycle 4 
< _._5-
9 
3 
0 
1 
> 3.5-4.5 
32 
14 
2 
0 
>4.5-5.5 
16 
12 
9 
0 
> 5.5-6.5 
71 
37 
14 
2 
> 6.5 
17 
8 
0 
Results: 
A. Toxicity: Nuclear medicine physicians responsible for 177Lu-PSMA RL T and subsequent 
follow-up reported potentially related or unrelated adverse events based on a standard template. 
In addition toxicity was determined by baseline and follow-up findings for serum creatinine, 
AST, ALT, white blood cell count, hemoglobin and platelet count for 121 of 145 (83%) 
patients. The follow-up period for adverse events was 2 to 30 weeks. Reported toxicity sorted 
by organ system is given in Table l. Grade 3-4 anemia occurred in 15 (10%) patients and grade 
3-4 tbrombocytopenia occurred in 5 (4%) patients. The rate of grade 3-4 events was low for 
all other categories (0 to 3 patients; 0 to 2%). 
There were fewer hematologic adverse events when compared to patients with metastatic 
castration resistant prostate cancer treated with placebo or 223Ra within the ALSYMPCA trial 
[7] (grade ::::3 anemia: 14% in the placebo and 13% in the 223Ra group; grade::: 
tbrombocytopenia: 3% in the placebo and 7% in the 223Ra group). Toxicity data thus indicate 
a favorable safety profile for RL T using 2-7 GBq 177Lu-PSMA-617 per cycle in patients with 
metastatic castration resistant prostate cancer. 
Majority of patients received 5.5-6.5 GBq (median 6.0 GBq) or>6.5 GBq (median 7.4 GBq) 
per cycle. Toxicity rates were comparably low: 9 of 71 (13%) patients with 5.5 - 6.5 GBq and 
3 of 17 (18%) patients with >6.5 GBq during the first RLT developed grade 3-4 toxicity. 
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Table 2. Adverse events after 177Lu-PSMA-617 as determined by blood tests (n=l21) or 
ph:fSician...r..epoi:ts-(.n=l 4 
Organ system 
Category 
Evaluated for N 
All grades 
Grade3-4 
Blood and 
Lymphatic disorders 
Leukopenia 
121 
48 (40%) 
4(3%) 
Anemia 
145 
50 (34%) 
15 (10%) 
Thrombocytopenia 
121 
38 (31%) 
5 (4%) 
Gastrointestinal 
disorders 
AST elevation 
121 
27 (19%) 
0(0%) 
ALT elevation 
121 
11 (8%) 
0 (0%) 
Xerostomia 
145 
11 (8%) 
0 (0%) 
Nausea 
145 
9 (6%) 
0 (0%) 
Dysgeusia 
145 
6 (4%) 
0 (0%) 
Ascites 
145 
2 (1%) 
0 (0%) 
Biliary obstruction 
145 
0 (0%) 
1 (1%) 
General disorders 
.,-., 
Fatigue 
145 
19 (13%) 
1 (1%) 
Pain 
145 
5 (3%) 
0 (0%) 
Ileus 
145 
1 (1%) 
0 (0%) 
Urinary disorders 
I 
Renal failure 
121 
14 (12%) 
0 (0%) 
Urinary tract inf. 
145 
1 (1%) 
0 (0%) 
Cardiovascular 
disorders 
Edema 
145 
2 (1%) 
0 (0%) 
Lrmg embolism 
145 
0(0%) 
3 (2%) 
Respiratory, thoracic 
and mediastinal 
disorders 
Pleural effusion 
145 
1 (1%) 
0 (0%) 
Dyspnea 
145 
1 (1%) 
0 (0%) 
Neurologic disorders 
Vertigo 
145 
1 (1%) 
0 (0%) 
Stroke 
145 
0 (0%) 
2 (1%) 
Musculoskeletal 
disorders 
Bone fracture 
145 
0 (0%) 
3 (2%) 
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PSMA.-617-02 
Efficacy 
SeriaTP"S-A levels at baseline and follow-up were tec:ordeti-for~9-of-I-4"5-patients-(-6·8%+.--------
Response was expressed as percent change in serum PSA from baseline to the lowest PSA 
level measured at follow-up (best PSA response). 
Over the entire follow-up period 45 of 99 (45%) patients demonstrated a PSA decline 2:: 50% 
and were considered biochemical responders. Any PSA decline occurred in 59 of99 (60%) 
patients (Figure 7). After the first cycle a PSA d~cline 2:: 50% occurred in 40 o~99 (40%), any 
PSA decline in 65 of 99 ( 66%) patients (Figure 8A). After the second therapy cycle of 177Lu-
PSMA-617 RLT aPSA decline 2:: 50% occurred in 35 of 61 (57%) and anyPSA decline in 44 
of 61 (72%) patients (Figure 8B). Patients receiving a third or fourth cycle of therapy showed 
a PSA decline 2:: 50% in 13 of20 (65%) and 3 of 3 (100%) patients, respectively. 
ii:;-
.;: 
""' .. 
£ .. i 
'5 
< "' 
a. 
x 
A 
100 
5;!; 
-5!l 
.. I 
... .55~---
Q;. 
,i ... 
:i: 
Figure 7. Waterfall plot of maximum PSA change (%) from baseline over total follow-up period. PSA 
increase of more than 100% was cropped due to simplification. 
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100-m:lllmi:RI-ITT:;,Ff.lDIC::------:0-=--;:S:::::S-----------, 
.. 1:, 
50 
-50 
; l ~: l i: ; 
·. 
I I' '.llf.l,lilllflllHIUt:1'11:l'IU 
: :::i!i 
-100 .__ _________________ ___, 
Patients 
Figure 8. Waterfall plots of maximum PSA change('¼) after the first cycle (A) and after the second cycle (B). PSA 
increase of more than 100'¼ was cropped due to simplification. 
Response rate was higher than the rate in patients with metastatic castration resistant prostate 
cancer treated with abiraterone (best PSA response >50% after abiraterone plus prednisone: 
43% (25 of 58) patients) [53]. Data thus indicate good efficacy for 177Lu-PSMA RLT in 
patients with metastatic castration resistant prostate cancer. Response rates were not 
significantly associated with mean activity per cycle (p=0.46) or cumulative activity after two 
cycles (p=0.22). 
2. Study Objectives 
Primary Objectives: 
I. To assess the clinical safety of 177Lu-PSMA-617 by evaluation of adverse events (AE) 
using the Common Terminology Criteria for Adverse Events (CTCAE) 
2. To assess the efficacy as defmed by proportion of patients with PSA-response of2:::50% 
decline at 12-week:s from baseline 
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Secondary Objectives: 
I. Maximum PSA response: Maximal baseline to follow-up PSA decline at any time 
during or after therapy [1] 
2. To determine the time to PSA progression, separate for treatment doses: time from 
inclusion to date until PSA progression or death.(whichever occurs first) [1] 
a. for patients with PSA decline: Time from baseline to time the PSA increase to 
25% and 2 ng/rn.1 above nadir which is confrrmed by a second value 2::3 weeks 
later 
b. for patients without PSA decline: Time from baseline to time the PSA increase 
to 25% and 2 ng/rn.1 above baseline 
3. To determine radiographic Progression-free Survival (rPFS), for each treatment dose: 
time from inclusion to date when first site of disease is found to progress or death 
(whichever occurs first) 
a. Nodal and visceral disease is evaluated on cross-sectional 'imaging using 
RECIST 1.1/PCWG criteria 
. 
b. Bone metastases are evaluated using bone scintigraphy and new lesions have to 
be confirmed on a second scan (2+2 rule) using PCWG criteria 
4. To determine. disease control rate (DCR) defined as the proportion of patients 
achieving RECIST 1.1/PCWG criteria stable disease (SD), partial response (PR) or 
complete response (CR). 
5. Change in Pain and Quality of Life: Pain and "Epic-26" Questionnaires will be 
completed at baseline and at 3, 6, 9, 12, 18 and 24 mo. Pain response will be determined 
in accordance with PCWG [1]. 
6. Change in ECOG Performance Score. 
3. Investigational Plan 
3.1 Overall Study Design and Dosing of Targeted PSMA Radioligand Therapy 
(RLT) 
This is a open-labei multicenter, prospective trial. Upon inclusion patients will be randomized 
into two treatment doses. RLT will be performed by repeated i.v. appl_ication of 6.0 GBq 
(±10%) or 7.4 GBq (±10%) 177Lu-PSMA-617 every 8±1 weeks until reaching four cycles or 
threshold maximum dose to the kidneys of23 Gy. All doses after labeling will be presented in 
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buffered solution for intravenous injection. 
In tota1;-"2oe>-subJects--with-histologicaHyproven-prostate-cancer-and-mGRPG wi-H-be-em-elled-. --·----
Salivary protection will be accomplished by applying ice pack starting 30 minutes prior to 
infusion of radiopharmaceutical and will continue for 4 hours. Subjects will be recruited at up 
to 3 Nuclear Medicine sites selected for this projeqt. Each subject will undergo a screening 
visit within 14 days prior to receiving study drug. 
Dosimetry was required to be performed in the initial versions of the study according to 
dosimetry protocol (Appendix V) provided by Prof.r. 
 
 to determine dose to the 
kidneys. Treatment was continued until either of the following conditions applied: 
• PSA/radiographic progression at ?:12 weeks as defined above 
• Completion of four RL T cycles 
• 23 Gy kidney dose would be exceeded by the next cycle as estimated by dosimetry 
• Patient withdrawal (e.g. appearance of intolerable adverse events) 
Dosimetry data for 20 patients on study (16 from UCLA and 4 from Excel Diagnostics) was 
analyzed and it was found that the permitted renal dose of 23 Gy was not exceeded in any patient 
after 4 cycles demonstrating overall favorable renal dosimetry and dosimetry is no longer 
required per protocol. (see Section 8.4.3 for additional details) 
Primary objectives of the study 
efficacy and safety. 
Efficacy is determined by PSA response rate: Patients with baseline to follow-up decline in 
tumor marker level (PSA) ?:50% at 12 (±1) week will be considered responders. 
For safety assessment, vital signs will be measured within 20 minutes before and for up to an 
hour after administration of 177Lu-PSMA-617. Blood samples will be collected for CBC and 
C:MP with eGFR at baseline (within 72 hours of first treatment dose) and then every 2 weeks 
(+/- 3 days) after first dose continued until 12 weeks after the last dose and then every 3 months 
(+/- 1 week) thereafter until the end of follow-up visits (24 months from 1st therapy date). The 
CBC and CMP within 2 weeks of each subsequent treatment cycle will be used to assess 
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eligibility of the corresponding treatment cycle. CBC will be performed every 7 days for patients 
who expenenced toxicity more than grade 1Ia.uetothissttrdy (base-d-on-Ner-ere:A:E-V-er:4J 
until recovery which is defined as grade 2 toxicity or lower. CTCAE v 4.0 will be used to 
evaluate renal toxicity. For more information, please refer to the Schedule of Events (Appendix 
ID-
3.2 Rationale for Study Design 
3.2.1 Rationale for a regimen with multiple therapy cycles 
Activity given during targeted radionuclide therapy is limited by radiation dose to healthy 
organs. Based on dosimetry radiation dose to healthy organs and subsequent maximal 
cumulative activity can be calculated. To obtain optimal safety margin maximal cumulative 
activity is not given in one treatment session but approached by application of a defined 
,_..__ 
fraction of this activity in several cycles. The administration of a standard activity over several 
treatment cycles allows for early and individual estimation of radiation dose and tolerability. 
The efficacy and safety of a sequential approach was proven in patients with 223Ra therapy for 
metastatic castration-resistant prostate cancer (mCRPC) [7] and in patients with 177Lu-
DOTATA TE tp.erapy for midgut neuroendocrine tumor (NET) [ 54] each in prospective, 
double-blind, randomized, international, and multicenter phase ID trials. Based on this 
evidence targeted PSMA Radioligand Therapy (RLT) will be performed by sequential 
applications of 177Lu-PSMA-617 with treatment-free intervals. 
3.2.2 Rationale for eight weeks interval 
Highest level of evidence for subacute adverse events after radionuclide therapy was published 
for patients with non-Hodgkin's lymphoma. Witzig et al analyzed safety and efficacy of 90Y-
Ibritumomab Tiuxetan in 73 patients in a prospective Phase ID randomized trial. Tbis study 
reports neutrophil, platelet and 
nadir approximately six weeks after application of 
the beta emitter [55]. Based on this study 177Lu-PSMA-617 RLT will be performed by 
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PSMA-617-02 
sequential applications with a treatment-free interval of eight weeks to minimize risk of 
repearea-1-7-'lDi=PSMA.··=617-tnetapy oefore-rea-chingbfo·otl-levetnad.ir:-This-scheme-is-als,A--------
supported by safety data from the phase ill NETIBR-1 trial on safety and efficacy of 177Lu-
DOTATATE in patients with midgut NET. Here 177Lu-DOTATATE was administered at 
seven to nine week intervals and rate of severe adverse events was below 10% for 115 patients 
in the treatment arm [54]. 
3.2.3 Rationale for dose regimen 
Ahmadzadehfar et al reports safety and efficacy after application of a mean activity of 6.0 GBq 
. 
-
1Z7Lu-PSMA-617 in 24 patients with mCRPC [50]. Patients were treated with up to two cycles 
of 177Lu-PSMA-617 RL T at eight week intervals. Grade 3 hematotoxicity occurred in two 
patients. No nephrotox.icity or hepatotox.icity grade 2:3 was documented. Kratochwil et al 
reports safety and efficacy after repeated application of 177Lu-PSMA-617 in 30 mCRPC 
patients [49]. 19 of 30 patients (63%) received 6.0 GBq 177Lu-PSMA-617 every two mo. One 
patient developed grade 3 anemia, one patient grade 3 thrombocytopenia. Both patients had 
diffuse pattern of bone marrow infiltration at baseline. The German Society ofNuclear 
Medicine (DGN) performed a questionnaire based survey on the use ofinLu-PSMA-617 RLT 
in December 2015. Nuclear Medicine Clinics in Germany reported compassionate use of 177Lu-
PSMA-617 RLT in 145 mCRPC patients until June 30th 2015 [52]. Majority of patients received 
5.5 -6.5 GBq (median 6.0 GBq) or >6.5 GBq (median 7.4 GBq) per cycle (Table 1) and rate of 
serious adverse events was below 20% for both subgroups. Phase ill data for 177Lu-
DOTATATE, a similar RLT for midgut NET patients, demonstrates a rate of severe adverse 
events below .10% after application of four cycles of 7.4 GBq in 115 patients [ 54]. Thus, 
present evidence indicates that repeated applications of 6.0 or 7.4 GBq 177Lu-PSMA-617 RLT 
are well tolerated with low to very low rates of serious adverse events. 
Standard activities of 6.0 and 7.4 GBq are also supported by dosimetry data available in more 
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than ten patients [56] [57]. Maximal cumulative activity is limited by the absorbed dose in 
cntical organs. Do-sittfetiyidentifies-kidney--and·sa:livary-gl-ands-as-organs-with-highes;-•t---------
absorbed dose [56] [57]. Thus maximum cumulative activity is determined by absorbed kidney 
dose. Based on earlier evidence obtained from external beam radiotherapy the maximum 
tolerable per kidney dose is generally accepted 23 Gy [58]. Dosimetry after 177Lu-PSMA-617 
application revealed absorbed doses of 0.6 Gy/GBq per kidney [56] [57]. Therefore maximum 
cumulative activity for 177Lu-PSMA-617 RL Tis considered 38.3 GBq (38.3 GBq x 0.6 
Gy/GBq = 23.0 Gy radiation dose per kidney). Both the application of four cycles of 6.0 GBq 
(total 24.0 GBq) or 7.4 GBq (total 29.6 GBq) 177Lu-PSMA-617 results in lower cumulative 
activities with acceptable safety margin. Whether either activity regimen is associated with 
longer rPFS is unknown and will be evaluated as secondary endpoint of this trial. 
Salivary glands receive highest off-target radiation dose according to dosimetry [56] [57]. 
Absorbed dose after four cycles of 6.0 or 7.4 GBq 177Lu-PSMA-617 (34.0 Gy or 41.6 Gy 
respectively) falls within the range of maximum tolerable dose reported for salivary glands in 
the literature [58] [59] [60]. Maximum tolerable dose to the bone marrow is generally accepted 
2 Gy [61]. Bone marrow dose will not exceed this limit after four cycles of 6.0 or 7.4 GBq 
177Lu-PSMA-617 [57] 
1 
3.2.4 Determination of Sample Size 
Sample size calculation was based on the primary endpoint of this protocol, i.e. baseline to 12-
week decline in tumor marker level (PSA) 2::50% [53]. Based on a recent publication [52], we 
estimate that the proportion of patients who meet the primary end point will range between 
38% and 65% for both treatment doses. We thus define the following null hypothesis: Less 
than 40% ofpati~nts will reach the endpoint after 177Lu-PSMA RL T. 177Lu-PSMA RLT would 
therefore be considered worthy of further study if 50% or more patients met the end point and 
not worthy of :further study if 40% and less achieved the end point. This rationale was adapted 
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-· ----··•··-·,.·-·-·-· 
.,· 


PSMA.-617-02 
from a single-arm study on mCRPC patients with same end point definition,_published 2010 
ini:he-JomnaI-of-elinical-0ncologyf53-]:-We-have-performea-pewer-anal:ysis-for-the-tw-0-side..,._ ____ _ 
binomial test (beta 0.2, alpha 0.95) to measure the efficacy of 177Lu-PSMA RLT. A sample 
size of200 achieves 78% power (beta 0.2) at a given alpha of0.05 to distinguish between 40% 
versus 50% response rates. The power analysis was performed by a trained Biostatistician from 
the Department of Biostatistics, University of California at Los Angeles using Power Analysis 
and Sample Size (PASS) 14 software (NCSS LLC). 
3.3 Study Duration and Dates 
The duration of subject participation will be from the time of signing informed consent through 
the 24 months post-injection visit or progression. Subjects will be deemed enrolled in the study 
once the subject signs informed consent. 
3.4 Randomization protocol 
Randomization will be performed in accordance with Vickers et al. [62]. In order to obtain 
adequate "allocation concealment'' a list_ofrandom allocations was created for patients 1 
through 200. This list will be stored at investigator's sites and will not be modified. The list will 
only be accessible for researchers or study personnel not actively involved in the recruitment 
process. 
3.5 Dose modification 
In some circumstances, it might be necessary to suspend treatment with 177Lu-PSMA-617, 
adapt the posology (ie. administer a half activity), or even definitively stop administration, 
as described in the following tables. Table 3 lists conditions, if deemed study related by the 
DS1\1B, will result in permanent discontinuation. 
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Table 3: Criteria for permanent discontinuation of treatment with 177Lu-PSMA-617 
Definitively-stop-furth·eradministrations-in·-patien·ts-who-ha:ve-eq1er-ien-eed-or-ar,~ 
at risk of anv of the followine: conditions durine: treatment: 
a) Severe heart failure (defmed as ,uade ill or IV of the NYHA classification) 
b) Hypersensitivity to the active substance or to any of the components of this 
radiopharmaceutical 
c) Grade 3 hematologic toxicities that persist> 12 weeks and Grade 4 that persist 
> 3 weeks. 
d) Grade 3 renal toxicity as determined by serum creatinine measurements 
e) AST/ALT> 3x ULN and bilirubin > 2x ULN 
f) Grade 3-4 non-hematologic toxicities with select exceptions for 
- Grade 3 fatigue < 10 days 
- Grade 3 nausea, vomiting, and diarrhea and grade 4 vomiting arid diarrhoea that 
persist for < 72 hours in the absence of maximum medical therapy 
- Asymptomatic grade 3 non-hematological laboratory abnormalities that resolve in 
72hours 
- Grade 3 infections which do not improve under i.v. medication within 10 days 
In case some specific adverse reactions to 177Lu-PSMA-617 persist or reoccur, 
see Table 5 
C<Jnfidenti 
VS.0 OlJUN2018 


PSMA-617-02 
Table 4: When to suspend treatment with 177Lu-PSMA-617? 
Suspend treafiiienfwitli i.:r.:r1:;u..;PSM1\:-6~7i.n-patients-wh·o--have experienced-or-are-at-risk: 
of anv of the followin2 conditions durin2 treatment: 
Criterion 
Action 
Occurrence of an intercurrent disease ( e.g. 
Suspend administration until resolution or 
urinary tract obstruction, ... ) which according 
stabilization. Treatment can be resumed, after 
to the physician opinion could increase the 
resolution or stabilization. 
risks linked to mLu-PSMA-617 
administration. 
Resolution is defmed as grade II toxicity or 
lower. (by CTCAE) at the time of the next 
treatment 
'· .... 
Treatment can-be suspended up to 12 weeks 
after the last infusion. After that treatment 
with 177Lu-PSMA-617 must be definitively 
stopped. 
In case of some specific adverse reactions to 
See Table 5 
177Lu-PSMA-617, see Table 5 
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PSMA.-617-02 
Table 5: When to adapt 177Lu-PSMA-617 posology? 
Ao.apt inmsm=-617 posology according-to tlie following-actto-us-in-p-aiients-who-have-·i-----
resented an of the followin severe adverse reactions: 
Severe adverse reactions / Dose-modifying 
Action 
toxici 
criteria 
Anemia, thrombocytopenia or neutropenia of 
1. Suspend treatment with 177Lu-PSMA-617 
1-='--e~3...:o.;;.r.;;.su,;,;..i;_;e.;;_ri...:o.;;.r..;..C.;;_T~C.;;_AE=-4..;.. . .;;.0.__ ___ --1 2. Monitor biological parameters every 2 
Renal toxicity as defined by grade 3 toxicity 
weeks, and eventually treat appropriately if 
b serum creatinine CTCAE 4.0 
needed; in case ofrenal function impairment, 
l--''--------,--,--,...-'-----''--------1 
Liver toxicity as defined as AST and ALT 
good hydration is recommended if not 
>3xULN 
otherwise contraindicated. 
1--,;;.._.;...:;;.;;__ ____________ 
Any serious or intolerable adverse event not 
a. If the observed toxicity continues beyond 
listed in Table 2 that in the opinion of the 
12weeks after the last infusion, treatment with 
investigator, requires the subject's 
177Lu-PSMA-617 must be defmitively 
discontinuation 
stopped. 
4. Study Population Selection 
4.1 Study Population 
definitively stopped. 
b. If the observed toxicity resolves within 
12weeks after the last infusion, it is possible 
to continue treatment with 177Lu-PSMA-617 
by infusing a half activity. · 
3. Even if the half activity is well tolerated 
(ie. no DMT re-occurrence), the next 
remaining treatment administration should be 
continued with the reduced (half) activity but, 
if DMT recurs after treatment with a half 
dose, treatment with 177Lu-PSMA-617 must 
be ermanentl sto 
ed. 
It is anticipated that a total of 200 subjects will be recruited. Such a number is considered 
appropriate to achieve statistical power for the endpoints of this clinical trial. The patients will 
be recruited at up to 3 clinical sites. The dose being administered will be prepared at 
. 
 and shipped to the trial sites. 
9mrfiderztia 
e.age-48--0/-9--
vs.a 01JuN201s 


. ·r 
' 
'rl. 
PSMA-617-02 
4.2 Inclusion Criteria 
-------<I,....J,,,..L:erostate_c.ancer_pro:v:en.by_hlstopatb.olo.~---------------------
2. Unresectable metastases 
3. Progressive disease, both docetaxel/cabazitaxel naive and docetaxel/cabazitaxel 
treated~ 
4. Castration resistant disease with confirmed testosterone level :550 ng/ml under prior 
androgen deprivation therapy (ADT) 
5. Positive 68Ga-PSMA-11 PET/CT or diagnostic 177Lu-PSMA-617 scintigraphy 
or any equivalent PSMA-directed imaging 
6.ECOG0-2 
7. Sufficient bone marrow capacity as defmed by WBC ~500/µl, PLT count 
~100.000/µ1, Hb2::9.9 g/dl and AN~1500 mm3 for the first cycle and WBC ~2.000/µl, 
PLT count ~75.000/µl, Hb2::8.9 g/dl and AN~l 000 mm.3 for the subsequent cycles 
_8. Signing of the Informed Consent Form 
9. Patients enrolling in this trial should have received either enzalutamide or abiraterone. 
4.3 Exclusion Criteria 
1. Less than 6 weeks since last myelosuppressive therapy (including Docetaxel, 
Cabazitaxel, 223:Ra, 153Sm) 
2. Glomerular Filtration Rate (GFR) <40 ml/min 
3. Serum creatinine > l .5xULN; AST and ALT >5xULN 
4. Urinary tract obstruction or marked hydronephrosis 
5. Diffuse bone marrow involvement confirmed by super-scans 
5. Study Treatment(s) 
5.1 Description ofTreatments(s) 
5.1.1 Study drug 
The agent to be evaluated in the present study is 177Lu-PSMA-617. Its chemical name is 
lutetium-177-Na.-2-[3-(l-Carboxy-5-{3-naphthalen-2-yl-2-[(4-{[2-(4,7,10-tris-carboxymethyl-
=fidentiaf: 
vs.a 01JuN201s 
_____ 
,,_, ................. .. 


PSMA.-617-02 
1,4, 7, 1 0-tetraaza-cyclododec-1-yl)-acetylamino ]-methyl }-cyclohexanecarbonyl)-amino ]-
----~Pi.:..:r:..::.opionylamino }-pentyl)-ureido ]-pentanedioic acid. 
177Lu-PSMA-617 is radio labelled with carrier-free lutetium-177 (mLu), a synthetic, low-energy 
beta and gamma emitting isotope of lutetium, the last element in the lanthanide series of metallic 
elements. Carrier-free ·177Lu is generated by neutron irradiation of the isotope ytterbium-17 6 
(176Yb) and subsequent fractionation of l 77Lu and l 76Yb with caution chromatography. Key 
physical characteristics of l 77Lu are summarised below: 
Physical 
Decay 
Main 
Maximum 
Main 
Half-life T1/2 
Product 
Emission (It) 
Ran2e (It) 
Emission (y) 
6.6 d 
l77Hf 
498keV 
1.7mm 
208keV 
113 keV 
The structural formula of 177Lu-PSMA-617 is shown below: 
The chemical formula of 177Lu-PSMA-617 is Lu1C49H6&N9O16. The molar weight is 1214.1 
g/mol. 
G0rif:idential 
Page.:51).jjj.. 
VS.O 01JUN2018 


5 .1.2 Pharmaceutical Properties of 177Lu-PSMA-617 
177Lu-PSMA-617 is administered intravenously. 
A description of 177Lu-PSMA-617 solution for infusion is shovm in below table: 
· Composition of 177Lu-PSMA-617 solution 
Pharmaceutically active compone:µt 
177Lu-PSMA-617 
Physical dose 
:5 7 .4 GBq / cycle 
Substance dose 
 µg PSMA-617 
PSMA-617-02 
Primary unit dose container 
20 mL glass vial containing 5 - 15 rnL of 
stabilised aqueous solution 
. 
Clear, colourless or slightly yellowish 
Appearance 
solution, without visible particles 
pH 
4.0 - 7.5 
Bac.terial endotoxin 
:5100 EU/Dose 
Radionuclidic purity 
~99.99% 
Sterility 
Sterile 
The components include 177Lu-PSMA-617, 
, and 
water for injection. The labelled drug product is produced, tested and released under GMP 
conditions by
. as a sterile solution for injection infusion, ready for use. The 
labelled drug product will be manufactured upon individual order and delivered directly to the 
study sites. 
Patients will be randomized into two treatment doses; radio ligand therapy (RL1) by repeated i.v. 
application of6.0 GBq (±10%, arm 1) or 7.4 GBq (±10%, arm 2) 177Lu-PSMA-617 every 8±1 
weeks; RL Twill be performed until reaching four cycles or threshold maximum dose to the 
kidneys of 23 Gy as determined by dosimetry, after the first treatment. 
5.2. Treatment(s) administered 
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PSMA-617-02 
Cold ice pack in the region of salivary glands will start 30 minutes prior to administration of the 
investigational drug and will continue for 4 hours. Intravenous access will be inserted in either 
arm. Assurance will be made to have reliable IV line with no evidence of extravasation or 
infiltration. Investigational drug will be infused over approximately 15-30 minutes using 
infusion pump. Patients will be monitored for any evidence of pain, or burning sensation during 
the infusion. 
5.3 Restrictions 
5.3.1 Fluid arid Food Intake 
Subjects should follow their normal diet before and after the administration of the study drug. 
Subjects should be encouraged to increase fluid intake at baseline and after each image 
acquisition to maintain proper hydration throughout the study period and decrease radiation 
exposure to the urinary bladder. There are no dietary or food restrictions for this study. 
5.3.2 Subject Activity Restriction 
There are no activity restrictions. 
5.4 Dosing Compliance 
All study drug administration will be administered under the supervision of the investigator. 
Details of study drug injection will be captured in each subject's source documents. 
5.5 Packaging and Labeling 
177Lu-PSMA-617 will be supplied in vials for injection in appropriate packaging. 
Toe outer packaging of 177Lu-PSMA-617 will contain label(s) Vvhich will include the following 
minimum information: 
• Name and address of Manufacturer Study number 
• Investigator identification 
• Name of study drug and formulation 
• Dosage strength 
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. •••- •W•-~••• • -••:•. •-•••• 
---·--- -··-- -· ---~-


PSMA-617-02 
• Batch number 
• Patient number 
• Expiry date ( or retest date) 
• Storage instructions 
• ''For Clinical Trial Use only" 
A system of medication numbering in accordance with all requirements of Good Manufacturing 
Practice (GMP) and any other applicable regulatory requirement will be used for all study drugs. 
This will ensure that for each patient, any dose of study drug can be identified and traced back to 
the original bulk ware of the active ingredients. Lists linking all numbering levels will be 
maintained by the institutions in charge of study drug packaging. 
5.6 Storage and Accountability 
5.6.l Storage 
The drug product contains radioactive material and should only be handled by personnel 
trained in the use of radioactive isotopes with proper shielding and monitoring. Receipt and 
use is limited to a facility licensed by applicable government regulations and/or local/state 
laws. Unused or residual waste should be disposed of as radioactive waste following the 
institution's standard operating procedures (SOPs) and/or applicable regulations or guidance. 
5.6.2 Accountability 
In accordance with International Conference on Harmonization (ICH) and US Food and Drug 
Administration (FDA) requirements, the investigator and/or drug dispenser must at all times 
be able to account for all study drugs :furn,ished to the institution. The appropriate site 
personnel must sign, date and immediately fornrard to the sponsor or sponsor's designee the 
packing slip for clinical shipment included with each shipment. 
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~--··········-······· 


. -,, 
PSMA-617-02 
No study drug is to be used outside of this study. The investigator or designee will record the 
use of the study drug on the appropriate Drug Accountability record. All study 
radiopharmaceuticals must be accounted for, whether used or unused, during the course of and 
at the conclusion of the study. The shipment of drugs from the sponsor or designee to the 
investigator or other designated persons cooperating with the investigator will be accompanied 
by a receipt form that indicates the lot number(s) and the amount of drug provided for the 
study. This form will be signed, dated and returned to the sponsor or designee. 
The investigator is responsible for ensuring that study drug is recorded, handled and stored 
safely and properly in accordance with ICH and applicable government regulations, local/state 
laws, and used in accordance with this protocol. 
5. 7 Investigational Product Retention at Study Site 
Unused product will be disposed of according to institutional regulations. Record the use 
and/or disposal of the study drug on the Drug Accountability record This Drug Accountability 
record should account for the receipt and disposition of all clinical supplies shipped to the 
investigator and must be available for review by the study monitor. 
6. Study Procedures 
6.1 Informed Consent 
All subjects must sign .and personally date an IRB/IEC approved informed consent form after 
receiving detailed written and verbal information about the reason, the nature and the possible 
risks associated with the administration of the study drug prior to the initiation of any study-
related procedures. This must be done according to the guidelines provided in the Declaration 
of Helsinki, ICH E6 Guideline for Good Clinical Practice (GCP) and government regulations, 
including (as applicable) the US Code of Federal Regulations Title 21 CFR 50.20 through 
50.27 . 
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PSMA.-617-02 
The subject must be made aware and agree that personal information may be reviewed during 
an audit by competent authorities and properly authorized persons. However, personal 
information will be treated as strictly confidential and will not be publicly available. A copy 
of the Informed Consent Form is attached as Exhibit. 
6.2 Medical Hi.story 
A relevant medical history and subject demographics will be obtained at the screening visit. 
Cancer medical history includes review of disease history, cancer staging, biopsy results, any 
past/present cancer therapies (e.g., hormone, drug, biologic, radiologic, or surgical treatment). 
Demographic information to be collected includes date of birth, race, ethnicity, height, and 
weight. 
6.3 Vital Signs 
Vital signs will include measurement of blood pressure,.temperature, respiratory rate, pulse 
Oximetry ( only at baseline) and heart rate. 
6.4 Dispensing Study Drug 
The estimated radioactive dose will be determined by measuring the amount of radioactivity 
in the syringe pre- and post-injection, using an appropriately calibrated radioisotope dose 
calibrator in accordance with the nuclear medicine department's SOPs. 
Any complication related to administration of the drug (e.g., overdose, observable 
) 
extravasation, medication error) is a protocol-related event and will be reported to the 
pharmacovigilance designee. Refer to Section 7 for contact information. 
6.5 Clinical Laboratory Tests 
Clinical laboratory tests will include hematology and clinical chemistry. Clinical laboratory 
analytes to be assessed in the study are shown in Table 6. Timing of collection of clinical 
______ C.Qr_ifj/feJ2,ti.qj~-----------f-a=ge~55~o,,..,.f~2.8~----------------------
-------,,--, 5':0-0:tll:IN2n-t1:i-------------------------------------
. --" 
---...,.,...,.,-,------·-----
•, 
• • -• •~• ••••A•-,-~•••~• 0 '•• 


PSMA-617-02 
laboratory tests are presented in Section 8. 
Table 6: Laboratory Analytes Assessed 
Hematolo2V 
Clinical Chemistry 
Hematocrit 
eGFR 
Hemoglobin 
Bilirubin 
RBC count 
Creatinine 
WBCcount 
Glucose 
WBC differential 
Urea nitrogen 
Platelets 
BUN/creatinine 
ANC 
AST/SGOT 
MCV /MCHIJY.{CHC 
ALT/SGPT 
Eosinophils 
Alkaline phosnhatase 
Basophils 
PSA* 
Lvmphocvtes 
RDW 
*PSA will be done only at the time intervals called by the protocol. 
6.6 Sample Collection, Storage and Shipping 
Blood samples will be collected using accepted phlebotomy techniques by trained site perso:i;mel 
All samples for clinical laboratory testing will be processed and analyzed at an accredited 
laboratory 
6. 7 Electrocardiogram 
Continuous ECG monitoring at least 15 minutes prior to administration of the study drug and up 
to at least I hour after administration will be performed during treatment cycle I and 2. Also a 
12 lead ECG will be performed at two time points: before injection ofLu-177 PSMA-617 for all 
treatment cycles and after the salivary protection is completed. 
6.8 Adverse Events 
Immediate adverse drug reactions will be collected from the time of 177Lu-PSMA-617 injection 
------=Cqnfj_dential 
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-.-.... -... -.--.-... -... -.. -----•······-······· 


_,.,.....:...... 
PSMA.-617-02 
until 24 hours post-injection visit Data will be collected for any adverse events (AEs) as 
defined in Section 7. 
All study monitoring will be performed at the primary clinical study sites in accordance with 
Good Clinical Practice (GCP). All records related to this study will be retained at each clinical 
site. Serious adverse reactions will be collected and reported to FDA and IRB according to 21 
CFR 312.32. Annual reports on the progress of the investigation and any adverse events related 
to the investigational drug will be prepared and reported to FDA according to 
21 CFR312.33. 
6.9 Removal of Subjects from the Trial or Study Drug 
The investigator may withdraw a subject from the trial for any of the following reasons: 
1. Protocol violation 
2. Serious or intolerable adverse event (that in the opinion of the investigator, requires the 
subject's discontinuation), 
3. Investigator withdraws the subject (at the investigator's discretion for reasons other 
than an adverse event), 
4. Sponsor terminates the study, 
5. Subject requests to be discontinued from the study, or 
6. Subject is lost to follow-up 
During course of the study patients have the right to withdraw their consents any time without 
need for explaining the reason of consent withdrawal to the investigator or sponsor. Principal 
investigator will closely monitor patients during the course of the study and will consider 
tepninating investigational product administration or any other trial related procedures in order 
to maintain the safety of subjects. In cases of withdrawal either in patient's favor or principal 
investigator decision due to the safety issues or technical issues, withdrawn subjects will be 
replaced in order to maintain data integrity but follow up visits will be continued to maintain 
safety of patients based on the visits predicted in the protocol. 
Confidential 
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PSMA-617-02 
7~R~p~rtin-g-S-afetyfnform~tron----------------
Any untoward medical event that occurs from the time that the subject is administered 177 Lu-
PSMA-617 until the subject completes the study will be reported. Serious adverse events and 
non-serious adverse events will be collected and reported as required under 21 CFR 31232 
until the final study visit. Toxicity will be evaluated according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
7 .1 Adverse Events 
7.1.1 Deimitions 
An adverse event (AE) is any untoward medical occurrence in a study subject that is 
administered a pharmaceutical product, at any dose, which does not necessarily have a causal 
relationship with the treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a study 
drug, w!i,ether or not considered related to the study drug. 
A serious adverse event (SAE) is any untoward medical occurrence that falls into one or more 
of the following categories: 
1. Results in death 
2. Is life-threatening: An event which, in the view of the investigator, places the subject 
at immediate risk of tleath from the event as it occurred and does not include an event 
which hypothetically might have caused death if it were more severe. 
3. Requires subject hospitalization or prolongation of existing hospitalization: For the 
seriousness criterion of subject hospitalization to apply, an overnight stay in the 
hospital is required. Admission to an emergency room and release without an 
overnight stay would not satisfy the subject hospitalization seriousness criterion. 
4. Results in persistent or significant disability/incapacity: Persistent or significant 
---------'C.orifid,t!f:Ztia.~l __________ 
~P~a=g;=e~58~o=f.~9~8 _____________________ _ 
------'\--1: s-:cront1N201:-o------------------------------------


... -, 
PSMA-617-02 
disability/incapacity is defined as a substantial disruption of a person's ability to 
conduct normal life :functions, either reported or defined as per clinical judgment. 
5. A congenital anomaly/birth defect: A congenital anomaly/birth defect is defined as a 
condition believed to have been the result of exposure to study drug just before 
conception or during pregnancy. 
6. Any other important medical event: An important medica! event may not result in 
death, be life-threatening, or require hospitalization, but based upon appropriate 
medical ju<lc,oment, the event may significantly jeopardize the subject's health or may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
serious definitions above. An important medical event may include development of 
drug dependency or drug abuse. 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. 
7.1.2, Reporting Serious Adverse Events 
Seriousness is based on subject, event outcome, or action criteria that are usually associated 
with events that pose a threat to a subject's life or functioning. Seriousness (not severity) 
serves as the guide for defining the sponsor's regulatory reporting obligations to the applicable 
regulatory authorities. Adverse event severity and seriousness should be assessed 
" 
independently by investigators. If the investigator is unsure·ifthe event is serious it should be 
classified.as serious. 
Sponsors of the study, and the investigators are responsible for reporting relevant SAEs as 
safety reports to the FDA and other applicable regulatory authorities, and participating 
investigators, in accordance with ICH guidelines, the US Code of Federal Regulations Title 21 
CFR 312.32 for Good Clinical Practice, and/or local regulatory requirements. The investigators 
must report all SAEs to project pharmacovigilance designee within 24 hours, by telephone, 
Co,rfidential 
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,--..., 
PSMA-617-02 
email or fax, and confirm that the information was received. 
A Serious Adverse Event Report (SAER) must be completed by the investigator or designee and 
faxed or emailed to project pharmacovigilance designee within 24 hours after the investigator 
first becomes aware of the serious event. A separate SAER will be needed for each reported SAE 
so that the onset, resolution date, causality and outcome can be assessed for each event. A copy 
of the source documents relevant to the event should be forwarded to sponsor's 
pharmacovigilance designee with the SAER form. The SAER form must be signed and dated by 
the investigator. If paper SAE forms are used, the original copy of the SAER form should remain 
at the investigational site. All SAEs are also to be entered into the CRF. 
In case of death, a comprehensive narrative report of the case should be prepared by the 
investigator and sent to project pharmacovigilance designee with the SAER. If an autopsy is 
performed, a copy of the· autopsy report should be actively sought by the investigator and sent 
to the sponsor or designee as soon as available. A copy of the autopsy report should remain at 
the investigational site with the subject's source documents. 
A new follow-up SAER form will be completed by the investigator jf important follow-up 
information (i.e., diagnosis, outcome, causality assessment, results of specific investigations) 
are made available after submission of the initial form. Toe follow-up SAER must be signed 
and dated by the investigator. The follow-up form and any additional source documentation 
regarding the event will be sent to project pharmacovigilance designee. 
If a serious medical·occurrence or death is reported to the investigator outside the follow up 
window which is believed .~o be related to the administration of the study drug, it is the 
investigator's responsibility to report this occurrence to project pharmacovigilance designee. 
Such occurrences will be reported using a SAER form or other form of communication deemed 
appropriate by the investigator and pharmacovigilance designee. 
Sites must contact project pharmacovigilance designee to report all SAEs within 24 hours, by 
telephone, e-mail, or fax. Contact information for SAE reporting is presented in Table 7. 
Confidential 
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-----~~~=·s-:Oi:ltil:IN201 


PSMA-617-02 
 
 
 
 
PHONE: 
 
FAX: 
 
Email: 
 
Sites must also report all overdoses, extravasations and medication errors to the project 
phannacovigilance designee. 
7.2 Adverse Event Data Collection 
The investigator will elicit information through non-leading questioning and examination of 
the subject about the occurrence of adverse events from the time that the subject is administered 
177Lu-PSMA-617 until study completion. 
AE monitoring will be performed through following mechanisms, also listed in Appendix II: 
a. Safety lab tests: CBC and CMP with eGFR will be performed at baseline (within 72 
hours of first treatment dose) and then every 2 weeks(+/- 3 days) after first dose, 
continued until 12 weeks after the last dose and then every 3 months(+/- 1 week) 
thereafter until the end of follow-up visits (24 months from 1st therapy date) or upon 
disease progression. The CBC and CMP within 2 weeks of each subsequent treatment 
cycle will be used to assess eligibility of the corresponding treatment cycle. 
b. Telephone follow up: 7 (:1:3) days after each treatment cycle and for follow-up phase, 
every 3 (±1) month until the end of follow up visits (24 months). 
-~---~ 
... c..,:~:=N-2-01:~---_-_-_-_-_-_-_-:__-_-_-_-_-:__-_-:.._-:__-"-P~age~:::-6.._J~o-fw:_!)=8..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::..:::.:::..:::..:::..:::.:::.:::..:::..:::.:::..:::..:::..:::..:::.:::.:::.= 


PSMA.-617-02 
AEs can be reported any time after study enrollment until the end of the subject's study 
participation. For each event, the following information will be recorded in the subject's source 
documents and entered into the Adverse Event CRF according to the instructions below: 
Classification of the Event as serious or non-serious: Classify the event as serious or non-
serious (see definitions in Section 7). 
Description of Signs or Symptoms: Whenever possible, record a specific diagnosis for the 
event. If a diagnosis cannot be made, then record each sign or symptom representing a distinct 
medical concept separately, (e.g. nausea and vomiting should be recorded as separate events). 
Onset Date and Time: Record the date and time the event starts. If a laboratory result is 
reported as an AE, record the start date as the date of collection of the first lab sample that 
shows the change. 
Stop Date and Time: Record the date and time the event resolves, returns to baseline, or 
resolves with sequelae. 
Grade: Refer to the common terminology criteria for adverse events (CTCAE) Version 4. 
Relationship to the Study Drug: 
We make every effort to evaluate the relationship between the study drug and the AE as 
determined by the investigator per the definitions below: 
1. Related: The event is reasonably suspected of a causal relationship to the study 
· drug. Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes 
of IND safety reporting, 'reasonable possibility' means there is evidence to 
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PSMA-617-02 
suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
ASSESSING RELATIONSHIP TO STUDY TREATMENT 
Items to be considered when assessing the relationship of an AE to the study 
treatment are: 
• Temporal relationship of the onset. of the event to the initiation of the study 
treatment; 
• The course of the event, considering especially the effect of discontinuation 
of study treatment or reintroduction of study treatment, as applicable; 
• Whether the event is known to be associated with the study treatment or 
with other similar treatments; 
• The presence of risk factors in the study subject known to increase the 
occurrence of the event; 
• The presence of non-study treatment-related factors which are known to be 
associated with the occurrence of the event. 
2. Not Related: The event is definitely due to causes separate from study drug 
administration such as: 
• documented pre-existing condition 
• technical and manual procedural problem 
• concpmitant medication 
• subject's clinical state 
______ 
C.,~==-1'il-20_1
_-o--:._-_-_-:._-_-_-_-:._-_-_-_-_-_-_-_-:._-_-_"""'P_a~ge,:___,,_6_3=--_=o_::9~'8,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::-,::--= 


3. Adverse Event Outcome: 
• Recovered/Resolved without sequelae 
• Recovered/Resolved with sequelae 
• Not Recovered/Not Resolved: event is ongoing at the end of the AE 
collection period. 
PSMA-617-02 
• Death (Fatal): the event description must be the primary cause of death. 
7.3 Clinical Significance 
7.3.1 Reporting and Evaluation of Clinical Laboratory Test Results 
The investigator should assess all clinical laboratory results for clinical significance and 
record the assessment in source documents. 
The investigator should evaluate any laboratory result change from pre- and post-study drug 
administration to determine if the change meets the definition of an AB or SAE. Record any 
clinically significant lab results determined to meet the definition of an AE and SAE on 
the AE CRF and SAER form, respectively. 
7.3.2 Repeat Testing 
Additional laboratory testing may be performed at the discretion of the investigator. 
7.3.3 Vital Signs 
The investigator should evaluate any vital sign changes pre-·and post-study drug 
administration to determine if the change meets the definition of AE or SAE. Vital sign 
measurements may be repeated at the discretion of the investigator. Record any clinically 
significant vital sign measurement that meets the definition of an AE and SAE on the 
AE CRF and SAER form, respectively. 
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PSMA.-617-02 
8. Study Activities 
Visit-specific schedule for efficacy and safety variables is presented in Appendix II. 
8.1 Screening Visit 
• Written informed consent 
• Demographic information 
• Relevant medical history 
• Prior therapy for Prostate cancer 
• Medication assessment 
• Histology 
• Vital signs 
• Questionnaires 
• Morphological and PSMA"'.ligand imaging studies ifno comparable available within 12 
weeks of treatment. 
8.2 Within 2 Weeks of Screening 
• Clinical laboratory testing (see Section 6) 
8.3.1 Pre-dose and Dosing Procedures 
• Pre-dose vital signs -within 20 minutes before dose 
• Blood tests (CBC, Clv.lP and PSA) within 72 hours of first treatment crcle 
• Apply Ice pack to the salivary glands approximately 30 minutes prior to investigational 
drug injection and continue for 4 hours. 
• Adequate hydration of the patient (IV or oral). 
• Inject study drug 177Lu-PSMA-617 
• Post-dose vital signs 
• Adverse events 
______ 
CQrifi.~JJ#sz=l __ ~-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_~P,::a_ge= _'-'6:::5:::o_f,_,9:::8:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::. 
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8.3.2 Post-Dose Procedures 
Adverse events during the entire stay. 
One post-therapy whole body scintigraphy will be performed ( optional). 
8.3.3 ECG Procedures 
PSMA-617-02 
Continuous ECG monitoring at least 15 minutes prior to administration of the study drug and up 
to at least 1 hour after administration will be performed during treatment cycle 1 and 2. Also a 
12 lead ECG will be performed at two time points: before injection of Lu-177 PSMA-617 for all 
treatment cycles and after the salivary 
protection is completed. · 
8.4 Follow-up 
8.4.1 PSA Measurements 
At baseline, then every 6 weeks during the treatment period and every 3 (±1) 
months after the last treatment until reaching endpoint or 24 month after the first 
treatment. 
8.4.2 Imaging Studies 
Baseline imaging within 12 weeks of start of therapy including (a) CT of the chest 
Preferably with contrast and CT or MRI of the Abdomen and pelvis preferably 
with contrast and (b) bone scintigraphy or ( c) equivalent to above [1]. 
Relevant imaging studies will be performed before third RLT cycle, 3 (±1) months 
after the last RLT, then every 3 (±1) months in follow-up period until reaching the 
endpoint or 24 month after the first treatment. 
At each subsequent RLT cycle visit and with every long term follow-up visit, any 
concomitant cancer-related therapy since last visit will be documented. 
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·=------· 
----~8.4.3-Dosim-etr-y.-------------------------------
Prior versions of the protocol mandated dosimetry studies aimed at assessing kidney dosimetry 
associated with the intravenous application of 177Lu-PSMA-617. 
Dosimetry data of 20 patients (16 from UCLA and 4 from Excel Houston) was analyzed and it 
was found that the renal dose limit of 23 Gy was not exceeded in any patient after 4 cycles and 
no additional on study dosimetry is required. 
Below are the individual dosimetry measurements for each patient performed during cycle #1. 
Table 8: Individual Dosimetry Measurements for Patients Performed During Cycle 1. 
Pt.# 
Activity 
Dosimetry Right 
Dosimetry Righf 
Dosimetry Left 
Dosimetry Left 
(GBq) 
Kidney (Gy/GBq) 
Kidney(Gy) 
Kidney (Gy/GBq) 
Kidney(Gy) 
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PSMA-617-02 
After an average injected activity of 6.75 ±0.81 GBq (range 5.1-8.1) the mean absorbed kidney 
dose was 0.42 ±0.17 Gy/GBq (range 0.21-0.9) corresponding to a cumulated absorbed dose of2.79 
± 1.12 Gy (range 1.37-5.61). 
These results are consistent with prior studies as shown in the following table. 
Table 9: Prior Completed Study Dosimetry Measurements 
Activity 
Activity 
mean kidney dose 
Author 
Journal 
vear 
n= 
GBa 
ran2e 
Gv/GBa 
Scarpa et al. 
Eur J Nucl Med Mol Jmaf!:inf! 
2017 
10 
6.1 
5.~.5 
0.60:1:0.36 
Yadavetal. 
NuclMedCom 
2017 
26 
2.52 
1.1-5.5 
0.99:!: 031 
Kabasakal et al. 
Mol lma!!ini; Radionucl Titer 
2017 
7 
5.2 
3.6-7.4 
0.82:1:0.25 
Fendler et al. 
Oncotarf!et 
2017 
15 
5.23 
3.7-6.0 
0.6:!:0.3 
B8llllletal. 
JNuclMed 
2016 
30 
5.76 
3.6-S.7 
0.8:1:0.4 
Delker et al. 
Eur J Nucl Med Mol ImafTinr, 
2016 
5 
3.6 
3.4-3.9 
0.6±0.2 
Furthermore the absorbed kidney dose limit of 23 Gy is an assumption derived from external beam 
radiation therapy (63) which probably does not predict renal toxicity from radionuclides. 
Correction of these data for radionuclide therapy suggested a renal absorbed biologic effective 
dose (BED) limitof37 Gy(64). 
8.4.4 Follow-up Labs for Hematological and Kidney Toxicities 
All enrolled patients will follow the scheduled follow up visits. 
Hematologic laboratory testing (CBC and C1v.1P with eGFR) will be performed 
every 2 weeks(+/- 3 days) after first dose, continued until 12 weeks after the last 
dose and then every~ months(+/- 1 month) thereafter until the end of follow-up 
visits (24 months from 1st therapy date) or upon disease progression. The CBC and 
C1v.1P within 2 weeks of each subsequent treatment cycle will be used to assess 
eligibility of the corresponding treatment cycle. CBC will be performed every 7 
______ 
_._.,,r.ifi,den ... 
tia .... l----------~P.......,agp...68..oj9_, ______________________ _ 
VS.0l>JJON2-ol:8 


days for patients who experienced toxicity more than grade II due to this study 
------Chased on NCI CTCAE Ver.4) until recovery which is defined as grade 2 toxicity 
or lower. · 
In order to detect myelodysplasia, patients who withdrawn by the investigator for 
safety reasons will only perform CBC test until the end of their follow up visits as 
long as they do not start other cytotoxic therapies. 
Patients on protocol should also have a physical exam and in-person physician 
evaluation periodically while on study and until recovery from last dose. During 
dosing period and longterm follow up period local physical exam will be done as 
per clinical routine. 
8.4.5 Telephone Follow ups 
7 (± 3) days after each treatment cycles until completion of 4 cycles and for follow 
up phase , every 3 months ( +/- 1 month) until the end of follow up visits (24 
months). 
8.4.6 Longterm Follow ups 
At each follow-up visit (every 3 (±1) months) following tasks will be performed: 
1. Physical exam, vital signs 
2. Documentation of concomitant cancer related therapies since last visit 
3. Laboratory tests (CBC, CMP with eGFR and PSA) 
4. Relevant imaging studies 
PSMA.-617-02 
5. Quality of life questionnaire and ECOG performance score (baseline, 3, 6, 9, 
12, 18, 24 months from first RLT cycle) 
______ ......,,.,,/!lftden-tia.u-l---------__,_Pn.ge..69..Dj-9...,_ ____________________ _ 
s-:-0-0-:1:rm,r:rors 
____ .. ___ ,.._, ________ _ 


_.,.,--.., ' 
PSMA-617-02 
9. Quality Control and Assurance 
The study sites are chosen with regard to the capability and expertise of the principal 
investigators and the site staff. Prior to initiation of the study, the investigator and the sponsor's 
representative will meet to discuss the study design and conduct of the study. The investigator 
will sign the protocol aclmowledging that he understands-the design and all procedures and 
intends to conduct the study and all procedures according to protocol. 
During the study, a representative of the sponsors will make periodic visits·to the 
investigational site while the study is in progress to check the accuracy and completeness of 
the data being entered. Site visits will be conducted to inspect study data, subjects' medical 
records, and CRFs in accordance with ICH guidelines, GCPs, and the respective local and 
national government regulations and guidelines. The investigator will permit authorized 
representatives and the respective local and national health authorities to inspect facilities and 
records relevant to this study, if needed. 
Subject data will be collected on source documents and entered in the CRF. Data will be 
; 
. 
reviewed and validated. The investigator will sign and date a declaration on the CRF attesting 
to his/her responsibility for the quality of all data recorded and that the data represents a 
complete and accurate record of each subject in the study. 
Records of subjects, source documents, monitoring visit logs, inventory of study product, 
regulatory documents (e.g., protocol and amendments, IRB/IEC correspondence and 
approvals, approved and signed informed consent forms, Investigator's Agreement, clinical 
supplies receipts, and distribution and return records), and other sponsor correspondence 
pertaining to the study will be kept in the appropriate study files at the site. Source documents 
include all ~ecordings and observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. At the end of the 
study, CRF data will be provided to the sponsor. 
------~..arif.i.dentiai 
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EageJJl..oi_.a,_ _____ 
.c..._ _______________ 
_ 


PSMA-617-02 
10. Planned statistical methods 
10.1 Primary endpoints 
1. Safety of 177Lu-PSMA-617 RL Twill be assessed by analysis of toxicity. Descriptive 
statistics (number and percentage) will be reported sepa.Fately for AE in total and SAE 
based on CTC. These descriptive statistics will be presented for the who le treatment 
as well as separate for each cycle. In addition, the relationship of AE to the study drug 
(related, not related) will be reported. Both results from laboratory test, physical 
examinations and patients surveys will be included. 
2. Efficacy of 177Lu-PSMA-617 will be reported using descriptive statistics by means of 
number and percentage of patients with ?:50% decline at 12-weeks from baseline. 
10.2. Secondary endpoints 
1. Descriptive analyses (median, standard deviation) will be used to determine the 
progression-free survival (PFS), measured from start of therapy until death or PSA 
progression. PSA progression is defined a) for patients with PSA decline after start of 
treatment as ·time from baseline to time the PSA increases to 25% and 2 ng/ml above 
\ 
nadir which is confirmed by a second value ?:3 weeks later or b) for patients without 
PSA decline as time from baseline to time the PSA increases to 25% and 2 ng/ml 
above baseline which is confirmed by a second value ?:3 weeks later [1]. Data will be 
given separately for the both treatment groups (6.0 vs. 7.4 GBq 177Lu-PSMA-617) and 
a statistical significant difference will be tested. 
2. Each clinical site will perform image analysis on their own patients. Descriptive 
analyses (median, standard deviation) will be used to determine the radiographic 
______ 
_,__C=onfideotiat 
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PSMA.-617-02 
progression-free survival (rPFS), measured from start of therapy until death or 
_______ 
........_ .... dio.graphic_p.r.Qgr.ession...RadiQgr_~p_hic progression is defined as a) for extraskeletal 
disease progressive disease (PD) following Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 [65] and/orb) skeletal disease the development of~ new 
-lesions on first post-trea1ment bone scan, with at least two additional lesions on the 
next scan (2+2 rule). The date of progression is the date of the first post-trea1ment 
scan, when the first two new lesions were documented. This approach is applied in 
accordance to PCWG criteria to exclude pseudoprogression in the absence of 
symptoms or other signs of progression [1]. Data will be given separately for the both 
treatment groups (6.0 vs. 7.4 GBq 177Lu-PSMA-617) and a statistical significant 
difference will be tested. 
3. Descriptive analysis will be used to determine the disease control rate (DCR) at the 
end of each cycle defined as the number and percentage of patients achieving a) 
RECIST stable disease (SD), partial response (PR) or complete response (CR) for 
extraskeletal tumor manifestation and b) PCWG non-progressive disease for skeletal 
manifestations. 
4. Descriptive analysis will be used to evaluate the impact on bone pain level by 
determining the proportion of patients with pain response defined by improvement 
from baseline ( all patients with 2::4/10) of at least 2-point absolute improvement 
without an overall increase in opiate use. 
5. Change in Quality of Life over time will be documented by comparing the summary 
scores investigated by the Quality oflife questionnaire ''EPIC-26" at baseline and at 3, 
6, 9, 12, 18 'and 24 months after start of 177Lu-PSMA-617 RLT [66]. 
6. Changes in performance status (ECOG) from baseline will be evaluated over time at 
3, 6, 9, 12, 18 and 24 i:'nonths after start of 177Lu-PSMA-617 RLT. 
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11. Administrative Considerations 
11.1 Investigators and Study Administrative Structure 
This study will be conducted in accordance with the Declaration of Helsinki, ICH E6 Guideline 
and government regulations, including (as applicable) the US Code of Pederal Regulations 
Title 21 CPR 312.50 through 312. 70, directive 2001/20/EC of 4 April 2001 and implementing 
directives and regulations. To ensure compliance the investigator agrees, by written consent to · 
this protocol, to fully cooperate with compliance checks by allowing access to all 
documentation by authorized individuals. The investigator must conduct the trial as outlined 
in the protocol and in accordance with the Declaration of Helsinki and government regulations, 
including (as applicable) the US Code of Federal Regulations Title 21 CPR 56-Institutional 
Review Boards. The administrative structure of the study (e.g., monitoring and vendor 
· personnel, statistician, and laboratory facilities) and a complete and controlled list of the 
investigators participating in this study can be found in the study file maintained by the sponsor 
or its agent. 
11.2 Institutional Review Board (IRB) or Independent Ethics ·committee (IEC) 
Approval 
The protocol, informed consent form, and any advertisement for the recruitment of subjects 
must be reviewed and approved by an appropriately constituted IRB or IEC, as required in 
Chapter 3 of the ICH E6 Guideline and government regulations, including (as applicable in the 
region) the US Code of Federal Regulations Title 21 CPR 56.107 through 56.115 of Good 
Clinical Practice. Written IRB approval must be provided to sponsor or designee prior to 
shipment of study drug or subject enrollment. The investigator is committed in accordance 
with local requirements to provide the IRB with updates, and to inform the IRB of any 
emergent problem, SAEs, and/or protocol amendments. 
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=============--•·········-·-·---


PSMA-617-02 
___ ...,,11..,.~3..EthicaLConduct-of-the-Study.---------------------
it is mandatory that all considerations regarding the protection of human subjects be carried 
out in accordance with the Declaration of Helsinki. 
11.4 Subject Information and Consent 
It is the responsibility of the investigator to obtain written informed consent from subjects. All 
subjects must sign and personally date an approved informed consent form after receiving 
detailed written and verbal information about the reason, the nature and the possible risks 
associated with the administration of the study drug. This must be done according to the 
guidelines provided in the Declaration of Helsinki, ICH E6 Guideline for GCP, and the 
requirements of (as applicable in the region) the US Code of Federal Regulations Title 21 CFR 
50.20 through 50.27 of Go.od Clinical Practice. 
The subject must be made aware and agree that personal information may be scrutinized during 
audit by competent authorities and properly authorized persons. However, personal 
information will be treated as strictly confidential and will not be publicly available. Prior to 
IRB/IEC submission, the investigator must send a copy of the informed consent form to be 
used at their institution to sponsor or designee for review to assure compliance with the ICH 
E6 and government regulations of the region. 
11.5 Subject Confidentiality 
Data collected during this study may be used to support the development, registration or 
marketing of 177Lu-PSMA-617. All data collected during the study will be controlled by 
sponsor or designee and sponsor will abide by all relevant data protection laws. In order to 
maintain subject privacy, all CRFs, study drug accountability records, study reports and 
communications will identify the subject by initials and the assigned subject number. The 
investigator will grant monitor(s) and auditor(s) from sponsor or its designee and regulatory 
_____ ___,Corif-identiaf.------------1<-a-ege-74-ef-9•~------------------------
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PSMA-617-02 
authority (ies) access to the subject's original medical records for verification of data entered 
____ j_nto__the_C.RE._and..to..audit.the..data-collection..pr,ocesg,;:fhe-subject.:s-com-identiaJity-w-ill-be-------
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Written authorization is to be obtained from each subject prior to enrollment into the study in 
accordance with the applicable privacy requirements [ e.g., the Health Insurance Portability and 
Accountability Act (H1P AA) of 1996 Standards for Privacy of Individually Identifiable Health 
Information. 
11.6 Study Monitoring 
11.6.1 Data and Safety Monitoring Plan (DSMP) 
Excel Diagnostics is the lead site; the Excel Diagnostics Data Safety Monitoring Board (DSJ:\.1B) 
will serve as overall DSMB for both sites. At UCLA, DSMB oversight will be provided by 
JCCC Data Safety Monitoring Board (DSlvfB). The monitoring board will meet quarterly to 
review safety recor<:15 including co:r:npliance with follow up visits. 
The Excel Diagnostics DSMB consists of: 
• 
, MD Radiologist, 
 
• 
, MD Radiologist, 
 
• 
, MD Oncologist, 
 
• 
, MD Family Practitioner, 
 
The Data Safety Monitoring Boards will evaluate safety throughout the study. The DSMB will 
advise the Sponsor, ·Investigators and investigational sites regarding the continuing safety of 
study patients and the patients yet to be recruited to the study as well as maintaining validity and 
scientific merit of the study. The DSMB will review ongoing examinations of safety data and 
promptly give recommendations to continue, continue with modification, or terminate the study. 
Each DSMB will evaluate and advise locally throughout the trial at the pre-specified milestones 
vs.a 01JUN201s 


_...-,. 
PSMA-617-02 
of 25%, 50%, 75% and 100% completion. UCLA JCCC DSl\tfB will send their reports to the 
lead site DSNIB for overall analysis. 
Copies of all monitoring and audit reports must be submitted by Endocyte to the lead site 
DSl\tfB within 10 working days of receipt by Endocyte. . 
Endocyte will be responsible for ensuring that all reportable adverse events are 
submitted to the appropriate regulatory body.(FDA, NIH, etc.).Adverse events will be recorded 
and reported to the FJ?A as well as applicable IRBs and the JCCC DSl\tfB per the regulatory 
body and institutional committee requirements (refer to JCCC DSl\tfB) website. 
Specific interim safety analyses will be done as follows: . 
Interim safety analyses: 4 interim safety analyses will be conducted by both DSl\tffis Analyses 
will be initiated at the time when 25%, 50%, 75% and 100% of the total 177Lu-PSMA-617 
treatments in the trial have been completed. The DSl\tffis will meet and assess up-to-date safety 
information within two weeks of a treatment exposure rate being achieved (i.e., the point when 
25%, 50%, 75% and 100% of subjects have completed their treatments). Further patients may 
only be randomized two weeks after the treatment exposure rate has been reached and after a 
positive opinion from the DSl\tfBs. An interim analysis for overall survival will be performed at 
the time of the final PPS analy~is. UCLA JCCC DSl\tfB will send its summary reports based,on 
a predetermined frequency to the lead site DSl\tfB for overall safety analysis as the Excel 
Diagnostics DSl\tfB will be serving as the overall DSl\tfB for both sites. 
11.6.2 Monitoring Procedures 
An appropriate representative of the sponsors (Study Monitor) will oversee the progress of the 
study, and ensuring it is conducted, recorded, and reported in accordance with the protocol, 
.. -., 
SOPs, GCP, and applicable regulatory requirements. 
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PSMA-617-02 
An initiation visit will be made by the study monitor at each site to discuss the protocol and 
the obligations of both the Sponsor and the mvestigator.Tne inve-strgator-musraltowi:h:e-studv· -----
monitor to perform periodic, interim monitoring visits. The actual frequency of monitoring 
visits will be dependent on the enrollment rate and performance at each site. The purposes of 
these visits are to verify that written informed consent was obtained prior to each subject's 
\ 
participatJon in the trial, and to: 
• assess the progress of the study 
• review the compliance with the study protocol 
• determine whether all AEs and SAEs were appropriately reported 
• determine whether the investigator is maintaining the essential documents 
• discuss any emergent problem 
• check the CRF for accuracy and completeness 
• validate the contents of the CRF against source 
• assess the status of drug storage, dispensing and retrieval 
•. retrieve study data 
All data required by the ·protocol must be reported accurately on the CRF and must be 
consistent with the source documents. Source documents are original documents, data and 
records ( e.g., hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, ~crofilm or magnetic media, x-rays or 
other di~onostic images, subject files, pharmacy records and laboratory records). The 
investigator will make available the source documents for inspection. This information will be 
considered as confidential 
During scheduled monitoring visits, the investigator and the investigational site staff should be 
available to meet with the study monitor in order to discuss the progress of the study, make 
necessary corrections to CRF entries, respond to data clarification requests and respond to any 
onfidentii 
VS.O 01JUN2018 


PSMA-617-02 
other study-related inquiries of the monitor. The investigational site staff in addition to the 
study coordinator should also mclude nuclear medicine staff,-ra.1:ltopharma:cist,-and-radiofogy------
staff. 
The study monitor will perform a closeout visit at the conclusion of the investigator's 
involvement in the study. 
11.6.3 Auditing 
The investigator will make all pertinent records available including source documentation for 
inspection by regulatory authorities and for auditing by the sponsor. This information will be 
considered as confidential Clinical Research Compliance Officers from the UCLA JCCC Office 
of Regulatory Compliance will be conducting the auditing for the U~LA site. 
Representattves of local or foreign. health authorities may review the conduct or results of the 
study at the investigational site. The investigator must promptly inform the sponsor of any audit 
requests by health authorities, (Ind will provide sponsor with the results of any such audits and 
with copies of any regulatory documents related to such_ audits. 
11. 7 Case Report Forms and Study Records 
Sponsor will provide a CRF and CRF instructions for the entry of study data. CRFs must be 
completed for each subject. All study data will be entered on CRFs from original source data. 
Entries should be made on the case report forms directly and promptly onscreen. 
The CRF will be reviewed, signed and dated by the investigator. 
11.8 Protocol Violations/Deviations 
Co'f!Zll.entia1 
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PSMA-617-02 
Protocol violations/deviations will be documented by investigator and submitted to the 
IRB/IEC, as required by IRB/IEC requirements. 
11.9 Access to Source Documentation 
During the study, a representative of the sponsor will make periodic visits to the investigational 
sites while the study is in progress to check the accuracy and ~ompleteness of the data being 
entered. Site visits will be conducted to inspect study data, subjects' medical records, and CRFs 
in accordance with ICH guidelines, GCPs, and the respective local and national government 
regulations and guidelines. 
The investigator will permit authorized representatives of the sponsor and the respective local 
And national health authorities to inspect facilities and records relevant to this study, if needed. 
11.10 Data Generation and Analysis 
Sponsor(s) or its designee will be responsible for data collection, data management, generation 
of data outputs and statistical analysis of all data. 
11.11 Retention of Data 
As described in the ICH GCP Guidelines, 'essential documents', including copies of the 
protocol, subject identification codes, CRF, source data, informed consent form(s) and other 
documents pertaining to the study conduction must be kept for the maximum period of time as 
required by the study site. This time period must be at least two years after the last follow up 
of the patients enrolled. 
No study document should be destroyed without prior written agreement between sponsors 
and the investigators. Originals of all documentation generated by sponsor and copies of 
Conjidentlal 
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outgoing sponsor correspondence concerning the study will be stored and retained in a safe 
area under the control of sponsor for tlielifetune ofllie product. In parb.cw.ar, 'tlie-fma:1-rep·o 
must be retained by sponsor, or the subsequent owner, for 5 years beyond the lifetime of the 
study drug. 
11.12 Financial Disclosure 
All investigators must provide :financial disclosure information in accordance with the US 
Code of Federal Regulations Title 21 CFR 54.2 through 54.6. 
11.13 Publication and Disclosure Policy 
All unpublished documentation (including the protocol, CRF and Investigator Brochure (IB) 
given to the investigator is strictly confidential All recipients must agree not to disclose the 
information herein contained to any person without the prior written authorization of sponsor. 
The submission of these documents to the IRB is expressly permitted. The investigator agrees 
that sponsor maintains the right to use the results of this study in their original form and/or in 
a global report for submission to governmental and regulatory authorities of any country. 
The results of the study may be presented during scientific symposia or published in a scientific 
journal only after review by sponsor in accordance with the guidelines set forth in the 
applicable publication or financial agreement. 
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PSMA.-617-02 
12. References 
1. 
Scher, H.I., et al., Trial Design and.Objectives for Castration-Resistant Prostat,e Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. 
J Clin Oncol, 2016. 34(12): p. 1402-18. 
2. 
Cancer Facts and Statistics 2015 I Research I American Cancer Socie-ty 
http://www. cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015. 
3. 
Heidenreich, A., et al., EAU guidelines on prostate cancer. part 1: screening, diagnosis, 
and local treatment with curative intent-update 2013. Eur Urol, 2013. 65(1): p. 124-37. 
4. 
de Bono, J.S., et al., Abiraterone and increased survival in metastatic prostate cancer. N 
Engl J Med, 2011. 364(21): p. 1995-2005. 
5. 
de Bono, J.S., et al., Prednisone plus cabazita:xel or mitoxantronefor metastatic 
castration-resistant prostate cancer progressing after doceta:xel treatment: a randomised 
open-label trial. Lancet, 2010. 376(9747): p. 1147-54. 
6. 
Fizazi, K., et al., Abiraterone acetate for treatment of metastatic castration-resistant 
prostate cancer:final overall survival analysis of the COU-AA-301 randomised, double-
blind, placebo-controlled phase 3 study. Lancet Oneal, 2012. 13(10): p. 983-92. 
7. 
Parker, C., et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. N 
Engl J Med, 2013. 369(3): p. 213-23. 
8. 
Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after 
chemotherapy. N Engl J Med, 2012. 367(13): p. 1187-97. 
9. 
Kantoff, P. W ., et al., Sipuleucel-T immunotherapy for castration-resistant prostate 
cancer. N Engl J Med, 2010. 363(5): p. 411-22. 
10. 
Ratbkopf, D .E., et al., Updated interim efficacy analysis and long-term safety of 
, abiraterone acetate in metastatic castration-resistant prostate cancer patients without ., 
prior chemf!therapy (COU-AA-302). European Urology, 2014. 66(5): p. 815-825. 
11. 
Tannock, l.F ., et al., Doceta:xel plus prednisone or mitoxantrone plus prednisone for 
advanced prostate cancer. N Engl J Med, 2004. 351(15): p. 1502-12. 
12. 
Oudard, S., et al., Doceta:xel rechallenge after an initial good response in patients with 
metastatic castration-resistant prostate cancer. BJU Int, 2014. 115(5): p. 744-52. 
13. 
Araujo, J.C., et al., Overall survival (OS) and safe-ty of dasatinib/doceta:xel versus 
docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): 
Corzjfdential 
:?-age 81 u/9 
vs.a o:uuN201s 


PSMA-617-02 
Results from the rand<;>mizedphase m READY trial. Journal of Clinical Oncology, 2013. 
-------31(-suppl-6~abstr-l:,.BA-8-%lJ-http:/Jmeetinglibrarv..asc.o_org/content/l 06127-134 ). 
14. 
Caffo, 0., et al., Multiple rechallengesfor castration-resistant prostate cancer patients 
responding to fzrst-line docetaxel: assessment of clinical outcomes and predictive factors. 
Urology, 2012. 79(3): p. 644-9. 
15. 
Loriot, Y., et al., The interval from the last cycle of docetaxel-based chemotherapy to 
progression is associated with the efficacy of subsequent docetaxel in patients with 
prostate cancer. Eur J Cancer, 2010. 46(10): p. 1770-2. 
16. 
Pfister, D .J .K.P ., et al., Comparison of second-line treatments in patients with castration-
resistant prostate cancer with PSA relapse after or during docetaxel chemotherapy. 
Journal of Clinical Oncology, 2012. 30(5_suppl): p. 243-243 
17. 
http:/ /ascopubs.org.eaccess.ub.tum.de/ doi/abs/10.1200/jco.2012.30 .5 suppl.243. 
Goodman, 0.B., et al., Exploratory analysis of the visceral disease subgroup in a phase 
m study of abiraterone acetate in metastatic castration-resistant prostate cancer. 
Prostate Cancer and Prostatic Disease, 2014.17(1): p. 34-39 
http:/ /~.nature.com/ doifinder/.10.1038/pcan.2013 .41. 
18. 
Albiges, L., et al., Is there a withdrawal syndrome with abiraterone acetate (AA)? 
Journal of Clinical Oncology, 2013. 3l(suppl 6; abstr 89 ¾U 
http:/ /meetinglibrary.asco.org/content/107277-134 ). 
19. 
Clayton, R., et al., A multicenter population-based experience with abiraterone acetate 
(AA) in patients with metastatic castration resistant prostate cancer (mCRPC). Journal of 
Clinical Oncology, 2013. 31(suppl 6; abstr 113 %U 
http://meetinglibrazy.asco.org/content/107187-134). 
20. 
Scher, H.I., et al., Impact of on-study corticosteroid use on efficacy and safety in the 
phase m AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor. 
Journal of Clinical Oncology, 2013. 3l(suppl 6; abstr 6 %U 
http://meetinglibrary.asco.org/content/107227-134). 
21. 
Sternberg, C.N., et al., Outcomes in elderly patients with metastatic castration-resistant 
prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: . 
Results from the phase m AFFIRM trial. Journal ofClinical Oncology, 2013. 3 l(suppl 6; 
abstr 16 %U http://meetinglibrary.asco.om/content/106560-134). 
22. 
Fleming, M.T., et al., Long-term responders to enzalutamide (ENZA) during the phase m 
AFFIRM trial: Baseline characteristics and efficacy outcomes. Journal of Clinical 
Oncology, 2013. 31(suppl 6; abstr 20 %U hm,://meetinglibrary.asco.orvcontent/106597-
134). 
"Corffiaerrt,a1 
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.-, 
PSMA.-617-02 
23. 
Heidenreich, A., et al., Cabazita:xel plus prednisone for metastatic castration-resistant 
-------pr0state-eaneer-pr,egr-essing-after-docetaxel.'..r..esults--fr-om..the_Ge.1Y.JJ...@_t;Qm,P-assionate-use 
programme. Eur Urol, 2012. 63(6): p. 977-82. 
24. 
Heidenreich, A., et al., Safety of cabazitaxel in senior adults with metastatic castration-
resistant prostate cancer: results of the European compassionate-use programme. Eur J 
Cancer, 2014. 50(6): p. 1090-9. 
25. 
Lipton, A., Implications of bone metastases and the benefits of bone-targeted therapy. 
Sero.in Oneal, 2010. 37 Suppl 2: p. S15-29. 
26. 
Fizazi, K., et al., Denosumab versus zoledronic acid for treatment of bone metastases in 
men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet, 
2011. 377(9768): p. 813-22. 
27. 
Smith, M.R., et al., Denosumab and bone-metastasis-free survival in men with 
castration-resistant prostate cancer: results of a phase 3, randomised, placebo-
controlled trial. Lancet, 2011. 379(9810): p. 39-46. 
28. 
George, D.J., et al., Sqfety and activi'ty of the investigational agent orteronel (ortl) 
without prednisone in men with nonmetastatic castration-resistant prostate cancer 
(nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a phase II 
study. Journal of Clinical Oncology, 2012. 30(suppl; abstr 4549 %U 
htl;p:/ /meetinglibrary.asco .org/content/97724-114 ). 
29. 
Bruno, R.D., et'al., 17alpha-Hydroxylase/17,20 l:yase inhibitor VN/124-1 inhibits growth 
of androgen-independent prostate cancer cells via induction of the endoplasmic 
reticulum str~ss response. Mol Cancer Th.er, 2008. 7(9): p. 2828-36. 
30. 
Taplin, M.-E., et al., Abstract CT-07: ARMOR]: Safety of galeterone (TOK-001) in a 
Phase I clinical trial in chemotherapy na'ive patients with castration resistant prostate 
cancer (CRPC). Cancer Research, 2012. 72(8 Supplement): p. CT-07-CT-07 ©2012 
American Association for Cancer Research U 
ht1;p://cancerres.aactjoumals.org.eaccess.ub.tum.de/content/72/8 Supplement/CT-07. 
31. 
Rathkopf, D. and H.I. Scher, Androgen receptor antagonists in castration-resistant 
prostate cancer. Cancer J, 2013. 19(1): p. 43-9. 
32. 
lschia, J ., F. Saad, and M. Gleave, The promise of heat shock protein inhibitors in the 
treatment of castration resistant prostate cancer. Curr Opin Urol, 2013. 23(3): p. 194-
200. 
33. 
Smith, D.C., et al., Cabozantinib in patients with advanced prostate cancer: results of a 
phase II randomized discontinuation trial. J Clin Oncol, 2012. 31(4): p. 412-9. 
Confidentlal 
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34. 
35. 
36. 
37. 
38. 
39. 
PSMA.-617-02 
Kwekkeboom, DJ., et al., Radiolabeled somatostatin analog [177Lu-
D0T-:A:0;T-yr3joctreotate-in-pat-ient-s-with-endocr-ine-gastr..oenter..opanereatic_tum_ars..~------
Journal of Clinical Oncology: Official Journal of the American Society of Clinical 
Oncology, 2005. 23(12): p. 2754-2762. 
Pemer, S., et al., Prostate-specific membrane antigen expression as a predictor of 
prostate cancer progression. Hum Patho4 2007. 38(5): p. 696-701. 
Bradford, T.J., et al., Molecular markers of prostate cancer. Urol Onco4 2006. 24(6): p. 
538-51. 
Wibmer, A.G., et al., Molecular Imaging of Prostate Cancer. Radiographies, 2015. 36(1): 
p. 142-59. 
Sweat, S.D., et al., Prostate-specific membrane antigen e~pression is greatest in prostate 
adenocarcinoma and lymph node metastases. Urology, 1998. 52(4): p. 637-640. 
Milowsky, M.I., et al., Vascular targeted therapy with anti-prostate-specific membrane 
antigen monoclonal antibody J591 in advanced solid tumors. J Clin Oncol, 2007. 25(5): 
p. 540-7. 
40. 
Bander, N.H., et al., Phase I trial of 177Zutetium-labeledJ591, a monoclonal antibody to 
prostate-specific membrane antigen., in patients with androgen-independent prostate 
cancer. J Clin Onco4 2005. 23(21): p. 4591-601. 
41. 
Banerjee, S.R., et al., Synthesis and evaluation of technetium-99m- and rhenium-labeled 
inhibitors of the prostate-specific membrane antigen (PSMA). J Med Chem, 2008. 
51(15): p. 4504-17. 
42. 
Chen, Y., et al., Radiohalogenated prostate-specific membrane antigen (PSMA)-based 
ureas as imaging agents for prostate cancer. J Med Chem, 2008. 51(24): p. 7933-43. 
43. 
Eder, M., et al., 68Ga-complex lipophilicUy and the targeting property of a urea-based 
PSMA inhibitor for PET imaging. Bioconjug Chem, 2012. 23(4): p. 688-97. 
44. 
Banerjee, S.R., et al., 68Ga-labeled inhibitors of prostate-specific membrane antigen 
(PSMA) for _imaging prostate cancer. J Med Chem, 2010. 53(14): p. 5333-41. 
45. 
Liu, T., et al., Spacer length effects on in vitro imaging and surface accessibility of 
fluorescent inhibitors of prostate specific membrane antigen. Bioorg Med Chem Lett, 
2011. 21(23): p. 7013-6. 
46. 
Benesova, M., et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA 
Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate 
Cancer. JNucl Med, 2015. 56(6): p. 914-20. 
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. ··-·-•' ...... ··--.. · .. . 


PSMA.-617-02 
47. 
Kratochwil, C., et al., [(1)(7)(7}Lu]Lutetium-labelled PSMA ligand-induced remission in 
-------....,a~p=atzeYltWith-m:etastaticpro-state-cancer:-Bur--J-Nucl-Med-MG-1-Imaging,-2.0l5-42.(6);_p.. ____ _ 
987-8. 
48. 
Ahmadzadehfar, H., et al., Early side effects and first results of radioligand therapy with 
(177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre 
study. EJNMIY.1I Res, 2015. 5(1): p. 114. 
49. 
Kratochwil, C., et al., PSMA-Targeted Radionuclide Therapy of Metastatic Castration-
Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. JNucl Med, 2016. 57(8): p. 
1170-6. 
50. 
Ahmadzadehfar, H., et al., Therapeutic response and side effects of repeated radio ligand 
therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. 
Oncotarget, 2016. 7(11): p. 12477-88. 
51. 
Yadav, M.P., et al., 177Lu-DKFZ-PSMA.-617 therapy in metastatic castration resistant 
prostate cancer: safety, efficacy, and quality of life assessment. Eur J Nucl Med Mol 
Imaging, 2016. . 
52. 
Rahbar, K., et al., German multicenter study i'nvestigating 177Lu-PSMA-617 radioligand 
therapy in advanced prostate cancer patients. J Nucl Med, 2016. 
53. 
Danila, D.C.-, et al., Phase II multicenter study of abiraterone acetate plus prednisone 
therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin 
Oncol, 2010. 28(9): p. 1496-501. 
54. 
Strosberg, J., et al., 177-Lu-Dotatate Significantly Improves Progression-Free Survival in 
Patients with Midgut Neuroendocrine Tumors: Results of the Phase llI NETTER-I Trial, 
in PANCREAS. 2016, LIPPINCOTT "WILLIAMS & "WILKINS TWO COMMERCE SQ, 
2001 MARKET ST, PIDLADELPHIA, PA 19103 USA. p. 483-483 %U 
https://www .nanets.net/nanets cd/20 l 5/pdfs/C3 9 .pdf. 
55. 
Witzig, T.E., et al., Randomized controlled trial ofyttrium-90-labeled ibritumomab 
tiu:xetan radioimmunotherapy versus ritu:ximab immunotherapy for patients with relapsed 
or refractory low-grade,follicular, or transformed B-cell non-Hodgkin's lymphoma. J 
Clin Oncol, 2002. 20(10): p. 2453-63. 
56. 
K.abasakal, L., et al., Pre-therapeutic dosimetry of normal organs and tissues of (177}Lu-
PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with 
castration-resistant prostate cancer. Eur JNucl Med Mol Imaging, 2015. 42(13): p. 
1976-83. 
57. 
Delker, A., et al., Dosimetry for (l 77)Lu-DKFZ-PSMA-617: a new radiopharmaceutical 
for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol Imaging, 2015. 
43(1): p. 42-51. 
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58. 
Emami, B., et al., Tolerance of normal tissue to therapeutic irradiation. Int J Radiat 
·~-------troo-li3io-l-Phys;-l99i.--:-21fl-):--p:-l-09-2-2-=--·--· ----------------
,..-.., 
59. 
Hey, J:, et al., Parotid gland-recovery after radiotherapy in the head and neck region--36 
months follow-up of a prospective clinical study. Radiat Oneal, 2011. 6: p. 125. 
60. 
Gensheimer, M.F ., -et al., Submandibular gland-sparing radiation therapy for locally 
advanced oropharyngeal squamous cell carcinoma: patterns of failure and xerostomia 
outcomes. Radiat Oncoi 2014. 9: p. 255. 
61. 
Kwekkeboom, DJ., et aL, Treatment of patients with gastro-entero-pancreatic (GEP) 
tumours with the novel radiolabelled somatostatin analogue [177Lu-
62. 
63. 
64. 
65. 
66. 
DOTA(0), Tyr3 Joctreotate. Eur J Nucl Med Mol Imaging, 2003. 30(3): p. 417-22. 
Vickers, A.J., How to randomize. J Soc Integr Oneal, 2006. 4(4): p. 194-8. 
Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. 
IntJRadiat Oncol Biol Phys. 1991;21(1):109-122. 
Zechmann CM, Afsh~-Oromieh A, Armor T, et al. Radiation dosimetry and first therapy 
results with a (124)!/ (131)1-labeled small molecule (MIP-1095) targeting PSMA for 
prostate cancer therapy. Eur JNucl Med Mol Imaging. 2014;41(7):1280--1292. 
Eisenhauer, EA., et al., New response evaluation criteria in solid tumours: revised 
RE,CIST guideline (version I.I). Eur J Cancer, 2008. 45(2): p. 228-47. 
Szymanski, K.M., et al., Development and Validation of an Abbreviated Version of the 
Expanded Prostate Cancer Index Composite Instrument (EP IC-26) for Measuring 
Health-Related Quality of Life Among Prostate Cancer Survivors. Urology, 2010. 76(5): 
p. 1245-50 .. 
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PSMA-617-02 
Appendices 
Appendix 1- Preclinical Toxicity studies 
Th.is exhibit is 303 pages. Therefore we are providing it in the attached CD. 
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-=========··-....................... ·.:::.::::.::::.::::::::::::::::=====-


Appendix II: Visit Specific Schedule 
l 
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. 
------···•-··---· 
........ . 


Appendix III: Principal Investigator Signature 
I have read this clinical protocol, no. 177Lu-PSMA-617-02, in its entirety and: 
• 
I agree to implement and conduct this clinical study diligently and in strict compliance 
with the protocol, good clinical practices, and all applicable national, federal, and local 
laws and/or regulations. 
• 
I agree that this clinical protocol will not be modified by me or any member of my staff 
without the written consent ofEndocyte, Inc. and, if required, I will receive approval of 
these modifications by my institution's IRB/REB/Independent Ethics Committee (IEC). 
• 
I certify that neither I nor any member of my staff has been disqualified or debarred by the 
Food and Drug Administration (FDA), European or any other regulatory bodies for clinical 
investigations or any other purpose. 
• 
I understand that this clinical protocol and the accompanying clinical Investigator's 
Brochure contains trade secrets and/or commercial information that are privileged and/or 
confidential and may not be disclosed unless such disclosure is required by national, 
federal, or local laws and/ or regulations. 
Pursuant to 21 CFR § 312.53(c), each US investigator will complete and sign FDA Form 1572, 
Statement of Investigator, prior to participating in the study. The completed form, along with a 
curriculum vitae, will be returned to Endocyte and maintained on record. 
Form FDA 1572, Statement of Investigator, which must be completed, is available at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManua1sForms/Forms/UCM074728.pdf 
Principal Investigator Signature 
Date 
Name (Printed) 
Title (Printed) 
-·-------·-··---------------------------------------------
........ -· ··----·--
... -~----
..... -. _-.-... -... -... 


PSMA-617-02 
Baseline and follow-Up Questionnaire for Pain and Adverse Events 
PATIENT INFORMATION 
last name: ___________ _ 
First Name: _______________ _ 
Date of Birth: __________ _ 
Medical Record Number: __________ _ 
Change of pain medication since last 177Lu-PSMA-617 cycle 
No change 
Change in dosage/administration: medication _______ increase or 
decrease 
Addition/removal of medication: medication 
addition or 
removal 
Pain 
No or 
Yes: 
Locations:---------------------------------
Overall level: 
Vemal 
clesaiptDr 
scare 
0 
l 
2 
3 
r-r~=~;·"-·I 
Ile 
Mild: 
pam 
paia 
4 
5 
I 
I 
!i!odeate 
pain, 
6 
7 
& 
9 
10 
I. 
I, 
i 
I 
l 
Madera1.!i 
Severe 
Woi& 
pain: 
pain: 
~le> 
Change since last cycle: 
increase, 
no change, 
decrease 
Nausea 
No nausea 
Nausea with loss of appetite only 
Nausea with eating/drinking less than usual 
Had to go to hospital for nausea 
Dry mouth 
No dry mouth 
Dry or thick saliva 
Normal eating only with water/lubricants possible 
Tube feeding or total i.v. nutrition 
Fatigue 
No fatigue 
Fatigue relieved by rest 
Fatigue not relieved by rest, limiting work 
Fatigue not relieved by rest, limiting self-care 
Fever 
No fever 
38.0 • 39.0 oc (100.4 • 101.2 OF) 
>39.0 -40.0 degrees °C (101.3 - 104.0 °F) 
>40.0 oc (>104.0 OF) 
Diarrhea 
Normal bowel movements 
Increase by <4 stools per day 
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Vomiting 
No vomiting 
1 - 2 episodes per day 
3 - 5 episodes per day 
more than 5 episodes per day 
Taste 
Normal taste 
Altered taste but no change in diet 
Altered taste with change in diet 
Hematoma 
No Hematoma 
Occurrence of hematoma without known event 
Urinary retention 
Able to void normally 
Able to void with some pressure 
Unable to void or voiding only after 
catheter/intervention/treatment 
Other (symptom, grade: mild/moderate/severe): 


PSMA-617-02 
Increase by 4-6 stools per day 
-----s-lncrease-by-mor:e..tt:iar.i-6-Stools-per....da)v-' -----===-----------------------
Had to go to hospital for diarrhea 
Date: _________ Name: ________ Signature: ________ _ 
-! 
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~: e-p1c;:25· 
.· .. Tti¢/Exp'~~ded i>rost~ie -~an·cer !ncle},()C:omp9site ... 
' 
,.• .·.·, 
:·short ·f<>rrri 
This questionnaire is designed to measure Quality of Life issues in patients 
with Prostate cancer. To help us get the most accurate measurement, it is 
important that you answer all questions honestly and completely. 
Re.member, as with all medical records, information contained within this 
survey will remain strictly confidential. 
Today's Date (please enter date when survey completed): Month __ Day __ 
Year. __ 
_ 
Name (optional): _________________ _ 
Date of Birth (optional): Month ____ Day ____ Year ___ 
_ 
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PSMA-617-02 
Do Not Mark in This Space 
1. Over the past 4 weeks, how often have you leaked urine? 
More than once a day ...................... 1 
About once a day ............................. 2 
More than once a week .................... 3 
(Circle one number) 
About once a week ........................... 4 
Rarely or never................................ 5 
2. Which of the following best describes your urinary control during the last 4 weeks? 
No urinary control whatsoever........... . ............•.............. 1 
Frequent dribbling .......................................................... 2 
(Circle one number) 
Occasional dribbling ....................................................... 3 
Total control. .................................................................. 4 
.-•1 
L How many pads or adult diapers per day did you usually use to control leakage 
during the last 4 weeks? 
None......................................................................... 
0 
1 pad per day............................................................. 
1 
2 pads per day............................................................ 
2 
(Circle one number) 
3 or more pads per day............................................... 
3 
4. How big a problem, if any, has each of the following been for you during the last 4 weeks? 
(Circle one number on each line) 
No 
Very Small 
Small 
Moderate 
Big 
Problem 
Problem 
Problem 
Problem 
Problem 
a. Dripping or leaking urine ......... 
0 
1 
2 
3 
4 
b. Pain or burning on urination ..... 
0 
1 
2 
3 
4 
C. Bleeding with urination ............. 
0 
1 
2 
3 
4 
,d. Weak urine stream 
or incomplete emptying ............ a 
1 
2 
3 
4 
·,-r· Need to urinate frequently d~ring 
the day ..................................... 
0 
1 
2 
3 
4 
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PSMA-617-02 
5. Overall, how big a problem has your urinary function been for you during the last 4 weeks? 
__ N._q_problem .................................. : ... 1 
Very small problem .......................... 2 
Small problem .................................. 3 
(Circle one number) 
Moderate problem ........................... 4 
Big problem ..................................... 5 
6. How big a problem, if any, has each of the following been for you? (Circle one number on each line) 
No 
Very Small 
Small 
Moderate 
Big 
Problem 
Problem 
Problem 
Problem 
Problem 
a. 
Urgency to have 
a bowel movement .................. 
0 
1 
2 
3 
4 
b. 
Increased frequency of 
.--, 
: >wel movements ..................... 
0 
1 
2 
3 
4 
c. 
Losing control of your stools ...... 
0 
1 
2 
3 
4 
d. 
Bloody stools ............................ 
0 
1 
2 
3 
4 
e. 
Abdominal/ Pelvic/Rectal pain ... 
0 
1 
2 
3 
4 
7. Overall, how big a problem have your bowel habits been for you during the last 4 weeks? 
No problem ...................................... 1 
Very small problem .......................... 2 
Small problem .................................. 3 
(Circle one number) 
Moderate problem ........................... 4 
Big problem ..................................... 5 
8. How would you rate each of the following during the last 4 weeks? (Circle one number on each line) 
Very 
a. Your ability to have an erection? ............................... . 
-~'"-'r. Your ability to reach orgasm (climax)? .................................. ... 
i 
Corifi,dential 
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Poor 
to 
Very 
None Poor 
Fair 
Good Good 
1 
1 
2 
2 
3 
3 
4 
4 
5 
5 
34/ 
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Space 
49/ 
50/ 
52/ 
53/ 
54/ 
55/ 
57/ 
58/ 


PSMA.-617-02 
9. How would you describe the usual QUALITY of your erections during the last 4 weeks? 
None at all......................................................................................... 
1 
Not firm enough for any sexual activity.............................................. 2 
Firm enough for masturbation and foreplay only............................... 3 
Firm enough for intercourse.............................................................. 4 
(Circle one number) 
10. How would you describe the FREQUENCY of your erections during the last 4 weeks? 
I NEVER had an erection when I wanted one................................... 1 
I had an erection LESS THAN HALF the time I wanted one............. 2 
I had an erection ABOUT HALF the time I wanted one .................... 3 
I had an erection MORE THAN HALF the time I wanted one............ 4 
I had an erection WHENEVER I wanted one..................................... 5 
(Circle one number) 
11. Overall, how would you rate your ability to function sexually during the last 4 weeks? 
Very poor.............................................................. 1 
Poor...................................................................... 2 
Fair ..................................................................... 
3 
Good .................................................................... 
4 
Very good............................................................. 
5 
(Circle one number) 
12. Overall, how big a problem has your sexual function or lack of sexual function been for you 
during the last 4 weeks? 
No problem........................................................... 1 
Very small problem............................................... 
2 
Small problem....................................................... 
3 
Moderate problem................................................ 
4 
Big problem.......................................................... 
5 
(Circle one number) 
--T~. How big a problem during the last 4 weeks, if any, has each of the following been for you? 
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,,-i---
1 
I 
a. 
b. 
c. 
d. 
e. 
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PSMA-617-02 
(Circle one number on each line) 
--~ma11---sma11--·----rv1oderate--si-g 
Problem 
Problem 
Problem 
Problem 
Problem 
Hot flashes ................................ 
0 
1 
2 
3 
4 
Breast tenderness/enlargement.. 
0 
1 
2 
3 
4 
Feeling depressed ..............•........ 
0 
1 
2 
3 
4 
Lack of energy ............................ 
0 
1 
2 
3 
4 
Change in body weight.. ............ 
0 
1 
2 
3 
4 
THANK YOU VERY MUCH!! 
EPIC-SF 6.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
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--
1 
1 
Appendix VI: Dosimetry protocol attached as ~df copy 
*Not applicable to preVIous versions of protocol 
onjiaential 
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PSMA-617-02 

SAP_001.pdf: 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
Page 1 of 29 
 
 
 
 
Final 
 
STATISTICAL ANALYSIS PLAN 
 
Study PSMA-617-02 
 
 
Title: (as per protocol/amendment) 
PSMA-Directed Endoradiotherapy Of  
Castration-Resistant Prostate Cancer  
(RESIST-PC). A Phase II Clinical Trial 
 
 
Version: 
Final, Version 2.0 
 
 
Date: 
15-May-2020 
 
CONFIDENTIAL 
 
 
 
 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
Page 2 of 29 
 
DOCUMENT HISTORY 
1 
VERSION HISTORY 
Version # 
Version Date 
Final v1.0 
24Sep2019 
Final v2.0 
15May2020 
2 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
Final v1.0 
N/A 
Initial release 
N/A 
Final v.2.0 
2.3.2 
Definition of secondary objectives updated  
PSA progression is defined as the date that a ≥ 25% 
increase in PSA and an absolute increase of 2 
ng/mL or more from the nadir is documented and 
confirmed by a second value obtained 3 or more 
weeks later. Rises in PSA within the first 12 weeks 
will be ignored in the absence of other evidence of 
disease progression (PCWG3 Guidance). 
and 
PSA progression is defined as a 25% increase from 
the baseline value along with an increase in 
absolute value of 2 ng/mL or more after 12 weeks of 
treatment 
To be in line with the Prostate 
Cancer Clinical Trials Work 
Group 3 (Scher et al 2016) 
and to have comparable data 
for the two main studies in 
this indication, VISION and 
RESIST-PC. 
 
2.5 
MedDRA version changed from 22.0 to 22.1 
The clinical database was 
updated to the most current 
version of MedDRA; to 
correctly reflect the MedDRA 
version used in the study. 
 
3.4.1 
Rules for imputation of missing dates clarified. 
To be consistent with the SAP 
sections 3.11.8-9. 
 
3.4.2 
Rules for visit assignment for laboratory tests, PSA, 
Epic-26, ECG, vital signs, ECOG and AE 
questionnaire were added. 
To account for the CRF 
structure, where data 
collected at different 
timepoints is presented under 
the same visit name, 
 
3.4.2 
Baseline definition: 
If there is no time, only date of assessment is 
collected, then the last non-missing assessment 
prior or on date of first administration of Lu-PSMA-
617 is used. 
To clarify how baseline for 
assessments for which only 
date is collected is derived. 
 
3.5 
Selection of the first result for the same assessment 
collected during a visit extended to all assessments. 
To account for the changes in 
section 3.4.2, visit 
assignment. 
 
3.9 
Clarification on data analyzed as Prior Cancer 
Related Therapy added. 
To clarify based on the CRF 
structure. 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
Page 3 of 29 
 
3.9 
Best overall response categories removed from the 
summaries for Other Treatment and Radiotherapy, 
Patients could have multiple 
therapies recorded; therefore, 
a summary of best overall 
response would not be 
informative. 
 
3.10.2 
PSA progression-free survival (PFS): 
PSA PFS is measured from date of randomization 
until death or PSA progression. 
date that a ≥ 25% increase in PSA and an absolute 
increase of 2 ng/mL or more from the nadir (from all 
visits prior to the current visit being evaluated) is 
documented and confirmed by a second   value 
obtained 3 or more weeks later. Rises in PSA within 
the first 12 weeks of date of first dose will be ignored 
and  
PSA progression is defined as a ≥ 25% increase 
from the baseline value along with an increase in 
absolute value of 2 ng/mL or more after 12 weeks 
from the date of first dose of treatment (without 
confirmation) as specified in PCWG3 guidelines. 
 
PSA PFS is calculated as the time from 
randomization to the date of first 
documentation of PSA progression or date of 
death due to any cause, whichever occurs first: 
 
PSA PFS = Date of PSA progression or death - 
date of randomization + 1 
Additional analysis for PSA PFS was added: 
Median follow-up (months) with 95% CI, censoring 
for deaths or PSA Progression, and range will be 
provided. 
To be in line with the Prostate 
Cancer Clinical Trials Work 
Group 3 (Scher et al 2016) 
and to have comparable data 
for the two main studies in 
this indication, VISION and 
RESIST-PC. 
 
3.10.2 
Change in ECOG-PS 
The changes in ECOG from baseline will be 
evaluated over time at treatment visit 1, 2, 3 and 4, 
and at follow-up visits. 
Data for ECOG was captured 
in CRF with each 177Lu-
PSMA-617 treatment visit and 
during follow-up 
 
3.11.3 
MedDRA version changed from 22.0 to 22.1 
The clinical database was 
updated to the most current 
version of MedDRA; to 
correctly reflect the MedDRA 
version used in the study. 
 
3.11.8-11 
Best overall Response removed from the summaries 
for Concurrent and Post-Treatment Radiotherapy 
and Other Treatments, and for the Post-Treatment 
Chemotherapy 
Patients could have multiple 
therapies recorded; therefore, 
a summary of best overall 
response would not be 
informative. 
 
2.1 
The PSA related efficacy will not be analyzed. Only 
listing will be presented  
The PSA related efficacy will 
not be analyzed due to the 
significantly smaller sample 
size and investigator’s 
inconsistent timing of PSA 
data collection. PSA data will 
only be able to be listed 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
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Page 4 of 29 
 
2.4.1-2.4.2, 
3.10 
Efficacy endpoints associated with efficacy 
objectives will not be analyzed.  
The PSA related efficacy will 
not be analyzed due to the 
significantly smaller sample 
size and investigator’s 
inconsistent timing of PSA 
data collection. PSA data will 
only be able to be listed 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
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3 
APPROVAL SIGNATURES 
STUDY TITLE: PSMA-Directed Endoradiotherapy Of Castration-Resistant Prostate Cancer (RESIST-
PC). A Phase II Clinical Trial 
PROTOCOL NUMBER: PSMA-617-02 
SAP Final version 2.0, 15May2020 
 
PSI: 
Author: 
, 
 
Signature: 
................................................................ 
Date: 
...................... 
 
: 
 
Signature: 
...............................................................  
Date: 
...................... 
 
Endocyte, Inc.: 
 
Reviewed/Approved By: 
, Biostatistician 
Signature: 
................................................................ 
Date: 
...................... 
 
Reviewed/Approved By: 
 
Signature: 
................................................................ 
Date: 
...................... 
 
Reviewed/Approved By: 
 
Signature: 
................................................................ 
Date: 
...................... 
 
Reviewed/Approved By: 
, M.D., M.H.S., M.Sc., 
 
Signature: 
................................................................ 
Date: 
...................... 
 
 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
Page 6 of 29 
Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse event 
ALT/SGPT 
Alanine aminotransferase/Serum glutamic-pyruvic transaminase 
ANC 
Absolute neutrophil count 
AST/SGOT 
Aspartate aminotransferase/Serum glutamic-oxaloacetic transaminase 
ATC 
Anatomic Therapeutic Chemical Classification 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence interval 
CMP 
Comprehensive metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eGFR 
estimated Glomerular Filtration Rate 
EPIC 
Expanded prostate cancer index composite 
FT 
Frequency table (prototype) 
GBq 
Gigabecquerel 
Gy 
Gray 
IND 
Investigational New Drug (application) 
ITT  
Intent-to-treat  
i.v. 
Intravenous 
177Lu 
Lutetium 177 
mCRPC  
Metastatic castration-resistant prostate cancer 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
 


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Statistical Analysis Plan 
 
 
 
 
 
 
 
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Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities 
ND/UNK/NA 
Not determined / unknown / not applicable 
PASS 
Power Analysis and Sample Size (PASS 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PSA 
Prostate-specific antigen 
PSMA 
Prostate-specific membrane antigen 
PT 
Preferred term 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RECIST 
Response evaluation criteria in solid tumors 
RLT 
Radioligand therapy 
rPFS 
(radiographic) Progression-free survival 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
UCLA 
University of California at Los Angeles 
WBC 
White blood cell 
 
 


PSMA-617-02 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
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Table of Contents 
 
1 
VERSION HISTORY ..................................................................................................................... 2 
2 
REVISION HISTORY .................................................................................................................... 2 
3 
APPROVAL SIGNATURES .......................................................................................................... 5 
1 
RELEVANT DOCUMENTS AND STANDARDS .......................................................................... 9 
1.1 
PROTOCOL VERSION AND AMENDMENTS ................................................................................ 9 
1.2 
CHANGES FROM PROTOCOL................................................................................................... 9 
2 
STUDY DESIGN AND OBJECTIVES ......................................................................................... 10 
2.1 
STUDY DESIGN .................................................................................................................... 10 
2.2 
SAMPLE SIZE DETERMINATION ............................................................................................. 10 
2.3 
STUDY OBJECTIVES ............................................................................................................. 11 
2.3.1  Primary objectives .................................................................................................. 11 
2.3.2  Secondary objectives .............................................................................................. 11 
2.4 
PRIMARY AND SECONDARY ENDPOINTS ................................................................................. 11 
2.4.1  Primary endpoints ................................................................................................... 11 
2.4.2  Secondary endpoints .............................................................................................. 11 
2.5 
CODING DICTIONARIES ......................................................................................................... 12 
3 
STATISTICAL EVALUATION .................................................................................................... 12 
3.1 
POPULATIONS FOR ANALYSIS ............................................................................................... 12 
3.2 
INTERIM ANALYSES .............................................................................................................. 12 
3.3 
SUBGROUP ANALYSES ......................................................................................................... 13 
3.4 
DERIVED DATA AND DATA SETS ........................................................................................... 13 
3.4.1  Rules for incomplete data ....................................................................................... 13 
3.4.2  General Analysis Definitions ................................................................................... 13 
3.4.3  Rules for adverse events ........................................................................................ 19 
3.4.4  Rules for vital signs ................................................................................................. 19 
3.5 
GENERAL VARIABLE DEFINITIONS ......................................................................................... 20 
3.6 
PATIENT DISPOSITION, DEVIATIONS, DEMOGRAPHY .............................................................. 20 
3.7 
BASELINE DISEASE CHARACTERISTICS ................................................................................. 21 
3.8 
MEDICAL HISTORY ............................................................................................................... 21 
3.9 
PRIOR CANCER RELATED THERAPY ..................................................................................... 21 
3.10  EFFICACY ANALYSIS ............................................................................................................ 22 
3.11  SAFETY ANALYSIS ............................................................................................................... 23 
3.11.1 Safety Variable Definitions ..................................................................................... 23 
3.11.2 Extent of Exposure ................................................................................................. 24 
3.11.3 Adverse Events ....................................................................................................... 24 
3.11.4 Laboratory Data ...................................................................................................... 25 
3.11.5 Vital Signs ............................................................................................................... 26 
3.11.6 12-Lead ECG Data ................................................................................................. 26 
3.11.7 Physical Exam ........................................................................................................ 26 
3.11.8 Concomitant Medications ....................................................................................... 26 
3.11.9 Concurrent and Post Chemotherapy ...................................................................... 26 
3.11.10  Concurrent and Post Radiotherapy .................................................................... 26 
3.11.11  Concurrent and Post Other Treatments .............................................................. 27 
3.12  OTHER ANALYSES ............................................................................................................... 27 
3.13  SCHEDULE OF EVENTS ........................................................................................................ 27 
3.14  REFERENCES ...................................................................................................................... 28 
APPENDIX I GENERALIZED REFERENCE RANGES ....................................................................... 28 


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Statistical Analysis Plan 
 
 
 
 
 
 
 
Statistical Analysis Plan/ Final 2.0 / 15-May-2020 / RESIST-PC 
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1 
Relevant Documents and Standards 
1.1 
Protocol Version and Amendments 
The statistical analysis plan is based on version 5.0 of the study protocol of study PSMA-617-02 dated 
01 June 2018.  
1.2 
Changes from Protocol 
The protocol does not include any planned interim analyses.  Enrollment was ceased when Endocyte 
acquired the Investigational New Drug (IND) application in order to do a phase 3 study of 177Lu-PSMA-
617, now currently under way. The RESIST-PC study (NCT03042312), now identified as PSMA-617-
02, was ongoing when Endocyte acquired global development rights to the clinical development of 
PSMA-617 and to the PSMA-617 IND. It was agreed with the two principal investigators that the study 
was to stay open until the start of the Phase 3 VISION study (NCT03511664) in the USA. On 23 May 
2018, the first site for the Phase 3 VISION study was opened to enrollment; therefore, the investigators 
were notified that enrollment to PSMA-617-02 would end on 22 June 2018, prior to full enrollment of the 
study. All enrolled patients were to continue to follow the protocol visit schedule. 
 
To support the phase 3 study, a database lock of the RESIST phase 2 study is to occur after randomized 
patients have completed the treatment phase and 2 years follow-up period of the study. 
 
Using the locked database, protocol analyses will be performed to summarize only safety. Most of the 
objectives will not be able to be met due to the early stopping of enrollment into the study; the modeling 
approaches stated in the protocol cannot be carried out as there is insufficient data to perform the 
analyses. Limited imaging data is available, and thus the endpoints associated with it will not be 
analyzed nor described with summary statistics (i.e., radiographic Progression-free survival [rPFS] and 
disease control rate [DCR]). The PSA related efficacy will not be analyzed due to the significantly smaller 
sample size than the planned 200 and investigator’s inconsistent timing of PSA data collection. PSA 
data will only be able to be listed. Statistical testing will also not be applied to EPIC 26 Quality of life 
(QoL) questionnaire results and ECOG performance status, but summary statistics will be presented for 
these endpoints. Bone level pain data will only be able to be listed due to the nature of the data (i.e., 
free text pain levels).  
 
For the laboratory parameters listed in Table 6 in the protocol, there is no data for white blood cell (WBC) 
differential (percentage), mean corpuscular hemoglobin concentration (MCHC), BUN/creatinine, and 
glucose; however, there is additional data for white blood cell (WBC) differential (absolute), sodium, 
chloride, potassium and albumin. All laboratory parameters for which most patients have data will be 
included in the summary tables. All laboratory parameters for which there is any data will be listed. 
 
Section 2.3.2 and 3.10.2 - Definition and algorithm of PSA Progression Free Survival was updated to 
be in line with the Prostate Cancer Clinical Trials Work Group 3 (Scher et al 2016) and to have 
comparable data for the two main studies in this indication, VISION and RESIST-PC.  
 
Section 3.10.2 – Timepoints for Changes in performance status (ECOG) from baseline was to be 
evaluated over time at 3, 6, 9, 12, 18 and 24 months after start of 177Lu-PSMA-617 RLT; however, the 
eCRFs only captured ECOG with each 177Lu-PSMA-617 treatment visit and during follow-up. 
 




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2.3 
Study Objectives 
2.3.1 
Primary objectives 
1. To assess the clinical safety of 177Lu-PSMA-617 by evaluation of adverse events (AE) using 
severity (mild moderate and severe). SAE will be assessed by Common Terminology Criteria 
for Adverse Events (Common Terminology Criteria for Adverse Events (CTCAE) 
2. To assess the efficacy as defined by proportion of patients with PSA-response of ≥50% decline 
at 12-weeks from baseline  
2.3.2 
Secondary objectives 
1. Maximum PSA response: Maximal baseline to follow-up PSA decline, at any time during or 
after therapy [1].  
2. PSA Progression Free Survival (PFS): To determine the time to PSA progression, separate for 
treatment doses: time from inclusion (date of randomization) to date of PSA progression or 
death (whichever occurs first) [1]. 
a. For patients with PSA decline from baseline at any time during or after therapy:  PSA 
progression is defined as the date that a ≥ 25% increase in PSA and an absolute 
increase of 2 ng/mL or more from the nadir is documented and confirmed by a second   
value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks will be 
ignored in the absence of other evidence of disease progression (PCWG3 Guidance). 
b. For patients without PSA decline from baseline:  PSA progression is defined as a 
≥25% increase from the baseline value along with an increase in absolute value of 2 
ng/mL or more after 12 weeks of treatment. 
3. rPFS: To determine the radiographic progression free survival (rPFS), for each treatment 
dose: time from randomization to date when first site of disease is found to progress or death 
(whichever occurs first). 
a. Nodal and visceral disease is evaluated on cross-sectional imaging using Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1/ Prostate Cancer Working Group 
(PCWG3) criteria. 
b. Bone metastases are evaluated using bone scintigraphy and new lesions have to be 
confirmed on a second scan (2+2 rule) using PCWG3 criteria. 
4. To determine disease control rate (DCR) defined as the proportion of patients achieving 
RECIST 1.1/PCWG3 criteria stable disease (SD), partial response (PR) or complete response 
(CR). 
5. Change in Bone Pain Level and Quality of Life: Pain and Expanded prostate cancer index 
composite (“Epic-26”) Questionnaires will be completed at baseline and at 3, 6, 9, 12, 18 and 
24 months. Pain response will be determined in accordance with PCWG3 [1]. 
6. Change in Eastern cooperative oncology group (ECOG) performance score. 
2.4 
Primary and secondary endpoints 
2.4.1 
Primary endpoints 
1. Safety of 177Lu-PSMA-617RLT will be assessed by analysis of toxicity through adverse events. 
Both results from laboratory tests, physical examination and patient surveys will be included. 
2. Efficacy of 177Lu-PSMA-617 will be assessed at week 12 by means of number and percentage 
of patients with ≥50% decline in PSA at 12 weeks from baseline. Due to not enough patients 
to ensure the statistical power, and investigator’s inconsistent timing of PSA data collection. 
PSA data will only be able to be listed.  
2.4.2 
Secondary endpoints 
1. Maximum PSA response, time to PSA nadir, PSA PFS (Due to not enough patients to ensure 
the statistical power, and investigator’s inconsistent timing of PSA data collection. PSA data 
will only be able to be listed. 


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2. Radiographic progression-free survival (rPFS) (only limited imaging data is available for this 
endpoint) 
3. Disease control rate (DCR) (only limited imaging data is available for this endpoint) 
4. Bone pain level (as measured in the Baseline and Follow-Up Questionnaire for Pain and 
Adverse Events CRF) 
5. Quality of Life by the Quality of life questionnaire “EPIC-26”  
6. Performance status (ECOG)  
 
Due to the early stopping of enrollment into the study an abbreviated CSR will be written primarily 
concentrating on the primary endpoints. 
2.5 
Coding dictionaries  
 
Adverse events:  
Medical Dictionary for Regulatory Activities (MedDRA) version 22.1, 
CTCAE version 4.0 
3 
Statistical Evaluation 
The analysis cut-off date for the final analysis of study data will be established after all randomized 
patients have completed last follow-up visit or have discontinued study. All statistical analyses will be 
performed using all data collected in the database up to the data cutoff date. All data with an assessment 
date or event start date (e.g. vital sign assessment date or start date of an adverse event) prior to or on 
the cut-off date will be included in the analysis. Any data collected beyond the cut-off date will not be 
included in the analysis and will not be used for any derivations. The cutoff date for the final analysis is 
database lock date. 
All events with start date before or on the cut-off date and end date after the cut-off date will be reported 
as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off date and not having 
documented end date. This approach applies, in particular, to adverse event and concomitant 
medication reports. For these events, the end date will not be imputed and therefore will not appear in 
the listings. 
 
3.1 
Populations for Analysis 
 
Population 
Description 
Intention-to-Treat (ITT) 
Population 
All randomized patients.  Patients will be included in the treatment arm 
to which they were randomized regardless of actual treatment 
received. 
Safety Population (SAF) 
The subset of patients in the ITT population who received at least one 
dose of randomized therapy. Patients will be included in the treatment 
arm corresponding to the actual treatment received. 
 
Baseline summaries will be presented for the Safety and ITT populations. 
All efficacy analyses will be performed on the ITT population. 
Safety analyses will be presented for the Safety population. 
3.2 
Interim analyses 
None are planned in the protocol, however due to the early stopping of the study enrollment a database 
lock is to occur at some time after randomized patients have completed the treatment phase of the 
study. Using the locked database, the analyses described in this SAP will be performed to summarize 


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Statistical Analysis Plan 
 
 
 
 
 
 
 
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efficacy and safety (see section 1.2 for more details). At end of study, the safety summary will be updated 
to include all data collected during follow-up.  
3.3 
Subgroup analyses 
All Safety endpoints will have summary statistics provided by the following subgroup: 
1. Age (<65 years old, >= 65 years old) 
3.4 
Derived Data and Data Sets 
3.4.1 
Rules for incomplete data 
Missing data will not be replaced. Only partial dates as described below will be imputed for purposes of 
assignment of adverse events to treatment emergent. The imputed dates will not be listed. 
 
For the calculation of the time since initial cancer diagnosis, the following imputation rules will be 
applied when the date of initial diagnosis is incomplete: 
• If the day is missing: first day of the month. 
• If the day and month are missing: first day of January. 
For the assignment of AEs to treatment emergent, the following rules will be applied in case of 
incomplete dates: 
• If start date is incomplete:  
Missing 
Element 
Rule 
day, 
month, 
and year 
 
No imputation will be done for completely missing dates 
day, month 
 
If available year = year of study treatment start date then  
o 
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = 01JanYYYY  
o 
Else set start date = study treatment start date.  
 
If available year > year of study treatment start date then 01JanYYYY 
 
If available year < year of study treatment start date then 01JulYYYY 
day 
 
If available month and year = month and year of study treatment start date 
then  
o 
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 01MONYYYY.  
o 
Else set start date = study treatment start date. 
 
If available month and year > month and year of study treatment start date 
then 01MONYYYY   
 
If available month and year < month year of study treatment start date then 
15MONYYYY   
 
Any adverse events and concomitant medications with partial/missing dates will be displayed as such 
in the data listings. 
Also, any adverse events and concomitant medications which are continuing as per data cut-off will be 
shown as ‘ongoing’ rather than the end date provided.  
 
3.4.2 
General Analysis Definitions 


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Study day 
The study day describes the day of the event or assessment date, relative to the reference date.  
The study day is defined as: 
 
Study Day= Assessment date – Reference date +1 if assessment date is after or on the 
reference date 
 
 Study Day= Assessment date – Reference date if assessment date is before the reference date 
For visit’s assignment during treatment phase for the laboratory tests and PSA, and for Epic-26, for both 
treatment and follow-up phase, the reference date is defined as specified below in the table.   
For visit’s assignment during follow-up phase for the laboratory tests and PSA the reference date is 
defined the reference date for FU should be date of last dose + 1, as specified below in the table.  
 
Data collected for the following procedures according to the visit windows as specified below in the 
table: 
Parameters  
Analysis visit  
Reference day  
Target 
day 
of 
assessment 
compare to the 
reference day 
Time interval  
start 
(>=)  
end 
(<)  
 
Lab test 
Baseline  
 
 
The last  assessment 
on 
or 
before 
first 
injection 
Week 2 
First dose Day 1 
14  
Day 7 to day 21 
Week 4 
28 
Day 21 to day 35 
Week 6 
42 
Day 35 to day 49 
Week 2k 
(till week 36) 
D=7*2k 
Day D-7 to day D+7 
FU week 2 
Day 1 is the day 
after 
treatment 
end 
date, 
treatment 
end 
date is defined 
as the date of 
last injection 
14  
Day 7 to day 21 
FU week 4 
28 
Day 21 to day 35 
FU week 6 
42 
Day 35 to day 49 
FU week 2k 
(till FU week 12) 
D=7*2k 
Day D-7 to day D+7 
FU Month 6 
168 
Day 140 to day 196 
FU Month 9 
252 
Day 224 to day 280 


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Parameters  
Analysis visit  
Reference day  
Target 
day 
of 
assessment 
compare to the 
reference day 
Time interval  
start 
(>=)  
end 
(<)  
 
FU Month 12 
336 
Day 308 to day 364 
FU Month 3k 
(till FU MONTH 24) 
D=28*3k 
Day D-28 to day D+28 
 
PSA 
Baseline 
 
 
Safety analysis with 
SAF: 
the 
last 
assessment 
on 
or 
before treatment start 
date  
(PSA 
baseline 
disease characteristic 
uses last assessment 
on 
or 
before 
randomization 
for 
both ITT and SAF) 
Week 6 
SAF:First 
dose 
Day 1 
42 
Day 35 to day 49 
Week 12 
84 
Day 77 to day 91 
Week 18 
126 
Day 119 to day 133 
Week 6k (till end of the 
last dose) 
D=7*3k 
Day D-7 to day D+7 
FU Week 6  
Day 1 is the day 
after 
treatment 
end date 
42 
Day 35 to day 49 
FU month 3  
84 
Day 56 to day 112 
FU month 6  
168 
Day 140 to day 196 
FU month 9  
252 
Day 224 to day 280 
FU month 3k  
(Till early termination of 
study  or 24 month after 
the first treatment) 
D=28*3k 
Day D-28 to day D+28 
 
ECOG 
Baseline 
 
 
the last assessment 
before treatment start 
date 


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Parameters  
Analysis visit  
Reference day  
Target 
day 
of 
assessment 
compare to the 
reference day 
Time interval  
start 
(>=)  
end 
(<)  
 
Treatment visit 1 
 
 
Treatment visit  +-
7days 
Treatment visit 2 
 
Treatment visit 3 
 
Treatment visit 4 
 
FU month 3 
Day 1 is the day 
after 
treatment 
end date 
84 
Day 56 to day 112 
FU month 6 
168 
Day 140 to day 196 
FU month 9 
252 
Day 224 to day 280 
FU month 3k 
(Till early termination of 
study  or 24 month after 
the first treatment) 
D=28*3k 
Day D-28 to day D+28 
 
Epic-26 
Baseline 
 
 
the last assessment 
before or on treatment 
start date 
Month 3 
First dose Day 1 
84 
Day 56 to day 112 
Month 6 
 
168 
Day 140 to day 196 
Month 9 
 
252 
Day 224 to day 280 
Month 3k 
 
D=28*3k 
Day D-28 to day D+28 
FU month 3 
Day 1 is the day 
after 
treatment 
end date 
84 
Day 56 to day 112 
FU month 6 
 
168 
Day 140 to day 196 
FU month 9 
 
252 
Day 224 to day 280 
FU month 3k 
(Till early termination of 
study  or 24 month after 
the first treatment) 
 
D=28*3k 
Day D-28 to day D+28 
 


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Parameters  
Analysis visit  
Reference day  
Target 
day 
of 
assessment 
compare to the 
reference day 
Time interval  
start 
(>=)  
end 
(<)  
 
Pain and AE 
questionnaire  
Baseline 
Injection 1 
Day of the first 
injection  
Cycle 1 pre-dose 
Cycle 1 Post Dose 
Injection 1 
Day of the first 
injection +1 
For pre dose, a 
window of 10 days 
before will be applied 
and the last 
assessment within 
this window will be 
used for the table, 
 
For post dose, a 
window of 10 days 
after will be applied 
and the earliest 
assessment within 
this window will be 
used for the table  
 
 
Cycle 2 Pre Dose 
Injection 2 
Day of the second 
injection 
Cycle 2 Post Dose 
Injection 2 
Day of the second 
injection +1  
Cycle 3 Pre Dose 
Injection 3 
Day of the third 
injection 
Cyce 3 Post Dose 
Injection 3 
Day of the third 
injection +1 
Cycle 4 Pre Dose 
Injection 4 
Day of the fourthe 
injection 
Cycle 4 Post Dose 
Injection 4 
Day of the fourth 
injection +1 
FU month 3 
Day 1 is the day 
after 
treatment 
end date 
84 
Day 56 to day 112 
FU month 6 
 
168 
Day 140 to day 196 
FU month 9 
 
252 
Day 224 to day 280 
FU month 3k 
(Till early termination of 
study  or 24 month after 
the first treatment) 
 
D=28*3k 
Day D-28 to day D+28 
 
Vital sign 
Baseline  
 
 
Treatment visit 1, pre-
dose,  
Treatment visit 1, 30 
mins post dose, 60 mins 
post dose 
Injection 1 
 
Treatment visit x is 
from injection x to the 
day before injection 


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Parameters  
Analysis visit  
Reference day  
Target 
day 
of 
assessment 
compare to the 
reference day 
Time interval  
start 
(>=)  
end 
(<)  
 
Treatment visit 2, pre-
dose, 30 mins post 
dose, 60 mins post dose 
Injection 2 
 
x+1. For the last 
injection Treatment 
visit y is from the last 
injection to last 
injection + 28 days. 
Treatment visit 3, pre-
dose, 30 mins post 
dose, 60 mins post dose 
Injection 3 
 
Treatment visit 4, pre-
dose, 30 mins post 
dose, 60 mins post dose 
Injection 4 
 
FU month 3 
Day 1 is the day 
after 
treatment 
end date 
84 
Day 56 to day 112 
FU month 6 
 
168 
Day 140 to day 196 
FU month 9 
 
252 
Day 224 to day 280 
 
 
 
 
FU month 3k 
(Till early termination of 
study  or 24 month after 
the first treatment) 
 
D=28*3k 
Day D-28 to day D+28 
 
12 lead ECG 
Baseline 
 
 
Treatment visit 1, pre-
dose 
Treatment visit 1, post-
dose 
Injection 1 
 
Treatment visit x is 
from injection x to the 
day before injection 
x+1. For the last 
injection Treatment 
visit y is from the last 
injection to last 
injection + 28 days. 
Treatment visit 2, pre-
dose, post-dose 
Injection 2 
 
Treatment visit 3, pre-
dose, post-dose 
Injection 3 
 
Treatment visit 4, pre-
dose, post-dose 
Injection 4 
 
 
If more than one assessment is done within the same time window, the assessment performed closest 
to the target date will be used. If two assessments within a time window are equidistant from the target 
date, then the earlier of the two assessments will be used. If multiple assessments on the same date 


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then the worst case will be used.  Data from all assessments (scheduled and unscheduled), including 
multiple assessments, will be listed. For those parameter analysis at timepoints should be analyzed 
separately at timepoints, not be considered as multiple test within one window.  
Time unit 
A year length is defined as 365.25 days.  A month length is 30.4375 days (365.25/12).  If duration is 
reported in months, duration in days will be divided by 30.4375; if duration is provided in days, duration 
in months will be multiplied by 30.4375.  If duration is reported in years, duration in days will be divided 
by 365.25. 
Baseline 
For safety evaluations, the last available assessment on or before the date of start of study treatment is 
taken as ‘‘baseline” assessment. Evaluation of EPIC-26 will use safety definition for baseline. 
For PSA relevant safety analysis, baseline for safety evaluation definition will be used with SAF 
population. PSA data will only be able to be listed. 
ECOG Baseline is defined as last assessment before treatment start date 
3.4.3 
Rules for adverse events 
Intensity 
AE is collected in eCRF based on severity (mild, moderate and severe), SAE is based on CTCAE 
Grading. 
 
Body System 
Adverse events will be categorized by MedDRA preferred term (PT) and system organ class (SOC). 
 
Attribution of the AE to Study Drug 
A frequency table will be presented showing the information on attribution of the AE to study drug using 
the categorization given on the case report forms (CRFs): 
 
 
1  ‘none’, 
   2  ‘unlikely’, 3  ‘possible’, 4  ‘probable’, 5  ‘definite’. 
 
Moreover, this categorization will be used in data listings. 
3.4.4 
Rules for vital signs 
Systolic blood pressure 
Following categories will be used for analysis of changes:  
1  'Decrease (Dec) >40 
 
(i.e. Difference (D) < -40 mm Hg)' 
2  'Dec >20-40 
 
 
(i.e. -40 mm Hg  D < -20 mm Hg)'  
3  'Difference (+/-) 0-20 
 
(i.e. -20 mm Hg  D  20 mm Hg)'  
4  'Increase (Inc) >20-40 
 
(i.e. 20 mm Hg <  D  40 mm Hg)'  
5  'Inc >40 
 
 
 
(i.e. D > 40 mm Hg)'. 
 
Diastolic Blood Pressure 
Following categories will be used for analysis of changes:  
1  'Dec >30 
 
(i.e. D < -30 mm Hg)' 
2  'Dec >15-30 
(i.e. -30 mm Hg  D < -15 mm Hg)'  
3  '+/- 0-15 
 
(i.e. -15 mm Hg  D  15 mm Hg)'  
4  'Inc >15-30  
(i.e. 15 mm Hg <  D  30 mm Hg)'  
5  'Inc >30 
 
(i.e. D > 30 mm Hg)'. 
 


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Heart Rate 
Following categories will be used for analysis of changes:  
1  'Dec >30 
 
(i.e. D < -30 beats/min)' 
2  'Dec >15-30 
(i.e. -30 beats/min  D < -15 beats/min)'  
3  '+/- 0-15 
 
(i.e. -15 beats/min  D  15 beats/min)'  
4  'Inc >15-30  
(i.e. 15 beats/min <  D  30 beats/min)'  
5  'Inc >30 
 
(i.e. D > 30 beats/min)'. 
 
3.5 
General Variable Definitions 
Data will be analyzed using SAS version 9.4 or higher.  
Descriptive statistics will be presented in tables as follows:  
• Categorical data will be summarized in contingency tables presenting frequencies and 
percentages. 
• Continuous data will be summarized using number of non-missing values (n), mean, standard 
deviation, median, minimum, and maximum values. 
Unless otherwise indicated, for frequency tables, patients with missing data will be excluded from the 
denominator of percentage calculations.  
Individual patient listings will include all study-related data. The sort order of the listings will be by 
treatment, patient ID, and date of assessment (if available). 
If multiple results for the same assessment are collected during a visit time window, the first result will 
be utilized unless indicated otherwise.  
The following definitions will be used: 
 Age (years): year of informed consent - year of birth  
 Time since initial cancer diagnosis (years): (Date of randomization - Date of initial cancer 
diagnosis)/(365.25) 
 Weight (kg) = weight (lb) * 0.45359237 
 Height (cm) = height (in) * 2.54 
3.6 
Patient Disposition, Deviations, Demography 
The following patient data will be summarized in tables for all patients: 
• Number (%) of patients who signed informed consent 
• Number (%) of patients in each analysis population  
The following patient data will be summarized in tables for the ITT population: 
 Number (%) of patients discontinued from study treatment 
 Number (%) of patients discontinued from the study  
 Number (%) for the primary reason for discontinuation for each of the above 
 
For the ITT population, protocol deviations will be listed by treatment and patient ID. 
 
Demographic data (age (years), age categorical (< 65 years, >= 65 years), ethnicity, race, weight (kg), 
height (cm), and pulse oximetry (%)) will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum for quantitative variables; frequency counts by category will 


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be given for qualitative variables). All demographic summary tables will be based on the ITT and Safety 
populations. An individual listing will be provided for demographic data for the ITT population.  
 
For demographic and baseline characteristics, the last available assessment on or before the date of 
start of study treatment is taken as ‘‘baseline” assessment for both ITT and safety population analyses. 
3.7 
Baseline Disease Characteristics 
Descriptive statistics of patient disease characteristics at baseline will be presented for the following 
variables for the ITT and Safety population: 
• Time since initial cancer diagnosis (years) 
• Initial Histopathological Classification (type of prostate cancer tumor) 
• Initial Gleason score 
o 
Categorical: 2-3,4-7,8-10, unknown 
• Baseline PSA doubling time (months): continuous and categorical (≤ 6 months vs. >6 months) 
Baseline PSA doubling time (months):  PSA doubling time will be calculated as natural log of 2 
(0.693) divided by the sum of the fixed slope (common to all patients) and the random slope (specific 
for the patient)  of the random coefficient linear model between the natural log of PSA and time of 
PSA measurement (Svatek et al., 2006).  If the PSA doubling time is less than zero (i.e. stable, 
nonincreasing, or decreasing PSA levels as defined by a negative slope from the random coefficient 
linear model), the PSA doubling time is set to 0. PSA is collected at screening visit and for the most 
recent 2 PSA measurements available prior to screening.  Calculations will be performed only for 
subjects with (1) all 3 PSA values with each value ≥ 0.2 ng/mL and (2) for which the interval between 
the first and last PSA values are ≥8 weeks but ≤ 12 months as stated in PCWG3 guidelines (Scher 
et al., 2016; Pound et al., 1999). 
For interpretation of PSA doubling time it should be noted that PCWG3 guidelines state the calculation 
should be based on the most recent PSA values during androgen deprivation therapy, and that 3 PSA 
values ≥ 0.2 ng/mL should be consecutive.  These additional criteria will not be applied since the 
information is not available.  
• Baseline PSA 
For Baseline PSA as baseline disease characteristic, the last available assessment on or before the 
date of randomization is taken as ‘‘baseline” assessment for both ITT and safety population analyses. 
 
 
Listings of baseline disease characteristics will be provided for the ITT population. 
3.8 
Medical History  
A medical history listing will be provided for the ITT population. 
3.9 
Prior Cancer Related Therapy 
Descriptive statistics with respect to prior therapy collected on the Prostate Cancer Treatment History 
CRF pages (Chemotherapy, Other Treatment, and Radiotherapy) will be displayed for the ITT 
population.  A listing of data recorded on the Prostate Cancer Treatment History CRF pages 
(Chemotherapy, Other Treatment, and Radiotherapy) will also be provided for the ITT population. 
The variables to be summarized in tables are: 
 
Prostate Cancer Treatment History: Chemotherapy 


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- 
Prior number of therapies 
- 
Prior number of taxane-containing regimens 
- 
Number of unique agents 
 
 
Prostate Cancer Treatment History: Chemotherapy - Last Taxane Therapy 
- 
Number of cycles 
- 
Duration of therapy (months) 
- 
Best overall response (BOR) to last taxane-therapy (Complete response (CR), Partial 
response (PR), Stable disease (SD), Progressive Disease (PD), Missing) 
 
 
Prostate Cancer Treatment History: Chemotherapy - Last Therapy 
- 
Type of last prior therapy 
- 
Number of cycles 
- 
Duration of therapy (months) 
- 
Best Response (CR, PR, SD, PD, Missing) 
 
 
Prostate Cancer Treatment History: Other Treatment 
- 
Number of patients with at least one prostate cancer-related other treatment 
- 
Type of other treatment 
- 
Prior number of other treatments 
 
 
Prostate Cancer Treatment History: Radiotherapy 
- 
Number of patients with at least one prostate cancer-related radiotherapy 
- 
Type of prior radiotherapy 
- 
Prior number of radiotherapies 
3.10 Efficacy Analysis 
 
All efficacy analyses will be based on the ITT population.   
 
Due to not enough patients to ensure the statistical power, and investigator’s inconsistent timing of PSA 
data collection. PSA efficacy endpoints will not be analyzed and therefore are not described in this SAP. 
PSA results will be listed by visit for all patients in the SAF population 
 
Due to only limited imaging data being available, the relevant endpoints (i.e., rPFS and DCR) will not be 
analyzed and therefore are not described in this SAP. 
 
Bone pain level 
 
Bone pain level will be listed by visit for all patients in the ITT population.     
 
QoL: EPIC-26 
 
Quality of Life questionnaire “EPIC-26” item value will be transformed into score as below. HRQOL 
domain score will be calculated as below. If >20% of the items that comprise a domain summary score 
or subscale score are missing a response, the corresponding domain summary or subscale score 
cannot be calculated. Domain scores at each time point, along with the change from baseline, will be 
summarized as continuous variable at baseline and at treatment visits and follow-up 3, 6, 9, 12, 18 and 
24 months after start of 177Lu-PSMA-617 RLT. Results will be presented separately for both treatment 
groups (6.0 vs. 7.4 GBq 177Lu-PSMA-617) and overall. Item value with standardized score will also be 
listed. 
 


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Item numbers are indicated along the right border of the questionnaire (question numbers on left of 
questionnaire pages are not used for scoring because some questions contain multiple items).  
 
Change in ECOG-PS 
 
The changes in ECOG from baseline will be evaluated over time at treatment visit 1, 2, 3 and 4 
administration, and at follow-up visits. Shift tables will be provided for each post administration time point 
and FU visits compared to baseline. Results will be presented separately for both treatment groups (6.0 
vs. 7.4 GBq 177Lu-PSMA-617) and overall. Results will also be listed for the ITT population. 
 
Exploratory efficacy analysis not planned. 
3.11 Safety Analysis 
The safety analysis will be based on the safety population.  Tables will show results by treatment arm 
and for all patients combined. Listings will be created by treatment arm. 
 
For all safety summary tables, the tables will also be provided by age (<65 years old, >= 65 years old). 
 
Reference date is the date of first dose of Lu-PSMA-617 unless otherwise noted. 
3.11.1 Safety Variable Definitions 
 
177Lu-PSMA-617 exposure variables:  
Duration of exposure/study treatment (months) = (Date of last study drug administration – 
Reference date + 1)/30.4375 


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Dose per cycle 
Dose for each cycle/overall (GBq/cycle) = (actual total dose during the cycle/study) / (1 or actual 
# of cycles) 
Planned dose for each cycle/overall (GBq/cycle) = (planned total dose during the cycle) / (1 or 
planned # of cycles)  
Note:  Planned number of cycles = received number of cycles unless there was a missed dose 
Relative dose per cycle/overall (%) = (dose by cycle/overall) / (planned dose by cycle/overall) 
3.11.2 Extent of Exposure 
A listing of study drug administration will be provided. 
Randomized Treatment Exposure, Summary of Cycles 
For the Safety population, summary of treatment cycle variables to be included are: 
 Duration of study treatment (months) 
 Number of cycles started per patient (both as categorical and continuous variable)  
 Average duration of treatment cycles (months) 
Randomized Treatment Exposure, By Cycle and Across Cycles Combined 
For the Safety population, 177Lu-PSMA-167 exposure variables to be summarized for the entire study 
and for each cycle are: 
 Cumulative dose (GBq) of patient 
 Dose per cycle/overall (GBq/cycle) 
 Relative dose per cycle/overall (%) 
To convert from mCi units to GBq units the conversion 1 mCi = 0.037 GBq will be used. 
3.11.3 Adverse Events 
Safety of 177Lu-PSMA-617 RLT will be assessed by analysis of toxicity.  
Adverse events (AE) will be coded using MedDRA version 22.1, by SOC and PT. Serious AEs will be 
graded according to the NCI CTCAE criteria version 4.0 while AEs will be described by severity (i.e., 
Mild, Moderate, Severe).  
In case a patient experienced the same event more than once, the maximum toxicity grade will be 
presented. 
In all AE tables, multiple occurrences of the same adverse events occurring in one individual are counted 
only once. 
 
Definition of Treatment Emergent Adverse Event (TEAE) 
A randomized treatment TEAE is defined as an AE that was not present prior to initiation of randomized 
treatment, defined as first dose of 177Lu-PSMA-617, but appeared following treatment, or was present 
at treatment initiation but worsened during treatment. An AE that was present at treatment initiation but 
resolved and then reappeared while the patient was on treatment is a TEAE (regardless of the intensity 
of the AE when the treatment was initiated).  
Any event that is considered study drug-related (stated as possible, probably, definite relationship, or 
missing assessment of relatedness), regardless of the start date of the event, or any event that worsens 
in toxicity grade while on treatment or is subsequently considered study drug-related by the investigator 
is also defined as a treatment-emergent adverse event. 


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The treatment-emergent period will be defined as the period from the date of initiation of randomized 
treatment up to 30 days after date of last administration of study treatment or the day prior to the initiation 
of subsequent anticancer treatment, whichever occurs first. 
Randomized Treatment Adverse Events 
A summary table including the number of patients with at least one event, will be presented for the AE 
variables below.    
• TEAE1, 3                       
• Serious TEAE1, 2, 3 
• Drug-related TEAE1 
• Serious drug-related TEAE1 
• TEAE leading to reduction of 177Lu-PSMA-617 dose1  
• TEAE leading to permanent discontinuation of 177Lu-PSMA-617 treatment1  
• Fatal TEAE1 
1AE variables to be tabulated by SOC and PT.  
 
2Serious AE variables to be tabulated by SOC and PT by CTCAE grade. 
 
3AE variables are to be tabulated by SOC and PT, CTCAE grade (serious AEs) or severity grade 
(TEAEs), and cycle. 
 
A listing for each patient will include the same variables as mentioned above and will also include action 
taken regarding 177Lu-PSMA-617. 
Deaths 
All deaths will be summarized by treatment groups (6.0 vs. 7.4 GBq 177Lu-PSMA-617) and overall with 
the End of Treatment status table; deaths will also be listed. 
Specific Adverse Events Questionnaire 
Adverse events as captured on the pain and adverse events questionnaire form will be summarized and 
listed by treatment arm. A listing will also be created. 
3.11.4 Laboratory Data 
Laboratory parameters will be analyzed descriptively by summary tables.  
 
Hematology 
Clinical Chemistry 
Hematocrit 
eGFR 
Hemoglobin 
Bilirubin 
Red blood cell (RBC) count (Erythrocytes) 
Creatinine 
WBC count (Leukocytes) 
Sodium 
Absolute Monocyte count 
Urea nitrogen (BUN) 
Platelets 
Chloride 
Absolute neutrophil count (ANC) 
AST/SGOT 
Mean corpuscular volume (MCV) / Mean 
corpuscular hemoglobin (MCH) 
ALT/SGPT 
Absolute Eosinophil count 
Alkaline phosphatase 
Absolute Basophil count 
PSA* 
Absolute Lymphocyte count 
Albumin 
RDW (Erythrocytes Distribution Width) 
Potassium 


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*PSA will be done only at the time intervals called by the protocol (see Schedule of Events in Section 3.13). 
 
Laboratory values and, for assessments measured over time, change from baseline will be summarized 
by visit. Frequency statistics for qualitative laboratory parameters will also be presented by visit. 
Shift tables of high-normal-low laboratory values from baseline to each measurement time point will be 
provided for each parameter that has a reference range. The abnormal flag be derived based on the 
upper and lower limits of normal range. Reference ranges are taken from the Merck Manual Professional 
Version, 2018 and the Merck Manual Consumer Version for Complete Blood Count for all parameters 
except estimated Glomerular Filtration Rate (eGFR; reference range from National Kidney Foundation).  
The mean (±standard error) values over time will be plotted for PSA by treatment arm.  
Patient listings of all lab values will be provided, values outside of the laboratory’s reference range will 
be flagged for all parameters with ranges. The patient listings will indicate the CTCAE grade if one is 
provided in the data.  
3.11.5 Vital Signs 
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (bpm), temperature (C), 
and respiratory rate (breaths per min) will be analyzed descriptively by summary tables noting observed 
values and change from baseline. Transition tables will be provided for the transitions from baseline to 
each follow-up time point.   
3.11.6 12-Lead ECG Data 
Overall ECG interpretation will be summarized. Heart rate (bpm), PR (msec), QRS (msec), QT (msec) 
and QTc (msec; measured by both sites as QTcB using Bazett’s formula) intervals will be summarized 
as continuous variables.  All ECG variables will also be listed.  
3.11.7 Physical Exam  
Physical examination results will be listed for the Safety population 
 
3.11.8 Concomitant Medications  
Medications as recorded on the Concomitant Medications CRF will be listed. 
Medications will be classified as prior and/or concomitant. Prior medications are all medications taken 
or occurring prior to first dose of 177Lu-PSMA-617. Concomitant medications are all medications 
continued or started on or after the date of the first randomized study drug administration 
3.11.9 Concurrent and Post Chemotherapy 
Descriptive statistics for Concurrent Chemotherapy and Post-Treatment Chemotherapy will be 
displayed using the data collected on the Treatment Visit Concomitant Cancer-related Therapy 
Chemotherapy CRF and Follow-up Concomitant Cancer-related Therapy Chemotherapy CRF, 
respectively.  Separate listings of Concurrent Chemotherapy and Post-Treatment Chemotherapy will be 
provided.  
 
The variables to be summarized in the table are: 
- 
Number of patients with at least one chemotherapies 
- 
Number of chemotherapies 
- 
Type of chemotherapies 
 
3.11.10 Concurrent and Post Radiotherapy  


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Descriptive statistics for Concurrent Radiotherapy and Post-Treatment Radiotherapy will be displayed 
using the data collected on the Treatment Visit Concomitant Cancer-related Therapy Radiotherapy CRF 
and Follow-up Concomitant Cancer-related Therapy Radiotherapy CRF, respectively.  Separate listings 
of Concurrent Radiotherapy and Post-Treatment Radiotherapy will be provided.  
 
The variables to be summarized in the table are: 
- 
Number of patients with at least one radiotherapy 
- 
Number of radiotherapies 
- 
Type of radiotherapies 
 
3.11.11 Concurrent and Post Other Treatments 
Descriptive statistics for Concurrent Other Therapy and Post-Treatment Other Therapy will be displayed 
using the data collected on the Treatment Visit Concomitant Cancer-related Therapy Other Therapy 
CRF and Follow-up Concomitant Cancer-related Therapy Other Therapy CRF, respectively.  Separate 
listings of Concurrent Other Therapy and Post-Treatment Other Therapy will be provided.  
 
The variables to be summarized in the table are: 
- 
Number of patients with at least one other treatments 
- 
Number of other treatments 
- 
Type of other treatments 
 
3.12 Other Analyses 
None.  
3.13 Schedule of Events 
 


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Note: ECOG was done at every treatment visit then every three month FU visits  
3.14 References 
1. Scher, H.I., et al., Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. 
J Clin Oncol, 2016. 34(12): p. 1402-18. 
 
2. Rahbar, K., et al., German multicenter study investigating 177Lu-PSMA-617 radioligand 
therapy in advanced prostate cancer patients. J Nucl Med, 2016. 
 
3. Danila, D.C., et al., Phase II multicenter study of abiraterone acetate plus prednisone 
therapy in patients with docetaxel-treated castration-resistant prostate cancer. J ClinOncol, 2010. 
28(9): p. 1496-501. 
 
Appendix I Generalized Reference Ranges  
Laboratory Test 
Units 
Merck 
Low  
Merck 
High 
National 
Kidney 
Foundation 
Low  
National 
Kidney 
Foundation 
High 
Albumin 
g/dL 
3.5 
5.4 
  
  
Alkaline Phosphatase 
U/L 
36 
150 
  
  
Alanine Aminotransferase 
U/L 
0 
35 
  
  
Aspartate 
Aminotransferase 
U/L 
0 
35 
  
  
Bilirubin 
mg/dL 
0.3 
1.2 
  
  
Chloride 
mEq/L 
98 
106 
  
  
Creatinine 
mg/dL 
0.7 
1.3 
  
  
Glomerular Filtration Rate, 
Estimated* 
mL/min/1.73 
m2 
  
  
>90 
  
Potassium 
mEq/L 
3.5 
5 
  
  
Sodium 
mEq/L 
136 
145 
  
  
Urea Nitrogen 
mg/dL 
8 
20 
  
  
Basophils 
x10^3/mcL 
0 
0.3 
  
  
Basophils/Leukocytes 
% 
0 
3 
  
  
Eosinophils 
x10^3/mcL 
0 
0.9 
  
  


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Eosinophils/Leukocytes 
% 
0 
8 
  
  
Hematocrit 
% 
41 
51 
  
  
Hemoglobin 
g/dL 
14 
17 
  
  
Lymphocytes 
x10^3/mcL 
1.0 
4.8 
  
  
Lymphocytes/Leukocytes 
% 
22 
44 
  
  
Ery. 
Mean 
Corpuscular 
Hemoglobin 
pg 
28 
32 
  
  
Ery. 
Mean 
Corpuscular 
Volume 
fL 
80 
100 
  
  
Monocytes 
x10^3/mcL 
0.2 
1.2 
  
  
Monocytes/Leukocytes 
% 
4 
11 
  
  
Neutrophils 
x10^3/mcL 
1.8 
7.7 
  
  
Neutrophils/Leukocytes 
% 
40 
70 
  
  
Platelets 
x10^3/mcL 
150 
450 
  
  
Erythrocytes 
x10^6/mcL 
4.2 
5.9 
  
  
Erythrocytes 
Distribution 
Width 
% 
11.5 
14.5 
  
  
Leukocytes 
x10^3/mcL 
4.5 
11 
  
  
Prostate Specific Antigen 
ng/mL 
0 
4 
  
  
Prostate Specific Antigen 
ng/mL 
0 
4 
  
  
Ranges taken from Merck Manual Professional Version, 2018 and the Merck Manual Consumer Version for Complete Blood  
*estimated Glomerular Filtration Rate (eGFR) taken from the National Kidney Foundation 
 


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PSMA-617-02  
Statistical Analysis Plan Addendum 1  
  
  
  
  
  
  
 
  
Statistical Analysis Plan Addendum 1/ Final / 15-Dec-2020 / RESIST-PC  
Page 1 of 7  
  
  
  
  
Final  
  
STATISTICAL ANALYSIS PLAN ADDENDUM 1  
  
Study PSMA-617-02  
  
  
Title: (as per protocol/amendment)       PSMA-Directed Endoradiotherapy Of   
Castration-Resistant Prostate Cancer   
(RESIST-PC). A Phase II Clinical Trial  
  
  
Version:  
Final Addendum 1  
  
  
Date:  
 15-Dec-2020  
  
  
CONFIDENTIAL  
  
  
  
 
 
 
 
 


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Statistical Analysis Plan Addendum 1  
  
  
  
  
  
  
 
  
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1 
APPROVAL SIGNATURES  
STUDY TITLE: PSMA-Directed Endoradiotherapy Of Castration-Resistant Prostate Cancer 
(RESISTPC). A Phase II Clinical Trial  
PROTOCOL NUMBER: PSMA-617-02  
SAP Addendum 1 Final, 15-Dec-2020  
  
Endocyte, Inc.:   
  
Reviewed/Approved By: 
, 
  
 
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                                                                                                                                                                                                                                                                                                                               Reason: I am approving this document  
                                                                                                                                                                                                                                                                                                                               Date: 2020.12.16 19:38:11 +01'00 
 
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Reviewed/Approved By:
    
Signature:  
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Reviewed/Approved By:
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Signature:  
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Date:  ......................  
  
Reviewed/Approved By: 
, M.D., M.H.S., M.Sc., 
  
 
................................................................ 
Date:  ......................  
  
  
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Reason: I am approving this document  
Date: 2020.12.15 15:47:42 -05'00                                                                                                           
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Reason: I am approving this document 
Date: 2021.01.11 16:10:41 -05'00' 
       Signature: 


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Statistical Analysis Plan Addendum 1  
  
  
  
  
  
  
 
  
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2 
Abbreviations  
  
Abbreviation  
Description  
CR  
Complete response  
DCR  
Disease control rate  
ITT   
Intent-to-treat   
PCWG3  
Prostate Cancer Working Group 3  
PD  
Progressive disease  
PFS  
Progression-free survival  
PR  
Partial response  
PSA  
Prostate-specific antigen  
RECIST  
Response evaluation criteria in solid tumors  
rPFS  
(radiographic) Progression-free survival  
SD  
Stable disease  
  
 


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3 
Table of Contents  
  
1  APPROVAL SIGNATURES .................................................................................................................2 
2  ABBREVIATIONS ................................................................................................................................3 
3  TABLE OF CONTENTS .......................................................................................................................4 
4  REASON FOR ADDENDUM ...............................................................................................................5 
5  OBJECTIVES AND ENDPOINTS FOR SAP ADDENDUM ................................................................5 
5.1  STUDY OBJECTIVES ...................................................................................................................... 5 
5.1.1 Primary objectives ...........................................................................................................................5 
5.1.2 Secondary objectives ......................................................................................................................5 
5.2  PRIMARY AND SECONDARY ENDPOINTS .......................................................................................... 6 
5.2.1 Primary endpoints ...........................................................................................................................6 
5.2.2 Secondary endpoints.......................................................................................................................6 
6  ANALYSES ..........................................................................................................................................6 
7  STATISTICAL METHODS AND DEFINITIONS FOR ADDENDUM ...................................................6 
 
 
 


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Statistical Analysis Plan Addendum 1  
  
  
  
  
  
  
 
  
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4 
Reason for addendum  
The original statistical analysis plan (SAP), Version 2.0, dated 15-May-2020, describes the analyses 
planned for the abbreviated clinical study report (aCSR) that summarized the safety data and listed the 
efficacy data. The efficacy data was not summarized for the aCSR due to the significantly smaller sample 
size than the planned 200 patients since enrollment into the study was stopped early. The modeling 
approaches stated in the protocol could not be carried out as there was insufficient data to perform the 
analyses that would allow for appropriate evaluation of effectiveness.    
  
Clinicaltrials.gov requires all available data for primary and secondary endpoints to be disclosed.  The 
purpose of this SAP addendum is to describe the analyses planned for clinicaltrials.gov using the limited 
data available. Due to only limited imaging and PSA data being available, some secondary endpoints 
could not be analyzed as planned in the protocol and the changes to the analyses are described in this 
SAP addendum. The source of the data is the clinical database.     
5 
Objectives and Endpoints for SAP Addendum  
5.1 
Study Objectives  
5.1.1 
Primary objectives  
1. To assess the efficacy as defined by proportion of patients with PSA-response of ≥50% decline  
at 12-weeks from baseline   
5.1.2 
Secondary objectives  
1. Maximum PSA response: Maximal baseline to follow-up PSA decline, at any time during or 
after therapy.   
2. PSA Progression Free Survival (PFS): To determine the time to PSA progression, separate for 
treatment doses: time from inclusion (date of randomization) to date of PSA progression or 
death (whichever occurs first). SAP Addendum Note: Time to PSA progression will not be 
analyzed; only number of PSA progression or death events can be summarized for this 
objective.   
a. For patients with PSA decline from baseline at any time during or after therapy:  PSA  
progression is defined as the date that a ≥ 25% increase in PSA and an absolute 
increase of 2 ng/mL or more from the nadir is documented and confirmed by a second   
value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks will be 
ignored in the absence of other evidence of disease progression (PCWG3 Guidance).  
b. For patients without PSA decline from baseline:  PSA progression is defined as a 
≥25% increase from the baseline value along with an increase in absolute value of 2 
ng/mL or more after 12 weeks of treatment.  
3. rPFS: To determine the radiographic progression free survival (rPFS), for each treatment 
dose: time from randomization to date when first site of disease is found to progress or death 
(whichever occurs first). SAP Addendum Note: rPFS cannot be analyzed; only investigator 
assessment of RECIST 1.1 overall response by each follow-up assessment and investigator 
assessment of PCWG3 bone scan clinical impression by visit can be summarized for this 
objective.   
a. Nodal and visceral disease is evaluated on cross-sectional imaging using Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1/ Prostate Cancer Working Group 
(PCWG3) criteria.  


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b. Bone metastases are evaluated using bone scintigraphy and new lesions have to be 
confirmed on a second scan (2+2 rule) using PCWG3 criteria.  
4. To determine disease control rate (DCR) defined as the proportion of patients achieving 
RECIST 1.1/PCWG3 criteria stable disease (SD), partial response (PR) or complete response 
(CR). SAP Addendum Note: Only RECIST 1.1 disease control rate by each follow-up 
assessment can be summarized for this objective.  
5.2 
Primary and secondary endpoints  
5.2.1 
Primary endpoints  
1. Efficacy of 177Lu-PSMA-617 will be assessed at week 12 by means of number and percentage of 
patients with ≥50% decline in PSA at 12 weeks from baseline.    
5.2.2 
Secondary endpoints  
1. Maximum PSA response  
2. PSA-PFS   
3. Radiographic progression-free survival (rPFS)   
4. Disease control rate (DCR)   
6 
Analyses  
Tables will show results by treatment arm and for all patients combined. The following patient data will 
be summarized in tables for the ITT population: • PSA Response at Week 12  
• 
Percent change in PSA from baseline to Week 12  
• 
Maximum PSA response  
• 
PSA Progression and Death Events  
• 
RECIST 1.1 Overall Response by Follow-up Assessment Visit  
• 
RECIST 1.1 Disease Control Rate by Follow-up Assessment visit  
• 
PCWG3 Bone Scan Clinical Impression by Visit  
7 
Statistical Methods and Definitions for Addendum  
The same statistical methods as described the original SAP will be followed, with any exceptions noted 
below. Table shells are created along with this document.   
  
• 
Baseline PSA is defined as the last available assessment prior to or on first dose date of 
177LuPSMA-617.  
• 
PSA response at Week 12:  PSA response is defined as the proportion of patients who have a 
≥50% decrease in PSA from baseline at Week 12.  
• 
Maximum PSA response includes all available PSA results, including unscheduled, up to and 
including the last assessment visit.  
• 
PSA progression is defined as:   
(a) 
For patients with PSA decline: PSA progression is defined as the date that a ≥ 25% 
increase in PSA and an absolute increase of 2 ng/mL or more from the nadir is documented and 
confirmed by a second consecutive value obtained 3 or more weeks later. Rises in PSA within 
the first 12 weeks will be ignored (PCWG3 Guidance),   


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(b) 
For patients without PSA decline:  PSA progression is defined as a ≥25% increase from 
the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks 
of treatment.  
• 
RECIST 1.1 Overall Response = Number of patients with an overall response of Complete 
Response (CR),  Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) 
according to RECIST v1.1 using investigators assessments.  
o 
There is no minimum time after first dose of 177Lu-PSMA-617 to when first assessment 
is included in analysis.  
o 
Data is summarized by assessment visit; therefore, the data presented is unconfirmed 
response.  
• 
RECIST 1.1 Disease Control Rate = Proportion of patients with Overall Response of CR, PR, or 
SD according to RECIST v1.1 using investigators assessments.  
• 
PCWG3 Bone Scan Clinical Impression = Number of patients with a clinical impression of 
Improved, Stable or Progression according to PCWG3 using investigators assessments.  
As stated in the original SAP, the investigator’s had inconsistent timing of PSA data collection; therefore 
PSA-PFS will not be derived because censoring rules are not applicable given this inconsistent timing 
of PSA data collection. Instead, number and percentage of patients with a PSA progression event or 
death event will be summarized.   
As stated in the original SAP, limited imaging data is available.  The date of radiographic tumor 
assessment for the RECIST 1.1 follow-up assessments is not available; therefore, the rPFS analysis 
cannot be performed. Instead, the available RECIST v1.1 overall response and disease control rate will 
be summarized by number and percentage of patients at each follow-up assessment and the available 
PCWG3 bone scan clinical impression will be summarized by number and percentage of patients at 
each visit.