VISION: An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-positive Metastatic Castration-resistant Prostate Cancer (mCRPC)
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Endocyte

PROTOCOL NO. PSMA-617-01 / NCT03511664 
VISION: AN INTERNATIONAL, PROSPECTIVE, OPEN-LABEL, MULTICENTER, 
RANDOMIZED PHASE 3 STUDY OF 177LU-PSMA-617 IN THE TREATMENT OF 
PATIENTS WITH PROGRESSIVE PSMA-POSITIVE METASTATIC CASTRATION-
RESISTANT PROSTATE CANCER (MCRPC) 
 Clinical Protocol No.: 
PSMA-617-01 
Version No.: 
7.0 
Date: 
14 September 2022 
IND No.: 
133,661 (177Lu-PSMA-617) 
133,925 or site equivalent (68Ga-PSMA-11) 
EudraCT No. 
2018-000459-41 
Phase of Study: 
Phase 3 
Investigational Products: 
177Lu-PSMA-617; 68Ga-PSMA-11 
Sponsor: 
Endocyte, Inc., A Novartis Company 
8910 Purdue Road - Suite 250 
Indianapolis, Indiana 46268 
Medical Officer: 
Novartis Pharma AG 
Oncology DU GDD 
Fabrikstr, WSJ-103.5 
CH-4002 Basel, Switzerland 
Approval: 
[signed electronically in MasterControl] 
Medical Officer Signature 
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 take 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 
such 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. 

Page 2 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Site Principal Investigator Signature 
The investigator signature page is provided in Appendix 3 along with a link to form FDA 1572 
or equivalent if the site is outside of the United States. 

Page 3 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table of Contents 
Site Principal Investigator Signature .......................................................................................... 2 
Table of Contents ........................................................................................................................ 3 
Revision History ......................................................................................................................... 7 
Clinical Trial Summary ............................................................................................................. 10 
List of Abbreviations and Definitions....................................................................................... 13 
1. 
Introduction ...................................................................................................................... 15 
1.1 
Background information .............................................................................................. 15 
1.2 
Summary of nonclinical studies with clinical significance ......................................... 19 
1.3 
Summary of known and potential risks and benefits ................................................... 20 
2. 
Trial Objectives and Endpoints ........................................................................................ 20 
2.1 
Trial objectives ............................................................................................................ 20 
2.1.1 
Primary objective ...............................................................................................20 
2.1.2 
Key secondary objectives ...................................................................................21 
2.1.3 
Additional secondary objectives ........................................................................21 
2.2 
Trial endpoints ............................................................................................................. 21 
2.2.1 
Alternate Primary endpoints ..............................................................................21 
2.2.2 
Key Secondary endpoints ...................................................................................21 
2.2.3 
Additional Secondary endpoints ........................................................................22 
3. 
Trial Design ...................................................................................................................... 23 
3.1 
Overview of the clinical trial design ........................................................................... 23 
3.1.1 
Study design update ...........................................................................................26 
3.2 
Rationale for the study design ..................................................................................... 26 
3.3 
Measures taken to minimize/avoid bias ...................................................................... 26 
3.4 
Description of the clinical trial .................................................................................... 26 
3.4.1 
Description of investigational medicinal product ..............................................26 
3.4.2 
Dosage and rationale for dose selection .............................................................27 
3.4.3 
Subject allocation to treatment ...........................................................................28 
3.4.4 
End of treatment visit .........................................................................................28 
3.4.5 
Duration of Subject Participation .......................................................................28 
3.5 
End of trial definition .................................................................................................. 29 
4. 
Selection and Discontinuation of Subjects ....................................................................... 29 
4.1 
Inclusion criteria .......................................................................................................... 29 
4.2 
Exclusion criteria ......................................................................................................... 31 
4.3 
Subject withdrawal of consent for study or treatment ................................................. 32 
5. 
Treatment of Subjects ....................................................................................................... 32 
5.1 
Treatment with the investigational medicinal product ................................................ 32 

Page 4 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
5.1.1 
Administration of 68Ga-PSMA-11 .....................................................................32 
5.1.2 
Administration of 177Lu-PSMA-617 ..................................................................33 
5.1.3 
Toxicity risk reduction and supportive care for 177Lu-PSMA-617 injections ...33 
5.1.4 
Management of toxicity adverse events: dosing delays and modification .........34 
5.2 
Best supportive/best standard of care .......................................................................... 35 
5.3 
Concomitant medications/ supportive care ................................................................. 36 
5.3.1 
Permitted concomitant medications/ supportive care ........................................36 
5.3.2 
Prohibited concomitant medications ..................................................................37 
5.4 
Monitoring treatment compliance ............................................................................... 37 
5.5 
Treatment discontinuation ........................................................................................... 37 
6. 
Study Assessments and Procedures .................................................................................. 37 
6.1 
Screening procedures and baseline assessments ......................................................... 37 
6.2 
Efficacy assessments ................................................................................................... 39 
6.2.1 
Radiographic imaging for tumor assessments ...................................................39 
6.2.2 
Additional Imaging Analyses .............................................................................40 
6.2.3 
RECIST criteria ..................................................................................................40 
6.2.4 
Symptomatic skeletal events ..............................................................................40 
6.2.5 
Pain score ...........................................................................................................40 
6.2.6 
Health-related quality of life ..............................................................................41 
6.2.7 
Health Economics ..............................................................................................42 
6.2.8 
Clinical progression ...........................................................................................42 
6.2.9 
PSA levels ..........................................................................................................42 
6.3 
Safety assessments....................................................................................................... 42 
6.3.1 
Clinical laboratory evaluations ..........................................................................42 
6.3.2 
Vital signs ..........................................................................................................43 
6.3.3 
Electrocardiograms ............................................................................................43 
6.3.4 
Birth Control ......................................................................................................43 
6.4 
End of treatment visit procedures ................................................................................ 43 
6.5 
Long-term follow-up procedures ................................................................................. 43 
7. 
Adverse Events ................................................................................................................. 44 
7.1 
Adverse event definitions ............................................................................................ 44 
7.2 
Evaluating and recording adverse events .................................................................... 45 
7.3 
Immediate Adverse Event Reporting .......................................................................... 46 
7.3.1 
Serious Adverse Events .....................................................................................47 
7.3.2 
Serious adverse event subject follow-up ............................................................47 
7.3.3 
Sponsor Contact Information for Immediate Reporting ....................................47 
8. 
Statistics ............................................................................................................................ 47 

Page 5 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
8.1 
Revision to the protocol and statistical analyses of rPFS and OS ............................... 48 
8.2 
Revisions to planned analyses ..................................................................................... 48 
8.3 
Sample size and power determination ......................................................................... 48 
8.4 
Analysis populations ................................................................................................... 49 
8.5 
Demographics and baseline disease characteristics .................................................... 50 
8.6 
Patient disposition ....................................................................................................... 50 
8.7 
Efficacy analyses ......................................................................................................... 50 
8.7.1 
Alternate primary endpoint efficacy analysis ....................................................50 
8.7.2 
Secondary efficacy analyses ..............................................................................52 
8.8 
Safety analyses ............................................................................................................ 53 
8.8.1 
Extent of exposure .............................................................................................53 
8.8.2 
Analysis of adverse events .................................................................................53 
8.8.3 
Analysis of laboratory assessments ....................................................................54 
8.8.4 
Analysis of vital sign data ..................................................................................54 
8.9 
IDMC and Interim Data Evaluation ............................................................................ 54 
8.9.1 
IDMC .................................................................................................................54 
8.9.2 
Formal Interim Analysis of OS ..........................................................................54 
9. 
Access to Source Data/Documents ................................................................................... 54 
10. Ethics ................................................................................................................................ 55 
10.1 Institutional Review Board/Independent Ethics Committee/ 
Research Ethics Board (IRB/IEC/REB) ...................................................................... 55 
10.2 Informed consent ......................................................................................................... 55 
10.3 Health Insurance Portability and Accountability Act .................................................. 56 
10.4 Confidentiality ............................................................................................................. 56 
11. Compliance and quality control ........................................................................................ 56 
11.1 Compliance with Monitoring and Audits .................................................................... 56 
12. Data Handling, Record Keeping, and Compliance .......................................................... 57 
12.1 Investigational medicinal product accountability ........................................................ 57 
12.2 Breaking the blind ....................................................................................................... 57 
12.3 Data collection forms and source document identification ......................................... 57 
12.4 Record maintenance and retention .............................................................................. 58 
12.5 Archiving ..................................................................................................................... 58 
13. Publication Policy ............................................................................................................. 58 
14. References ........................................................................................................................ 59 
Appendix 1 
Schedules of Assessments ............................................................................. 66 
Appendix 2 
Suggested treatment guidelines ..................................................................... 73 
Appendix 3 
Principal Investigator Signature .................................................................... 74 

Page 6 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 4a 
Eastern Cooperative Oncology Group performance status 
scale and Karnofsky Performance Status comparison ...................................................... 75 
Appendix 4b 
Eastern Cooperative Oncology Group performance status 
scale and Karnofsky Performance Status comparison ...................................................... 76 
Appendix 5 
Common Terminology Criteria for Adverse Events ..................................... 77 
Appendix 6 
Response Evaluation Criteria in Solid Tumors ............................................. 78 
Appendix 7 
Prostate Cancer Working Group 3 Recommendations ................................. 79 
Appendix 8 
BPI-SF (sample only, not for patient use) ..................................................... 81 
Appendix 9 
 EQ-5D-5L (European Quality of Life (EuroQol) – 5 
Domain 5 Level scale) (sample only, not for patient use) ................................................ 84 
Appendix 10 
 FACT-P (Functional Assessment of Cancer Therapy – 
Prostate) (sample only, not for patient use) ...................................................................... 88 
Appendix 11 
PCCTC Bone Scan Assessment Tool ............................................................ 92 
 
List of tables 
Table 1 
Toxicity management and dose modification recommendations ............................ 34 
Table 2 
Screening procedures and baseline assessments ..................................................... 38 
Table 3 
Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of 
care arm (Cycle 1) ......................................................................................................................... 67 
Table 4 
Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of 
care arm (Cycles 2 to LTFU) ........................................................................................................ 68 
Table 5 
Schedule of assessments: Best supportive/best standard of care only arm (Cycle 1)
 
70 
Table 6 
Schedule of assessments: Best supportive/best standard of care only arm 
(Cycles 2 to LTFU) ....................................................................................................................... 71 
 
List of figures 
Figure 1 
Diagram of trial design ........................................................................................... 23 
 
 

Page 7 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Revision History 
 
Version No. 
Date 
Summary of Changes 
1.0 
22 March 2018 
Not applicable; initial clinical trial protocol. 
1.1  
03 July 2018  
GB only amendment: 
AE assessment timing to start from consent. 
Added wording regarding birth control 
1.2  
26 September 2018  
DE only amendment: 
AE assessment timing to start from consent. 
Added wording regarding birth control 
2.0 
16 January 2019 
Incorporated GB and DE only amendment changes. 
Added statement of compliance as required by Sweden. 
Incorporated the addition of the alternative primary endpoint of 
rPFS and update to 1 rPFS analysis and 1 overall survival analysis. 
Clarified inclusion of and timing of start for best supportive/best 
standard of care. 
Clarified inclusion/exclusion criteria. 
Clarified procedures and timing 
Clarified progression of disease is not considered an AE or SAE. 
Clarified start and end timing for 68Ga-PSMA-11 TEAEs, 177Lu-
PSMA-617 TEAEs and best supportive/best standard of care dosing 
and intervention TEAEs. 
 
3.0 
01 April 2019  
• Updated sponsor name. 
• Updated background information data. 
• Clarified rPFS is an alternate primary endpoint. 
• Clarified inclusion/exclusion criteria and added specific criteria 
regarding best supportive/best standard of care options to be 
identified for patients as part of eligibility.  
• After Cycle 6, visits are now every 12 weeks (+/- 4 days) 
• Additional details regarding long-term follow were added 
including a second consent to be signed by patients who withdraw 
consent or leave the active part of the study for any reason other 
than radiographic disease progression. This now includes 
radiographic follow up. 
• Plasma testosterone was added as an acceptable form of 
testosterone testing. 
• Window for QOL and Pain questionnaires added. 
• Updated reference section 
 
4.0 
 
 
 
08 July 2019 
• Increased total number of patients randomized in the study by 64 
to ensure sufficient events in order to maintain power for total 
enrollment of 814 patients.  
• Details for confirmatory analysis of OS (based on all randomized 
patients on an Intent to Treat (ITT) basis i.e., all patients enrolled 
since the start of the study) and the rPFS analysis based on 
randomized patients on or after March 5th, 2019 were added. 

Page 8 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
 
 
 
 
 
 
• Adjusted the allocation of alpha between rPFS and OS while still 
maintaining the original power for both rPFS (approximately 
85%) and OS (90%). Allocated alpha=0.004 to rPFS, 0.001 to 
interim OS and alpha of 0.02 to 0.025 for OS. Previously, 
allocation was rPFS=0.001 and OS=0.023. 
• Additional imaging analyses details were added for 
study 68Ga PSMA 11 scan data and the role of the Independent 
Review with reviewer variability assessment, as well as 
Quantitative Analysis was added to assess tumor burden and 
tumor characteristics with rPFS, OS, and other response measures, 
as determined by PCWG3 criteria. 
•  Further clarification on the start and end timing for 68Ga-PSMA-
11 TEAEs, 177Lu-PSMA-617 TEAEs and best supportive/best 
standard of care dosing and intervention TEAEs. 
• Additional wording to clarify intent to collect radiographic 
imaging for patients who stop treatment for reasons other than 
radiographic progression, 
5.0 
26 April 2021 
• Extend Long-Term Follow-Up for up to an additional 12 months 
after V5.0 of the protocol is implemented at each site. 
• Reduce the procedures required for each Long-Term Follow-Up 
visit. 
• Add the requirement to report Serious Adverse Events related to 
the study drug during Long-Term Follow-Up as well as reporting 
details of renal toxicities and secondary malignancies. 
• Updated Serious Adverse Event reporting to reflect the change to 
Novartis Safety vs PrimeVigilance. 
• Update footers and headers so that all pages read V5.0. In V4.0 
pages 73 to 95 still read “V3.0”. No change was made to the 
content of these pages from V3.0 to V4.0; the error was 
typographical.  
6.0 
26 May 2022 
• 
Extend the Long-Term Follow-Up for patients on this study to 
ensure consistent collection of long-term safety data until a new 
long-term safety follow-up study is available (to comply with 
FDA Postmarketing Requirement; estimated in 2Q2023). 
7.0 
14 September 2022 
The purpose of this protocol amendment V7 is to document 
the gap between the last visit of the patient under protocol 
amendment V5 and the first visit of the patient under protocol 
amendment V6 as there might be a time gap due to late 
finalization of protocol amendment V6.  
 
Details of the protocol amendments are as follows: 
·        V5 extended the long-term follow-up by one 
year.  
·        V6 extended further the long-term follow-up until 
a separate long-term follow-up study is available. 
 
Despite the time gap between these two protocol amendments 
V5 and V6, we suggest to continue the patient on the trial in 
order to comply with FDA post marketing requirements, so 
we continue to collect long-term safety data (with the same 
patient ID) for reconsented patient. 

Page 9 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
An additional addendum of the informed consent is released 
with this protocol amendment V7 to document the patient's 
understanding to continue on study. 

Page 10 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Clinical Trial Summary 
Protocol title: 
VISION: An international, prospective, open label, multicenter, randomized Phase 3 
study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-
positive metastatic castration-resistant prostate cancer (mCRPC) 
Clinical phase: 
Phase 3 
Objectives: 
The primary objective of this study is to compare the two alternate primary 
endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) 
in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 
in addition to best supportive/best standard of care versus patients treated with best 
supportive/best standard of care alone. 
Key secondary objectives are an arm-to-arm comparison of the following: 
• 
Response Evaluation Criteria in Solid Tumors (RECIST) response 
• 
Time to a first symptomatic skeletal event (SSE)  
Additional Secondary Objectives: 
• 
Safety and tolerability of 177Lu-PSMA-617 
• 
Health-related quality of life (HRQoL; EQ-5D-5L, FACT-P and Brief Pain 
Inventory – Short Form (BPI-SF)) 
• 
Health economics 
• 
Progression-free survival (PFS) (radiographic, clinical, or prostate-specific 
antigen [PSA] progression-free survival) 
• 
Biochemical response as measured by PSA. Alkaline phosphatase [ALP] 
levels and lactate dehydrogenase [LDH] levels will also be measured. 
Study design: 
Patients with PSMA positive scans will be randomized in a 2:1 ratio to receive either 
177Lu-PSMA-617 plus best supportive/best standard of care or to receive best 
supportive/best standard of care only. Best supportive/best standard of care will be 
determined by the treating physician/investigator but will exclude investigational 
agents, cytotoxic chemotherapy, immunotherapy, other systemic radioisotopes, and 
hemi-body radiotherapy. Novel androgen axis drugs [NAADs] (such as abiraterone 
or enzalutamide) are allowed.  
The care of cancer patients must include cancer specialists accomplished in the care 
of patients with advanced prostate cancer, (e.g., medical, radiation oncologists) with 
a clear understanding of the PCWG3 2+2 rules for progression, management of 
adverse events (AEs) related to the natural course of the disease, as well as pre-
existing AEs and study-related AEs. 
The study is open-label and patients will be monitored throughout the 6 to 10-month 
treatment period for survival, disease progression, and adverse events. 
rPFS will be analyzed in these patients once 364 events have accrued. At time of the 
rPFS primary analysis, there will also be an interim analysis of OS. 
 
Before final analysis of alternate primary endpoint OS: 
When a patient discontinues from the treatment portion of the study, they will have 
an end of treatment visit and will then continue to be followed in long-term follow-
up.  
A long-term follow-up period will include the collection of rPFS survival and 
information about new treatments, along with the patient’s response to these 
treatments, adverse events assessment, and hematology and chemistry testing. 
During follow-up, patients will be contacted every 3 months (±1 month) via phone, 
email, or letter for up to 24 months or until 508 deaths have occurred.  
Patients who withdraw their consent to participate in the treatment portion of the 
study or come off the treatment portion of the study for any reason other than 

Page 11 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
radiographic disease progression will be asked for permission to continue long-term 
status updates which may include, in addition to the above, collection of 
radiographic images (bone scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-
term follow-up assessments and study updates they will agree to. They will also be 
able to designate a contact person (e.g. study doctor, local doctor, friend, or family 
member) who may be contacted on their behalf to obtain follow-up status updates. 
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study after the final analysis of 
alternate primary endpoint OS will have an EOT visit at the next planned visit after 
implementation of V5.0 of the protocol and will move into long-term follow-up. All 
patients in long-term follow-up will continue to be followed on this study under the 
same patient ID until a long-term safety follow-up study is available in the 
respective country, until death or until withdrawal of consent, whichever occurs first. 
The long-term follow-up period in this study will include the collection of survival 
and new treatment information, adverse events assessment for renal toxicity and 
secondary malignancies, and results of hematology and chemistry testing. During 
follow-up, patients will be followed for safety and survival. They will be seen or 
contacted by a clinician every 3 months (±1 month) via phone, in person or via 
telemedicine visit, email or letter until a long-term safety follow-up study is 
available for enrollment, until death or until withdrawal of consent, whichever 
occurs first. Every opportunity to continue to collect long-term safety data should be 
made for each willing participant, regardless of gap between release of protocol 
amendment v5.0 and v6.0. 
The planned enrollment for this study is 814 patients. 
Study population: 
The study population includes patients with progressive PSMA-positive mCRPC 
who received at least one novel androgen axis drug [NAAD] (such as enzalutamide 
or abiraterone) and were previously treated with 1 to 2 taxane regimens. Patients 
treated with only 1 prior taxane regimen are eligible if the patient is unwilling or the 
patient’s physician deems the patient unsuitable to receive a second regimen.  
Investigational product: 
Patients randomized to receive the investigational product will receive 7.4 GBq 
(±10%) 177Lu-PSMA-617 intravenously every 6 weeks (±1 week) for a maximum of 
6 cycles. After 4 cycles, patients will be assessed for (1) evidence of response, (2) 
residual disease, and (3) tolerance to 177Lu-PSMA-617. If the patient meets the 
criteria above and agrees to continue with additional treatment of 177Lu-PSMA-617 
radioligand therapy, the investigator may administer 2 additional cycles. A 
maximum of 6 cycles of radioligand therapy is allowed. After the last cycle of 177Lu-
PSMA-617, patients can continue best supportive/best standard of care alone. 
If the patient does not meet all of the criteria or does not agree to additional 177Lu-
PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617 will be 
administered after Cycle 4. These patients can continue on best supportive/best 
standard of care alone after Cycle 4. 
Assessment schedule: 
Radiographic imaging will be done every 8 weeks (±4 days) during the first 
24 weeks of treatment and every 12 weeks (± 4 days) thereafter, regardless of 
treatment delays, through the End of Treatment visit.  
The previous 2 PSA values will be noted before randomization. Serum/plasma 
testosterone and PSA levels will be measured up to 3 days prior to Day 1 of each 
cycle. Hematology and chemistry will be done weekly during Cycle 1 (up to 3 days 
prior to each time point) and up to 3 days prior to Days 1, 15, and 29 in Cycles 2 to 6 
(i.e. every two weeks). After Cycle 6, hematology and chemistry will be done every 
12 weeks (±4 days) until the patient starts long-term follow-up.  
Patients will complete the BPI-SF, EQ-5D-5L and FACT-P questionnaires about 
their pain level and HRQoL during screening and prior to treatment on Day 1 of 

Page 12 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
each cycle and through the End of Treatment visit. Patients will be monitored 
throughout the study for SSEs. 
After the final analysis of OS, patients in the active part of the study will have an 
end of treatment (EOT) visit and move into long-term follow-up. Long-term follow-
up will be extended on this study until a long-term safety follow-up study is 
available in the respective country (estimated in 2nd quarter of 2023). 
Statistical methodology: 
Subsequent to the implementation of measures to minimize early dropouts from the 
best supportive/best standard of care alone arm, the primary analysis of rPFS will 
focus on patients randomized on or after March 5th, 2019; rPFS will be analyzed in 
these patients once 364 events have accrued and the alpha level applied will be 
0.004 1-sided. At time of the rPFS analysis, there will be an interim analysis of OS 
and the alpha level applied will be 0.001 1-sided; unlike rPFS, the analysis of OS 
will include all randomized patients (i.e., including those randomized before March 
5th, 2019). Following the analysis of rPFS and the interim analysis of OS, a final 
analysis of OS will be performed when 508 deaths have accrued and the alpha level 
applied will be 0.02 1-sided. 
This trial has at least 90% overall power and an overall Type I error rate of at most 
0.025 1-sided. 
After the final analysis of OS is performed, additional analyses of the primary 
endpoints (e.g. OS) will be presented descriptively without statistical inference and 
at the same nominal alpha level used for the primary analysis for each endpoint. 
Duration of Study: 
Total duration of the study will be up to approximately 66 months.  
 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
List of Abbreviations and Definitions 
Abbreviation 
Term/Definition 
ANC 
Absolute neutrophil count 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ASCO 
American Society of Clinical Oncology 
BPI-SF 
Brief Pain Inventory – Short Form 
CFR 
United States Code of Federal Regulations 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical study report 
CT  
Computed tomography  
CTCAE 
Common Toxicity Criteria for Adverse Events 
DCR 
Disease control rate 
DOR 
Duration of response 
ECOG  
Eastern Cooperative Oncology Group  
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life (EuroQol) – 5 Domain 5 Level scale 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate 
GCSF 
Granulocyte colony-stimulating factors 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
68Ga 
Gallium-68 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 

Page 14 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Abbreviation 
Term/Definition 
LDH 
Lactate dehydrogenase 
177Lu 
Lutetium-177 
mCRPC 
Metastatic castration-resistant prostate cancer 
NAAD 
Novel androgen axis drug (such as abiraterone or enzalutamide) 
ORR 
Overall response rate 
OS 
Overall survival 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PSA 
Prostate specific antigen 
PSMA 
Prostate-specific membrane antigen 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SSE 
Symptomatic Skeletal Event 
TEAE 
Treatment-emergent adverse event 
SOD 
Sum of the diameter 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
90Y 
Yttrium-90 
 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
The following clinical protocol describes the scientific rationale, objectives, design, statistical 
considerations, and organization of the planned trial including the plan to assure the safety and 
health of the trial participants. Additional details for conducting the clinical trial are provided in 
documents referenced in the protocol, such as an Investigator's Brochure (IB), the Pharmacy 
Manual, or in the Appendices. 
The format and content of this clinical trial protocol complies with the Guideline for Good 
Clinical Practice (GCP) [E6(R2)] issued by the International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as well as 
applicable local regulations, i.e. LVFS 2011:19 (Sweden), and the latest version of the 
Declaration of Helsinki. The study will be conducted according to this clinical trial protocol. 
  
The term subject, participant, and patient are used interchangeably throughout this protocol and 
are used to denote an individual who participates in a clinical trial, either as a recipient of the 
investigational product(s) or as a control. 
1. 
INTRODUCTION 
1.1 
Background information 
Prostate cancer and unmet medical need 
An estimated 1.1 million men worldwide were diagnosed and 307,000 died due to prostate 
cancer in 2012. Almost 70% of the cases are diagnosed in more developed regions due to the use 
of prostate-specific antigen (PSA) testing, but there is only modest variation in mortality rates 
globally which is driven by metastatic, and often castration-resistant disease (Ferlay et al 2013, 
Bray et al 2012). 
There is an urgent need for more effective treatments to improve outcomes for patients with 
metastatic castration-resistant prostate cancer (mCRPC). Prostate cancer is the third leading 
cause of cancer mortality in United States (US) men (Siegel et al 2017), driven by prostate 
cancer patients who no longer respond to hormonal therapy. Once patients reach the mCRPC 
stage, their expected overall survival is low as was seen in the randomized phase 3 study of 
cabozantinib vs prednisone in men with mCRPC who had received prior docetaxel and 
abiraterone acetate and/or enzalutamide; the median overall survival of the prednisone control 
arm was 9.8 months (Smith et al 2016). Post-docetaxel mCRPC patients have an annual death 
rate of 73% (Scher et al 2015).  
The median age at diagnosis of mCRPC is 70 years (Flaig et al 2016). Metastatic prostate cancer 
has a predilection for bone. As a result, approximately 90% of mCRPC patients develop bone 
metastases (Kirby et al 2011), and 49% of them will develop a serious skeletal event within 
2 years (Saad et al 2004). Common presentations include bone pain, bone marrow failure, 
fatigue, or complications such as fractures and cord compression. These presentations typically 
require radiation or bone surgery, which can significantly impair physical, emotional, and 
functional well-being (Weinfurt et al 2005). These patients, many of whom are elderly, can be 
extremely symptomatic and at risk of serious oncological complications. They can be a 
considerable challenge in the clinic due to the symptoms of metastatic soft tissue and visceral 
disease, general frailty, bone marrow impairment, and because they have exhausted approved 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
agents. In mCRPC patients facing advanced illness with little hope for a cure, the focus of 
treatment shifts from active anti-cancer treatment to palliative care for relief of physical 
symptoms, maintaining function, and attempting to improve their health-related quality of life 
(Cella et al 2009). Therefore, in addition to tracking essential clinical outcomes, it is also 
important to assess and evaluate changes in HRQoL of such fragile patients as they receive 
treatment. 
Several agents have been approved for the treatment of mCRPC, and NCCN, ASCO, ESMO, and 
APCCC guidelines provide some consensus and guidance for their use. Regardless, none of these 
therapies are proven to prolong survival after enzalutamide or abiraterone. In practice, 
abiraterone acetate or enzalutamide are often used in the first-line mCRPC setting; Sipuleucel-T 
is best used in mildly asymptomatic small volume disease; and 223Radium is used to treat men 
with bone-only disease. Taxane-based chemotherapy is most often used today after abiraterone 
or enzalutamide and for symptomatic patients, particularly with visceral disease. Docetaxel is 
used more commonly that cabazitaxel. Because both agents have a typical chemotherapy side 
effect profile, they are often not considered for patients due to comorbidity, poor hematological 
reserve, or patient refusal (Zielinski et al 2014).  
Six small published series with a total of 499 patients have examined the efficacy of either 
abiraterone or enzalutamide in men previously exposed to a taxane and either abiraterone or 
enzalutamide. These modern hormonal agents produced only modest activity, including PSA 
decline >50% in 4% to 22% of patients, a median PFS of 2.7 to 4.6 months and a median OS of 
7.2 to 12.2 months (Azad et al 2015, Cheng et al 2015, Badrising et al 2014, Brasso et al 2015, 
Loriot et al 2013, Noonan et al 2013). It’s important to note that this is in contrast with the level 
of anti-tumor activity demonstrated in the pivotal clinical trials for these agents that led to 
approval. In that setting, patients had only received prior docetaxel and had not been exposed to 
prior therapy with either abiraterone or enzalutamide. As these modern hormonal agents have 
been used in earlier lines of therapy, the use of a second agent following docetaxel has resulted 
in diminished efficacy, likely due to cross resistance. 
Therefore, there are limited options available to patients who fail or refuse taxane-based 
chemotherapy, particularly if alternative agents currently approved in this setting (abiraterone 
and enzalutamide) have been used earlier in the disease. 
Prostate-specific membrane antigen  
Prostate-specific membrane antigen (PSMA) is a transmembrane protein, also known as folate 
hydrolase or glutamate carboxypeptidase II. PSMA is highly overexpressed in nearly all prostate 
cancers, but has restricted, and several hundred-fold lower, expression in some normal tissues 
such as the duodenal mucosa, proximal renal tubules, and salivary glands (Bostwick et al 1998, 
Ghosh and Heston 2004, Mannweiler et al 2009). Additionally, PSMA overexpression also 
correlates with advanced, high-grade, metastatic, androgen-independent disease (Ross et al 
2003). The differential expression of PSMA from tumor to non-tumor tissue has resulted in 
numerous targeted strategies involving both disease localization using radioactive imaging as 
well as therapeutic intervention, and therefore may be an attractive target for men with mCRPC. 
In addition to the expression pattern, the functionality of PSMA plays an equally important role 
in its value as a tumor-specific targeting mechanism. Specifically, the binding of a high affinity 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
ligand to PSMA, such as the targeting moiety in 177Lu-PSMA-617, leads to internalization 
through endocytosis and a sustained retention of the ligand and its bound radioactive cargo 
within the cancer cell (Rajasekaran et al 2003). This functional feature of PSMA allows for the 
development of low-molecular-weight targeted radiopharmaceuticals with favorable 
pharmacokinetic and tumor penetration properties, rather than being restricted to antibody-based 
targeting strategies (Haberkorn et al 2016). 
The result of both selective expression and ligand-based uptake using PSMA as a target is a 
reduction in background uptake and off-target toxicities as well as an increase in the amount of 
radioactivity that localizes at the tumor site. 
177Lu-PSMA-617 mechanism of action 
The novel PSMA-targeted radioligand therapy 177Lu-PSMA-617 consists of the PSMA-binding 
ligand glutamate-urea-lysine and a DOTA-chelator, which are connected by a naphthyl-
containing linker. By design, 177Lu-PSMA-617 exhibits high PSMA binding affinity and 
internalization, prolonged tumor retention, and rapid kidney clearance (Benešová et al 2015). 
PSMA-617 was uniquely developed for both imaging and radioligand therapy of prostate cancer 
and can be radiolabeled with gallium-68 (68Ga), lutetium-177 (177Lu), indium-111, copper-64, 
scandium-44, actinium-225, or yttrium-90 (90Y). 
177Lu, the radioactive cargo being delivered by PSMA-617, has physical properties that make it 
an ideal radionuclide for the treatment of mCRPC. 177Lu is a medium-‐energy β‐-emitter (490 
keV) with a maximum energy of 0.5 MeV and a maximal tissue penetration of <2 mm. The 
shorter β‐range of 177Lu provides better irradiation of small tumors, in contrast to the longer 
β-range of 90Y (Emmett et al 2017). The shorter path length also acts to direct the energy within 
the tumor rather than in the surrounding normal tissues, while the path length is still sufficient to 
create bystander and crossfire effects within the tumor lesion. 177Lu has a relatively long physical 
half‐life of 6.6 days that combines with the intratumoral retention of 177Lu-PSMA-617 to reduce 
the necessary dosing frequency. It is these physical properties, and the benefit of PSMA-
targeting, that allow for the delivery of effective activities of 177Lu to prostate cancer cells. 
177Lu-PSMA-617 for metastatic castration-resistant prostate cancer 
The novel therapeutic drug 177Lu-PSMA-617 was developed by the German Cancer Research 
Center, Deutsches Krebsforschungszentrum (DKFZ) in collaboration with University Hospital 
Heidelberg for the treatment of patients with metastatic prostate cancer (Kratochwil et al 2015, 
Hillier et al 2009). Based on preclinical data that demonstrated high PSMA binding affinity and 
compound internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-
background ratio, 177Lu-PSMA-617 proceeded into clinical development at investigative sites in 
Germany. 
Data evaluations based on compassionate use according to the German Medicinal Product Act, 
AMG §13 2b, Clinical Trial Notification (Australia) regulations, and other countries where 
expanded access programs are in place per local regulations, reported a favorable safety profile 
and promising results for PSA response rates of systemic radioligand therapy with 177Lu-PSMA-
617 in patients with mCRPC. 
Dosimetry data suggest that 177Lu-PSMA-617 is targeted to PSMA-expressing tissue, which may 
include the salivary glands, kidneys, and small and large bowel. The highest exposure is to 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
salivary glands, however in the prospective study xerostomia appears low grade and occurs at a 
rate of approximately 87% in treated patients. Clearance of 177Lu PSMA-617 from the kidney 
occurs rapidly. To date nephrotoxicity has not been notable in any safety series. There are no 
reports of Grade 3/4 nephrotoxicity in the literature. The exposure to normal bone marrow tissue 
is predictably low as it does not express PSMA and corresponds with normal plasma clearance. 
There was some evidence of reversible hematological toxicity that occurred following 
177Lu-PSMA-617 treatment that manifested as leukopenia and thrombocytopenia, with rates of 
0 to 40% and 4% to 67% respectively.  
The first published clinical series of 177Lu-PSMA-617 consisted of 10 patients (Ahmadzadehfar 
et al 2015) treated between November 2013 and January 2014, with 5.6 GBq/150mCi (4.1–6.1 
GBq/110–165 mCi). PSA decline >50% occurred in 50% of subjects, which increased to 60% 
after 2 cycles of 6 GBq/160 mCi (4.1–7.1 GBq/110–190 mCi). The level of PSA decline >50% 
(most commonly used to assess tumor response in these studies) has remained remarkably 
consistent across several clinical series when 2 or more doses of ≥6 GBq/160 mCi are given. 
Hofman presented the first prospective open-label, single-arm, non-randomized Phase 2 study of 
177Lu-PSMA-617 in 50 metastatic castration-resistant prostate cancer patients dosed with up to 4 
cycles of 4–8 GBq/110–220 mCi administered every 6 weeks (Hofman et al 2018, Hofman et al 
2019). The primary endpoints of this study were to evaluate both safety and efficacy, as 
measured by PSA response, bone pain score, quality of life measurements, imaging response and 
survival. 
Of the screened patients, 70% were identified as PSMA-positive via PET imaging and eligible 
for treatment. Most subjects had been exposed to at least 1 taxane chemotherapy and either 
abiraterone or enzalutamide in the mCRPC setting. In this heavily pre-treated patient population 
with few therapeutic alternatives, 64% of patients on 177Lu-PSMA-617 showed a PSA response 
defined by a reduction in PSA of at least 50%, and 44% had a reduction of PSA of 80% or more. 
In 27 patients with measurable disease, the objective response rate in measurable disease as 
defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 56% (complete 
response [CR] and partial response [PR]). Median overall survival was 13.3 months (95% 
confidence interval [CI] 10.5-18.0). Therapy with 177Lu-PSMA-617 was well tolerated. These 
safety and efficacy data also translated into significantly improved quality of life scores and 
reduction in pain scores. 
In summary, over 40 compassionate use publications and prospective Phase 2 clinical trial data 
describe the use of 177Lu-PSMA-617 in patients who have been exposed to approved agents. In 
the post-taxane, post-androgen axis inhibitor setting 177Lu-PSMA-617 has demonstrated a well-
established, predictable, well tolerated safety profile. Clinical series indicate the most common 
adverse effects, predominately Grade 1-2, of 177Lu-PSMA-617 treatment are dry mouth, nausea, 
vomiting, diarrhea, constipation, fatigue, anemia, thrombocytopenia and neutropenia. The 
incidence of Grade 3/4 toxicity in the series was very low, and mainly restricted to reversible 
hematological events. Efficacy has been demonstrated on multiple clinically significant 
endpoints, including PSA response, soft tissue lesion response measured by RECIST, PFS, OS, 
pain and quality of life. No standard dose and schedule have been developed. 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
The preliminary clinical evidence indicates 177Lu-PSMA-617 may demonstrate clinical benefit in 
patients with mCRPC in a setting where patients had been exposed to chemotherapy and NAADs 
and there is no recommended standard of care. 
This Phase 3 study will assess the efficacy of 177Lu-PSMA-617 in patients with progressive 
PSMA-positive mCRPC by measuring overall survival and rPFS in a randomized, prospective, 
open-label trial. 
1.2 
Summary of nonclinical studies with clinical significance 
In vitro PSMA affinity and internalization studies 
According to Benešová et al, the results of the binding assay of PSMA-617 in PSMA-positive 
LNCaP cells demonstrated a very high binding affinity, with an equilibrium dissociation constant 
(Ki) value of 2.34 ± 2.94 nM. The internalization of PSMA-617 is highly effective with an 
internalized fraction of 17.51 ± 3.99 percent of the added activity/106 LNCaP cells (n = 3) at 
37°C (Benešová et al 2015). 
Organ distribution in mice bearing PSMA-positive LNCaP tumors 
The organ distribution with 177Lu-PSMA-617 in mice showed a high specific uptake in LNCaP 
tumors and in the murine kidneys, as expected. Importantly, the high initial kidney uptake is 
almost completely cleared within 24 hours whereas the tumor uptake remained high or even 
tended to slightly increase during that time frame. Other organs such as the liver, lung and spleen 
demonstrated low uptake at 24 hours after injection (Benešová et al 2015). 
Biodistribution in Wistar rats 
Pharmacokinetic evaluation of 177Lu-PSMA-617 in normal healthy male Wistar rats exhibited 
major renal clearance with no significant uptake in any of the major organ/tissue (Das et al 
2016). More than 80% of the injected activity was excreted within 3 hours post-injection. 
Retention of residual activity was observed in intestine, liver, kidneys and skeleton at 24 hours 
post-administration. However, uptake in these organs, except skeleton, was observed to 
gradually decrease with the time. 
Repeat-dose toxicity in Wistar rats 
The toxicity of non-radioactive PSMA-617 administered once weekly by intravenous (IV) 
administration to male Wistar rats over 22 days was tested in a toxicology study. The animals 
were treated with 40, 160, or 400 µg PSMA-617/kg b.w. by IV bolus injection on test days 1, 8, 
15, and 22. The control group was treated with physiological saline. The no-observed-adverse-
effect-level was found to be above 400 µg PSMA-617/kg body weight administered once weekly 
by IV bolus injection (Leuschner 2016). The estimated mass of the PSMA-617 precursor which 
is applied per treatment cycle is likely to be approximately 150 to 250 µg. Using the NOAEL for 
repeat dosing of PSMA-617 of 400 µg/kg in rats, this accounts for a safety margin of 
approximately 16-27-fold, assuming that the average patient has a body surface are of 1.7 m2. 
However, considering that a more intensive dosing schedule was tested in rats, relative to the 
proposed, and well-studied, clinical regimen of once every 6 to 8 weeks, this safety margin may 
be a conservative estimate. 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
1.3 
Summary of known and potential risks and benefits 
Preclinical work, dosimetry studies, and clinical experience with 177Lu-PSMA-617 since 2013, 
suggest positive response rates and a favorable safety profile in patients with mCRPC 
(Kratochwil et al 2016, Rahbar et al 2017, Kulkarni et al 2016, Haug et al 2016, Rathke et al 
2017, Soydal et al 2016, Rathore et al 2016, Rahbar et al 2016a, Ahmadzadehfar et al 2016, 
Fendler et al 2017, Ferdinandus et al 2017, Rahbar et al 2016b, Yadav et al 2017). 
Dosimetry studies have confirmed that 177Lu PSMA-617 is targeted and normal tissues that 
express PSMA are exposed to radiation (Delker et al 2016). These tissues are salivary glands, 
renal, and small and large bowel. Renal absorbed dose is cleared rapidly, and exposure appears 
similar to that seen with 177Lu-DOTATATE. The exposure to normal bone marrow tissue should 
be low and correspond with normal plasma clearance. 
Nephrotoxicity has not been notable in any safety series. There are no reports of Grade 3/4 
nephrotoxicity in the literature. There was some evidence of reversible hematological toxicity 
that occurred following 177Lu-PSMA-617 treatment that manifested as leukopenia and 
thrombocytopenia, with rates of 0 to 40% and 4% to 67% respectively. Rahbar (2017) reported 
177Lu-PSMA-617 was associated with asymptomatic Grade 3 or 4 leukopenia, anemia, 
thrombocytopenia in 3%, 10%, 4%, respectively. Mild reversible xerostomia occurred in 8% of 
subjects. No significant diarrhea or renal impairment were reported from a retrospective review 
of doctor reports (Rahbar et al 2017). 
Hofman et al. presented results from the first prospective clinical trial with 177Lu-PSMA-617 
(Hofman et al 2019). In the trial, 50 mCRPC patients were dosed with up to 4 cycles of 4–
8 GBq. Prospective common toxicity criteria for adverse events (CTCAE) v4 safety data was 
defined. He found his regimen to be well-tolerated. The most common non-hematological 
toxicities attributed to 177Lu-PSMA-617 occurring in >25% of patients included transient G1-2 
dry mouth (66%), G1-2 nausea (48%), G1-3 fatigue (38%), and G1-2 vomiting (26%). The most 
common hematological toxicities attributed to 177Lu-PSMA-617 occurring in >25% of patients 
included G1-3 lymphocytopenia (72%), G1-4 thrombocytopenia (38%), G1-3 neutropenia (30%) 
and G1-3 anemia (28%). G3-4 toxicities attributed to 177Lu-PSMA-617 were infrequent with 
lymphocytopenia (32%), thrombocytopenia (10%), anaemia (10%), neutropenia (6%) and fatigue 
(2%).  
Potential risks of 177Lu-PSMA-617 include the effects of radiological toxicity, namely 
xerostomia, fatigue, myelosuppression and mild nausea and vomiting. 
Additional details of the nonclinical and clinical experience with 177Lu-PSMA-617 are provided 
in the IB.  
2. 
TRIAL OBJECTIVES AND ENDPOINTS  
2.1 
Trial objectives 
2.1.1 
Primary objective 
The primary objective of this study is to compare the two alternate endpoints of radiographic 
progression free survival (rPFS) and overall survival (OS) in patients with progressive PSMA-

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care 
versus patients treated by best supportive/best standard of care alone. 
2.1.2 
Key secondary objectives 
Key secondary objectives are an arm-to-arm comparison of the following: 
1. RECIST response to include: 
a. Overall Response Rate (ORR) as measured by RECIST v1.1 criteria 
b. Disease control rate (DCR) as measured by RECIST v1.1 criteria  
2. Time to a first symptomatic skeletal event (SSE) 
2.1.3 
Additional secondary objectives 
1. Safety and tolerability of 177Lu-PSMA-617 
2. Periodic assessment of health-related quality of life to evaluate impact of intervention on 
patient well-being (HRQoL; EuroQol 5-dimensions 5-level [EQ-5D-5L] questionnaire, 
Functional Assessment of Cancer Therapy – Prostate [FACT-P] questionnaire and Brief 
Pain Inventory – Short Form [BPI-SF]) 
3. Health Economics 
4. Progression-free survival (PFS) (radiographic, clinical, or PSA progression-free survival) 
5. Biochemical response as measured by PSA. Alkaline phosphatase [ALP] and lactate 
dehydrogenase [LDH] levels will also be collected. 
 
2.2 
Trial endpoints 
2.2.1 
Alternate Primary endpoints 
rPFS and OS are designated as alternate primary endpoints. rPFS is defined as the time from the 
date of randomization to the date of radiographic disease progression as outlined in Prostate 
Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death from any cause. OS 
is defined as the time from randomization to the date of death from any cause. 
rPFS will be assessed locally by each site. Additionally, patient scans will be collected for 
independent central review. The independent central review will be used to support the primary 
rPFS analysis. The local rPFS assessment will be supportive.  
The statistical design of the study is such that, to be declared positive, the study would be 
required to reach statistical significance on either the primary analysis of rPFS or OS at the 
respective allocated alpha level; it is not required to statistically meet both rPFS and OS to be 
declared a positive study. Alpha allocation and recycling is used to ensure control of the overall 
Type I error rate.  
2.2.2 
Key Secondary endpoints 
The key secondary endpoints include the following: 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
1. RECIST response to include: 
a. Objective response rate (ORR) (CR + PR) as measured by RECIST v1.1 response in 
soft tissue, lymph node and visceral lesions. Duration of Response (DOR) will also be 
measured in patients with a CR or PR from date of first response to the date of 
RECIST progression or death. 
b. Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by 
RECIST v1.1 response in soft tissue, lymph node and visceral lesions.  
2. The time to a first SSE defined as date of randomization to the date of first new 
symptomatic pathological bone fracture, spinal cord compression, tumor-related 
orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or 
death from any cause, whichever occurs first. 
2.2.3 
Additional Secondary endpoints 
1. To evaluate the safety and tolerability of 177Lu-PSMA-617 
2. Aspects of HRQoL will be reported using the EuroQol 5-dimensions 5-level [EQ-5D-5L] 
questionnaire, Functional Assessment of Cancer Therapy – Prostate [FACT-P] 
questionnaire and Brief Pain Inventory – Short Form [BPI-SF] 
3. Health economics 
4. Progression-free survival is defined as the date of randomization to the date of first 
evidence of radiographic progression, clinical progression, PSA progression, or death 
from any cause, whichever occurs first. 
a. Radiographic progression is defined as the date of radiographic disease 
progression as outlined in the Prostate Cancer Working Group 3 (PCWG3) 
Guidelines. 
b. Unequivocal clinical progression. Unequivocal evidence of clinical progression is 
defined as:  
 Marked escalation in cancer related pain that is assessed by the 
investigator to indicate the need for other systemic chemotherapy 
 Immediate need for initiation of new anticancer treatment, surgical or 
radiological intervention for complications due to tumor progression even 
in the absence of radiological progression 
 Marked deterioration in ECOG performance status to ≥ Grade 3 and/or in 
the opinion of the investigator ECOG deterioration indicates clinical 
progression 
 In the opinion of the investigator, it is in the best interest of the patient to 
discontinue treatment due to clinical progression  
c. 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 in the absence of other evidence of 
disease progression (PCWG3 Guidance). Where no decline from baseline is 

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
documented, 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. 
5. Biochemical response endpoints:  
a. Proportion of subjects who are PSA responders, defined as a patient who has 
achieved a ≥50% decrease from baseline that is confirmed by a second PSA 
measurement ≥4 weeks.  
b. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be 
collected. 
3. 
TRIAL DESIGN 
3.1 
Overview of the clinical trial design 
This is a Phase 3, open-label, international, randomized study to evaluate the efficacy and safety 
of 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC, when administered in 
addition to best supportive/best standard of care as compared to best supportive/best standard of 
care alone (Figure 1). 
 
 
Figure 1 
Diagram of trial design 
ECOG = Eastern Cooperative Oncology group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 
Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic castration-
resistant prostate cancer; PSMA+ = prostate-specific membrane antigen positive; RECIST = Response Evaluation 
Criteria in Solid Tumors  

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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
 
Best supportive/best standard of care includes available care for the eligible patient according to 
best institutional practice and at the discretion of the investigator. Novel androgen axis drugs 
[NAADs] (i.e., enzalutamide or abiraterone) are allowed. 
Investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radio isotopes 
(e.g. radium-223) or hemi-body radiotherapy treatment may not be administered on study. 
At screening, potential subjects will be assessed for eligibility and will undergo a 68Ga-PSMA-11 
PET/computed tomography (CT) scan to evaluate PSMA positivity. Only patients with PSMA-
positive cancer will be randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus best 
supportive/best standard of care (investigational arm) or to receive best supportive/best standard 
of care alone (BS/BSC-only arm). Randomization will be stratified by 4 factors (Section 3.4.3). 
Patients randomized to the investigational arm must begin 177Lu-PSMA-617 dosing within 
28 days after randomization. These patients will receive best supportive/best standard of care and 
7.4 GBq (±10%) 177Lu-PSMA-617 once every 6 weeks (±1 week) for a maximum of 6 cycles.  
After the Cycle 4 dose of 177Lu-PSMA and prior to Cycle 5 Day 1, the investigator should 
determine if: 
• The patient shows evidence of response (i.e. radiological, PSA, clinical benefit) and  
• Has signs of residual disease on CT with contrast/MRI or bone scan and 
• Has shown good tolerance to the 177Lu-PSMA-617 treatment. 
 
If the patient meets all of the criteria above, and agrees to continue with additional treatment of 
177Lu-PSMA-617, the investigator may administer a further 2 cycles. A maximum of 6 cycles of 
radioligand therapy is allowed. If the patient does not meet any of the criteria or does not agree 
to additional 177Lu-PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617 will be 
administered after Cycle 4. After the last cycle of 177Lu-PSMA-617, patients can continue best 
supportive/best standard of care alone. 
Best supportive/best standard of care for each patient will be selected at the discretion of the 
patient’s physician, prior to randomization and will be administered per the physician’s orders 
and continued until the patient comes off the treatment part of the study and enters the long-term 
follow-up stage. 
A patient may choose to discontinue randomized treatment part of the study at any time.  
Before final analysis of alternate primary endpoint OS: 
If a patient chooses only to discontinue from the randomized treatment in the study for a reason 
other than radiographic progression, the patient will be asked to confirm if they consent to 
continue to be followed for long-term safety, rPFS, and survival follow-up. The patient will 
continue to be followed for long-term follow-up unless they specifically withdraw consent from 
long-term follow-up of the study. An End of Treatment (EOT) visit should occur once a patient 
discontinues randomised treatment for any reason (patient or investigator decision, going on to 
long-term follow-up, etc.). 

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The EOT visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or the 
date of the best supportive/best standard of care end of treatment decision (whichever occurs 
later), but before the initiation of subsequent anti-cancer treatment, outside of what is allowed on 
study. 
If a patient discontinues randomized treatment for any reason other than radiographic 
progression, they will be asked for permission to continue collecting radiographic images (bone 
scans and CT scans and/or MRIs) for the purpose of continuing to assess rPFS. 
After the EOT visit, patients will enter the long-term follow-up period. The long-term follow-up 
period will include the collection of rPFS (if discontinuing for reasons other than radiographic 
progression), survival and information about new treatments, along with the patient’s response to 
these treatments, adverse events assessment, and results of hematology and chemistry testing. 
During follow-up, patients will be followed for safety and survival. They will be contacted every 
3 months (±1 month) via phone, email, or letter for up to 24 months or until 508 deaths have 
occurred. 
Patients who withdraw their consent to participate in the study for any reason other than 
radiographic disease progression will be asked for permission to continue long-term status 
updates which may include, in addition to the above, collection of radiographic images (bone 
scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-term follow-
up assessments and study updates they will agree to. They will also be able to designate a contact 
person (i.e. study doctor, local doctor, friend or family member) who may be contacted on their 
behalf to obtain follow-up status updates. 
For any of these patients who are unable to sign the second consent (i.e. does not return to the 
site, etc.) every effort will be made to document the extent of long-term follow-up they will 
agree to. This will be documented in their source records.  
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study, after the final analysis of the OS primary 
endpoint will have an EOT visit at the next planned visit after implementation of V5.0 of the 
protocol at the site and will move into long-term follow-up. All patients in long-term follow-up 
will continue to be followed on this study under, the same patient ID, until a long-term safety 
follow-up study is available in the respective country, until death or until withdrawal of consent, 
whichever occurs first. Every opportunity to continue to collect long-term safety data should be 
made for each willing participant, regardless of time gap between release of protocol amendment 
v5 and v6.0. 
The long-term follow-up period will include the collection of survival and new treatment 
information, adverse events assessment for renal toxicity and secondary malignancies, and 
results of hematology and chemistry testing. During follow-up, patients will be followed for 
safety and survival. They will be seen or contacted by a clinician every 3 months (±1 month) via 
phone, in person or via telemedicine visit, email or letter on this study until a long-term safety 
follow-up study is available, until death or until withdrawal of consent, whichever occurs first. 
This study will enroll approximately 814 patients involving about 110 sites worldwide. 

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3.1.1 
Study design update 
The trial was originally designed to randomize 750 patients, targeting the primary analysis of 
rPFS with 457 events, an interim analysis of OS, to be conducted contemporaneously with the 
primary analysis of rPFS, and a final analysis of OS with 489 deaths. 
However, shortly after commencement of the trial, a high, early dropout rate amongst those 
randomized to BS/BSC only became evident with the majority of these dropouts withdrawing 
consent to follow-up. This meant that rPFS data could not be collected for these patients which 
consequently could result in bias in the analysis of rPFS. Remedial measures to curtail this 
phenomenon were implemented and made effective on March 5th, 2019. As part of the plan to 
address the early withdrawal of consent in the BS/BSC-only arm, the primary analysis of rPFS 
was altered to focus on patients prospectively randomized on or after March 5th, 2019; therefore, 
rPFS will be analyzed in these patients once 364 events have accrued. At time of the rPFS 
primary analysis, there will also be an interim analysis of OS; this OS analysis will be on an 
intent to treat (ITT) basis and will include all randomized patients (i.e., including those 
randomized before March 5th, 2019). Following the analysis of rPFS and the interim analysis of 
OS, a final ITT analysis of the OS primary objective will be performed when 508 deaths have 
accrued. To achieve these analyses, the total number of subjects randomized into the trial was 
increased from N=750 to N=814. The revisions described do not alter the hypothesized treatment 
effects for rPFS and OS upon which the study was originally powered. 
3.2 
Rationale for the study design 
The primary objective of this study is to compare the two alternate endpoints of rPFS and overall 
survival (OS) in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-
617 in addition to best supportive/standard of care versus patients treated by best supportive/best 
standard of care alone. The statistical design of the study is such that, to be declared positive, the 
study would be required to reach statistical significance on either rPFS or OS at the respective 
allocated alpha level; it is not required to statistically meet both rPFS and OS to be declared a 
positive study. Secondary endpoints have been defined by PCWG3 as well as FDA and EMEA 
guidance. In view of the highly symptomatic nature of advanced mCRPC both validated pain 
(BPI-SF) and HRQoL (EQ-5D-5L and FACT-P) measurements will be collected using various 
questionnaires. 
3.3 
Measures taken to minimize/avoid bias 
Patients will be randomized to 1 of 2 treatment arms. Randomization will be stratified to avoid 
bias in treatment selection (Section 3.4.3). Treatment will be open-label. 
Reading of the baseline 68Ga-PSMA-11 PET/CT scan will be done by central readers for 
consistency. 
3.4 
Description of the clinical trial 
3.4.1 
Description of investigational medicinal product  
The 68Ga-PSMA-11 radiopharmaceutical will be administered intravenously at a dose of 111 - 
185 MBq (3 - 5 mCi). For background and additional details on 68Ga-PSMA-11, refer to the 
68Ga-PSMA-11 Investigator’s Brochure.  

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Refer to the Fendler et al 2017 publication “68Ga-PSMA PET/CT: Joint EANM and SNMMI 
procedure guideline for prostate cancer imaging: version 1.0 guideline” for an overview of 68Ga-
PSMA-11 recommendations. Details of the patient preparation and administration can be found 
in the Imaging Manual. 
The 177Lu-PSMA-617 solution for injection consists of a sterile solution in glass vials containing 
7.4 (±0.74) GBq of 177Lu-PSMA-617 at time of injection. 
Refer to the 177Lu-PSMA-617 IB for additional details of the investigational medicinal product 
including the pharmacological class and action, the dosage form including excipients, and any 
available packaging and labelling. 
3.4.2 
Dosage and rationale for dose selection 
In the investigational arm, patients will receive best supportive/best standard of care regimen and 
IV 7.4 GBq (±10%) 177Lu-PSMA-617 once every 6 weeks (±1 week) for a maximum of 6 cycles. 
After 4 cycles patients will be reassessed to determine if a further 2 cycles can be given for a 
maximum of 6 cycles (Section 3.1). 
The basic principle of 177Lu-PSMA-617 radioligand therapy is to systemically deliver low dose 
rate radiation specifically to multiple PSMA positive prostate cancer lesions, while sparing 
normal tissues. To date, 11 dosimetry studies have been conducted and published in over 100 
patients. The results are consistent across the studies and demonstrate exposure that correlates 
well with the expected rapid clearance of a small molecule, and the limited distribution pattern of 
a PSMA-targeted radionuclide. The primary sites of non-tumor uptake were the salivary glands, 
lacrimal glands, and kidneys, with excretory mechanisms contributing to exposure in the kidneys 
where approximately 50% of the injected dose is cleared within 48 hours (Kratochwil et al 
2016). PSMA-negative tissues like the bone marrow, are exposed transiently to 177Lu-PSMA-617 
while in circulation, however this exposure is minimized due to its rapid elimination.  
177Lu-PSMA-617 is well tolerated according to the clinical experience that has been documented 
in 42 publications, summarizing the safety and or efficacy information from over 800 subjects. 
Across these studies doses have ranged from 1.1-12.0 GBq, and schedules have typically 
followed an administration schedule of once every 4 to 12 weeks, for 1-9 cycles. The majority of 
these publications have used a regimen of 4 cycles of 6 GBq every 8 weeks, as published by the 
German Radiopharmaceutical Society in 2015. However, efficacy and safety information from 
the prospective phase 2 study suggested that dosing of 6-8 GBq every 6 weeks for 4 cycles was 
well tolerated and efficacious (Hofman et al 2018). 
Clinical series now show reports of more than 4 cycles of 177Lu PSMA-617 being administered 
safely as a means to maximize the benefit to the patient (Rahbar et al 2018, Kulkarni et al 2018, 
Bräuer et al 2017, Yordanova et al 2017). In addition, a recent review suggests optimal dosing of 
6 cycles of 177Lu-PSMA-617 administered every 6 weeks in a decreasing scale reaching a total 
cumulative absorbed dose of 44 GBq (Emmett et al 2017). Six fractions of 7.4 GBq, delivers a 
similar total dose of 44.4 GBq.  
In the ANZUP1603 study in 200 Australian patients (NCT03392428), which is comparing 177Lu-
PSMA-617 with cabazitaxel, the dose starts at 8.5 GBq 177Lu-PSMA-617 and reduces by 0.5 
GBq per cycle, i.e. 8.5, 8, 7.5, 7, 6.5, 6 (cycle #6). A maximum of 6 cycles given every 6 weeks 

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is what is being evaluated, which equates to a cumulative dose that is similar to that for this 
proposed study.  
The clinical safety review and detailed analyses of the radiation exposure support the intended 
dose and frequency of 177Lu-PSMA-617 administration in this clinical trial. 
3.4.3 
Subject allocation to treatment 
Patients will be randomized by an interactive response system in a 2:1 ratio to the investigational 
treatment arm (177Lu-PSMA-617 plus best supportive/best standard of care) or the best 
supportive/best standard of care-only arm using a permuted block scheme. Randomization will 
be stratified by the following factors: 
• LDH (≤ 260 IU/L vs. > 260 IU/L) 
• Presence of liver metastases (yes vs. no) 
• ECOG score (0 or 1 vs. 2) 
• Inclusion of NAAD in best supportive/best standard of care at time of randomization (yes 
vs no) 
3.4.4 
End of treatment visit 
An EOT visit should occur once a patient discontinues the treatment part of the study for any 
reason (patient or investigator decision, going on to long-term follow-up, etc.).  
This visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or the date 
of the best supportive/best standard of care end of treatment decision (whichever occurs later), 
but before the initiation of subsequent anti-cancer treatment, outside of what is allowed on study. 
3.4.5 
Duration of Subject Participation 
Patients may continue treatment until radiographic progressive disease, withdrawal of consent, 
the occurrence of unacceptable toxicity, or a determination by the investigator the patient is not 
clinically benefiting. As per the patient’s physician, when the participant requires care that is not 
allowed on study, the participant will discontinue treatment and enter the long-term follow-up 
period. While the patient and/or physician may decide prematurely to cease taking randomized 
therapy at any time, full follow-up of all randomized patients for the intended duration of the 
trial is planned by design for the collection of rPFS and OS data. 
It is anticipated that it will take approx. 14 months to randomize the required 814 patients in the 
study. After the last patient is randomized patients will be followed for up to 24 months or at 
least until 508 deaths have occurred. The maximum duration of the study, from first date of 
randomization to last follow-up, will therefore be approximately 38 months.  
After final analysis of the OS primary endpoint, long-term follow-up will be extended until a 
separate long-term safety follow-up study is available in the respective country, until patient 
death or until patient withdrawal of consent, whichever occurs first. The maximum duration of 
the study, from first date of randomization to last follow-up, will therefore be up to 
approximately 66 months. 

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3.5 
End of trial definition 
The trial and long-term follow-up procedures are expected to continue at least until 508 deaths 
have occurred. Long-term follow-up for safety and survival will continue until a separate long-
term safety follow-up study is available. For timing of the rPFS and OS analyses and any rules 
for early statistical curtailment, refer to Section 8.1. 
4. 
SELECTION AND DISCONTINUATION OF SUBJECTS 
Written informed consent must be obtained prior to any study-related procedures. The 
Investigator will ensure that the participant is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
participant’s financial responsibility. While full follow-up is intended in the ITT population for 
the planned duration of the trial, participants must also be notified that they are free to 
discontinue from the study at any time. The participant will be given the opportunity to ask 
questions and allowed time to consider the information provided. A copy of the signed written 
informed consent form (ICF) will be given to the participant for their review and signature.  
4.1 
Inclusion criteria 
To qualify for enrollment, patients must meet the following criteria: 
1. Patients must have the ability to understand and sign an approved ICF. 
2. Patients must have the ability to understand and comply with all protocol requirements. 
3. Patients must be ≥18 years of age. 
4. Patients must have an ECOG performance status of 0 to 2. 
5. Patients must have a life expectancy >6 months. 
6. Patients must have histological, pathological, and/or cytological confirmation of prostate 
cancer. 
7. Patients must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the 
sponsor’s central reader.  
8. Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 
nmol/L).  
9. Patients must have received at least one NAAD (such as enzalutamide and/or 
abiraterone). 
10. Patients must have been previously treated with at least 1, but no more than 2 previous 
taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a 
taxane. If a patient has received only 1 taxane regimen, the patient is eligible if: 
a. The patient’s physician deems him unsuitable to receive a second taxane regimen 
(e.g. frailty assessed by geriatric or health status evaluation, intolerance, etc.). 

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11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based 
on at least 1 of the following criteria: 
a. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a 
previous reference value measured at least 1 week prior. The minimal start value is 
2.0 ng/mL. 
b. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter 
(SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target 
lesions based on the smallest SOD since treatment started or the appearance of one or 
more new lesions. 
c. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan 
(2+2 PCWG3 criteria, Scher et al 2016). 
12. Patients must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan 
imaging obtained ≤28 days prior to beginning study therapy. 
13. Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related 
to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.). 
14. Patients must have adequate organ function: 
a. Bone marrow reserve: 
• White blood cell (WBC) count ≥2.5 × 109/L (2.5 × 109/L is equivalent to 
2.5 × 103/µL and 2.5 × K/µL and 2.5 × 103/cumm and 2500/µL) OR absolute 
neutrophil count (ANC) ≥1.5 × 109/L (1.5 × 109/L is equivalent to 1.5 × 103/µL 
and 1.5 × K/µL and 1.5 × 103/cumm and 1500/µL) 
• Platelets ≥100 × 109/L (100 × 109/L is equivalent to 100 × 103/µL and 100 × K/µL 
and 100 × 103/cumm and 100,000/µL) 
• Hemoglobin ≥9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L) 
b. Hepatic: 
• Total bilirubin ≤1.5 x the institutional upper limit of normal (ULN). For patients 
with known Gilbert’s Syndrome ≤3 × ULN is permitted 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 × 
ULN OR ≤5.0 × ULN for patients with liver metastases 
c. Renal:  
• Serum/plasma creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min 
15. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) 
[Inclusion #16 has been removed] 
17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are 
included in this trial. 

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18. For patients who have partners of childbearing potential: Partner and/or patient must use 
a method of birth control with adequate barrier protection, deemed acceptable by the 
principle investigator during the study and for 6 months after last study drug 
administration. 
19. The best standard of care/ best supportive care options planned for this patient: 
a. Are allowed by the protocol  
b. Have been agreed to by the treating investigator and patient 
c. Allow for the management of the patient without 177Lu-PSMA-617 
4.2 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Previous treatment with any of the following within 6 months of randomization: 
Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body 
irradiation. Previous PSMA-targeted radioligand therapy is not allowed. 
2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological 
therapy [including monoclonal antibodies]) within 28 days prior to day of randomization. 
3. Any investigational agents within 28 days prior to day of randomization. 
4. Known hypersensitivity to the components of the study therapy or its analogs. 
5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or 
investigational therapy. 
6. Transfusion for the sole purpose of making a subject eligible for study inclusion.  
7. Patients with a history of CNS metastases must have received therapy (surgery, 
radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not 
receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients 
with epidural disease, canal disease and prior cord involvement are eligible if those areas 
have been treated, are stable, and not neurologically impaired. For patients with 
parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent 
radiological imaging must include evaluation of the brain (MRI preferred or CT with 
contrast). 
8. A superscan as seen in the baseline bone scan. 
9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending 
cord compression. 
10. Concurrent serious (as determined by the Principal Investigator) medical conditions, 
including, but not limited to, New York Heart Association class III or IV congestive heart 
failure, history of congenital prolonged QT syndrome, uncontrolled infection, known 
active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the 
investigator would impair study participation or cooperation. 

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11. Diagnosed with other malignancies that are expected to alter life expectancy or may 
interfere with disease assessment. However, patients with a prior history of malignancy 
that has been adequately treated and who have been disease free for more than 3 years are 
eligible, as are patients with adequately treated non-melanoma skin cancer, superficial 
bladder cancer.  
 
4.3 
Subject withdrawal of consent for study or treatment 
A patient may choose to withdraw his consent for participation in the study at any time at which 
time all follow-up procedures will end.  
Before final analysis of alternate primary endpoint OS: 
If a patient chooses only to discontinue from the randomized treatment in the study, the patient 
will be asked to confirm if they consent to continue to be followed for long-term safety, rPFS (if 
discontinuing for reasons other than radiographic progression), and survival follow-up. This may 
include blood work results, radiographic follow up and information about new treatments and his 
response to these treatments. Patients may also choose to be followed for survival only long-term 
follow-up.  
After final analysis of alternate primary endpoint OS: 
All randomized subjects on the active part of the study after the final analysis of the OS primary 
endpoint, will have an EOT visit and will move into long-term follow-up. This may include 
collection of survival and new treatment information, adverse events assessment for renal 
toxicity and secondary malignancies, and results of hematology and chemistry testing. Patients 
may choose to be followed for survival only long-term follow-up. 
All randomized patients on the active part of the study at the time of final analysis of the 
alternate primary endpoint OS are to be followed for safety and survival on this study, under the 
same patient ID, until a long-term safety follow-up study is available, until death, or until 
withdrawal of consent, whichever occurs first. Every opportunity to continue to collect long-term 
safety data should be made for each willing participant, regardless of time gap between release of 
protocol amendment v5.0 and v6.0. 
5. 
TREATMENT OF SUBJECTS  
5.1 
Treatment with the investigational medicinal product 
5.1.1 
Administration of 68Ga-PSMA-11 
For background and additional details on 68Ga-PSMA-11, refer to the 68Ga-PSMA-11 
Investigator’s Brochure. The 68Ga-PSMA-11 radiopharmaceutical will be administered 
intravenously at a dose of 111 - 185 MBq (3 - 5 mCi). 
Refer to the Fendler et al 2017 publication “68Ga-PSMA PET/CT: Joint EANM and SNMMI 
procedure guideline for prostate cancer imaging: version 1.0 guideline” for an overview of 68Ga-
PSMA-11 recommendations. Details of the patient preparation and administration can be found 

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in the Imaging Manual. 
 
5.1.2 
Administration of 177Lu-PSMA-617 
Once every 6-weeks (± 1 week), 7.4 GBq (±10%) 177Lu-PSMA-617 will be administered. A 
7.4 GBq dose is equivalent to 200 mCi or 7400 MBq. 
Treatment with 177Lu-PSMA-617 must be performed in accordance with national and/or local 
radiation and safety requirements. 
A saline flush with ≥10 mL of normal saline must be administered to ensure patency of the 
intravenous line before administering with 177Lu-PSMA-617 administration. 
177Lu-PSMA-617 will be administered slowly by intravenous route and followed by a saline 
flush. The time of administration must be recorded. The total activity administered must be 
measured (GBq). 
Vital signs will be collected 15(+/- 5) minutes before and at 30(+/- 5) and 60(+/- 5) minutes 
following administration.  
Patients should also be monitored for any evidence of pain or burning sensation during the 
injection. Patients should be encouraged to maintain a good fluid intake on the day of treatment 
and following therapy. 
Date and time of patient discharge following 177Lu-PSMA-617 administration should be 
recorded. 
A decision to order 177Lu-PSMA-617 should be communicated to the sponsor or designee no 
later than 10 business days prior to the planned administration for each cycle.  
 
5.1.3 
Toxicity risk reduction and supportive care for 177Lu-PSMA-617 injections 
Supportive care should be provided as deemed necessary by the treating physician. 
Oral hygiene 
Patients should be advised to use sodium bicarbonate mouthwash during the first 3 days of each 
cycle. 
Nausea and vomiting 
Mild nausea and vomiting may occur without prophylactic therapy and antiemetic treatment is 
recommended. Oral or IV ondansetron (or equivalent) and/or dexamethasone or equivalent 
institutional anti-emetic regimen should be administered on the day of 177Lu-PSMA-617 
administration. If oral administration is given, it should occur at least 30 minutes before dosing 
and, if by injection, at least 15 minutes prior to infusing 177Lu-PSMA-617. 
Additionally, dexamethasone and domperidone/metoclopramide or institutional anti-emetic 
regimen may be administered on Days 2 and 3 of each cycle if required at the discretion of the 
investigator. 
Other anti-emetics should be used as required as per standard clinical practice.  

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Additional suggested treatment guidelines 
A listing of additional suggested treatment guidelines can be found in Appendix 2. These are to 
be used at the discretion of the investigator. 
5.1.4 
Management of toxicity adverse events: dosing delays and modification 
Within the first few days of treatment the most common adverse events (AEs) are general fatigue 
and an increase in bone pain. Symptomatic hematologic toxicity may occur but is not common. 
Every effort should be made to keep the treatment cycle of 6 weeks (±1 week) at the prescribed 
doses. Physical exams, assessment of toxicities, along with hematology and chemistry results 
must all be assessed prior to dosing with 177Lu-PSMA-617. At the discretion of the investigator, 
a dose of 177Lu-PSMA-617 may be delayed or reduced. Table 1 provides dose modification 
recommendations. Only one reduction in administered activity is permitted. If a patient has 
further toxicity that would require an additional reduction in administered activity, treatment 
with 177Lu-PSMA-617 must be discontinued. Once a dose is reduced, treatment with 177Lu-
PSMA-617 should not be re-escalated. 
If a treatment delay due to adverse event or toxicity management persists for >4 weeks, treatment 
with 177Lu-PSMA-617 must be discontinued. If treatment with 177Lu-PSMA-617 is discontinued 
due to an AE, abnormal laboratory value, or toxicity, treatment with best supportive/best 
standard of care may continue at the discretion of the investigator if the patient has not 
radiographically progressed as measured by PCWG3 criteria. 
 
Table 1 Toxicity management and dose modification recommendations 
Event 
Grade 
Management recommendations 
Anemia, leukopenia, or neutropenia: 
• 
Hemoglobin <10 g/dL 
• 
WBC count <3.0 × 109/L 
• 
ANC <1.5 × 109/L 
≥Grade 2 
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
Manage as deemed appropriate by investigator. The use 
of growth factors is permitted but should be discontinued 
once the AE resolves to Grade 1 or baseline. Checking 
hematinic levels (iron, B12, and folate) and providing 
supplementation is advocated. Transfusions may be given 
as clinically indicated for anemia. 
 
Thrombocytopenia  
(platelet count of < 75 x 109/L) 
≥ Grade 2  
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
 
Transfusions may be given as clinically indicated for 
thrombocytopenia. 
Hematological toxicity (except 
lymphocytopenia that responds to 
medical intervention) 
Grade 3 or 
Grade 4 
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Serum/plasma creatinine increased 
≥40% from baseline AND calculated 
creatinine clearance decreased >40% 
from baseline 
 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 

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Table 1 Toxicity management and dose modification recommendations 
Event 
Grade 
Management recommendations 
Salivary gland toxicity 
≥ Grade 2 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Non-hematological, clinically 
significant toxicity not otherwise stated  ≥ Grade 2 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 1 or baseline 
Electrolyte or metabolic abnormalities 
that are correctable within a 48 hr 
period without sequela  
≥ Grade 2 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 1 or baseline 
Gastrointestinal toxicity (not amenable 
to medical intervention) 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Fatigue 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Pain 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Spinal cord compression 
 
Hold 177Lu-PSMA-617 administration until the 
compression has been adequately treated and 
hematological parameters have returned to Grade 1 or 
baseline and ECOG performance status has returned to 
baseline at the time the next cycle administration is due 
Fracture in weight bearing bones 
 
Hold 177Lu-PSMA-617 administration until fracture is 
adequately stabilized/treated and hematological 
parameters have returned to Grade 1 or baseline and 
ECOG performance status has returned to baseline at the 
time the next cycle administration is due 
AST or ALT >5 × ULN in the absence 
of liver metastases 
 
Discontinue 177Lu-PSMA-617 
Renal toxicity 
≥ Grade 3 
Discontinue 177Lu-PSMA-617 
Any serious AE that requires drug 
discontinuation or treatment delay of 
>4 weeks 
 
Discontinue 177Lu-PSMA-617 
Any unacceptable toxicity 
 
Discontinue 177Lu-PSMA-617 
Note: Hematologic parameters (i.e., CBC with differential analysis) will be monitored every week in Cycle 1 only. 
Cycles 2 to 6, it will be monitored every 2 weeks. After Cycle 6, it will be monitored every 12 weeks. 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ECOG = Eastern Cooperative Oncology Group; Lu = Lutetium; PSMA = prostate-specific 
membrane antigen; ULN = upper limit of normal; WBC = white blood cell 
5.2 
Best supportive/best standard of care 
The care of cancer patients must include cancer specialists accomplished in the care of patients 
with advanced prostate cancer, (e.g., medical, radiation oncologists) with a clear understanding 
of the PCWG3 2+2 rules for progression, management of AEs related to the natural course of the 
disease, as well as pre-existing AEs and study-related AEs. 
The best supportive/best standard of care for the patient in either arm should be administered as 
per physician’s orders and protocol at the institution, and whenever feasible, best supportive/best 
standard of care should be optimized for all study participants prior to randomization. Patients 

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will continue to be treated with best supportive/best standard of care until they require a 
treatment regimen not allowed on this study or have radiographic progressive disease as 
measured by PCWG3 criteria. 
Other treatments for prostate cancer, not specifically excluded as part of the study, should be 
used in accordance with the routine clinical practice and at the discretion of the investigator. 
These may include, but are not limited, to any of the interventions mentioned below. 
Supportive measures (pain meds, hydration, transfusions, etc.), and ketoconazole are allowed on 
study. 
Hormonal agents (single or combinations), estrogens including diethylstilbestrol (DES) and 
estradiol are allowed on study. 
Luteinizing hormone-releasing hormone (LHRH) analogue for testosterone suppression 
including both agonists and antagonists are allowed on study.  
Any corticosteroid such as dexamethasone, prednisone, etc. and 5-alpha reductases including 
finasteride and dutasteride is allowed on study. 
Abiraterone, enzalutamide, apalutamide or any other NAAD is allowed on study. 
Radiation in any external beam or seeded form is allowed on the study. This can include 
stereotactic body radiation therapy (SBRT) or palliative external beam or radiation involving 
seeds but no systemic radiopharmaceuticals. Y90 beads are allowed for approaches to liver 
metastasis as they are FDA approved.  
Bone targeted agents including zoledronic acid, denosumab and any bisphosphonates are allowed 
on study. 
It is important to recognize that combinations of any, and all, of the above are allowed on the 
study and can be modified over time as needed. 
5.3 
Concomitant medications/ supportive care 
5.3.1 
Permitted concomitant medications/ supportive care 
Consideration should be given to using concomitant bone health agents such as bisphosphonates 
on either arm of the study. Patients receiving bisphosphonates, denosumab, zoledronic acid or 
similar therapy prior to randomization may be maintained on this therapy during the study. 
Bisphosphonates denosumab, zoledronic acid or similar therapy can be stopped or started at the 
discretion of the investigator throughout the study. 
Patients must maintain castrate levels of serum/plasma testosterone either by chemical castration 
or by having had an orchiectomy. 
Medications for myelosuppression 
Blood transfusion or erythropoietin stimulation agents are allowed throughout the study after 
randomization. Routine prophylaxis with GCSF/granulocyte-macrophage colony-stimulating 
factor and erythropoietin is not recommended. Nevertheless, use is permitted at the investigator’s 
discretion. 
Refer to Section 5.1.4 for guidance on the management of toxicity. 

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5.3.2 
Prohibited concomitant medications 
Investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radio isotopes 
(e.g., radium-223), or hemi-body radiotherapy treatment may not be administered on study. 
5.4 
Monitoring treatment compliance 
The investigational medicinal product will be administered only at the investigational site under 
the direction of the investigator. Compliance with 177Lu-PSMA-617 therapy will be monitored 
and ensured. 
5.5 
Treatment discontinuation 
Patients may discontinue the treatment part of the study for any of the following reasons: 
• Evidence of tumor progression by radiological assessment as measured by PCWG3 
criteria 
• Unacceptable toxicity 
• Patient non-compliance or voluntary withdrawal 
• Required use of a prohibited treatment 
• Evidence that the patient is no longer clinically benefiting 
• At the sponsor’s or investigator’s discretion 
Patients that discontinue treatment due to unacceptable toxicity should return to the clinic for the 
End of Treatment visit. Participants who discontinue 177Lu-PSMA-617 due to unacceptable 
toxicity may continue to receive best supportive/best standard of care alone during the treatment 
part of the study until they discontinue the treatment part of the study and enter long-term follow-
up.  
 
Before final analysis of alternate primary endpoint OS: 
If a patient discontinues the treatment part of the study for any reason other than radiographic 
progression, they will be asked for permission to continue collecting radiographic images (bone 
scans and CT scans and/or MRIs) for the purpose of continuing to assess rPFS, unless they 
specifically withdraw consent from continued participation in the study.  
 
After final analysis of alternate primary endpoint OS: 
If a patient discontinues the treatment part of the study for any reason other than radiographic 
progression, no additional scanning will be required. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Screening procedures and baseline assessments 
Screening procedures and baseline assessments will be performed within 4 weeks of 
randomization except for baseline imaging. Any procedure or assessment done within this time 
frame may be accepted as the baseline procedure or assessment. Baseline medical imaging (CT 
with contrast/ MRI, and bone scan) is to be performed within 28 days of start of treatment. Any 

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medical imaging done within this time frame may be accepted as the baseline imaging. The 
screening procedures are detailed in Table 2. 
Table 2 Screening procedures and baseline assessments 
Screening Procedure or 
Baseline Assessment 
Notes 
Informed consent 
As per local/central IRB/IEC/REB timing requirements but prior to the 
performance of any study specific procedures. 
Inclusion/exclusion criteria 
Refer to Section 4.1 and Section 4.2 for additional details. 
Medical history 
Collect medical history, including the following details about prior 
prostate cancer treatment(s): 
• 
Date of initial diagnosis 
• 
Approximate start and stop date of each therapy 
• 
Date and type of progression (e.g. PSA, radiological, bone, or 
no clinical benefit) 
• 
Site of progression (new lesions, existing lesions, or both) when 
available 
Prior/concomitant 
medication review 
 
Full physical examination 
Should be performed by a qualified medical practitioner. 
Height 
 
Weight 
 
ECOG performance score 
Refer to Appendix 4 for the ECOG performance score scale.  
Vital signs  
Includes: blood pressure, pulse, and respiratory rate 
CT with contrast/MRI 
CT with contrast /MRI tumor assessments should include evaluations of 
the chest, abdomen, and pelvis using the RECIST v1.1 criteria with 
caveats outlined in the PCWG3 recommendations 
The radiological technique used for measurement of the baseline 
images should also be the radiological technique used for each 
reassessment. 
99mTc diphosphonate bone 
scan 
Baseline and follow up radiological disease assessments must include 
bone scans performed with technetium-99m labeled diphosphonates as 
per the local standard of care for patients with prostate cancer. Use the 
PCCTC bone scan assessment tool or equivalent to document lesions 
(included in Appendix 11).  
Histology 
Pathology report of the most recent biopsy required at enrollment.  
Disease pattern 
Bone, visceral, soft tissue, and lymph nodes 
12-lead ECG 
 
Hematology  
Refer to Section 6.3.1 for list of tests 
Chemistry  
Refer to Section 6.3.1 for list of tests 
Urinalysis, macroscopic 
(microscopic when 
indicated) 
Refer to Section 6.3.1 for list of tests 

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Table 2 Screening procedures and baseline assessments 
Screening Procedure or 
Baseline Assessment 
Notes 
Serum/plasma testosterone 
 
PSA 
Includes PSA results and dates of 2 previous measurements. Prior 
measurements are needed to assess PSA velocity/doubling time. 
BPI-SF, EQ-5D-5L and 
FACT-P 
Baseline pain score assessment (BPI-SF) and HRQoL (EQ-5D-5L, 
FACT-P) assessments. HRQoL assessments may be either self-
completed by the subject or administered via face-to-face interview and 
completed by a caretaker/clinician. 
Best supportive/best 
standard of care 
determination 
To be decided prior to randomization, as part of screening. 
PSMA PET/CT scan 
To be done once all other eligibility requirements are confirmed. The 
metastatic lesion requirement may be confirmed at the same time as the 
baseline 68Ga-PSMA-11 PET/CTa scan. 
Baseline 68Ga-PSMA-11 PET/CTa scan must be done within 4 weeks (+ 
2 weeks) of start of treatment but not within the 6 days prior to start of 
treatment. 
Study eligibility based on PSMA positivity will be determined by 
central readers. 
Screening registration 
Initial screening registration should take place after the patient has 
signed the Informed Consent Form. It should be completed once all 
screening assessments have been completed and results confirmed 
except for metastatic lesion requirement and PSMA positivity.  
Study enrollment 
Study enrollment should take place after screening registration is 
completed and once the metastatic lesion requirement is confirmed by 
the site and PSMA positivity has been confirmed by the central readers. 
Patients randomized to the investigational arm are to begin dosing with 
177Lu-PSMA-617 within 28 days after randomization. 
a 
For background and additional details on 68Ga-PSMA-11, refer to the 68Ga-PSMA-11 Investigator’s 
Brochure. 
BPI-SF = Brief Pain Inventory – Short Form; CT= computed tomography; ECG = electrocardiography; 
ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 
Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; HRQoL = Health-related quality of 
life; IEC = Independent Ethics Committee; IRB = Institutional Review Board; MRI = magnetic resonance 
imaging; PCCTC = Prostate Cancer Clinical Trials Consortium; PET = positron emission tomography; PSA = 
prostate-specific antigen; PSMA = prostate-specific membrane antigen; REB = Research Ethics Board; RECIST 
= Response Evaluation Criteria in Solid Tumors;  
6.2 
Efficacy assessments 
For the timing of efficacy assessments, refer to the schedule of assessments provided in 
Appendix 1. 
6.2.1 
Radiographic imaging for tumor assessments 
Radiologic assessment should follow PCWG3 guidelines. Periodic radiographic imaging will 
include both: 

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• CT with contrast/MRI imaging 
• Bone scans with technetium-99m labeled diphosphonates 
CT with contrast/MRI tumor assessments should include evaluations of the chest, abdomen, and 
pelvis.  
Disease progression by bone scan will be defined as at least 2 new bone lesions at the first post-
treatment scan, with at least two additional lesions on the next (confirmatory) scan (2+2 PCWG3 
criteria, Scher et al 2016). For scans after the first post-treatment scan, at least two new lesions 
relative to the first post-treatment scan confirmed on a subsequent scan (2+2 PCWG3 criteria). If 
the second scan confirms the metastases, then the date of progression is the date of the scan when 
the first 2 new metastases were documented. 
6.2.2 
Additional Imaging Analyses 
The baseline eligibility 68Ga-PSMA-11 scan data will be used for additional exploratory 
analyses. The 68Ga-PSMA-11 PET/CT and corresponding diagnostic CT/MRI scans will be used 
in a retrospective Independent Review assessing inter-reviewer variability. The Independent 
Review will serve to evaluate the reading procedure for 68Ga-PSMA-11 PET/CT scans by 
assessing the variability and reproducibility of visual assessment. Visual assessment will be 
independently performed by three reviewers on 68Ga-PSMA-11 PET/CT scans and 
corresponding diagnostic CT/MRI scans. 
In addition, Quantitative Analysis will also be performed to assess tumor burden and tumor 
characteristics on 68Ga-PSMA-11 PET/CT scans at the time of enrolment. The association of 
these baseline data with rPFS, OS, and other efficacy endpoints will be assessed in exploratory 
analyses. 
An imaging charter will provide a detailed and expanded description of the planned analyses. 
  
6.2.3 
RECIST criteria 
The responses of soft tissue, lymph node, and visceral lesions to treatment will be characterized 
using the RECIST v1.1 criteria with caveats outlined in the PCWG3 recommendations (see 
Appendix 6 and Appendix 7). 
6.2.4 
Symptomatic skeletal events 
The time to the first SSE will measure the time to the first new symptomatic pathological bone 
fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement 
for radiation therapy to relieve bone pain or death from any cause, whichever occurs first. 
6.2.5 
Pain score 
Pain will be assessed using the Brief Pain Inventory – Short Form (BPI-SF).  
The Brief Pain Inventory- Short Form will be used as part of this study to assess the severity of 
pain and the impact of pain on daily functions. Full details regarding the BPI-SF, its validation 
and clinical application are available in the Brief Pain Inventory User Guide (Cleeland 2009). 
A copy of the BPI-SF questionnaire is provided in Appendix 8. 

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6.2.6 
Health-related quality of life 
The ECOG Performance Status scale will be used to assess patients’ ability to perform daily 
living tasks and their range of basic physical ability. A copy of the ECOG scale is provided in 
Appendix 4. 
The EQ-5D-5L questionnaire will also be administered as a part of this study to assess HRQoL. 
EQ-5D is an international, validated, standardized, generic questionnaire for describing and 
valuing HRQoL (Rabin 2001). EQ-5D was developed by the EuroQol Group in order to provide 
a simple, generic measure of health for clinical and economic appraisal (EuroQoL Group 1990). 
This instrument generates a preference-based health-state utility score (EQ-5D utility index) and 
an overall health-state score based on a visual analogue scale (EQ-5D VAS).  
EQ-5D is designed for self-completion by respondents and is ideally suited for use in clinics and 
face-to-face interviews. It is cognitively undemanding, taking only a few minutes to complete. 
Instructions to respondents are included in the questionnaire. The most recent version of EQ-5D 
is the EQ-5D-5L, which was developed to improve the instrument’s sensitivity and to reduce 
ceiling effects. The number of dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) has not changed, however the new version includes five levels of severity in 
each of the existing dimensions in place of three (EuroQoL Group 2015). Full details regarding 
the EQ-5D-5L questionnaire, including references, are available at the EQ-5D website: 
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about. 
A copy of the EQ-5D-5L questionnaire is provided in Appendix 9 
The FACT-P questionnaire will also be administered as part of this study to specifically assess 
the HRQoL of prostate cancer patients. The FACT-P is made up of 2 parts: the FACT-G 
(general) questionnaire with 27 questions, and the Prostate Cancer Subscale (PCS) with an 
additional 12 questions. The FACT-G (Functional Assessment of Cancer Therapy – General) 
questionnaire is one of the most widely used HRQoL instruments and measures HRQoL in four 
different domains: Physical well-being, Functional well-being, Emotional well-being, and 
Social/Family well-being (Cella et al 1993). The PCS is designed specifically to measure 
prostate cancer-specific quality of life. Each item in both the FACT-G and PCS is rated on a 0 to 
4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as 
global quality of life score with higher scores representing better QoL. The FACT system has a 
number of advantages as a method of measuring QoL: 
• Questionnaires have been developed to reflect patients’ concerns 
• Measurements are reliable, reproducible, and have been validated in numerous studies 
(Cella et al 1993, Esper et al 1997) 
• Available in over 45 different languages 
• Designed for patient self-administration, but can also be administered by interview 
format (Webster et al 2003) 
Full details regarding the FACT-P questionnaire, including references, are available at the 
FACIT website: http://www.facit.org/FACITOrg/Questionnaires. 
A copy of the questionnaire (FACT-P version 4) is provided in Appendix 10. 

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HRQoL will be periodically assessed at baseline, prior to administration of each cycle of 177Lu-
PSMA-617, and through the End of Treatment visit. 
6.2.7 
Health Economics 
A health economics (HE) sub-study will be performed. Core health resource use information will 
be collected, using case report forms (CRFs) on days in hospital and any outpatient visits. Data 
collected on concomitant medication may also be used in the economic analysis.  
For the economic modelling, costs will be imputed on the basis of representative country unit 
costs at the point of analysis using standard fee schedules. Health outcomes will be assessed in 
terms of quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Quality 
adjustments will be based on patients’ responses to the EQ-5D health status measure which will 
be administered at baseline, before each cycle of therapy, and each point of follow-up as part of 
the QoL questionnaire. 
 
6.2.8 
Clinical progression 
Clinical progression will be assessed by the investigator. The following criteria should be used to 
determine when a patient has met the standard for unequivocal evidence of clinical progression:  
• Marked escalation in cancer-related pain that is assessed by the investigator to indicate 
the need for other systemic chemotherapy 
• Immediate need for initiation of new anticancer treatment, surgical, or radiological 
intervention for complications due to tumor progression even in the absence of 
radiological progression 
• Marked deterioration in ECOG performance status to ≥ Grade 3 and a finding of the 
investigator that the deterioration indicates clinical progression 
• In the opinion of the investigator, it is in the best interest of the patient to discontinue 
treatment due to clinical progression 
6.2.9 
PSA levels 
Local labs will measure PSA levels. Increases and decreases will be tracked to assess PSA 
responses as per PCWG3 (Appendix 7). 
6.3 
Safety assessments 
6.3.1 
Clinical laboratory evaluations 
Local labs will perform hematology, chemistry, serum/plasma testosterone, and urinalysis 
testing.  

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Chemistry, urinalysis, and hematology testing will include the following: 
Chemistry 
*total carbon 
dioxide or 
equivalent is 
acceptable 
 
** urea is 
acceptable 
• 
Sodium 
• 
potassium 
• 
total and direct bilirubin 
• 
ALP 
• 
AST 
• 
ALT 
 
• 
LDH 
• 
blood urea 
nitrogen**  
• 
creatinine 
• 
uric acid 
• 
phosphorus 
• 
chloride 
• 
bicarbonate* 
• 
calcium 
• 
glucose 
• 
total protein 
• 
albumin 
Urinalysis 
• 
urine pH 
• 
protein content 
• 
specific gravity 
• 
appearance and color 
 
• 
glucose 
• 
ketones 
 
 
Hematology 
• 
complete blood count (white blood cell count and differential) 
• 
red blood cell count 
• 
hemoglobin 
• 
hematocrit 
• 
platelet count 
 
6.3.2 
Vital signs 
Blood pressure, pulse and respiratory rate will be assessed. 
6.3.3 
Electrocardiograms 
A 12-lead ECG will be done at screening. 
6.3.4 
Birth Control 
It is recommended that male patients who are sexually active practice an effective barrier method 
of birth control (e.g, condom and spermicidal jelly). Effective birth control methods should be 
used from day of the 68Ga-PSMA-11 dose, throughout study treatment and for at least 6 months 
following the last dose of 177Lu-PSMA-617. 
6.4 
End of treatment visit procedures 
The assessments and procedures to be done at the EOT visit are defined in the Schedule of 
Assessments tables, provided in Appendix 1. 
6.5 
Long-term follow-up procedures 
Before final analysis of alternate primary endpoint OS: 
A long-term follow-up period will collect, long-term follow-up specific self-reported AE 
assessments, rPFS (if discontinuing for reasons other than radiographic progression), survival 
and treatment updates from patients every 3 months (± 1 month) via phone, email, or letter. 
Hematology and chemistry blood work results will also be collected. Patients who withdraw their 
consent to participate in the treatment portion of the study or come off the treatment portion of 
the study for any reason other than radiographic disease progression will be asked for permission 

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to continue long-term status updates which may include, in addition to the above, collection of 
radiographic images (bone scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-term follow-
up assessments and study updates they will agree to. They will also be able to designate a contact 
person (i.e. study doctor, local doctor, friend or family member) who may be contacted on their 
behalf to obtain follow-up status updates. 
For any of these patients who are unable to sign the second consent (i.e. does not return to the 
site, etc.) every effort will be made to document the extent of long-term follow-up they will 
agree to. This will be documented in their source records.  
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study at the time of final analysis of the 
alternate primary endpoint OS will have an EOT visit at the next planned visit after 
implementation of V5.0 of the protocol and will move into long-term follow-up. All patients in 
long-term follow-up will continue to be followed on this study, under the same patient ID, until a 
separate long-term safety follow-up study is available in the respective country, until death or 
until withdrawal of consent, whichever occurs first. 
The long-term follow-up period will include the collection of survival and new treatment 
information, adverse events assessment for renal toxicity and secondary malignancies, and 
results of hematology and chemistry testing. During follow-up, patients will be followed for 
safety and survival. They will be seen or contacted by a clinician every 3 months (±1 month) via 
phone, in person or via telemedicine visit, email or letter on this study until a long-term safety 
follow-up study is available, until death or until withdrawal of consent, whichever occurs first. 
Every opportunity to continue to collect long-term safety data should be made for each willing 
participant, regardless of time gap between release of protocol amendment v5.0 and v6.0. 
7. 
ADVERSE EVENTS 
7.1 
Adverse event definitions 
The following definitions comply with the ICH E2A guidance, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, and the safety definitions of 
the World Health Organization (WHO) International Drug Monitoring Center. 

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Term 
Definitionsa 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Progression of disease is not considered an AE or SAE for this study.  
Adverse Drug 
Reaction  
For an investigational medicinal product all noxious and unintended response to a 
medicinal product related to any dose should be considered adverse drug reactions.  
Response in this context means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility. 
Serious Adverse Event 
(SAE) or  
Adverse Drug 
Reaction 
A serious adverse event or reaction is any untoward medical occurrence that at any 
dose:  
• 
results in death; except for deaths due to progression of disease 
• 
is life-threatening;  
• 
requires inpatient hospitalization or prolongation of existing hospitalization;  
• 
results in persistent or significant disability/incapacity; or  
• 
is a congenital anomaly/birth defect. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.  
Unexpected Adverse 
Drug Reactionb 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (i.e., Investigator's Brochure for an unapproved investigational 
medicinal product). 
a 
ICH E2A, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 
b 
Also referred to as a Suspected Unexpected Serious Adverse Reaction (SUSAR). 
AE = adverse event; SAE = serious adverse event 
7.2 
Evaluating and recording adverse events 
Before final analysis of alternate primary endpoint OS: 
All AEs will be graded according to CTCAE v5.0. All AE monitoring and SAE recording and 
reporting will begin at the time of consent and will continue up to and including 30 days after the 
last dose of 177Lu-PSMA-617 or the date of best supportive/best standard of care end of 
treatment decision, whichever is later. For patients that are not randomized, AE monitoring will 
continue up to and including 6 days after administration of 68Ga-PSMA-11. 
All AEs and abnormal test findings, regardless of suspected causal relationship to 68Ga-PSMA-
11, 177Lu-PSMA-617, and/or best supportive/best standard of care, will be recorded in the 
patients’ case histories. For all AEs sufficient information will be obtained to permit an adequate 
determination of the outcome of the event and an assessment of the casual relationship between 
the AE and 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best supportive/best standard of care. AEs 
or abnormal test findings felt to be associated with 68Ga-PSMA-11, 177Lu-PSMA-617, and/or 
best supportive/best standard of care will be followed until the event or its sequelae or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
The investigator will promptly review AEs and abnormal test findings to determine if: 1) the 
abnormal test finding should be classified as an AE; 2) there is a reasonable possibility that the 

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AE was caused by 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best supportive/best standard of 
care; and 3) the AE meets the criteria for a serious adverse event (SAE). If the final 
determination of causality is “unknown and of questionable relationship to the study drug” the 
adverse event will be classified as associated with the use of the study drug for reporting 
purposes. If the final determination of causality is “unknown but not related to the study drug” 
the determination and rationale will be documented in the patient’s case history. 
After final analysis of alternate primary endpoint OS: 
All AEs will be graded according to CTCAE v5.0. All AE monitoring and SAE recording and 
reporting will begin at the time of consent and will continue up to and including 30 days after the 
last dose of 177Lu-PSMA-617 or the date of best supportive/best standard of care end of 
treatment decision, whichever is later. In addition, SAE recording and reporting will be 
continued in the long-term follow-up period. During long-term follow-up, SAEs are to be 
reported only if the investigator suspects a causal relationship to the study treatment.  
SAEs experienced after the 30-day period following the last administration of randomized 
treatment, including during long-term follow-up, should be reported to Novartis Safety if the 
investigator suspects a causal relationship to the study treatment. 
During long-term follow-up, for all renal toxicities, secondary malignancies and all SAEs, 
sufficient information will be obtained to permit an adequate determination of the outcome of the 
event and an assessment of the casual relationship between the AE and 177Lu-PSMA-617, and/or 
best supportive/best standard of care. SAEs, renal toxicities and secondary malignancies felt to 
be associated with 177Lu-PSMA-617, and/or best supportive/best standard of care will be 
followed until the event or its sequelae or the abnormal test finding resolves or stabilizes at a 
level acceptable to the investigator. 
The investigator will promptly review AEs and abnormal test findings to determine if: 1) the 
abnormal test finding should be classified as an AE; 2) there is a reasonable possibility that the 
AE was caused by, 177Lu-PSMA-617, and/or best supportive/best standard of care; and 3) the AE 
meets the criteria for a serious adverse event (SAE). If the final determination of causality is 
“unknown and of questionable relationship to the study drug” the adverse event will be classified 
as associated with the use of the study drug for reporting purposes. If the final determination of 
causality is “unknown but not related to the study drug” the determination and rationale will be 
documented in the patient’s case history. Renal toxicities and secondary malignancies will be 
recorded as AEs. Any AE determined to meet the criteria for a serious adverse event and 
considered related to the study drug (even a questionable relationship) should be recorded as an 
AE and reported as an SAE. 
 
7.3 
Immediate Adverse Event Reporting 
Endocyte will ensure that all relevant safety information as required by local and/or national 
laws, directives and/or regulations are reported to the appropriate Competent Authorities as well 
as the Principal Investigator and/or IRBs/Ethics Committees. 

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7.3.1 
Serious Adverse Events 
SAEs require expeditious handling and MUST IMMEDIATELY be reported upon discovery so 
the sponsor may comply with regulatory requirements. 
Any SAE, regardless of causal relationship, must be reported to the Sponsor Contact listed in the 
Sponsor Contact section (Section 7.3.3) immediately (no later than 24 hours after the investigator 
becomes aware of the SAE) by emailing or faxing a completed SAE form to the number/email 
indicated. Compliance with this time requirement is essential so that the sponsor may comply 
with its regulatory obligations. 
Follow-up information relating to an SAE must be reported to the Sponsor Contact in 
Section 7.3.3 within 24 hours of receipt by the investigator by emailing or by faxing a completed 
SAE form to the number indicated. The patient should be observed and monitored carefully until 
the condition resolves or stabilizes or its cause is identified. 
SAEs which are: 1) associated with 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best 
supportive/best standard of care; 2) fatal or life-threatening; and 3) unexpected, will be reported 
to the principal investigator and/or IRBs/Ethics Committee/Research Ethics Boards (REBs) and 
the Regulatory Authorities within 7 days of awareness of the respective information. Other SAEs 
which are: 1) associated with the investigational drug or study treatment; 2) non-fatal or non-life-
threatening; and 3) unexpected will be reported to the principal investigator and/or IRBs/Ethics 
Committee/REBs and Regulatory Authorities within 15 days of awareness of the respective 
information. 
7.3.2 
Serious adverse event subject follow-up 
Follow-up information to a reported SAE will be submitted to the principal investigator and/or 
IRBs/Ethics Committees and Competent Authorities in accordance with local regulations and 
international guidelines. If the results of the follow-up investigation show that an SAE that was 
initially determined to not require reporting does, in fact, meet the requirements for reporting, the 
investigator will report the SAE to the principal investigator and/or IRBs/Ethics 
Committees/REBs in accordance with local regulations and international guidelines. 
7.3.3 
Sponsor Contact Information for Immediate Reporting 
Serious adverse events and follow-up information should be reported on a completed serious 
adverse event report form to Novartis Safety. Detailed instructions regarding the submission 
process can be found in the Change in Safety Reporting Process Training provided to each site 
detailing the reporting of SAEs to Novartis Safety. 
8. 
STATISTICS 
This section outlines the general study design, study endpoints, and statistical analysis strategy 
for the study.  
All statistical analyses will be carried out using SAS version 9.4 (or later). The SAP will be 
written and finalized prior to the first planned analysis and without knowledge of any 
by-treatment group accumulated data. The SAP will provide a detailed and expanded description 

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of the statistical methods outlined in this protocol. Additional analyses, such as important 
subgroups, will be described. 
After the final analysis of OS is performed, additional analyses of the primary endpoints (e.g. 
OS) will be presented descriptively without statistical inference and at the same nominal alpha 
level used for the primary analysis for each endpoint. Final safety analyses will be performed 
when the last patient is followed on this study until a long-term safety follow-up study is 
available in the respective country, dies or withdraws consent, whichever occurs first. 
8.1 
Revision to the protocol and statistical analyses of rPFS and OS 
The trial was originally designed to randomize 750 patients, targeting the primary analysis of 
rPFS with 457 events with a 1-sided alpha level of 0.001, an interim analysis of OS with a 1-
sided alpha level of 0.001, to be conducted contemporaneously with the primary analysis of 
rPFS, and a final primary analysis of OS with 489 deaths with a 1-sided alpha of 0.023. 
However, shortly after commencement of the trial, a high early dropout rate amongst those 
randomized to BS/BSC-only arm became evident with the majority of these dropouts 
withdrawing consent to follow-up. This meant that rPFS data could not be collected for these 
patients which consequently could result in bias in the analysis of rPFS. Remedial measures to 
curtail this phenomenon were implemented and made effective on March 5th, 2019. As part of 
the plan to address the early withdrawal of consent in the BS/BSC-only arm, the primary analysis 
of rPFS was altered to focus on patients prospectively randomized on or after March 5th, 2019; 
therefore, rPFS will be analyzed in these patients once 364 events have accrued with a 1-sided 
alpha level of 0.004. At time of this rPFS primary analysis, there will be an interim analysis of 
OS with a 1-sided alpha level of 0.001; this OS analysis will be on an ITT basis and will include 
all randomized patients (i.e., including those randomized before March 5th, 2019). Following the 
analysis of rPFS and the interim analysis of OS, a final ITT primary analysis of OS will be 
performed when 508 deaths have accrued with a 1-sided alpha level of 0.020. To achieve these 
analyses, the total number of subjects randomized into the trial was increased from N=750 to 
N=814. The revisions described do not alter the hypothesized treatment effects for rPFS and OS 
upon which the study was originally powered. 
8.2 
Revisions to planned analyses 
Subsequent to the protocol revision, if further changes are made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
further amended (consistent with ICH Guideline E9). Any changes to exploratory or non-
confirmatory analyses made after the protocol has been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR). |Any post hoc 
exploratory analyses will be clearly identified in the CSR. Full details will be in the SAP. Any 
deviations from the statistical plan will be described and justified in a protocol amendment 
and/or in the CSR. 
8.3 
Sample size and power determination 
The sample size was determined based on the alternate primary endpoints of rPFS and overall 
survival. Planned enrollment for this study is approximately 814 subjects. 

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Under the null hypothesis for survival, median survival is assumed to be 10 months on 
177Lu PSMA-617 and best supportive/best standard of care (active) for a hazard ratio (HR) of 
1.00. Under the alternative hypothesis, median overall survival on active is assumed to be 
13.7 months for a HR of 0.7306.  
Under the null hypothesis for rPFS, median rPFS is assumed to be 4 months on 177Lu-PSMA-617 
and best supportive/best standard of care (active) for a hazard ratio (HR) of 1.00. Under the 
alternative hypothesis, median rPFS on active is assumed to be 6 months for a HR of 0.67.  
Based on a non-linear patient accrual profile over 14 months, a total of 814 patients randomized 
and followed on an ITT basis for a minimum of 13 months is expected to yield 508 deaths. This 
number of events provides at least 90% power to test the hypothesis that the HR for OS is 0.7306 
or better with a 1-sided alpha level of at least 0.020. 
For rPFS, a total of approximately 557/814 patients are expected to be randomized on or after 
5 March 2019, these being the patients to be included in the primary analysis of rPFS; with a 
minimum of approximately 6 months follow-up, these patients are expected to yield 364 rPFS 
events which will be sufficient to provide 84% power to test the hypothesis that the HR of rPFS 
is or 0.67 or better with a 1-sided alpha level if 0.004. At the time of this rPFS analysis, 341 
deaths are expected amongst all randomized patients. These interim OS data will be analyzed 
with a 1-sided alpha level of 0.001. Central independent assessments will be used to determine 
rPFS events. 
The alpha level applicable to OS in the final analysis will depend upon the earlier rPFS and 
interim OS results: 
• if p<0.004 1-sided is achieved for rPFS and p<0.001 1-sided is achieved for interim OS, 
then the alpha level for the final analysis of OS will be raised to 0.025 1-sided. 
• if p<0.004 1-sided is achieved for rPFS but p<0.001 1-sided is not achieved for interim 
OS, then the alpha level for the final analysis of OS will be 0.024 1-sided. 
• if p<0.004 1-sided is not achieved for rPFS but p<0.001 1-sided is achieved for interim 
OS, then the alpha level for the final analysis of OS will be raised to 0.021 1-sided. 
• if p<0.004 1-sided is not achieved for rPFS and p<0.001 1-sided is not achieved for 
interim OS, then the alpha level for the final analysis of OS will remain at 0.020 1- sided. 
This design provides at least 90% power for OS and 84% power for rPFS; with an overall Type I 
error rate ≤0.025 1-sided.  
The observed HRs that will meet p<0.004 for rPFS and the interim analysis of OS are 0.745 and 
0.701 respectively; and the observed HR that will meet p<0.020 to p<0.025 in the final analysis 
of OS are 0.824 to 0.823. 
8.4 
Analysis populations 
Analysis datasets are defined as follows: 
• Full Analysis Set (FAS): All randomized patients. OS will be assessed on an ITT basis 
and related data will be summarized by randomized treatment. 

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• PFS Analysis Set (PFS-FAS): All patients randomized on or after March 5th, 2019. The 
primary analysis of rPFS will be based on this dataset on an ITT basis and related data 
will be summarized by randomized treatment. 
• Response Evaluable Analysis Set: The subset of patients in the PFS-FAS with evaluable 
disease by RECIST at baseline. Soft tissue response as measured by RECIST will be 
assessed in this dataset. 
• Safety Analysis Dataset: There will be two safety datasets 
o The subset of patients who received as least one dose of 68Ga-PSMA-11.  
o The subset of patients in the FAS who received as least one dose of randomized 
therapy. Patient safety data in this dataset will be summarized by treatment 
received. 
8.5 
Demographics and baseline disease characteristics 
Demographic and baseline disease characteristic data will be summarized in the FAS and PFS-
FAS for each treatment with frequency distributions and/or descriptive statistics (mean, standard 
deviation, median, range, and/or relevant percentiles). Formal statistical tests comparing 
treatment groups will not be provided. 
8.6 
Patient disposition 
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. This will be done for the FAS and the PFS-FAS. If 
known, a reason for their discontinuation will be given. Reporting of patient disposition will 
include: 
• A summary of data on patient discontinuation 
• A summary of data on overall qualification status of all patients 
• An account of all significant protocol deviations 
All patients enrolled in the study will be accounted for in the summation. The number of patients 
who do not qualify for analysis, who die, or who discontinue before treatment begins, will be 
specified. 
8.7 
Efficacy analyses 
8.7.1 
Alternate primary endpoint efficacy analysis 
8.7.1.1 
rPFS 
Radiographic progression-free survival (rPFS) is defined as the time from the date of 
randomization to the date of radiographic disease progression as outlined in Prostate Cancer 
Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death from any cause. rPFS as 
determined by the independent central assessment will be used for this analysis. The primary 
analysis of rPFS will be based upon the PFS-FAS and will take place once 364 rPFS events have 
been reached. The allocated alpha level for the rPFS analysis is 0.004 1-sided. 

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Patients who are alive without radiographic progression at the analysis data cut-off or are lost to 
follow-up at the time of analysis will be censored for rPFS at the time of their last radiographic 
assessment or at the data cut-off date. rPFS data will be displayed using Kaplan Meier curves 
from which median rPFS times will be estimated for both treatment arms. 
A stratified log-rank test model will be the primary statistical methodology used to analyze rPFS 
in the PFS-FAS dataset, stratified for the randomization stratification factors.  
Supportive analyses of rPFS will be performed in terms of (i) a stratified Cox regression model 
on the PFS-FAS dataset with a single covariate for randomized treatment, and stratifying again 
for the randomization stratification factors; and (ii) the same as (i) but based upon the FAS 
dataset. The HR and CI from (i) will be used as an adjunct to the primary stratified log rank test 
p-value to provide the quantification of the treatment effect on rPFS. 
 
8.7.1.2 
OS 
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause and will be assessed in the FAS. A formal interim analysis of OS is planned to 
occur at the time of the rPFS analysis (with 364 rPFS events in PFS-FAS); it is anticipated that 
approximately 341 deaths will have accrued in the FAS at the time of the rPFS analysis in the 
PFS-FAS. The allocated alpha level for OS in this interim analysis is 0.001 1-sided. The final 
analysis of OS is event driven and will take place once 508 deaths have occurred in the FAS. As 
described in Section 8.3, the allocated alpha level for the final OS analysis will be between 0.020 
and 0.025 1-sided, depending on the results of the earlier primary rPFS analysis and interim OS 
analysis. 
Patients who are lost to follow-up or are alive at the time of the OS analysis (for both interim and 
final analyses) will be censored at the time they were last known to be alive or at the date of 
event cut-off for the OS analysis. OS data will be displayed using Kaplan Meier curves from 
which median OS will be estimated for both treatment arms. 
OS will be analyzed using the same statistical methodology as described for the primary analysis 
of rPFS. Supportive analyses of OS will be performed at the interim and final in terms of Cox 
regression model on the FAS dataset with a single covariate for randomized treatment, stratifying 
for the randomization stratification factors. The HR and CI from these analyses be used as an 
adjunct to the primary stratified log rank test p-values to provide the quantification of the 
treatment effect on OS. 
 
8.7.1.3 
Statistical Interpretation of Alternate Primary Endpoints 
The statistical design of the study is such that, to be declared positive, the study would be 
required to reach statistical significance on either the primary analysis of rPFS or OS at the 
respective allocated alpha level; it is not required to meet both rPFS and OS to be declared a 
statistically positive study.  
Note, this applies to OS assessed at either the interim or the final analysis, i.e. for the study to be 
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allocated alpha level at either (i) the formal OS interim analysis (conducted at the time of the 
rPFS analysis) or (ii) at the final OS analysis with 508 deaths.  
Alpha allocation and recycling are used to ensure control of the overall Type I error rate as 
described in Section 8.3. 
8.7.2 
Secondary efficacy analyses 
Key secondary endpoints 
Key secondary endpoints will be subject to Type I error control. These endpoints are: 
1. RECIST ORR and DCR 
2. Time to SSE  
The primary evaluation of these endpoints will be assessed in the PFS-FAS dataset. Time to SSE 
will be analyzed using a Cox regression model with a single covariate for randomized treatment, 
stratifying for the randomization stratification factors. ORR and DCR will be analyzed using 
logistic regression with a single covariate for randomized treatment and stratification for the 
randomization stratification factors. The odds ratio (active: control), its 95% confidence interval 
and associated 2-sided p-value will be presented. The DOR for binary response endpoint ORR 
will also be summarized and presented using Kaplan-Meier curves. 
To control the overall Type I error rate, if either alternate primary endpoint is met, then the key 
secondary endpoints will be assessed using the Hochberg closed test procedure at the alpha level 
applicable to the successful alternate primary endpoint. This procedure is reasonable given the 
positive correlation between the two key secondary endpoints. 
Supportive analyses of ORR, DCR and time to SSE will be performed in the FAS dataset using 
the same methods as described for the primary evaluation of these endpoints. 
Additional Secondary Endpoints 
Additional Secondary Endpoints will be assessed at the nominal 5% level, i.e. there will be no 
alpha control applied. These endpoints will be assessed in PFS-FAS with the exception of safety 
which will be assessed using the Safety analysis sets and are: 
1. To evaluate the safety and tolerability of 177Lu-PSMA-617  
2. Aspects of HRQoL will be self-reported by patients (or via interview format) using the 
EQ-5D-5L and FACT-P questionnaires, and pain will be assessed by patients using the 
BPI-SF. 
3. Health economics 
4. PFS as defined as the date of randomization to the date of first evidence of radiographic 
progression, clinical progression, PSA progression, or death from any cause, whichever 
occurs first.  
5. Biochemical response endpoints:  
d. Proportion of subjects who are PSA responders, defined as a patient who has 
achieved a ≥50% decrease from baseline that is confirmed by a second PSA 
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e. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be 
collected. 
Event-free survival endpoints (e.g., PFS, time to pain worsening) will be analyzed using a Cox 
regression model in the same manner as described for time to SSE except using a 2-sided p-
value. DCR will be analyzed in the same manner as ORR and HRQoL will be analyzed in the 
same manner as pain score over time. Time to pain improvement response after initial pain 
worsening will be analyzed using mixture distribution methodology akin to that described by 
Ellis et al 2008. 
8.8 
Safety analyses 
All safety evaluations will be based on the Safety Analysis Set. 
8.8.1 
Extent of exposure 
The duration of exposure and dose intensity will be calculated. The relationship between dose 
intensity, duration of exposure, and frequency and severity of adverse events will be explored by 
data tabulation. 
8.8.2 
Analysis of adverse events 
The frequency of treatment emergent adverse events (TEAEs) and SAEs will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class. 
The maximum NCI CTCAE grade and frequency of AEs will be summarized. 
A 68Ga-PSMA-11 TEAE is defined as an AE that was not present prior to dosing with 
68Ga-PSMA-11 but appeared following dosing or was present at time of initial dosing but 
worsened during or after dosing. The treatment-emergent period will be defined as the period 
from the date of 68Ga-PSMA-11 dosing up to 6 days after the date of 68Ga-PSMA-11 dosing as 
long as prior to the first dose of 177Lu-PSMA-617 for the investigational arm and Cycle 1 Day 1 
for the best supportive/best standard of care-only arm. Adverse events reported as “possibly”, 
“probably”, or “definitely” related to 68Ga-PSMA-11 that occur beyond the 6-day reporting 
window but occur before the initiation of randomized treatment are also 68Ga-PSMA-11 TEAEs. 
Unrelated 68Ga-PSMA-11 adverse events that occur beyond 6 days will not be TEAEs. 
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 for the investigational arm and 
Cycle 1 Day 1 for the BS/BSC arm, 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). The treatment-emergent period will be 
defined as the period from the initiation of randomized treatment up to 30 days after the date of 
the last dose or intervention of randomized treatment or the day prior to the initiation of 
subsequent anticancer treatment, whichever occurs first.  
Adverse events leading to permanent discontinuation of study drug and/or leading to death will 
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8.8.3 
Analysis of laboratory assessments 
Laboratory values and change from baseline will be summarized by visit and treatment using 
descriptive statistics. Shift tables of the worst on-study laboratory toxicity based on CTCAE v5.0 
grading relative to baseline will be presented by treatment group. Subject listings of laboratory 
toxicities ≥ Grade 3 will be provided. 
8.8.4 
Analysis of vital sign data 
Vital sign data (observed and change from baseline) will be summarized using descriptive 
statistics by time point and treatment. Abnormal findings from physical examinations will be 
assessed for clinical significance which will be included in the AE listings and summaries. 
8.9 
IDMC and Interim Data Evaluation  
8.9.1 
IDMC 
An IDMC will be convened to review accumulating safety and safeguard patient interest in the 
study. Safety data monitoring will be conducted quarterly by the IDMC. These safety reviews 
will commence following the completion of the first three months of study accrual. 
In addition, a summary of efficacy data will also be provided to the IDMC at the time of routine 
safety data reviews; these efficacy data will be provided for information only, no statistical 
analyses will be conducted. The only analyses of efficacy data are those formally planned for 
rPFS in the PFS-FAS at 364 events, interim OS (in the FAS) at the time of the rPFS analysis and 
final OS (in the FAS) with 508 deaths. 
The IDMC will review these formal efficacy analyses. The IDMC may recommend early 
curtailment of trial on the basis of meeting one of the preplanned formal efficacy analyses or due 
to the emergence of an unforeseen safety concern placing patient safety at risk. 
An IDMC Charter will be approved and finalized by the IDMC members prior to the initiation of 
any formal efficacy analysis. 
The IDMC can recommend a course of action, but the sponsor will make the final decision 
regarding whether or not to continue or stop the trial, based on any analysis for reasons related to 
safety or efficacy. 
8.9.2 
Formal Interim Analysis of OS 
As described above in Section 8.3, one formal interim analysis is planned for OS in the FAS to 
take place at the time of the primary rPFS analysis in the PFS-FAS. The allocated alpha level for 
the interim OS analysis is 0.001 1-sided. Regardless of whether a positive result is attained at this 
time, for either rPFS or interim OS, patient follow-up will continue until 508 OS events have 
accrued in the FAS at which time a final OS analysis will be performed.  
9. 
 ACCESS TO SOURCE DATA/DOCUMENTS 
During the course of the study, a representative of Endocyte or its designee will be contacting 
and/or visiting the study sites to monitor the progress of the study. Contacts with the investigator 
and on-site visits for the purpose of data audits, including the comparison of source documents 

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with case report forms (CRFs) and study agent accountability logs, will occur. The principal 
investigator or his/her representative will need to be available to the representative of Endocyte 
or its designee during these visits. 
By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, Endocyte, its designee, or responsible 
government agencies (as required by law) may review or copy source documents in order to 
verify case report form (CRF) data. 
10. 
ETHICS 
10.1 
Institutional Review Board/Independent Ethics Committee/ Research 
Ethics Board (IRB/IEC/REB) 
The investigator will obtain approval from the IRB/IEC/REB of the proposed clinical protocol 
and ICF for study recruitment and the approval will be provided to Endocyte or its designee prior 
to beginning the clinical trial. The only circumstance in which a deviation from the 
IRB/IEC/REB-approved clinical protocol/ICF may be initiated in the absence of prospective 
IRB/IEC approval is to eliminate an apparent immediate hazard to the research participants. In 
such circumstances, the investigator will promptly notify the IRB/IEC/REB of the deviation. 
The investigator will promptly notify Endocyte of any regulatory inspection relating to this 
study, including either the institution or the IRB/IEC/REB, and will promptly provide Endocyte 
with a copy of any inspection report. 
10.2 
Informed consent 
The investigator will make certain that an appropriate informed consent process is in place to 
ensure that potential participants, or their authorized representatives, are fully informed about the 
nature and objectives of the clinical study, the potential risks and benefits of study participation, 
and their rights as research participants. The investigator, or his/her authorized designee, will 
obtain the written, signed ICF of each participant, or the participant’s authorized representative, 
prior to performing any protocol-specific procedures on the participant. The date and time that 
the participant, or the participant’s authorized representative, signs the ICF and a narrative of the 
issues discussed during the informed consent process will be documented in the participant’s 
case history. The investigator will retain the original copy of the signed ICF, and a copy will be 
provided to the participant, or to the participant’s authorized representative. 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled participants are adequately addressed and 
that the participants are informed of any new information that may affect their decision to 
continue participation in the clinical study. In the event of substantial changes to the clinical 
study or the risk-to-benefit ratio of study participation, the investigator will obtain the informed 
consent of enrolled participants for continued participation in the clinical study. 

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10.3 
Health Insurance Portability and Accountability Act 
Preparation of the Health Insurance Portability and Accountability Act (HIPAA) authorization 
form is the responsibility of the investigator and must include all elements required by the United 
States (US) Department of Health and Human Service’s Privacy Rule. Prior to the beginning of 
the study, the investigator must have the IRB or the appropriate institution privacy board’s 
written approval/favorable opinion of the HIPAA authorization form. 
The HIPAA authorization must be signed and personally dated by the participant or their legally 
acceptable representative. 
For sites located outside of the US, local regulations regarding protection of individually 
identifiable health information must be followed. 
10.4 
Confidentiality 
All records will be kept confidential and the participant’s name will not be released at any time. 
Participant records will not be released to anyone other than Endocyte or its designee(s) and 
responsible government agencies. Data sets for each participant will be identified by a unique 
number. If participant records are sent to Endocyte or its affiliates or designees, the participant’s 
name or other identifying information will be masked and participant registration number or 
other unique identifier substituted. 
11. 
COMPLIANCE AND QUALITY CONTROL 
Independent auditing of the clinical study for protocol and GCP compliance may be conducted 
periodically at selected clinical sites by the Endocyte, Inc. Quality Assurance. 
The purpose of the sponsor’s audit is to evaluate trial conduct and compliance with the protocol, 
standard operating procedures, GCP, and the applicable regulatory requirements. 
Site monitoring visits will be conducted periodically at each clinical site. During site monitoring 
visits the following but not exhaustive list of points will be reviewed: patient informed consent, 
patient recruitment and follow-up, AE reporting including SAE documentation, outcome events 
documentation and reporting, investigational drug allocation, storage and accountability, 
concomitant therapy use, and quality of data. 
11.1 
Compliance with Monitoring and Audits 
Representatives of Endocyte or its designee must be allowed to visit (scheduled in advance) all 
study site locations periodically to assess the data, quality, and study integrity. On site, they will 
review study records and directly compare them with CRFs and discuss the conduct of the study 
with the investigator and verify that the facilities remain acceptable. It is the responsibility of the 
investigator (or designee) to be present or available for consultation during such monitoring 
visits. 
In addition, the study may be evaluated by Endocyte (or designee’s) internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, investigational 
medication records, and other study files. The sponsor’s (or designee’s) audit reports will be kept 

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confidential to the extent permitted by law. The investigator must notify Endocyte promptly of 
any inspections scheduled by regulatory authorities and promptly forward copies of inspection 
reports to Endocyte. The investigator agrees to promptly take any reasonable steps that are 
requested by Endocyte as a result of monitoring or auditing activities to address deficiencies in 
study conduct or documentation. In the event that Endocyte is unable to secure compliance with 
the Statement of investigator or study protocol and prematurely terminates a trial site, Endocyte 
will notify the FDA (as required by 21 CFR § 312.56) the site’s IRB/IEC/REB, and other 
regulatory authorities, as required. 
12. 
DATA HANDLING, RECORD KEEPING, AND COMPLIANCE 
12.1 
Investigational medicinal product accountability 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug destroyed. 
12.2 
Breaking the blind 
Not applicable. 
12.3 
Data collection forms and source document identification 
All source data will be retained by the trial site to ensure that, if requested, a monitor, auditor, or 
regulatory agency has access to the source documents. 
Source data are the clinical findings and observations, laboratory and test data, and other 
information contained in source documents. Source documents are the original records (and 
certified copies of original records) including, but not limited to, hospital medical records, 
physician or office charts, physician or nursing notes, participant diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, x-rays, biopsy reports, 
ultrasound reports, pharmacy records, or any other similar reports or records of any procedures 
performed in accordance with the protocol. Source documentation may also include any sponsor 
CRF when source data is recorded directly onto a CRF.  
The health-related quality of life questionnaires will utilize electronic Clinical Outcome 
Assessments (eCOA) technology for direct entry of the patient’s responses. The eCOA will serve 
as source data. 
A CRF will be completed for each participant enrolled into the clinical study. Patients are to be 
identified by, year of birth, patient screening number and patient enrollment number. Information 
recorded on the CRF must match the source data recorded on the source documents. 
The investigator will review, approve, and sign/date completed CRFs. Their signature serves as 
attestation ensuring that all clinical and laboratory data entered on the CRF are complete, 
accurate, and authentic. This review and sign-off may be delegated to a qualified physician 
appointed as a sub-investigator by the principal investigator. The transfer of duties must be 
recorded on the Delegation Log (kept on file at the site) and all sub-investigators must be listed 
on FDA Form 1572 or equivalent regulatory statement. The investigator must ensure that all 

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sub-investigators are familiar with the protocol and all study-specific procedures and have 
appropriate knowledge of the study agent(s). 
12.4 
Record maintenance and retention  
The investigator will maintain records in accordance with GCP guidelines including the 
following: 
• IRB/IEC/REB correspondence (including approval notifications) related to the clinical 
protocol, including copies of adverse event reports and annual or interim reports 
• All versions of the IRB/IEC/REB approved clinical protocol and corresponding ICFs and, 
if applicable, participant recruitment advertisements 
• Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in 
the clinical protocol and laboratory certification 
• Instructions for on-site preparation and handling of the investigational drug, study 
treatment, and other study-related materials if not addressed in the clinical protocol; 
• Participant screening and enrollment logs and signed ICFs 
• Investigational drug accountability records, including documentation of drug return or 
destruction 
• A summary of the final clinical study results 
12.5 
Archiving 
Endocyte and the investigator will retain the records and reports associated with the clinical trial 
as required by local regulatory requirements after the marketing application is approved for the 
investigational drug. If a marketing application is not submitted or approved for the 
investigational drug the information will be retained until two years after investigations under the 
Investigational New Drug Application/Clinical Trial Application have been discontinued and the 
FDA/EMA/CA notified. 
13. 
PUBLICATION POLICY 
Endocyte and the investigators are committed to the publication and widespread dissemination of 
the results of this study. This study represents a joint effort between Endocyte and the 
investigators, and as such, the parties agree that the recommendation of any party concerning 
manuscripts or texts shall be taken into consideration in the preparation of final scientific 
documents for publication or presentation. All proposed publications and presentations by the 
investigators or their personnel and associates resulting from or relating to this study must be 
submitted to Endocyte for review 60 days before submission for publication or presentation. 
If the proposed publication or presentation contains patentable patient matter, which, at 
Endocyte’s sole discretion, warrants intellectual property protection, Endocyte may delay any 
publication or presentation for up to 60 days after approval for the purpose of pursuing such 
protection. 

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14. 
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Appendix 1 
Schedules of Assessments 

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Table 3 Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of care arm (Cycle 1) 
Study Period: 
Cycle 1 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Concomitant medication review 
X---------------------------------------------------------------------------------------------------------------X 
AE monitoringa 
X---------------------------------------------------------------------------------------------------------------X 
Weight 
Xb 
 
 
 
 
 
ECOG 
Xb 
 
 
 
 
 
Directed physical exam 
Xb 
 
 
 
 
 
Vital signsc 
Xb 
 
 
 
 
 
EQ-5D-5L 
Xd,f  
 
 
 
 
 
FACT-P 
Xd,f 
 
 
 
 
 
BPI-SF 
Xd,f 
 
 
 
 
 
Administer 177Lu-PSMA-617 
X 
 
 
 
 
 
Best supportive/best standard of care  
As per physician’s orders 
Hematologye 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Chemistrye 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Serum/plasma testosterone 
Xb 
 
 
 
 
 
PSA 
Xb 
 
 
 
 
 
Radiographic imaging (CT with 
contrast/MRI and bone scan) 
Every 8 weeks (± 4 days) after first dose of 177Lu-PSMA-617 for the first 24 weeks (independent of dose 
delays), then every 12 weeks (± 4 days)  
a Adverse event monitoring will commence at time of consent. 
b Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 8, 15, 22, 29, and 36. 
c Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1) and at 15(+/-5) minutes before, 30 (+/-5) minutes post,  
and 60 (+/-5) minutes post 177Lu-PSMA-617 administration. 
d To be completed prior to drug administration on Day 1. Can be completed up to 3 days prior to Day 1. 
e Hematology and chemistry to be done every week for Cycle 1 only.  
f  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
AE = adverse event; BPI-SF Brief Pain Inventory – Short Form; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of 
Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; MRI = magnetic resonance imaging; PSA = prostate-specific antigen 

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Table 4 Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of care arm (Cycles 2 to LTFU) 
Study Period: 
Cycles 2-6* 
After Cycle 
6** 
End of 
Treatmentg 
Long-term follow-up 
(Before final analysis of 
alternate primary endpoint 
OS) 
Long-term follow-up 
Extension (after final 
analysis of primary 
alternate endpoint OS) 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Every 12 weeks 
(± 4 days) 
 
Every 3 months 
(± 1 month) 
Every 3 months 
(± 1 month) 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• Best response 
• Type of response 
• AE assessment 
• Radiographic 
imaging (only if pt 
came off the active 
part of the study for 
any reason other 
than radiographic 
disease 
progression) 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• AE assessment for 
renal toxicity and 
reporting of 
secondary 
malignancies. 
• SAE reporting: 
only if the 
investigator 
suspects a causal 
relationship to 
study treatment. 
 
Concomitant 
medication review 
X------------------------------------------------------------------------------------------Xa 
 
X 
AE monitoringb 
X------------------------------------------------------------------------------------------Xa 
X 
Weight 
Xc 
 
 
 
 
 
Xc 
X 
ECOG 
Xc 
 
 
 
 
 
Xc 
X 
Directed physical 
exam 
Xc 
 
 
 
 
 
Xc 
X 
Vital signsd 
Xc 
 
 
 
 
 
Xc 
X 
EQ-5D-5L 
Xe,h  
 
 
 
 
 
Xe,h  
Xh  
FACT-P 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
BPI-SF 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
Administer 
177Lu-PSMA-617 
X 
 
 
 
 
 
 
 
Best supportive/ 
best standard of 
care  
As per physician’s orders 
 
 
Hematologyf 
Xc 
 
Xc 
 
Xc 
 
Xc 
X 
Chemistryf 
Xc 
 
Xc 
 
Xc 
 
Xc 
X 
Serum/plasma 
testosterone 
Xc 
 
 
 
 
 
Xc 
X 
PSA 
Xc 
 
 
 
 
 
Xc 
X 
Radiographic 
imaging (CT with 
contrast/MRI and 
bone scan) 
To be conducted every 8 weeks (± 4 days) after first dose of 177Lu-PSMA-617 for the 
first 24 weeks (independent of dose delays), then every 12 weeks (± 4 days)  
 

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* After the Cycle 4 dose of 177Lu-PSMA-617 and prior to Cycle 5 Day 1, the investigator should determine if: 
- The patient shows evidence of response (i.e. radiological, PSA, clinical benefit) and  
- Has signs of residual disease on CT with contrast/MRI or bone scan and 
- has shown good tolerance to the 177Lu-PSMA-617 treatment. 
If the patient meets the criteria above, and agrees to continue with additional treatment of 177Lu-PSMA-617, the investigator may administer a further 2 cycles. A maximum of 6 
cycles of radioligand therapy is allowed. If the patient does not meet all of the criteria or does not agree to additional 177Lu-PSMA-617 treatment, then no additional doses of 
177Lu-PSMA-617 will be administered after Cycle 4. After the last cycle of 177Lu-PSMA-617, patients can continue best supportive/best standard of care alone. 
** Cycles 2-6 are 6 weeks long. Cycle 7 Day 1 should occur after 6 full weeks from C6D1 (Day 43 of Cycle 6). Starting with Cycle 7, all cycles are 12 weeks long. The stipulated 
windows apply to C7D1 required procedures and for all cycles afterwards.  
 a Phone evaluations are allowed, but are not required for visits after Day 1 of each cycle.  
b Adverse event monitoring will commence at time of consent. 
c Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 15, and 29. 
d Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1) and at 15(+/-5) minutes before, 30(+/-5) minutes post, and 60(+/-
5) minutes post 177Lu-PSMA-617 administration. 
e To be completed prior to drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
f For Cycles 2 to 6: Hematology and chemistry to be done at Days 1, 15, and 29 (every 2 weeks). After Cycle 6, to be done on Cycle 7 Day 1 and then every 12 weeks (± 4 days).  
g To be done once a patient is to enter the long-term follow-up part of the study. To occur approximately 30 days from the last dose of 177Lu-PSMA-617 or last dose or 
intervention of best supportive/best standard of care end of treatment decision, but before the initiation of subsequent anticancer treatment, outside of what is allowed on study 
h  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
 
AE = adverse event; ANC= absolute neutrophil count; BPI-SF Brief Pain Inventory – Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; 
MRI = magnetic resonance imaging; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; WBC = white blood cell 
 
 
 

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Table 5 Schedule of assessments: Best supportive/best standard of care only arm (Cycle 1) 
Study Period: 
Cycle 1 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Concomitant medication review 
X--------------------------------------------------------------------------------------------------------------X 
AE monitoringb 
X--------------------------------------------------------------------------------------------------------------X 
Weight 
Xa 
 
 
 
 
 
ECOG 
Xa 
 
 
 
 
 
Directed physical exam 
Xa 
 
 
 
 
 
Vital signsc 
Xa 
 
 
 
 
 
EQ-5D-5L 
Xd,f  
 
 
 
 
 
FACT-P 
Xd,f 
 
 
 
 
 
BPI-SF 
Xd,f 
 
 
 
 
 
Best supportive/ best standard of care 
As per physician’s orders 
Hematologye 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Chemistrye 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Serum/plasma testosterone 
Xa 
 
 
 
 
 
PSA 
Xa 
 
 
 
 
 
Radiographic imaging (CT with 
contrast/MRI and bone scan) 
Every 8 weeks (± 4 days) after Cycle 1 Day 1g for the first 24 weeks (independent of dose delays), then every 
12 weeks (± 4 days) through the End of Treatment visit 
a Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 8, 15, 22, 29, and 36. 
b Adverse event monitoring will commence at time of consent. 
c   Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1). 
d To be completed prior to any drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
e Hematology and chemistry to be done every week for Cycle 1 only. 
f  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
g    Cycle 1 Day 1 for patients on the Best supportive/best standard of care only arm is considered as the day that the majority of the day 1 assessments are conducted 
 
AE = adverse event; BPI-SF Brief Pain Inventory – Short Form; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of 
Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; MRI = magnetic resonance imaging; PSA = prostate-specific antigen 
 

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Table 6 Schedule of assessments: Best supportive/best standard of care only arm (Cycles 2 to LTFU) 
Study Period: 
Cycles 2-6** 
After Cycle 
6** 
End of 
Treatmentg 
Long-term 
follow-up (Before 
final analysis of 
alternate primary 
endpoint OS) 
Long-term 
follow-up 
Extension (After 
final analysis of 
alternate primary 
endpoint OS) 
Cycle Week: 
Week 1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Every 12 
weeks (± 4 
days) 
 
Every 3 months 
(± 1 month) 
Every 3 months 
(± 1 month) 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• Best response 
• Type of 
response 
• AE assessment 
• Radiographic 
imaging (only if 
pt came off the 
active part of 
the study for 
any reason other 
than 
radiographic 
disease 
progression) 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New 
treatment: 
• Start/stop 
dates 
• AE 
assessment for 
renal toxicity 
and secondary 
malignancies. 
• SAE 
reporting: 
only if the 
investigator 
suspects a 
causal 
relationship to 
study 
treatment. 
 
Concomitant 
medication review 
X-----------------------------------------------------------------------------------------------
Xa 
X 
AE monitoringb 
X-----------------------------------------------------------------------------------------------
Xa 
X 
Weight 
Xc 
 
 
 
 
 
Xc 
X 
ECOG 
Xc 
 
 
 
 
 
Xc 
X 
Directed physical 
exam 
Xc 
 
 
 
 
 
Xc 
X 
Vital signsd 
Xc 
 
 
 
 
 
Xc 
X 
EQ-5D-5L 
Xe,h  
 
 
 
 
 
Xe,h 
Xh  
FACT-P 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
BPI-SF 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
Best supportive/best 
standard of care 
As per physician’s orders 
 
 
Hematologyf 
Xc 
 
Xc 
 
Xc 
 
Xb 
X 
Chemistryf 
Xc 
 
Xc 
 
Xc 
 
Xb 
X 
Serum/plasma 
testosterone 
Xc 
 
 
 
 
 
Xb 
X 
PSA 
Xc 
 
 
 
 
 
Xb 
X 
(continued) 
 
 
 
 
 

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Radiographic 
imaging (CT with 
contrast/MRI and 
bone scan) 
To be conducted every 8 weeks (± 4 days) after Cycle 1 Day 1 for the first 24 
weeks (independent of dose delays), then every 12 weeks (± 4 days) 
** Cycles 2-6 are 6 weeks long. Cycle 7 Day 1 should occur after 6 full weeks from C6D1 (Day 43 of Cycle 6). Starting with Cycle 7, all cycles are 12 weeks long. The stipulated 
windows apply to C7D1 required procedures and for all cycles afterwards.  
 
 
 
a  Phone evaluations are allowed, but are not required for visits after Day 1 of each cycle. 
b Adverse event monitoring will commence at time of consent. 
c Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 15, and 29. 
d Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1). 
e To be completed prior to drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
f For Cycles 2 to 6: Hematology and chemistry to be done at Days 1, 15, and 29 (every 2 weeks). After Cycle 6, to be done every12 weeks (± 4 days).  
g To be done once a patient is to enter the long-term follow-up part of the study. To occur approximately 30 days from the date of the last dose or intervention of best 
supportive/best standard of care end of treatment decision, but before the initiation of subsequent anticancer treatment, outside of what is allowed on study. 
h  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
AE = adverse event; ANC = absolute neutrophil count; BPI-SF Brief Pain Inventory – Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; 
MRI = magnetic resonance imaging; PSA = prostate-specific antigen; WBC = white blood cell count 
 
 

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Appendix 2 
Suggested treatment guidelines  
The following are suggested guidelines for clinical support during 177Lu-PSMA-617 
administration. They are to be used at the discretion of the investigator. 
• Cooling the salivary glands from 30 min. before and up to 4 hours after the 177Lu-PSMA-
617 injection for reducing the risk of salivary glands radiation injuries is optional and 
depends on center practice. 
• 500 mL of 0.9% (i.e., normal) saline may be infused at a rate of 125 mL/hour to begin 
after administration of 177Lu-PSMA-617. Additionally, fluid intake should be encouraged 
on the day of treatment.  
• In patients with high tumor burden or gout allopurinol may be started within 7 days and 
up to 10 days following 177Lu-PSMA-617 therapy 

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Appendix 3 
Principal Investigator Signature 
I have read this clinical protocol, no. PSMA-617-01, 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 of Endocyte, 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/ReportsManualsForms/Forms/UCM074728.pdf  
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Name (Printed) 
 
 
 
 
 
Title (Printed) 
 
 
 
 

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Appendix 4a Eastern Cooperative Oncology Group performance status scale 
and Karnofsky Performance Status comparison 
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 

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Appendix 4b Eastern Cooperative Oncology Group performance status scale 
and Karnofsky Performance Status comparison 
ECOG PERFORMANCE STATUS 
KARNOFSKY PERFORMANCE 
STATUS 
0—Fully active, able to carry on all pre-disease 
performance without restriction 
100—Normal, no complaints; no 
evidence of disease 
90—Able to carry on normal activity; 
minor signs or symptoms of disease 
1—Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
80—Normal activity with effort, some 
signs or symptoms of disease 
70—Cares for self but unable to carry 
on normal activity or to do active work 
2—Ambulatory and capable of all selfcare but unable to 
carry out any work activities; up and about more than 50% 
of waking hours 
60—Requires occasional assistance 
but is able to care for most of 
personal needs 
50—Requires considerable 
assistance and frequent medical care 
3—Capable of only limited selfcare; confined to bed or 
chair more than 50% of waking hours 
40—Disabled; requires special care 
and assistance 
30—Severely disabled; 
hospitalization is indicated although 
death not imminent 
4—Completely disabled; cannot carry on any selfcare; 
totally confined to bed or chair 
20—Very ill; hospitalization and 
active supportive care necessary 
10—Moribund 
5—Dead 
0—Dead 
*Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, ed. Evaluation of Chemotherapeutic 
Agents. New York, NY: Columbia University Press; 1949:191–205. 
**Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic trial of nitrogen mustard and 
thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33. 

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Appendix 5 
Common Terminology Criteria for Adverse Events  
The complete NCI CTCAE (version 5.0) can be found at the following site:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/ 
 
 

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Appendix 6 
Response Evaluation Criteria in Solid Tumors 
The latest RECIST guidelines (version 1.1) can be found at the following site: 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf 
 

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Appendix 7 
Prostate Cancer Working Group 3 Recommendations  
The sections that apply to this trial are the criteria for prostate-specific antigen (PSA) response and 
progression, and the criteria for bone lesion “prevent/delay end points” (progression). It is based on 
the PCWG3 recommendations. Please note that not all the recommendations listed below are 
applicable to this patient population or to the specifics of this study.  
Variable 
PCWG3 (2016) 
PSA 
• 
Recognize that a favorable effect on PSA may be delayed for 12 weeks or more, even for a 
cytotoxic drug 
• 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless 
other evidence of progression 
• 
Ignore early rises (prior to 12 weeks) in determining PSA response 
For control/relieve/eliminate endpoints: 
• 
Describe absolute changes in PSA over time from baseline to best response 
For delay/prevent endpoints: Decline from baseline: 
• 
Record time from start of therapy to first PSA increase that is ≥25% and ≥2 ng/mL above the 
nadir, and which is confirmed by a second value 3 or more weeks later (ie, a confirmed rising 
trend) 
No decline from baseline: 
• 
PSA progression ≥25% and ≥2 ng/mL after 12 weeks 
Soft-tissue lesions For control/relieve/eliminate end points: 
Use Response Evaluation Criteria in Solid Tumors (RECIST) with caveats: 
• 
Record up to 5 lesions per site of disease 
• 
Record changes in nodal, lung, liver adrenal and central nervous system (CNS) sites separately 
• 
Only report changes in lymph nodes that were ≥1.5 cm in diameter in short axis at baseline 
• 
Record changes in pelvic (regional) nodes vs extrapelvic (distant/metastatic) nodes separately 
• 
Only report changes in visceral lesions (liver, lung, adrenal, CNS) that were ≥1.0 cm in the 
longest dimension 
• 
Record complete elimination of disease at any site separately 
• 
Confirm favorable change with second scan 
• 
Record changes using waterfall plot 
For delay/prevent end points: 
• 
Record changes in nodal and visceral disease separately 
• 
Record up to 5 lesions per site of spread 
• 
Use RECIST 1.1 criteria for progression, but clearly record type of progression (growth of 
existing lesions vs development of new lesions) separately by site. With additional requirement 
that progression at first assessment be confirmed by a second scan 6 or more weeks later. 
(Particularly important when anticipated effect on PSA is delayed or for biologic therapies) 
• 
Previously normal (<1.0 cm) lymph nodes must have grown by ≥5 mm in the short axis from 
baseline or nadir and be ≥1.0 cm in the short axis to be considered to have progressed. Nodes that 
have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable. For existing pathologic adenopathy (≥1.5 cm), progression is defined per 
RECIST 1.1 

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Bone 
For control/relieve eliminate end points: 
• 
Record outcome as new lesions, no new lesions or resolved lesion 
• 
First scheduled reassessment: 
o 
No new lesions: continue therapy 
o 
New lesions: perform a confirmatory scan 6 or more weeks later 
• 
Confirmatory scan: 
o 
No new lesions: continue therapy 
o 
Additional new lesions: progression 
• 
Subsequent scheduled reassessments:  
o 
No new lesions: continue  
o 
New lesions: progression 
• 
Changes in intensity or uptake do not constitute regression or progression 
For prevent/delay end points (progression): 
• 
Exclude pseudoprogression in the absence of symptoms or other signs of progression 
• 
At least two new lesions on first post-treatment scan, with at least two additional lesions on the 
next scan (2+2 rule) 
• 
If at least two additional new lesions are seen on the next (confirmatory) scan, the date of 
progression is the date of the first post-treatment scan, when the first two new lesions were 
documented 
• 
For scans after the first post-treatment scan, at least two new lesions relative to the first post-
treatment scan confirmed on a subsequent scan 
• 
Date of progression is the date of the scan that first documents the second lesion 
• 
Changes in intensity of uptake alone do not constitute either progression or regression 
• 
Report the proportion of patients who have not progressed at fixed time intervals (6 and 12 
months) 
Symptoms 
 
Pain palliation assessment requires a patient population with clinically meaningful pain at baseline (eg, 
≥4 on a 10-point pain intensity scale) and response defined as a clinically meaningful score improvement 
at a subsequent time point (eg, a 30% relative or 2-point absolute improvement from baseline at 12 
weeks, confirmed at least 2 weeks later, without an overall increase in opiate use).  
For control/relieve eliminate end points: 
• 
Serial (eg, daily x 7 days) assessments at each time point can improve the stability of values 
Principles may be extended for any PRO for which a clinically meaningful baseline PRO score has been 
determined together with a responder definition that is based on a sustained clinically meaningful score 
improvement. 
For delay/prevent end points: 
Patients with any level of baseline pain, including no pain, are eligible to be evaluated for prevent/delay 
end points; those without pain are followed for development of pain, whereas those with baseline pain are 
followed for progression (eg, a 2-point increase without an overall decrease in opiate use). 
Pain assessment should be administered at treatment discontinuation and once again if feasible (eg, 2 to 4 
weeks later). 
Time to deterioration of physical function and/or health-related quality of life (HRQoL) scores should also 
be included, with a priori thresholds defining clinically meaningful deterioration score changes that are 
based on prior published data for the selected questionnaire. 
Refer to Scher et al 2016 for more details. 
CNS = central nervous system; HRQoL = health-related quality of life; PCWG3 = Prostate Cancer Working Group 3; PSA = 
prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors. 

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Appendix 8 
BPI-SF (sample only, not for patient use)  

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Appendix 9 
 EQ-5D-5L (European Quality of Life (EuroQol) – 5 Domain 5 
Level scale) (sample only, not for patient use) 

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Appendix 10  FACT-P (Functional Assessment of Cancer Therapy – 
Prostate) (sample only, not for patient use) 

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Appendix 11 PCCTC Bone Scan Assessment Tool  

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