A Phase 3, Open-Label, Randomized Study Evaluating Metastatic Castrate Resistant Prostate Cancer Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH)
Phase: PHASE3
Conditions: Metastatic Castration-Resistant Prostate Cancer
Sponsor: POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

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Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of 177Lu-PNT2002 Injection (LY4187525), 18F-DCFPyL 68Ga-PSMA-11, unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
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Acronym: 63/$6+
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
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Table of Contents 
Title Page ...................................................................................................................................... 1 
Protocol Amendment Summary of Changes Table .................................................................. 3 
1.
Protocol Summary ...................................................................................................... 18 
1.1. 
Synopsis ....................................................................................................................... 18 
1.2. 
Schedule of Activities (SOA) ..................................................................................... 41 
1.2.1. 
Screening and Treatment Period Assessments ........................................................ 41 
2.
Introduction ................................................................................................................ 53 
2.1. 
Background ................................................................................................................. 53 
2.1.1. 
Prostate Cancer .......................................................................................................... 53 
2.1.2. 
General Principles of Radioligand Therapy ............................................................ 53 
2.1.3. 
PSMA ........................................................................................................................... 54 
2.1.3.1. PSMA as an Imaging Target ..................................................................................... 54 
2.1.3.2. PSMA-Based Radioligand Therapy .......................................................................... 55 
2.1.4. 
PNT2002 (PSMA-I&T) .............................................................................................. 56 
2.1.4.1. PSMA-I&T 177Lu-radiosynthesis and Characterization ....................................... 56
2.1.4.2. 177Lu-labeled PSMA-I&T Characterization ........................................................... 56
2.1.4.3. 177Lu-labeled PSMA-I&T Clinical Experience ...................................................... 57
2.1.4.4. Radiation Dose of 177Lu-PSMA-I&T ...................................................................... 57
2.2. 
Study Rationale ........................................................................................................... 58 
2.2.1. 
Rationale for Control Arm ........................................................................................ 58 
2.2.2. 
Justification for Dose of 177Lu-PNT2002 ................................................................ 59
2.2.3. 
Expected Risks/Benefits of Treatment ...................................................................... 60 
3.
Objectives and Endpoints .......................................................................................... 62 
3.1. 
Primary Efficacy Objective and Endpoint ............................................................... 62 
3.2. 
Secondary Objectives and Endpoints ....................................................................... 62 
3.3. 
Safety Objectives ........................................................................................................ 63 
3.4. 
Exploratory Objectives .............................................................................................. 63 
4.
Study Design ............................................................................................................... 64 
4.1. 
Overall Design............................................................................................................. 64 
4.2. 
End of Study Definition ............................................................................................. 67 
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5. 
Study Population ........................................................................................................ 68 
5.1. 
Number of Patients ..................................................................................................... 68 
5.2. 
Inclusion Criteria........................................................................................................ 68 
5.3. 
Exclusion Criteria ....................................................................................................... 69 
5.4. 
Screening ..................................................................................................................... 70 
5.5. 
Screen Failures............................................................................................................ 70 
5.6. 
Contraception ............................................................................................................. 71 
5.7. 
Study Intervention ...................................................................................................... 71 
5.7.1. 
Dosimetry Phase ......................................................................................................... 71 
5.7.2. 
Pre-specified Criteria for Dose Selection on the Randomized Phase .................... 72 
5.7.3. 
Randomized Treatment Phase .................................................................................. 73 
5.7.4. 
Long-term Follow-up Phase ...................................................................................... 74 
5.7.5. 
68Ga-PSMA-11 and 18F-DCFPyL ........................................................................... 75 
5.7.6. 
177Lu-PSMA2002 ....................................................................................................... 75 
5.7.6.1. 177Lu-PSMA2002 Characteristics ............................................................................ 75 
5.7.6.2. 177Lu-PNT2002 Packaging and Labeling ............................................................... 76 
5.7.6.3. 177Lu-PNT2002 Storage and Handling ................................................................... 76 
5.7.6.4. 177Lu-PNT2002 Preparation and Administration .................................................. 76 
5.7.7. 
Control Arm ................................................................................................................ 77 
5.7.8. 
Continued Access to Study Intervention after Study Completion ........................ 77 
5.7.9. 
Treatment Overdose .................................................................................................. 78 
5.8. 
Drug Accountability ................................................................................................... 79 
5.9. 
Treatment Compliance .............................................................................................. 79 
5.10. 
Randomization, Stratification, and Blinding ........................................................... 79 
5.10.1. 
Randomization ............................................................................................................ 79 
5.10.2. 
Patient Stratification .................................................................................................. 80 
5.10.3. 
Blinding ....................................................................................................................... 80 
5.11. 
Prior and Concomitant Therapy ............................................................................... 80 
5.12. 
Permitted/Prohibited Medications ............................................................................ 80 
5.12.1. 
Permitted Medications ............................................................................................... 80 
5.12.2. 
Prohibited Medications .............................................................................................. 81 
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5.13. 
Dose Modification ....................................................................................................... 82 
5.13.1. 
Control Arm ................................................................................................................ 82 
5.13.2. 
177Lu-PNT2002 Dose Reduction .............................................................................. 82 
5.13.3. 
177Lu-PNT2002 Dose Delay ...................................................................................... 82 
6. 
Discontinuation of Study Intervention and Patient Withdrawal from Study ....... 83 
6.1. 
Discontinuation of Study Intervention ..................................................................... 83 
6.2. 
Withdrawal of Patient from the Study ..................................................................... 83 
6.3. 
Early Study Termination ........................................................................................... 84 
7. 
Study Assessments and Procedures .......................................................................... 85 
7.1. 
Informed Consent Process ......................................................................................... 85 
7.2. 
Screening Procedures ................................................................................................. 85 
7.2.1. 
Demographics ............................................................................................................. 86 
7.2.2. 
Medical History .......................................................................................................... 86 
7.3. 
Treatment Period ....................................................................................................... 87 
7.3.1. 
Dosimetry Phase ......................................................................................................... 87 
7.3.2. 
177Lu-PNT2002 Randomized Treatment Period .................................................... 88 
7.3.3. 
PK Analysis Set ........................................................................................................... 90 
7.3.4. 
Control Arm Treatment ............................................................................................. 90 
7.4. 
Progression Visit and Crossover ............................................................................... 92 
7.5. 
End-of-Treatment Visit .............................................................................................. 94 
7.6. 
Long-Term Follow-up Phase ..................................................................................... 94 
7.7. 
Unscheduled Visit ....................................................................................................... 95 
7.8. 
Efficacy Assessments .................................................................................................. 95 
7.8.1. 
Radiographic Assessments ......................................................................................... 95 
7.8.1.1. CT/MRI ....................................................................................................................... 95 
7.8.1.2. Whole Body Bone Scan .............................................................................................. 95 
7.8.1.3. 18F-FDG PET (Optional) .......................................................................................... 95 
7.8.1.4. PSMA-PET .................................................................................................................. 95 
7.8.2. 
Progression .................................................................................................................. 96 
7.8.2.1. Radiographic Progression .......................................................................................... 96 
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7.8.2.2. Biochemical Progression ............................................................................................ 97 
7.8.2.3. Unequivocal Clinical Progression ............................................................................. 97 
7.8.3. 
Symptomatic Skeletal-Related Event ........................................................................ 97 
7.8.4. 
PSA Measurements and Response ............................................................................ 98 
7.8.5. 
 ...................................................................................................... 98 
7.9. 
Safety Assessments ..................................................................................................... 99 
7.9.1. 
Height and Weight ..................................................................................................... 99 
7.9.2. 
Physical Examinations ............................................................................................... 99 
7.9.2.1. Complete Physical Examination ............................................................................... 99 
7.9.2.2. Limited Physical Examination .................................................................................. 99 
7.9.3. 
Vital Signs ................................................................................................................... 99 
7.9.4. 
Electrocardiogram ...................................................................................................... 99 
7.9.5. 
Clinical Safety Laboratory Assessments .................................................................. 99 
7.9.5.1. Blood Chemistry ....................................................................................................... 100 
7.9.5.2. Hematology ............................................................................................................... 100 
7.9.5.3. Testosterone .............................................................................................................. 100 
7.10. 
Correlative Research Samples ................................................................................. 101 
7.11. 
 .................................... 101 
7.11.1. 
 ............................................................................................ 101 
7.12. 
 ...................................................................................................... 101 
7.12.1. 
 .................................................. 101 
7.12.2. 
Analgesic Quantification Algorithm ....................................................................... 101 
7.13. 
Adverse Event Recording and Reporting ............................................................... 102 
7.13.1. 
Adverse Events ......................................................................................................... 102 
7.13.1.1. Definition of Adverse Events ................................................................................... 102 
7.13.1.2. Definition of a Serious Adverse Event .................................................................... 102 
7.13.1.3. Suspected Unexpected Serious Adverse Reactions ................................................ 103 
7.13.1.4. Definition of an Adverse Event of Special Interest ................................................ 103 
7.13.1.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments ............. 103 
7.13.1.6. Adverse Event Severity ............................................................................................ 104 
7.13.1.7. Relationship to Study Drug ..................................................................................... 104 
7.13.2. 
Collection of AE and SAE Information .................................................................. 104 
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7.13.3. 
Adverse Event of Special Interest Reporting ......................................................... 105 
7.13.4. 
Pregnancy .................................................................................................................. 105 
7.14. 
Pharmacokinetics ...................................................................................................... 106 
7.14.1. 
Blood Pharmacokinetics ........................................................................................... 106 
7.14.2. 
Urine Pharmacokinetics ........................................................................................... 106 
8. 
Data Management and Statistical Methods ........................................................... 107 
8.1. 
Data Collection .......................................................................................................... 107 
8.2. 
Clinical Data Management ...................................................................................... 107 
8.3. 
Statistical Considerations ......................................................................................... 107 
8.4. 
Sample Size Estimation ............................................................................................ 107 
8.5. 
Analysis Populations ................................................................................................ 108 
8.5.1. 
Imaging Set ............................................................................................................... 108 
8.5.2. 
Dosimetry Safety Analysis Set  Part 1 .................................................................. 108 
8.5.3. 
Intention to Treat Set  Part 2 ................................................................................ 108 
8.5.4. 
Per Protocol Analysis Set  Part 2 .......................................................................... 108 
8.5.5. 
Randomization Safety Analysis Set  Part 2 .......................................................... 108 
8.5.6. 
PK Analysis Set ......................................................................................................... 108 
8.6. 
Hypothesis Testing and Multiplicity Control......................................................... 109 
8.7. 
Primary Endpoint ..................................................................................................... 109 
8.7.1. 
Sensitivity Analyses of rPFS .................................................................................... 111 
8.7.2. 
Key Secondary Endpoints ........................................................................................ 111 
8.7.2.1. Overall Objective Response Rate Assessed by Imaging ....................................... 111 
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8.7.2.2. Overall Survival ........................................................................................................ 112 
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8.7.2.3. Time to Symptomatic Skeletal-Related Event (SSRE) ............................................ 113 
8.7.2.4. Duration of Response ............................................................................................... 113 
8.7.2.5. PSA Response ........................................................................................................... 114 
8.7.2.6. Biochemical Progression-Free Survival ................................................................. 114 
8.7.2.7. Safety Endpoints ....................................................................................................... 114 
8.8. 
Interim Analysis........................................................................................................ 115 
8.9. 
Safety Monitoring ..................................................................................................... 115 
8.9.1. 
Independent Data Safety Monitoring Board ......................................................... 115 
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8.9.2. 
Exploratory Endpoints ............................................................................................. 116 
9. 
Trial Conduct Risks/Benefits Considerations ........................................................ 117 
9.1. 
Potential External Risks ........................................................................................... 117 
9.2. 
Potential Benefits ...................................................................................................... 117 
10. 
Supporting Documentation and Operational Considerations .............................. 118 
10.1. 
Regulatory and Ethical Considerations .................................................................. 118 
10.1.1. 
Ethics ......................................................................................................................... 118 
10.1.2. 
Good Clinical Practice ............................................................................................. 118 
10.1.3. 
Ethical and Regulatory Authority Review ............................................................. 118 
10.1.4. 
European Union ....................................................................................................... 118 
10.2. 
Financial Disclosure ................................................................................................. 118 
10.3. 
Data Confidentiality ................................................................................................. 118 
10.4. 
Data Quality Assurance ........................................................................................... 119 
10.4.1. 
Case Report Forms and Study Records ................................................................. 119 
10.4.2. 
Retention of Records ................................................................................................ 119 
10.5. 
Source Documents .................................................................................................... 119 
10.5.1. 
Access to Source Data .............................................................................................. 119 
10.6. 
Study Monitoring ..................................................................................................... 120 
10.6.1. 
Study Activation ....................................................................................................... 120 
10.6.2. 
Audits and Inspections ............................................................................................. 120 
10.7. 
Publication Policy ..................................................................................................... 120 
10.8. 
Dissemination of Clinical Study Data ..................................................................... 120 
11. 
References ................................................................................................................. 122 
12. 
APPENDICES .......................................................................................................... 128 
12.1. 
APPENDIX 1 New York Heart Association (NYHA) Functional Classification 128 
12.2. 
APPENDIX 2 Prostate Cancer Working Group 3 Recommendations ................ 129 
12.2.1. 
Bone Progression Status Categories (PCWG3) for CRF Completion ................. 131 
12.3. 
APPENDIX 3 Response Evaluation Criteria In Solid Tumors (RECIST) .......... 132 
12.3.1. 
Overall Visit Soft Tissue Responses (RECIST 1.1) ............................................... 132 
12.3.2. 
Overall radiological visit response (RECIST/PCWG3) for CRF completion ..... 132 
12.4. 
 ................. 133 
12.5. 
 ................................................... 136 
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12.6. 
 .............................. 138 
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Table of Tables 
Table 1 
Schedule of Activities (SOA) Dosimetry Phaser 
Table 2 
Schedule of Activities Arm A - 177Lu-PNT2002 Infusionv 
Table 3 
Schedule of Activities Arm B  Control Arm 
Table 4 
Schedule of Activities - Continued Access 
Table 5 
Summary of Screening Procedures and Timing 
Table 6 
Summary of Investigations and Timing for Patients in the Dosimetry Phase 
Table 7 
Summary of Investigations and Timing for Patients Undergoing 177Lu- PNT2002 
Treatment 
Table 8 
Summary of Investigations for Patients Randomized to Arm B Undergoing Control Arm 
Treatment 
Table 9 
ECOG Scale of Performance Status 
Table 10 Blood Sampling Schedule 
Table 11 Urine Sampling Schedule 
Table 12 Censoring Rules for rPFS Analysis 
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Table of Figures 
Figure 1 Chemical structure of DOTAGA-(I-y)fk (Sub-KuE) (PSMA-I&T), a third- generation 
PSMA ligand (adapted from Weineisen, 2015). 
Figure 2 SPLASH Study Design 
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1. 
Protocol Summary  
 
1.1. 
Synopsis  
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Protocol title 
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Investigational 
medicinal 
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End of Study 
Definition 
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Study objectives 
and endpoints 
Primary Efficacy 
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Secondary Efficacy 
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Screeninga 
Cycle 1 
Cycle 2 
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Table 4 
Schedule of Activities - Continued Access  
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CA Treatment 
CA EOT 
Visita 
CA 
LTFUb 
 
Procedurec 
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Instructions
177Lu-PNT2002 
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2. 
Introduction  
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2.1. 
Background  
2.1.1. 
Prostate Cancer  
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2.1.2. 
General Principles of Radioligand Therapy  
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2.1.3. 
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2.1.3.1. 
PSMA as an Imaging Target  
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2.1.4. 
PNT2002 (PSMA-I&T)  
 
2.1.4.1. 
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Figure 1 
Chemical structure of DOTAGA-(I-y)fk (Sub-KuE) (PSMA-I&T), a third- generation 
PSMA ligand (adapted from Weineisen, 2015).  
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2.1.4.2. 
177Lu-labeled PSMA-I&T Characterization  
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2.1.4.3. 
177Lu-labeled PSMA-I&T Clinical Experience  
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2.1.4.4. 
Radiation Dose of 177Lu-PSMA-I&T  
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2.2. 
Study Rationale  
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2.2.1. 
Rationale for Control Arm  
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2.2.2. 
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4.2. 
End of Study Definition  
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5. 
Study Population  
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5.1. 
Number of Patients  
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5.2. 
Inclusion Criteria  
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E 6RIWWLVVXHSURJUHVVLRQGHILQHGDVDQLQFUHDVHLQWKHVXPRIWKHGLDPHWHU62'
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5.3. 
Exclusion Criteria  
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FDQFHUVKRXOGUHVXOWLQH[FOXVLRQ
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OLQHORFDOH[WHUQDOEHDP$5$7OXWHLQL]LQJKRUPRQHUHOHDVLQJKRUPRQH/+5+DJRQLVWRU
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5.4. 
Screening  
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5.5. 
Screen Failures  
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5.6. 
Contraception  
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5.7. 
Study Intervention  
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5.7.1. 
Dosimetry Phase  
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5.7.2. 
Pre-specified Criteria for Dose Selection on the Randomized Phase  
The following criteria will be used to confirm the dose will remain the same for the Randomized 
Treatment Phase: 
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Phase: 
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5.7.3. 
Randomized Treatment Phase  
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Long-term Follow-up Phase  
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5.7.5. 
68Ga-PSMA-11 and 18F-DCFPyL  
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177Lu-PNT2002 Packaging and Labeling  
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177Lu-PNT2002 Storage and Handling  
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177Lu-PNT2002 Preparation and Administration  
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Drug Accountability  
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Treatment Compliance  
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Permitted/Prohibited Medications  
 
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Prohibited Medications  
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Dose Modification  
 
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Discontinuation of Study Intervention and Patient Withdrawal from Study  
 
6.1. 
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Study Assessments and Procedures  
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7.1. 
Informed Consent Process  
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Screening Procedures  
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Table 5 
Summary of Screening Procedures and Timing  
Investigations 
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7.2.1. 
Demographics  
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7.2.2. 
Medical History  
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7.3. 
Treatment Period  
 
7.3.1. 
Dosimetry Phase  
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177Lu-PNT2002 Randomized Treatment Period  
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Table 7 Summary of Investigations and Timing for Patients Undergoing 177Lu- PNT2002 
Treatment   
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7.7. 
Unscheduled Visit  
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7.8. 
Efficacy Assessments  
 
7.8.1. 
Radiographic Assessments  
7.8.1.1. 
CT/MRI 
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7.8.1.2. 
Whole Body Bone Scan  
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7.8.1.3. 
18F-FDG PET (Optional)  
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7.8.1.4. 
PSMA-PET  
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7.8.2. 
Progression  
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7.8.2.1. 
Radiographic Progression  
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7.8.2.1.1. CT and MRI Tumor Assessment  
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7.8.2.1.2. Bone scans  
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7.8.2.2. 
Biochemical Progression  
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7.8.2.3. 
Unequivocal Clinical Progression  
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7.8.3. 
Symptomatic Skeletal-Related Event  
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7.8.4. 
PSA Measurements and Response  
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7.9. 
Safety Assessments  
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7.9.1. 
Height and Weight  
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7.9.2. 
Physical Examinations  
 
7.9.2.1. 
Complete Physical Examination 
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7.9.2.2. 
Limited Physical Examination  
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7.9.3. 
Vital Signs  
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7.9.4. 
Electrocardiogram  
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7.9.5. 
Clinical Safety Laboratory Assessments  
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7.9.5.1. 
Blood Chemistry  
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7.9.5.2. 
Hematology  
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7.9.5.3. 
Testosterone  
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7.10. 
Correlative Research Samples  
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7.13. 
Adverse Event Recording and Reporting  
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7.13.1. 
Adverse Events  
 
7.13.1.1. Definition of Adverse Events 
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7.13.1.2. Definition of a Serious Adverse Event  
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7.13.1.3. Suspected Unexpected Serious Adverse Reactions  
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7.13.1.4. Definition of an Adverse Event of Special Interest  
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7.13.1.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments  
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7.13.1.6. Adverse Event Severity  
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7.13.2. 
Collection of AE and SAE Information  
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7.13.3. 
Adverse Event of Special Interest Reporting  
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7.13.4. 
Pregnancy  
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7.14. 
Pharmacokinetics  
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7.14.1. 
Blood Pharmacokinetics  
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Table 10 
Blood Sampling Schedule  
Day 
Day of Infusion 
Day 1 
Day 2 
Day 3 
Day 7 
7LPH
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7.14.2. 
Urine Pharmacokinetics  
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Table 11 
Urine Sampling Schedule  
Day 
Day of Infusion 
Day 2-3 
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8. 
Data Management and Statistical Methods  
 
8.1. 
Data Collection  
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8.2. 
Clinical Data Management  
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8.3. 
Statistical Considerations  
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8.4. 
Sample Size Estimation  
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8.5. 
Analysis Populations  
 
8.5.1. 
Imaging Set  
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8.5.2. 
Dosimetry Safety Analysis Set  Part 1  
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8.5.3. 
Intention to Treat Set  Part 2  
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8.5.4. 
Per Protocol Analysis Set  Part 2  
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8.5.5. 
Randomization Safety Analysis Set  Part 2  
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8.5.6. 
PK Analysis Set  
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8.6. 
Hypothesis Testing and Multiplicity Control  
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8.7. 
Primary Endpoint  
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8.7.1. 
Sensitivity Analyses of rPFS  
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8.7.2. 
Key Secondary Endpoints  
 
8.7.2.1. 
Overall Objective Response Rate Assessed by Imaging  
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Overall Survival  
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8.7.2.3. 
Time to Symptomatic Skeletal-Related Event (SSRE)  
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8.7.2.4. 
Duration of Response  
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8.7.2.5. 
PSA Response  
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Biochemical Progression-Free Survival  
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8.7.2.7. 
Safety Endpoints  
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8.8. 
Interim Analysis  
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8.9. 
Safety Monitoring  
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8.9.1. 
Independent Data Safety Monitoring Board  
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Exploratory Endpoints  
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9. 
Trial Conduct Risks/Benefits Considerations  
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9.1. 
Potential External Risks  
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9.2. 
Potential Benefits  
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10. 
Supporting Documentation and Operational Considerations  
 
10.1. 
Regulatory and Ethical Considerations  
 
10.1.1. 
Ethics  
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10.1.2. 
Good Clinical Practice  
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10.1.3. 
Ethical and Regulatory Authority Review  
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European Union  
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Financial Disclosure  
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10.3. 
Data Confidentiality  
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10.4. 
Data Quality Assurance  
 
10.4.1. 
Case Report Forms and Study Records  
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Retention of Records  
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10.5. 
Source Documents  
 
10.5.1. 
Access to Source Data  
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Study Monitoring  
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Study Activation  
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Audits and Inspections  
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10.7. 
Publication Policy  
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11. 
References  
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12. 
APPENDICES  
 
12.1. 
APPENDIX 1 
New York Heart Association (NYHA) Functional Classification 
 
NYHA Classification - The Stages of Heart Failure: 
 
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12.2. 
APPENDIX 2 
Prostate Cancer Working Group 3 Recommendations  
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12.2.1. 
Bone Progression Status Categories (PCWG3) for CRF Completion  
 
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APPENDIX 3 
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Signature Page for VV-CLIN-194959 v2.0
Signature Page for VV-CLIN-194959 v2.0
Approved on 22 Jul 2025 GMT