PSMAfore: A Phase III, Open-label, Multi-Center, Randomized Study Comparing 177Lu-PSMA-617 vs. a Change of Androgen Receptor-Directed Therapy in the Treatment of Taxane Naïve Men With Progressive Metastatic Castrate Resistant Prostate Cancer
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
AAA617 
Clinical Trial Protocol CAAA617B12302 / NCT04689828
PSMAfore: A phase III, Open-label, Multi-Center, 
Randomized Study Comparing 177Lu-PSMA-617 vs. a 
Change of androgen receptor-directed therapy in the 
Treatment of Taxane Naïve Men with Progressive 
Metastatic Castrate Resistant Prostate Cancer 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-003969-19 
Version number: 
03 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
21-Feb-2023 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 

Novartis 
Confidential 
Page 2 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Table of contents 
Table of contents ........................................................................................................... 2 
List of tables .................................................................................................................. 6 
List of figures ................................................................................................................ 6 
List of abbreviations ...................................................................................................... 7 
Glossary of terms ........................................................................................................ 12 
Amendment 3 (21-Feb-2023) ...................................................................................... 15 
Amendment 2 (04-Aug-2022) ..................................................................................... 17 
Amendment 1 (13-Jan-2022) ...................................................................................... 22 
Protocol summary ....................................................................................................... 41 
1 
Introduction ................................................................................................................ 49 
1.1 
Background ....................................................................................................... 49 
1.2 
Purpose ............................................................................................................. 53 
2 
Objectives, endpoints and estimands .......................................................................... 53 
2.1 
Primary estimands ............................................................................................ 55 
2.2 
Secondary estimands ........................................................................................ 56 
3 
Study design ............................................................................................................... 57 
4 
Rationale ..................................................................................................................... 62 
4.1 
Rationale for study design ................................................................................ 62 
4.1.1 
Rationale for choice of background therapy ....................................... 62 
4.2 
Rationale for dose/regimen and duration of treatment ..................................... 62 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ................................................................................................................ 63 
4.4 
Purpose and timing of interim analyses/design adaptations ............................. 64 
4.5 
Risks and benefits ............................................................................................. 64 
4.6 
Rationale for Public Health Emergency mitigation procedures ....................... 67 
5 
Study Population ........................................................................................................ 67 
5.1 
Inclusion criteria ............................................................................................... 67 
5.2 
Exclusion criteria .............................................................................................. 68 
6 
Treatment .................................................................................................................... 70 
6.1 
Study treatment ................................................................................................. 70 
6.1.1 
Additional study treatments ................................................................ 70 
6.1.2 
Investigational and control drugs ........................................................ 70 
6.1.3 
Supply of study treatment ................................................................... 72 
6.1.4 
Treatment arms/group ......................................................................... 73 
6.1.5 
Guidelines for continuation of treatment ............................................ 73 
6.1.6 
Treatment duration .............................................................................. 73 

Novartis 
Confidential 
Page 3 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
6.2 
Other treatment(s) ............................................................................................. 74 
6.2.1 
Concomitant therapy ........................................................................... 74 
6.2.2 
Prohibited medication ......................................................................... 76 
6.3 
Participant numbering, treatment assignment, randomization ......................... 76 
6.3.1 
Participant numbering ......................................................................... 76 
6.3.2 
Treatment assignment, randomization ................................................ 77 
6.4 
Treatment blinding ........................................................................................... 77 
6.5 
Dose escalation and dose modification ............................................................ 77 
6.5.1 
Definitions of dose limiting toxicities (DLTs) .................................... 77 
6.5.2 
Dose modifications ............................................................................. 78 
6.5.3 
Follow-up for toxicities ....................................................................... 82 
6.6 
Additional treatment guidance .......................................................................... 84 
6.6.1 
Treatment compliance ......................................................................... 84 
6.6.2 
Treatment of overdose ........................................................................ 85 
6.7 
Preparation and dispensation ............................................................................ 85 
6.7.1 
Handling of study treatment and other treatment ................................ 85 
6.7.2 
Instruction for prescribing and taking study treatment ....................... 87 
7 
Informed consent procedures ..................................................................................... 90 
8 
Visit schedule and assessments .................................................................................. 91 
8.1 
Screening ........................................................................................................ 104 
8.1.1 
Eligibility screening .......................................................................... 105 
8.1.2 
Information to be collected on screening failures ............................. 105 
8.2 
Participant demographics/other baseline characteristics ................................ 105 
8.3 
Efficacy ........................................................................................................... 106 
8.3.1 
Radiographic imaging for tumor assessment .................................... 106 
8.3.2 
Symptomatic skeletal events ............................................................. 111 
8.3.3 
Clinical progression .......................................................................... 112 
8.3.4 
PSA levels ......................................................................................... 112 
8.3.5 
Appropriateness of efficacy assessments .......................................... 112 
8.4 
Safety .............................................................................................................. 112 
8.4.1 
Laboratory evaluations ...................................................................... 114 
8.4.2 
Electrocardiogram (ECG) ................................................................. 115 
8.4.3 
Pregnancy and assessments of fertility ............................................. 116 
8.4.4 
Appropriateness of safety measurements .......................................... 116 
8.5 
Additional assessments ................................................................................... 116 
8.5.1 
Clinical Outcome Assessments (COAs) ........................................... 116 

Novartis 
Confidential 
Page 4 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
 119 
 
 121 
9 
Discontinuation and completion ............................................................................... 122 
9.1 
Discontinuation from study treatment and discontinuation from study ......... 122 
9.1.1 
Discontinuation from study treatment ............................................... 122 
9.1.2 
Discontinuation from study ............................................................... 123 
9.1.3 
Lost to follow-up ............................................................................... 123 
9.2 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights .............................................................................................................. 124 
9.3 
Study completion and post-study treatment ................................................... 124 
9.4 
Early study termination by the sponsor .......................................................... 125 
10 Safety monitoring and reporting ............................................................................... 126 
10.1 Definition of adverse events and reporting requirements ............................... 126 
10.1.1 Adverse events .................................................................................. 126 
10.1.2 Serious adverse events ...................................................................... 128 
10.1.3 SAE reporting ................................................................................... 129 
10.1.4 Pregnancy reporting .......................................................................... 130 
10.1.5 Reporting of study treatment errors including misuse/abuse ............ 130 
10.2 Additional Safety Monitoring ......................................................................... 131 
10.2.1 Data Monitoring Committee ............................................................. 131 
10.2.2 Steering Committee ........................................................................... 131 
11 Data Collection and Database management ............................................................. 131 
11.1 Data collection ................................................................................................ 131 
11.2 Database management and quality control ..................................................... 132 
11.3 Site monitoring ............................................................................................... 132 
12 Data analysis and statistical methods ....................................................................... 133 
12.1 Analysis sets ................................................................................................... 133 
12.2 Participant demographics and other baseline characteristics ......................... 134 
12.3 Treatments ...................................................................................................... 134 
12.4 Analysis supporting primary objectives ......................................................... 135 
12.4.1 Definition of primary endpoint(s) ..................................................... 135 
12.4.2 Statistical model, hypothesis, and method of analysis ...................... 135 
12.4.3 Handling of intercurrent events of primary estimand ....................... 136 
12.4.4 Handling of missing values not related to intercurrent event ........... 136 
12.4.5 Sensitivity analyses ........................................................................... 136 
12.4.6 Supplementary analysis ..................................................................... 136 

Novartis 
Confidential 
Page 5 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
12.5 Analysis supporting secondary objectives ...................................................... 137 
12.5.1 Efficacy and/or Pharmacodynamic endpoint(s) ................................ 137 
12.5.2 Safety endpoints ................................................................................ 140 
 143 
12.5.4 Patient reported outcomes ................................................................. 144 
 145 
 146 
12.7 Interim analyses .............................................................................................. 147 
12.8 Sample size calculation .................................................................................. 148 
12.8.1 Primary endpoint(s) ........................................................................... 148 
12.8.2 Secondary endpoint(s) ....................................................................... 149 
13 Ethical considerations and administrative procedures ............................................. 149 
13.1 Regulatory and ethical compliance................................................................. 149 
13.2 Responsibilities of the investigator and IRB/IEC ........................................... 149 
13.3 Publication of study protocol and results ....................................................... 150 
13.4 Quality Control and Quality Assurance.......................................................... 150 
14 Protocol adherence ................................................................................................... 150 
14.1 Protocol amendments ..................................................................................... 150 
15 References ................................................................................................................ 152 
16 Appendices ............................................................................................................... 159 
16.1 Appendix 1: Common Terminology Criteria for Adverse Events ................. 159 
16.2 Appendix 2: Guidelines for Response, Duration of Overall Response, 
TTF, TTP, Progression-Free Survival, and Overall Survival (based on 
RECIST 1.1) .................................................................................................. 159 
16.2.1 Introduction ....................................................................................... 161 
16.2.2 Efficacy assessments ......................................................................... 161 
16.2.3 Efficacy definitions ........................................................................... 170 
16.2.4 Data handling and programming rules .............................................. 180 
16.2.5 References (available upon request) ................................................. 184 
16.3 Appendix 3: PCWG3 ...................................................................................... 185 
16.4 Appendix 4: Study Specific Adjustments of Response Evaluation Criteria 
in Solid Tumor .............................................................................................. 186 
16.5 EQ-5D-5L (European Quality of Life (EuroQol) 5 Domain 5 Level scale), 
sample only, not for patient use .................................................................... 189 
16.6 FACT-P (Functional Assessment of Cancer Therapy Prostate), sample 
only, not for patient use ................................................................................. 192 
16.7 BPI-SF, sample only, not for patient use ........................................................ 195 

Novartis 
Confidential 
Page 6 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 53 
Table 6-1 
Investigational and control drug ............................................................ 71 
Table 6-2 
Toxicity management and dose modifications for 177Lu-PSMA-617 
treatment for adverse drug reactions ..................................................... 78 
Table 6-3 
Dose reduction steps for 177Lu-PSMA-617 ........................................... 82 
Table 6-4 
Guidance on specific clinical and diagnostic assessments .................... 84 
Table 8-1 
Window periods for Visit Schedule ...................................................... 92 
Table 8-2 
Assessment Schedule, 177Lu-PSMA-617 and ARDT treatment arms ... 93 
Table 8-3 
Assessment Schedule, crossover of ARDT arm participants to 
177Lu-PSMA-617 treatment ................................................................. 100 
Table 8-4 
Overall Time Point Response per PCWG3 modified RECIST v1.1 ... 106 
Table 8-5 
Bone disease response per PCWG3 criteria ........................................ 108 
Table 8-6 
Disease Progression on Bone Scan ..................................................... 108 
Table 8-7 
Imaging Assessment Collection Plan .................................................. 109 
Table 8-8 
Assessments & Specifications............................................................. 113 
Table 8-9 
ECOG performance status scale .......................................................... 114 
Table 8-10 
Laboratory Assessments ...................................................................... 115 
 
 119 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 131 
Table 16-1 
Response criteria for target lesions ..................................................... 166 
Table 16-2 
Response criteria for non-target lesions .............................................. 168 
Table 16-3 
Overall lesion response at each assessment ........................................ 170 
Table 16-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 177 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response ........ 178 
Table 16-6 
PCWG3 ............................................................................................... 185 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 61 
 

Novartis 
Confidential 
Page 7 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
List of abbreviations 
68Ga-PSMA-11 
Radiolabeled compound gallium (68Ga) gozetotide (AAA517 / [68Ga]Ga-PSMA-11) 
177Lu-PSMA-
617 
Therapeutic agent lutetium (177Lu) vipivotide tetraxetan (AAA617 / [177Lu]Lu-PSMA-617) 
177Lu 
Lutetium-177 
68Ga 
Gallium-68 
ADR 
Accord Dangereux Routier (European regulations concerning the international transport of 
dangerous goods by road) 
ADT 
Androgen deprivation therapy 
AE 
Adverse Event 
AEs 
Adverse Events 
AESI 
Adverse event of special interest 
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear antibodies 
ANC 
Absolute neutrophil count  
Anti-HAV 
Serum antibody to hepatitis A virus 
anti-HCV 
Anti Hepatitis C Virus 
anti-HEV 
Anti Hepatitis E Virus 
APTT 
Activated partial thromboplastin time 
AR 
Androgen receptor 
AR-V7 
Androgen receptor variant 7 
ARDT 
Androgen receptor-directed therapy 
ASMA 
Anti smooth muscle antibody 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AV 
Atrioventricular 
BCR 
Biochemical recurrence 
BICR 
Blinded independent central review 
BOR 
Best overall response 
BP 
Blood pressure 
BPI-SF 
Brief Pain Inventory - Short Form 
BRCA 
Breast Cancer gene 
BSC 
Best supportive care  
CABG 
Coronary artery bypass graft 
CBC 
Complete blood count 
CD-transferrin 
Carbohydrate-Deficient-Transferrin 
CFR 
Code of federal regulation 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 

Novartis 
Confidential 
Page 8 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
COVID 
Coronavirus disease 
CR 
Complete response 
CRO 
Contract Research Organization 
CRPC 
Castrate resistant prostate cancer 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
CVD 
Cardiovascular disease 
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate 
DDE 
eSource Direct Data Entry 
DILI 
Drug-induced liver injury 
DKFZ 
German Cancer Research Center, Deutsches Krebsforschungszentrum 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
 
 
DOR 
Duration of response 
DOTA 
Dodecane tetraacetic acid 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EF 
Ejection fraction 
EMA 
European Medicines Agency 
EOP 
End of Production 
EOT 
End of treatment 
EOT2 
End of Treatment 2 
EPO 
Epoetin 
EQ-5D VAS 
EQ-5D visual analogue 
EQ-5D-5L 
European Quality of Life (EuroQol) 5 Domain 5 Level scale 
ERCP 
Endoscopic retrograde cholangiopancreatography 
ESMO 
European Society for Medical Oncology 
Eu. Ph. 
European Pharmacopoeia 
FACIT 
The Functional Assessment of Chronic Illness Therapy  
FACT-G 
Functional Assessment of Cancer Therapy - General 
FACT-P 
Functional Assessment of Cancer Therapy Prostate 
FAS 
Full Analysis Set 
FDG- PET 
Fluorodeoxyglucose - Positron emission tomography 
FFPE 
Formalin-fixed, paraffin embedded  
GBq 
Gigabecquerel 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
GMP 
Good manufacturing practice 

Novartis 
Confidential 
Page 9 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
 
HCV 
Hepatitis C Virus 
HEOR 
Health Economics & Outcomes Research  
HEV 
Hepatitis E Virus 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
HSPC 
Hormone sensitive prostate cancer 
HSV 
Herpes simplex virus 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
immunoglobulin M 
IgM & IgG anti-
HBc 
Immunoglobulin M & Immunoglobulin G antibody to hepatitis B core antigen 
IMP 
Investigational Medical Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent to treat principle 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
MBq 
Megabecquerel 
MCH 
Mean corpuscular hemoglobin 
mCi 
Millicuries 
mCRPC 
Metastatic castrate resistant prostate cancer 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical dictionary for regulatory activities  
mHSPC 
Metastatic hormone-sensitive prostate cancer 
mL 
milliliter(s) 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NED 
Non Evidence of Disease 
NS 
Normal saline 
OR 
Overall response 
ORR 
Overall response rate 
OS 
Overall survival 
PARP 
Poly (adenosine diphosphate-ribose) polymerase 
PAS 
Patient Administration Systems 
PC 
Prostate Cancer 

Novartis 
Confidential 
Page 10 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
PCS 
Prostate Cancer Subscale 
PCWG 
Soft Tissue Rules of Prostate Cancer Working Group 
PCWG3 
Prostate Cancer Working Group 3  
PD 
Progression Disease 
PDc 
Progressive Disease confirmed 
PDu 
Progressive Disease unconfirmed 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PR 
Partial response 
PRO 
Patient Reported Outcomes 
PS 
Patient safety 
PSA 
Prostate specific antigen 
PSA50 
Proportion of participants who have achieved a ≥ 50% decrease from baseline that is 
confirmed by a second PSA measurement ≥4 weeks 
PSMA 
Prostate-specific membrane antigen 
QC 
Quality control 
QMS  
Quality Management System 
QT 
QT refers to an interval seen in an electrocardiogram (ECG) test of heart function 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RANKL 
Receptor activator of nuclear factor kappa-Β ligand 
RAS 
RECIST Analysis Set 
RBC 
red blood cell(s) 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RLT 
Radioligand therapy 
RMST 
Restricted mean survival time 
rPD 
Radiographic progressive disease  
rPFS 
Radiographic progression free survival 
RPSFT 
Rank preserving structural failure time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SD 
Stable disease 
SMQ 
Standardized MedDRA  
SoC 
Standard of Care 
SOD 
Sum of the diameter 
 
 
SPOP 
Speckle-type POZ protein 
SSE 
Symptomatic skeletal events 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1D 
Type 1 Diabetes 
T3 
Triiodothyronine 
T4 
Thyroxin 
tc 
calibration time 
TD 
Study Treatment Discontinuation 
TEAE 
Treatment emergent adverse event 

Novartis 
Confidential 
Page 11 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
TMPRESS2-
ERG 
Transmembrane protease, serine 2 
TSH 
thyroid stimulating hormone 
TTCT 
Time to chemotherapy 
TTPP 
Time from randomization to pain progression 
TTPSAP 
Defined as time from randomization to PSA progression 
TTR 
Time to response 
TTSE 
Time to first symptomatic skeletal event 
TTSSE 
Time to symptomatic skeletal events  
TTSTP  
Time from randomization to radiographic soft tissue progression per PCWG-modified 
RECIST 1.1. 
ULN 
upper limit of normal 
UNK 
Unknown 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
 

Novartis 
Confidential 
Page 12 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study participant 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, or a 
group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days) 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific request is 
made to stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study drug administration, if any). Participant 
agrees to the other protocol required assessments including follow-up. No specific 
request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from source data/documents used at 
the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or at a later 
point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained. 
The action of enrolling one or more participants.  
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data electronically, 
at the point of care. eSource Platform/Applications combines source documents and case 
report forms (eCRFs) into one application, allowing for the real time collection of clinical 
trial information to sponsors and other oversight authorities, as appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It summarizes 
at a population-level what the outcomes would be in the same participants under different 
treatment conditions being compared. Attributes of an estimand include the population, 
variable (or endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary for the 
variable. 
Intercurrent 
events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Off-site 
Describes trial activities that are performed at remote location by an off-site healthcare 
professional, such as procedures performed at the participant's home. 
Off-site healthcare 
Professional 
(OHP) 
A qualified healthcare professional, such as include those used in the study e.g. Nurse, 
Phlebotomist, Physician, who performs certain protocol procedures for the participant in 
an off-site location such as a participant's home. 

Novartis 
Confidential 
Page 13 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple dose 
part, or a part in participants with established disease and in those with newly-diagnosed 
disease 
Participant 
A trial participant (can be a healthy volunteer or a patient). 
"Participant" terminology is used in the protocol whereas term "Subject" is used in data 
collection. 
Participant 
number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to identify 
the participant throughout the study for all data collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about the status of 
a participant's health condition without amendment or interpretation of the patient's report 
by a clinician or anyone else. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical trial 
database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Remote 
Describes any trial activities performed at a location that is not the investigative site 
where the investigator will conduct the trial, but is for example a home or another 
appropriate location. 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation in 
the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent by the first 
participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants as 
part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy 
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 

Novartis 
Confidential 
Page 14 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Withdrawal of 
study consent 
(WoC) / 
Opposition to use 
of data /biological 
samples 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and biological samples (opposition to use data and biological 
samples) AND no longer wishes to receive study treatment, AND does not agree to 
further protocol required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. This request should be 
distinguished from a request to discontinue the study. Other study participant's privacy 
rights are described in the corresponding informed consent form Opposition to use 
data/biological samples occurs in the countries where collection and processing of 
personal data is justified by a different legal reason than consent. 
 

Novartis 
Confidential 
Page 18 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Section 3, End of treatment: “Unequivocal clinical progression” was removed from sub-
section “End of Treatment”, as it was inconsistent with trial design  
• e.g. Section 3, Treatment period states “In the absence of safety concerns, every effort 
should be made to keep the participant on the randomized treatment until BICR-
determined radiographic progression or completion of the 6 cycles of 177Lu-PSMA-617.” 
• Section 3: Post-treatment Follow-up period; Additional guidance provided on safety data 
to be collected. 
• Section 3: Post-treatment Follow-up period; Updated to indicate that physical exam will 
be collected. 
• Section 3: Post-treatment Follow-up period; Updated to provide guidance that following 
withdrawal of consent for collection of blood samples, physical exams, PROs, and 
imaging assessments during the long-term follow-up, information on survival and AEs 
will be collected as specified in the protocol. 
• Section 3, Crossover; Updated to provide guidance that any unresolved toxicity from prior 
therapy should be controlled and must be no greater than CTCAE grade 2 or baseline at 
the time of registration for crossover and not from start of treatment with 177Lu-PSMA-
617. And ECOG performance status must be 0-1 at the time of registration and organ 
function must be adequate and at the time of registration. 
• Section 3: Post-treatment Follow-up period; Information provided on what will happen to 
participants who received 177Lu-PSMA-617 and remain on the trial in follow-up at the 
time of sponsor’s completion of the study. 
• Section 4.5, Risks and benefits: Information from AAA517 Investigator’s Brochure 
Edition 6 was added. “68Ga-PSMA-11 is approved in the US under the trademark of 
LOCAMETZ® as a radioactive diagnostic agent indicated for PET imaging of PSMA-
positive lesions in men with prostate cancer with suspected metastasis who are candidates 
for initial definitive therapy, with suspected recurrence based on elevated serum PSA level 
and for selection of patients with metastatic prostate cancer for whom lutetium 177Lu-
PSMA-617 PSMA-directed therapy is indicated. It has demonstrated a favorable safety 
profile with about 1% of patients experiencing mild reactions such as fatigue, nausea, 
constipation, and vomiting. Further details can be found in the 68Ga-PSMA-11 
Investigator's Brochure.” 
• Section 4.5, Risks and benefits: Information on approval of Pluvicto in United States 
added. “177Lu-PSMA-617 was approved in the United States on 23-Mar-2022 under the 
brand name of PLUVICTO® for the treatment of adult patients with prostate-specific 
membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer 
(mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and 
taxane-based chemotherapy.” 
• Section 5.2, exclusion criteria: Exclusion criteria 3a revised to “Prior treatment with 
cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., 
taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or 
biological therapy [including monoclonal antibodies]. [Note: Taxane exposure (maximum 
6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since 
completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is 
allowed.] “PARP inhibitor” was removed from the list of prior excluded therapies.  

Novartis 
Confidential 
Page 20 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Table 8-3,Adverse events/SAEs: footnote 18 added “For participants who received 177Lu-
PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the following adverse events will 
be captured beyond the 30 day safety period regardless of relationship to study treatment 
and whether new anticancer therapy has been initiated: hematologic toxicities (including 
need for transfusion or use of growth factors), renal failure, xerostomia, xerophthalmia, 
secondary malignancies.” 
• Section 8.2, Participant demographics/other baseline characteristics: Sentence “In 
addition, we need to assess the diversity of the study population 
 
 was removed and replaced with “In addition, these data are necessary to 
assess the diversity of the study population 
” in line with 
the current Novartis protocol template.  
• Section 8.3.1, Radiographic imaging for tumor assessment: language on radiographic 
imaging assessments was updated to better instruct on applying the 2+2 PCWG3 criteria. 
“For scans after the 12-week flare window, the first observation of at least two new 
lesions relative to the baseline scan must be confirmed on a subsequent scan at least 
6 weeks later (2 + 2 PCWG3 criteria). 
• Section 8.3.1, Radiographic imaging for tumor assessment: New tables added for 
additional guidance with response criteria: “Table 8-4 Overall Time Point Response per 
PCWG3 modified RECIST v1.1, Table 8-5 Bone disease response per PCWG3 criteria 
and Table 8-6 Disease Progression on Bone Scan” 
• Section 8.3.1, Radiographic imaging for tumor assessment: PCWG3 guidelines specified 
as PCWG3 modified RECIST v1.1 guidelines for clarity. 
• Section 8.3.1, Radiographic imaging for tumor assessment: Clarification added to indicate 
that for disease progression by bone scan criteria, the confirmatory scan must be outside 
the 12-week flare window. 
• Section 8.3.1, Radiographic imaging for tumor assessment: Guidance on imaging 
assessment updated that whole body bone scan with technetium-99m labeled 
diphosphonates should be performed per study imaging site manual. The text that “per 
institutional standard of care” was removed 
• Section 8.3.3, Clinical progression: Statement indicating participants requiring palliative 
therapy up to 8 weeks after first study treatment dose deleted as it was redundant and 
conflicting with earlier bullet in the section describing administration of any radiotherapy 
as qualifying event for clinical progression. Additionally, criterion regarding need for 
immediate initiation of new anticancer intervention for complications due to tumor 
progression was updated from “even in the absence of radiological progression” to even in 
the absences of confirmed radiological progression” 
• Table 8-10, Blood urea nitrogen (BUN) was removed from required assessments and the 
word “fasting” was remove from “glucose” Additionally Urea was updated to “urea 
nitrogen” 
• Section 8.5.1, Clinical outcome assessments (COAs): “or designee” added to allow 
appropriately trained personnel other than the Investigator to review complete measures 
for potential AEs and SAEs. 

Novartis 
Confidential 
Page 23 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• The term “Study treatment discontinuation” has been changed to “Discontinuation 
from study treatment” and the definition changed from “When the participant 
permanently stops taking any of the study drug(s) prior to the defined study treatment 
completion date (if any) for any reason; may or may not also be the point/time of 
study discontinuation” to “Point/time when the participant permanently stops 
receiving the study treatment for any reason (prior to the planned completion of study 
drug administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use of their 
samples or data.” 
• Definition of “Electronic Data Capture (EDC)” was revised to clarify that EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to capture 
data transcribed from source data/documents used at the point of care and not only 
data transcribed from paper source forms used at the point of care. 
• Definition of enrolment has been updated from “Point/time of participant entry into 
the study at which informed consent must be obtained” to ‘Point/time of participant 
entry into the study at which informed consent must be obtained. The action of 
enrolling one or more participants.” 
• Definition of “Estimand” was updated to indicate the source which is ICH E9(R1) 
addendum. 
• The term “Off-site” was added to the glossary terms and defined as “Describes trial 
activities that are performed at remote location by an off-site healthcare professional, 
such as procedures performed at the participant's home.” 
• The term “Off-site healthcare Professional (OHP)” was added to glossary terms and 
defined as “A qualified healthcare professional, such as those used in the study e.g. 
nurse, phlebotomist, physician, who perform certain protocol procedures for the 
participant in an off-site location such as a participant's home." 
• The term “Patient-Reported Outcome (PRO)” was added to the glossary and 
definition provided as “A measurement based on a report that comes directly from the 
patient about the status of a participant's health condition without amendment or 
interpretation of the patient's report by a clinician or anyone else.” 
• The term “Remote” was added to the glossary and definition provided as “Describes 
any trial activities performed at a location that is not the investigative site where the 
investigator will conduct the trial, but is for example a home or another appropriate 
location.” 
• “Withdrawal of study consent (WoC)” has been updated to “Withdrawal of study 
consent (WoC) / Opposition to use of data /biological samples” and definition revised 
from “Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further collection of 
personal data” to “Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples (opposition to use 
data and biological samples) AND no longer wishes to receive study treatment, AND 
does not agree to further protocol required assessments. This request should be in 
writing (depending on local regulations) and recorded in the source documentation. 

Novartis 
Confidential 
Page 25 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• At the time of crossover, the criterion regarding any unresolved toxicity from prior 
therapy at the start of 177Lu-PSMA-617 was changed from CTCAE grade 1 to 
CTCAE grade ≤2 or baseline for consistency with inclusion criterion #10. 
• Clarified that, Baseline assessments must be performed within 28 days of registration 
for crossover and are described in Table 8-3. If the EOT1 visit has been performed 
within prior 28 days of registration for crossover, those results can be used to confirm 
patient eligibility to the crossover. Revision is to provide consistency with screening 
period for assessments. 
• Clarified that, if a participant has not undergone required assessments within 28 days 
prior to registration for crossover, then they must complete or repeat the assessments 
in order to ensure the criteria are met. CT/MRI and bone scan within 28 days prior to 
registration for crossover must be available as new baseline images.  
• Guidance to have ECOG PS, vital signs, hematology, biochemistry and adverse 
events assessments performed within 7 days prior to commencing treatment in 
crossover was removed for consistency. 
• Section 3, Long term follow-up:  
• Week numbers in which radiographic imaging assessment is to be performed were 
corrected. 
• Clarified that, patient reported outcomes (PROs) and PSA will be collected during 
long term follow-up period. 
• Clarified that, radiographic imaging will be collected during long term follow-up only 
for participants with no rPFS event. 
• PRO has been added to the list of assessments for which if a participant withdraws 
consent for their collection during long term follow-up, survival information, SAEs 
related to study treatment and post-treatment antineoplastic therapy will still be 
collected. The change was made to allow for safety monitoring. 
• Section 4.1, Rationale for study design: A statement indicating that VISION 
(NCT03511664) study is ongoing was deleted as the study is now completed and a 
summary of results from the study has been provided. 
• Section 4.1.1, Rationale for choice of background therapy: addition of biological products 
and immunotherapy to the list of prohibited medication.  
• Section 4.5, Risks and benefits: 
• Reference made to 177Lu-PSMA-617 IB v4.0 was removed as it is no longer the most 
current IB and updates to the list of events 
• COVID-19 pandemic related risks: Clarified that, a delay in bone scan for more than 
4 weeks no longer leads to treatment discontinuation. 
• COVID-19 pandemic related risks: IMP changed to study drug. 
• Section 4.6, Rationale for Public Health Emergency mitigation procedures: Section 4.6 
was introduced. 
• Section 5.1, Inclusion criteria:  
• Inclusion criterion #7 was reworded for clarity from “Participants must have received 
one prior approved ARDT (for example, abiraterone, enzalutamide, darolutamide, or 

Novartis 
Confidential 
Page 26 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
apalutamide, etc.) and have documented progression on therapy” to “Participants 
must have progressed only once on prior second generation ARDT (abiraterone, 
enzalutamide, darolutamide, or apalutamide).  
• first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed 
but not considered as prior ARDT therapy  
• second generation ARDT must be the most recent therapy received” 
• Inclusion criterion #8 – In order to align with PCWG3 criteria, PSA progression was 
changed from requiring 2 consecutive increases in PSA over previous reference value 
to requiring 2 increases in PSA levels at least a week apart. The minimum start value 
remains unchanged (2.0 ng/ml). Further clarification provided that, if PSA is the only 
indication of disease progression, the minimum level of PSA must be 1.0 ng/ml. To 
align with PCWG3, Criterion for progression of bone disease was also revised from 
“evaluable disease or one or more new bone lesions(s) by bone scan” to “two new 
lesions; only positivity on the bone scan defines metastatic disease to bone” 
• Inclusion criterion #9 – ‘begining study therapy’ was replaced with ’randomization’ 
• Inclusion criterion #13 –Added clarification “Participants cannot have previously 
progressed nor had intolerable toxicity to both enzalutamide and abiraterone” in order 
to clarify conditions for this criterion.  
• Section 5.2, Exclusion criteria  
• Exclusion criterion #3 – Prior treatment that would exclude candidates from 
participation in the study was updated to include PARP inhibitors. Additional 
information is provided to indicate that prior treatment with sipuleucel-T is allowed.  
• Exclusion criterion #6 – Concurrent treatment that would exclude candidates from 
participation in the study was updated to include PARP inhibitors and biological 
therapy. The update was made to align the criterion with concomitant medication 
section. 
• Exclusion criterion #11 – For candidates who had active documented COVID-19 
infection at time of informed consent and had completely recovered (in accordance 
with local guidance) to be enrolled only when they had no symptoms for at least 28 
days before the first dose of study medication was revised to remove the requirement 
to have no symptoms for at least 28 days. 
• Exclusion criterion #12 was clarified that for participants with a prior history of other 
malignancy that has been adequately treated and who are disease and treatment free, 
the reference point for assessing disease and treatment free condition is 
randomization. 
• Exclusion #13: The period after stopping study treatment for which sexually active 
males should agree to continue using condoms was changed from for at least 6 
months to for at least 14 weeks after stopping study treatment per guidance document 
“Guidance Pregnancy Prevention in Clinical Trials, version dated Nov-2021” in line 
with One CTP V4.0 
• Exclusion criterion #14 was updated to clarify that unmanageable concurrent bladder 
outflow obstruction or urinary incontinence would exclude a candidate from 
participation in the study however candidates with bladder outflow obstruction or 

Novartis 
Confidential 
Page 27 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
urinary incontinence, which is manageable and controlled with best available standard 
of care (incl. pads, drainage) are allowed. The update is in response to DMC’s request 
to provide more clear definition to investigators. 
• Exclusion criterion #17: “as assessed by the investigator” was deleted to remove 
ambiguous language. 
• Section 6.1, Study treatment: addition of biological products and immunotherapy to the 
list of prohibited medication 
• Table 6-1:  
• Dosage form for 177Lu-PSMA-617 was updated from “Radiopharmaceutical 
solution” to “Radiopharmaceutical solution for infusion/injection” 
• Column header “Supply type” has been changed to “Presentation”. 
• Section 6.1.2, 68Ga-PSMA-11 Imaging:  
• The read criteria for 68Ga-PSMA-11 eligibility screening assessments were added. 
• Clarification provided that if a potential participant received 68Ga-PSMA-11 as part 
of a routine local exam prior to signing informed consent for this study, then he must 
wait at least 3 days prior to repeating 68Ga-PSMA-11 PET imaging as screening for 
this study. 
• Guidance provided on which 68Ga-PSMA-11 products may be used for the study.  
• Section 6.1.2, ARDT: Need to also follow local guidelines on contraceptive requirements 
when using ARDT was added
 
• Section 6.1.3: Partner Radiopharmacy changed to central Radiopharmacy to correct the 
nomenclature. 
• Section 6.1.4, Treatment arms/group:  
• Clarified that prior ARDT use will be determined by the setting (CRPC vs HSPC) 
when the patient initiated treatment with enzalutamide, abiraterone, apalutamide, or 
darolutamide then suffered disease progression. 
• Section 6.1.6, Treatment duration:  
• Window of +3 days has been introduced at C1D1 to accommodate potential 
scheduling delays. 
• Clarified that, for participants on the 177Lu-PSMA-617 arm who complete the 
planned 6 cycle course therapy, the treatment period ends after the week 37 imaging 
and C6W5 visit is completed. 
• Section 6.2.1, Concomitant therapy: 
• Subsection: Palliative radiotherapy:  
• Time-point for first post baseline scan was corrected from 12 weeks to 8 weeks.  
• Guidance provided for better clarity that when the need for palliative radiation to 
lesions other than bone is seen after the baseline scan, palliative radiation to the 
target lesion should be possibly avoided, the lesion should be assessed per 
RECIST 1.1 criteria, and initiation of palliative radiation may result in study 
discontinuation when radiographic progression is confirmed. 

Novartis 
Confidential 
Page 28 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Guidance provided for better clarity that if palliative radiation treatment is 
planned to be initiated during the study in the absence of radiographic 
progression, the investigator should use best clinical judgement to assess the 
potential clinical benefit of palliative radiation weighed against the risk of 
overlapping side effects of radiation and study treatment when considering 
timing and doses of palliative radiotherapy. Any interruption of study treatment 
greater than 4 weeks from the next scheduled dose requires permanent 
discontinuation of study treatment 
• Subsection: Medications for myelosuppression: Clarified that the use of growth 
factors should follow published guidelines of the ASCO and /or other 
international/national guidelines at the discretion of the investigator/attending 
physician. 
• Section 6.2.2, Prohibited medication: addition of biological products and immunotherapy 
to the list of prohibited medication. Guidance provided that enzalutamide has potential 
drug interactions with medications that are strong CYP3A4 inducers and strong CYP2C8 
inhibitors. Abiraterone has potential drug interactions with medications that are strong 
CYP3A4 inducers or inhibitors. The treating investigator must follow the dose 
modification recommendations per the labeling for each agent in cases where such 
medications are unavoidably co-administered with study treatment for ARDT arm 
participants. 
• Section 6.5.2, Dose modification:  
• Information from Table 6-2 regarding dose modification management if central lab 
results are not available in time to review prior to dosing and discontinuation of 
treatment with 177Lu-PSMA-617 if any toxicity is determined to be unacceptable to 
the participant or the investigator was put in the paragraph preceding the table. 
• Clarification was added for dose modification due to casual relationship between 
177Lu-PSMA-617 and an adverse event 
• Clarification was added on toxicity management 
• Table 6-2: 
• Table header updated from “Dose modifications” to “Toxicity management and dose 
modifications for 177Lu-PSMA-617 treatment for adverse drug reactions” to clarify 
that the table is applicable to treatment related events. 
• Serum creatinine: the terms ‘within 24hours’ were changed to ‘before the next 
administration’ 
• Amylase and/or lipase elevation: The term asymptomatic amylase and/or lipase 
elevation” was changed to “Amylase and/or lipase elevation”. Criteria for dose 
modification due to elevated amylase/lipase was updated. 
• Electrolyte and metabolic abnormalities: The term used for the abnormality ≥ Grade 2 
has been updated from “Electrolyte or metabolic abnormalities that are correctable 
within a 48 hr period without sequela” to “Electrolyte or metabolic abnormalities that 
persist for greater than 48 hrs with sequela” 
• Removal of events ‘Any AE that requires drug discontinuation or treatment delay of > 
4 weeks’ and ‘Any unacceptable toxicity’ 

Novartis 
Confidential 
Page 29 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Note: updated frequency of hematologic parameters monitoring from 8 to 12 weeks 
• Table 6-3: Added to provide guidance for dose reduction for 177Lu-PSMA-617. 
Subsequent table numbering was impacted 
• Section 6.3.2, Wording added clarifying randomization procedures.  
• Section 6.5.3.1, Follow up on potential drug-induced liver injury (DILI) cases: A 
recommendation added that Glutamate Dehydrogenase testing is additionally 
recommended if available for the assessment of DILI. Updated for better monitoring of 
DILI. 
• Section 6.7, Preparation and administration: Guidance provided that immediately before 
dispensing the medication kit to the participant, site personnel will detach the outer part of 
the tear-off label from the packaging and affix it to the source document. 
• Section 6.7.1, Handling of study treatment and additional treatment updated header to 
‘Handling of study treatment and other treatment’ 
• Section 6.7.1.1, Handling of study treatment 
• 
68Ga-PSMA-11: the term ‘bolus’ was updated to ‘single intravenous injection’. 
• Guidance provided that technical complaints are to be reported to the respective 
Novartis contact/associate or 3rd party representative 
• Advised that medication labels will be in the local language and in compliance with 
the legal requirements of each country. They will include storage conditions for the 
study treatment but no information about the participant except for the medication 
number. 
• Clarified that a site may destroy and document destruction of unused study treatment, 
drug labels and packaging as appropriate in compliance with site processes, 
monitoring processes, and per local regulation/guidelines. 
• Section 6.7.2, Instruction for prescribing and taking study treatment 
• Guidance provided that when a participant with manageable bladder outflow/urinary 
incontinence is randomized to receive treatment with 177Lu-PSMA-617, the 
investigator should consult local nuclear medicine expert and ensure, that local 
radiation safety standards can be followed, and there is no additional potential impact 
of radiation safety (for trial participant, site staff, environment). Guidance provided in 
response to DMC request for better guidance for sites. 
• Clarified that management of bladder outflow/urinary incontinence is at the discretion 
of the investigators and may include best available standard of care options which are 
considered appropriate by the investigator. Guidance provided in response to DMC 
request for better guidance for sites. 
• Clarification provided that guidelines for administration of ARDT include also 
contraceptive measures as requested by HA. 
• Additional clarification was provided on management of extravasation or site 
irritation when administering 177Lu-PSMA-617 
• COVID-19 pandemic was removed and replaced with “Public Health emergency as 
declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster” 
• Section 7, Informed consent procedures 

Novartis 
Confidential 
Page 34 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Clarified that if the 68Ga-PSMA-11 PET/CT needs to be repeated then a new 
eligibility read by the central imaging vendor is required. Further that, baseline 
imaging (CT/MRI and bone scan) must continue to be within window for the new 
anticipated randomization date, and repeated if necessary.  
• Guidance provided that the investigator should immediately notify the study sponsor 
and central imaging vendor if any participant is to be rescreened, and whether scans 
already submitted to the central imaging vendor need to be linked to the new 
participant identification. 
• Section 8.1.1, Eligibility screening:  
• A statement that the key eligibility criteria checklist will be completed prior to the 
first dose of study drug in the IRT system was removed because no checklist is 
designed to be completed. 
• A statement that the eligibility check will be embedded in the IRT system was 
removed because there is no such checklist. 
• Clarified that randomization is performed as per Section 6.3.2. 
• Section 8.1.2, Information collected on screening failures: Clarified that the AE eCRF 
should also be completed for all participants who have received 68Ga-PSMA-11. 
• Section 8.2, Participant’s demographics/other baseline characteristics: 
• Updated to provide clarification that participant’s demographics will include: full date 
(only if required and permitted) or year of birth or age, sex, race/predominant 
ethnicity (if permitted) and relevant medical history/current medical conditions until 
date of signature of informed consent will be recorded in the eCRF. And where 
possible diagnosis and not symptoms should be recorded. 
• Updated to provide clarification why participant’s race/ethnicity data are collected 
and analyzed. Clarified also that, all prescription medications, over-the-counter drugs 
and significant non-drug therapies prior to the start of the study must be documented. 
• Clarified that prostate cancer history should include also Gleason score at diagnosis, 
AJCC stage at diagnosis and extent of disease. 
• Section 8.3.1, Radiographic imaging for tumor assessment 
• Guidance provided that sites of “soft-tissue” disease will be characterized as either 
target or non-target lesions based on CT/MRI images and that the distribution of the 
target and non-target lesions should be representative of the subject’s overall disease. 
Detailed guidance provided on the number of lesions and how they will be chosen for 
measurement over the course of the study.  
• Guidance provided that sites of bone disease will be recorded based on bone scan, 
with exception to bone metastasis with soft tissue component which may qualify for 
target/non-target when detectable at CT/MRI and that for the purpose of the study, 
bone lesion(s) should be assessed by bone scan only. 
• COVID-19 pandemic removed and replaced with “Public Health emergency as 
declared by Local or Regional authorities i.e pandemic, epidemic or natural disaster” 
• Table 8-4:  

Novartis 
Confidential 
Page 35 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Week numbers in which radiographic and bone scan assessments are to be 
performed were corrected. 
• Repeat instructions regarding procedure for localized bone CT, MRI or X-ray 
was removed from the table. 
• Specified that bone scan should be done with technetium-99m labeled 
disphosphonate in alignment with other sections of the protocol. 
• Guidance on management of contraindication to CT intravenous contrast media 
was moved from the paragraph below the table and added as a footnote to the 
table. 
• Baseline imaging assessment:  
• Clarified that whole body bone scan is to be performed using technetium-99m 
labeled diphosphonates. 
• Option for whole body bone MRI, Fluorodeoxyglucose positron emission 
tomography (FDG-PET) or sodium fluoride (NaF) PET] was removed as 
technetium-99m labeled diphosphonates must be used. Additionally, statement 
that “Localized CT, MRI, or X-rays should be acquired for all skeletal lesions 
identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen and pelvis CT/MRI” was deleted to remove ambiguity. 
• Clarified also that X-ray should not be used to measure tumor lesions. 
• Post-baseline imaging assessment:  
• Clarified that for “soft-tissue” disease, determination of CR or PR requires 
confirmation by repeat assessments that should be performed at least 4 weeks 
after the criteria for response are first met. 
• Clarified that investigators may perform FDG-PET scans to corroborate 
progressive disease per the PCWG3 Guidelines, but will not be used by itself to 
determine radiographic progression. 
• Section 8.3.3, Clinical progression: Duration of palliative therapy not considered 
potentially indicative of disease progression was corrected from 12 weeks to 8 weeks after 
first study treatment dose. 
• Section 8.3.4, PSA level: The statement that increases and decreases will be tracked to 
assess PSA responses as per PCWG3 (Section 16.3) removed as is Section 16.3 is no 
longer applicable to PSA. 
• Section 8.4 Safety:  
• COVID-19 pandemic deleted and replaced with “Public Health emergency as 
declared by Local or Regional authorities i.e pandemic, epidemic or natural disaster” 
• Clarified that following Public Health emergency that limited/prevented onsite visit, 
onsite visit may resume only when it is safe for the participant to visit the site again. 
• Table 8-5: Clarified that vital signs include temperature and that temperature needs to 
be recorded only once at the 15 min pre-dose timepoint. Duplicate information that 
“Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature.” was removed. 
• Section 8.4.1 Laboratory evaluation 

Novartis 
Confidential 
Page 37 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Situation when discontinuation of study treatment for a participant is considered to 
occur was updated for better clarity. 
• Circumstances under which study treatment must be discontinued was revised to 
remove ambiguity and provide better clarity: 
• Clarified that permanently stopping study treatment after completion of the 6 
cycles of 177Lu-PSMA-617 per protocol is no longer considered a discontinuation 
and is removed reasons for study treatment discontinuation. 
• Clarified that use of prohibited medication is a criterion for discontinuation from 
study treatment irrespective of the reason why the prohibited medication was 
used. 
• Correction made to indicate that, the time limit of a maximum of 4 weeks of 
treatment interruption beyond which treatment must be permanently discontinued 
was made applicable to all interruptions irrespective of reason for interruption.  
• A delay in bone scan for more than 4 weeks was removed from the reasons for 
treatment discontinuation.  
• Unequivocal clinical progression has been added for consistency. 
• Section 9.1.2 Discontinuation from study: A new section “Discontinuation from study” 
was introduced to define a situation when a participant is considered discontinued from 
study. 
• Section 9.1.2 Withdrawal of consent: Previously in Section 9.1.2 was moved to  
Section 9.2 
• Section 9.1.3 Lost to follow-up: Revised for better clarity and states what the participant 
did not state the intention to discontinue from or withdraw ie discontinue from study 
treatment or discontinue from study or withdraw consent/oppose to the use of their 
data/biological samples. 
• Section 9.1.4, Early study termination by sponsor: Previously in Section 9.1.4 was moved 
to Section 9.4. 
• Section 9.2 Title updated from “Withdrawal of consent” to “Withdrawal of consent / 
opposition to use data/biological samples” 
• Guidance updated 
from: 
Withdrawal of consent occurs only when a participant Does not want to participate 
in the study anymore, and Does not want any further visits or assessments and Does 
not want any further study related contacts and Prohibits further collection and use 
of their data and samples 
to: 
Withdrawal of consent / opposition to use data/biological samples occurs when a 
participant explicitly requests to stop use of their biological samples and/or data 
(opposition to use participant’s data and biological samples) and No longer wishes 
to receive study treatment and Does not want any further visits or assessments 
(including further study related contacts) 
• This request should be in writing (depending on local regulations) and recorded in the 
source documentation. 

Novartis 
Confidential 
Page 38 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Use of personal data was updated  
from  
Where consent to the use of personal and coded data is not required, participant 
therefore cannot withdraw consent. They still retain the right to object to the further 
use of personal data.  
to  
Where consent to the use of Personal and Coded Data is not required in a certain 
country’s legal framework, the participant therefore cannot withdraw consent. 
However they still retain the right to object to the further collection or use of their 
Personal Data. 
• Section 9.3 Study completion and post study treatment: Guidance provided that for 
participants who are able to complete the planned 6 cycles of 177Lu-PSMA617, the end of 
the treatment period is upon completion of the C6W5 visit and the response assessment 
imaging due at week 37.  
• Section 9.4 Title “Early study termination by the sponsor” has been moved from section 
9.1.4 to Section 9.4. 
• Section 10.1.1 Adverse events:  
• Instruction regarding duration was modified to indicate that an outcome is expected 
for all events whether they ended or are ongoing.  
• Options regarding outcome has been updated to include recovering/resolving. 
• Section 10.1.3 SAE reporting:  
• Clarified that SAE must be reported to Novartis Safety immediately, without undue 
delay, but under no circumstances later than within 24 hours of obtaining knowledge 
of the events. And noted that, if local regulations regarding reporting timelines are 
more stringent, then local regulations prevail. And that, detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder 
provided to each site. 
• Additional clarification provided regarding reporting SAE experienced after the 30-
day safety follow-up to indicate that local law/regulation will prevail if different from 
protocol guidance. 
• Clarified that follow-up to the original episode must be reported immediately, without 
undue delay, but under no circumstances later than within 24 hours of the investigator 
receiving the follow-up information. And noted that, if local regulations regarding 
reporting timelines are more stringent, then local regulations prevail.  
• Section 10.2 Additional Safety Monitoring: Phrase “not applicable” was deleted to remove 
inconsistency. 
• Section 12.1, definitions of RECIST Analysis Set and 68Ga-PSMA-11 Full Analysis Set 
clarified. Addition of 177Lu-PSMA-617 Safety Set to analyze safety in all patients 
receiving 177Lu-PSMA-617 
  
• Section 12.4 Analysis of the primary endpoint(s)/estimand(s)  
• Header was updated to ‘Analysis of the supporting primary objectives’ 
• Section 12.4.1, Definitions of the primary endpoints(s)/estimand(s): removal of the word 
‘estimands’ 

Novartis 
Confidential 
Page 40 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

Novartis 
Confidential 
Page 41 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Protocol summary 
Protocol number 
CAAA617B12302 
Study Title 
PSMAfore: A phase III, Open-label, Multi-Center, Randomized Study Comparing 177Lu-
PSMA-617 vs. a Change of androgen receptor-directed therapy in the Treatment of 
Taxane Naïve Men with Progressive Metastatic Castrate Resistant Prostate Cancer 
Brief Title 
Open-label study comparing 177Lu-PSMA-617 vs. a change of androgen receptor-
directed therapy drugs in the treatment of mCRPC 
Sponsor and 
Clinical phase 
Novartis, 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine whether 177Lu-PSMA-617, given for 6 cycles at 
a dose of 7.4 Gigabecquerel (GBq) (200 Millicuries (mCi)) +/- 10%, improves the 
radiographic progression free survival (rPFS) or death compared to a change in 
androgen receptor-directed therapy (ARDT) in metastatic castrate resistant prostate 
cancer (mCRPC) participants that were previously treated with an alternate ARDT and 
not exposed to a taxane-containing regimen in the castrate resistant prostate cancer 
(CRPC) or metastatic hormone-sensitive prostate cancer (mHSPC) settings. 
Primary Objective 
To evaluate whether treatment with 177Lu-PSMA-617 improves the time to radiographic 
progression by BICR according to Prostate Cancer Working Group 3 (PCWG3)-modified 
RECIST v1.1 or death in participants with progressive PSMA-positive mCRPC 
compared to participants treated with ARDT 
Key Secondary 
Objective 
To evaluate whether treatment with 177Lu-PSMA-617 improves the overall survival (OS) 
in participants with progressive PSMA-positive mCRPC compared to participants treated 
with ARDT treatment 
Secondary 
Objectives 
• 
To estimate the time to radiographic progression by BICR or death in participants 
treated with ARDT who subsequently crossover to 177Lu-PSMA-617 after radiographic 
progression (rPFS2) 
• 
To evaluate Progression free survival (PFS) by investigator's assessment 
• 
To evaluate the second progression Free Survival (PFS2) by investigator's 
assessment 
• 
To evaluate whether treatment with 177Lu-PSMA-617 improves the biochemical 
response as detected by Prostate specific antigen (PSA) halving compared to 
participants treated with ARDT 
• 
To evaluate whether treatment with 177Lu-PSMA-617 improves the time to first 
symptomatic skeletal event (TTSE) compared to participants treated with ARDT 
• 
To evaluate whether treatment with 177Lu-PSMA-617 improves the time to 
radiographic soft tissue progression compared to participants treated with ARDT 
• 
To evaluate whether treatment with 177Lu-PSMA-617 improves the time to 
chemotherapy compared to participants treated with ARDT 
• 
To evaluate whether treatment with 177Lu-PSMA-617 improves the health-related 
quality of life (HRQoL) compared to participants treated with ARDT 
• 
To evaluate the safety and tolerability of 177Lu-PSMA-617 
Exploratory 
Objectives  

Novartis 
Confidential 
Page 43 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
may be used. After the last day of study treatment (treatment discontinuation for any 
reason) or upon radiographic progression as assessed by blinded centralized review, 
the participants must have an End of Treatment (EOT) visit performed ≤ 7 days and 
enter the Post-treatment Follow-up. 
In absence of safety concerns, every effort should be made to keep the participant on 
the randomized treatment until BICR-determined radiographic progression. 
End of Treatment 
Randomized treatment may be discontinued if: 
• 
The participant, sponsor or investigator chooses to discontinue treatment 
• 
Toxicity 
• 
Completion of the 6 cycles of 177Lu-PSMA-617 
• 
Serious non-compliance to the protocol 
• 
BICR-determined progression 
It is important that the scheduled imaging assessments continue until BICR-determined 
progression. PSA progression is strongly discouraged as a criterion for initiation of a 
new neoplastic therapy prior to BICR-determined progression. PCWG3 guidelines 
should be followed to guide discontinuation of treatment 
End of Treatment visit must be performed ≤ 7 days after the last day of study treatment 
period. EOT is to occur before the participant is to enter the post-treatment Follow-up 
period of the study and before the initiation of any subsequent anticancer treatment, 
outside of what is allowed in the study. 
If a participant withdraws consent for the treatment period of the study, an EOT must be 
done and the participant will enter the Post-treatment Follow-up unless he specifically 
withdraws post-treatment Follow-up. 
Crossover period 
Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm will either 
be allowed to cross over to receive 177Lu-PSMA-617 within 28 days of central 
confirmation of radiographic disease progression, or may continue to receive any other 
therapy per the discretion of the treating physician in the Post-treatment Follow-up. 
In order for a participant randomized to the change in ARDT arm to cross over to receive 
177Lu-PSMA-617, he must meet the following criteria: 
• 
Confirmed radiographical progression as assessed by BICR  
• 
No intervening antineoplastic therapy is administered after the randomized treatment 
• 
Any unresolved toxicity from prior therapy should be controlled and must be no 
greater than CTCAE grade ≤2 or baseline at the time of registration. for crossover 
• 
ECOG performance status 0-1 at the time of registration for crossover 
• 
Adequate organ function at the time of registration for crossover: 
• 
Bone Marrow reserve: 
• 
ANC ≥1.5 x 109/L  
• 
Platelets ≥100 x 109/L  
• 
Hemoglobin ≥9 g/dL 
• 
Hepatic 
• 
Total bilirubin (TBIL) ≤ 2 x ULN (upper limit of normal). For participants with 
known Gilbert’s Syndrome ≤3 x ULN is permitted  
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 
x ULN OR ≤5.0 x ULN for patients with liver metastases 
• 
Renal:  
• 
eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease 
(MDRD) equation  
 
• 
Agreement to continue with the study visit schedule 
 
A participant, who is deemed to have disease progression per investigator assessment, 
but not by BICR, is not eligible to cross over at that time. Such participant should 
continue to receive randomized study treatment until progression determined by BICR. 
Please refer to Section 8 for visit schedule and assessments following crossover. 
If crossover to 177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered 
with the same dose/schedule as for participants who were initially randomized to receive 

Novartis 
Confidential 
Page 44 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
177Lu-PSMA-617 as described above. 
After the last day of study treatment period of 177Lu-PSMA-617 or upon second 
radiographic progression (rPFS2), the participants must have a second End of 
Treatment (EOT2) visit performed ≤ 7 days and enter the Post-treatment Follow-up. The 
participant can receive any other therapy per the discretion of the treating physician in 
the Post-treatment Follow-up. 
Post-treatment Follow-up period 
• 
30 day Safety Follow-up 
All randomized and/or treated participants should have a safety follow-up conducted 
approximately 30 days after the EOT visit. 
• 
Long term follow-up 
Long term follow-up starts after the 30 Days Safety follow-up and lasts until the accrual 
of events for the planned OS-based analysis (key secondary endpoint). 
In long term follow-up safety and efficacy information will be collected: 
• 
Safety: During the long term follow-up, all medically significant adverse events (all 
SAEs) deemed to be related to 177Lu-PSMA-617 will be collected. This will include 
potential late onset radiation toxicity. For participants who received 177Lu-PSMA-617 in 
the 177Lu-PSMA-617 arm or in crossover, the following adverse events will be captured 
beyond the 30 day safety period regardless of relationship to study treatment and 
whether new anticancer therapy has been initiated: hematologic toxicities with primary 
focus on myelosuppression and thrombocytopenia (including need for transfusion or use 
of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies. 
• 
Efficacy: In any participant entering long term follow-up discontinuing for reasons 
other than BICR-determined radiographic progression, tumor assessments must be 
performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 
9, 17, 25) and then every 12 weeks (week 37, 49, etc) until confirmation of radiographic 
progression by BICR 
The long-term follow-up period will also include the collection of survival information and 
other assessments included in Table 8-2 and Table 8-3. 
Other: Other data collected during long-term follow-up includes blood sampling for 
hematology, chemistry testing, coagulation, 
 as 
per Table 8-2 and Table 8-3. The visits will be carried out every 12 weeks (± 28 days) 
until death, lost to follow-up, withdrawal of consent (WoC) / opposition to use 
data/biological samples or accrual of the number of events required for the planned 
analyses for OS for the study, whichever occurs first. This follow-up will allow to collect 
information on medically significant long-term toxicities such as long-term radiotoxicity. 
Duration of long term follow-up is expected to continue till end of study. 
If the participant withdraws consent for the collection of blood samples, physical exams 
PROs and imaging assessments during the long-term follow-up, information on survival, 
AEs related to study treatment and post-treatment antineoplastic therapy will be 
collected.  
Participants who have received 177Lu-PSMA-617 and remain in follow-up on the trial at 
the sponsor’s completion of the study will be asked to join a separate study of long-term 
safety for a duration of up to 10 years. 
Study Population 
Adult PSMA-positive men previously treated with an ARDT where it is considered 
appropriate to delay taxane-based chemotherapy. 
Approximately 450 participants will be randomized (225 per treatment group). 
Inclusion Criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Participants must be adults ≥ 18 years of age 
3. Participants must have an ECOG performance status of 0 to 1 
4. Participants must have histological pathological, and/or cytological confirmation of  
adenocarcinoma of the prostate 
5. Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as 
determined by the sponsor’s central reader 
6. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or 
< 1.7 nmol/L) 
7a. Participants must have progressed only once on prior second generation ARDT  
(abiraterone, enzalutamide, darolutamide, or apalutamide). 

Novartis 
Confidential 
Page 45 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but 
not considered as prior ARDT therapy  
• 
second generation ARDT must be the most recent therapy received  
8. Participants must have progressive mCRPC. Documented progressive mCRPC will  
be based on at least 1 of the following criteria: 
• Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 
week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting 
value if confirmed rise in PSA is the only indication of progression. 
• Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 
2009, Scher et al 2016)] 
• Progression of bone disease: two new lesions; only positivity on the bone scan 
defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016)) 
9a. Participants must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or  
bone scan imaging obtained prior to randomization 
10. Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities 
related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia 
11. Participants must have adequate organ function: 
 
• Bone marrow reserve: 
 
• ANC ≥ 1.5 x 109/L 
 
• Platelets ≥100 x 109/L 
 
• Hemoglobin ≥ 9 g/dL 
 
• Hepatic: 
 
• Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants  
with known Gilbert’s Syndrome ≤ 3 x ULN is permitted 
 
• ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases 
 
• Renal: 
 
• eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD)  
equation 
12. Albumin ≥ 2.5 g/dL 
13a. Candidates for change in ARDT as assessed by the treating physician 
• Participants cannot have previously progressed nor had intolerable toxicity to both 
enzalutamide and abiraterone. 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this 
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 
2. Previous PSMA-targeted radioligand therapy 
3a. Prior treatment with cytotoxic chemotherapy for castration resistant 
or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine,  
vincristine, methotrexate, etc.), immunotherapy or biological therapy [including  
monoclonal antibodies]. [Note: Taxane exposure (maximum 6 cycles) in the adjuvant  
or neoadjuvant setting is allowed if 12 months have elapsed since completion of this 
adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed] 
4. Any investigational agents within 28 days prior to day of randomization 
5. Known hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar classes 
6a. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP 
inhibitor, biological therapy, or investigational therapy 
7. Transfusion or use of bone marrow stimulating agents for the sole purpose of making  
a participant eligible for study inclusion 
8a. Participants with a history of CNS metastases who are neurologically unstable, 
symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic  
integrity. Participants with CNS metastases are eligible if received therapy (surgery,  
radiotherapy, gamma knife), asymptomatic and neurologically stable without  
corticosteroids. Participants with epidural disease, canal disease and prior cord 
involvement are eligible if those areas have been treated, are stable, and not  

Novartis 
Confidential 
Page 46 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
neurologically impaired. 
9. Symptomatic cord compression, or clinical or radiologic findings indicative of  
impending cord compression 
10. History or current diagnosis of the following ECG abnormalities indicating significant  
risk of safety for study participants: 
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular  
tachycardia, complete left bundle branch block, high-grade AV block (e.g.,  
bifascicular block, Mobitz type II and third degree AV block) 
• History of familial long QT syndrome or known family history of Torsades de Pointe 
• Cardiac or cardiac repolarization abnormality, including any of the following: History  
of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to  
starting study treatment 
11a. 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. 
• HIV-infected participants who are at a low risk of AIDS-related outcomes may  
participate in this trial. 
• Participants with an active documented COVID-19 infection (any grade of disease  
severity) at time of informed consent may be included only when completely  
recovered (in accordance with local guidance).  
12a. Diagnosed with other malignancies that are expected to alter life expectancy or 
may interfere with disease assessment. However, participants with a prior history  
of malignancy that has been adequately treated and who have been disease free 
and treatment free for more than 3 years prior to randomization, are eligible, as are 
participants with adequately treated non-melanoma skin cancer and superficial  
bladder cancer 
13a. Sexually active males unwilling to use a condom during intercourse while taking  
study treatment and for 14 weeks after stopping study treatment. A condom is 
required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. 
In addition, male participants must not donate sperm for the time period specified 
above. If local regulations deviate from the contraception methods listed above to  
prevent pregnancy, local regulations apply and will be described in the ICF 
14a. Unmanageable concurrent bladder outflow obstruction or urinary incontinence.  
Note: Participant with bladder outflow obstruction or urinary incontinence, which is 
manageable and controlled with best available standard of care (incl. pads,  
drainage) are allowed. 
15. History of somatic or psychiatric disease/condition that may interfere with the  
objectives and assessments of the study 
16. Any condition that precludes raised arms position 
17a. 
Eligible for treatment(s) other than ARDT based on presence of any mutations 
or biomarkers that are known as predictors of better 
response (e.g., AR-V7 or BRCA).  
18. Not able to understand and to comply with study instructions and requirements  
Study Treatment 
177Lu-PSMA-617 or approved ARDT (abiraterone or enzalutamide) 
Treatment of 
interest 
177Lu-PSMA-617 
Efficacy 
Assessments 
• 
Radiographic imaging for tumor assessments: 
 
• CT with contrast/magnetic resonance imaging (MRI) 
 
• Bone scans with technetium-99m labeled diphosphonates 
• 
PCWG3-modified RECIST v1.1 
• 
Symptomatic skeletal events 
• 
Clinical progression 
• 
PSA levels 

Novartis 
Confidential 
Page 47 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Key safety 
assessments 
• 
Adverse Events (AEs) 
• 
Serious Adverse Events (SAEs) 
• 
Vital signs, physical examinations 
• 
ECGs 
• 
Laboratory parameters including hematology, clinical chemistry and coagulation 
• 
Concomitant medications and/or therapies 
Other 
assessments 
 
• 
ECOG Performance Status scale 
• 
 
• 
Health-related quality of life: 
 
• European Quality of Life (EuroQol) 5 Domain 5 Level scale questionnaire (EQ-5D-
5L) 
 
• Functional Assessment of Cancer Therapy - Prostate (FACT-P) 
 
• Brief Pain Inventory - Short Form (BPI-SF) 
Data analysis 
The following data analyses are planned for the study: 
• 
Primary rPFS Analysis 
Assuming proportional hazards model for rPFS, the null hypothesis will be tested at one-
sided 2.5% level of significance: H01 (null hypotheses): Θ ≥ 0 vs. Ha1 (alternative 
hypotheses): Θ < 0, where Θ is the log hazard ratio of rPFS in the 177Lu-PSMA-617 
(investigational) arm vs. a change of ARDT treatment (control) arm. 
The primary efficacy analysis to test this hypothesis and compare rPFS, the primary 
efficacy variable, between the two treatment groups will be using a stratified log-rank 
test at an overall one-sided 2.5% level of significance in favor of the 177Lu-PSMA-617 
arm. The stratification will be based on following randomization stratification factors 
(prior ARDT use: CRPC vs. HSPC setting; and symptomatology: asymptomatic or mildly 
symptomatic (score of 0-3 on Brief Pain Inventory Short Form (BPI-SF) questionnaire) 
vs symptomatic (score >3 on BPI-SF questionnaire). 
Analyses will be based on the FAS population according to the randomized treatment 
group and strata assigned at randomization. The rPFS distribution will be estimated 
using the Kaplan-Meier method, and Kaplan-Meier curves, median and associated 95% 
confidence intervals will be presented for each treatment group. The hazard ratio for 
rPFS will be calculated, along with its 95% confidence interval, from a stratified Cox 
model using the same stratification factors as for the log-rank test. 
The primary rPFS analysis will only be carried out after all participants have been 
randomized and 156 events have been observed. 
• 
OS Interim and Final Analysis 
OS, as the key secondary variable, will be formally statistically tested, if the primary 
variable rPFS is statistically significant. 
The key secondary efficacy analysis is to compare the two treatment groups and will 
consist of a stratified log-rank test at an overall one-sided 2.5% level of significance 
using randomization stratification factors (prior ARDT use: CRPC vs. HSPC setting; and 
symptomatology: asymptomatic or mildly symptomatic vs symptomatic). The key 
secondary efficacy variable, OS, will be analyzed at the interim analyses and final 
analysis of a 4-look group sequential design with a Lan-DeMets (O’Brien-Fleming) alpha 
spending function using estimated information fractions of (0.135,0.42,0.75, 1).  
Initially, a 3-look design was planned for OS using estimated information fractions of 
(0.25, 0.75, 1).  
However, the first interim occurred when the rPFS primary analysis was performed at 
which time the actual information fractionwas only 0.135. Therefore, an additional interim 
analysis was added, with a data cut-off approximately 9 months after the data cut-off for 
the primary rPFS analysis at which time an information fraction of 0.42 is expected. The 
third interim OS analysis will be performed at approximately 0.75 information fraction, 
corresponding to when approximately 223 of the 297 targeted OS events have been 
observed. The primary intent of the interim analyses is to stop early for superior efficacy. 
There is no intent to assess futility at these interim analyses. Analyses will be based on 
the full analysis set (FAS) population according to the randomized treatment group and 
strata assigned at randomization. The OS distribution will be estimated using the 
Kaplan-Meier method, and Kaplan-Meier curves, median and associated 95% 
confidence intervals will be presented for each treatment group. The hazard ratio for OS 

Novartis 
Confidential 
Page 48 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
will be calculated, along with its 95% confidence interval, from a stratified Cox model 
using the same stratification factors as for the log-rank test. Other secondary endpoints 
including time to Symptomatic skeletal events (SSE), Objective Response Rate (ORR), 
Disease Control Rate (DCR), duration of response, Proportion of participants who have 
achieved a ≥ 50% decrease from baseline that is confirmed by a second PSA 
measurement ≥4 weeks (PSA50 response), time to PSA progression, and Health-
Related Quality of Life (HRQoL) (FACT-P, BPI-SF, EQ-5D-5L) will also be analyzed. 
Detailed statistical methodology for these analyses will be provided in the statistical 
analysis plan. 
Key words 
177Lu-PSMA-617, ARDT, mCRPC, rPFS, CRPC, HSPC, PSMA 

Novartis 
Confidential 
Page 49 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
1 
Introduction 
1.1 
Background 
Prostate cancer is the second leading cause of cancer mortality in United States (US) and the 
third leading cause of cancer-related death in Europe in men (Malvezzi et al 2019, Siegel et al 
2017). An estimated 1.1 million men worldwide were diagnosed and 307,000 died due to 
prostate cancer in 2012. Almost 70% of the diagnosed cases are 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 
(Bray et al 2012). 
There is an urgent need for more effective treatments to improve outcomes for participants with 
metastatic castration-resistant prostate cancer (mCRPC). The median age at diagnosis of 
mCRPC is 70 years (Flaig et al 2016). Once participants 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). In addition, there are significant comorbidities associated with mCRPC. 
Approximately 90% of mCRPC participants develop bone metastases (Kirby et al 2011) and 
49% of them will develop a serious skeletal event within 2 years (Saad et al 2004). As a result, 
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 participants, can be extremely symptomatic and at risk of serious 
oncological complications. There can be a considerable challenge in the clinic due to the 
symptoms of metastatic soft tissue and visceral disease, general frailty and bone marrow 
impairment. 
Four main drug classes have been approved for treatment for prolonging survival in mCRPC 
participants. These include ARDTs (i.e., abiraterone and enzalutamide), taxanes (docetaxel and 
cabazitaxel), immunotherapy (sipuleucel-T) and bone-targeted radiopharmaceutical (radium 
223 dichloride). With the evolution in the treatment landscape of prostate cancer, some of these 
life-prolonging therapies (ARDT and docetaxel) are increasingly used in earlier stages (e.g. 
metastatic hormone sensitive prostate cancer and non-metastatic prostate cancer). This creates 
an even greater unmet medical need in mCRPC. Among participants who have previously 
received an ARDT therapy, several mechanisms have been implicated in development of 
resistance to the treatment (Attard et al 2009). The rPFS for participants that change ARDTs 
ranges from 3.6 to 15 months and OS from 11 to 23 months (de Bono et al 2020, 
de Wit et al 2019, Komura et al 2019). On the other hand, many participants do not receive 
chemotherapy primarily because of preexisting medical conditions or associated toxic effects. 
(Harris et al 2011, Engel-Nitz et al 2011, Lissbrant et al 2013, Zielinski et al 2014). Sipuleucel-
T is best used in mildly asymptomatic small volume disease; and radium 223 is used to treat 
men with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their 
use is restricted in a subgroup of mCRPC participants with homologous recombination repair 
gene mutations [PROfound (de Bono et al 2020, Hussain et al 2019) and TRITON2 (Abida et 
al 2019) studies]. 

Novartis 
Confidential 
Page 50 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
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 et al 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 
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 (Benesova et al 2015). 
PSMA-617 was uniquely developed for both imaging and radio ligand 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. 
177Lu, the radioactive cargo being delivered by PSMA-617, has physical properties that make it 
an appropriate radionuclide for the treatment of mCRPC. 177Lu is a medium energy P emitter 
(490 ke V) with a maximum energy of 0.5 Me V and a maximal tissue penetration of < 2 mm. 
The shorter p - range of 177Lu provides better irradiation of small tumors, in contrast to the 
longer P-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. 

Novartis 
Confidential 
Page 51 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
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 participants with metastatic prostate cancer (Hillier et al 2009, 
Kratochwil et al 2015, Kulkarni et al 2018c). 
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 participants 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 salivary glands; however in the prospective study xerostomia appears low grade and occurs 
at a rate of approximately 87% in treated participants. 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 participants 
(Ahmadzadehfar et al 2015) treated between Nov-2013 and Jan-2014, with 5.6 GBq/150 mCi 
(4.1-6.1 GBq/110-165 mCi). PSA decline > 50% occurred in 50% of participants, 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 participants 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 participants, 70% were identified as PSMA-positive via PET imaging and 
eligible for treatment. Most participants had been exposed to at least 1 taxane chemotherapy 
and either abiraterone or enzalutamide in the mCRPC setting. In this heavily pre-treated 
participant population with few therapeutic alternatives, 64% of participants 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 participants with measurable disease, the objective 

Novartis 
Confidential 
Page 52 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
response rate in measurable disease as defined by 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. 
More recently Hofman presented the first randomized prospective open-label Phase-II study of 
177Lu-PSMA-617 vs cabazitaxel in 200 docetaxel progressing metastatic castration-resistant 
prostate cancer. Participants dosed with up to 6 cycles of 177Lu-PSMA-617 (Hofman 2020). The 
primary endpoint was PSA response, defined as ≥ 50% reduction in PSA from baseline. 
Secondary endpoints, included PSA progression-free survival, overall survival, and quality of 
life. 
This first ever randomized study, showed that a significantly greater proportion of patients on 
177Lu-PSMA-617 (66%) had a PSA decline >=50% compared to cabazitaxel (37%) (P<0.0001). 
In summary, over 40 compassionate use publications and prospective Phase 2 clinical trial data 
describe the use of 177Lu-PSMA-617 in participants 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 side 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 were 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, 
progression-free survival (PFS), OS, pain and quality of life. No standard dose and schedule 
have been developed. 
The preliminary clinical evidence indicates that 177Lu-PSMA-617 may demonstrate clinical 
benefit for men with mCRPC, improving rPFS and OS compared with a change in ARDT and 
there is no recommended standard of care. Data from this study will complement the data from 
the VISION study for 177Lu-PSMA-617 as a treatment in mCRPC prior to the use of taxanes. 
VISION (NCT03511664), a phase III trial evaluating best standard of care with or without 
177Lu-PSMA-617 in men who had metastatic castration-resistant prostate cancer previously 
treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens 
and who had PSMA-positive Gallium (68Ga) gozetotide ([68Ga]Ga-PSMA-11) positron 
emission tomographic–computed scans. VISION was designed as a registration trial for 177Lu-
PSMA-617 with alternate primary endpoints of radiographic progression-free or overall 
survival. Key secondary endpoints were objective response, disease control, and time to 
symptomatic skeletal events. 
177Lu-PSMA-617 plus standard care significantly prolonged (Sartor et al 2021), as compared 
with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; 
hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; 
P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% 
CI, 0.52 to 0.74; P<0.001). All the key secondary end points favored 177Lu-PSMA-617. Among 
the 248 patients who had measurable target lesions according to RECIST, version 1.1, on 
independent central review at baseline, a complete response was noted in 17 of 184 patients 

Novartis 
Confidential 
Page 56 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
2. Variable: rPFS defined as the time from date of randomization to the date of first 
documented radiographic progression-free survival as assessed by BICR and outlined in 
PCWG3 guidelines or death due to any cause. Further details on rPFS are provided in 
Section 12.4.1 
3. Treatment of interest: the investigational treatment is 177Lu-PSMA-617 with best supportive 
care regardless of subsequent anti-neoplastic treatment. The control treatment is ARDT with 
best supportive care regardless of subsequent anti-neoplastic treatment. Further details 
about the investigational treatment and control treatment are provided in Section 6. 
4. Handling of remaining intercurrent events: 
• Discontinuation of study treatment for any reason 
• Change in best supportive care 
• Start of anti-neoplastic therapy prior to radiographic progression 
Details on how to handle intercurrent events are provided in Section 12.4.3. 
5. Summary measure: rPFS hazard ratio (177Lu-PSMA-617 with BSC versus ARDT with BSC) 
along with 95% confidence interval, estimated using a Cox proportional hazard model 
stratified by the randomization stratification factors. Further details on how the summary 
measure will be tested are provided in Section 12.4.2 
2.2 
Secondary estimands 
Key secondary clinical question (hypothetical) of interest: what is the effect of 177Lu-PSMA-
617 with BSC versus ARDT with BSC with regard to overall survival in the treatment of taxane 
naïve men with Progressive PSMA-positive Metastatic Castrate Resistant Prostate Cancer as 
defined through inclusion/exclusion criteria, had crossover not occurred and regardless of 
treatment discontinuations for any reasons and regardless of change in best supportive care or 
start of new antineoplastic therapy? Further details can be found in Section 12. 
The justification for the key secondary estimand is that it will capture both the effect of the 
study treatment and the effect of additional medications while accounting for the impact of 
crossover. Further details can be found in Section 12. 
The key secondary estimand (hypothetical) is described by the following attributes: 
1. Population: same as that of primary estimand 
2. Variable: Overall Survival (OS) defined as the time from randomization to death due to 
any cause. Further details on OS provided in Section 12.5.1.1 
3. Treatment of interest: same as that of primary estimand 
4. Handling of remaining intercurrent events: 
• Discontinuation of study treatment for any reason 
• Change in best supportive care 
• Start of new anti-neoplastic therapy 
• Crossover to 177Lu-PSMA-617 arm for participants in the ARDT arm 
Details on how to handle the intercurrent events are provided in Section 12.5.1.1 
5. Summary measure: OS hazard ratio (177Lu-PSMA-617 with BSC versus ARDT with BSC) 
along with 95% confidence interval, estimated using a Cox proportional hazard model 

Novartis 
Confidential 
Page 57 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
stratified by the randomization stratification factors. Further details on how the summary 
measure will be tested are provided in Section 12.5.1.1 
3 
Study design 
This is a phase III, open label, multicenter randomized study for PSMA-positive mCRPC 
participants previously treated with an ARDT where it is considered appropriate to delay 
taxane-based chemotherapy. 
The study aims at evaluating the superiority of 177Lu-PSMA-617 over a change of ARDT 
treatment in prolonging rPFS. The primary endpoint of rPFS will be assessed via blinded 
centralized review of radiographic images provided by the treating physician and as outlined in 
PCWG3 Guidelines. 
The study will also evaluate whether 177Lu-PSMA-617 improves the overall survival (OS) in 
participants with progressive PSMA-positive mCRPC compared to participants treated with a 
change in ARDT treatment. OS is defined as the time from randomization to death due to any 
cause (Figure 3-1). 
Written informed consent form (ICF) must be obtained prior to any screening procedures. 
Screening procedures are carried out after ICF signature and within 28 days of randomization 
in IRT system. The participant must be registered in the IRT for screening and 177Lu-PSMA-
617 requested. All procedures described in the Assessment Schedule as per Table 8-2 and 
Table 8-3 must be carried out, prioritizing laboratory and imaging assessments to allow time to 
obtain the results. 
The participants will be assessed for eligibility and will undergo a 68Ga-PSMA-11 PET / CT 
scan to evaluate PSMA positivity by central review. Only participants with PSMA positive 
cancer and confirmed eligibility criteria will be randomized. Randomization will be stratified 
by prior ARDT use in castrate-resistant prostate cancer (CRPC) vs. HSPC setting and by 
symptomatology i.e. asymptomatic or mildly symptomatic (score on item 3 of the Brief Pain 
Inventory Short Form (BPI-SF) questionnaire (symptomatic = score >3 on item 3 of the BPI-
SF questionnaire). 
For all participants, the treating physician will make a choice of which ARDT (abiraterone or 
enzalutamide) will be administered to the participant should they get randomized to the ARDT 
arm. If the participant gets randomized to receive 177Lu-PSMA-617, the choice of change of 
ARDT treatment will be discarded. 
Randomization period 
Randomization should occur within the 28 days screening period once all eligibility criteria are 
met. The participants will be randomized 1:1 to receive 177Lu-PSMA-617 or a change of the 
ARDT treatment. 
If the participant is randomized to the 177Lu-PSMA-617 arm, the drug needs to be ordered 
immediately and allow 2 weeks to reach the site. 
For the participants randomized to the ARDT arm, the change of ARDT treatment will include 
approved AR axis targeted therapy (abiraterone or enzalutamide). 

Novartis 
Confidential 
Page 58 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Supportive care will be allowed in both arms and includes available care for the eligible 
participant according to best institutional practice for mCRPC treatment, including androgen 
deprivation therapy (ADT) and at the discretion of the investigator. Other Investigational agents, 
biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. 
radium-223), Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemi-body 
radiotherapy treatment must not be administered during the study treatment period. ARDT must 
not be administered concomitantly with 177Lu-PSMA-617. 
Treatment period 
• 
177Lu-PSMA-617 treatment arm 
Participants randomized to the investigational arm must begin 177Lu-PSMA-617 dosing within 
14 days after randomization. C1D1 can be delayed by up to an additional 3 days for unexpected 
scheduling delays. Participants will receive 7.4 GBq (200 mCi) +/- 10% 177Lu-PSMA-617 once 
every 6 weeks for 6 cycles as per Table 8-2. Best supportive care, including ADT, may be used. 
After the last day of study treatment period of 177Lu-PSMA-617 (i.e. after completion of 6 
cycles of treatment OR treatment discontinuation for any reason) [for e.g. upon radiographic 
progression as assessed by blinded centralized review]), the participants must have an End of 
Treatment (EOT) visit performed ≤ 7 days and enter the Post-treatment Follow-up. For 
participants who are able to complete all planned 6 cycles of 177Lu-PSMA-617, the end of the 
treatment period is after completion of C6W5 visit and the fourth imaging assessment due at 
week 37. 
In the absence of safety concerns, every effort should be made to keep the participant on the 
randomized treatment until BICR-determined radiographic progression or completion of the 6 
cycles of 177Lu-PSMA-617. 
• ARDT treatment arm 
For participants randomized to the ARDT treatment arm, the change of ARDT treatment for 
each participant will be selected by the treating physician prior to randomization and will be 
administered per the physician’s orders. Best supportive care, including ADT, may be used. 
After the last day of study treatment (treatment discontinuation for any reason) or upon 
radiographic progression as assessed by blinded centralized review, the participants must have 
an End of Treatment (EOT) visit performed ≤ 7 days and enter the Post-treatment Follow-up. 
In absence of safety concerns, every effort should be made to keep the participant on the 
randomized treatment until BICR-determined radiographic progression. 
End of Treatment 
Randomized treatment may be discontinued if: 
• Completion of the 6 cycles of 177Lu-PSMA-617 
• Evidence of tumor progression by central radiological assessment as measured by 
PCWG3-modified RECIST v1.1 criteria 
• Unacceptable toxicity as assessed by Investigator 
• Participant non-compliance or voluntary withdrawal from study or from study treatment 

Novartis 
Confidential 
Page 59 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Required ongoing use of a prohibited treatment for participant safety reasons 
• Evidence that the participant is no longer clinically benefiting from study treatment 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• At the sponsor's or investigator's discretion 
It is important that the scheduled imaging assessments continue until BICR-determined 
progression. PSA progression is strongly discouraged as a criterion for initiation of a new 
neoplastic therapy prior to BICR-determined progression. PCWG3 guidelines should be 
followed to guide discontinuation of treatment 
EOT visit must be performed ≤ 7 days after the last day of study treatment period. EOT is to 
occur before the participant is to enter the post-treatment Follow-up period of the study and 
before the initiation of any subsequent anticancer treatment, outside of what is allowed in the 
study. 
If a participant withdraws consent for the treatment period of the study, an EOT must be done 
and the participant will enter the Post-treatment Follow-up unless he specifically withdraws 
consent for post-treatment Follow-up. 
Crossover period 
Upon confirmation of rPD by BICR, participants randomized to the ARDT arm will either be 
allowed to cross over to receive 177Lu-PSMA-617 within 28 days of confirmation of 
radiographic disease progression determined by BICR, or may continue to receive any other 
therapy per the discretion of the treating physician in the Post-treatment Follow-up and start of 
new 
intervening 
antineoplastic 
therapies 
disqualifies 
patient 
for 
crossover.  
Following confirmation of patient eligibility for the crossover, the participant can be assigned 
to the crossover via the IRT system. The participant should start receiving 177Lu-PSMA-617 
within 14 (+3) days after registration of crossover in IRT system.  
In order for a participant randomized to the change in ARDT arm to cross over to receive 177Lu-
PSMA-617, he must meet the following criteria: 
• Confirmed radiographical progression as assessed by BICR within prior 28 days 
• No intervening antineoplastic therapy is administered after the randomized treatment 
• Any unresolved toxicity from prior therapy should be controlled and must be no greater 
than CTCAE grade 2 or baseline at the time of registration for crossover  
• ECOG performance status 0-1 at the time of registration for crossover 
• Adequate organ function at the time of registration for crossover: 
• Bone marrow reserve: 
• ANC ≥ 1.5 x 109/L 
• Platelets ≥100 x 109/L 
• Hemoglobin ≥ 9 g/dL 
• Hepatic: 

Novartis 
Confidential 
Page 60 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Total bilirubin < 2x the institutional upper limit of normal (ULN). For 
participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted 
• ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases 
• Renal: 
• eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease 
(MDRD) equation 
• Agreement to continue with the study visit schedule 
Baseline assessments must be performed within 28 days of registration for crossover and are 
described in Table 8-3. If the EOT1 visit has been performed within prior 28 days of registration 
for crossover, those results can be used to confirm patient eligibility to the crossover. If the 
patient has not undergone specific assessments defined below within 28 days prior to 
registration for crossover, they must complete or repeat the assessments in order to ensure the 
above criteria are met. CT/MRI and bone scan within 28 days prior to registration for crossover 
must be available as new baseline images.  
A participant, who is deemed to have disease progression per investigator's assessment, but not 
by BICR, is not eligible to cross over at that time. Such participant should continue to receive 
randomized study treatment until progression determined by BICR. Please refer to Section 8 
for visit schedule and assessments following crossover. 
If crossover to 177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with 
the same dose/schedule as for participants who were initially randomized to receive 177Lu-
PSMA-617 as described above. 
After the last day of study treatment period of 177Lu-PSMA-617 or upon rPFS2, the participants 
must have a EOT2 visit performed ≤ 7 days and enter the Post-treatment Follow-up. The 
participant can receive any other therapy per the discretion of the treating physician in the Post-
treatment Follow-up. 
Post-treatment Follow-up period 
• 30 day Safety Follow-up 
All randomized and/or treated participants should have a safety follow-up conducted 
approximately 30 days after the EOT visit (or EOT2 visit if crossover occurs). 
• Long term follow-up 
Long term follow-up starts after the 30 Day Safety follow-up and lasts until the accrual of events 
for the planned OS-based analysis (key secondary endpoint). In long term follow-up safety and 
efficacy information will be collected: 
• Safety: During the long term follow-up, all medically significant adverse events (all SAEs) 
deemed to be related to study treatment will be collected including potential late onset 
radiation toxicity. For participants who received 177Lu-PSMA-617 in the 177Lu-PSMA-617 
arm or in crossover, the following adverse events will be captured beyond the 30 day safety 
period regardless of relationship to study treatment and whether new anticancer therapy has 
been initiated: hematologic toxicities with primary focus on myelosuppression and 

Novartis 
Confidential 
Page 63 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
177Lu-PSMA-617 is well tolerated according to the clinical experience that has been 
documented in over 53 publications, summarizing the safety and or efficacy information from 
over 1280 participants. 
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. Although the 
German Society of Nuclear Medicine 2016 recommended a 6.0 GBq dose every 8 weeks for 3 
cycles, the majority of these publications have used a regimen of 4 cycles of 6 GBq every 8 
weeks. However, efficacy and safety information from a prospective phase 2 study suggested 
that dosing of 4.0-8.9 (mean 7.5) GBq every 6 weeks for 4 cycles was well tolerated and 
efficacious (Violet et al 2020). 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 participant 
(Bräuer et al 2017, Kessel K et al 2019, Kulkarni et al 2018a, Kulkarni et al 2018b, Kulkarni et 
al 2018c, Maffey Steffan et al 2020, Rahbar et al 2018, Yadav et al 2020, Yordanova et al 2017, 
van Kalmthout et al 2019). 
In the phase II TheraP study (ANZUP protocol 1603, NCT03392428), 200 Australian men with 
mCRPC were randomly allocated (1:1) to treatment with either 177Lu-PSMA-617 or cabazitaxel. 
The starting dose for 177Lu-PSMA-617 was 8.5 GBq and was reduced by 0.5 GBq per cycle, i.e. 
8.5, 8, 7.5, 7, 6.5, 6, for a maximum of 6 cycles given every 6 weeks. This equates to a 
cumulative dose of 43.5 GBq, which 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. 
Further details on 177Lu-PSMA-617 can be found in the [Investigator's Brochure]. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Four main drug classes have been approved for treatment for prolonging survival in mCRPC 
participants. These include ARDTs (i.e., abiraterone and enzalutamide), taxanes (docetaxel and 
cabazitaxel), immunotherapy (sipuleucel-T) and bone-targeted radiopharmaceutical (radium 
223 dichloride). With the evolution in the treatment landscape of prostate cancer, some of these 
life-prolonging therapies (ARDT and docetaxel) are increasingly used in earlier stages (e.g. 
metastatic hormone sensitive prostate cancer and non-metastatic prostate cancer). This creates 
an even greater unmet medical need in mCRPC. Among participants who have previously 
received an ARDT therapy, several mechanisms have been implicated in development of 
resistance to the treatment (Attard et al 2009). The rPFS for participants that change ARDT 
treatment ranges from 3.6 to 15 months and OS from 11 to 23 months (de Bono et al 2020,de 
Wit et al 2019, Komura et al 2019). On the other hand, many participants do not receive 
chemotherapy primarily because of preexisting medical conditions or associated toxic effects. 
(Engel-Nitz et al 2011, Harris et al 2011, Lissbrant et al 2013, Zielinski et al 2014). Sipuleucel-
T is best used in mildly asymptomatic small volume disease; and radium 223 is used to treat 
men with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their 
use is restricted in a subgroup of mCRPC participants with homologous recombination repair 
gene mutations [PROfound (de Bono et al 2020, Hussain et al 2019) and TRITON2  
(Abida et al 2019) ESMO 2019 studies]. 

Novartis 
Confidential 
Page 64 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
ARDTs such as abiraterone and enzalutamide have shown efficacy and are approved for 
treatment of mCRPC among participants who have not previously been treated with taxane-
based chemotherapy, and are a relevant comparator for this study.  
4.4 
Purpose and timing of interim analyses/design adaptations 
No interim analysis is planned for rPFS. The final rPFS analysis will only be carried out after 
all participants have been randomized. 
OS Interim Analysis 
A hierarchical testing procedure will be adopted and the statistical tests for OS will be 
performed only if the primary efficacy endpoint rPFS is statistically significant. 
A maximum of three interim analyses are planned. The first interim analysis was performed at 
the time of the final rPFS analysis. The second interim analysis is not event-driven but instead 
will be performed at approximately 9 months of additional follow-up from the data cut-off used 
for the primary analysis, by which time approximately 125 of the 297 targeted OS events (42% 
information fraction) are expected. This interim analysis is expected to occur around 24 months 
from the date of first participant randomized in the study. 
The third interim analysis is planned after approximately 223 of the approximately 297 targeted 
OS events (i.e., at approximately 75% information fraction) have been observed. This interim 
analysis is expected to occur around 38 months from the date of first participant randomized in 
the study. The primary intent of these interim analyses is to stop early for superior efficacy. 
There is no intent to assess futility at these interim analyses.  
More details on OS interim analyses can be found in Section 12.5.1.1 and Section 12.7. 
4.5 
Risks and benefits 
PSMA is over-expressed in prostate cancer, and this over-expression increases further in cases 
of de-differentiated, metastatic or hormone-refractory disease (Israeli et al 1993, Sweat et al 
1998, Wright et al 1995, Wright et al 1996). This study will enroll participants with mCRPC 
who have progressed on ARDT and taxane naïve for advance stage. These participants have 
very limited treatment options. Participants who are determined by 68Ga-PSMA-11 as PSMA-
positive will be administered 177Lu-PSMA-617. 
The use of 68Ga-PSMA-11 for PET scanning of prostate cancer participants has been ongoing 
since 2011 to assess disease burden in the setting of both biochemical recurrence (BCR); rising 
PSA in advanced/metastatic disease. Publications that report clinical use have demonstrated 
better sensitivity and specificity than choline-based imaging for prostate cancer, with a very 
low rate of adverse events. 68Ga-PSMA-11 has also been the most commonly used radioactive 
imaging agent to evaluate PSMA-expressing mCRPC in participants being considered for 
177Lu-PSMA-617 radioligand therapy. 68Ga-PSMA-11 has been shown to be well tolerated with 
no adverse events following infusion in a retrospective analysis of 1007 participants 
(Afshar-Oromieh et al 2017). 68Ga-PSMA-11 is approved in the US under the trademark of 
LOCAMETZ® as a radioactive diagnostic agent indicated for PET imaging of PSMA-positive 
lesions in men with prostate cancer with suspected metastasis who are candidates for initial 

Novartis 
Confidential 
Page 65 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
definitive therapy, with suspected recurrence based on elevated serum PSA level and for 
selection of patients with metastatic prostate cancer for whom 177Lu-PSMA-617 PSMA-
directed therapy is indicated. It has demonstrated a favorable safety profile with about 1% of 
patients experiencing mild reactions such as fatigue, nausea, constipation, and vomiting. Further 
details can be found in the 68Ga-PSMA-11 Investigator's Brochure. 177Lu-PSMA-617 is 
approved in the US under the brand name of PLUVICTO™ for the treatment of adult patients 
with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant 
prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway 
inhibition and taxane-based chemotherapy. 
Preclinical work, dosimetry studies, and clinical experience with 177Lu-PSMA-617 since 2013, 
suggest positive response rates and a favorable safety profile in participants with mCRPC 
(Ahmadzadehfar et al 2016, Fendler et al 2017, Ferdinandus et al 2017, Haug et al 2016, 
Kratochwil et al 2016, Kulkarni et al 2016, Rahbar et al 2016a, Rahbar et al 2016b, Rahbar et 
al 2018, Rathke et al 2017, Yadav et al 2017). 
Dosimetry studies have confirmed that 177Lu-PSMA-617 is targeted and some 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 clinical studies so far. There has been evidence of 
reversible hematological toxicity. No significant diarrhea or renal impairment was reported 
from a retrospective review of doctors’ reports (Rahbar et al 2017). In the prospective studies 
sponsored by Endocyte (VISION study and RESIST-PC study), the commonly reported adverse 
events (> 10% of participants) to date include: anemia, dry mouth, constipation, diarrhea, 
nausea, vomiting, fatigue, decreased appetite, arthralgia and back pain (Refer to [177Lu-PSMA-
617 IB]). A small number of hematological events (thrombocytopenia, anemia and 
pancytopenia) have been reported as fatal (Refer to [177Lu-PSMA-617 IB]). 
Hofman et al. presented results from the first prospective clinical trial with 177Lu-PSMA-617 
(Hofman et al 2019). In the trial, 50 mCRPC participants 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 nonhematological 
toxicities attributed to 177Lu-PSMA-617 occurring in > 25% of participants included transient 
Gl-2 dry mouth (66%), Gl-2 nausea (48%), Gl-3 fatigue (38%), and Gl-2 vomiting (26%). The 
most common hematological toxicities attributed to 177Lu-PSMA-617 occurring in > 25% of 
participants included Gl-3 lymphocytopenia (72%), Gl-4 thrombocytopenia (38%), Gl-3 
neutropenia (30%) and G 1-3 anemia (28%). G3-4 toxicities attributed to 177Lu-PSMA-617 
were infrequent with lymphocytopenia (32%), thrombocytopenia (10%), anemia (10%), 
neutropenia (6%) and fatigue (2%). In a subsequent open labeled Phase-II randomized study of 
177Lu-PSMA-617 vs cabazitaxel in 200 docetaxel progressing metastatic castration-resistant 
prostate cancer, Hofman 2020 showed that a significantly greater proportion of patients on 
177Lu-PSMA-617 (66%) had a PSA decline >=50% compared to cabazitaxel (37%) (P<0.0001). 
Cabazitaxel was associated with more Grade 3/4 neutropenia, febrile neutropenia, diarrhea, 
change in taste, and neuropathy than LuPSMA, whereas more thrombocytopenia, dry mouth, 
and dry eye occurred in LuPSMA-treated patients. 

Novartis 
Confidential 
Page 66 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Potential risks of 177Lu-PSMA-617 include the effects of radiological toxicity (such as increased 
risk of carcinogenicity, risk of infertility), late renal toxicity and bleeding events. 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. Appropriate eligibility criteria and 
stopping rules are included in this protocol. Guidance of toxicity risk reduction and supportive 
care for 177Lu-PSMA-617 and toxicity management and dose modification for 177Lu-PSMA-
617 are provided in Table 6-2. 
Sexually active males must be informed that taking the study treatment may involve unknown 
risks to the fetus if their female partner were to become pregnant during the study, and agree 
that in order to participate in the study they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. 
The risk-benefit ratio is expected to be favorable to the 68Ga-PSMA-11 imaging agent and 
177Lu-PSMA-617 therapy. 
Additional details of the nonclinical and clinical experience with 177Lu-PSMA-617 are provided 
in the [Investigator's Brochure]. 
COVID-19 pandemic related risks 
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented with approval from Novartis. The investigator 
and sponsor might consider: 
• The Investigator may conduct the informed consent discussion remotely as described in 
Section 7. 
• Sending the study participant to another imaging center (when feasible) and performing 
local labs or visits by site staff/home nursing service to the participant's home depending 
on local regulations and capabilities as described in Section 8. If visits by site staff to a 
participant’s home are not feasible the collection of samples may be modified by Novartis 
and will be communicated to the Investigator. If the treatment (with 177Lu-PSMA-617 or 
ARDT) is interrupted for more than 4 weeks due to COVID-19 pandemic, the participant 
must have an EOT visit performed in ≤ 7 days and enter the Post-treatment Follow-up 
• For safety monitoring, to arrange phone calls, virtual contacts (e.g. teleconsult) to replace 
on-site study visits, for the duration of the pandemic until it is safe for the participant to 
visit the site again as described in Section 8.4 
• Delivery of study drug directly to a participant’s home, as described in Section 6.7.2 
• Clinical Outcome Assessments may be collected remotely (e.g. web portal) if data cannot 
be obtained due to COVID-19 pandemic, depending on local regulations, technical 
capabilities, and following any applicable training in the required process, as described in 
Section 8.5.1 
The site must communicate immediately to Novartis any COVID-19 related issues that could 
impact the performance of the study to assess potential mitigation measures. 

Novartis 
Confidential 
Page 67 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
4.6 
Rationale for Public Health Emergency mitigation procedures 
In the event of a Public Health emergency as declared by local or regional authorities i.e. 
“pandemic, epidemic or natural disaster”, mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 
5 
Study Population 
In this study, the participant population will consist of male participants ≥ 18 years of age, with 
mCRPC cancer who were previously treated with another ARDT as last treatment and have not 
been exposed to a taxane-containing regimen in the CRPC or HSPC settings and who are 
considered appropriate for delaying taxane-based chemotherapy. 
Approximately 450 participants will be randomized (225 per treatment group). 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Participants must be adults ≥ 18 years of age 
3. Participants must have an ECOG performance status of 0 to 1 
4. Participants must have histological pathological, and/or cytological confirmation of 
adenocarcinoma of the prostate 
5. Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by 
the sponsor’s central reader 
6. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 
nmol/L)  
7a. Participants must have progressed only once on prior second generation ARDT (abiraterone, 
enzalutamide, darolutamide, or apalutamide). 
• 
first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but 
not considered as prior ARDT therapy 
• 
second generation ARDT must be the most recent therapy received 
8. Participants must have progressive mCRPC. Documented progressive mCRPC will be 
based on at least 1 of the following criteria: 
• Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week 
apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if 
confirmed rise in PSA is the only indication of progression 
• Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 
2009, Scher et al 2016)] 
• Progression of bone disease: two new lesions; only positivity on the bone scan defines 
metastatic disease to bone (PCWG3 criteria (Scher et al 2016)) 

Novartis 
Confidential 
Page 68 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
9a. Participants must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, 
or bone scan imaging obtained ≤ 28 days prior to randomization 
10. Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities 
related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia 
11. Participants must have adequate organ function: 
• Bone marrow reserve: 
• ANC ≥ 1.5 x 109/L 
• Platelets ≥100 x 109/L 
• Hemoglobin ≥ 9 g/dL 
• Hepatic: 
• Total bilirubin < 2 x the institutional upper limit of normal (ULN). For 
participants with known Gilbert’s Syndrome ≤ 3 x ULN is permitted 
• ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases 
• Renal: 
• eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease 
(MDRD) equation 
12. Albumin ≥ 2.5 g/dL 
13a. Candidates for change in ARDT as assessed by the treating physician 
• Participants cannot have previously progressed nor had intolerable toxicity to 
both enzalutamide and abiraterone 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this 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 
2. Previous PSMA-targeted radioligand therapy 
3a. Prior treatment with cytotoxic chemotherapy for castration resistant or castrate sensitive 
prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), 
immunotherapy or biological therapy [including monoclonal antibodies]. [Note: Taxane 
exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months 
have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with 
sipuleucel-T is allowed]. 
4.Any investigational agents within 28 days prior to day of randomization 
5. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar 
classes 
6a. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, 
biological, or investigational therapy 
7. Transfusion or use of bone marrow stimulating agents for the sole purpose of making a 
participant eligible for study inclusion 

Novartis 
Confidential 
Page 69 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
8a. Participants with a history of CNS metastases who are neurologically unstable, 
symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic 
integrity. Participants with CNS metastases are eligible if received therapy (surgery, 
radiotherapy, gamma knife), asymptomatic and neurologically stable without 
corticosteroids. Participants with epidural disease, canal disease and prior cord 
involvement are eligible if those areas have been treated, are stable, and not neurologically 
impaired. 
9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending 
cord compression 
10. History or current diagnosis of the following ECG abnormalities indicating significant risk 
of safety for study participants: 
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, complete left bundle branch block, high-grade AV block (e.g., 
bifascicular block, Mobitz type II and third degree AV block) 
• History of familial long QT syndrome or known family history of Torsades de Pointe 
• Cardiac or cardiac repolarization abnormality, including any of the following: History 
of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to 
starting study treatment 
11a. 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 
• HIV-infected participants who are at a low risk of AIDS-related outcomes may 
participate in this trial. 
• Participants with an active documented COVID-19 infection (any grade of disease 
severity) at time of informed consent may be included only when completely 
recovered (in accordance with local guidance).  
12a. Diagnosed with other malignancies that are expected to alter life expectancy or may 
interfere with disease assessment. Participants with a prior history of malignancy that 
has been adequately treated and who have been disease free and treatment free for more 
than 3 years prior to randomization are eligible, as are participants with adequately 
treated non-melanoma skin cancer and superficial bladder cancer 
13a. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 14 weeks after stopping study treatment. A condom is required for all 
sexually active male participants to prevent them from fathering a child AND to prevent 
delivery of study treatment via seminal fluid to their partner. In addition, male 
participants must not donate sperm for the time period specified above. If local 
regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF 
14a. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: 
Participants with bladder outflow obstruction or urinary incontinence, which is 
manageable and controlled with best available standard of care (incl. pads, drainage) are 
allowed. 

Novartis 
Confidential 
Page 70 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
15. History of somatic or psychiatric disease/condition that may interfere with the objectives 
and assessments of the study 
16. Any condition that precludes raised arms position 
17a. Eligible for treatments other than ARDT based on presence of any mutations or  
biomarkers that are known as predictors of better response (e.g., AR-V7 or BRCA)  
18. Not able to understand and to comply with study instructions and requirements 
6 
Treatment 
6.1 
Study treatment 
In this study, the term “study treatment” indicates the randomized assignment of either 177Lu-
PSMA-617 or a change in the approved ARDT treatment. The investigational product 
radioligand imaging compound 68Ga-PSMA-11 is used as imaging agent during screening. 
Participants will be administered 177Lu-PSMA-617 intravenously as per best practice and 
Investigator's decision. (Refer to Section 6.7 for study drug preparation and dispensation). 
Study participants will be randomized at a 1:1 ratio to receive either 177Lu-PSMA-617 or a 
change in the approved ARDT treatment (abiraterone or enzalutamide). Supportive care will be 
allowed in both arms and includes available care for the eligible participant according to best 
institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT) and 
at the discretion of the investigator. Changes to Concomitant Medications will be captured in 
the CRF. Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, 
other systemic radioisotopes (e.g. radium-223), Poly (adenosine diphosphate-ribose) 
polymerase (PARP) inhibitors or hemi-body radiotherapy treatment must not be administered 
while on study treatment. 
The general doses of the study treatment are listed in Table 6-1. ARDT treatment are approved 
drugs and will be provided locally by the study site, subsidiary or designee as commercially 
available, or locally by Novartis, according to local clinical practices and local regulations. 
Please refer to the Package Insert for complete guidelines for administration and for safety 
monitoring guidelines. 
6.1.1 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.2 
Investigational and control drugs 

Novartis 
Confidential 
Page 71 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global 
or local) 
177Lu-PSMA-617 
(1 GBq/mL at End of 
Production) 
Radiopharmaceutical 
solution for 
infusion/injection 
Intravenous use 
Open label, vial 
Sponsor (global) 
68Ga-PSMA-11 
(25 µg) 
Either provided as Kit 
for the 
radiopharmaceutical 
preparation of 68Ga-
PSMA-11 or as ready 
to use 
radiopharmaceutical 
solution for injection  
Intravenous use 
Open label, vial or 
syringe  
Sponsor (global) 
ARDT 
See package insert 
Oral Use 
Locally by the study site, subsidiary or 
designee as commercially available, or 
locally by Novartis, according to local 
clinical practices and local regulations 
68Ga-PSMA-11 Imaging 
During screening, all participants will undergo imaging with the investigational product 68Ga-
PSMA-11 for the purpose of eligibility determination. Participants must have disease that 
expresses PSMA as seen on a 68Ga-PSMA-11 PET/CT scan by central review. 
For subjects with soft tissue disease (with or without bone disease), the following five (5) 
requirements must be met in order for a subject to be deemed eligible:  
• There must be at least one (1) 68Ga-PSMA-11 PET positive lesion (osseous or 
extraosseous), irrespective of size.  
• All lymph nodes that measure ≥ 25 mm in short axis must be 68Ga-PSMA-11 PET 
positive. 
• All bone metastases with a soft tissue component ≥ 10 mm in the longest diameter must be 
68Ga-PSMA-11 PET positive (PSMA-negative bone metastases without a soft tissue 
component, do not exclude patients).  
• All solid organ metastases (e.g. lung, liver, adrenal glands, etc.) ≥ 10 mm in the longest 
diameter must be 68Ga-PSMA-11 PET positive.  
• All intraprostatic lesions, regardless of size, must be 68Ga-PSMA-11 PET positive.  
For subjects with bone only disease, at least one (1) site of bone involvement must be 68Ga-
PSMA-11 PET positive. 
If the potential participant received 68Ga-PSMA-11 as part of a routine local exam prior to 
signing informed consent for this study, he must wait at least 3 days prior to repeating 68Ga-
PSMA-11 PET imaging as screening for this study. 
For background and additional details on 68Ga-PSMA-11, refer to Section 6.7 for study drug 
preparation and dispensation and to the 68Ga-PSMA-11 Investigator’s Brochure. The 68Ga-
PSMA-11 will be administered as a single intravenous (i.v.) dose of approximately 150 MBq. 

Novartis 
Confidential 
Page 72 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Administered dose must not be lower than 111 MBq or higher than 185 MBq (Refer to 
Pharmacy Manual for details on dose preparation and administration). 
Imaging assessment must be performed only with use of Sponsor supplied kits for the 
radiopharmaceutical preparation of 68Ga-PSMA-11 or with ready to use 68Ga-PSMA-11 
radiopharmaceutical solution for injection supplied by the Sponsor’s central radiopharmacy. 
Other Ga-containing PSMA-targeting radiopharmaceuticals must not be used for imaging at 
screening to evaluate PSMA-positivity. When such imaging assessments are performed locally 
at investigator’s discretion during the study, they will be considered an exposure to 
investigational medicinal product (with exception when use is approved and administered 
according to the local label), their results must not be used to make decisions related to response 
assessment and/or study treatment. 
Treatment with 177Lu-PSMA-617 
Study participants randomized to the investigational drug will receive a dose of 7.4 GBq 
(200 mCi) +/- 10% of 177Lu-PSMA-617 which will be administered once every 6 weeks (1 cycle) 
for 6 cycles. (Refer to Section 6.7 for study drug preparation and dispensation). 
ARDT 
The change of ARDT treatment will include approved AR-axis targeted therapy abiraterone or 
enzalutamide for participants randomized on ARDT arm. ARDT treatment should be dosed as 
per approved local labels and guidelines including contraceptive requirements. 
6.1.3 
Supply of study treatment 
177Lu-PSMA-617 will be provided as a single dose ready to use radiopharmaceutical solution, 
with a volumetric activity of 1 GBq/mL at the reference date and time (calibration time (tc), 
that corresponds to the End of Production (EOP)). The volume of the solution dispensed varies 
between 7.6 mL and 12.3 mL in order to provide the required amount of radioactivity at the 
date and time of administration. The shelf life of the product is defined as 120 hours (5 days) 
after calibration time. 
The Investigational Product 68Ga-PSMA-11 will be provided: 
• as a kit for radiopharmaceutical preparation: single vial with a white lyophilized powder to 
be locally reconstituted with a solution of gallium-68 chloride (68GaCl3) in HCl eluted 
from an approved 68Ge/68Ga generator (for the clinical sites equipped with an approved 
68Ge/68Ga generator). 
• as a single dose ready to use radiopharmaceutical solution: vial or syringe with the 
radiopharmaceutical solution supplied by the central radiopharmacy (for the clinical sites 
not equipped with an approved 68Ge/68Ga generator). 
The volume of 68Ga-PSMA-11 solution for injection, corresponding to the radioactive dose to 
be administered, is calculated according to the estimated time of injection, on the basis of the 
current activity provided by the generator and of physical decay of the radionuclide (half-life = 
68 min). After reconstitution, the 68Ga-PSMA-11 solution must be used within 6 hours. 

Novartis 
Confidential 
Page 73 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
The process of ordering and delivery, as well as the procedure for 68Ga-PSMA-11 solution 
preparation is described in the Pharmacy Manual. 
Both products must be handled and administered by qualified/authorized personnel only and 
must be prepared in accordance with pharmaceutical quality requirements and radiation safety 
regulations. 
ARDT should be administered orally on a continuous basis, as per package insert and guidelines 
to the participants randomised to the ARDT arm. 
6.1.4 
Treatment arms/group 
During screening, potential participants will be assessed for eligibility and will undergo a 68Ga-
PSMA-11 PET / CT scan to evaluate PSMA positivity by central review. Only participants with 
PSMA- positive cancer and confirmed eligibility will be randomized. Randomization will be 
stratified by prior ARDT use and by symptomatology. Prior ARDT use will be determined by 
the setting (CRPC vs HSPC) when the patient initiated treatment with enzalutamide, abiraterone, 
apalutamide, or darolutamide then suffered disease progression. Symptomatology 
(asymptomatic or mildly symptomatic vs symptomatic) will be determined by score on item 3 
of the Brief Pain Inventory Short Form (BPI-SF) questionnaire (symptomatic = score >3 on 
item 3 of the BPI-SF questionnaire). 
Once eligibility criteria are confirmed, participants will be randomized to one of the following 
2 treatment arms in a ratio of 1:1 
• Study treatment: 177Lu-PSMA-617 
• Comparator Approved change in ARDT (abiraterone or enzalutamide) 
The change of ARDT treatment for each participant will be selected by the treating physician 
prior to randomization. If the participant gets randomized to receive 177Lu-PSMA-617, the 
choice of change of ARDT treatment will be discarded. 
Supportive care will be allowed in both arms and includes available care for the eligible 
participants according to best institutional practice and at the discretion of the investigator. 
6.1.5 
Guidelines for continuation of treatment 
Refer to Section 3 for study treatment and Section 6.5 for dose modifications. 
6.1.6 
Treatment duration 
Participants randomized to the investigational arm must begin 177Lu-PSMA-617 dosing within 
14 days after randomization. Up to an additional 3 days are allowed to accommodate other 
scheduling delays for C1D1. Participants will receive best supportive care and a dose of 7.4 
GBq (± 10%) of 177Lu-PSMA-617 once every 6 weeks for 6 cycles as per Table 8-2. After the 
last day of study treatment period of 177Lu-PSMA-617 or upon radiographic progression, the 
participants must have an End of Treatment (EOT) visit performed ≤ 7 days and enter the Post-
treatment Follow-up period. For participants on the 177Lu-PSMA-617 arm who complete the 
planned 6 cycle course therapy, the treatment period ends after the week 37 imaging and C6W5 
visit is completed. 

Novartis 
Confidential 
Page 74 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
For both arms, upon EOT visit, participants might be treated with any other medications per 
discretion of the treating physician. 
Please refer to Section 9.2, Table 8-2 and Table 8-3 for further details. 
The change of ARDT treatment for each participant will be selected by the treating physician 
prior to randomization and will be administered per the physician’s orders and continued until 
the participant comes off the treatment period of the study. 
Participants may be discontinued from treatment earlier due to unacceptable toxicity (refer to 
Table 6-2), or disease progression and/or at the discretion of the investigator or the participant. 
While the participant and/or at the physician's discretion may decide prematurely to cease taking 
randomized therapy at any time, full follow-up of all randomized participants for the intended 
duration of the trial is planned by design for the collection of rPFS and OS data. 
6.1.6.1 
Treatment beyond disease progression 
Upon occurrence of radiographic progression as assessed by blinded centralized review, 
participants randomized to 177Lu-PSMA-617 should stop study treatment and receive any other 
therapy per the discretion of the treating physician and local regulations in the long-term follow-
up period. However, if the investigator determines that the participant is still benefiting from 
continuation of study treatment, the participant may continue 177Lu-PSMA-617 treatment for 
up to 6 cycles. 
Upon the occurrence of radiographic progression, as assessed by BICR, participants 
randomized to the ARDT treatment arm will be allowed to cross over to receive 177Lu-PSMA-
617 treatment or may continue to receive any other therapy per the discretion of the treating 
physician in the Post-treatment Follow-up. If crossover to 177Lu-PSMA-617 is selected, then 
177Lu-PSMA-617 will be administered with the same dose/schedule as for participants who 
were initially randomized to receive 177Lu-PSMA-617 as described above in Section 6.1.6. 
Please refer to Section 9.1.1 for reasons for treatment discontinuation. 
6.2 
Other treatment(s) 
Supportive care will be allowed in both arms and includes available care for the eligible 
participants according to best institutional practice and at the discretion of the investigator. 
6.2.1 
Concomitant therapy 
Supportive Care 
Participants should receive full supportive care while on study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. 
Within the first few days of treatment with 177Lu-PSMA-617, the most common adverse events 
(AEs) are general fatigue and an increase in bone pain. The treatment-related bone pain is 
transient in nature, often occurring within the first 24-48 hours post the initial 1-2 cycles of 
administration of 177Lu-PSMA-617 and may be managed by administering narcotic analgesics. 

Novartis 
Confidential 
Page 75 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Antiemetics may be used at the discretion of the attending physician. Diarrhea management is 
per the discretion of the treating physician. Diarrhea could be managed conservatively with 
medications such as loperamide. Participants with severe diarrhea should be assessed for 
intravenous hydration and correction of electrolyte imbalances. 
ADT treatment may be modified for reasons of intolerance at the discretion of the investigator 
throughout the study. It is discouraged to change ADT treatment in both arms based solely on 
PSA changes. 
Bone Health Agents 
Consideration should be given to using concomitant bone health agents such as bisphosphonates 
and RANKL inhibitors on either arm of the study. Participants receiving bisphosphonates (for 
example zoledronic acid), RANKL inhibitors (for example denosumab), or similar therapy prior 
to randomization may be maintained on this therapy during the study. These may be stopped or 
started at the discretion of the investigator throughout the study. 
Participants must maintain castrate levels of serum/plasma testosterone either by chemical 
castration or by having had an orchiectomy. 
Medications for myelosuppression 
Blood and/or blood component transfusion or erythropoiesis stimulation agents are allowed 
throughout the study after randomization. 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the American Society of Clinical Oncology Clinical Practice Guideline Update 
(Smith et al 2015) and American Society of Clinical Oncology – American Society of 
Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult 
Patients with Cancer (Rizzo et al 2010), and/or other international/national guidelines at the 
discretion of the investigator/attending physician. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
Anticoagulants and platelet aggregation inhibitors are allowed, and for participants who 
experience thrombocytopenia is to be used with caution. 
Palliative radiotherapy 
Palliative radiation therapy may be administered to symptomatic bone disease and it is not 
considered as prohibited medication. The need for palliative radiation may not be counted as an 
rPFS (i.e., radiographic progression) event, however, it will be listed as clinical progression and 
meet criteria for a Symptomatic Skeletal Event. 
After the 1st post-baseline scan, the need for palliative radiation may indicate radiographic 
disease progression and should be assessed per the PCWG3 modified RECIST v1.1 criteria, 
and may result in study treatment discontinuation. When the need for palliative radiation to 
lesions other than bone is seen after the baseline scan, palliative radiation to the target lesion 

Novartis 
Confidential 
Page 76 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
should be possibly avoided, the lesion should be assessed per RECIST 1.1 criteria, and initiation 
of palliative radiation may result in study treatment discontinuation when radiographic 
progression is confirmed. 
If palliative radiation treatment is planned to be initiated during the study in the absence of 
radiographic progression, the investigator should use best clinical judgement to assess the 
potential clinical benefit of palliative radiation weighed against the risk of overlapping side 
effects of radiation and study treatment when considering timing and doses of palliative 
radiotherapy. Any interruption of study treatment greater than 4 weeks from the next scheduled 
dose due to administration of radiation or recovery from effects of radiation will require 
permanent discontinuation of study treatment. All medications, procedures, and significant non-
drug therapies (including physical therapy and blood transfusions) administered after the 
participant enter the study must be recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
6.2.2 
Prohibited medication 
Other investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, 
immunotherapy, other systemic radio isotopes (e.g., radium-223), Poly (adenosine diphosphate-
ribose) polymerase (PARP) inhibitors or hemi-body radiotherapy treatment must not be 
administered on study. ARDT must not be administered concomitantly with 177Lu-PSMA-617. 
ARDT drugs have potential drug interactions with medications that include but not limited to 
CYP3A4 strong inducers or inhibitors. Concomitant use of restricted drugs should be avoided. 
The treating investigator must review the local full prescribing information regarding potential 
drug interactions and follow restrictions to drug use or dose modification recommendations per 
the labeling for each agent in cases where such medications are unavoidably co-administered 
with ARDT. 
Refer to the Exclusion criteria (Section 5.2) for the list with prohibited medications or treatment 
which makes a potential participant not eligible to enter the study. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening through the clinical data management 
interface and is retained for the participant throughout his participation in the trial. A new 
Participant No. will be assigned at every subsequent enrollment if the participant is re-screened. 
The Participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant’s 
participation is numbered uniquely across the entire database. Upon signing the informed 
consent form, the participant is assigned to the next sequential Participant No. available. 

Novartis 
Confidential 
Page 77 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
6.3.2 
Treatment assignment, randomization 
During screening period at day -14, all eligible participants will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms in a 1:1 ratio: 177Lu-PSMA-617 or a 
change in a Comparator Approved ARDT (abiraterone or enzalutamide). The investigator or 
his/her delegate will contact the IRT after confirming that the participant fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the participant, 
which will be used to link the participant to a treatment arm. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider, or by a delegate under 
Novartis supervision, using a validated system that automates the random assignment of 
participant numbers to randomization numbers. These randomization numbers are linked to the 
different treatment arms. 
The investigator or his/her delegate will order each 177Lu-PSMA-617 dose within 10 working 
days prior to the scheduled cycle. Each administration will be tracked by the investigator or 
his/her delegate via IRT. Detailed instructions of IMP ordering and IRT use will be provided in 
the Pharmacy Manual. 
The change of ARDT treatment for each participant will be selected by the treating physician 
prior to randomization. If the participant gets randomized to receive 177Lu-PSMA-617, the 
choice of change of ARDT treatment will be discarded. 
6.4 
Treatment blinding 
Treatment assignment will be open to participants, investigator staff, persons performing the 
assessments, and the Novartis study team. In order to minimize the potential impact on the 
integrity of the study, until the primary analysis is conducted, no aggregate statistical analyses 
(efficacy or safety across the study) shall be performed by treatment. BICR will remain blinded 
to the identity of the treatment. 
6.5 
Dose escalation and dose modification 
Supportive care should be provided as deemed necessary by the treating physician. 
Dose modifications are summarized in Table 6-2. 
Dose escalation and modification for ARDT should be managed as per the local label for the 
respective drug and/or local clinical practice guidelines. 
6.5.1 
Definitions of dose limiting toxicities (DLTs) 
Not applicable. 

Novartis 
Confidential 
Page 78 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
6.5.2 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment. 
These dose modifications are summarized in Table 6-2. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2. 
These dose changes must be recorded on the appropriate eCRF. 
For ARDT treatment and any supportive care medication, please refer to the medication label 
for drug interactions and toxicities. 
For 177Lu-PSMA-617, the most common adverse events (AEs) within the first few days of 
treatment 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 central labs for hematology, 
chemistry and coagulation results must all be assessed prior to dosing with 177Lu-PSMA-617. 
If central lab results are not available in time to review prior to dosing, local labs may be 
additionally sent to expedite clearing the patient for treatment. In case of adverse events 
determined not related to 177Lu-PSMA-617, a dose of 177Lu-PSMA-617 may be delayed or 
reduced according to dose management guidance at the discretion of the investigator. Table 6-2 
provides dose modification criteria and guidance on dose management which must be followed 
when a causal relationship between 177Lu-PSMA-617 and an adverse event is confirmed by the 
investigator. Only one reduction in administered activity is permitted. If a participant 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 the treatment is delayed due to an AE for more than 4 weeks, or any toxicity is determined to 
be unacceptable to the participant or the investigator, then 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 participant has not radiographically 
progressed as measured by PCWG3 criteria. 
Table 6-2 
Toxicity management and dose modifications for 177Lu-PSMA-617 
treatment for adverse drug reactions 
Laboratory finding / event 
Grade (lab values)a 
Dose management 
Anemia, leukopenia, or 
neutropenia 
Grade 1 
Recommendation: maintain dose and 
administration schedule. 
Grade 2 
Hemoglobin < 10.0 – 8.0 g/dL 
WBC count < 3.0 – 2.0 × 109/L 
ANC < 1.5 – 1.0 × 109/L 
Management recommendation: hold 
177Lu-PSMA-617 administration until 
improvement to Grade 1 or baseline. 
Recommendation: Manage clinically as 
appropriate. The use of growth factors is 
permitted but should be discontinued 

Novartis 
Confidential 
Page 79 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Laboratory finding / event 
Grade (lab values)a 
Dose management 
once the event resolves to Grade 1 or 
baseline. Check hematinic levels (iron, 
B12, and folate) and provide 
supplementation as required. 
Transfusions may be given as clinically 
indicated for anemia. 
≥ Grade 3 
Hemoglobin < 8.0 g/dL 
WBC count < 2.0 × 109/L 
ANC < 1.0 × 109/L 
Or other non-platelet 
hematological values ≥ Grade 3 
Mandatory: hold 177Lu-PSMA-617 
administration until improvement to 
Grade 1 or baseline. 
Reduce 177Lu-PSMA-617 dose by 20% 
on the next cycle (except 
lymphocytopenia that responds to 
medical intervention). 
Recommendation as for grade 2. 
Thrombocytopenia 
Grade 1 
Recommendation: maintain dose and 
administration schedule. 
≥ Grade 2 
(platelet count of < 75 × 109/L) 
Mandatory: hold 177Lu-PSMA-617 
administration until improvement to 
Grade 1 or baseline. 
Reduce 177Lu-PSMA-617 dose by 20% 
on the next cycle. 
Recommendation: platelet transfusions 
may be given as clinically indicated. 
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Recommendation: maintain dose and 
administration schedule. 
Grade 2 (> 1.5 - 3.0 x baseline, 
or > 1.5 - 3.0 x ULN) 
Mandatory: hold 177Lu-PSMA-617 until 
resolved to ≤ Grade 1 or baseline, then 
maintain dose level. 
Increased ≥ 40% from baseline 
AND calculated creatinine 
clearance decreased > 40% from 
baseline 
Mandatory: Reduce 177Lu-PSMA-617 
dose by 20% on the next cycle. 
Grade 3 (> 3.0 x baseline, > 3.0 
– 6.0 x ULN) 
Mandatory: discontinue 177Lu-PSMA-
617. If corrected to grade 1 by 
supportive care measures (i.e., fluid 
hydration) before the next administration 
and continue but reduce 177Lu-PSMA-
617 dose by 20% on the next cycle. 
Grade 4 (> 6.0 x ULN) 
Mandatory: discontinue 177Lu-PSMA-
617. 
Isolated total bilirubin elevation 
> ULN - 1.5 x ULN 
Recommendation: maintain dose and 
administration schedule. 
> 1.5 - 3.0 x ULN 
Recommendation: maintain dose and 
administration schedule. Repeat liver 
function tests (LFTs)b within 48-72 hours, 
then monitor LFTs weekly, or more 
frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN or to baseline. 
> 3.0 - 10.0 x ULN 
Mandatory: Hold treatment Repeat 
LFTsb within 48-72 hours, then monitor 
LFTs weekly, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 
x ULN or to baseline: treatment re-
initiation is possible if clinically indicated. 
Note: If total bilirubin > 3.0 x ULN is due 
to the indirect (non-conjugated) 

Novartis 
Confidential 
Page 80 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Laboratory finding / event 
Grade (lab values)a 
Dose management 
component only, and hemolysis as the 
etiology has been ruled out as per 
institutional guidelines (e.g. review of 
peripheral blood smear and haptoglobin 
determination), then earlier treatment re-
initiation is possible at the discretion of 
the investigator. 
> 10.0 x ULN 
Mandatory: Discontinue participant from 
treatment. 
The participant should be monitored 
weekly (including LFTsb), or as clinically 
indicated, until total bilirubin has 
resolved to baseline. 
Isolated AST or ALT elevation 
> ULN – 3 x ULN 
Recommendation: maintain dose and 
administration schedule. 
If normal at baseline: 
> 5.0 x ULN for more than 2 
weeks, OR >10xULN 
 
If elevated at baseline: 
> 3.0x baseline AND > 10x ULN  
Mandatory: Hold 177Lu-PSMA-617. 
Repeat LFTsb within 48-72 hours from 
awareness of the abnormal results; 
monitor LFTsb weekly, or more 
frequently if clinically indicated, until 
resolved to ≤ULN or to baseline. 
If resolved, reduce 177Lu-PSMA-617 
dose by 20% on the next cycle. 
> 20.0 x ULN 
Mandatory: Permanently discontinue 
177Lu-PSMA-617. 
Repeat LFTsb as soon as possible, 
preferably within 48-72 hours from 
awareness of the abnormal results; 
monitor LFTsb weekly, or more 
frequently if clinically indicated, until 
resolved to baseline or stabilization over 
4 weeks. 
Combinedc elevations of AST 
or ALT and total bilirubin 
For participants with normal 
baseline ALT and AST and total 
bilirubin value: 
AST or ALT > 3.0 x ULN 
combined with total bilirubin > 
2.0 x ULN without evidence of 
cholestasisd 
OR 
 
For participants with elevated 
baseline AST or ALT or total 
bilirubin value: 
AST or ALT > 3x baseline OR > 
8.0 x ULN, whichever is lower, 
combined with total bilirubin > 2x 
baseline AND > 2.0 xULN* 
*Note: For participants with 
Gilbert’s syndrome, at least 2-
fold increase in direct bilirubin.  
Mandatory: Hold 177Lu-PSMA-617 and 
assess for DILI: 
Repeat as soon as possible, preferably 
within 48 hours from awareness of the 
abnormal results, then with weekly 
monitoring of LFTsb, or as clinically 
indicated, until AST, ALT, or total 
bilirubin have resolved ≤ ULN or to 
baseline. (Refer to the Section 6.5.3.1 
for additional follow-up evaluations as 
applicable). 
If causality assessment indicates that 
DILI is probable: Permanently 
discontinue participant from treatment. 
If not DILI: Treat the identified cause 
according to institutional guidelines. 
Once resolved, reduce by one dose 
level. 
Amylase and/or lipase 
elevation 
≤ Grade 2 (> 1.5 - 2.0 x ULN) 
Recommendation: maintain dose and 
administration schedule. 
Grade 3 
(> 2.0 - 5.0 x ULN with signs or 
symptoms) 
Recommendation: Hold 177Lu-PSMA-617 
until resolved to Grade ≤,1 or baseline 
then: 

Novartis 
Confidential 
Page 81 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Laboratory finding / event 
Grade (lab values)a 
Dose management 
OR 
(> 5.0 x ULN and asymptomatic) 
If resolved in ≤ 7 days, then maintain 
dose level. 
If resolved in > 7 days, reduce 177Lu-
PSMA-617 dose by 20% on the next 
cycle. 
Perform imaging**. 
Grade 4 (> 5.0 x ULN and with 
signs or symptoms) 
Mandatory: Discontinue 177Lu-PSMA-
617. 
Perform imaging**. 
Pancreatitis 
Grade 2 
Mandatory: Hold 177Lu-PSMA-617 
administration until resolved to Grade 1 
or baseline. 
Grade ≥ 3 
Mandatory: Discontinue 177Lu-PSMA-
617. 
Gastrointestinal toxicity 
≤ Grade 2 
Recommendation: maintain dose and 
administration schedule. 
≥ Grade 3 
Mandatory: Hold 177Lu-PSMA-617 
administration until resolved to Grade 2 
or baseline. 
Salivary gland toxicity 
≥ Grade 2 
Mandatory: Reduce 177Lu-PSMA-617 
dose by 20% on the next cycle. 
Electrolyte or metabolic 
abnormalities that persist for 
greater than 48 hrs with 
sequela 
≥ Grade 2 
Mandatory: Hold 177Lu-PSMA-617 
administration until resolved to Grade 1 
or baseline. 
Fatigue/ Asthenia 
≤ Grade 2 
Recommendation: maintain dose and 
administration schedule. 
≥ Grade 3 
Mandatory: Hold 177Lu-PSMA-617 
administration until resolved to Grade 2 
or baseline. 
Pain 
≥ Grade 3 
Persistent G3 pain not amenable 
to medical therapy. 
Mandatory: Hold 177Lu-PSMA-617 
administration until resolved to Grade 2 
or baseline. 
Spinal cord compression 
Any grade 
Mandatory: 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 
Any grade 
Mandatory: 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. 
Non-hematological, clinically 
significant toxicity not 
otherwise stated 
≥ Grade 2 
Recommendation: Hold 177Lu-PSMA-617 
administration until resolved to Grade 1 
or baseline. 
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. 
All dose modifications should be based on the worst preceding toxicity. 

Novartis 
Confidential 
Page 82 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Laboratory finding / event 
Grade (lab values)a 
Dose management 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (ALP) (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x 
ULN) 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if meeting a criterion for dose reduction 
d “Cholestasis” defined as ALP elevation (>2.0 xULN and R value <2) in participants without bone metastasis or 
elevation of ALP liver fraction in participants with bone metastasis 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular 
(R ≥ 5), or mixed (R >2 and < 5) liver injury 
* Note: For participants with Gilbert's syndrome, at least 2-fold increase in direct bilirubin. 
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 
elevations of lipase and/or amylase occur again at the reduced dose, participants will be discontinued 
permanently from study treatment. 
Table 6-3 
Dose reduction steps for 177Lu-PSMA-617 
Dose reduction for 177Lu-PSMA-617 
  
Starting dose level – 0 
Dose level – 1 (-20%) 
Dose level – 2 
177Lu-PSMA-617  
7.4 GBq (200mCi) 
5.9 GBq (160mCi) 
Not applicable 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.  
**Refer to pharmacy manual for practical details in on dose reduction. 
6.5.3 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
All participants must be followed up for adverse events and serious adverse events for 30 days 
following end of treatment visit and long term follow up period as described in Table 8-2 and 
Table 8-3. Long term follow up starts after 30 Day Safety follow-up and lasts until death, loss 
to follow up, withdrawal of consent / opposition to use data/biological samples or accrual of the 
pre-specified number of events for the OS-based (key secondary endpoint) analysis, whichever 
occurs first. All medically significant adverse events (all SAEs) deemed to be related to 177Lu-
PSMA-617, including potential late onset radiation toxicity, will be collected during this period. 
6.5.3.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI, and should be considered as clinically important events 

Novartis 
Confidential 
Page 83 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever occurs first, combined 
with [total bilirubin > 2.0 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyl transferase (GGT), prothrombin time (PT)/International Normalized Ratio 
(INR), alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. 
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
Cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury (//livertox.nih.gov/rucam.html). 
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 

Novartis 
Confidential 
Page 84 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
Table 6-4 
Guidance on specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
• immunoglobulin M (IgM), Serum antibody to hepatitis A 
virus (anti-HAV); Hepatitis B surface antigen (HBsAg), 
immunoglobulin M & Immunoglobulin G antibody to 
hepatitis B core antigen (IgM & IgG anti-HBc), Hepatitis B 
Virus (HBV) DNA; anti Hepatitis C Virus (anti-HCV), 
Hepatitis C Virus (HCV) RNA, IgM & IgG anti Hepatitis E 
Virus (anti-HEV), Hepatitis E Virus (HEV) RNA 
cytomegalovirus (CMV), HSV (Herpes simplex 
virus), Epstein-Barr virus (EBV) infection 
• IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-
EBV 
Autoimmune hepatitis 
• antinuclear antibodies (ANA) and antismooth muscle 
antibody (ASMA) titers, total IgM, Immunoglobulin G 
(IgG), Immunoglobulin E (IgE), Immunoglobulin A (IgA) 
Alcoholic hepatitis 
• Ethanol history, GGT, Mean corpuscular volume (MCV), 
Carbohydrate-Deficient-Transferrin (CD-transferrin) 
Nonalcoholic steatohepatitis 
• Ultrasound or Magnetic resonance imaging (MRI) 
Hypoxic/ischemic hepatopathy 
• Medical history: acute or chronic congestive heart failure, 
hypotension, hypoxia, hepatic venous occlusion. 
Ultrasound or MRI. 
Biliary tract disease 
• Ultrasound or MRI, Endoscopic retrograde 
cholangiopancreatography (ERCP) as appropriate. 
Wilson disease (if <40 yrs old) 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – Triiodothyronine (T3), Thyroxin (T4), thyroid 
stimulating hormone (TSH); cardiovascular disease (CVD) / ischemic hepatitis – ECG, prior 
hypotensive episodes; Type 1 Diabetes (T1D) / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a Drug-induced liver 
injury (DILI) case and should be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
For the participants on ARDT arm the investigator must promote compliance by instructing the 
participant to take the study treatment exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study. The participant must also be 
instructed to contact the investigator if he is unable for any reason to take the study treatment 

Novartis 
Confidential 
Page 85 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
as prescribed. Compliance will be assessed by the investigator and/or study personnel at each 
visit using pill counts (if applicable) and information provided by the participant. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log and in the 
corresponding eCRF pages. 
Participants on 177Lu-PSMA-617 arm will have the treatment administered during site visits as 
per schedule of events, Table 8-2 and Table 8-3. All study treatment must be recorded in the 
Drug Accountability Log and in the corresponding eCRF pages. 
6.6.2 
Treatment of overdose 
In the event of administration of a radiation overdose with 177Lu-PSMA-617, the radiation 
absorbed dose to the patient should be reduced where possible by increasing the elimination of 
the radionuclide from the body by frequent micturition or by forced diuresis and frequent 
bladder voiding. 
Follow standard clinical practice for overdose of systemically administered radionuclidetherapy 
with radioligands. For overdose of ARDT, follow the guidance per product label.  
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.2). 
For 177Lu-PSMA-617 and 68Ga-PSMA-11 preparation and administration, please refer to 
procedure and instructions contained in the Pharmacy Manual. 
For ARDT, please refer to package insert. 
 As per the treatment assigned to the participant by the IRT, investigator staff will identify the 
study treatment to dispense to the participant.For 177Lu-PSMA-617 and 68Ga-PSMA-11, 
immediately after administration to the participant, site personnel will complete the 
accountability logs for traceability purposes. For more detailed instructions please refer to the 
Pharmacy Manual. 
6.7.1 
Handling of study treatment and other treatment 
6.7.1.1 
Handling of study treatment 
Investigational study treatment 177Lu-PSMA-617 must be received by a designated person at 
the study site, handled and stored safely and properly and kept in a secured location to which 
only the investigator and designated site personnel have access. Upon receipt, all study 
treatment must be stored according to the instructions specified on the label and the 
Investigator's Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol.Technical complaints 
are to be reported to the respective Novartis contact/associate or 3rd party representative. 

Novartis 
Confidential 
Page 86 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
177Lu-PSMA-617 
The packaging 177Lu-PSMA-617 consists in a white glass vial (Type I of the Eu. Ph.) containing 
a maximum of 12.3 mL of radioactive solution. The vial is inserted into a lead shielded container 
(secondary packaging) closed in a Type A box (according to ADR and IATA regulations). 
177Lu-PSMA-617 solution should be handled by the user in a manner which satisfies both 
radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions 
should be taken, complying with the requirements of Good Manufacturing Practice for 
pharmaceuticals. 
Since 177Lu-PSMA-617 is a ready-to-use solution, no manipulation of the investigational 
product is intended at the clinical site. The only quality control (QC) tests that must be 
performed at the clinical site are; 1) confirm correct product certificate of release; 2) measure 
radioactivity in the vial before and after administration using a calibrated radioactivity 
measurement system; 3) control the appearance of the solution (clear, colorless to slightly 
yellow solution, free from visible particles). 
Once received, 177Lu-PSMA-617 has to be stored upright according to storage conditions as 
described on the medication label, in the original package to protect from ionizing radiation 
(lead shielding).  
Storage of radiopharmaceuticals should be in accordance with national regulation on 
radioactive materials. In these conditions the product has a shelf life of 120 hours after the end 
of production. 
The radioactive 177Lu-PSMA-617 will be locally discarded according to all disposal 
requirements and local regulations for radioactive materials. The disposal of all study 
medication will be documented appropriately: copy of the completed drug accountability log to 
the Novartis monitor or to the Novartis address provided in the investigator folder at each site. 
177Lu-PSMA-617 labels will be in the local language and comply with the legal requirements 
of each country. They will include storage conditions, expiry date and participant ID. 
68Ga-PSMA-11 
The packaging of 68Ga-PSMA-11 consists in a box (secondary packaging) and one 10 mL glass 
vials (primary packaging). 
68Ga-PSMA-11 will be supplied by Sponsor as a sterile, one-vial kit for reconstitution with 68Ga 
solution eluted from approved commercial GMP 68Ge/68Ga generator to: 
1. the clinical site, in case of the kit’s reconstitution and radiolabelling will be performed at 
hospital’s radiopharmacy 
2. the radiopharmacy appointed by the sponsor, in case of an external radiopharmacy will be 
in charge of the kit’s reconstitution and radiolabeling 
In the second case, the clinical site will order the 68Ga-PSMA-11 single dose ready to use 
solution for injection following the instructions described in the Pharmacy manual. 
68Ga-PSMA-11 must be prepared and administered as a single intravenous injection at the 
investigational site by appropriately trained personnel. The instruction for radiolabeling 

Novartis 
Confidential 
Page 87 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
procedure and dispensing 68Ga-PSMA-11, cautionary notes, analytical controls and stability of 
the radiolabeled product will be provided to each site (please refer to the Pharmacy Manual). 
After reconstitution with 68Ga solution eluted from GMP 68Ge/68Ga generator, the 
investigational product is a radioactive substance which must be used within 6 hours; it must 
be handled and administered by qualified/authorized personnel only and must be prepared in 
accordance with pharmaceutical quality requirements and radiation safety regulations. 
The kit for the preparation of 68Ga-PSMA-11 should be stored upon receipt according to storage 
conditions as described in the medication label. 
Kit labels will be in the local language and comply with the legal requirements of each country. 
They will include storage conditions, expiry date. 
68Ga-PSMA-11 labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions, expiry date and participant ID. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.  
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
6.7.1.2 
ARDT 
ARDT should be handled as per package insert and guidelines. 
6.7.2 
Instruction for prescribing and taking study treatment 
177Lu-PSMA-617 
• Preparation 
177Lu-PSMA-617 is a ready-to-use single-dose vial. The solution should be inspected visually 
prior to use, and only clear colorless to yellowish solutions free of visible particles should be 
used. The visual inspection of the solution should be performed under a shielded screen for 
radioprotection purposes. 177Lu-PSMA-617 is not to be used before receipt of the batch release 
certificate. The amount of radioactivity in the radiopharmaceutical vial must be measured with 
an appropriate and calibrated device prior to administration in order to confirm that the actual 
amount of radioactivity to be administered is equal to the planned amount at the time of 
administration. 

Novartis 
Confidential 
Page 88 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
• Administration 
Treatment with 177Lu-PSMA-617 must be performed in accordance with national and/or local 
radiation and safety requirements. When a participant with manageable bladder outflow/urinary 
incontinence is randomized to receive treatment with 177Lu-PSMA-617, the investigator should 
consult local nuclear medicine expert and ensure, that local radiation safety standards can be 
followed, and there is no additional potential impact of radiation safety (for trial participant, 
site staff, environment) 
177Lu-PSMA-617 will be administered at a starting dose of 7.4 GBq (±10%) once every 6-weeks 
(± 1 week). A 7.4 GBq dose is equivalent to 200 mCi or 7400 MBq. 
A saline flush with ≥10 mL of normal saline must be administered to ensure patency of the 
intravenous line before 177Lu-PSMA-617 administration. 
177Lu-PSMA-617 will be administered intravenously as per best practice and Investigator's 
decision. 
The total activity administered must be recorded (GBq, mCi or MBq) by measuring the residual 
radioactivity in the vial or in the syringe before and after administration. To guarantee a reliable 
measure, the dose calibrator (or activimeter) must be previously calibrated with a source 
equivalent to the dose that will be provided for the participants. Such calibration should be 
performed at least yearly and before the administration of the first participant first cycle, using 
a dose supplied for the participant (before the administration). 
A saline flush of ≥10 mL NS (normal saline) should be administered after administration of 
177Lu-PSMA-617 to assure that there isn’t any residual drug in the intravenous line. 
Vital signs will be collected approximately 15 minutes before and approximately at 30 and 
60 minutes following administration. 
Participants should also be monitored for any evidence of pain or burning sensation during 
177Lu-PSMA-617 administration. Participants should be encouraged to maintain a good fluid 
intake on the day of treatment and following therapy. 
To minimize irradiation of the urinary bladder, participants will be encouraged to increase fluid 
intake and to void frequently through the first days after administration. Participants should be 
advised to observe rigorous hygiene to avoid contamination risk of others using the same toilet 
facility. Management of bladder outflow/urinary incontinence is at the discretion of the 
investigators. Management may include best available standard of care options which are 
considered appropriate by the investigator. Use of pads, catheters, other drainage is allowed to 
control these conditions. As a precaution, participants may be kept in radiation isolation 
following administration as per local recommendations, and should be allowed to urinate during 
this time, and before release. General rules for bathroom use and hygiene (i.e. flush tissue paper 
and anything from your body) in the Therapy Discharge Instructions should be followed for at 
least 2 days after treatment. 
 
Date and time of participant discharge following 177Lu-PSMA-617 administration should be 
recorded. 

Novartis 
Confidential 
Page 89 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
It is not known if 177Lu-PSMA-617 is a vesicant. Extravasation of 177Lu-PSMA-617 may lead 
to localized tissue retention of the radiopharmaceutical agent and prolonged local exposure to 
ionizing radiation resulting in tissue damage and necrosis. In order to minimize the risk of 
extravasation or site irritation when administering 177Lu-PSMA-617, the solution should only 
be infused through a confirmed free-flowing (i.e., patent) intravenous line. If extravasation of 
177Lu-PSMA-617 solution occurs, management should follow institutional guidelines, and may 
include, but not be limited to, dispersive intervention on the affected arm such as warming the 
extravasation area to increase blood flow and lymphatic drainage. 
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. 
68Ga-PSMA-11 
• Preparation 
In case of the kit’s reconstitution and radiolabelling will be performed at hospital’s 
radiopharmacy. 
The instruction for radiolabeling procedure, cautionary notes, analytical controls and stability 
of the radiolabeled product will be provided to each site (please refer to the Pharmacy Manual). 
In case of an external radiopharmacy will be in charge of the kit’s reconstitution and 
radiolabeling, the clinical site will receive the 68Ga-PSMA-11 single dose ready to use solution 
for injection. 
• Administration 
68Ga-PSMA-11 must be administered as a single intravenous injection at the investigational site 
by appropriately trained personnel. The instruction for radiolabeling procedure and dispensing 
68Ga-PSMA-11, cautionary notes, analytical controls and stability of the radiolabeled product 
will be provided to each site (please refer to the Pharmacy Manual). 
After reconstitution with 68Ga solution eluted from GMP 68Ge/68Ga generator, the 
investigational product is a radioactive substance which must be used within 6 hours: it must 
be handled and administered by qualified/authorized personnel only and must be prepared in 
accordance with pharmaceutical quality requirements and radiation safety regulations. The total 
activity administered must be recorded (GBq, mCi or MBq) by measuring the residual 
radioactivity in the vial or in the syringe before and after administration with the dose calibrator 
(or activimeter). 
ARDT 
ARDT should be administered orally on a continuous basis, as per package insert and guidelines 
including contraceptive measures. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
delivery of IMP directly to a participant’s home is generally permitted in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 

Novartis 
Confidential 
Page 92 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
PRO measure(s) must be completed before any clinical assessments are performed at any given 
visit. 
As per Section 4.6, during a Public Health emergency as declared by local or regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented as the situation dictates. 
If allowable by a local Health Authority and depending on operational capabilities, phone calls, 
virtual contacts (e.g. tele consult) or visits by site staff/ home nursing staff to the participant´s 
home, or sending the participant to another imaging center (when feasible) can replace on-site 
study visits, for the duration of the disruption until it is safe for the participant to visit the site 
again. 
For participants randomized to the 177Lu-PSMA-617 treatment where COVID-19 pandemic 
limits or prevents on-site study visits, any alternative methods as described above may be used 
with approval from Novartis to carry out the study assessments as outlined in Table 8-2. If the 
treatment with 177Lu-PSMA-617 is interrupted for more than 4 weeks due to COVID-19 
pandemic, treatment must be discontinued and the participant must have an EOT (or EOT2 if 
is a crossover participant) visit performed in ≤ 7 days and enter the Post-treatment Follow-up. 
For participants randomized to the ARDT treatment where COVID-19 pandemic limits or 
prevents on-site study visits, delivery of IMP (as described in Section 6.7.2) and any alternative 
methods as described above may be used with approval from Novartis to continue with the 
study assessments as per Table 8-2 and Table 8-3. If the treatment with ARDT is interrupted 
for more than 4 weeks due to COVID-19 pandemic, the participant must have an EOT visit 
performed in ≤ 7 days and enter the Post-treatment Follow-up. The participant can continue 
with the ARDT treatment till the EOT visit. 
Table 8-1 
Window periods for Visit Schedule 
Screening 
After ICF signature and within 28 days of randomization in IRT 
system  
Cycle 1 Day 1 
Within 14 days after randomization in IRT system - (Maximum 
time needed to provide 177Lu-PSMA-617 to the site) up to an 
additional 3 days to allow for unexpected schedule delays 
Cycle 1 (all visits excluding C1D1 visit) 
±3 days 
Cycle 2-6 (all visits) of all subsequent cycles 
±7 days 
Imaging evaluations 
±7 days 
EOT 
≤ 7 days 
30-Day Safety FUP 
+7 days 
Long-term follow-up 
± 28 days 

Novartis 
Confidential 
Page 93 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 8-2 
Assessment Schedule, 177Lu-PSMA-617 and ARDT treatment arms 
Period 
Screening 
Treatment Period - Cycle 1 
Treatment Period - Cycles 
2-6 
(6 week cycles, no 
assessments 
on weeks 2, 4, 6)1 
Treatment period – 
Cycle 7 onward 
for ARDT arm (12 week 
cycles)6 
EOT 
Post-Treatment 
FU 
Visit Name 
Screeni
ng 
Randomizati
on 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
C7W1, C8W1, etc. 
EOT1/E
OT 2 
30 
day 
Safet
y FU 
Long 
term FU 
(every 12 
Weeks) 
Days 
-42 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
36 
1 
15 
29 
1 
 
≤ 7 days + 7 
days 
+/- 28 
days 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order of 
[68Ga]Ga-
PSMA-1118 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform 
[68Ga]Ga-
PSMA-11 
PET/CT scan18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant 
medical 
history/current 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomit
ant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

Novartis 
Confidential 
Page 94 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Period 
Screening 
Treatment Period - Cycle 1 
Treatment Period - Cycles 
2-6 
(6 week cycles, no 
assessments 
on weeks 2, 4, 6)1 
Treatment period – 
Cycle 7 onward 
for ARDT arm (12 week 
cycles)6 
EOT 
Post-Treatment 
FU 
Visit Name 
Screeni
ng 
Randomizati
on 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
C7W1, C8W1, etc. 
EOT1/E
OT 2 
30 
day 
Safet
y FU 
Long 
term FU 
(every 12 
Weeks) 
Days 
-42 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
36 
1 
15 
29 
1 
 
≤ 7 days + 7 
days 
+/- 28 
days 
End of period 
Disposition 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X (at end 
of FU) 
Physical Exam 
S (full)3 
 
S 
(short
)3 
 
 
 
 
 
S (short)3 
 
 
 
S 
(short)3 
S 
(short
)3 
S (short)3 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECOG 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vital Signs4 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
ECG 
X 
As clinically indicated 
X 
 
 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X23 
X23 
SAEs related 
to study 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X23 
Hematology 
X 
 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X5 
X 
X 
X 
Clinical 
Chemistry 
X 
 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X5 
X 
X 
X 
Coagulation 
Panel 
X 
 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X5 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 

Novartis 
Confidential 
Page 96 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Period 
Screening 
Treatment Period - Cycle 1 
Treatment Period - Cycles 
2-6 
(6 week cycles, no 
assessments 
on weeks 2, 4, 6)1 
Treatment period – 
Cycle 7 onward 
for ARDT arm (12 week 
cycles)6 
EOT 
Post-Treatment 
FU 
Visit Name 
Screeni
ng 
Randomizati
on 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
C7W1, C8W1, etc. 
EOT1/E
OT 2 
30 
day 
Safet
y FU 
Long 
term FU 
(every 12 
Weeks) 
Days 
-42 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
36 
1 
15 
29 
1 
 
≤ 7 days + 7 
days 
+/- 28 
days 
and bone 
scan)10 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X15 
FACT-P 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X15 
BPI-SF 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X15 
Trial Feedback 
Questionnaire 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
IRT participant 
registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT arm 
randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT drug 
administration 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
IRT arm 
crossover 
 
 
 
 
 
 
 
 
 
 
 
 
X22 
X22 
X22 
Order 177Lu-
PSMA-617 
 
X16 
 
 
 
 
X16 
 
 
 
X16 
 
X17 
 
 
Administer 
177Lu-PSMA-
617 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 

Novartis 
Confidential 
Page 97 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Period 
Screening 
Treatment Period - Cycle 1 
Treatment Period - Cycles 
2-6 
(6 week cycles, no 
assessments 
on weeks 2, 4, 6)1 
Treatment period – 
Cycle 7 onward 
for ARDT arm (12 week 
cycles)6 
EOT 
Post-Treatment 
FU 
Visit Name 
Screeni
ng 
Randomizati
on 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
C7W1, C8W1, etc. 
EOT1/E
OT 2 
30 
day 
Safet
y FU 
Long 
term FU 
(every 12 
Weeks) 
Days 
-42 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
36 
1 
15 
29 
1 
 
≤ 7 days + 7 
days 
+/- 28 
days 
Administer 
ARDT 
 
 
AS per label. For ARDT treatment arm only 
 
 
 
Best 
supportive care 
 
 
X 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X19 
New 
antineoplastic 
therapies since 
study drug 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Symptomatic 
skeletal events 
X 
X 
Clinical 
Progression 
 
 
X20 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 6 cycles of 177Lu-PSMA-617 therapy 
2 EOT visit must be performed ≤ 7 days after the last day of study treatment period 
3 S = assessment to be recorded in the source documentation only 
4 Blood pressure, pulse and respiratory rate to be assessed approximately 15 mins before study treatment and also approximately 30 mins and 60 mins post 177Lu-
PSMA-617 administration. Temperature only needs to be recorded once approximately 15 minutes prior to study treatment. 
5Central labs for hematology, chemistry and coagulation results must all be assessed prior to dosing. If central lab results are not available in time to review prior to 
dosing, local labs may be additionally sent to expedite clearing the patient for treatment. 

Novartis 
Confidential 
Page 99 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Period 
Screening 
Treatment Period - Cycle 1 
Treatment Period - Cycles 
2-6 
(6 week cycles, no 
assessments 
on weeks 2, 4, 6)1 
Treatment period – 
Cycle 7 onward 
for ARDT arm (12 week 
cycles)6 
EOT 
Post-Treatment 
FU 
Visit Name 
Screeni
ng 
Randomizati
on 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
C7W1, C8W1, etc. 
EOT1/E
OT 2 
30 
day 
Safet
y FU 
Long 
term FU 
(every 12 
Weeks) 
Days 
-42 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
36 
1 
15 
29 
1 
 
≤ 7 days + 7 
days 
+/- 28 
days 
23 For participants who received 177Lu-PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the following adverse events will be captured beyond the 30 day safety 
period regardless of relationship to study treatment and whether new anticancer therapy has been initiated: hematologic toxicities (including need for transfusion or use 
of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies. 

Novartis 
Confidential 
Page 100 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 8-3 
Assessment Schedule, crossover of ARDT arm participants to 177Lu-PSMA-617 treatment 
Period 
Baselin
e14 
Treatment Period - Cycle 1 
Treatment Period - Cycles 2-6 (6 week cycles, no assessments on 
weeks 2, 4, 6)1 
EOT2 
Post-Treatment 
Follow-Up 
Visit Name 
 
Baselin
e14 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
EOT22 
30 Day 
Safety 
FU 
Long term FU 
(every 12 
weeks) 
Days 
-28 to -1 1  
8 
15 
22 
29 
36 
1 
15 
29 
≤ 7 
days 
+ 7 
days 
+/- 28 days 
Prior/Concomi
tant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
End of period 
disposition 
X 
 
 
 
 
 
 
 
 
 
X 
 
X (at end of 
FU) 
Physical Exam 
S 
S 
(short
)3 
 
 
 
 
 
S (short)3 
 
 
S 
(short)
3 
S 
(short)3 
S (short)3 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECOG 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Vital Signs 
X 
X4 
 
 
 
 
 
X4 
 
 
X 
X 
 
ECG 
 
As clinically indicated 
X 
 
 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
SAEs related 
to study 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X18 
Hematology 
X 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
Clinical 
Chemistry 
X 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
Coagulation 
Panel 
 
X5 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Serum/plasma 
testosterone 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
PSA 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X  

Novartis 
Confidential 
Page 102 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Period 
Baselin
e14 
Treatment Period - Cycle 1 
Treatment Period - Cycles 2-6 (6 week cycles, no assessments on 
weeks 2, 4, 6)1 
EOT2 
Post-Treatment 
Follow-Up 
Visit Name 
 
Baselin
e14 
C1W
1 
C1W
2 
C1W
3 
C1W
4 
C1W
5 
C1W
6 
C#W1 
C#W3 
C#W5 
EOT22 
30 Day 
Safety 
FU 
Long term FU 
(every 12 
weeks) 
Days 
-28 to -1 1  
8 
15 
22 
29 
36 
1 
15 
29 
≤ 7 
days 
+ 7 
days 
+/- 28 days 
Best 
supportive 
care 
 
X 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
New 
antineoplastic 
therapies 
since study 
drug 
discontinuatio
n 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Symptomatic 
skeletal 
events 
X 
 
Clinical 
Progression 
 
 
X16 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 6 cycles of 177Lu-PSMA-617 therapy 
2 EOT visit must be performed ≤ 7 days after the last day of study treatment period 
3 S = assessment to be recorded in the source documentation only 
4 Blood pressure, pulse and respiratory rate to be assessed approximately 15 mins before study treatment and also approximately 30 mins and 60 mins post 177Lu-
PSMA-617 administration.  
Body temperature needs to be recorded only once, approximately 15 mins before study treatment. 
5Central labs for hematology, chemistry and coagulation results must all be assessed prior to dosing. If central lab results are not available in time to review prior to 
dosing, local labs may be additionally sent to expedite clearing the patient for treatment. 

Novartis 
Confidential 
Page 104 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
8.1 
Screening 
Screening 
Written informed consent must be obtained prior to any screening procedures. Please refer to 
Section 7 for the Informed Consent procedures. After informed consent is collected, the 
participant must be registered in IRT and [68Ga]Ga-PSMA-11 requested for the PET / CT scan 
to evaluate PSMA positivity by central review. Only participants with PSMA- positive cancer 
will be randomized after eligibility is confirmed. Randomization will be stratified by prior 
ARDT use in castrate-resistant prostate cancer (CRPC) vs. HSPC setting and by 
symptomatology. 
Laboratory assessments are carried out as priority to allow the necessary time to obtain the 
results prior to randomization. All Screening assessments to confirm eligibility into the study 
should be performed after ICF signature and within 28 days prior to randomization. 
(Table 8-2). 
During the screening visit, inclusion and exclusion criteria will be assessed. Screening 
assessments to confirm eligibility must be performed prior to randomization. 
The central reading of PET/computed tomography (CT) scan to evaluate PSMA positivity as 
well as the results of the hematology and chemistry screen must be available prior to 
randomization to evaluate eligibility. 
A participant who has any screening assessment results that do not satisfy eligibility criteria 
may have the tests repeated as long as all required assessments are performed within 28 days of 
randomization. In this case, the participant will not be required to sign a new ICF, and the 
original participant identification (ID) number assigned by the investigator will be used. 
In the event that screening assessments cannot be performed within the screening visit window, 
or the re-tests do not meet eligibility criteria, or eligibility criteria have changed and therefore 
not met anymore, the participant is considered a screening failure, and must be discontinued 
from the study. It is permissible to re-screen a participant if he fails the initial screening; 
however, each case must be discussed and agreed with the Sponsor on a case-by-case basis. A 
new ICF will have to be signed if the investigator chooses to re-screen the participant thereafter, 
and the participant will be assigned a new participant ID number. All required screening 
activities, except the 68Ga-PSMA-11 requested for the PET/computed tomography (CT) scan if 
the previous was done during the last 6 weeks, must be performed when the participant is re-
screened for participation in the study. Only in the case when a new [68Ga]Ga-PSMA-11 
PET/CT needs to be repeated, will a new eligibility read by the central imaging vendor be 
required. Baseline imaging (CT/MRI and bone scan) must continue to be within window for the 
new anticipated randomization date, and should be repeated if necessary. The study sponsor 
and central imaging vendor should be simultaneously notified immediately of any participant 
to be rescreened, and whether scans already submitted to the central imaging vendor need to be 
linked to the new participant identification number. 
A participant may only be re-screened once for the study. Once the number of participants 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 

Novartis 
Confidential 
Page 105 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
further screening. In this case, the participants who screen failed will not be permitted to re-
screen. 
8.1.1 
Eligibility screening 
When all screening procedures are completed and once the participant’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified, including 
[68Ga]Ga-PSMA-11 positivity confirmed by central review) the investigator or designee may 
proceed with randomization per Section 6.3.2.  
Please refer as well as to the detailed guidelines in the IRT Manual. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form (CRF). The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
The AE eCRF should also be completed for all participants who have received [68Ga]Ga-
PSMA-11. No other data will be entered into the clinical database for participants who are 
screen failures, unless the participant experienced a serious adverse event during the screening 
period (see SAE section for reporting details). If the participant fails to be randomized, the 
IRT must be notified within 2 days of the screen fail that the participant was not 
randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Participant demographics: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and relevant medical history/current medical 
conditions (until date of signature of informed consent will be recorded in the eCRF. Where 
possible diagnosis and not symptoms should be recorded. Participant race/ethnicity data are 
collected and analyzed to identify any differences in the safety and/or efficacy profile of the 
treatment due to these characteristics. In addition, these data are necessary to assess the diversity 
of the study population as required by health authorities. All prescription medications, over-
the-counter drugs and significant non-drug therapies prior to the start of the study must be 
documented. See the protocol Section 6.2.1 Concomitant Therapy for further details on what 
information must be recorded page of the eCRF. 
Participant demographic and baseline characteristic data to be assessed on all participants 
include: 
• Demographic information: age, gender, ECOG PS, height and weight, body temperature, 
blood pressure and pulse measurements 

Novartis 
Confidential 
Page 106 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Laboratory evaluations: hematology, chemistry, coagulation, urinalysis test, PSA and serum 
testosterone 
 
 
Medical history: 
• Prostate cancer prior history including date of initial diagnosis, Gleason score at diagnosis, 
AJCC stage at diagnosis, extent of disease, and PSMA result with [68Ga]Ga-PSMA-11 
PET/CT scan 
• Prior and current concomitant medications which related to the prostate therapy and best 
supportive care/ standard of care 
• Date and type of progression (e.g. PSA, radiological, bone, soft tissue or no clinical benefit) 
and date of disease progression 
• Site of progression (new lesions, existing lesions, or both) when available 
• Ongoing medical conditions, symptoms and diseases which are recorded on the Medical 
History eCRF should include the toxicity grade when applicable 
• Other all important medical, surgical, and allergic conditions that could have an impact on 
the participant's evaluation) / current medical conditions (e.g. all relevant current medical 
conditions which are present at the time of signing informed consent). 
8.3 
Efficacy 
For the timing of efficacy assessments, refer to the schedule of assessments provided in  
Table 8-2 and Table 8-3. 
8.3.1 
Radiographic imaging for tumor assessment 
Radiologic assessment to monitor radiographic progression should follow PCWG3 modified 
RECIST v1.1 guidelines. Periodic radiographic imaging will include both: 
• CT with contrast/MRI imaging 
• Bone scans with technetium-99m labeled diphosphonates 
Table 8-4 
Overall Time Point Response per PCWG3 modified RECIST v1.1 
Soft Tissue (PCWG3-modified 
RECIST 1.1) TPR 
Bone Lesion (PCWG-modified 
RECIST) TPR 
Combined Overall PCWG-
modified RECIST 1.1 TPR 
PD 
Any 
PD 
Any 
PD 
PD 
Any (except PD) 
PDu 
PDu 
Any (except PD) 
UNK* 
UNK 
UNK 
Non-PD or NED 
UNK 
NED1 
Non-PD 
Non-CR/Non-PD 
NED1 
NED 
NED 
SD 
Non-PD or NED 
SD 
Non-CR/Non-PD 
Non-PD or NED 
Non-CR/Non-PD 
PR 
Non-PD or NED 
PR 
CR 
Non-PD 
PR2 

Novartis 
Confidential 
Page 107 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
CT with contrast/MRI tumor assessments should include evaluations of the chest, abdomen, 
and pelvis. Sites of “soft-tissue” disease will be characterized as either target or non-target 
lesions based on CT/MRI images. The distribution of the target and non-target lesions should 
be representative of the subject’s overall disease. Note, that for the purpose of the study a 
maximum of five (5) target lesions per site of metastatic spread (e.g., lung, liver, adrenal glands, 
lymph nodes, etc.) will be chosen for measurement over the course of the study. 
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs/sites of metastatic spread, but in 
addition should be those that lend themselves to reproducible repeated measurements. 
• Target lesion must be measurable at screening/baseline  
• The number of target lesions representing one (1) site of metastatic spread may be up to 
five (5).The total number of target lesions may be more than five (5) in order to represent 
all sites of metastatic spread.  
• Lesion(s) in a prostate should not be selected as target or non-target  
• Lesion(s) in a prostate bed in the participants with a history of prostatectomy should not 
be selected as target or non-target  
• Lymph nodes (pelvic, extra pelvic) may be selected as target or non-target when 
qualifying criteria met 
• Lesions/areas of tumor spread located in pelvis, which are extraosseous and other than 
prostate/prostate bed/lymph nodes (e.g. pelvic masses, invaded bladder, seminal vesicles) 
may be selected as target or non-target  
Sites of bone disease will be recorded based on bone scan, with exception to bone metastasis 
with soft tissue component which may qualify for target/non-target when detectable at CT/MRI 
as described above. Note, that for the purpose of the study, bone lesion(s) should be assessed 
by Bone scan only 
Disease progression by bone scan criteria will be met if at least 2 new bone lesions at the first 
“post treatment” scan that persist, with at least two additional lesions on the next (confirmatory) 
scan 
outside 
the 
12-week 
flare 
window 
(2 
+ 
2 
PCWG3 
criteria),  
(Scher et al 2016) by BICR. 
For scans after the 12-week flare window, the first observation of at least two new lesions 
relative to the baseline scan must be confirmed on a subsequent scan at least 6 weeks later (2 + 
2 PCWG3 criteria). 
If the second scan confirms the metastases by BICR, then the date of progression is the date of 
the scan when the first 2 new metastases were documented. 
Non-CR/Non-PD3 
CR 
NED 
CR 
* 
If the bone scan is entirely missing or was not done, then the combined overall TPR is UNK. 
(1) NED for soft tissue, defined as no target or non-target soft tissue lesions identified at Screening/Baseline 
and no new soft tissue lesions identified. 
(2) The combined overall TPR will be PR if target lesions were present at Screening/Baseline. 
(3) The combined overall TPR will be Non-CR/Non-PD if no targets lesions were present at 
Screening/Baseline. 

Novartis 
Confidential 
Page 108 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 8-5 
Bone disease response per PCWG3 criteria 
Terms 
Definition 
No Evidence of Disease (NED) 
No bone lesions present. 
Non-Progression (Non-PD) 
Bone lesions present but requirements for NED, PDu, or PD are 
not met 
Progressive Disease Unconfirmed (PDu) 
Temporary designation when 2 or more new bone lesions are 1st 
observed 
Progressive Disease Confirmed (PDc) 
2 more new bone lesions have been confirmed 
Flare Window 
Considered the 1st Post-Treatment Scan. May be performed up to 
Week 12. 
Outside Flare Window 
Any time points after the 1st Post-Treatment Scan 
Table 8-6 
Disease Progression on Bone Scan 
Date Progression 
Detected 
Criteria for 
Progression 
Criteria for 
Confirmation of 
Progression (Timing) 
Criteria for 
Documentation of PD on 
Subsequent Scan 
<12 weeks of treatment 
Two (2) or more new 
lesions within the flare 
window 
At least six (6) weeks 
after progression is 
initially identified 
Two (2) or more additional 
new lesions outside the 
flare window compared to 
the prior scan 
>12 weeks of treatment 
Two (2) or more new 
lesions outside the flare 
window 
At least six (6) weeks 
after progression is 
initially identified 
Persistence of bone 
lesions compared to prior 
scan 
The disease progression will be assessed via blinded centralized review of radiographic images 
provided by the treating physician for participants randomized in either arm according to 
PCWG3-modified RECIST v1.1. 
For rPFS (defined as the time from the date of randomization to the date of first documented 
radiographic disease progression confirmed by BICR or death from any cause) upon the 
occurrence of radiographic progression confirmed by BICR, participants randomized to 
177Lu-PSMA-617 may enter the long-term follow up period and continue to receive any other 
therapy per the discretion of the treating physician. Upon confirmation of rPFS by BICR, 
participants randomized to ARDT treatment will be allowed to cross over to receive 177Lu-
PSMA-617 or may enter the long-term follow up period and continue to receive any other 
therapy per the discretion of the treating physician. 
For rPFS2 defined as the time from the date of crossover (ARDT to 177Lu-PSMA-617) to the 
date of radiographic disease progression by BICR or death from any cause) upon the occurrence 
of radiographic progression confirmed by BICR, crossover participants on 177Lu-PSMA-617 
may enter the long-term follow up period and continue to receive any other therapy per the 
discretion of the treating physician. Tumor response of soft tissue, lymph node, and visceral 
lesions to treatment will be assessed locally and centrally using the PCWG3-modified RECIST 
v1.1 criteria (Eisenhauer et al 2009, Scher et al 2016) with caveats outlined in the PCWG3 
recommendations (Section 16.2 and Section 16.3). Details of the central review process will be 
described in the Independent Review Charter. 
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used to screen the study participants for eligibility (PET imaging with 68Ga-PSMA-11) 

Novartis 
Confidential 
Page 109 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
and for study endpoints analysis (BICR for CT with contrast / MRI and bone scan) purposes. 
The local investigator’s assessment will be used for treatment decision making. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
the investigator and sponsor might consider sending the participant to another imaging center, 
when feasible. Those visits might be scheduled as close as possible to study schedule. If the 
treatment (with 177Lu-PSMA-617 or ARDT) is interrupted for more than 4 weeks due to 
COVID-19 pandemic, the participant must have an EOT visit performed in ≤ 7 days and enter 
the Post-treatment Follow-up. 
Table 8-7 
Imaging Assessment Collection Plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Chest, abdomen and pelvis CT 
or MRI (with intravenous 
contrast enhancement*) 
Mandated 
Mandated, every 8 weeks after first dose of study 
treatment for the first 24 weeks (week 9, 17, 25) 
and then every 12 weeks (week 37, 49, etc) until 
confirmation of radiographic progression by BICR 
Brain CT or MRI* 
If clinically indicated 
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, and 
pelvis 
Whole body bone scan with 
technetium-99m labeled 
diphosphonate 
Mandated 
Mandated, every 8 weeks after first dose of study 
treatment for the first 24 weeks (week 9, 17, 25) 
and then every 12 weeks (week 37, 49, etc) until 
confirmation of radiographic progression by BICR 
CT or MRI of other metastatic 
sites (e.g. neck) 
If clinically indicated 
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, and 
pelvis 
*If a participant is known to have a contraindication to CT intravenous (IV) contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (MRI is not recommended due to respiratory 
artifacts; however, if CT is not feasible per local regulations, MRI can be performed instead) plus a contrast-
enhanced MRI (if possible) of the abdomen and pelvis should be performed. 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of randomization. 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to randomization, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images. The following assessments are required 
at screening/baseline: 
• Chest, abdomen, and pelvis CT or MRI 
• Brain CT or MRI, if clinically indicated 
• Whole body bone scan, with technetium-99m labeled diphosphonates 
• CT or MRI of other metastatic sites (e.g. neck), if clinically indicated 
Participants 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 purpose of maintaining neurologic integrity. Participants with epidural 
disease, canal disease and prior cord involvement are eligible if those areas have been treated, 

Novartis 
Confidential 
Page 110 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
are stable, and not neurologically impaired. For participants 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). 
Whole body bone scan with technetium-99m labeled diphosphonates should be performed per 
study imaging site manual. If clinically indicated, CT or MRI of other areas (e.g. spinal column) 
of disease as appropriate should be performed. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
X-rays and ultrasound should not be used to measure tumor lesions. 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-2 and Table 8-3 should be performed using the 
same imaging modality used at baseline. Imaging assessments are to be performed every 8 
weeks after first dose of 177Lu-PSMA-617 or ARDT for the first 24 weeks (independent of dose 
delays), then every 12 weeks and at End of Treatment Visit (if not done within 28 days of EOT). 
For participants who completed 6 cycles/treatment periods and did not have radiographic 
progression confirmed by BICR or participants in either arm who discontinue treatment for 
reasons other than documented radiographic progression, death, lost to follow-up, or 
withdrawal of consent/ opposition to use data/biological samples, tumor assessments must 
continue to be performed every 8 weeks from first dose of study treatment for the first 24 weeks, 
then every 12 weeks until documented radiographic progression, death, lost to follow-up, or 
withdrawal of consent / opposition to use data/biological samples. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. For 
“soft-tissue” disease, determination of CR or PR requires confirmation by repeat assessments 
that should be performed not less than 4 weeks after the criteria for response are first met. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method) and when possible, the same local radiologist/physician throughout the study 
so that the comparison is consistent. If an off-schedule imaging assessment is performed 
because progression is suspected, subsequent imaging assessments should be performed in 
accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to corroborate progressive disease per the 
Prostate Cancer Working Group 3 (PCWG3) Guidelines, but will not be used by itself to 
determine radiographic progression. 

Novartis 
Confidential 
Page 111 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control and central review. 
Time points at which progression is determined locally 
All participants who have disease progression determined by the local investigator require an 
expedited central review by BICR. Rapid image transmission to the imaging CRO may be 
accomplished by transferring the images electronically, e.g. via the Internet. In all instances, 
the process at the imaging CRO will ensure that the central reviewers remain blinded to the 
results of the local assessment and the expedited nature of the review. The investigator seeking 
an expedited review must indicate “progressive disease is suspected” to the imaging CRO on a 
designated form or by alternative means, please refer to the imaging vendor site manual for 
details. The imaging will undergo expedited central review (within 5 business days from the 
time of image receipt at the imaging CRO and once all applicable queries are resolved) and the 
results of the central review will be communicated to the site. While the investigator is awaiting 
the results of the central review, it is preferable that the participant continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for his 
participant. 
If the central review determines disease progression, then the participant will discontinue study 
treatment and subsequent tumor assessments are no longer required. 
If the central review does not determine disease progression, the participant should continue 
receiving the study treatment unless there is a medical need (i.e., rapid progression or clinical 
deterioration) for an immediate change in therapy. 
Participants will continue to have imaging performed as per protocol (Table 8-2 and Table 8-3) 
until the central review determines disease progression. 
The imaging vendor will ensure that the central reviewers involved are blinded to the expedited 
status of the reading. 
Time points without locally determined progression 
All imaging time points without locally determined progression will be read on an ongoing, 
non-expedited basis as detailed in the imaging manual to be provided by the designated imaging 
CRO and independent review charter. Results of these readings will not be communicated to 
the sites. 
For participants who cross over to 177Lu-PSMA-617 after their first rPFS event confirmed by 
BICR, participants will continue to have imaging performed as per protocol (Table 8-3) until 
the BICR determines second radiographic disease progression. 
8.3.2 
Symptomatic skeletal events 
The time to the first symptomatic skeletal events (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. 

Novartis 
Confidential 
Page 112 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
8.3.3 
Clinical progression 
Clinical progression will be assessed by the investigator. The following criteria should be used 
to determine when a participant 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 confirmed 
radiological progression 
• Deterioration in ECOG performance status to Grade 3 or higher 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 participant to discontinue 
treatment due to clinical progression. 
8.3.4 
PSA levels 
Central labs will measure PSA levels (Section 8.4.1).  
As per Section 4.6, during the COVID-19 pandemic that limits or prevents on-site study visits 
regular, home nursing visits might be considered (as close as possible to the visits as per 
schedule), blood samples collection might be done at home and sent to the central lab, until the 
participant can again visit the site. Local labs might be used if needed. 
8.3.5 
Appropriateness of efficacy assessments 
The measurements are standard based on the PCWG3-modified RECIST v1.1  
(Eisenhauer et al 2009), (Scher et al 2016). PCWG3 is an international working group of clinical 
and translational experts in prostate cancer who developed internationally recognized 
recommendations. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits 
regular phone or virtual calls will occur (as close as possible to the visits as per schedule) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again. 
For details on AE collection and reporting, refer to the AE section. 

Novartis 
Confidential 
Page 113 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 8-8 
Assessments & Specifications 
Assessment 
 
Specification 
Physical 
examination 
 
A complete physical examination will be 
carried out during screening. This will 
include the examination of general 
appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, 
vascular, and neurological. 
A short physical exam will include the 
examination of general appearance and vital 
signs (blood pressure [systolic blood 
pressure (SBP) and diastolic blood pressure 
(DBP)] and pulse). A short physical exam 
will be carried out as described in Table 8-2 
and Table 8-3. 
Information for all physical examinations 
must be included in the source 
documentation at the study site. Clinically 
relevant findings that are present prior to 
signing informed consent must be recorded 
on the appropriate eCRF that captures 
medical history. Significant findings made 
after signing informed consent which meet 
the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
 
Vital signs include temperature, BP, pulse 
and respiratory rate measurements. After 
the participant has been sitting for five 
minutes, with back supported and both feet 
placed on the floor, systolic and diastolic 
blood pressure will be measured three times 
using an automated validated device, e.g. 
OMRON, with an appropriately sized cuff. 
The repeat sitting measurements will be 
made at 1 - 2 minute intervals and the mean 
of the three measurements will be used. In 
case the cuff sizes available are not large 
enough for the participant's arm 
circumference, a sphygmomanometer with 
an appropriately sized cuff may be used. 
Temperature needs to be recorded only 
once at the 15 min pre-dose timepoint. 
Height and 
weight 
 
Height in centimeters (cm) and body weight 
(to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be 
measured as specified in Table 8-2 and 
Table 8-3. 
ECOG 
Performance 
status 
 
ECOG Performance status scale will be 
used as described in Table 8-2 and 
Table 8-3. 
ECOG Performance status scale will be used as described in Table 8-9 

Novartis 
Confidential 
Page 114 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 8-9 
ECOG performance status scale 
Score 
Performance Status 
0 
Fully active, able to carry on all pre disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, light housework, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
8.4.1 
Laboratory evaluations 
Central laboratory will be used for analysis of hematology, chemistry, coagulation, urinalysis, 
serum/plasma testosterone and PSA testing (safety monitoring) according to the schedule of 
assessments as described in Table 8-2 and Table 8-3. Local laboratory assessments will be 
allowed in specific cases where central laboratory analysis is not possible according to local 
regulations or central laboratory capabilities considering the radioactive nature of the study 
treatment. Additionally, lab tests may be performed at local labs instead of central labs when 
medically indicated or in case a visit is done at the end of the week preceding the following 
cycle and hematology/chemistry results are needed in less than 48 hours to confirm a dose 
reduction or a dose delay. The samples need to be taken prior to the administration of the 
Investigational Product. Details on the collections, shipment of the samples and reporting of 
results by the central laboratory are provided to investigators in the laboratory manual. If local 
laboratory is used for the analysis of samples, the local procedures will be followed. 
Local laboratories may be used during the screening period to determine the eligibility criteria 
for a patient or during study treatment, if necessary, although the use of the central laboratory 
is recommended. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 1) they induce clinical signs or symptoms, 2) they are considered 
clinically significant, or 3) they require concomitant therapy or procedures. Clinically 
significant abnormal laboratory values or test results should be identified through a review of 
values outside of normal ranges/clinically notable ranges, significant changes from screening 
or the previous visit. 
Unscheduled local laboratory assessments may be performed if medically indicated to assess a 
(potential) adverse event or when the treating physician cannot wait for central laboratory 
results for decision making (e.g. therapeutic intervention, interruption of study treatment). In 
this particular situation, if possible, the blood sample obtained at the same time point should be 
submitted to the central laboratory for analysis in parallel with local analysis. The results of the 
local laboratory will be recorded in the eCRF if any of the following criteria are met: 
• A treatment decision was made based on the local results, or 
• Local lab results document an adverse event not reported by the central laboratory, or 
• Local lab results document an adverse event severity is worse than the one reported by the 
central laboratory, or 

Novartis 
Confidential 
Page 115 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• There are no concomitant central results available 
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page. Laboratory data will be summarized using the CTCAE version 5 (Section 16.1). 
Additional analyses are left to the discretion of the investigator. 
Novartis must be provided with a copy of the local laboratory’s certification (if applicable), and 
a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study must 
be reported via an updated tabulation indicating the date of revalidation. Additionally, if at any 
time a participant has laboratory parameters obtained from a different laboratory, Novartis must 
be provided with a copy of the certification and a tabulation of the normal ranges and units for 
this laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
participants in the study and evaluating any abnormalities for clinical significance. 
If participants cannot visit the site for safety lab assessments conducted through central labs, 
local lab collection may be used during a Public Health emergency as declared by Local or 
Regional authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site 
study visits. 
Table 8-10 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands) 
Chemistry 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphate, Chloride, Sodium, 
Potassium, Creatinine, eGFR (at screening and EOT only), Creatine kinase (CK), Direct 
Bilirubin,Total Bilirubin, Urea nitrogen, Uric Acid, Amylase, Lipase, Glucose  
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
If needed Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells) will be added 
Coagulation 
International normalized ratio (INR), Activated partial thromboplastin time (APTT) 
Others 
Testosterone, PSA 
8.4.2 
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions. 
Single 12 lead ECGs are collected. The original ECG on non-heat-sensitive paper or a certified 
copy on non heat sensitive paper, appropriately signed must be collected and archived at the 
study site. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding and the investigator should document the clinical evaluation in the 

Novartis 
Confidential 
Page 116 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
source. A monitoring or review process should be in place for clinically significant ECG 
findings throughout the study and especially at baseline before administration of study 
treatment. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate eCRF. Any identifier details must be redacted e.g. participant initials, date of birth 
(where regulations permit), participant number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present at screening should be reported on the 
appropriate eCRF. Clinically significant findings must be discussed with Novartis prior to 
enrolling the participant in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded as adverse events. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
8.4.3 
Pregnancy and assessments of fertility 
A condom is required for all male participants who are sexually active with women of child-
bearing potential to prevent them from fathering a child AND to prevent delivery of study 
treatment via seminal fluid to their partner. In addition, male participants should not donate 
sperm for at least 14 weeks following the last dose of 177Lu-PSMA-617. 
Effective birth control methods should be used from the day of 68Ga-PSMA-11 dose 
administration, throughout study treatment and for at least 14 weeks following the last dose of 
177Lu-PSMA-617. 
Contraception methods are not required for the participants and their partners, who have been 
administered 68Ga-PSMA-11 but did not start treatment with 177Lu-PSMA-617, due to the 
microdose nature of this single administration. However, due to the potential radiation 
exposure/ contamination to partners, it is recommended that study patients refrain from sexual 
activity/ intercourse for 12 hours following administration of 68Ga-PSMA-11. (Please refer to 
latest IB).  
Participants receiving ARDT must follow contraceptive requirements as per the local label for 
the respective drugs. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 
A PRO is a measurement based on a report that comes from the study participant about the 
status of a participant’s health condition without interpretation of the participant’s report by a 

Novartis 
Confidential 
Page 117 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Medical Lead or anyone else. Symptoms or other unobservable concepts known only to the 
participant (e.g. pain severity or fatigue) can only be assessed using PRO measures. 
PROs will be collected on an electronic tablet device at the clinic. Web portal will also be 
available in case of technical faults with the tablet. 
The participant must be given the PRO measure(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation. Handling of protocol deviations can be modified if needed per 
study protocol. 
Participant questionnaires should be completed in the language most familiar to the participant. 
The participant should be given sufficient space and time to complete the PRO measure(s). 
The site personnel should check PRO measure(s) for completeness and ask the participant to 
complete any missing responses. The responses stored electronically in the database will be 
considered the source file. 
Completed measure must be reviewed and assessed by the investigator or designee for 
responses which may indicate potential AEs or SAEs before any clinical study examinations. 
This assessment should be documented in study source records. If AEs or SAEs are confirmed, 
study investigators should not encourage the participant to change responses reported in the 
completed questionnaires. Study investigators must follow reporting instructions outlined in 
Section 10 of the study protocol. 
The PRO measures used in this study will be the BPI-SF, FACT-P and the EQ-5D-5L. PRO 
measures will be assessed as described in Table 8-2 and Table 8-3. Assessments will be 
collected during post treatment follow-up at week 24 and week 48 for patients who prematurely 
discontinued for any other reasons than disease progression, lost to follow-up or withdrawal of 
consent / opposition to use data/biological samples at the same time point as the radiographic 
assessments. 
HRQoL will be periodically assessed at baseline, prior to administration of study treatment, at 
predefined timepoints, at the End of Treatment visit and during post treatment follow up period. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data may be collected remotely (e.g. web portal) depending on local regulations, technical 
capabilities, and following any applicable training in the required process. 
8.5.1.1 
Pain Score 
Pain will be assessed using the Brief Pain Inventory- Short Form. 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 et al 2009). 

Novartis 
Confidential 
Page 118 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
8.5.1.2 
Health-related quality of life 
The ECOG Performance Status scale will be used to assess participants' ability to perform daily 
living tasks and their range of basic physical ability. 
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 et al 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 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 2015). Full details regarding the 
EQ-5D-5L questionnaire, including references, are available at the EQ-5D website: 
//euroqol.org/eq-5d-instruments/eq-5d-51-about. 
8.5.1.3 
FACT-P Questionnaire 
The FACT-P questionnaire will also be administered as part of this study to specifically assess 
the HRQoL of prostate cancer participants. 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 participants' 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 participant 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: //facit.org/FACIT0rg/0uestionnaires. 

Novartis 
Confidential 
Page 122 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and discontinuation from 
study 
9.1.1 
Discontinuation from study treatment  
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator. 
In addition to mandatory discontinuation of study treatment for toxicity listed in Table 6-2, 
study treatment must also be discontinued under the following circumstances: 
• Evidence of tumor progression by central radiological assessment as measured by 
PCWG3-modified RECIST v1.1 criteria 
• Unacceptable toxicity as assessed by Investigator 
• Participant non-compliance or voluntary withdrawal from study or from study treatment 
• Required use of a prohibited treatment  
• Evidence that the participant is no longer clinically benefiting from study treatment 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• At the sponsor's or investigator's discretion 
• If the treatment (with 177Lu-PSMA-617 or ARDT) is interrupted for more than 4 weeks for 
any reason. 
• Participants who have delay of treatment due to interruption of study drug supply can 
restart study treatment if they have recovered from all drug related toxicities per dose 
modification Table 6-2, do not demonstrate radiographic progression on most recent 
scheduled or unscheduled imaging, have not started other anticancer therapy, and 
every effort has been made to reschedule treatment as early as possible to minimize 
deviations from the treatment schedule. 
Study participants for whom study treatment is discontinued should return to the clinic for the 
End of Treatment visit. 
If a study participant discontinues the treatment period of the study for any reason other than 
death, radiographic progression or withdrawal of consent / opposition to use data/biological 
samples, they will be asked for permission to continue collecting radiographic images (bone 
scans and CT scans and/or MRls) for the purpose of continuing to assess rPFS. 
The investigator should make a reasonable effort to understand the primary reason for the 
participant’s discontinuation from study treatment and record this information in the source and 
corresponding eCRF pages. The investigator must also contact the IRT to register the 
participant’s discontinuation from study treatment. 
Participants who discontinue from study treatment or who decide they do not wish to participate 
in the study further should NOT be considered withdrawn from the study UNLESS the 

Novartis 
Confidential 
Page 123 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
participants withdraw their consent (see withdraw of informed consent section). Where possible, 
they should return for the assessments indicated in the assessment schedule (Table 8-2 and 
Table 8-3). If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the participant/pre-designated contact 
person as specified in the lost to follow-up section. This contact should be done according to 
the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, the following data should be 
collected at clinic visits or via telephone/email contact: 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
These information should be collected for a period of 30 days after study drug discontinuation, 
or longer for the SAEs where the Investigator considers that there is a possible relationship in 
between the SAEs and study treatment. 
For participants who discontinue from study treatment for reasons other than documented 
disease progression, death, lost to follow-up, or withdrawal of consent/ opposition to use 
data/biological samples, assessments must continue to be performed as per Table 8-2 and 
Table 8-3. The visits will be carried out every 12 weeks (± 28 days) until death, lost to follow-
up, withdrawal of consent / opposition to use data/biological samples or accrual of the number 
of events required for the planned analyses for OS for the study, whichever occurs first. 
9.1.1.1 
Replacement policy 
Participants will not be replaced on study. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. If the 
participant agrees, a final evaluation at the time of the participant’s study discontinuation should 
be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 

Novartis 
Confidential 
Page 124 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
9.2 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent / opposition to use data/biological samples occurs when a 
participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.  
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his consent/ 
opposition to use data/biological samples and record this information. The Investigator shall 
clearly document if the participant has withdrawn his consent for the use of data in addition to 
a study discontinuation. 
Where consent to the use of Personal and Coded Data is not required in a certain’ country’s 
legal framework, the participant therefore cannot withdraw consent. However they still retain 
the right to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes the last visit for the study or, 
in the event of an early study termination decision, the date of that decision. 
All randomized and/or treated participants should have a safety follow-up conducted 
approximately 30 days after the EOT visit, followed by the long-term follow-up visits carried 

Novartis 
Confidential 
Page 125 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
out every 12 weeks (± 28 days) until death, lost to follow-up, withdrawal of consent / opposition 
to use data/biological samples or accrual of the number of events required for the planned 
analyses for OS for the study, whichever occurs first. Please refer to Table 8-2 and Table 8-3 
for the required assessments at these visits. 
Participants randomized on the 177Lu-PSMA-617 arm will reach the end of study treatment after 
the last day of study treatment period of 177Lu-PSMA-617 or upon radiographic progression. 
The participants must have an EOT visit performed ≤ 7 days and enter the Post-treatment 
Follow-up. For participants who are able to complete the planned 6 cycles of 177Lu-PSMA617, 
the end of the treatment period is upon completion of the C6W5 visit and the response 
assessment imaging due at week 37. 
Participants randomized on the ARDT arm will reach the end of study treatment upon the 
occurrence of radiographic progression by BICR. The participants will have a choice of 
crossover to the 177Lu-PSMA-617 arm. If this option is selected, they will reach the end of study 
treatment after the last day of study treatment period of 177Lu-PSMA-617 or upon second 
radiographic progression (rPFS2) by BICR. The participants will have a EOT2 visit performed 
≤ 7 days and enter the Post-treatment Follow-up. 
For participants discontinuing for reasons other than radiographic progression for both arms, 
tumor assessments must be performed every 8 weeks (± 7 days) after first dose of study 
treatment for the first 24 weeks, then every 12 weeks (± 7 days) until documented radiographic 
progression confirmed by BICR. 
Post treatment Access 
In case of termination of the study by the sponsor due to attainment of the rPFS and OS 
thresholds for success as cited in Section 12 (Data Analysis and Statistical Methods), strategy 
decision on 177Lu-PSMA-617 development/launch or reimbursement (as applicable), post study 
treatment access to 177Lu-PSMA-617 may be provided as per protocol and as permitted by local 
legislation to all participants remaining at the time of study termination, and will be 
administered at the discretion of the investigating physician. 
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 

Novartis 
Confidential 
Page 126 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
In the situation where the primary rPFS analysis is statistically not significant, the decision to 
continue or stop the trial will be made following discussions between the sponsor, the Steering 
Committee and the DMC. 
In the situation where the primary rPFS analysis is statistically significant, the study will 
continue as initially planned, in order to collect further survival information and perform 
planned interim and final OS analyses. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. The Participant-Reported Outcomes are considered as 
assessments to detect (Section 8.5.1). 
Adverse events will be assessed and graded according to the CTCAE version 5.0. 
Grade 1 to 5 will be used to characterize the severity of the Adverse Event. If CTCAE grading 
does not exist for an adverse event, the severity of mild, moderate, severe, life-threatening and 
death due to the AE, corresponding respectively to Grades 1 - 5, will be used. Information about 
any deaths (related to an Adverse Event or not) will also be collected through a Death form. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade according to the Common Toxicity Criteria (CTC) AE grade version 5.0 
2. Its relationship to the investigational product 68Ga-PSMA-11, or the study treatment 177Lu-
PSMA-617 or ARDT. If the event is due to lack of efficacy or progression of underlying 
illness (i.e. progression of the study indication) the assessment of causality will usually be 
‘Not suspected.’ The rationale for this guidance is that the symptoms of a lack of efficacy 
or progression of underlying illness are not caused by the trial drug, they happen in spite of 

Novartis 
Confidential 
Page 127 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
its administration and/or both lack of efficacy and progression of underlying disease can 
only be evaluated meaningfully by an analysis of cohorts, not on a single participant 
3. Its duration (start and end dates or ongoing)and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Drug interrupted/withdrawn 
• Dose Reduced/increased 
• Dose not changed 
6. Its outcome 
• not recovered/not resolved 
• recovering/resolving 
• recovered/resolved 
• recovered/resolved with sequelae 
• fatal 
• unknown 
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the EOT visit (or 
EOT2 visit if crossover occurs). For participants who received 177Lu-PSMA-617 in the 177Lu-
PSMA-617 arm or in crossover, the following adverse events will be captured beyond the 30 
day safety period regardless of relationship to study treatment and whether new anticancer 
therapy has been initiated: hematologic toxicities with primary focus on myelosuppression and 
thrombocytopenia (including need for transfusion or use of growth factors), renal failure, 
xerostomia, xerophthalmia, secondary malignancies.  
For participants that are not randomized, AE monitoring will continue up to and including 14 
days after administration of 68Ga-PSMA-11. 
For all AEs sufficient information will be obtained to permit an adequate determination of the 
outcome of the event and an assessment of the causal relationship between the AE and 68Ga-
PSMA-11, 177Lu-PSMA-617, ARDT and/or supportive care. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 

Novartis 
Confidential 
Page 128 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event, except if the 
investigator considers that progression of malignancy is related to study treatment. 
Adverse events separate from the progression of malignancy (for example deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was 
at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe (please refer to the 
ICH-E2D Guidelines 2020). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (i.e. exceptional hospitalization for any study specific 
procedure) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study has not worsened since signing the informed consent 

Novartis 
Confidential 
Page 129 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical even has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after EOT (or EOT2 visit if crossover occurs) 
visit must be reported to Novartis Safety immediately, without undue delay, and under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If local 
regulations regarding reporting timelines are more stringent, then local regulations prevail. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced after the 30-day safety evaluation follow-up assessment, should be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment 
(either ARDT or 177Lu-PSMA-617), unless otherwise specified by local law/regulations. For 
participants who received 177Lu-PSMA-617 in the 177Lu-PSMA-617 arm or in crossover, the 
following SAEs will be captured beyond the 30 day safety period regardless of relationship to 
study treatment and whether new anticancer therapy has been initiated: hematologic toxicities 
with primary focus on myelosuppression and thrombocytopenia (including need for transfusion 
or use of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 

Novartis 
Confidential 
Page 130 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information (Note: If local regulations regarding 
reporting timelines are more stringent, then local regulations prevail). The follow-up 
information should describe whether the event has resolved or continues, if and how it was 
treated, and whether the participant continued or withdrew from study participation. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
participant Safety (CMO&PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. Follow-up will be made after the Expected Delivery Date 
for information regarding the outcome of the pregnancy, the health of the newborn at birth and 
infant health status and development up to 12 (twelve) months after delivery, and for any other 
relevant information. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 

Novartis 
Confidential 
Page 131 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.2.2 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial, i.e., not being members of the DMC and Novartis representatives from the Clinical Trial 
Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR part 11 requirements, Investigator site staff will not be given access to the EDC system 

Novartis 
Confidential 
Page 132 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment(s) dispensed to the participant and all 
dosage and treatment changes will be tracked using an Interactive Response Technology (IRT). 
The system will be supplied by Novartis, who will also manage the database. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after the lock, can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 

Novartis 
Confidential 
Page 133 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
12 
Data analysis and statistical methods 
The primary efficacy and safety analyses will be performed after observing approximately 156 
rPFS events as per BICR assessment. The primary Clinical Study Report (CSR) will be 
produced after the primary rPFS analysis and once all patients randomized to 177Lu-PSMA-617 
arm have had the opportunity to complete the full course of treatment. Any additional data for 
participants continuing to receive study treatment past this time and for participants continuing 
for efficacy follow-up (rPFS, OS), as allowed by the protocol, will be further summarized in a 
study report at the time of the final OS analysis after observing approximately 297 deaths, or 
when statistical significance is reached at any interim OS analysis. 
It is planned that the data from all centers participating in the study will be combined, so that 
an adequate number of participants are available for analysis. Novartis and/or a designated CRO 
will perform all analyses. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set comprises all participants to whom study treatment has been assigned 
by randomization. According to the intent to treat principle (ITT), participants will be analyzed 
according to the treatment and strata they have been assigned to during the randomization 
procedure. The FAS will be the primary population for all efficacy analyses. 

Novartis 
Confidential 
Page 135 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
The duration of exposure to 177Lu-PSMA-617 and ARDT (as described in Section 6.1) as well 
as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by means of descriptive statistics using the 
safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 
12.4 
Analysis supporting primary objectives 
The primary objective of the study is described in Table 2-1. 
12.4.1 
Definition of primary endpoint(s) 
The primary estimand is defined in Section 2.1. The primary endpoint (variable attribute of the 
primary estimand) of the study is radiographic progression-free survival (rPFS), defined as the 
time from the date of randomization to the date of the first documented radiographic progression 
as outlined in PCWG3 or death due to any cause. rPFS will be assessed via blinded independent 
central review (BICR) of radiographic images provided by the treating physician. 
Participants 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. Clinical deterioration without objective radiographic evidence will 
not be considered as documented radiographic progression. 
Handling of missing data are provided in Section 12.4.4. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Assuming proportional hazards for rPFS, the following statistical hypotheses will be tested to 
address the primary efficacy objective: 
H01:θ1 ≥ 1 vs. HA1:θ1 < 1 
where θ1 is the rPFS hazard ratio (177Lu-PSMA-617 with BSC arm versus ARDT with BSC 
arm). 
The primary efficacy analysis to test these hypotheses and compare the two treatment groups 
will consist of a stratified log-rank test at an overall one-sided 2.5% level of significance. The 
stratification will be based on the randomization stratification factors, i.e. prior ARDT use in 
CRPC vs HSPC; asymptomatic and mildly symptomatic vs symptomatic participants (score of 
0-3 on item 3 of the Brief Pain Inventory Short Form (BPI-SF) questionnaire) vs symptomatic 
(score >3 on item 3 of the BPI-SF questionnaire). 
The primary efficacy variable, rPFS, will be analyzed when 156 rPFS events are observed. 
Analyses will be based on the FAS population according to the randomized treatment group 
and strata assigned at randomization (strata formed using the randomization factor as obtained 
via IRT). The rPFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-
Meier curves, medians and 95% confidence intervals of the medians will be presented for each 

Novartis 
Confidential 
Page 137 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Analyses may be also performed in the FAS for rPFS per BICR censoring for initiation of new 
anti-neoplastic therapy using the same analysis conventions as the primary efficacy analysis. 
Subgroup analyses for rPFS 
If the primary endpoint analyses for rPFS (per BICR) is statistically significant, subgroup 
analyses to assess the homogeneity of the treatment effect across demographic and baseline 
disease characteristics will be performed. Important subgroups will be specified in the 
Statistical Analysis Plan (SAP). 
Further supplementary analyses will be specified in the SAP. 
12.5 
Analysis supporting secondary objectives 
The secondary objectives are described in Table 2-1 and the key secondary estimand is defined 
in Section 2.2. 
OS is identified as the key secondary endpoint (primary variable attribute of the secondary 
estimand). A hierarchical testing strategy will be used to control the overall type I error rate, 
where OS will only be formally tested and interpreted if the primary analysis of PFS is 
statistically significant. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
12.5.1.1 Key secondary estimand 
Assuming proportional hazards model for OS, the following statistical hypotheses will be tested 
only if rPFS is statistically significant: 
H02:θ2 ≥ 1 vs. HA2:θ2 < 1 
where θ2 is the OS hazard ratio (177Lu-PSMA-617 + BSC arm versus ARDT + BSC arm). 
The analysis to test these hypotheses will consist of a 
stratified log-rank test at an overall one-sided 2.5% level of significance. 
The final OS analysis will not be performed at the time point of the final rPFS analysis, but 
after additional follow-up. Therefore, a four-look group sequential design is considered for OS. 
OS will be hierarchically tested in the following way: 
• The time point for the first OS interim analysis was at the same time as the rPFS analysis 
at which point a very limited information fraction was observed. 
• The time point for the second OS interim analysis will be after approximately 9 months of 
additional follow-up from the data cut-off used for the primary analysis, at which time 
approximately 42% of deaths (125 deaths) are expected to have been recorded in the 
clinical database. This interim analysis will not be event driven. 
• If OS is not statistically significant at the second interim analysis, the time point for the 
third OS interim analysis will be after approximately 75% of deaths (223 deaths) are 
expected to have been recorded in the clinical database.  

Novartis 
Confidential 
Page 138 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• If OS is not statistically significant at the interim analyses, a final analysis is planned at 
the time approximately 297 deaths have been recorded. 
The type I error probability will be controlled by using a Lan-DeMets (O’Brien-Fleming) alpha 
spending function for OS which is independent of the one used for rPFS. This guarantees the 
protection of the overall type I error (α = 2.5%) across all hypotheses and the repeated testing 
of the OS hypotheses at the interim and the final analyses (Glimm et al 2010). 
OS will be analyzed in the FAS population according to the treatment group and strata assigned 
at randomization. The OS distribution will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented 
for each treatment group. The hazard ratio for OS will be calculated, along with its 95% 
confidence interval, from a stratified Cox model using the same stratification factors as for the 
log-rank test. 
The OS primary analysis will account for different intercurrent events as explained in the 
following: 
1. discontinuation of study treatment for any reason: OS data collected irrespective of 
discontinuation of study treatment will be used for the analysis (treatment policy strategy) 
2. change in best supportive care: OS data collected irrespective of change in best supportive 
care will be used for the analysis (treatment policy strategy) 
3. start of a new anti-neoplastic therapy: OS data collected irrespective of initiation of new 
anti-neoplastic therapy will be used for the analysis (treatment policy strategy) 
4. crossover to 177Lu-PSMA-617 arm for participants in the ARDT : survival time will be re-
calculated based on time spent on 177Lu-PSMA-617 based on appropriate methods as 
described below(hypothetical strategy). 
Restricted Mean Survival Time (RMST) method may be conducted for OS to account for the 
possible non-proportional hazards effect. 
Since participants in the ARDT arm are allowed to cross over to 177Lu-PSMA-617 arm upon 
confirmation of rPFS by BICR, adjustment for the effect of crossover on OS may be performed 
based on recognized methods, e.g., a two-stage method or the Rank Preserving Structural 
Failure Time (RPSFT) model proposed by (Robins et al 1991). RPFST is intended to be used 
as a primary analysis, however other methods will also be used based on an examination of the 
appropriateness of the data to the assumptions required by the methods. Further details of 
sensitivity analyses will be described in the SAP as needed. 
Supplementary OS analyses based on FAS will be performed without accounting for crossover. 
12.5.1.2 Other secondary efficacy endpoints 
PFS is defined as time from date of randomization to the first documented progression by 
investigator's assessment (radiographic, clinical, or PSA progression) or death from any cause, 
whichever occurs first. 
PFS2 is defined as time from date of randomization to the first documented progression 
(radiographic progression, clinical progression, PSA progression) on next-line therapy or death 
from any cause, whichever occurs first. The first documented progression on next-line treatment 
is based on investigator's assessment of progression disease (PD) (i.e. as captured on the anti-

Novartis 
Confidential 
Page 139 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
neoplastic therapy after discontinuation from study treatment CRF page); it is not necessary to 
continue to collect tumor assessments data for subsequent anti-neoplastic therapies for the 
purpose of PFS2. 
• Next-line therapy is defined as the first new (systemic) anti-neoplastic therapy initiated 
after discontinuation of study treatment regardless of EoT reason. Drugs given as part of 
the same regimen should be considered as first line (i.e. part of the next-line therapy). 
• New anti-neoplastic therapies after EoT will be collected in the anti-neoplastic therapy 
after discontinuation from study treatment eCRF page including start/end date, reason for 
discontinuation, date and type of progression («clinical» vs «radiologic»). 
• PFS2 will be censored if no PFS2 event (progression or death) is observed during next-
line therapy before the analysis cut-off date; the censoring date will be the last contact 
date. 
• However, in case a second new anti-neoplastic therapy is introduced without prior PFS2 
event, then PFS2 will be censored at the end date of the first new anti-neoplastic therapy 
(i.e. next line therapy). 
• Any death prior to initiation of next-line therapy will be considered as an event for PFS2. 
Any death occurring following end of next line therapy will be considered as an event if 
no second new anti-neoplastic therapy has been introduced. 
• PFS and PFS2 may be identical if a participant did not experience an event (i.e. 
progression) prior to initiation of next-line therapy, and adequate tumor assessments 
continue until documented disease progression after initiation of next-line therapy. 
• Note: for patients in ARDT arm who cross over, the 177Lu-PSMA-617 treatment is 
considered the next line therapy, therefore data on progressive disease will be collected from 
the RECIST/PCWG3/PSA/Clinical progression respective CRF pages for the crossover. 
PFS2 will be analyzed in the FAS population according to the randomized treatment group and 
strata assigned at randomization. The PFS2 distribution will be estimated using the Kaplan-
Meier method, and the Kaplan-Meier curves, medians, and 95% confidence intervals of the 
medians will be presented for each treatment group. The hazard ratio for PFS2 will be calculated, 
along with its 95% confidence interval, in the targeted population had crossover not occurred, 
estimated using Cox proportional hazard model stratified by the randomization stratification 
factors. 
Restricted Mean Survival Time (RMST) method may be conducted for PFS2 to account for the 
possible non-proportional hazards effect. Since participants in the ARDT arm are allowed to 
crossover to 177Lu-PSMA-617 after progressive disease, adjustment for the effect of crossover 
on PFS2 may be performed based on recognized methods, e.g., a two-stage method or the Rank 
Preserving Structural Failure Time (RPSFT) model proposed by (Robins et al 1991), based on 
an examination of the appropriateness of the data to the assumptions required by the methods. 
Further details of sensitivity analyses will be described in the SAP as needed. 
Time to SSE (TTSSE) is defined as the time from the date of randomization to the date of the 
first SSE or death from any cause. SSE date is 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 due to any cause, whichever occurs first. 

Novartis 
Confidential 
Page 140 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
SSE data for this endpoint is collected up through EOT visit. Censoring date is date of the last 
study visit (on or before EOT visit). 
TTSSE will be analyzed in the FAS population according to the randomized treatment group 
and strata assigned at randomization. The TTSSE distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of 
the medians will be presented for each treatment group. The hazard ratio for TTSSE will be 
calculated, along with its 95% confidence interval, using a stratified Cox model. Restricted 
Mean Survival Time (RMST) method may be conducted for TTSSE to account for the possible 
non-proportional hazards effect. 
PSA50 response will be calculated at 12, 24 and 48 weeks based on the FAS and according to 
the ITT principle. PSA will be measured every 6 weeks for the first 6 cycles of treatment and 
then every 12 weeks during long term FUP or continued ARDT cycles. Any PSA measurement 
included in the above timepoints +/- 2 weeks will be included in the analyses, whether scheduled 
or unscheduled. PSA response at 12, 24 and 48 months, and along with 95% confidence 
intervals will be presented by treatment group. Waterfall graphs, which display the best percent 
change from baseline in maximum decline in PSA for each participant may be used to depict 
the antitumor activity for each treatment group. 
Time to chemotherapy (TTCT) defined as time from randomization to initiation of the first 
subsequent chemotherapy or death, whichever occurs first. TTCT will be summarized with the 
same analysis conventions as TTSSE, except it will be censored at the last contact date. 
Time to soft tissue progression (TTSTP) defined as time from randomization to radiographic 
soft tissue progression per PCWG3-modified RECIST v1.1 assessed by BICR. TTSTP will be 
summarized with the same analysis conventions as TTSSE, except it will be censored at the last 
scan date and based on RAS. 
rPFS2 defined as the time from the date of crossover (ARDT to 177Lu-PSMA-617) to the date 
of radiographic disease progression assessed via blinded independent central review or death 
from any cause on the next line of therapy based on the Crossover Analysis Set. 
The rPFS2 distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curve, medians and 95% confidence intervals of the medians will be presented. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication 

Novartis 
Confidential 
Page 141 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
2. On-treatment period: from day of first dose of study medication to 30 days after EOT/EOT2 
or (last 177Lu-PSMA-617 dose date + 41 days, last dose date of ARDT + 30 days), whichever 
is later, or the day before crossover date, if applicable 
3. Post-treatment period: starting at day 31 after EOT/EOT2 or (last 177Lu-PSMA-617 dose 
date + 42 days, last dose date of ARDT + 31 days), whichever is later. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. The study treatments for this study are 177Lu-PSMA-617 or ARDT. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
The number (and proportion) of participants with AESI will be summarized by treatment. AESI 
consist of one or more well-defined safety events which are similar in nature and for which 
there is a specific clinical interest in connection with the study treatment(s). AESI will be 
defined at the project level and may be regularly updated. The grouping of AEs in AESI 

Novartis 
Confidential 
Page 142 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
according to project standards will be specified in the Case-Retrieval Sheet and/or the SAP. For 
each specified AESI, the number and percentage of participants with at least one event part of 
the AESI will be reported by dose cohort in the safety run-in part and by treatment group in the 
study. 
68Ga-PSMA-11 treatment emergent adverse events (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 14 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 control arm. Adverse events reported related to 
68Ga-PSMA-11 are also 68Ga-PSMA-11 TEAEs, irrespective of time of onset or start of 
randomized treatment. Summary tables for 68Ga-PSMA-11 TEAEs using the Ga-PSMA-11 Full 
Analysis Set including the number of participants with at least one event, and the total number 
of events will be presented. 
During long-term follow-up, serious adverse events related to 177Lu-PSMA-617 will be 
collected. Summary tables will be provided in the Safety Set. 
Vital signs 
All vital signs data will be summarized by treatment and visit/time. 
12-lead ECG 
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally 
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics of notable ECG values will be provided by treatment. 
Clinical laboratory evaluations 
All laboratory data will be summarized by treatment group. and visit/time. Shift tables using 
the low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
5.0. The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 

Novartis 
Confidential 
Page 145 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
the time of each assessment will be summarized. participants with an evaluable baseline score 
and at least one evaluable post baseline score during the treatment period will be included in 
the change from baseline analyses. 
The number of participants completing each questionnaire and the number of missing or 
incomplete assessments will be summarized by treatment group for each scheduled assessment 
timepoint. No formal statistical tests will be performed for PRO data and hence no multiplicity 
adjustment will be applied. 
In addition, a repeated measurement analysis model for longitudinal data will be used to 
estimate differences in utility scores of the EQ-5D-5L, FACT-P and BPI-SF between treatment 
arms. The differences in least square means between the treatment arms and corresponding 95% 
confidence interval at selected timepoints will be presented. Details, including handling of 
missing data, will be specified in the SAP. 

Novartis 
Confidential 
Page 146 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 

Novartis 
Confidential 
Page 148 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Since the observed number of events at the interim analyses may not be exactly equal to the 
planned 40, 125 and 223 OS events, the efficacy boundary will need to be recalculated using 
the pre-specified α-spending function and based on the actual number of observed events at 
interim and the total number of targeted events to calculate the exact information fraction. The 
observed p-value (or Z-test statistic) at the interim analysis will then be compared against the 
re-calculated efficacy boundary. 
If the study continues to the final OS analysis, the final OS analysis will be performed when 
approximately 297 OS events have been observed. In practice, the final analysis will be based 
on the actual number of OS events observed at the cut-off date for the final OS analysis and α 
already spent at the interim analyses. The boundary for the final analysis will be derived 
accordingly from the pre-specified α-spending function such that the overall significance level 
across all analyses is maintained at 0.025. 
12.8 
Sample size calculation 
The sample size calculation is based on the primary variable rPFS and key secondary 
variable OS. 
Overall, a total study sample size of approximately 450 participants will be randomly assigned 
to each treatment arm in a 1:1 ratio (225 participants in 177Lu-PSMA-617 with BSC arm and 
225 participants in ARDT with BSC arm). These calculations were made using the software 
package East 6.4. 
12.8.1 
Primary endpoint(s) 
The sample size calculation is based on the primary variable rPFS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4.2. 
Based on available data, the median rPFS in the control arm is expected to be around 6 months 
in this population (de Bono et al 2020, de Wit et al 2019, Komura et al 2019). It is expected that 
treatment with 177Lu-PSMA-617 and BSC will result in a 44% reduction in the hazard rate for 
rPFS compared to the control arm i.e., an expected hazard ratio of 0.56, which corresponds to 
an increase in median rPFS by 4.7 months under the exponential model assumption (from 6 to 
10.7 months). 
In order to ensure at least 95% power to test any null hypothesis: rPFS hazard ratio = 1, versus 
the alternative hypothesis: rPFS hazard ratio = 0.56, it is calculated that a total of 156 rPFS 
events need to be observed. This calculation assumes analysis by a one-sided log-rank test at 
the overall 2.5% level of significance, participants randomized to the two treatment arms in a 
1:1 ratio. 
Assuming that enrolment will continue for 10.5 months at a non-uniform rate for a total of 
approximately 450 patients and losses to follow-up for rPFS of approximately 10% and 20% in 
the 177Lu-PSMA-617 and BSC and control arm, respectively, the targeted 156 rPFS events are 
expected to occur at about 3 months after the randomization date of the last participant. 

Novartis 
Confidential 
Page 149 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
12.8.2 
Secondary endpoint(s) 
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
variable rPFS is statistically significant. 
The median OS in the control arm is expected to be around 18 months (de Bono et al 2020,  
de Wit et al 2019, Komura et al 2019). It is hypothesized that treatment with 177Lu-PSMA-617 
will result in a 28% reduction in the hazard rate for OS compared to the control arm i.e., an 
expected hazard ratio of 0.72, which corresponds to an increase in median OS by 7 months 
under the exponential model assumption (from 18 months to 25 months). 
Then in order to ensure 80% power to test the null hypothesis: OS hazard ratio = 1, versus the 
alternative hypothesis: OS hazard ratio = 0.72, it is calculated that a total of 297 deaths need to 
be observed. This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% 
level of significance, participants randomized to the two treatment arms in a 1:1 ratio, and a 4-
look group sequential design with a Lan-DeMets (O’Brien-Fleming) alpha spending function 
using information fractions of (approximately 0.135, 0.42, 0.75, 1). 
Assuming that enrolment will continue for 10.5 months at a non-uniform rate and losses to 
follow-up for OS of approximately 5%, a total of approximately 450 participants will need to 
be randomized to observe the targeted 297 deaths events.Based on the assumptions above and 
a sample size of approximately 450 participants, the rPFS analysis is estimated to occur at 
approximately 13.5 months. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH GCP), with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21), and with 
the ethical principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 

Novartis 
Confidential 
Page 150 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 

Novartis 
Confidential 
Page 151 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

Novartis 
Confidential 
Page 154 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
EuroQoL Group (2015) EQ-5D-5L User Guide Basic information on how to use the EQ-5D-
5L instrument p. Accessed from: //euroqol.org/wpcontent/uploads/2016/09/EO-5D-5L 
UserGuide 2015.pdf. (Accessed 19-SEP-2020) 
Fendler WP, Biber M, Beheshti M, et al (2017) 68Ga-PSMA PET/CT: Joint EANM and 
SNMMI procedure guideline for prostate cancer imaging: version 1.0. Jun 44(6):1014-1024. 
Ferdinandus J, Eppard E, Gaertner FC, et al (2017) Predictors of Response to Radio ligand 
Therapy of Metastatic Castrate-Resistant Prostate Cancer with 177LuPSMA-617 Feb, 
58(2):312-319. 
Fizazi K, Herrmann K, Krause BJ, et al (2021) Health-related quality of life (HRQoL), pain 
and safety outcomes in the phase 3 VISION study of 177Lu-PSMA-617 patients with 
metastatic castration-resistant prostate cancer [abstract]. Ann Oncol; 32 Suppl 5: S626-S677. 
Flaig TW, Potluri RC, Ng Y, et al (2016) Treatment evolution for metastatic castration-
resistant prostate cancer with recent introduction of novel agents: retrospective analysis 
ofreal-world data 5(2):182-91. 
Ghosh and Heston WD (2004) Tumor target prostate specific membrane antigen (PSMA) and 
its regulation in prostate cancer. 91:528-39. 
Glimm E, Maurer W, Bretz F (2010) Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med 219-28. 
Haberkorn U, Eder M, Kopka K, et al (2016) New Strategies in Prostate Cancer: Prostate-
Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy. Jan 1;22(1):9-15. 
Harris V, Lloyd K, Forsey S, et al (2011) A Population-based Study of Prostate Cancer 
Chemotherapy 23, 706-708. 
Haug AR, Shariat S, Eidherr H, et al (2016) Initial experience with aggressive treatment of 
metastastic prostate cancer using 3 cycles of 7.4 GBq [177Lu]PSMA every 4 weeks. (Suppl 
1):S212 EPWl 1. 
Hillier SM, Maresca KP, Femia FJ, et al (2009) Preclinical evaluation of novel glutamate-
urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging 
pharmaceuticals for prostate cancer. (17), 6932-40. 
Hofman (2020) TheraP: A Randomised Phase II Trial of 177Lu-PSMA-617 Theranostic 
Versus Cabazitaxel in Metastatic Castration Resistant Prostate Cancer Progressing after 
Docetaxel: Initial Results (ANZUP protocol 1603) 1-5. 
Hofman MS, Violet J, Hicks RJ, et al (2018) 177Lu]-PSMA- 617 radionuclide treatment in 
patients with metastatic castration-resistant prostate cancer (Lu.PSMA trial): a single-centre, 
single-arm, phase 2 study 19(6):825- 833. 
Hofman MS, Violet J, Hicks RJ, et al (2019) Results of a 50 patient single-centre phase II 
prospective trial of Luteium-177 PSMA-617 theranostics in metastatic castrate-resistant 
prostate cancer. 37 (suppl 7S): 228. 

Novartis 
Confidential 
Page 160 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
LPLV 
Last patient last visit 
MRI 
Magnetic resonance imaging 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 

Novartis 
Confidential 
Page 161 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
16.2.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 16.2.2 and the definition of best response in 
Section 16.2.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.2.3.2.2 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.2.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
16.2.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 
16.2.2.1 Definitions 
16.2.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 16.2.3.2.8 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ³15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ³10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 

Novartis 
Confidential 
Page 162 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ³ 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
16.2.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in  
Section 16.2.3.2.8. 
16.2.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 

Novartis 
Confidential 
Page 163 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned. 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable 
• Physical exams: Evaluation of lesions by physical examination is accepted when 
lesions are superficial, with at least 10mm size, and can be assessed using calipers. 
• Ultrasound: When the primary endpoint of the study is objective response 
evaluation, ultrasound (US) should not be used to measure tumor lesions, unless pre-
specified by the protocol. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained 

Novartis 
Confidential 
Page 164 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) 
can be integrated as non-target disease. If markers are initially above the upper 
normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
16.2.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ) 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.2.2.1.1. 
• Nodal target: See Section 16.2.2.1.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 

Novartis 
Confidential 
Page 165 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
16.2.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions. 
16.2.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are participant to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 

Novartis 
Confidential 
Page 166 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
16.2.2.4.2 
Determination of target lesion response 
Table 16-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to < 
10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm 2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on target 
lesion response and methodology change in Section 16.2.2.2). 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 

Novartis 
Confidential 
Page 167 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at baseline 
and appears to be one mass can split to become two or more smaller sub-lesions. When this 
occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of the two 
split lesions should be added together and the sum recorded in the diameter field on the case 
report form under the original lesion number. This value will be included in the sum of 
diameters when deriving target lesion response. The individual split lesions will not be 
considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of diameters 
for target lesions. On the case report form, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be entered 
for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 

Novartis 
Confidential 
Page 168 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response should 
be assigned when all nodal target lesions shrink to less than 10 mm and all non-nodal target 
lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if either 
a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm and 
there is at least 20% increase in sum of the diameters of all nodal target lesions relative to 
nadir with at least 5 mm increase in the absolute sum of the diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression in 
which case the investigator might assign an SD target lesion response; however, this should 
be done with caution and conservatively as the response categories have well defined 
criteria. 
16.2.2.4.3 
Determination of non-target lesion response 
Table 16-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2. 
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer does 
prevail. 
2. It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details) 
Notes on non-target lesion response 
• The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned. 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions returned 
to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or there are 

Novartis 
Confidential 
Page 169 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
any abnormal nodal lesions (i.e. ³ 10 mm) the response can only be ‘Non-CR/Non-PD’ 
unless there is unequivocal progression of the non-target lesions (in which case response is 
PD) or it is not possible to determine whether there is unequivocal progression (in which 
case response is UNK). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 
at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 16.2.2.4.2 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied. 
16.2.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.2.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ³ 10 mm for the first time in the study plus 5 mm 
absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.2.2.2. 
16.2.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in  
Table 16-3. 

Novartis 
Confidential 
Page 170 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Table 16-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 16.2.2.4. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
16.2.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.2.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
16.2.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 

Novartis 
Confidential 
Page 171 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression £ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 
6 week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment. 
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (³30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ³20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 

Novartis 
Confidential 
Page 172 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of central 
blinded review overall lesion responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 8 
weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of (Dent S and Zee B 2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 

Novartis 
Confidential 
Page 173 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach). 
16.2.3.2 Time to event variables 
16.2.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
16.2.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
16.2.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 

Novartis 
Confidential 
Page 174 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
16.2.3.2.4 
PFS2 
A recent EMA guidance (EMA 2017) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 
16.2.3.2.5 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
16.2.3.2.6 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by (Morgan 
1988) 

Novartis 
Confidential 
Page 175 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in (Ellis et al 2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
16.2.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.2.3.2.6. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 

Novartis 
Confidential 
Page 176 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.2.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used. 

Novartis 
Confidential 
Page 177 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.2.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.2.3.2.9 
Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-1. 
Table 16-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 16.2.2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 

Novartis 
Confidential 
Page 178 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
16.2.3.2.10 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 16.2.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered: 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date 
(progression or censoring)1 
(1) = default unless specified 
differently in the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of 
treatment3 
Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression (2) Date of 
next scheduled assessment2 
Progressed Progressed 
C1 
Progression or death after 
exactly one missing 
assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled 
assessment2 
Progressed 
Progressed 
C2 
Progression or death after two 
or more missing assessments 
(1) Date of last adequate 
assessment2 
(2) Date of next scheduled 
assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate 
assessment 
Censored 

Novartis 
Confidential 
Page 179 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
Situation 
Options for end-date 
(progression or censoring)1 
(1) = default unless specified 
differently in the protocol or RAP 
Outcome 
E 
Treatment discontinuation due 
to ‘Disease progression’ 
without documented 
progression, i.e. clinical 
progression based on 
investigator claim 
(1) Ignore clinical progression and 
follow situations above 
(2) Date of discontinuation (visit 
date at which clinical progression 
was determined) 
As per above situations 
 
Progressed 
F 
New anticancer therapy given 
(1) Ignore the new anticancer 
therapy and follow situations above 
(ITT approach) 
(2) Date of last adequate 
assessment prior to new anticancer 
therapy 
(3) Date of secondary anti-cancer 
therapy 
(4) Date of secondary anti-cancer 
therapy 
As per above situations 
 
Censored 
 
Censored 
Event 
G 
Deaths due to reason other 
than deterioration of ‘Study 
indication’ 
(1) Date of last adequate 
assessment 
Censored (only TTP and 
duration of response) 
1. =Definitions can be found in Section 16.2.3.2.7. 
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in  
Section 16.2.3.2.7. 
3. =The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 

Novartis 
Confidential 
Page 180 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate tumor assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
16.2.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
16.2.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 

Novartis 
Confidential 
Page 181 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.2.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
Treatment duration completed as per protocol (optional, to be used if only a fixed number of 
cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial. 
16.2.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Death 

Novartis 
Confidential 
Page 182 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• Progressive disease 
• Study terminated by the sponsor 
16.2.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.2.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.2.4.5.1 
Calculation of time to event variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.2.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 

Novartis 
Confidential 
Page 183 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
assessment date is calculated as outlined in Section 16.2.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.2.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.2.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.2.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.2.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see  
Table 16-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
Adequate assessment is defined in Section 16.2.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 

Novartis 
Confidential 
Page 184 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent / opposition to use data/biological 
samples, loss to follow-up or alternative anti-cancer therapy) has occurred more than the 
specified period following the last adequate assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
16.2.5 
References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 

Novartis 
Confidential 
Page 185 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
16.3 
Appendix 3: PCWG3 
The sections that apply to this trial are the criteria for radiographic response assessments. It is 
based on the PCWG3 recommendations (Scher et al 2016). 
Table 16-6 
PCWG3 
Variable 
PCWG3 (2016) 
Soft-tissue 
lesions 
For control/relieve/eliminate end points: 
General 
• Record changes in nodal, lung, liver adrenal and central nervous system (CNS) sites 
separately 
• Record up to 5 lesions per site of disease 
• Use Response Evaluation Criteria in Solid Tumors (RECIST) with caveats:  
• 
Confirm favorable change with second scan 
• 
Record complete elimination of disease at any site separately 
Nodal 
• 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 
Visceral 
• Use Response Evaluation Criteria in Solid Tumors (RECIST) with caveats: 
• 
Record changes in liver, lung, adrenal, and CNS separately 
• 
Only report changes in visceral lesions (liver, lung, adrenal, CNS) that were ≥1.0 
cm in the longest dimension 
For delay/prevent end points: 
Nodal and visceral 
• Record changes in nodal and visceral disease separately 
• 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. 
• Record up to 5 lesions per site of spread 
• Note that for some treatments, a lesion may increase in size before it decreases. 
Nodal 
• 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, participant to 
clinical discretion, and nonmeasurable. 
• For existing pathologic adenopathy (≥1.5 cm), progression is defined per RECIST 1.1 
Bone 
For control/relieve eliminate end points: 
• Record changes as improved or stable (no new lesions) or worse (new lesions) 
• Changes in intensity of uptake alone do not constitute progression or regression 
• No new lesions: continue therapy in absence of other signs of progression 
• New lesions (See Progression below) 
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) 

Novartis 
Confidential 
Page 186 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• 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 
16.4 
Appendix 4: Study Specific Adjustments of Response Evaluation 
Criteria in Solid Tumor 
Study-specific Adjustments of Response Evaluation Criteria in Solid Tumors, Guideline based 
on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised RECIST 1.1 
guidelines RECIST Criteria (Appendix 2) 
Definitions. 
Measurable lesions 
• No trial-specific adjustment for definition of measurable non-nodal extraskeletal lesions (“soft tissue 
disease”, as per PCWG3). Non-nodal lesions will be considered measurable when their longest diameter 
is no less than double the slice thickness/reconstruction interval (RI) or 10 mm, whichever is greater, by 
CT/MRI scan (e.g., the minimum non-nodal lesion size for CT/MRI with 5 mm cuts will be 10 mm).  
• Measurement of lesions on chest x-ray will not be performed. Chest CTs will be required for lesion 
measurement.  
• Nodal lesions will be considered measurable at Screening/Baseline, when a lymph node is ≥15 mm in the 
short axis by CT/MRI. Nodal lesions may be measured by a local reader bidimensionally, however, at 
Screening/Baseline and on-study, only the short axis should be recorded and will contribute to the 
objective response. The lymphatic system is considered one (1) site of metastatic spread; however, pelvic 
and extrapelvic nodal lesions should be recorded separately to represent each group. 
• Lesions in a previously irradiated area may be considered measurable if lesions in those areas have 
documented progression.  
• Identifiable soft tissue components of the bone lesion, which can be assessed by CT/MRI, can be 
considered measurable if the soft tissue component meets the criteria for measurable disease. Note, that 
the bone lesions without soft tissue component will be assessed at screening/baseline and on-study by 
whole-body bone scan only  
Non-measurable lesions 
• All other extraskeletal lesions that do not meet the above criteria for measurable disease, including small 
lesions (<10 mm in longest diameter), or pathological lymph nodes ≥10mm to <15 mm in the short axis, or 
other truly non-measurable lesions, will be considered non-measurable 
Examples of non-measurable lesions include:  
• Identifiable soft tissue components of the bone lesion, which can be assessed by CT/MRI and do not 
meet above criteria for measurable lesion 
• Leptomeningeal disease and brain metastases.  
• Lymphangitis of the skin or lung.  
• Abdominal/pelvic masses 
• Pathological lymph nodes with a short axis measuring ≥10 mm and <15 mm.  
• Irradiated lesions that have not shown progression.  
• Groups of lesions that are small and numerous (e.g., miliary lung lesions, multiple small nodes).  
• Pleural/pericardial effusions and/or ascites  
Note: when the patient has  
• non-measurable disease only (with radiographic evidence of distant metastases by CT/MRI), OR 
• bone disease only by bone scan,  

Novartis 
Confidential 
Page 187 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
the patient is potentially eligible for the study (when meets other eligibility criteria) 
Extent of the disease at Screening/Baseline 
The sites of the disease present at screening/baseline will be identified. Sites of soft tissue (extraskeletal) 
disease will be characterized as either target or non-target lesions. Note, that for the purpose of this study, 
bone lesions will be identified based on whole-body bone scan and will not be selected as target or non-target 
(with exception for identifiable soft tissue component of bone lesions as described above; however, bone 
component will be assessed by bone scan according to PCWG3 recommendations).  
Target lesions 
• 
Target lesions must be measurable at Screening/Baseline. These lesions will generally be the largest 
tumor masses. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), and in addition should be assessable by reproducible repeated measurements  
• 
Target lesions should represent all involved organs/sites of metastatic spread (for example, lymph 
nodes, lung, liver, adrenal glands).  
• 
The number of target lesions representing one (1) site of metastatic spread may be up to five (5)  
• 
The lymphatic system is considered one (1) site of metastatic spread. When pathologic lymph nodes 
of ≥15 mm in the short axis are located in both pelvic and extra pelvic areas, both locations should be 
represented by selected target lesions 
• 
The total number of target lesions may be more than five (5) in order to represent all sites of 
metastatic spread  
• 
The lesion(s) in a prostate gland/prostate bed should not be selected as target even if they meet the 
criteria for measurable disease  
• 
The lesions in CNS should not be selected as target lesions even if they meet the criteria for 
measurable disease  
• 
Identifiable and measurable soft tissue components of the bone lesion, which can be assessed by 
CT/MRI, can be considered target lesion 
• 
Lesions that have been previously irradiated may be selected as target lesions when they have 
progressed on or after radiotherapy 
• 
Target lesions cannot be measured on plain films, FDG-PET, bone scans or ultrasounds.  
Non-target lesions 
• 
Sites of disease present at Screening/Baseline and not selected as target lesions will be classified as 
non-target lesions.  
• 
Non-target lesions may be reported and assessed collectively by region/organ.  
• 
Non-target lesions will include any measurable lesions beyond the maximum number of five (5) per 
site of metastatic spread.  
• 
A lymph node may be selected as non-target when considered abnormal and meets the criteria for a 
pathological lymph node: ≥10mm in a short axis.  
• 
If the abnormal node meets the criteria for pathological lymph nodes, then the entire group may be 
chosen as a non-target lesion. Subsequent evaluations for response will be based on the abnormal 
node as well as other nodes in that group.  
• 
The lesion(s) in a prostate gland/prostate bed should not be selected as non-target  
• 
The lesions in CNS will be selected as non-target even if they meet the criteria for measurable 
disease  
• 
Identifiable soft tissue components of the bone lesion, which can be assessed by CT/MRI, can be 
considered non-target lesion when does not meet criteria for target lesion 
• 
Lesions that have been previously irradiated may be selected as non-target lesions 
Effusions and ascites 
• 
Pleural effusions, pericardial effusions and ascites, present at screening/baseline, will be followed as 
non-target lesions 
• 
The presence or absence of effusions/ascites will be checked at each timepoint  
• 
To be considered new, a fluid collection must not have been present at Screening/Baseline 

Novartis 
Confidential 
Page 188 of 196 
Amended Protocol (Version 03 – Clean) 
Protocol No. CAAA617B12302 
 
 
• 
The cytologic confirmation of the neoplastic origin of any effusion which appears or worsens during 
the study is not required and at the discretion of the investigator 
Lesions that divide (split) or merge (coalesce) on treatment 
• 
If a target lesion splits into multiple parts after Screening/Baseline, the longest diameter or short axis 
of each part, as applicable, will be measured. The sum of the parts of the original tumor will be 
recorded as the total for the lesion measurement with the original lesion number. The individual split 
lesions will not be considered as new lesions, and will not qualify for progressive disease 
• 
When lesions merge, maximal diameter measurements of each individual lesion should be obtained, 
longest diameter or short axis as per RECIST 1.1 guidelines. If the lesions have truly coalesced such 
that they are no longer separable, the maximal diameter of the merged lesion should be measured, 
longest diameter or short axis, as per RECIST 1.1 guidelines 
New lesions 
• 
The presence of new lesions will be assessed at each time point  
• 
Unequivocal new lesions are those that were not present at Screening/Baseline 
• 
Unequivocal new multi-focal or miliary disease will determine a progressive disease unless there is 
clear radiographic evidence of a benign etiology.  
• 
Lesions that are seen (subsequent to the Screening/Baseline) in anatomic locations that were not 
scanned at Screening/Baseline will determine a progressive disease 
• 
The finding of a new soft tissue lesion should be unequivocal  
• 
Lesions in the prostate gland/prostate bed are not qualified as new lesions.  
• 
New nodal lesions must be pathologic in size and represent new metastatic disease 
• 
Note, that the appearance of a new bone lesion will be assessed by bone scan according to PCWG3 
Recommendations  
• 
Response at the time point when an equivocal new lesion was first identified may be updated to 
progressive disease if subsequent images confirm that it truly represents new disease  
New lesions, use of FDG-PET 
FDG-PET imaging may be used to identify new lesions in the following manner:  
• 
Positive FDG uptake (FDG-positive disease) is defined as a level of activity greater in intensity 
compared to either the tissue where the lesion is located or the surrounding tissue, which serves as 
the background activity level.  
• 
FDG-PET will only be used for the assessment of progression  
• 
New FDG-PET positive lesions refer to lesions which were not previously selected on CT as part of 
the Screening/Baseline extent of disease  
• 
If there is no screening/baseline (or interval) FDG-PET imaging for comparison, or if the on-study 
FDG-PET imaging shows an FDG-PET positive focus which was not present on the 
screening/baseline (or interval) FDG-PET imaging, then progression will be determined as follows:  
• If the positive FDG-PET focus on-study corresponds to a new site of disease confirmed by CT, 
then response will be assessed as PD  
• If the positive FDG-PET focus on-study is not confirmed as a new site of disease on CT, then 
additional follow-up CT/MRI is needed to determine/confirm progressive disease. When confirmed, 
response at prior time point may be updated to PD retrospectively 
If the positive FDG-PET scan on-study corresponds to a pre-existing site of disease on CT/MRI that is not 
progressing on the basis of the anatomic changes, then response cannot be assessed as PD 
Frequency of tumor re-evaluation while on treatment  
• 
Radiologic assessments (CT/MRI, bone scans) are to be performed every 12 weeks (±7 days) for the 
first 24 months, then every 16 weeks (±7 days) and at the end of treatment 
• 
Confirmation of Complete response/Partial response by additional CT/MRI of chest/abdomen/pelvis 
performed not less than 4 weeks after the criteria for response are first met is not mandated in this 
study