Phase I/ll Dose-escalation Study of Fractionated Dose 177Lu-PSMA-617 for Progressive Metastatic Castration Resistant Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University

PROTOCOL # 1609017542 
VERSION 6, DATE: 10/28/2021 
TITLE: Phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive 
metastatic castration resistant prostate cancer 
IRB Protocol #: 1609017542 
IND/IDE #: 131966, 124495 
Version Date: October 28, 2021 (v.6) 
Principal Investigator: 
Scott. T. Tagawa, M.D., M.S. 
Tel.: 646-962-2072 
Fax: 646-962-1603 
E-mail: stt2007@med.cornell.edu
Participating Sites: Weill Cornell Medicine, Dana Farber Cancer Institute, Tulane Cancer Center 
DFCI PI:  Lauren C. Harshman, M.D. 
Tulane PI:  A. Oliver Sartor, M.D. 
Version 1: August 18, 2016 
Version 2: January 11, 2017 
Version 3: April 14, 2017 
Version 4:  May 10, 2018 
Version 5: October 1, 2018 
Version 6: October 28, 2021
NCT#: NCT03042468

Protocol # 1609017542 
Version 6, Date: 10/28/2021 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential 
investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from WCM. 

Protocol # 1609017542 
Version 6, Date: 10/28/2021 
 
List of Abbreviations 
 
All abbreviations used throughout the protocol must be 
defined. 
 
 
 
 
ADT 
AE 
Androgen Deprivation Therapy 
Adverse Event 
CRF 
CTC 
Case Report Form 
Circulating Tumor Cells 
CTSC 
DLT 
Clinical Translational Science Center 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
IND 
Investigational New Drug 
IRB 
mAb 
mCRPC 
MTD 
PCa 
Institutional Review Board 
Monoclonal Antibody 
Metastatic Castration Resistant Prostate Cancer 
Maximum Tolerated Dose 
Prostate Cancer 
PSMA 
Prostate Specific Membrane Antigen 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
WCM 
Weill Cornell Medicine 

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Protocol Summary 
 
Full Title: 
Phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 
for progressive metastatic castration resistant prostate cancer 
Short Title: 
Fractionated 177Lu-PSMA-617 for mCRPC 
Clinical Phase: 
Phase I 
Principal Investigator: 
Scott T. Tagawa, MD, MS 
Sample Size: 
N= 4 - 63 (3+3 study design up to 6 dose-escalation cohorts in  
phase I (up to 36), additional 10-21 in phase II (up to 27 including 
phase I cohort) 
Accrual Ceiling: 
This study will enroll up to 63 subjects who receive treatment 
Study Population: 
Adult male patients of >18 years age with patients with 
documented progressive metastatic CRPC 
Accrual Period: 
3 years 
Study Design: 
Phase I dose escalation study with 177Lu-PSMA-617 using dose 
fractionation regimen will be performed in patients with 
documented progressive metastatic CRPC. The cumulative 
177Lu dose [100 mCi (3.7 GBq) – 600 mCi (22.2 GBq)] will be 
escalated in up to 6 different dose levels (3 + 3 study design). 
Additional 10-21 subjects will be enrolled at the MTD/RP2D 
level in 2-stage design to further assess safety and tolerability 
and to obtain a preliminary assessment of efficacy. 
 
Study Duration: 
Primary treatment phase is approximately 3 months after 
screening 
Study Agent/ 
Intervention Description:   1) 177Lu-PSMA-617 [50mCi (1.85GBq) - 300mCi (11.1GBq)] 
intravenous X2 doses, 2 weeks apart (Visit 1 and 3) 
2) 68Ga-PSMA-HBED-CC [5 ±2mCi or 185 ±74MBq] intravenous 
during screening and at 12 weeks (±1 week) with standard 
imaging 
Primary Objective: 
• Determine the dose limiting toxicity (DLT) of fractionated 
dose of 177Lu-PSMA-617 (phase I) 
• Determine the maximal tolerated and recommended phase II 
dose  of 177Lu-PSMA-617 in a  2-week dose-fractionation 
regimen (phase I) 
• To assess the proportion with PSA decline following treatment 
with the RP2D of fractionated dose 177Lu-PSMA-617 (Phase II) 
 

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Secondary Objectives: 
• To assess the rate of PSA decline following fractionated 
177Lu-PSMA-617 
• To assess radiographic response rate by RECIST 1.1 with 
PCWG3 modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory 
Objectives: 
• To assess biochemical and radiographic progression-free 
survival by PCWG3 criteria 
• To assess overall survival following fractionated 177Lu- 
PSMA-617 
• To assess safety of fractionated 177Lu-PSMA-617 as 
assessed by CTCAE 4.0 
• To assess changes in CTC count as measured by CellSearch 
and the rate of favorable CTC count and LDH at 12 weeks 
following fractionated 177Lu-PSMA-617 
• To examine whole body distribution of 177Lu-PSMA-617 
• Estimate radiation dosimetry of 177Lu-PSMA-617 and 
correlate toxicity with radiation dosimetry 
 
• Disease assessment with 68Ga-PSMA-HBED-CC PET/CT prior 
to and following investigational treatment 
• To assess genomic DNA repair pathways in relationship to 
outcome following fractionated dose 177Lu-PSMA-617 
• To assess patient reported outcomes using FACT-P and 
the Brief Pain Inventory short form 
• To assess the immune effect of 177Lu-PSMA-617 
• To assess reproducibility of 68Ga-PSMA-HBED-CC PET/CT 
 
 
Endpoints: 
Dose limiting toxicity (DLT), Adverse event rate, Maximum 
tolerated dose (MTD), Recommended phase II dose, 
response rate, progression free survival. 

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Table of Contents 
1. STUDY OBJECTIVES .................................................................................................................. 7 
1.1 
Primary Objectives ..........................................................................................................7 
1.2 
Secondary Objectives ......................................................................................................7 
1.3 
Exploratory Objectives.....................................................................................................7 
2. BACKGROUND ......................................................................................................................... 8 
2.1. 
Disease .............................................................................................................................8 
2.2. 
PSMA ...............................................................................................................................8 
2.3. 
Radionuclide-chelating PSMA ligands .............................................................................9 
2.3.1. 
Prior clinical experience with PSMA small molecule(s) in men with 
prostate cancer:  10 
2.4. 
Investigational Agent .....................................................................................................16 
2.5. 
Rationale .......................................................................................................................17 
2.6. 
Risk/Benefit Assessment ...............................................................................................25 
2.7. 
Correlative Studies Background ....................................................................................25 
2.7.1. 
Archival tissue and Cell-Free plasma DNA to assess genomic DNA-repair pathway 
alterations ......................................................................................................................... 25 
2.7.2. 
CTC Count ...............................................................................................................26 
2.7.3. 
PSMA Expression on CTC ........................................................................................26 
3. SUBJECT SELECTION .............................................................................................................. 27 
3.1. 
Study Population ...........................................................................................................27 
3.2. 
Inclusion Criteria ............................................................................................................27 
3.3. 
Exclusion Criteria ...........................................................................................................28 
4. OVERVIEW OF STUDY DESIGN AND METHODOLOGY ........................................................... 29 
4.1. 
Study Design ..................................................................................................................29 
4.2 
Rationale for Dose-Escalation Strategy .........................................................................30 
5. REGISTRATION PROCEDURES .................................................................................................. 2 
5.1. 
Identification of subjects .................................................................................................2 
5.2. 
Consent process ..............................................................................................................3 
6. STUDY PROCEDURES ............................................................................................................... 3 
6.1. 
Schedule of Evaluations ...................................................................................................5 
6.1.1. 
Screening Visit ..........................................................................................................6 
6.1.2. 
Treatment Phase ......................................................................................................7 
6.2. 
Treatment Administration .............................................................................................11 
6.2.1. 
Agent Administration .............................................................................................11 
6.2.2. 
Study drug preparation ..........................................................................................11 

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6.2.3. 
Route of Administration .........................................................................................12 
6.2.4. 
Dose levels for 177Lu-PSMA-617 .............................................................................12 
6.2.5. 
Dose levels for 68Ga-PSMA-HBED-CC ......................................................................12 
6.2.6. 
Study drug premedication ......................................................................................12 
6.2.7. 
Study drug administration ......................................................................................12 
6.2.8. 
Monitoring Vital signs pre/post 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 infusion 
12 
6.2.9. 
Imaging Plan ...........................................................................................................13 
6.2.10. 
Managing toxicity ................................................................................................13 
6.3. 
General Concomitant Medication and Supportive Care Guidelines ..............................14 
6.4. 
Duration of Therapy and Criteria for Removal from Study ...........................................15 
6.5. 
Duration of Follow Up ....................................................................................................15 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................................16 
8. 
PHARMACEUTICAL INFORMATION .......................................................................................16 
8.1. 
Investigational Agent .....................................................................................................16 
8.2. 
Availability .....................................................................................................................16 
8.3. 
Agent Ordering ..............................................................................................................16 
8.4. 
Agent Accountability ......................................................................................................17 
9. 
CORRELATIVE/SPECIAL STUDIES ...........................................................................................17 
9.1 
Laboratory Correlative Studies ......................................................................................17 
9.1.1. 
PSMA CTC expression analysis ...............................................................................17 
9.1.2. 
Cell-Free Plasma DNA .............................................................................................17 
9.1.3. 
Archival tissue .........................................................................................................17 
9.2. 
Special Studies ...............................................................................................................18 
10. MEASUREMENT OF EFFECT: .................................................................................................18 
10.1 
CTC count response ....................................................................................................18 
10.2 
Biochemical (PSA) response .......................................................................................18 
10.3 
Duration of PSA response ..........................................................................................18 
10.4 
Duration of CTC response ..........................................................................................19 
10.5 
PSA Progression .........................................................................................................19 
10.6 
PSA Stabilization .........................................................................................................19 
10.7 
Time to PSA Progression ............................................................................................19 
10.8 
Change in lesion size ..................................................................................................19 
10.9 
PSMA Expression on CTCs.............................................................................................. 20 
10.10 
Patient reported outcomes ........................................................................................21 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ..........................................................21 
11.1. 
Data Collection ...........................................................................................................21 

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11.1.1. 
REDCap ................................................................................................................21 
11.2. 
Regulatory Considerations .........................................................................................21 
12. STATISTICAL CONSIDERATIONS ............................................................................................22 
12.1. 
Study Design/Endpoint 
12.2. 
s ..................................................................................................................................22 
12.3. 
MTD Cohort Expansion ..............................................................................................22 
12.4. 
Sample Size/Accrual Rate .............................................................................................. 23 
12.5. 
Stratification Factors ..................................................................................................23 
12.6. 
Analysis of Endpoints .................................................................................................23 
12.6.1. 
Analysis of Primary Endpoints ............................................................................23 
12.6.2. 
Analysis of Secondary Endpoints ........................................................................23 
12.6. 
Interim Analysis ......................................................................................................24 
12.7. 
Reporting and Exclusions ...........................................................................................24 
12.7.1. 
Evaluation of toxicity ..........................................................................................24 
12.7.2. 
Evaluation of response........................................................................................24 
13. ADVERSE EVENT REPORTING REQUIREMENTS .....................................................................24 
13.1 
Adverse Event Definition ............................................................................................24 
13.1.1. 
Investigational Agent Risks .................................................................................... 25 
13.1.2. 
Adverse Event Characteristics and Related Attributions ....................................25 
13.1.3. 
Recording of Adverse Events ..............................................................................26 
13.1.4. 
Reporting of AE to WCM IRB...............................................................................26 
13.2. 
Definition of SAE ........................................................................................................27 
13.2.1. 
Reporting of SAE to IRB .......................................................................................27 
13.2.2. 
Reporting of SAE to FDA .....................................................................................27 
13.3. 
AE/SAE Follow Up.......................................................................................................27 
14. DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................................27 
14.1 Medical Monitor .............................................................................................................29 
15. REFERENCES .........................................................................................................................30 
APPENDIX A ..................................................................................................................................41 
APPENDIX B ..................................................................................................................................42 

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1. 
STUDY OBJECTIVES: 
 
The objectives of this clinical trial are as follows: 
 
1.1 Primary Objectives 
• Determine the Dose limiting toxicity (DLT) of fractionated dose of 177Lu-PSMA-617 
• Determine the cumulative maximum tolerated dose (MTD) and/or recommended 
phase II dose (RP2D) of 177Lu-PSMA-617 in a 2-week dose-fractionation regimen 
 
1.2 Secondary Objectives 
• To assess the rate of PSA decline following fractionated 177Lu-PSMA-617 
• To assess radiographic response rate by RECIST 1.1 with PCWG3 modifications 
• To  assess  biochemical  and  radiographic  progression-free  survival  by  
PCWG3 criteria 
• To assess overall survival following fractionated 177Lu-PSMA-617 
• To assess safety of fractionated 177Lu-PSMA-617 as assessed by CTCAE 4.0 
• To assess radiographic progression-free survival by PCWG3 criteria 
• To  assess  changes in  CTC count as  measured by CellSearch  and the rate  of favorable 
CTC count and LDH at 12 weeks following fractionated 177Lu-PSMA-617 
• To examine whole body distribution of 177Lu-PSMA-617 
• Estimate  radiation  dosimetry  of  177Lu-PSMA-617  and  correlate  toxicity  with 
radiation dosimetry 
 
1.3 Exploratory Objectives 
• Disease   assessment   with   68Ga-PSMA-HBED-CC   PET/CT   prior   to   and   
following investigational treatment 
• To assess genomic DNA repair pathways in relationship to outcome 
following fractionated dose 177Lu-PSMA-617 
• To assess patient reported outcomes using FACT-P and the Brief Pain 
Inventory short form 
• To assess the immune effect of 177Lu-PSMA-617 
• To assess the reproducibility of 68Ga-PSMA-HBED-CC PET/CT 
 
2. 
BACKGROUND: 
 
2.1. 
Disease 
 
Prostate cancer (PC) is a significant health burden, with 220,800 new diagnoses and 
27,540 deaths in the United States in 2015(Siegel, Miller et al. 2015). Despite advances 
in diagnostic technology and treatment strategies, up to 40% of patients treated with 

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primary therapy with curative intent will experience disease progression. Additionally, 
prostate cancer treatment can have a major detrimental impact on patients’ quality 
of life, with incontinence and sexual dysfunction rates up to 18% and 90%, 
respectively, 15 years after therapy (Resnick, Koyama et al. 2013). The poor quality of 
life and prognosis of these patients has invigorated research with the goals of 
understanding the biological mechanisms behind PC progression and identifying novel 
therapeutic targets. 
 
Localized PC is treated primarily with surgery or radiation therapy, with or without 
hormonal therapy, although another option for some men is active surveillance 
or observation, since some men will continue to be asymptomatic until death 
from another cause (Albertsen, Hanley et al. 1998, Albertsen, Hanley et al. 2005). 
Although therapy for localized disease may be successful at eradicating the 
disease, some patients suffer recurrence or present with advanced disease. 
 
First line therapy for advanced PC is androgen deprivation with a mean duration of 
efficacy of 12-18 months, although there is a wide variation in response in this 
heterogeneous disease. Upon progression, the disease becomes castration-resistant 
and subsequently many such patients develop frank metastasis. Metastatic 
castration-resistant prostate cancer (mCRPC) poses a particular clinical challenge in 
need of additional therapeutic approaches beyond classic androgen deprivation 
therapies. Currently, the chemotherapy compounds docetaxel and cabazitaxel, the 
androgen receptor signaling inhibitor enzalutamide, CYP-17-inhibitor abiraterone, 
autologous cellular immuno therapy with sipuleucel-T, and the bone-seeking α- 
emitter 223Ra have shown improved overall survival (OS) and most have demostrated 
quality of life advantages as well (Petrylak, Tangen et al. 2004, Tannock, de Wit et al. 
2004, de Bono, Oudard et al. 2010, Kantoff, Higano et al. 2010, Fizazi, Scher et al. 2012, 
Scher, Fizazi et al. 2012, Parker, Nilsson et al. 2013, Beer, Armstrong et al. 2014, Ryan, 
Smith et al. 2015). In all cases, however, these now established therapies become 
ineffective in controlling tumor progression over time(Antonarakis, Lu et al. 2014). 
Novel therapies are urgently needed in order to further ameliorate the course of the 
disease. 
 
 
 
2.2. 
PSMA 
 
In PC, the most well established, prostate-restricted, cell surface antigen yet identified is 
prostate specific membrane antigen (PSMA)(Horoszewicz, Kawinski et al. 1987, 
Israeli, Powell et al. 1993, Israeli, Powell et al. 1994, Troyer, Beckett et al. 1995, 
Wright, Haley et al. 1995). PSMA is a trans- membrane protein with a 707-amino-acid 
extracellular portion. The PSMA gene (FOLH1) is located on the short arm of 

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chromosome 11. 
 
Although first thought to be entirely prostate-specific, subsequent studies have 
demonstrated that PSMA is also expressed by cells of the small intestine, proximal 
renal tubules and salivary glands(Troyer, Beckett et al. 1995). PSMA is expressed in 
the apical region of normal prostatic cells, the epithelium surrounding prostatic 
ducts(DeMarzo, Nelson et al. 2003). Dysplastic changes in the prostate result in the 
expression of PSMA on the luminal surface of prostatic ducts (Huang, Teh et al. 2003, 
Wu, Xu et al. 2012). Increasing prostate cancer stage and grade result in higher cell 
membrane PSMA expression (Silver, Pellicer et al. 1997, Bostwick, Pacelli et al. 1998). 
The eventual progression to advanced prostate cancer and castrate resistance 
corresponds to further increases in PSMA expression (Evans, Smith-Jones et al. 2011). 
PSMA expression in prostate cancer cell membranes is 100- to 1000-fold that in 
normal cells (Silver, Pellicer et al. 1997, Bostwick, Pacelli et al. 1998). Thus, PSMA 
represents a promising target for imaging and therapy of prostate cancer. 
 
2.3. 
Radionuclide-chelating PSMA ligands 
 
Targeted radionuclide therapy (both monoclonal antibody and/or urea based peptides) 
is a state of the art and rapidly developing therapy option for different cancer types. The 
potential advantage of targeted radionuclide therapy is saving the normal tissue while giving 
a high radiation dose to the tumor. 
 
After rather unsuccessful therapy with 90Y-CYT-356 monoclonal antibody (mAb) that binds 
to the intracellular domain of PSMA(Deb, Goris et al. 1996), phases 1 and 2 clinical trials 
utilizing the PSMA mAb J591, radiolabelled with 90Y (Yetrium-90) or 177Lu (Lutetium-177), 
have shown promising results(Bander, Milowsky et al. 2005, Vallabhajosula, Goldsmith 
et al. 2005, Vallabhajosula, Goldsmith et al. 2005, Tagawa, Milowsky et al. 2013). 
 
Also, PSMA has recently been discovered as a promising target for radioisotope based 
approaches, both for PET imaging, for example, using 68Ga-labeled PSMA ligands(Afshar-
Oromieh, Haberkorn et al. 2012, Afshar-Oromieh, Haberkorn et al. 2013, Afshar-Oromieh, 
Zechmann et al. 2014, Chakraborty, Tripathi et al. 2015, Eiber, Nekolla et al. 2015, Uprimny, 
Kroiss et al. 2015), and for therapy, for example, using ligands labeled with either β- or α-
emitting nuclides such as 131I (Iodine-131), 177Lu (Lutetium-177), and 225Ac (Actinium-
225)(Zechmann, Afshar-Oromieh et al. 2014, Ahmadzadehfar, Rahbar et al. 2015, 
Kratochwil, Giesel et al. 2015). Despite encouraging early results, data about intended and 
unintended effects of PSMA- based radioligand therapies (RLTs) are still scarce. 
 
2.3.1. Prior clinical experience with PSMA small molecule(s) in men with prostate 
cancer: 
 

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Results from selective clinical trials using radiolabeled PSMA ligand for diagnosis 
and treatment of prostate cancer are reported here under: 
 
I. 
68Ga-PSMA: 
 
a) Diagnostic value of 68Ga-PSMA-HBED-CC PET/CT imaging in the diagnosis of 
recurrent prostate cancer(Afshar-Oromieh, Avtzi et al. 2015): 
 
The study reports data from a retrospective analysis of 319 patients who underwent 
68Ga-PSMA-ligand PET/CT from 2011 to 2014. The 68Ga-PSMA-HBED-CC solution was 
applied to the respective patient via an intravenous bolus injection (mean of 172.4 
MBq ±70.9, range 40 – 400 MBq, median 161 MBq). A non-contrast-enhanced CT 
scan was performed 1-hour post tracer injection. Histological verification was 
performed in 42 patients after the 68Ga-PSMA-ligand PET/CT. Tracer uptake was 
measured in 901 representative tumor lesions. 82.8% of the patients had at least 
one lesion indicative of PC was detected. Tumor-detection was positively associated 
with PSA level and Androgen deprivation therapy (ADT). Gleason Score and PSA 
doubling time (PSA-DT) were not associated with tumor-detection. The average 
maximum standardized uptake value (SUVmax) of tumor lesions was 13.3 ± 14.6 
(0.7-122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 
different patients, and all other lesions (n = 416) were true-positive or true- 
negative. A lesion-based analysis of sensitivity, specificity, negative predictive value 
(NPV) and positive predictive value (PPV) revealed values of 76.6%, 100%, 91.4% 
and 100%. A patient-based analysis revealed a sensitivity of 88.1%. 
 
 
b) PET imaging with a 68Ga-PSMA ligand for the diagnosis of prostate cancer: 
biodistribution in humans and first evaluation of tumor lesions (Afshar-Oromieh, 
Malcher et al. 2013): 
 
Initial clinical studies with the 68Ga-labeled PSMA-HBED-CC were conducted at 
Heidelberg University Hospital and the German Cancer Research Center to assess 

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the biodistribution of 68Ga-PSMA-HBED-CC in normal tissues and tumor lesions. A 
total of 37 patients with prostate cancer and rising PSA levels were subjected to 
68Ga-PSMA-HBED-CC PET/CT imaging. Quantitative assessment of tracer uptake was 
performed 1 and 3 h post-injection by analysis of mean and maximum standardized 
uptake values (SUVmean/max) of several organs and 65 tumor lesions. 
Subsequently, tumor to background ratios were calculated. 
 
The 68Ga-PSMA-HBED-CC PET/CT images showed intense tracer uptake in both 
kidneys and salivary glands. Moderate uptake was seen in lacrimal glands, liver, 
spleen and in small and large bowel. Quantitative assessment revealed excellent 
contrast between tumor lesions and most normal tissues. Of 37 patients, 31 (83.8 
%) showed at least one lesion suspicious for cancer at a detection rate of 60 % at 
PSA <2.2 ng/ml and 100 % at PSA >2.2 ng/ml. Median tumor to background ratios 
were 18.8 (2.4-158.3) in early images and 28.3 (2.9-224.0) in late images. Within 
healthy organs, kidneys and salivary glands demonstrated the highest radiotracer 
uptake. Lesions suspicious for prostate cancer presented with excellent contrast as 
early as 1-hour after injection with high detection rates even at low PSA levels. 
 
c) 68Ga-labeled PSMA ligand as superior PET tracer for the diagnosis of prostate 
cancer: Comparison with 18F-FECH (Afshar-Oromieh, Haberkorn et al. 2012): 
 
This study was also published by the Heidelberg group, compared 68Ga-PSMA- 
HBED-CC PET/CT imaging to standard choline-based PET/CT. Thirty-seven patients 
with biochemical relapse of prostate cancer [mean prostate-specific antigen (PSA) 
11.1 ± 24.1 ng/ml, range 0.01-116] were retrospectively analyzed after 18F- 
fluoromethylcholine and 68Ga-PSMA PET/CT within a time window of 30 days. 
Radiotracer uptake that  was visually considered as prostate cancer was semi- 
quantitatively analyzed by measuring the maximum standardized uptake values 
(SUVmax) of the scans acquired 1-hour after injection of 68Ga-PSMA complex solution 
(median 132 MBq, range 59-263 MBq) and 18F-fluoromethylcholine (median 237 
MBq, range 114-374 MBq), respectively. In addition, tumor to background ratios 
were calculated. 
 
The results showed a total of 78 lesions characteristic for prostate cancer that were 
detected in 32 patients using 68Ga-PSMA-HBED-CC PET/CT imaging and 56 lesions 
were detected in 26 patients using choline PET/CT. The higher detection rate in 68Ga- 
PSMA-HBED-CC PET/CT imaging was statistically significant (p=0.04). In five patients 
no lesion was found with both methods. All lesions detected by 
18F- 
fluoromethylcholine PET/CT were also seen by 
68Ga-PSMA-HBED-CC PET/CT 
imaging. In 68Ga-PSMA-HBED-CC PET/CT imaging SUVmax was clearly (>10 %) higher in 
62 of 78 lesions (79.1 %) and the tumor to background ratio was clearly (>10 %) 

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higher in 74 of 78 lesions (94.9 %) when compared to 18F-fluoromethylcholine 
PET/CT. 
 
The authors concluded that 68Ga-PSMA-HBED-CC PET/CT can detect lesions 
characteristic for prostate cancer with improved contrast when compared to 
standard 18F-fluoromethylcholine PET/CT, especially at low PSA levels. 
 
 
d) Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA 
ligand for the diagnosis of recurrent prostate cancer: initial experience (Afshar- 
Oromieh, Haberkorn et al. 2014): 
 
Subsequently, the Heidelberg group evaluated the feasibility of PET/MRI imaging 
with 
68Ga-PSMA-HBED-CC. Twenty patients underwent PET/CT 1-hour after 
injection of the 68Ga-PSMA-HBED-CC followed by PET/MRI 3-hours after injection. 
Data from the two investigations were first analyzed separately and then compared 
with respect to tumor detection rate and radiotracer uptake in various tissues. To 
evaluate the quantification accuracy of the PET/MRI system, differences in SUVs 
between PET/CT and corresponding PET/MRI were compared with differences in 
SUVs between PET/CT 1-hour and 3-hours after injection in another patient cohort. 
This cohort was investigated using the same PET/CT system. With PET/MRI, different 
diagnostic sequences, higher contrast of lesions and higher resolution of MRI 
enabled a subjectively easier evaluation of the images. In addition, four unclear 
findings on PET/CT could be clarified as characteristic of prostate cancer metastases 
by PET/MRI. However, in PET images of the PET/MRI, a reduced signal was observed at 
the level of the kidneys (in 11 patients) and around the urinary bladder (in 15 
patients). This led to reduced SUVs in six lesions. SUVmean values provided by the 
PET/MRI system were different in muscles, blood pool, liver and spleen. 
 
The authors concluded that prostate cancer was detected more easily and more 
accurately with Ga-PSMA PET/MRI than with PET/CT and with lower radiation 
exposure. Consequently, this new technique could clarify unclear findings on PET/CT. 
However, scatter correction was challenging when the specific 68Ga-PSMA- HBED-CC 
was used. Moreover, direct comparison of SUVs from PET/CT and PET/MR needs to 
be conducted carefully. 
 
 
II. 
177Lu-PSMA-617: 
 
a) 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer 
(Yadav, Ballal et al. 2016): 

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Thirty-one mCRPC patients with progressive disease despite second-line hormonal 
therapy and/or docetaxel chemotherapy were recruited for the study. All 
underwent 68Ga-PSMA-HBED-CC PET/CT, prior to therapy with 177Lu-DKFZ-PSMA- 
617. The mean activity administered was 5.07 ± 1.85 GBq ranging over one to 
four cycles. Study reported decline in PSA from baseline. Based on biochemical 
response criteria, 25/31 had either complete response, partial response or stable 
disease while 6 continued to have disease progression.  The mean ECOG performance 
status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I 
and grade II hemoglobin toxicity each, while none experienced nephrotoxicity or 
hepatotoxicity. 
 
b) 177Lu-PSMA-617  as  A  Novel  Therapeutic  Option  in  Patients  With  Metastatic 
Castration Resistant Prostate Cancer (Rahbar, Bode et al. 2016): 
 
28 consecutive patients with mCRPC who have exhausted conventional therapeutic 
options were treated with 1 or 2 cycles of 177Lu-PSMA-617. Mean administered 
activity at first therapy was 5.92 ± 0.44 GBq of 177Lu-PSMA-617 and 5.86 ± 0.73 GBq at 
the second therapy. All patients underwent 68Ga-PSMA-PET/CT prior to therapy. Any 
PSA decline occurred in 59% and 75% of patients after 1 and 2 Cycles. Similarly, a PSA 
decline of 50% or greater occurred in 32% and 50%. Hematologic and renal 
parameters changed insignificantly; permanent xerostomia or other safety-related 
toxicity did not occur. The estimated median survival was 29.4 weeks, which was 
significantly longer than survival in the historical best supportive care group. 
 
 
c) PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate 
Cancer with 177Lu-Labeled PSMA-617 (Kratochwil, Giesel et al. 2016): 
 
The authors reported their experience with 177Lu-PSMA-617-targeted radionuclide therapy in a 
case series of mCRPC patients resistant to other treatments. Patients were screened with either 
99mTc-MIP1427 SPECT/CT (500-700 MBq) or 68Ga-PSMA- 11 PET/CT (150 MBq ± 20%). 30 patients 
received 1 to 3 cycles of 177Lu-PSMA-617 (3.7 to 6 GBq per cycle) at 2 months interval. While 21 
had a PSA response, 13 had a >50% PSA decrease. After 3 cycles, 8 of the 11 patients achieved a 
sustained PSA response (>50%) for over 24 weeks, which also correlated with radiologic response 
(decreased lesion number and size). Acute hematological toxicity was mild. Diffuse bone marrow 
involvement was a risk factor for higher grade myelosuppression but could be identified by PSMA 
imaging in advance. Xerostomia, nausea, and fatigue occurred sporadically (<10%). 
Clearance of non-tumor-bound tracer was predominantly renal and widely completed by 
48 hours. Safety dosimetry revealed  kidney doses of approximately 0.75 Gy/GBq, red marrow 
doses of 0.03 Gy/GBq, and salivary gland doses of 1.4 Gy/GBq, irrespective of tumor burden and 
consistent on subsequent cycles. Mean tumor-absorbed dose ranged from 6 to 22 Gy/GBq during 
cycle 1. 
 

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4 
20.3 
44.0 
95.7 
126.3 
57.0 
5 
28.0 
33.2 
34.3 
95.0 
20.3 
6 
24.0 
22.4 
66.0 
142.4 
34.9 
7 
37.5 
44.9 
89.7 
181.3 
56.2 
Mean 
27.2 
30.3 
65.9 
124.1 
37.9 
SD 
6.9 
11.5 
23.7 
35.7 
14.8 
*Organ radiation-absorbed dose constraints in parentheses 
 
d) 177Lu-PSMA Radioligand Therapy of mCRPC: Safety and Efficacy (Baum, 
Kulkarni et al. 2016): 
 
This study analyzed the safety and efficacy of the 177Lu-labeled DOTAGA-based 
PSMA ligand 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA) in patients with 
mCRPC. 56 patients were enrolled and treated with 177Lu-PSMA. 68Ga-PSMA-
(N,N'-bis-[2- hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) 
(68Ga-PSMA) 
PET/CT was used for patient selection and follow-up after 
therapy. 177Lu-PSMA demonstrated high absorbed tumor doses (median 3.3 
mGy/MBq) compared with the levels in normal organs. Parotid glands received 
higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated 
the therapy without any acute adverse effects. Except for mild reversible 
xerostomia in 2 patients, no long-term side effects were observed. A decrease 
in PSA levels was noted in 45 patients (80.4%). Of the 25 patients monitored 
for at least 6 months after 2 or more therapy cycles, 68Ga-PSMA PET/CT revealed 
partial remission in 14, stable disease in 2, and progressive disease in 9 patients. 
Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and 
progressive disease in 7 patients. The median progression-free survival was 13.7 
months, and the median overall survival was not reached during follow-up for 28 
months. 
 
Additional therapeutic studies using different radiolabled PSMA ligands are 
summarized in the table below: 
 
 
 
 
 
 
 
 
 
 

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Table 3: 117Lu-PSMA-617: Pilot studies of targeted radionuclide therapy 
 
Radioligand Therapy 
N 
Dose (GBq), 
Range 
Total doses* 
Reference 
131I-MIP-1095 
28 
2 – 7.2 
1 
Zechmann 
177Lu-DKFZ-PSMA-617 
1 
7.4 
1 
Kratochwil 
177Lu-PSMA-617 
30 
3.7 – 6 
1-3 
Kratochwil 
177Lu-PSMA I&T 
56 
3.6 – 8.7 
1-5 
Baum 
177Lu-PSMA-617 
9 
5.28 – 5.77 
1 
Hohberg 
177Lu-DKFZ-PSMA-617 
5 
3.4 – 3.9 
2 
Delker 
177Lu-DKFZ-PSMA-617 
10 
4.1- 6.1 
1 
Ahmadzedehfar 
177Lu-PSMA-617 
7 
5.5 - 7.4 
1 
Das 
177Lu-PSMA-617 
23 
7.4 
1 
Demir 
177Lu-PSMA-617 
28 
6 
1-2 
Rahbar 
177Lu-PSMA-617 
31 
1.1- 5.5 
1-4 
Yadav 
177Lu-PSMA I&T 
1 
8 
1 
Weineisen 
177Lu-PSMA I&T 
22 
3.4 – 7.4 
1-4 
Heck 
177Lu-PSMA-617 
1 
? 
3 
Schlenkhoff 
177Lu-PSMA-617 
43 
6 
1-4 
Zimbelmann 
177Lu-PSMA-617 
5 
5.8 – 7.4 
1 
Chakraborty 

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e) German collaborative publication 
 
The largest published experience is a retrospective case series of 145 patients with 
mCRPC treated at 12 centers in Germany between February, 2014 and July, 
2015.(Rahbar et al, J Nuc Med 2017) While not a prospective research study, 
in general the patients included men who had tumor progression despite 
abiraterone 
(64%) and/or enzalutamide (52%) and had either received 
chemotherapy (54%) or were unfit/refused chemotherapy. Patients also received 
radium-223 if able/eligible (17%). Treatment was administered only if PSMA uptake 
was demonstrated on PSMA imaging. On average, 5.9 GBq was administered per 
dose (range 2-8 GBq). Retreatment was allowed at physician discretion. Of 
assessable patients (n=99), 60% had PSA decline after initial treatment, with at least 
50% PSA decline occurring in 40%. Safety was assess by retrospective chart review 
with charts available in all 145 and labs available in 121 (83.4%). Grade >2 
hematologic AEs occurred in 12% (grade 3/4 anemia in 10%, grade 3/4 leukopenia 
in 3%, and grade 3/4 thrombocytopenia in 4%). Other AEs of any grade that 
occurred >4% include AST elevation 19%, fatigue 13%, renal failure 12%, ALT 
elevation 8%, xerostomia 8%, nausea 6%, dysgeusia 4%. While retrospective in 
nature, this represents the largest published series and demonstrates 
some 
biochemical anti-tumor activity without a high occurrence of high-grade adverse 
events. 
 
2.4. 
Investigational Agent 
 
During the last two decades, many efforts have been undertaken to develop PSMA- 
ligands(Hillier, Maresca et al. 2009, Barrett, Coleman et al. 2013). One of these 
ligands, the small molecule Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)], also known 
as PSMA-11®, PSMAHBED, Glu-CO-Lys(Ahx)-HBED-CC, DKFZ-PSMA-11, PSMA-HBED- 
CC, 
PSMA-HBED, PSMA or ProstamedixTM, developed at the German Cancer Research 

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Center Heidelberg (DKFZ), has become the most clinically used radiotracer. This 
compound shows a strong binding affinity to PSMA as well as a highly efficient 
internalization into PCa cells(Eder, Schafer et al. 2012, Eder, Neels et al. 2014). PET/CT- 
imaging with 68Ga-PSMA-11 has demonstrated this novel method as an important 
imaging modality for diagnosing recurrent PCa(Afshar-Oromieh, Haberkorn et al. 
2014, Afshar-Oromieh, Zechmann et al. 2014, Afshar-Oromieh, Avtzi et al. 2015, Eiber, 
Maurer et al. 2015). Perera et al., did systematic review of 68Ga-PET articles and 
Sixteen articles involving 1309 patients were analyzed. On per-patient analysis, the 
summary sensitivity and specificity were both 86%. On per lesion analysis, the 
summary sensitivity and specificity were 80% and 97%, respectively(Perera, Papa et 
al. 2016). 
 
Meanwhile modifications of PSMA-11 have resulted in the development of another 
novel small molecule PSMA-ligand, PSMA-617. In preclinical studies, this ligand 
showed a significantly improved binding affinity to PSMA as well as a highly efficient 
internalization into PCa cells(Benesova, Schafer et al. 2015). PSMA-617 can be labeled 
with radionuclides like 68Ga(Gallium-68), 177Lu(Lutetium-177), 111In(Indium-111), and 
90Y(Yetrium-90) and, therefore, be used for PET-imaging as well as for radioligand- 
based therapy. Preclinical assays of PSMA-617 showed Ki values of 2.3 ± 2.9 nM, 
demonstrating a significant improvement compared to PSMA-11 (12.0 ± 2.8 nM). 
Based on these results, PSMA-617 has one of the highest binding affinities to the 
PSMA receptor, which have been published, so far. In preclinical studies, tumor-to- 
background ratios of up to 1,058 were observed at 24h post infusion. In addition, the 
internalization of the PSMA-617 into the PCa cells is highly effective: Internalized 
fraction: 17.67 ± 4.34 % IA/106 LNCaP cells (PSMA-11: 9.47 ± 2.56 % IA/106 LNCaP 
cells)(Eder, Schafer et al. 2012, Benesova, Schafer et al. 2015). Since 2013, 177Lu- 
PSMA-617 has been increasingly used for radioligand therapy of metastatic PCa 
patients in several centers (Bad Homburg, Bonn, Cologne, Freiburg, Heidelberg, 
Istanbul, Melbourne, LMU Munich, Münster)(Kratochwil, Giesel et al. 2015). 
 
Diagnostic evaluation with 68Ga-PSMA-HBED-CC followed by therapy with 177Lu- 
PSMA-617 is thus opening a new theranostic potential of nuclear medicine. Initial 
studies in patients have demonstrated the utility of 177Lu-PSMA-617 for the treatment 
of disseminated prostate cancer(Ahmadzadehfar, Rahbar et al. 2015, Kratochwil, 
Giesel et al. 2015). Dosimetric evaluation has shown that the critical organs are the 
parotid glands, and that up to 27 GBq (~700 mCi) of 177Lu-PSMA-617 can be 
administered without crossing the 30 Gy critical dose threshold to the parotid 
glands(Kabasakal, AbuQbeitah et al. 2015). 
 
2.5. 
Rationale 
 
A. Rationale for the appropriate radioisotope: 

1 9  
P R O T O C OL # 1 6 0 9 0 1 7 5 4 2  
V E R SI O N 6 , D A T E: 1 0/ 2 8/ 2 0 2 1  
 
 
 
As  d escri b e d  e arli er,  t ar g et e d r a di o n ucli d e t h er a p y as  a tr e at m e nt c h oic e f or m C R P C  
p ati e nts  is b ei n g  acti v ely  st u di e d at  v ari o us  c e nt ers i n t h e w orl d  ( es p eci all y E ur o p e  
a n d  A ustr ali a).  W h e n  c o m p ar e d t o m o n ocl o n al  a nti b o di es, t h e l o w m ol ec ul ar  w ei g ht  
c o m p o u n ds h a v e  a hi g h er  p er m e a bility  i nt o s oli d t u m ors, off er  a si g nific a nt a d v a nt a g e  i n 
ac hi e vi n g  hi g h er  t u m or u pt a k e  as  w ell  as   a hi g h  p erc e nt a g e  of  s p ecific bi n di n g.  
A d diti o n all y,  s m all m ol ec ul es  dis pl a y  m or e  r a pi d tiss u e distri b uti o n  a n d  f ast er bl o o d  
cl e ar a nc e c o m p ar e d wit h  i nt act i m m u n o gl o b uli ns. T h es e  pr o p erti es  oft e n  l e a d t o a n  
e n h a nc e d  t ar g et t o n o n -t ar g et tiss u e r ati o, w hic h  is i m p ort a nt n ot  j ust f or i m a gi n g b ut  
als o  f or s ucc essf ul a p plic ati o n of  t h er a p e utic a bs or b e d d os es.  
 
F oll o wi n g  t u m or l oc aliz ati o n, t h e r a di o m et al is tr a p p e d wit hi n  t h e c ell, l e a di n g t o 
hi g h er  accr eti o n  of  r a di o n ucli d e b y  t h e t u m or. 1 3 1I h as  l o w er e n er g y  β p articl es  a n d  
l o n g er p h ysic al  h alf -lif e ( m ax β - 0. 6 1  M e V;  T½ = 8. 0 4  d)  c o m p ar e d t o t h at wit h  9 0Y( m ax  
β - 2. 2 8  M e V;   T½ = 2. 6 7  d).  B ec a us e  of  its hi g h er  e n er g y,  9 0Y m a y  b e  a p pr o pri at e  f or 
l ar g er t u m ors w hil e  1 3 1I m a y  b e  m or e  cyt ot oxic f or s m all er, micr o -m et ast atic  l esi o ns. 
Si nc e  9 0Y d o es  n ot  e mit  a ny  γ p h ot o ns,  t h e c orr es p o n di n g 1 1 1I n l a b el e d a nti b o di es  ar e  
g e n er all y  us e d  as  c h e mic al a n d  bi ol o gic al  s urr o g at es t o st u d y bi o distri b uti o n  a n d  
esti m at e  r a di ati o n d osi m etr y  of  9 0Y l a b el e d a nti b o di es.  I n a d diti o n  t o 9 0Y,  t h e 
l a nt h a ni d e r a di o m et al, 1 7 7L u ( m ax β - 0. 4 9 7  M e V;  T½ = 6. 7 4  d)  is p ot e nti all y  us ef ul  f or 
RI T.  Als o  1 7 7L u h as  us ef ul  g a m m a  p h ot o ns   (γ = 0. 2 1  M e V)  f or bi o distri b uti o n  a n d  
d osi m etr y  st u di es. T h er ef or e,  1 7 7L u m a y h a v e t h e a d v a nt a g es of  b ot h 1 3 1I a n d  9 0Y a n d   
m a y  b e  t h e m ost  a p pr o pri at e  r a di o n ucli d e f or t h er a py. T y p e  of  r a di ati o n a n d  e n er g y  
ass oci at e d  wit h  s o m e of  t h e pr e v al e nt  r a di ois ot o p es is s u m m ariz e d i n t h e t a bl e 
h er e u n d er:  
 
T a bl e  4:  R a di o n ucli d es  f or T h er a p y  
 
 

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B. Rationale for Dose-Fractionated regimen: 
 
Pre-clinical models do not always predict toxicity in humans, but based upon the available 
data, the pre-clinical models combined with animal and human dosimetry data have 
predicted the toxicity seen with anti-PSMA radioimmunotherapy (i.e. radiolabeled 
monoclonal antibody) and anti-PSMA radioligand therapy (i.e. radiolabeled peptides). 
With radioimmunotherapy, one would predict that the  dose-limiting organ is bone 
marrow, based upon the kinetics / circulation time and exposure of the bone marrow to 
circulating radiolabeled antibody before it gets into tumors days later. With radioligand 
therapy, one would predict that there is comparatively very little bone marrow exposure, 
but there would be more exposure to sites of PSMA expression that are not exposed to 
(bulky) full-length antibodies. Based upon the available data, this has been born out in 
human subjects (for radioimmunotherapy) and human patients (for radioligand therapy). 
 
We have conducted a series of overlapping, but sequential phase I and II clinical trials 
evaluating radiolabeled anti-PSMA monoclonal antibody J591. These studies are 
summarized immediately below with additional details about dose-fractionation (as 
requested) following the summary. 
 
• Initial (1st in human) studies of trace-labeled 111In-DOTA-J591: demonstrated 
safety and targeting of J591 in men with mCRPC (Bander 2003, Nanus 2003, 
Morris 2005) 
• Phase I (single-dose) 90Y-J591: demonstrated safety, targeting, and preliminary  
• Phase I (single-dose) 
177Lu-J591: demonstrated safety, targeting, and 
preliminary efficacy in mCRPC (Bander 2005) 
• Phase II (single dose) 177Lu-J591: demonstrated efficacy in initial 32 subjects, 
subsequent analysis with significant dose-response and preliminary biomarkers 
(Tagawa 2008) 
• Phase I fractionated-dose 177Lu-J591 dose-escalation study: demonstrated 
safety, confirming hypothesis that higher cumulative doses could be 
administered as a split dose (Tagawa 2010) 
• Phase II (single dose) 177Lu-J591 expansion phase: confirmed efficacy and dose- 
response with exploratory biomarkers (Tagawa 2013) 
• Phase I fractionated-dose 177Lu-J591 plus docetaxel: demonstrated the ability to 
safely combine fractionated 177Lu-J591 with docetaxel 75 mg/m2 in men with 
mCRPC (Tagawa 2014) 
• Phase I fractionated-dose 177Lu-J591 expansion phase: provided efficacy data, 
confirmed dose-response, continued analysis of exploratory biomarkers (Tagawa 
2016) 
 
Taken together, with >250 patients treated on these sequential clinical trials, we have 

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drawn the following conclusions: (i) there is a clear dose-response with more responses 
and longer survival at higher doses; (ii) there is clear dose-toxicity response in terms of 
myelosuppression (which is both predictable and reversible); (iii) dose-fractionation allows 
higher cumulative dose with comparatively less toxicity (including allowing concurrent 
chemotherapy);  and (iv) without pre-selection for PSMA expression, approximately 90% 
have accurate tumor targeting, though the small minority with low/no PSMA expression by 
imaging have a lower likelihood of response. While 177Lu-J591 mAb demonstrated 
significant efficacy, the major limitation in the optimization of therapeutic dose is the 
hematological toxicity (described in greater detail below). 
 
With a single-dose, 70 mCi/m2 of 
177Lu-J591 was the MTD, with dose-limiting 
myelosuppression in those receiving 75 mCi/m2 (with 2 of 3 with dose-limiting 
hematologic toxicity).[Bander 2005] In the phase II study, this was confirmed with 70 
mCi/m2 of 177Lu-J591 being tolerable with reversible myelosuppression, but with a 
significant amount of manageable grade 4 myelosuppression (including approximately 
40% platelet transfusion).[Tagawa 2013] 
 
In radiotherapy, the anti-tumor response has been thought to be primarily due to induction 
of apoptosis by radiation (Meyn 1997, Mirzaie-Joniani 2002, Kroger 2001, DeNardo 2002). 
However, the degree of anti-tumor response following the administration of targeted 
radionuclides depends on several variables, especially total (cumulative) radiation dose to 
the tumor, dose-rate and tumor radiosensitivity. Single-agent RIT, although potentially 
useful for slowing solid tumor growth, has not been effective in  controlling aggressive 
tumors, which often have p53 and other mutations and are less susceptible to apoptosis, 
the apparent mechanism of cell death from low dose-rate radiation.(Burke 2002) Bone 
marrow is the dose-limiting organ in RIT in the absence of marrow reconstitution.(Larson 
2015, Ali 2016) Dose-fractionation is a practical strategy to decrease the dose to bone 
marrow while increasing the cumulative radiation dose to the tumor at an optimal dose-
rate.(DeNardo 2002, Shen 2002, O’Donoghue 2000) The main reason for using dose 
fractionation is to take advantage of the difference between early-responding and late-
responding tissues. The radiation effect on early-responding tissue can be reduced by 
prolonging the treatment time and dose fractionation. The radiation effect on late-
responding tissues will not be changed significantly if the total 
dose is not 
changed.(DeNardo 2002, O’Donoghue 2000) Preclinical data have shown that 
dose 
fractionation or multiple low dose treatments can decrease toxicity while increasing the 
efficacy.(Kroger 2001, Vriesendorp 1993, Buchsbaum 1995) Similarly, there is some clinical 
evidence that bone marrow toxicity can be reduced with some modest increase in the 
cumulative maximum tolerated dose.(DeNardo 1998, Steffens 1999, Hindorf 2003) Based 
upon these data, we performed two sequential studies of fractionated dose 177Lu- J591. 
 
As described in in the paragraph above, dose-fractionation of external-beam radiation as 
well as radioimmunotherapy has been demonstrated to have less toxicity and might be 
more efficacious by delivering active radiation over a more prolonged period of time to 

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tumor cells. Based upon the half-life of 177Lu-J591 combined with the kinetics of 
radiolabeled intact monoclonal antibody, we chose a 2-week interval between 177Lu-J591 
doses: 
 
i) Phase   I   trial   of   fractionated   dose   177Lu−J591 
in   men   with   metastatic 
castration−resistant prostate cancer (Tagawa et al 2010, Tagawa et al 2016) 
 
Men with progressive metastatic CRPC received 2 fractionated doses two weeks apart. 
Initially, 6 cohorts of 3-6 pts got 2 doses of 177Lu-J591 2 weeks apart (20 mCi/m2, 
escalating to 45 mCi/m2 x2). Subsequently, pts enrolled in 2 expansion cohorts at the 
recommended phase 2 doses (RP2D). Planar 177Lu-J591 imaging was semi- quantitatively 
scored. The endpoints were PSA changes and survival (OS); as well as CTC count 
(CellSearch) changes in the expansion cohorts. 49 patients, with median age 74.1 years 
(range 55-95), median PSA of 44.9 ng/mL (1.9-766.5); 83.7% with bone, 61.2% with lymph 
node, 40.8% with visceral metastasis. 8.2% were CALGB (Halabi) low, 34.7% were 
intermediate, 57.1% were in high-risk group. RP2D’s of fractionated 177Lu-J591 were 40 
mCi/m2 x2 or 45 mCi/m2 x2 with option for GCSF. PSA changes for the low dose group 
were reported as 6.3% showing >50% PSA decline, 12.5% reporting >30% PSA decline, and 
37.5% with any PSA decline. within RP2D group 21.2% showing >50% PSA decline, 42.4% 
reporting >30% PSA decline, and 66.7% with any PSA decline. The median overall survival 
for low dose group was 14.6 months and for RP2D group was 27.7 months. Accurate 
targeting of 177Lu-J591 was seen in 79.6%. Patients with lower PSMA expression by 
imaging were less likely to respond (p=0.07). Of 25 with CTC counts, 14 declined, 8 stably 
favorable, and 3 increased. RP2D was associated with more PSA declines (p=0.036) and 
longer OS (p=0.004), even after controlling for CALGB prognostic grouping (adjusted HR 
0.42 [95% CI 0.21, 0.84] p=0.01). Predictable, reversible myelosuppression was seen. 36 
(73.5%) patients had grade 3/4 heme toxicities; 19 (57.6%) had Grade 4 heme toxicities in 
RP2D cohorts with 45.4% receiving prophylactic platelet transfusions (median 1, range 1-
4) and 6 GCSF. 14 (28.6%) had infusion reactions (without pre-meds), with 1 patient having 
Grade 2 infusion reaction leading to withdrawing from the study prior to his 2nd dose. 5 
(10.2%) had transient Gr 1/2 AST/ALT. This study concluded that fractionated 177Lu−J591 
is well tolerated with predictable, reversible myelosuppression and PSA and CTC declines. 
Additionally, with dose-fractionation, the cumulative dose MTD is 14−28% higher than 
single dose MTD with similar toxicity. 
 
 
Table 5: Toxicities data from Phase 2 single dose 177Lu-J591 Study and Phase 1 
fractionated 177Lu-J591 study: 
 
 
Single Dose 
Fractionated Dose 
Cumulative 
Dose (mCi/m2) 
65 
70 
70 
(35 + 35) 
80 
(40 + 40) 
90 
(45 + 45) 

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Platelets Grade 
4 
27% 
56.3% 
40% 
50% 
58.8% 
Platelet 
Transfusion 
7% 
41% 
0% 
31.3% 
52.9% 
Neutropenia 
Grade 4 
0% 
37.5% 
0% 
31.3% 
29.4% 
Febrile 
Neutropenia 
0% 
2.1% 
0% 
0% 
5.8% 
 
In addition, fractionated dosing allowed concurrent dosing with myelosuppressive 
chemotherapy: 
 
ii) Phase I trial of fractionated dose 177Lu−J591 plus docetaxel/prednisone in men with 
metastatic castration−resistant prostate cancer (Tagawa et al 2014, Batra et al 2015): 
 
Following   progression   on   primary   hormonal   therapy,   chemotherapy   can   offer 
symptomatic improvement as well as incremental survival benefit.  However, responses  
are transient and all men eventually suffer from progression of disease as described 
above with single−agent anti−PSMA based radioimmunotherapy. The combination of 
taxane chemotherapy with radiotherapy has been used in several diseases because of 
the radiosensitizing effects of taxane−based chemotherapy. In addition to favorable 
results from fractionated RIT and the radiosensitizing effects of taxane−based 
chemotherapy, it is hypothesized that the additional debulking by chemotherapy will 
overcome some of the limits imposed by the physical characteristics of 177Lu. Based upon 
this theory, a phase I trial of docetaxel and prednisone with escalating doses of 
fractionated 177Lu−J591 was initiated. 15 men with median age 69.1 (49.3-80.8) were 
enrolled. The MTD/RP2D of 177Lu-J591 was 40 mCi/m2x2 doses (delivered with cycle 3 of 
docetaxel), with 73.3% showing >50% PSA decline, 80.0% reporting >30% PSA decline, 
and 86.7% with any PSA decline. Predictable, reversible myelosuppression was seen. Even 
at the highest dose level, no dose limiting toxicity was observed, with short-term / 
reversible grade 4 neutropenia in 33% and grade 4 thrombocytopenia in 13%. 
 
Aside from the overall rates of dose limiting toxicity, the combined studies have also 
consistently demonstrated the kinetics of myelosuppression, with nadir neutrophil and 
platelet counts 28-32 days following the last administered dose of 177Lu-J591. 
 
With small-molecule radioligand therapy, both the predicted and reported toxicities are 
much different.  One would predict very little myelosuppression, but if it were to occur, 
it would be expected to have kinetics similar to (or more quickly than) typical cytotoxic 
chemotherapy, as the clearance of the myelotoxic drug is quick (minutes to hours rather 
than days to weeks for antibodies). In fact (with the known caveats of retrospective 
studies), this is the reported human experience. Essentially no grade 4 neutropenia or 

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thrombocytopenia has been reported within months of exposure to 177Lu-PSMA 
radioligands (see details below). 
 
While we have published on the long-term follow up with 177Lu-J591 with no cases of 
attributable permanent myelosuppression and/or myelodysplasia/leukemia, results are 
unknown with 177Lu-PSMA RLT. The available data with up to 6 months of reported post- 
treatment follow up are: 
1. No attributable grade 4 hematologic (or other) toxicity has been reported at any 
time (the one case of grade 4 thrombocytopenia is reported with a patient 
with grade 4 platelet count at pre-treatment baseline) 
2. Repeat dosing has been performed in many patients at 8-12 weeks after initial 
dosing and in all cases, white blood cell count and platelet counts were 
acceptable prior to subsequent doses (up to 5 doses, with dose #5 approximately 
40 weeks after dose #1) 
 
The Table below is a summary of the prior summary anti-PSMA RLT Table which includes 
the severe leukocyte/neutrophil and platelet count rates following 177Lu-radiolabeled 
anti-PSMA peptides. In addition to the Table, a multicenter review of 177Lu-PSMA-617 
data of 82 patients receiving at single dose (mean 5.9 GBq) revealed no grade 4 
hematologic or non-hematologic toxicity.[Rahbar et al, J Nucl Med 2016] 
 
Table 6: Toxicities data following anti-PSMA radioligand therapy 
 
Radioligand Therapy 
N 
Dose 
(GBq), 
Range 
Total 
doses 
Grade 4 
neutropenia 
Grade 4 
platelets 
Reference 
177Lu-PSMA-617 
30 
3.7 – 6 
1-3 
0 
0* 
Kratochwil et al 
2015 
177Lu-PSMA I&T 
56 
3.6 – 8.7 
1-5 
0 
0 
Baum et al 2016 
177Lu-PSMA-617 
9 
5.28 – 5.77 
1 
NR 
NR 
Hohberg et al 
2016 
177Lu-DKFZ-PSMA- 
617 
5 
3.4 – 3.9 
2 
NR 
NR 
Delker et al 2015 
177Lu-DKFZ-PSMA- 
617 
10 
4.1- 6.1 
1 
0 
0 
Ahmadzedehfar 
et al 2016 
177Lu-PSMA-617 
7 
5.5 - 7.4 
1 
NR 
NR 
Das et al 2016 
177Lu-PSMA-617 
23 
7.4 
1 
NR 
NR 
Demir et al 2016 
177Lu-PSMA-617 
28 
6 
1-2 
0 
0 
Rahbar et al 
2016 
177Lu-PSMA-617 
31 
1.1- 5.5 
1-4 
0 
0 
Yadav et al 2016 
177Lu-PSMA I&T 
2 
5.7 - 8 
1 
0 
0 
Weineisen et al 
2015 

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177Lu-PSMA I&T 
22 
3.4 – 7.4 
1-4 
0 
0 
Heck et al 2016 
177Lu-PSMA-617 
43 
6 
1-4 
0 
0 
Zimbelmann et 
al 2016 
177Lu-PSMA-617 
5 
5.8 – 7.4 
1 
0 
0 
Chakraborty et 
al 2016 
*One patient had pre-treatment baseline platelet count of grade 4 
NR = not reported 
 
A dose fractionated regimen provides the theoretic benefit of higher cumulative 
radiation dose to the target tissue/organ while limiting toxicities secondary to non- specific 
binding of the radiolabeled ligand. In addition to the toxicity data provide above, our 
group has consistently seen evidence of dose-response (see Table below), justifying a dose-
escalation study. 
 
Group 
N 
Any PSA 
decline 
> 30% PSA 
decline 
> 50% PSA 
decline 
Median OS mo 
[95% CI]* 
Total 
49 
55.1% 
32.7% 
16.3% 
22.9 [16.2, 29.7] 
Low doses 
16 
37.5% 
12.5% 
6.3% 
14.6 [9.9, 19.4] 
RP2D 
33 
66.7% 
42.4% 
21.2% 
27.7 [15.8, 39.6] 
40 x2 cohort 
16 
50.0% 
25.0% 
12.5% 
19.6 [9.1, 30.2] 
45 x2 cohort 
17 
87.5% 
58.8% 
29.4% 
48.3 [16.0, 80.6] 
 
 
2.6. 
Risk/Benefit Assessment 
 
Based on findings by groups based in Europe, the most common toxicities reported 
are leukopenia, anemia, thrombocytopenia, transaminitis, fatigue, renal failure, and 
xerostomia. All of these toxicities are reportedly mild and transient. mCRPC patients 
treated with RIT using 177Lu-PSMA-617 have shown improved survival. 
 
2.7. 
Correlative Studies Background 
 
2.7.1. Archival tissue and Cell-Free plasma DNA to assess genomic alterations: 
 
PC is a clinically heterogeneous disease, with marked variability in patient outcomes. Defining 
the genomic alterations in PC has improved classification of tumors: 50% harbor TMPRSS2-
ERG gene fusion, and ERG+ and ERG- classes of prostate cancer are recognized as distinct 
biological entities. Recently described were mutations in SPOP in up to 15% of PC, and SPOP 
mutations define a novel, ERG- molecular subclass of PC. The ERG+ and SPOP mutant 
subclasses of PC remain relevant, at roughly similar frequencies, in advanced disease. These 
findings raise the possibility that PC could transition from a poorly understood, clinically 
heterogeneous disease to a collection 
of homogenous subtypes, identifiable by molecular 
criteria, associated with distinct risk profiles, and potentially amenable to specific therapeutic 
strategies. In PC models, ERG expression results in relative resistance to ionizing radiation. 

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Conversely, preliminary data from our collaborators has shown that SPOP mutant prostate 
cancers show increased genomic instability, that SPOP plays a role in double strand DNA break 
repair, and SPOP mutations result in increased sensitivity to DNA damage. Finally, PC with other 
specific defects in DNA repair genes (such as BRCA2) have also been shown to be preferentially 
sensitive to DNA damaging therapy. Therefore, distinct molecular phenotypes of prostate 
cancer may have predictable and exploitable differences in sensitivity to DNA damaging agents 
such as Lutetium-177. We will collect archival tumor tissue (preferentially from metastatic 
biopsies) plus a  single-sample of blood for germline control with the plan for 
utilization of our CLIA- approved whole exome platform.(Beltran 2012, Beltran 2015, 
Beltran 2016) In addition, we will collect samples for cfDNA analysis prior to 
treatment, at 1 month, and at 3- months, using the platform developed in 
collaboration with others as part of a PCF 
Challenge Award and other 
studies.(Beltran 2016, Romanel 2015, Carreira 2014) As discussed below, we will 
describe findings from this exploratory endpoint in this study with the plan to analyze 
these findings with relationship to efficacy and toxicity across current and prior 
studies, in particular at doses found to have efficacy. 
 
 
2.7.2. CTC Count: 
 
Circulating tumor cell (CTC) counts via the CellSearch platform were demonstrated to 
be prognostic in men with advanced prostate cancer prior to systemic therapy and a 
“conversion” from an unfavorable count (>5 CTCs/7.5 mL) was associated with a median 
similar to those starting with favorable counts, leading to clearance of this particular 
test by the FDA (de Bono, Scher et al. 2008). More recently, the combination of 
CellSearch CTC enumeration and serum LDH have been demonstrated to have 
prognostic value, meeting Prentice criteria for survival surrogacy in the setting of 
abiraterone/prednisone treatment in men with mCRPC 
previously treated with 
docetaxel (Scher, Heller et al. 2015) 
 
2.7.4 Immune assays 
 
While there are only a selected number of prospectively performed studies of PSMA- 
targeted radionuclide therapy, it is clear that there are a subset that respond well for a 
durable period of time (i.e. “the tail of the curve”) and those that do not respond or 
have PSA declines for a short period of time. It has been proposed that radiation may 
generate immune responses with an abscopal response documented. As in most 
cases, PSMA-targeted radionuclide therapy successfully targets (by imaging) all known 
sites of disease, an abscopal response is difficult to document. However, sublethal 
doses of radiation may still well generate an immune response. We plan to study this 
effect with assays of immunogenic cell death and antigen spread. We will assess 
immunogenic cell death by assessing high mobility group box 1 (HMGB1) in serum and 

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calreticulin on CTCs. We will also collect serum and assay antigen spread by comparing 
pre-treatment to post-treatment with cancer-associated protein microarrays. 
 
2.7.5 Molecular imaging: 
 
While there is an increasingly large body of clinical data for PSMA PET imaging (above), 
reproducibility of imaging has not been well studied in a test—retest format. 
 
 
3. 
SUBJECT SELECTION 
 
3.1. 
Study Population 
 
Subjects who have documented progressive metastatic CRPC disease, who meet the 
inclusion and exclusion criteria will be eligible for participation in this study. 
 
3.2. 
Inclusion Criteria 
 
1. 
Histologically or cytologically confirmed adenocarcinoma of prostate 
 
2. 
Documented progressive metastatic CRPC based on Prostate Cancer 
Working Group 3 (PCWG3) criteria, which includes at least one of the 
following criteria: 
 PSA progression 
 Objective radiographic progression in soft tissue 
 New bone lesions 
3. 
ECOG performance status of 0-2 
 
4. 
Have serum testosterone < 50 ng/dL. Subjects must continue primary 
androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) 
if they have not undergone orchiectomy. 
 
5. 
Have previously been treated with at least one of the following in any disease 
state: 
 Androgen receptor signaling inhibitor (such as enzalutamide) 
 CYP 17 inhibitor (such as abiraterone acetate) 
 
6. 
Have previously received taxane chemotherapy (in any disease state), 
been determined to be ineligible for taxane chemotherapy by their 
physician, or refused taxane chemotherapy. 
 
7. 
Age > 18 years 

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8. 
Patients must have normal organ and marrow function as defined below: 
o Absolute neutrophil count 
>2,000 cells/mm3 
o Hemoglobin 
≥9 g/dL 
o Platelet count 
>150,000 x 109/µL 
o Serum creatinine 
<1.5 x upper limit of normal (ULN) 
or calculated creatinine clearance 
≥ 60 mL/min/1.73 m2 by Cockcroft-
Gault 
o Serum total bilirubin 
<1.5 x ULN (unless due to Gilbert’s 
syndrome 
in which 
case direct 
bilirubin must be normal 
o Serum AST and ALT 
<3 x ULN in absence of liver 
metastases; < 5x ULN if due to 
liver metastases  (in  both  
circumstances bilirubin must meet 
entry criteria) 
 
9. 
Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.3. 
Exclusion Criteria 
 
1. 
Implantation of investigational medical device ≤4 weeks of Treatment Visit 
1 (Day 1) or current enrollment in oncologic investigational drug or device 
study 
2. 
Use of investigational drugs ≤4 weeks or <5 half-lives of Cycle 1, Day 1 
or current enrollment in investigational oncology drug or device study 
3. 
Prior systemic beta-emitting bone-seeking radioisotopes 
 
4. 
Known active brain metastases or leptomeningeal disease 
 
5. 
History of deep vein thrombosis and/or pulmonary embolus within 1 
month of C1D1 
 
6. 
Other serious  illness(es)  involving  the  cardiac,  respiratory,  CNS,  renal, 
hepatic or hematological organ systems which might preclude completion 
of this study or interfere with determination of causality of any adverse 
effects experienced in this study 
 
7. 
Radiation therapy for treatment of PC ≤4 weeks of Day 1 Cycle 1 

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8. 
Patients on stable dose of bisphosphonates or denosumab, which have 
been started no less than 4 weeks prior to treatment start, may continue 
on this medication, however patients are not allowed to initiate 
bisphosphonate/Denosumab therapy during the DLT-assessment period 
of the study. 
 
9. 
Having partners of childbearing potential and not willing to use a method 
of birth control deemed acceptable by the principle investigator and 
chairperson during the study and for 1 month after last study drug 
administration 
 
10. 
Currently active other malignancy other than non-melanoma skin cancer. 
Patients are considered not to have “currently active” malignancy if they 
have completed any necessary therapy and are considered by their 
physician to be at less than 30% risk of relapse. 
 
11. 
Known history of known myelodysplastic syndrome 
 
 
4. 
OVERVIEW OF STUDY DESIGN AND METHODOLOGY 
 
4.1. 
Study Design 
 
This is an open−label, single−center Phase I dose escalation trial designed to 
determine the cumulative MTD in a dose fractionation regimen in which 177Lu-PSMA- 
617 will be given in 2 doses, 2 weeks apart. The dose escalation will start at 100 mCi 
(3.7 GBq) x 2 doses and escalate in increments of 50 mCi (1.85 GBq) for each dose 
to a maximum of 300 mCi (11.1 GBq) x 2 doses. 
 
Patients must have documented progressive metastatic CRPC disease based on 
Prostate Cancer Working Group 3 (PCWG3) criteria in order to be eligible for 
enrollment. Upon meeting the inclusion and exclusion criteria and signing the 
informed consent and HIPPA form, subjects will undergo the screening. As part of the 
screening, subjects will get a single dose of 68Ga-PSMA-HBED-CC and will have 
a PET/CT. Nuclear Medicine physician(s) will review the PET/CT scans to 
document PSMA expression at tumor site(s). 
  
177Lu-PSMA-617 dose fractionation regimen will be performed in patients with 
documented progressive metastatic CRPC. The 177Lu dose (50 mCi – 300 mCi or 1.85 
– 11.1 GBq) will be escalated in up to 6 different dose levels (3+3 at each dose level). 
Initially 3 subjects will be enrolled in Cohort 1 (100 mCi or 3.7 GBq x2 doses 2 weeks 
apart) and if any grade ≥3 toxicity is reported, then the next 3 subjects will be enrolled 

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in Cohort -1 (50 mCi or 1.85 GBq x2 doses 2 weeks apart) before proceeding to higher 
dose cohorts. Subjects will have Lutetium-177 Planar/SPECT Imaging on Day 8 
(±1day) after the first dose of 177Lu-PSMA-617. Optimal images will be performed on 
selected consenting subjects between initial treatment on D1 and D4 and prior to 
treatment #2 on D15. The enrollment ceiling of the dose escalation portion of the 
study is up to 46 study participants (six groups, with 3+3 subjects in each group). Each 
patient would receive 2 doses of the investigational agent, 2 weeks apart. The total 
dose received in 2 treatments will be 100 – 600 mCi (3.7 – 22.2 GBq). 
 
Upon completion of investigational treatment with 2 doses of 177Lu-PSMA-617, 
subjects will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT at the end 
of study visit to document treatment response. Subsequently survival data and 
additional treatment(s) information will be captured from their routine Standard of 
care (SOC) visits. 
 
Table 7: Treatment Plan with 177Lu-PSMA-617  
 
Cohort 
Treatment Dose mCi (GBq) 
Total 
Dose 
Subjects 
Day 1 
Day 15 
mCi ( 
GBq) 
(n) 
-1 
50 (1.85) 
50 (1.85) 
100 ( 
3.7) 
1-6 
1 
100 (3.7) 
100 (3.7) 
200 ( 
7.4) 
1-6 
2 
150 (5.55) 
150 (5.55) 
300 ( 
11.1) 
1-6 
3 
200 (7.4) 
200 (7.4) 
400 ( 
14.8) 
3-6 
4 
250 (9.25) 
250 (9.25) 
500 ( 
18.5) 
3-6 
5 
300 (11.1) 
300 (11.1) 
600 ( 
22.2) 
3-6 

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4.2 
Rationale for Dose-Escalation Strategy: 
 
This study will use a modified phase I 3+3 dose-escalation study design, with the planned 
initial and subsequent cohorts described in Table 7. This study design is well-described 
and accepted by the clinical and scientific community, so we will not provide complete 
details here. Briefly, this design is constructed to reduce the chance of escalating the dose 
when the probability of DLT is high, and increase the chance of escalating the dose when 
the probability of DLT is low. Given the fact that some pre-existing clinical efficacy and 
toxicity data exists with the study drug, we will allow up to 6 subjects to be treated at 
a given dose-level even in the absence of DLT. The MTD is defined as the highest dose 
level with an observed incidence of DLT in no more than one out of six patients treated 
at a particular dose level. The dose escalation scheme provides the following 
probabilities of escalation based on the true chances of DLT at a specific dose level. 
One can see that the probability of escalation is high if the toxicity risks are low: 
 
True Probability of Toxicity: .05 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of Escalation: 
.97 
.91 
.71 
.49 
.31 
.17 
.08 
 
As there is a reasonably large pool of short- and long-term experience with PSMA-
directed 177Lu, we will transition to a phase II cohort will be enrolled at the 
MTD/RP2D to gain additional safety data as well as preliminary efficacy data. We 
will enroll up to 27 subjects in the Phase II trial utilizing a Simon two-stage design 
(including the 3-6 patients used for establishing the MTD ). For the phase II portion, 
we will define evaluable patients  as those who met eligibility requirements, have 
initiated therapy, and were not removed from the study for non-compliance or 
withdrawal.  Sample size recommendations for the two-stage design are 
determined according to Simons two-stage minimax design.  The first stage will 
accrue a total of 16 patients (including those who were treated at the MTD in the 
phase I portion), if 6 or fewer of the first 16 evaluable patients do not experience a 
30% decline in PSA, the study will be terminated and declared to have a negative 
result.  If 7 or more patients out of the first 16 evaluable patients experience a 30% 
decline in PSA, 9 more patients will be accrued in Stage 2 (total sample size of 27).  
The new regimen will be declared to have activity and be worthy of further testing 
if 13 or more patients experience a 30% PSA decline among the 27 patients who are 
part of the phase II trial. 
 
 
5. 
REGISTRATION PROCEDURES 
 
5.1. Identification of subjects: 
 
Patients diagnosed with documented progressive metastatic CRPC disease who 

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are visiting Oncology Clinic at NYPH-Cornell Campus for their standard of care visit, 
will be approached for recruitment for this study. Investigators or delegates under 
their direct supervision may perform pre–screening of these potential subjects. 
 
5.2. Consent process 
 
Potential subjects will have a discussion with the investigator/delegate including 
the rationale for the study, investigational nature of the protocol and study drug 
and the 
voluntary nature of participation, potential risks and benefits, 
alternatives to 
participation, and study procedures. Individuals will have the 
opportunity to read the 
written informed consent document at their leisure 
(preferably outside of the clinical area for > 1 day) and the opportunity to have 
questions answered in a private location with the understanding that should they 
decide not to participate, they will still be able to receive any available standard 
of care therapy. Potential subjects will also have the opportunity to obtain the 
advice of their treating physician. Investigators or delegates under their direct 
supervision will verify the subject’s understanding of the 
investigational and 
voluntary nature of the study, the potential risks and benefits, study procedures, 
and alternatives prior to signing of the written informed consent. 
 
5.3. Central Patient Registration 
 
Subjects will be assigned a sequence number for the protocol and will be centrally 
registered with the Weill Cornell Medicine (WCM), Division of Hematology and 
Medical Oncology Clinical Research Office with the following documents: 
 
• WCM Patient registration form 
• First and last page of the fully executed informed consent form (including 
HIPPA), plus additional pages if checkboxes for correlative studies are 
required. 
• Eligibility checklist signed and dated by investigator and research nurse 
• Documentation of any eligibility waivers granted 
• Entry of screening information into WCM web–based system 
 
Central registration information is reviewed and entered into the HemOnc 
centralized research database. Documentation of patient registration will be 
confirmed prior to release of study agent by nuclear medicine. 
 
 
6. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section can only be 
performed after obtaining informed consent. 
 

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All on–study visits and dosing should be scheduled from Day 1 (date of the first 
infusion) on the study. It is very important that protocol procedures are performed 
at the time–points stipulated below. When it is not possible to perform the study 
visit at the exact time–point, the visit maybe performed within the acceptable visit 
window as defined in the visit–specific section below. 
 
After obtaining informed consent from the enrolled subject(s), screening and study 
related treatment procedures will be performed as outlined in Table 8 and 
described in detail in Section 6.1. 

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VERSION 6, DATE: 10/28/2021 
 
 
 
7. 
Schedule of Evaluations Table 8: Schedule of trial events: 
 
Screening 
Treatment 
Visit 1 
(Day 1) 
Imaging 
visit 
(Day 8±1) 
Treatment 
Visit 2 
(Day 15 ±1) 
F/U 
Visit 1 
(Day 
22±3) 
F/U 
Visit 2 
(Day 
29 ±3 
F/U 
Visit 3 
(Day 
43 ±3) 
F/U 
Visit 4 
(Day 
57 ±3) 
F/U 
Visit 5 
(Day 
71 ±3) 
Scan 
Visit 
(Day 85±7) 
Short- 
Term 
F/Uk 
Progressi
on 
Long- 
Term 
F/U 
Informed 
Consent 
x 
 
Demographics 
x 
 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Performance 
Status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signsa 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PROl 
x 
x 
x 
x 
x 
x 
x 
x 
xl 
x 
CBC with diff, 
pltsb 
x 
x 
x 
xc 
x 
x 
x 
x 
x 
x 
x 
x 
Serum 
Chemistryd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PSA 
x 
x 
x 
x 
x 
x 
x 
x 
LDH 
x 
x 
x 
x 
x 
x 
x 
Testosterone 
x 
x 
x 
CTC Counte 
x 
xe 
x 
 
CTC for 
Researchf 
x 
xf 
x 
 
Cell-Free DNA 
Research 
sampleg 
x 
xg 
x 
x 

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Immune 
research 
samplem 
x 
xm 
x 
 
68Ga-PSMA 
infusion & PET 
CTn 
x 
x 
 
Radiographic 
evaluationh 
x 
x 
xh 
 
xh 
177Lu-PSMA-617 
infusion 
x 
x 
 
177Lu-PSMA-617 
Planar/SPECT 
imagingi 
xi 
xi 
 
Archival Tissue 
x 
 
Adverse Event 
Monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Survival 
Assessmentj 
x 
x 

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a: Vital signs will include height and weight during screening and at least weight thereafter 
b: Any subject with grade >2 neutropenia or thrombocytopenia at any time point will be followed at least weekly until resolution to grade 1 
c: Any subject with grade ≥2 neutropenia or thrombocytopenia at Treatment Visit 2 will initially not be eligible to receive the second 177Lu-PSMA-617 injection. The dose will be held until the 
toxicity has resolved to grade 1 for a maximum of 2 weeks. If the toxicity has not resolved after 2 weeks, the dose will be discontinued. 
d: CMP (with direct bilirubin in subjects with known Gilbert’s syndrome) 
e: CTC enumeration via CellSearch methodology may be obtained during screening or prior to Treatment Visit 1 
f:  CTC collection for research purposes may be performed during screening or prior to Treatment Visit 1: two 2.3% sodium citrate “light blue top” tubes (5.4 mL whole blood) 
g:  Cell-Free DNA BCT®   may be obtained during screening or prior to Treatment Visit 1 and will be whole blood collection in a tube intended for collection, stabilization and transportation of 
cell-free plasma DNA. 10 mL tube will be used for collecting whole blood for research purposes 
h: Radiographic evaluation will include bone scan, CT/MRI of abdomen/pelvis, and Chest x-ray (CXR waived if CT/MRI includes chest). Following mandatory repeat imaging with Scan/Efficacy visit, 
continued repeat imaging is recommended approximately 12 weeks until radiographic progression as part of standard care. 
i: Planar/SPECT imaging one week after the 177Lu-PSMA-617 1st dose infusion in all subjects. Optional imaging will be performed on consenting subjects betweenTreatment Visit 1 (Between D2-D4) 
or prior to Treatment Visit 2 (D15 ±1). 
j: Survival assessment and relevant medical history to be collected until death 
k: Short-term follow up to be completed q4 weeks following the scan visit until 6 months from the 1st treatment visit.  Subjects who are progression-free at 6 months will continue with q4-week labs 
and q12-week standard imaging per guidelines (as in h above). 
   l: PRO = patient reported outcomes = BPI-SF and FACT-P; to be performed at time points specified during treatment phase, then q12 weeks (at imaging time points)    
   during short-term follow up until radiographic progression 
m: serum for immune assays; 1 sample to be collected at any time during screening prior to Treatment Visit 1, then again during Scan/Efficacy visit 
n: PSMA imaging is planned for all subjects. However, in the event of unavailability of radiotracers, subjects will be allowed to enroll and receive treatment without PSMA imaging. Optional repeat 68Ga-
PSMA PET/CT will be repeated prior to treatment or 6-48 hours after treatment in consenting subjects. 

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6.1.1. Screening Visit 
 
The following procedures must be completed no more than 1 month prior to enrollment 
and no more than 4 weeks following enrollment. 
 
• 
Informed Consent 
• 
Demographics 
• 
Medical History 
• 
Previous therapy 
• 
Surgical report will include date and type of surgery +/- lymphadenectomy 
• 
Radiotherapy report will include modality of therapy with prescribed 
dose and field and dates of therapy 
• 
Previous systemic (hormonal, chemo, other) therapy – drugs, doses, 
dates of therapy 
• 
Complete Physical Exam including height and weight 
• 
Brief Pain Inventory 
• 
Vital Signs 
• 
ECOG Performance Status 
• 
CBC with differential and platelet count 
• 
CMP (with direct bilirubin with known Gilbert’s syndrome) 
• 
PSA 
• 
Testosterone 
• 
CTC count via CellSearch methodology (may be collected prior to 
treatment C1D1, do not need to repeat if has known result within 1 
month of C1D1) 
• CTC for Research (may be collected prior to treatment C1D1) 
• Cell-Free DNA BCT® Research blood sample (may be collected prior to treatment 
C1D1) 
• Immune research blood sample (may be collected prior to treatment C1D1) 
• CT or MRI (abdomen-pelvis), up to 1 month prior to enrollment 
• Bone scan, up to 1 month prior to enrollment 
• Any confirmatory tests to assess equivocal results of bone scan should also 
be completed within a month of enrollment 
• CXR, up to 1 month prior to enrollment (CXR waived if CT chest performed) 
• Single intravenous dose of 68Ga-PSMA-HBED-CC (5±2mCi or 185±74MBq) at least 1 
week prior to 177Lu-PSMA-617 infusion 
• 
68Ga-PSMA-HBED-CC PET/CT scan to confirm the PSMA expression at the tumor 
site(s). PET/CT scans will be obtained 1 to 3 hours after the infusion of 68Ga- 
PSMA-HBED-CC. Optional repeat 68Ga-PSMA-HBED-CC injection and PET/CT 
prior to treatment in consenting subjects for research purposes. 
• Archival tissue for PSMA expression and genomic studies to identify DNA 

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damage 
 
Screening (except required 68Ga-PSMA-HBED-CC PET/CT scan) and visit #1 may occur 
on the same day provided results are available, all entry criteria are met, and the 
subject is registered on the study prior to dosing. In this instance, duplicate 
procedures do not need to be performed. 68Ga-PSMA-HBED-CC should occur at least 
2 days prior to Treatment Visit #1. 
 
6.1.1.1. R e –screening 
 
Subjects who are unable to complete the initial screening or are not initially eligible 
will be permitted undergo repeat screening (with repeat written informed consent). 
 
6.1.2. Treatment Phase 
 
The treatment and early monitoring phase comprises of 8 visits spanning over 
approximately 12 weeks. 
Platelets, absolute neutrophil count,, bilirubin, transaminases, and serum 
creatinine must be performed with results available and within range of eligibility 
criteria within 1 week prior to treatment initiation on C1D1. 
Details for each visit are listed below: 
 
6.1.2.1 
177Lu-PSMA-617 infusion (Treatment Visit 1 Day 1) 
 
The following procedures must be completed on the day of treatment with 177Lu- 
PSMA-617: 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA 
• LDH 
• Single intravenous dose of 177Lu-PSMA-617 (Dose based on the Cohort in which 
the subject is enrolled) 
• Adverse event evaluation 
• Concomitant medications 
• Concomitant procedures 
 
As stated above, platelets, absolute neutrophil count,, bilirubin, transaminases, and 

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renal function assessment must be available within 1 week prior to treatment on 
D1 and meet eligibility criteria. 
 
For Treatment Visit 2 (Day 15 ±1 day), grade ≥ 2 thrombocytopenia or neutropenia 
within 24 hours of the second dose of 177Lu-PSMA-617 requires a subject’s treatment 
to be held until the toxicity has resolved to least grade 1. If the toxicity has not 
resolved after 2 weeks of monitoring, the subject’s 177Lu-PSMA-617 treatment will be 
permanently discontinued and will be termed dose-limiting toxicity 
 
6.1.2.2 Imaging visit (Day 8 ±1) 
 
• Planar/SPECT imaging 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• Adverse event evaluation 
• Concomitant medications 

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177Lu-PSMA-617 infusion (Treatment Visit 2 Day 15 ±1 day) 
 
The following procedures must be completed on the day of treatment with 177Lu- 
PSMA-617: 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA 
• LDH 
• Single intravenous dose of 177Lu-PSMA-617 (Dose based on the Cohort in which 
the subject is enrolled) 
• Adverse event evaluation 
• Concomitant medications 
• Concomitant procedures 
• Optional imaging will be performed on consenting subjects between Treatment Visit 1 
(Between D1-D4) and/or prior to Treatment Visit #2 on (D15 ± 1) 
 
6.1.2.2 Follow-up visits: Follow up Visit 1 (Day 22 ±3), Follow up Visit 2 (Day 29 ±3), 
Follow up Visit 4 (Day 57 ±3) 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA (Follow up Visits 2 & 4) 
• LDH (Follow up Visits 2 & 4) 
• Adverse event evaluation 
• Concomitant medications 
 
6.1.2.3 Follow-up lab visits: Follow up Visit 3 (Day 43 ±3); Follow up Visit 5 (Day 71 ±3) 
 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 

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These visits may be performed with any licensed provider at any CLIA certified lab, 
provided that the results are available/provided to the Investigator within allowable 
windows. 
 
6.1.3. Scan (initial efficacy) Evaluation Visit (Day 85 ± 7); note that these study 
procedures are not expected to occur on a single day) 
 
The following procedures must be completed during the initial scan visit(s): 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA 
• LDH 
• Testosterone 
• CTC count via CellSearch methodology 
• CTC for research 
• Cell-Free DNA BCT® Research blood sample 
• Immune research blood sample 
• Same standard radiographic imaging modality as baseline (CT/MRI and 
bone scan +/- CXR) 
• Single intravenous dose of 68Ga-PSMA-HBED-CC (5±2mCi or 185±74MBq) 
• PET/CT scan will be obtained between 1 and 3 hours post-injection of 
68Ga- PSMA-HBED-CC 
• Adverse event evaluation 
• Concomitant medications 
• Concomitant procedures 
 
6.1.4 Short term follow up (q4 week visits x3 following Efficacy/Scan visit) 
 
Unless subjects withdraw or initiate new treatment, the following procedures 
must be completed every 4 weeks (+/- 7 days) after the scan visit: 
 
• Targeted Physical Examination with vital signs and weight 
• Interim Medical History 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 

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• PSA 
 
• LDH 
 
These visits may be performed with any licensed provider at any CLIA certified lab, 
provided that the results are available/provided to the Investigator within allowable 
windows. Repeat CT and bone scan are recommended with the final short-term follow 
up visit (approx. 6 months after enrollment). 
 
6.1.5 Progression 
 
If a subject will not initiate a new treatment, then progression is considered to be by 
PCWG3 radiographic progression or clinical progression.  However, if a subject has PSA 
progression and will initiate a new systemic therapy, then progression procedures should 
be performed prior to starting new therapy.  Any procedure already performed for another 
visit within 2 weeks of the progression visit does not need to be repeated. 
 
The following procedures must be completed during the progression visit: 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT-P 
• ECOG Performance Status 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA 
• LDH 
• Testosterone 
• Cell-Free DNA BCT® Research blood sample 
• Immune research blood sample 
• Adverse event evaluation 
• Concomitant medications 
• Concomitant procedures 
 
 
6.1.6 Long Term Follow Up 
 
Survival assessment and relevant medical history to be collected until death. 
Information may be collected from external providers. 
Per PCWG3, we recommend follow up CT and bone scans q12 weeks until radiographic 
progression 
 
 
6.2. 
Treatment Administration 

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6.2.1. Agent Administration 
 
Treatment will be administered only to eligible subjects under the supervision of the 
investigator or identified co-investigator(s). Treatment will be administered on an 
outpatient basis. Reported adverse events and potential risks are described in Section 
13. Appropriate dose modifications/delays of the study drug are described in Section 
7. No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the subject’s malignancy. 
 
6.2.2. Study drug preparation 
 
 produces both 
peptides/ligands, PSMA-HBED-CC and PSMA-617. Upon purchase and shipment to 
Weill Cornell Medicine, they will be labeled with either 68Ga or 177Lu with final 
products being 68Ga-PSMA-HBED-CC and 177Lu-PSMA-617, respectively. Radionuclide 
conjugation will be done at the Division of Nuclear Medicine, Department of 
Radiology, Weill Cornell Medicine. 
 
The material produced are subjected to quality assurance testing as outlined in the 
Food and Drug Administration “Points to Consider”. All production data and 
supporting documents, together with the results of all quality assurance testing, have 
been provided to and reviewed by the Food and Drug Administration (68Ga-PSMA- 
HBED-CC, IND# 124495 and 177Lu-PSMA-617, IND # 131966). 
 
 
6.2.3. Route of Administration 
 
68Ga-PSMA-HBED-CC and 177Lu-PSMA-617 will be administered as an intravenous 
infusion. 
 
6.2.4. Dose levels for 177Lu-PSMA-617 
 
Subject(s) enrollment will be done as 3+3 study design at each dose level. Initially at 
least 3 subject(s) will be enrolled in Cohort 1 (100 mCi or 3.7 GBq x2 doses 2 weeks 
apart) with dose escalation (or de-escalation as described above in Section 4 / Table 
7).. The enrollment ceiling of the dose escalation portion of the study is up to 46 study 
participants (six groups, with 3+3 at each dose level). Additional 10 subjects will be 
enrolled at the MTD dose level to further assess safety and tolerability and to obtain 
a preliminary assessment of efficacy. Each patient would receive 2 doses of the 
investigational agent, 2 weeks apart. The total dose received in 2 treatments in phase 
1 will be  100 – 600 mCi or 3.7 – 22.2 GBq.  The total dose for phase 2 is 600 mCi (22.2 
GBq). 
 

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6.2.5. Dose levels for 68Ga-PSMA-HBED-CC 
 
All subjected enrolled will receive 5 ±2mCi or 185 ±74MBq of 68Ga-PSMA-HBED-CC 
during the screening visit and EOS visit. 
 
6.2.6. Study drug premedication 
 
No pre-medication is required. Individual subjects may receive pre-medication at the 
discretion of their treating physician provided that they are not prohibited 
medications per study. 
 
6.2.7. Study drug administration 
 
Intravenous access must be well established prior to initiating infusion. At the time 
of dosing, the IV line will be connected to an infusion container containing the 
prepared volume of 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617. 
 
6.2.8. Monitoring Vital signs pre/post 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 infusion 
 
The infusion of 177Lu-PSMA-617 and subsequent monitoring will occur in a facility 
that is equipped for cardio–pulmonary resuscitation. The dispensed dose will be 
infused under the supervision of nuclear medicine physician or designee under the 
supervision of a nuclear medicine physician. Infusion–related 
reactions (fever, rigors) will be treated with acetaminophen, meperidine and 
diphenhydramine hydrochloride as clinically appropriate. Other allergic events will be 
managed as follows: rash, pruritus, urticaria and wheezing will be  treated with 
diphenhydramine hydrochloride, meperidine and/or steroids as clinically appropriate. 
Anaphylaxis or anaphylactoid signs or symptoms will be treated with steroids and/or 
epinephrine as clinically indicated. Vital signs will be monitored during the infusion. 
Systolic and diastolic blood pressure (mm Hg), temperature, pulse rate 
(beats/minute), and respiratory rate (breaths/minute), will be recorded with the 
patient in sitting position. Any clinically significant change in the vital signs will be 
recorded as AEs. Serial vital signs including temperature, BP, and heart rate will be 
monitored within 30 minutes before the infusion, within 30 minutes and at 60 minutes 
(+/-10) after the infusion. If any subject has any adverse reaction at 60 minutes, they 
will stay longer until it is resolved. 
 
6.2.9.  Imaging Plan 
 
A. 68Ga-PSMA-HBED-CC PET/CT Scan 
 
Patient preparation should be according to the policies and procedures of the local 
imaging site (CIBC). The patient does not need to be fasting for either the infusion or 

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the scans. The use of intravenous or oral contrast will not be permitted. Specifications 
for acquiring the 68Ga-PSMA-HBED-CC PET/CT scans will be provided in study specific 
documentation by the study chair or the co-investigators from the Division of Nuclear 
Medicine. PET/CT should be obtained during the Screening Visit as well as at the end 
of study visit. The images are acquired between 1 and 3 hours after the 68Ga-PSMA- 
HBED-CC infusion. Image acquisition will be from vertex of skull to mid thighs. 
 
B. 177Lu-PSMA-617 Planar/SPECT imaging 
 
Patient preparation should be according to the policies and procedures of the local 
imaging site (CIBC). The patient does not need to be fasting for either the infusion or 
the scans. The use of intravenous or oral contrast will not be permitted. Specifications 
for acquiring the 177Lu-PSMA-617 planar/SPECT images will be provided in study 
specific documentation by the study chair or the co-investigators from the Division of 
Nuclear Medicine. Planar/SPECT images should be obtained during the Imaging Visit 
(Day 8 ±1) on all subjects after the 177Lu-PSMA-617 infusion. Image acquisition will be 
from vertex of skull to mid thighs. Optional images will be performed on selected 
consenting subjects between initial Treatment Visit (between D1 - D4) and prior to 
Treatment Visit 2 (Day 15 ±1). 
 
Managing toxicity 
 
 
NCI CTCAE version 4.0 is used to grade all adverse events. 
 
• Grade ≥ 2 thrombocytopenia or neutropenia within 24 hours of the second dose 
of 177Lu-PSMA-617 (Treatment Visit 2) requires a subject’s treatment to be held 
until the toxicity has resolved to least grade 1. If the toxicity has not resolved after 
2   weeks   of   monitoring,   the   subject’s   177Lu-PSMA-617  treatment   will   be 
permanently discontinued and will be termed dose-limiting toxicity. 
 
Dose-limiting toxicity (DLT) is defined as: 
 
• Grade 4 hematologic toxicity that is deemed at least possibly related to 177Lu- 
PSMA-617 will be termed dose-limiting toxicity. 
 
• Any grade > 2 non-hematologic toxicity deemed to be at least possibly related to 
177Lu-PSMA-617 will require a  subject’s 177Lu-PSMA-617  treatment to  be 
permanently discontinued and will be termed dose-limiting toxicity. 
 
 
Maximum Tolerated Dose (MTD) is defined as: 
 
• The dose that produces an “acceptable” level of toxicity or that, if exceeded, 
would put subjects at “unacceptable” risk for toxicity. Definition of the MTD 

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usually relies on the sample, as MTD is defined as the dose level at which more 
than two patients over six experienced dose-limiting toxicity (DLT). 
 
Note: toxicities as described above will be considered DLT if they are at least possibly 
related to 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 as judged by the investigator. 
Attribution will  be reviewed by the  study chair  and discussed with the  medical 
monitor if there are questions about severity or attribution. 
 
6.3. 
General Concomitant Medication and Supportive Care Guidelines 
 
All medications that are administered during the study must be recorded in the 
patient’s CRF and in the source documents. Concomitant medications for other 
medical conditions are permitted as clinically indicated subject to approval by the 
study chair. 
 
Subjects will be advised to use contraceptive precautions to avoid pregnancy during 
the treatment phase since the effects of investigational agents on sperms and 
embryos are unknown. 
 
 
6.4. 
Duration of Therapy and Criteria for Removal from Study 
 
Duration of treatment portion of the study (excluding screening time) will be 
approximately 85 Days (±7 days). By signing the informed consent form and agreeing 
to participate in this study, the subjects are required to participate in entirety up to 
the completion of all scheduled visits and study procedures, or until one of the 
following criteria applies: 
• A protocol violation occurs 
• Disease progression occurs 
• A  serious  or  intolerable  adverse  event  occurs  (that  in  the  opinion  of  
the Investigator, requires the subject’s discontinuation) 
• The Investigator withdraws the subject (at the Investigator’s discretion for 
reasons other than the adverse event) 
• The Principle Investigator terminates the protocol 
• The subject requests to be discontinued from the protocol 
• The subject is lost to follow–up 
• Intercurrent illness that prevents administration of 68Ga-PSMA-HBED-CC or 
177Lu- PSMA-617 
• Previous anaphylactic reaction to PSMA peptides/ligands 
 
The  investigators  or  physicians  may  stop  the  protocol  or  terminate  a  subject’s 
participation in the protocol at any time should they judge: 
 

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• That it is not in the subject’s best interest to continue 
• If the subject experiences a protocol–related injury 
• If the subject needs life–saving medications/procedures/treatment 
• If the subject does not comply with the study plan 
• General  or  specific  changes  in  the  patient’s  condition  render  the  
patient unacceptable for further treatment in the judgment of the investigator 
 
They may also remove the subject from the study for various other administrative 
and medical reasons. They can do this without the patient’s consent. 
 
 
6.5. 
Duration of Follow Up 
 
Patients will be followed until death for survival assessment. Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event. 
8. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
There will be no dosing modifications. Unless there are specific reasons not to do 
so, all patients who are eligible for the trial will receive 5 ±2 mCi (185 ±74 MBq) of 
68Ga- PSMA-HBED-CC during the Screening Visit and the Efficacy/Scan visit. 
During the treatment phase, the subject will receive 177Lu-PSMA-617 x 2 doses 
based on the dose-level/Cohort to which he is assigned. The study chair must 
clear any dosing delays due to logistical issues (e.g. subject scheduling and/or 
radionuclide shipping that fall outside of a 2–day window). 
 
 
9. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with Investigational Agent 
can be found in Section 13. 
 
9.1. 
Investigational Agent 
 
PSMA-617 and PSMA-HBED-CC were initially purchased from 
 
 and in the later part of the 
study PSMA-617 will be provided by 
 Lignads will be shipped to 
and stored at WCM as per manufacturer’s guidelines. Upon subject’s enrollment 
and confirmation of date of infusions, these peptides will be labeled with 
Lutetium-177 or Gallium-68 respectively. 
 
The material produced are subjected to quality assurance testing as outlined in 
the Food and Drug Administration “Points to Consider”. All production data and 

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supporting documents, together with the results of all quality assurance testing, 
have been provided to and reviewed by the Food and Drug Administration. 
 
9.2. 
Availability 
 
177Lu-PSMA-617   (IND#   131966)   and   68Ga-PSMA-HBED-CC   (IND#   124495)   are 
investigational agents supplied to investigators by Weill Cornell Medicine. 
 
9.3. 
Agent Ordering 
 
Upon enrollment of the subject, the WCM Study Coordinator will be notified about 
the 177Lu-PSMA-617 and 68Ga-PSMA-HBED-CC infusion dates. The WCM Study 
Coordinator will arrange with the staff of Nuclear Medicine Division at WCM for 
the timely labeling and delivery of the radiolabeled PSMA peptides to the site of 
infusion. 
 
The dates for study visits will be confirmed with the subject, site of infusion, and site 
of imaging. 
 
9.4. 
Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain 
a careful record of the inventory and disposition of all agents received from Sponsor 
on a Drug Accountability Record Form (DARF). 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1. Cell-Free Plasma DNA: 
 
Peripheral blood will be collected in two 10 mL Cell-Free DNA BCT® tubes (Streck) 
at the specified time points (Screening and EOS visit) and processed per the lab 
manual. These samples are collected for research purposes only and will not be 
billed to the subject. The cell-free plasma DNA will be analyzed for genomic studies 
and to identify DNA repair alterations. 
 
9.1.2. Archival tissue: 
 
Archival tissue will be requested during the screening visit. Unstained slides 
containing tumor material from archival paraffin-embedded tissue should be 
obtained per the lab manual. If available, metastatic tissue is preferred to prostate 
biopsy/prostatectomy specimens. The tissue will be analyzed for PSMA expression, 
DNA repair pathways, and other genomic analyses for research purposes only. 

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9.1.4 Immune assays 
 
Serum samples will be obtained during screening prior to treatment and at the main 
efficacy visit for immune biomarkers and processed as per the lab manual. CTC 
collection for calreticulin expression analysis will be collected during screening or on 
D1 prior to treatment and at the D85 scan visit and processed as per the lab manual.  
CTCs for immune analysis will be collected at the WCM site only. Results of these 
assays will not be billed to the patient and are for research purposes only. 
 
9.2. 
Imaging Studies 
 
Imaging studies (including 68Ga-PSMA-HBED-CC PET/CT and 177Lu-PSMA-617 
Planar/SPECT Imaging) will be performed as described in schedule as well as clinically 
indicated to assess disease response. In subjects enrolled in this study, the 
measurable disease response will be calculated using Response Evaluation Criteria 
in Solid Tumors (RECIST Version 1.1) with PCWG3 modifications. 
 
Consenting subjects will undergo an optional study involving two scans with 68Ga-
PSMA-HBED-CC (with a minimum of 6 h and maximum of 2 days between the two 
injections). This cohort of patients will be analyzed to ensure that the peak 
standardized uptake values (including SUVmean, SUVmax, SUVpeak (SUVpeak not 
applicable to brain) of the lesions in the same patient/lesion is within an acceptable 
range of repeatability (+/- 30%) as demonstrated by prior radionuclide repeatability 
studies such as FDG and FLT. 
 
 
10. 
MEASUREMENT OF EFFECT: 
 
10.1 
CTC count response 
 
All subjects in this study will get blood samples drawn (at screening and EOS visit) 
for CTC enumeration by CellSearch methodology. Our primary analysis will assess 
those whose CTC counts drop to less than 5 or stay below 5 (responders) vs. 
those who remain at least 5 or above (non-responders) at EOS visit. 
 
In addition, it appears that decreases in CTC counts with therapy are a favorable 
marker even if the count remains at least 5. We will also analyze % changes in CTC 
counts with at least 50% decline in CTC count from baseline considered a response 
at 12 weeks. Best response will also analyzed (% increase or best % decrease at any 
point will also be reported in a waterfall plot). 
 
As reported in phase III studies of men with mCRPC, a favorable CTC count and LDH 
level at 12 weeks has been associated with overall survival. We will report the 

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proportion of subjects who have CTC count <5 and normal LDH at the initial scan 
(efficacy) visit time point. 
 
Additional reports associate an undetectable CTC count at 12 weeks as prognostic.  
We will report the proportion of subjects who have an undetectable CTC count at 
the initial scan (efficacy) visit time point. 
 
10.2 
Biochemical (PSA) response 
 
PSA response will be determined by comparing the PSA levels after therapy to the 
baseline, pre-treatment PSA. Declines of ≥ 30% confirmed by a second PSA value 
≥ 2 weeks later, will be reported. Subjects must not demonstrate clinical or 
radiographic 
(CT and/or MR) evidence of disease progression during this time 
period. 
 
 
10.3 
Duration of PSA response 
Duration of PSA response is defined as the time from the first 25% PSA decline until 
the PSA value is confirmed to increase by 25% above the nadir, provided that 
the increase is at least 2 ng/mL above the nadir. 
 
10.4 
Duration of CTC response 
 
Duration of CTC response is defined from the first CTC count drop to <5 (or <50% 
of baseline) to the time CTC count increases to >5 (or >25% increase from nadir). 
 
10.5 
PSA Progression 
 
PSA progression will be defined as a rise of > 25% above either the pretreatment level 
or the nadir PSA level (whichever is lowest). PSA must increase by > 2 ng/ml to 
be considered progression. Confirmation requires a second consecutive rising 
PSA at least 2 weeks apart. 
 
10.6 
PSA Stabilization 
 
PSA stabilization is referred to as any set of PSA values that do not meet the criteria 
for PSA response or PSA progression. 
 
10.7 
Time to PSA Progression 
 
Time to PSA progression is defined as the interval between initiating treatment until 
the PSA rises 25% above nadir provided that the increase is at least 2 ng/mL. 
 

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10.8 
Change in lesion size 
 
In subjects with measurable disease, complete response (CR) is defined as complete 
disappearance of all measurable and evaluable lesions by physical examination 
or imaging studies and normalization of PSA with no appearance of new lesions 
for > 1 month. Partial response (PR) is defined as a 30% or greater reduction in 
the sum longest uni-dimensional diameter of all measurable lesions. There may 
be no new lesions. Stable Disease (SD) is characterized by subjects who do not 
meet the criteria of PR and who are without signs of progressive disease for at least 
1 month. Disease Progression (DP) is defined as a greater than 20% increase in 
the sum longest uni- dimensional diameters of the indicator lesions or the 
appearance of new lesions. Bone scan progression (evaluable disease only) is 
requires at least 2 new lesions seen 
 
on a scan subsequent to baseline followed by a repeat scan at least 6 weeks later with 
at least one new additional lesion. 
 
Conventional Imaging studies (MRI, CT, Bone Scan) along with investigational images 
(68Ga-PSMA-HBED-CCPET/CT imaging and 177Lu-PSMA-617) will be performed 
during the study visits or as clinically indicated to assess disease response. In 
subjects enrolled in this study, the measurable disease response will be 
calculated using Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
with PCWG3 modifications. 
 
Radiographic scans will be used to assess best overall response and radiographic 
progression based on modified RECIST criteria for soft-tissue lesions and protocol- 
specific criteria for bone lesions Baseline images should be taken during Screening 
as close as possible to, and never more than 28 days before study visit 1. Every 
effort must be made to ensure the same radiographic method is used before 
and after treatment at scheduled visits. Radiographic progression free survival will 
be evaluated based on these results. 
 
Analysis of Efficacy: 
Median bPFS, rPFS, and OS, including survival curves, will be estimated using Kaplan- 
Meier methodology. Greenwood’s formula will be used to calculate 95% confidence 
intervals for the Kaplan-Meier estimates. Percent change in PSA from baseline will 
be described by mean/median and standard deviation/inter-quartile range, as 
appropriate, depending on the distribution of percent change from baseline. 
Modified RECIST response (i.e., CR, PR, and CR/PR proportions), CTC count response 
proportion, defined favorable LDH/CTC proportion, and associated 95% confidence 
intervals, will be estimated via binomial proportions. 
 
All subjects will undergo baseline and subsequent 68Ga-PSMA-HBED-CC PET/CT, and 

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those treated with 177Lu-labeled products will undergo planar +/- SPECT imaging. We 
will analyze the data for associations with response to treatment as well as survival 
by chi-square tests/Fisher’s exact tests and log-rank tests, respectively. For pre/post 
imaging comparisons, McNemar’s chi-square test and paired t-tests/Wilcoxon 
signed- rank tests will be used, as appropriate. We plan to report data for each 
individual study as well as across the studies. 
 
10.9  Patient reported outcomes 
Initial bone-targeted β-emitters were approved for the control of painful bone 
metastases. 
Radium-223 
dichloride 
appears 
to 
be 
associated 
with 
improved/preserved patient reported outcomes as well. We will assess pain prior to 
and following treatment with the brief pain inventory (and will also collect pain 
medication data). We will assess global and prostate cancer specific patient reported 
outcomes with the FACT-P questionnaire. As with the other correlative studies, we 
will plan to report results for this individual study as well as across current and prior 
studies, particularly examining subjects that receive what we believe are efficacious 
doses. 
 
11. 
Data Reporting / Regulatory Considerations 
 
11.1. Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients. 
 
11.1.1. REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC. It is a tool 
for the creation of customized, secure data management systems that include Web- 
based data-entry forms, reporting tools, and a full array of security features including 
user and group based privileges, authentication using institution LDAP system, with 
a full audit trail of data manipulation and export procedures. REDCap is maintained 
on CTSC-owned servers that are backed up nightly and support encrypted (SSL-
based) connections. Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
 
11.2. Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the 
Principal Investigator. Should an external sponsor be identified, they will have the 
opportunity to review and approve the changes prior to submission of these changes 

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to the local IRB and distribution to participating sites. 
12. 
STATISTICAL CONSIDERATIONS 
 
 
12.1. Study Design/Endpoints 
 
This is a phase 1 study of subjects with documented progressive metastatic CRPC with 
the primary endpoint of determination of MTD (or recommended phase II dose). In 
general, if there are sufficient numbers of subjects, descriptive statistics (e.g., number 
of observations, means, standard deviations, medians, and ranges) will be used 
to summarize data and selected endpoints may be summarized by dosing 
regimen. Otherwise, subject listings will be provided. No formal hypothesis testing 
is planned. 
 
The dose-escalation schedule (using 3+3 modified Fibonacci escalation), definitions 
of DLT, and determination of MTD are defined above (Section 6.2.10). The design 
is constructed to reduce the chance of escalating the dose when the probability of 
DLT is high, and increase the chance of escalating the dose when the probability of 
DLT is low. The maximum tolerated dose is defined as the highest dose level  
with an observed incidence of DLT in no more than one out of six patients 
treated at a particular dose level. The dose escalation scheme provides the 
following probabilities of escalation based on the true chances of DLT at a specific 
dose level. One can see that the probability of escalation is high if the toxicity risks 
are low. 
 
True Probability of Toxicity 
0.05 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
Probability of Escalation 
0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
 
12.2. 
Phase II 
 
We will enroll up to 27 subjects into the Phase II portion (including the 3-6 used for 
establishing the MTD).  We will define evaluable patients as patients who met 
eligibility requirements, have initiated therapy, and were not removed from the 
study for non-compliance or patient withdrawal.   
 
Sample size recommendations for the two-stage design are determined according 
to Simon’s two-stage minimax design.  We project a 30% PSA decline proportion of 
35%, below which the regimen will be unacceptable and a 30% PSA decline 
proportion of 60%, above which the regimen will be considered worthy of further 
exploration.  The null hypothesis that the 30% PSA decline proportion is less than 
or equal to 35% will be tested against the alternative hypothesis that the 30% PSA 
decline proportion is greater than or equal to 60%. 
 

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The sample size computations were performed assuming a 0.10 one-sided level of 
significance and 90% power assuming a historical control value for PSA decline of 
35% and the alternative hypothesis of 60%.  If 6 or fewer of the first 16 evaluable 
patients do not experience a 30% decline in PSA (stage 1), the study will be 
terminated and declared to have a negative result.  If 7 or more patients out of the 
first 16 evaluable patients experience a 30% decline in PSA, ongoing accrual will 
proceed to the target sample size of 27 patients (stage 2).  The new regimen will be 
declared active in this patient population and worthy of further testing if 13 or more 
patients experience a 30% PSA decline among the 27 patients entered.  This two-
stage design yields a 0.90 probability of a positive result if the true 30% PSA decline 
proportion is 60%.  It yields a 0.90 probability of a negative result if the true 30% 
PSA decline proportion is 35%. An exact 95% binomial confidence interval will be 
constructed for the proportion of patients with PSA decline. 
 
 
12.3. Sample Size/Accrual Rate 
 
The planned sample size for this dose escalation Phase I study is between 6-36 and 
between 16-27 for phase II.  The accrual rate is anticipated to be 1-2 patients/month on 
average (with expected pauses between dose-escalation cohorts and between stage 1 
and stage 2 of the phase II trial). 
 
12.4. Stratification Factors 
 
This is not a randomized trial and there are no planned stratification factors. 
Descriptive statistics will be utilized. Stopping rules for futility are in place as per 
Section 4.2. 
 
 
12.5. Analysis of Endpoints 
 
12.5.1. Analysis of Primary Endpoints 
 
The primary endpoint will be the proportion of subjects with DLT from Treatment Visit 
1 through Efficacy/Scan Visit.. The MTD is the highest dose amongst the different 
dose-level cohorts in this study at which no more than 2 (33%) of the subjects in a 
cohort experience DLT. 
 
 
12.5.2. Analysis of Secondary Endpoints 
 
For PSA response, CTC response and Imaging response, descriptive analysis will be 
performed. For imaging response RECIST criteria with PCWG3 modifications will be 
applied. Biomarker and patient reported outcome data will be analyzed within this 

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study as well as across additional radiolabeled-PSMA studies. 
 
12.6. Interim Analysis 
 
No interim analysis is planned (though safety analyses will occur in real-time and 
prior to each dose-escalation).  During phase II, ongoing analysis during Step 1 will 
determine whether or not to proceed to step 2. 
 
12.7. Reporting and Exclusions 
 
12.7.1. Evaluation of toxicity 
 
All subjects will be evaluable for toxicity from the time of their first infusion with 68Ga- 
PSMA-HBED-CC as well as when they receive their first treatment with 177Lu-PSMA- 
617. The distributions of the maximum observed grade toxicity will be tabulated 
for each type of toxicity and presented by dose level and overall. Results will be 
summarized with descriptive statistics. 
 
12.7.2. Evaluation of response 
 
Subjects who complete 177Lu-PSMA-617 treatment and at least 12 weeks of 
subsequent follow-up evaluations (as described in the schedule calendar-section 
6.1.) will be considered evaluable (consistent with PCWG3 guidelines). As the 
timing of response is not known, should the anticipated time to response be 
determined to be earlier than with other therapies using alternative markers of 
response, we may not replace subjects who are not evaluable through week 12 on 
study. 
 
 
13. 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
The investigator will be required to provide appropriate information concerning any 
findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safe use of the drug or device under investigation. Safety 
will be monitored by evaluation of adverse events reported by patients or observed 
by investigators or research staff, as well as by other investigations such as clinical 
laboratory tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 

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causality. An adverse event can arise with any use of the drug (e.g., off-label use, use 
in combination with another drug) and with any route of administration, formulation, 
or dose, including an overdose. 
 
13.1.1. Investigational Agent Risks 
There are no known contraindications for 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617. 
Because of the potential for infusion or allergic reaction, the subject should be 
monitored for safety for one hour following the infusion. 
 
Based on prior studies, the known side effects, risks, and hazards associated with the 
administration of 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 include: infusion reaction 
(fever, chills, rash, hypotension, and/or hypertension after injection), xerostomia, 
renal insufficiency, hematological/bone marrow toxicity (thrombocytopenia, 
neutropenia) and transient hepatic enzyme elevations. In addition, allergic reactions 
including anaphylaxis are a possibility. 
 
Precautions/monitoring: 
 
The infusion of 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 and subsequent monitoring 
will occur in a facility that is equipped for cardio–pulmonary resuscitation. The 
dispensed dose will be infused under the supervision of nuclear medicine physician or 
designee under the supervision of a nuclear medicine physician. Infusion–related 
reactions (fever, rigors) will be treated with acetaminophen, meperidine and 
diphenhydramine hydrochloride as clinically appropriate. Vital signs will be monitored 
before/after the 68Ga-PSMA-HBED-CC or 177Lu-PSMA-617 infusion. Systolic and 
diastolic blood pressure (mm Hg), temperature, pulse rate (beats/minute), and 
respiratory rate (breaths/minute), will be recorded with the patient in sitting position. 
Any clinically significant change in the vital signs will be recorded as AEs. Serial vital 
signs including temperature, BP, and heart rate will be monitored within 30 minutes 
of the infusion, and within 30 minutes and 60 minutes (+/- 10) after the infusion. If 
any subject has any adverse reaction at 60 minutes, they will stay longer until it is 
resolved. 
 
13.1.2. Adverse Event Characteristics and Related Attributions 
CTCAE term (AE description) and grade:   The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting.  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• Attribution of the AE: 
• 
Definite – The AE is clearly related to the study treatment. A reaction that 
follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug. The 

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reaction can be confirmed with a positive re–challenge test or supporting 
laboratory data. 
• 
Probable – The AE is likely related to the study treatment. A reaction that 
follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug. The 
reaction cannot be reasonably explained by the known characteristics of the 
patient’s clinical state or other modes of therapy administered to the patient. 
• 
Possible – The AE may be related to the study treatment. A reaction that 
follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug. The 
reaction might have been produced by the patient’s clinical state or other 
modes of therapy administered to the patient. 
• 
Unlikely – The AE is doubtfully related to the study treatment. The current 
state of knowledge indicates that a relationship is unlikely. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. No 
relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or patient’s 
clinical state. 
 
13.1.3. Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be 
maintained by the research staff and kept in the patient’s research chart. 
 
13.1.4. Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link: 
 
  
13.2. Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, congenital 
anomalies and any other serious events that may jeopardize the subject or require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
13.2.1. Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 

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safety of subjects throughout the trial and reviews the risks and benefits, as well as 
the efficacy, of the study. The DSMB will also evaluate the overall trial conduct and 
progress.  Ultimately, the DSMB validates the continuation of the trial or determines 
if a study needs modification or termination. 
 
Reports to the DSMB will include the following items for review: 
1. Completed DSMB Periodic Review Form. 
2. Synopsis of the study to date. 
3. IRB approved consent form. 
4. IRB current protocol. 
5. Summary table of study results. 
6. Adverse event table. 
7. Data safety monitoring plan. 
 
Safety monitoring is carried out to ensure and maintain the scientific integrity of 
human subject research projects and to protect the safety of human subjects. Safety 
monitoring can be viewed as any process during a clinical trial that involves the 
review of accumulated outcome data for groups of patient−subjects to determine if 
any of the treatment procedures practiced should be altered or stopped. NIH 
Guidelines (1998, 2000) specify that all clinical trials should have a system in place 
for appropriate oversight and monitoring to ensure the safety of participants and 
the validity of the data. 
 
Monitoring activities will be commensurate with the nature, size, and complexity 
of the trial in accordance with institutional policies and will be determined after IRB 
and DSMB review of the protocol immediately prior to study activation. For a 
small, single−center study, usually a statistician in conjunction with a Safety Officer 
performs the monitoring. For that single−site, high−risk trials, a DSMB may be 
appropriate. For larger, single or multi−site studies, a committee, often called a Data 
Safety Monitoring 
Board (DSMB), usually performs the monitoring. Ongoing 
review of the data by an independent individual or committee assures the 
investigators, the IRB, the study’s sponsor, and the funding agency that the trial 
can continue without jeopardizing subjects’ safety. 
 
Weill Cornell Medicine requires that all research approved by the WCMC IRB include 
an appropriate plan for the monitoring of data to ensure the safety of human 
subjects. Research supported by Federal agencies will be monitored according to all 
regulations and guidelines of the relevant Federal agency. 
 
For this study, the DSMB will be notified after each cohort has been completed prior 
to dose escalation to the next cohort. In addition, a report will be made to the DSMB 
every 6 months. 
 

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14.1 Medical Monitor 
 
The medical monitor is required to review all unanticipated problems involving risk to 
subjects or others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event. At a minimum, the 
medical monitor must comment on the outcomes of the event or problem and in case 
of a serious adverse event or death, comment on the relationship to participation in 
the study. The medical monitor must also indicate whether he/she concurs with the 
details of the report provided by the principal investigator. Reports for events 
determined by either the investigator or medical monitor to be possibly or definitely 
related to participation and reports of events resulting in death must be promptly 
forwarded to t h e  appropriate committees/agencies. This individual will be a 
qualified physician, other than the principal Investigator, not associated with this 
particular study, able to provide medical care to research subjects for conditions that 
may arise during the conduct of t h i s  study, and will monitor the subjects during the 
conduct of the study. 
 
, MD will serve as the Medical Monitor for this study. 

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Appendix A 
 
Performance Status Criteria: 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percen 
t 
Description 
0 
Normal activity. Fully active, 
able to carry on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities. Up and 
about more than 50% of 
waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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Appendix B 
 
WCMC IRB SAE Reporting Forms  
http://www.med.cornell.edu/research/for pol/ins rev boa.html