Phase I Dose-Escalation Trial of 225Ac-J591 in Patients With Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University

i 
TITLE: Phase I dose−escalation trial of 225Ac−J591 in patients with 
metastatic castration−resistant prostate cancer 
IRB Protocol #: 1706018281 
IND/IDE # 135267 
Version Date: August 30, 2021 
Principal Investigator:  
Scott T. Tagawa, MD, MS 
525 E 68th St, Starr 341 
New York, NY 10065 
646−962−2072 
stt2007@med.cornell.edu 
Co−Investigators: 
Tulane Principal Investigator 
Oliver Sartor, M.D. 
C.E. & Bernadine Laborde Professor for Cancer Research
Medical Director, Tulane Cancer Center
Assistant Dean for Oncology
Tulane Medical School
1430 Tulane Ave., Box 8642
New Orleans, LA 70112
Ph: 504-988-7869
Fax: 504-988-1813
Statistician: 
Karla Ballman, PhD kab2053@med.cornell.edu 
Participating Sites:  Weill Cornell Medicine, Tulane Cancer Center 
NCT #:  NCT03276572

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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. 
 

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List of Abbreviations 
 
 
225Ac 
ADT 
AE 
AR 
Actinium−225 
Androgen Deprivation Therapy 
Adverse Event 
Androgen Receptor  
CFR 
Code of Federal Regulations 
CRF 
CRPC 
CTCAE 
CTEP 
Case Report Form 
Castration Resistant Prostate Cancer 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
CTSC 
DLT 
Clinical Translational Science Center  
Dose Limiting Toxicity  
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
68Ga 
Food and Drug Administration 
Gallium−68 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBAF 
Human Research Billing Analysis Form 
ICF 
Informed Consent Form 
IND 
Investigational New Drug 
IRB 
177Lu 
mCRPC 
MTD 
NA 
NCI 
PC 
Institutional Review Board 
Lutetium−177 
Metastatic Castration Resistant Prostate Cancer 
Maximum tolerated dose 
Not Applicable 
National Cancer Institute 
Prostate Cancer 
PHI 
Protected Health Information 
PI 
PSMA 
223Ra 
Principal Investigator 
Prostate Specific Membrane Antigen 
Radium−223 
REDCap 
RP2D 
Research Electronic Data Capture 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  

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UAP 
Unanticipated Problem 
WCM 
Weill Cornell Medicine 

 
 
  
1 
 
Protocol Summary 
 
Full Title: 
Phase I dose−escalation trial of 225Ac−J591 in patients with metastatic 
castration−resistant prostate cancer  
Short Title: 
225Ac−J591for mCRPC 
Clinical Phase: 
Phase I 
Principal Investigator:     Scott T. Tagawa, MD, MS  
Sample Size: 
N= 2 − 52 (accelerated dose−escalation study design up to 7 
dose−escalation cohorts) 
Accrual Ceiling: 
This study will enroll up to 52 subjects who receive treatment. 
Study Population: 
Adult male patients of >18 years age with documented progressive 
metastatic CRPC 
Accrual Period: 
3 years (approximately 1−2 patients per month).  
Study Design: 
Phase I dose escalation study with 225Ac−J591 using single dose 
regimen will be performed in patients with documented progressive 
metastatic CRPC. The cumulative 225Ac dose [13.3 KBq/Kg – 93.3 
KBq/Kg or 0.36 µCi/Kg – 2.52 µCi/Kg] will be escalated in up to 7 
different dose levels (accelerated dose−escalation study design).  
Study Duration: 
Approximately 3 months after enrollment, then transition to long−term 
follow up 
Study Agent: 
225Ac−J591, single dose, IV administration  
Primary Objectives: 
• Determine the dose limiting toxicity (DLT) of single dose of 
225Ac−J591 
• Determine the maximum tolerated dose (MTD) and recommended 
phase II dose (RP2D) of 225Ac−J591 in a single dose regimen 
Secondary Objectives: 
• To assess the proportion with PSA decline following single dose of 
225Ac−J591 
• To assess radiographic response rate by PCWG3 criteria 
• To assess biochemical and radiographic progression−free survival by 
PCWG3 criteria 
• To assess overall survival following single dose of 225Ac−J591 
• To assess safety of single dose 225Ac−J591 as assessed by CTCAE 4 
• To assess changes in CTC count as measured by CellSearch and the 
proportion with favorable and undetectable CTC count and LDH at 
12 weeks following single dose 225Ac−J591 
• To assess patient reported outcomes using FACT−P and the Brief 
Pain Inventory short form 
Exploratory Objectives: • Disease assessment with PSMA−ligand based imaging prior to and 
following investigational treatment 
• To assess genomic alterations in relationship to outcome following 
fractionated dose 225Ac−J591 

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• To assess immune effects of 225Ac-J591 
• To assess reproducibility of 68Ga-PSMA-HBEC-CC PET/CT 
 
Endpoints: 
Dose limiting toxicity (DLT), adverse event rate, Maximum tolerated 
dose (MTD), recommended phase II dose, response rate, and 
progression free survival.

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                        Schema  
 
 
 
                                                                   
 
                                                                                  
 
 
 
 
                                                                              
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening: Written informed consent, history, physical examination, conventional 
imaging modalities (CT/MRI, Bone scan), PSMA−ligand based PET/CT imaging  
Treatment visit: Injection of single dose of 225Ac−J591 
F/U visits: Adverse events, concomitant medications/procedures, PSA and LDH levels 
Efficacy Evaluation visit: Adverse events, concomitant medications/procedures, PSA, LDH and 
Testosterone levels, CTC count, CT/MRI, bone scan, PSMA−ligand based PET/CT imaging  
 
Short−term and Long−term Follow up 

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Table of Contents 
1. 
STUDY OBJECTIVES ........................................................................................................... 6 
1.1 
Primary Objectives ........................................................................................................... 6 
1.2 
Secondary Objectives ....................................................................................................... 6 
1.3 
Exploratory Objectives ..................................................................................................... 6 
2. 
BACKGROUND .................................................................................................................... 6 
2.1 
Disease ............................................................................................................................. 6 
2.2 
PSMA ............................................................................................................................... 7 
2.3 
Anti−PSMA Monoclonal humanized antibody (J591) .................................................... 7 
2.4 
Alpha particles................................................................................................................ 11 
2.5 
Radionuclide−chelating PSMA ligand ........................................................................... 13 
2.6 
Investigational Agent ..................................................................................................... 17 
2.7 
Rationale......................................................................................................................... 18 
2.9 
Risk/Benefit Assessment ................................................................................................ 20 
2.10  
Correlative Studies Background ................................................................................. 20 
3. 
SUBJECT SELECTION ....................................................................................................... 21 
3.1 
Study Population ............................................................................................................ 22 
3.2 
Inclusion Criteria ............................................................................................................ 22 
3.3 
Exclusion Criteria ........................................................................................................... 23 
4. 
OVERVIEW OF STUDY DESIGN AND METHODOLOGY ........................................... 24 
4.1 
Study Design .................................................................................................................. 24 
4.2 
Rationale for Dose−Escalation Strategy: ....................................................................... 25 
5. 
REGISTRATION PROCEDURES ...................................................................................... 25 
5.1 
Identification of subjects: ............................................................................................... 25 
5.2 
Consent process .............................................................................................................. 25 
5.3 
Central Patient Registration ........................................................................................... 26 
6.  STUDY PROCEDURES ...................................................................................................... 26 
6.1 
Schedule of Evaluations ................................................................................................. 27 
6.2 
Treatment Administration .............................................................................................. 32 
6.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 35 
6.4 
Duration of Therapy and Criteria for Removal from Study ........................................... 36 
6.5 
Duration of Follow Up ................................................................................................... 36 
7. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 37 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 37 
8.1. 
Investigational Agent ..................................................................................................... 37 
8.2. 
Availability ..................................................................................................................... 38 
8.3. 
Agent Ordering ............................................................................................................... 38 

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8.4. 
Agent Accountability ..................................................................................................... 38 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 38 
9.1 
Laboratory Correlative Studies ...................................................................................... 38 
9.2. 
Imaging Studies .............................................................................................................. 39 
MEASUREMENT OF EFFECT................................................................................................... 39 
10.1  
CTC count response.................................................................................................... 40 
10.2  
Biochemical (PSA) response ...................................................................................... 40 
10.3  
Duration of PSA response .......................................................................................... 40 
10.4  
PSA Progression ......................................................................................................... 40 
10.5  
PSA Stabilization ........................................................................................................ 40 
10.6  
Time to PSA Progression ........................................................................................... 41 
10.7  
Change in lesion size .................................................................................................. 41 
10.9  
Calreticulin Expression on CTCs ............................................................................... 42 
10.10  
Patient reported outcomes .......................................................................................... 42 
11.  DATA REPORTING / REGULATORY CONSIDERATIONS .......................................... 42 
11.1. 
Data Collection ........................................................................................................... 42 
11.2. 
Regulatory Considerations ......................................................................................... 42 
12. STATISTICAL CONSIDERATIONS.................................................................................. 43 
12.1 
Study Design/Endpoints ............................................................................................. 43 
12.2 
Sample Size/Accrual Rate .......................................................................................... 44 
12.3 
Stratification Factors................................................................................................... 44 
12.4 
Analysis of Endpoints ................................................................................................. 44 
12.5 
Interim Analysis ......................................................................................................... 45 
12.6 
Reporting and Exclusions ........................................................................................... 45 
13.  ADVERSE EVENT REPORTING REQUIREMENTS ....................................................... 45 
13.1 
Adverse Event Definition ........................................................................................... 46 
13.2. 
Definition of SAE ....................................................................................................... 48 
13.3. 
AE/SAE Follow Up .................................................................................................... 48 
14.  DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................... 48 
14.1   Medical Monitor ............................................................................................................. 50 
REFERNCES ................................................................................................................................ 50 
APPENDICES .............................................................................................................................. 58 
 
 
 

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1. 
STUDY OBJECTIVES 
 
 
1.1 
Primary Objectives  
To define the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) as well as to 
determine the recommended phase II dose of 225Ac−J591 in a single dose regimen for patients with 
progressive metastatic castration−resistant prostate cancer. 
 
1.2 
Secondary Objectives 
 
• To assess the proportion with PSA decline following single dose of 225Ac−J591 
• To assess radiographic response rate by PCWG3 criteria 
• To assess biochemical and radiographic progression−free survival by PCWG3 criteria 
• To assess overall survival following single dose of 225Ac−J591 
• To assess safety of single dose 225Ac−J591 as assessed by CTCAE 4 
• To assess changes in CTC count as measured by CellSearch and the proportion with favorable 
and undetectable CTC count and LDH at 12 weeks following single dose 225Ac−J591 
• To assess patient reported outcomes using FACT−P and the Brief Pain Inventory short form 
 
1.3 
Exploratory Objectives 
• Disease assessment with PSMA−ligand based imaging prior to and following investigational 
treatment 
• To assess genomic alterations in relationship to outcome following fractionated dose 
225Ac−J591 
• To assess immune effects of 225Ac-J591 
 
 
2. 
BACKGROUND 
 
2.1 
Disease 
Prostate cancer (PC) is a significant health burden, with 180,890 new diagnoses and 26,120 
deaths in the United States in 2016(1). Despite advances in diagnostic technology and treatment 
strategies, up to 40% of patients treated with primary therapy with curative intent will experience 
disease progression. PC deaths are typically the result of metastatic castration−resistant prostate 
cancer (mCRPC), and historically the median survival for men with mCRPC has been less than 
two years (2). The recent availability of novel treatments for mCRPC has given a resurgence of 
hope for these men as studies now demonstrate improved survival with a variety of new agents. 
However, the unfortunate reality is that mCRPC remains an incurable disease, and it is against 
this backdrop that we look to the future with cautious optimism and new hope for scientific 
discovery. 
 
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 

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develop frank metastasis. Exact mechanism of transformation from castration−sensitive prostate 
cancer to castration−resistant disease is still not fully understood, but with recent scientific 
innovations in basic research, there is now a better understanding. Now we know that despite 
castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive 
prostate cancer progression (3, 4). This understanding has led to the development of novel agents 
aimed at further decreasing androgen production or blocking AR function. However, there are 
also many other biologic pathways that function independent of androgen signaling resulting in 
CRPC. With a greater understanding of the tumor biology, there is hope for continued 
development of innovative treatment options that improve survival for men with mCRPC. 
 
Treatment of mCRPC has drastically changed over the past decade. 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 immunotherapy with 
sipuleucel−T, and the bone−seeking α−emitter 223Ra have shown improved overall survival (OS) 
and most have demonstrated quality of life advantages as well (5-13). These agents have been 
tested in multiple "disease states" of CRPC to determine if or when patients might benefit from 
each treatment. In all cases, however, these now established therapies become ineffective in 
controlling tumor progression over time(14). Novel therapies are urgently needed in order to 
further ameliorate the course of the disease. Other treatments for men with mCRPC have been 
shown to improve outcomes, but remain to be approved by the FDA (15). 
 
2.2 
PSMA 
 
In PC, the most well established, prostate−restricted, cell surface antigen yet identified is prostate 
specific membrane antigen (PSMA)(16-20). PSMA is a trans−membrane protein with a 
707−amino−acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of 
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 
(20). PSMA is expressed in the apical region of normal prostatic cells, the epithelium surrounding 
prostatic ducts(21). Dysplastic changes in the prostate result in the expression of PSMA on the 
luminal surface of prostatic ducts (22, 23). Increasing prostate cancer stage and grade result in 
higher cell membrane PSMA expression (24, 25). The eventual progression to advanced prostate 
cancer and castrate resistance corresponds to further increases in PSMA expression (26). PSMA 
expression in prostate cancer cell membranes is 100− to 1000−fold that in normal cells (24, 25). 
Thus, PSMA represents a promising target for imaging and therapy of prostate cancer. 
 
2.3 
Anti−PSMA Monoclonal humanized antibody (J591) 
 
J591 is a de−immunized monoclonal antibody directed at the extracellular domain of human 
PSMA. Initially J591 was developed as a mouse antibody by Dr. Neil Bander’s lab at Weill Cornell 

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Medical Center. Humanized J591 was derived from murine J591 using Biovation’s 
DeImmunization technology (Biovation, Aberdeen, Scotland, UK). In this technology, individual 
amino acids in predicted B and T cell epitopes were replaced with alternative amino acids such 
that the murine epitopes are no longer immunogenic to the human immune system.(27) The 
modification results in a non−immunogenic antibody that may be administered to patients on 
multiple occasions and over long periods without inducing an immune response. J591 is produced 
from NS0 cells by Lonza (Lonza Biologics, Slough, UK).  
 
The humanized version of J591 has provided promising results in imaging both localized PC and 
metastatic disease. Initial phase I/II studies using J591 trace−labeled with 111Indium (111In) and 
177Lutitium (177Lu) using a DOTA chelate showed that repetitive dosing was well tolerated without 
the development of a human anti−humanized antibody (HAHA) response (28-33). No dose 
limiting toxicity occurred at imaging doses of radionuclide conjugates and the maximum tolerated 
dose was not reached. Excellent tumor targeting could be detected at all dose levels of the mAb. 
No mAb targeting to sites other than those involved by PC was observed although, as seen in other 
trials using radiometals, the liver is the primary site of radiometal metabolism. Percent injected 
dose in the liver diminished with increasing dose of cold J591, and higher doses were associated 
with longer plasma clearance times (34-36). The future efforts are to explore further therapeutic 
options by radiolabeling J591 with more cytotoxic radionuclides like α– particle emitter 
Actenium−225 that holds the potential to induce a much stronger anti−tumor response. 
 
2.3.1 Prior clinical experience with J591 and radiolabeled−J591 in men with prostate 
cancer: 
 
2.3.1.1 Pilot study with huJ591 
Initial phase I studies using huJ591 trace−labeled with 111In using a DOTA chelate showed that 
repetitive dosing was well tolerated with total doses of up to 500 mg/m2 without the development 
of a human anti−humanized (de−immunized) antibody (HAHA) response(37). No dose limiting 
toxicity occurred and the maximum tolerated dose was not reached. Excellent tumor targeting 
could be detected at all dose levels of mAb. No mAb targeting to non−prostate cancer sites was 
observed although, as seen in other trials using radiometals, the liver is the primary site of 
excretion.   
 
 
2.3.1.2 Phase I and II studies with single dose radiolabeled J591 
 
Two independent phase I clinical trials were initally performed at WCMC using a single−dose of 
177Lu or   90Y linked via a DOTA chelate to huJ591 in subjects with metastatic, hormone−refractory 
prostate cancer (28, 31). The primary objectives of these trials were to define the maximum 
tolerated doses (MTD) of the isotopes as well as to further define dosimetry, pharmakokinetics, 
and HAHA of the radiolabeled mAb conjugates.  Anti−tumor responses were assessed as a 
secondary endpoint.  The design and entry criteria of the 2 trials were identical. Eligible subjects 
had a prior histologic diagnosis of prostate cancer and evidence of progressing, recurrent or 

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metastatic disease defined by at least 3 serially rising PSAs and/or radiographic studies.  As prior 
studies had demonstrated that all prostate cancers were PSMA−positive (38), no determination of 
PSMA expression was done.   
 
i. Phase 
I 
Trial 
of 
177Lutetium−Labeled 
J591 
in 
subjects 
with 
metastatic 
castration−resistant prostate cancer (CRPC)(28): 
 
177Lu−J591 was evaluated in patients with metastatic CRPC demonstrating acceptable toxicity 
(MTD=70 mCi/m2), excellent targeting of metastatic sites and biologic activity. Thirty−five 
subjects received 177Lu−J591, of whom 16 received up to three doses. Myelosuppression was dose 
limiting at 75 mCi/m2, and the 70 mCi/m2 dose level was determined to be the single−dose MTD. 
Repeat dosing at 45 to 60 mCi/m2 was associated with dose−limiting myelosuppression; however, 
up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not 
dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 
subjects with positive bone scan, computed tomography, or magnetic resonance images. No 
subject developed a human anti−J591 antibody response to deimmunized J591 regardless of 
number of doses. Biologic activity was seen with four subjects experiencing ≥50% declines in 
PSA levels lasting from 3+ to 8 months. An additional 16 subjects (46%) experienced PSA 
stabilization for a median of 60 days (range, 1 to 21+ months). 
 
ii. Phase 2 trial of 177Lutetium (177Lu) radiolabeled J591 (177Lu−J591) in subjects with 
metastatic castration−resistant prostate cancer (CRPC) (39): 
 
In a phase II trial patients with progressive metastatic CRPC received a single dose of 177Lu−J591 
in two cohorts (65 and 70 mCi/m2). Cohort 1: 15 patients; Cohort 2: 17 patients. The primary 
endpoint was PSA and measurable disease response assessed at week 12 and the secondary 
endpoint was to evaluate toxicity. One 177Lu imaging study was done at 1 week post−treatment to 
confirm tumor targeting. Three patients achieved PSA declines of >50%; 31% had at least 30% 
decrease in PSA (the cutoff associated with survival benefit in chemotherapy trials). Though the 
phase I MTD was 70 mCi/m2, based upon FDA restrictions, the initial cohort was treated at 65 
mCi/m2. In an exploratory analysis, there was a dose−response relationship. The >30% PSA 
response rates in the 65 mCi/m2and 70 mCi/m2 cohorts were 13% and 47% respectively (p=0.06); 
and any PSA decrease in 46% vs. 71% respectively. Hematological toxicity was similar to that in 
phase I trials; no significant drug−related non−heme toxicity occurred. Grade (Gr) 4 
thrombocytopenia occurred in 42% and 9 patients received platelet transfusions. Targeting of 
known sites of PC metastasis was observed in 30 of 32 (94%) patients. 
 
iii. Phase I trial of fractionated dose 177Lu−J591 in men with metastatic castration−resistant 
prostate cancer (40, 41): 
 
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 wks 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 

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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 hematologic 
toxicities; 19 (57.6%) had Grade 4 hematologic 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 1: Toxicities data from Phase 2 single dose 177Lu−J591 Study and Phase 1 
fractionated 177Lu−J591 study: 
 
 
In addition, fractionated dosing allowed concurrent dosing with myelosuppressive chemotherapy: 
 
iv. Phase I trial of fractionated dose 177Lu−J591 plus docetaxel/prednisone in men with 
metastatic castration−resistant prostate cancer (42): 
 
 
Single Dose 
Fractionated Dose 
Cumulative Dose 
(mCi/m2) 
65 
70 
 
70 
(35 + 35) 
 
80 
(40 + 40) 
 
90 
(45 + 45) 
Grade 4 
Thrombocytopenia 
27% 
56.3% 
40% 
50% 
58.8% 
Platelet 
Transfusion 
7% 
41% 
0% 
31.3% 
52.9% 
Grade 4 
Neutropenia 
0% 
37.5% 
0% 
31.3% 
29.4% 
Febrile 
Neutropenia 
0% 
2.1% 
0% 
0% 
5.8% 

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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%. 
 
2.4 
Alpha particles 
 
Radionuclides that emit alpha particles (helium nucleus consisting of 2 protons and 2 neutrons) 
deliver about 4,000−fold the energy of a beta particle (composed of an electron or positron). While 
thousands of beta particle hits are required to kill a cell, a single alpha hit is sufficient to kill by 
causing irreparable double strand DNA breaks. In addition to their high energy, the range of 
emission is only 50−100µ leading to less potential for toxicity to bystander cells.  Based upon 
strong early studies, an international phase 3 study led by co−investigator Dr. Sartor demonstrated 
an overall survival benefit in addition to an improvement in patient reported outcomes, leading to 
FDA approval (13, 43). Importantly, as predicted based upon the short path length, the toxicity 
profile of 223Ra (Radium−223) is favorable with only mild myelosuppression and gastrointestinal 
adverse events.  Very clearly, this established α−emitting radiopharmaceutical in the clinic. 
However, 223Ra is “targeted” simply because it chemically resembles calcium and is, therefore, 
preferentially deposited in sites of active bone formation. Because the bone−targeting 
radiopharmaceutical anti−tumor effect derives from accumulation in proximity to malignant cells 
and/or stroma, these agents entirely ignore soft tissue and extra−osseous visceral metastases. As 
such, a method of delivering an α−emitting particle directly to tumor cells would be a significant 
advance. 
 
Converting indirect bone targeting to direct tumor cell targeting via a PSMA−specific mAb will 
result in the alpha particle being internalized and deposited adjacent to the nucleus. Such proximity 
to the nucleus (and the DNA) yields even greater potency. In addition, unlike the 223Ra indirect 
approach, direct tumor targeting would enable treatment of PC outside the bone (e.g., in the soft 
tissue and circulation) and allow killing of bone marrow micro−metastases before they induce the 
increased bone turnover necessary for successful use of 223Ra. We expect that by targeting macro− 
and microscopic metastatic tumor sites with PSMA−targeted alpha particles, we will be able to 
demonstrate even greater efficacy than seen with β−emitters, potentially with less toxicity. There 
have been anecdotal reports of PSMA−targeted α−particles utilizing actinium−225 (225Ac) in 

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Europe, including a recent publication with impressive results(44). In addition, there are 
unpublished reports of “success” with PSA declines and scan improvements, with issues of 
impaired quality of life due to salivary gland toxicity. However, like the experience with 
PSMA−targeted β−radiation, there are no prospective trials. Based upon the high potency of 
α−particles, it may be even more important to target tumor rather than the other sites of low−levels 
of PSMA expression such as proximal renal tubules, salivary glands, and small bowel. In fact, a 
recent published report demonstrated significant proximal renal tubule uptake and late radiation 
nephropathy in mice models(45). Therefore, mAb−based α−particle delivery should be 
advantageous with less expected myelosuppression than seen with β−emitters. We have 
demonstrated the ability to deliver radioactive particles to both known (macroscopic) and unknown 
(micrometastatic, Figure 1) sites of disease (28, 31, 32, 39, 41, 46-56). Interestingly, but not 
surprisingly, in the study of 12 doses of 223Ra, there was good control of disease in the bone, but 
progression occurred in extraosseous sites of disease. There is essentially no resistance mechanism 
to the high energy of α−emitters provided the short−range particle can be delivered into PC cells 
in close proximity to the nucleus. 
 
 
2.4.1 Actinium−225 for Radioimmunotherapy: 
 
225Ac (T½, 9.9 d) decays to the daughters 221Fr (T½, 4.8 min), 217At (T½, 33 ms), and 213Bi (T½, 45.6 
min)(57). Since each of these nuclides disintegrates with emission of one α−particle, a total of 4 
α particles are emitted and deliver massive damage to the target cell. In order to ensure the energy 
is deposited within the cell, internalization of the Ac−225 into the tumor cells is desired.  
 
For PSMA−targeted therapy, the advantage of J591 mAb as an internalizing carrier molecule was 
previously demonstrated almost 2 decades ago(58). Early work with 225Ac labeled mAbs was 
limited by difficulty of preparing a very stable 225Ac−chelator−antibody complex. Recently, an 
efficient, 1−step radiolabeling method that produces high specific activity, stable, therapeutically 
active 225Ac−DOTA−mAb complex was developed(56). As a result, it is now possible to design 
an optimal clinical protocol to study the potential clinical utility of 225Ac−DOTA−J591 mAb for 
the treatment of mCRPC.   
 
 
 
ure 1: CT (left), FDG
T
T (middle), and 89Zr−J59  
CT (right) of a patient 
 
 
s hou ht to b  
l  
tastatic pros ate c
 

Protocol # 5 
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13 
 
2.4.2 Clinical studies:  
 
From a recent news publication by Joint Research Center (JRC), European Commission (59), 80 
patients have been treated over a three−year period. As per the report, several patients had a longer 
response, one of them being without relapse/progression for more than 2 years. Patients received 
a dose of 100 kBq/kg at bimonthly intervals, considered to be safe and effective with the only side 
effect being xerostomia. Most patients had received multiple lines of treatment prior to the 
investigational therapy. The expected median survival is 2−4 months. After treatment, 75% of the 
study population was alive at 24 weeks and 75% patients had a decline in tumor size and serum 
PSA. The same anecdotal reports describe toxicity from small−molecule ligand PSMA targeting 
particularly salivary glands clinically with the potential for renal toxicity as well) that is not present 
with mAb targeting 
 
A case report of 2 patients with mCRPC who received 100 KBq/Kg of 225Ac−PSMA−617 
bimonthly has been published (44). One patient was treated with 3 cycles of 9–10 MBq (100 kBq 
per kilogram of body weight) of 225Ac−PSMA−617 at bimonthly intervals. The patient received 
an additional 6 MBq of 225Ac−PSMA−617 as consolidation therapy atleast 2 months later and his 
PSA dropped to 0.1 ng/mL (from >3000 ng/mL at screening). Additionally, all previously 
PSMA−positive lesions on scans had visually disappeared on PSMA PET/CT. The second patient 
was considered resistant to 177Lu−PSMA−617 after 2 cycles and was instead offered 
225Ac−PSMA−617. He received 3 cycles of 6.4 MBq (100 kBq/kg) at bimonthly intervals. His 
PSA declined from 419 ng/mL to <0.1 ng/mL, along with a complete remission on PSMA PET/CT. 
Only toxicity reported was xerostomia. 
 
Based on an initial 89Zr−J591 mAb pilot PET/CT imaging study in 10 patients with PC, the 
radiation dosimetry for 225Ac−J591 mAb was estimated assuming an organ weighting factor of 
5(55). Since then we have completed additional clinical studies with 89Zr−J591 (56, 60).61,64 Data 
provided by McDevitt et al. is shown in Table−2. It appears that the dose−limiting organs for RIT 
are red marrow followed by liver, kidney and lung. Assuming the dose limit for red marrow is 2 
Gy, the maximum activity that can be administered is about 6.06 MBq or 160 µCi. 
   
Table 2: 225Ac−J591 Dosimetry 
 
 
 
 
 
 
 
 
 
 
2.5 
Radionuclide−chelating PSMA ligand 
 
Dose limit
Dose
Gy
mGy/MBq
MBq
mCi
Red Marrow
2
66
6.06
0.16
Kidney
23
382
12.04
0.33
Liver
40
591
13.54
0.37
Lung
20
79
50.93
1.38
* Activity limits estimated with weighting factor = 5
Activity limit*
Organ

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68Ga−PSMA−HBED−CC (68Ga−PSMA−11)  
 
PSMA has recently been discovered as a promising target for radioisotope based approaches for 
PET imaging, for example, using 68Ga−labeled PSMA ligands(61-66). All of these trials report 
retrospective data on case reports/case series. No well−designed prospective clinical trial has been 
published/reported yet. 
 
During the last two decades, many efforts have been undertaken to develop PSMA−ligands(67, 
68). 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 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(69, 70). PET/CT−imaging with 68Ga−PSMA−11 has demonstrated this novel 
method as an important imaging modality for diagnosing recurrent PCa(61, 71-73). 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(74). 
 
 produces PSMA−HBED−CC for 
clinical use. Upon purchase and shipment to Weill Cornell Medicine, the peptide will be labeled 
with 68Ga with the final product being 68Ga−PSMA−HBED−CC. 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). 
 
Results from selective clinical trials using 68Ga−PSMA−HBED−CC to evaluate its diagnositic 
value are reported here under: 
 
i. 
Diagnostic value of 68Ga−PSMA−HBED−CC PET/CT imaging in the diagnosis of 
recurrent prostate cancer(72): 
 
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 PCa was detected. Tumor−detection was 

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15 
 
positively associated with PSA level and Androgen deprivation therapy (ADT). Gelason 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%. 
 
ii. 
 PET imaging with a 68Ga−PSMA ligand for the diagnosis of prostate cancer: 
biodistribution in humans and first evaluation of tumor lesions (75): 
 
Initial clinical studies with the 68Ga−labeled PSMA−HBED−CC were conducted at Heidelberg 
University Hospital and the German Cancer Research Center to assess 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. 
 
iii. 
68Ga−labeled PSMA ligand as superior PET tracer for the diagnosis of prostate 
cancer: Comparison with 18F−FECH (63): 
 
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 

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16 
 
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 %) 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. 
 
iv. 
Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga−labelled PSMA 
ligand for the diagnosis of recurrent prostate cancer: initial experience (71): 
 
In a more recent publication, 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. 

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17 
 
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 
68Ga−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. 
These encouraging results suggest 68Ga−PSMA−HBED−CC to be an effective probe for the PC 
marker “PSMA” in metastatic prostate cancer patients and that it can provide a robust imaging 
scan to better detect PC tumor burden. We plan to utilize this probe to better understand its 
diagnostic role in prostate cancer patients with localized disease. 
 
2.6 
Investigational Agent 
 
• 
225Ac−J591 (IND # 135267) 
The humanized monoclonal antibody−huJ591 is provided by Dr. Neil Bander. Radionuclide 
conjugation will be done at the Division of Nuclear Medicine, Department of Radiology, Weill 
Cornell Medicine. 225Ac nitrate residue, 37 MBq (1.0 mCi) is supplied in a 2mL glass vial (by 
Department of Energy, Oak Ridge Laboratory), a radiochemical grade preparation. 
225Ac−DOTA−huJ591 mAb injection is manufactured by reacting 225Ac chloride with 
DOTA−huJ591 (3.0 mg) aseptically withdrawn from the packaged drug substance vial and 
allowing the DOTA chelator to chelate 225Ac in tetramethylammonium acetate buffer (TMAA). 
Following the reaction, the 225Ac−DOTA−J591 is challenged with an excess of the chelator DTPA 
to remove any free or loosely bound Ac−225. 225Ac−DOTA−huJ591 is then separated from 
225Ac−DTPA by gel filtration (Biogel P−6 column, Biorad, CA) using sterile saline solution 
containing 2% Human Serum Albumin as an eluent. The eluent fraction (4−8 mL) containing 
225Ac−DOTA−huJ591 is then sterilized by membrane filtration into a final drug product vial. QC 
Samples are removed for Quality Control. The specific activity of the 225Ac−DOTA−huJ591 
injection is estimated based on dose calibrator measurement of total 225Ac activity (50 – 300µCi) 
and the total DOTA−huJ591 (3 mg) precursor used. Expected SA is 16.6 – 100 µCi/mg. Labeling 
efficiency and radiochemical purity will be determined using ITLC. Immunoreactivity of 
radiolabeled J591 mAb preparations will be determined using PSMA+ LNCaP tumor cells. 
 
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 (225Ac−J591, IND# 135267). 
 
• 
68Ga−PSMA−HBED−CC (IND # 124495) 

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18 
 
PSMA has recently been discovered as a promising target for radioisotope based approaches for 
PET imaging, for example, using 68Ga−labeled PSMA ligands(61-66). All of these trials report 
retrospective data on case reports/case series. No well−designed prospective clinical trial has been 
published/reported yet. 
 
During the last two decades, many efforts have been undertaken to develop PSMA−ligands(67, 
68). 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 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(69, 70). PET/CT−imaging with 68Ga−PSMA−11 has demonstrated this novel 
method as an important imaging modality for diagnosing recurrent PCa(61, 71-73). 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(74). 
 
 produces PSMA−HBED−CC for 
clinical use. Upon purchase and shipment to Weill Cornell Medicine, the peptide will be labeled 
with 68Ga with the final product being 68Ga−PSMA−HBED−CC. 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). 
 
 
2.7 
Rationale 
 
Prostate cancer (PC) is the most common solid male cancer. For those patients with clinically 
organ−confined disease, radical prostatectomy (RP) remains the most commonly used treatment 
modality (76). However, even after surgical treatment, high risk PC is prone to recur and often 
becomes resistant to conventional hormonal therapy (77). For this reason, efforts have been made 
to optimize patient outcome in the adjuvant and neoadjuvant settings (78-80). Thus far, 
neoadjuvant therapies have yet to demonstrate a survival benefit (81). Therefore, newer strategies 
to prevent or rescue PC recurrences are highly desirable. 
 
It is now recognized that evasion of an effective immune response is a hallmark of cancer (82). 
Immunotherapy may induce tumor cell death with a relatively high degree of specificity unlike 
hormonal or chemotherapy, which has a non−specific action. PC is an ideal target for 
immunotherapy because of its indolent nature which allows adequate time to activate the immune 
system (83), and in fact, the first therapeutic cancer vaccine to be approved was for PC (10). 
Identification of PC tumor associated antigens (TAA) has provided ideal targets for 

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19 
 
immunotherapy, with prostate−specific membrane antigen (PSMA) as one of the most relevant 
targets in oncology as a highly restricted cell−surface membrane protein that is not secreted (18, 
19, 84, 85). 
 
Based on the knowledge that certain tumor types express significant amounts of one or several 
specific cell−surface proteins, the development of drugs aimed at these targets is becoming an 
increasingly important component in the treatment of cancer.  One example is the successful use 
of the mAb rituximab in patients with non−Hodgkin’s lymphoma (NHL). Rituximab targets CD20 
which is expressed on the surface of 95% of B cells in NHL (86). Another clinically validated 
target is human epidermal growth factor receptor 2 (HER2), which in breast cancer is targeted by 
trastuzumab (87). In PC, several studies, which will be addressed throughout this protocol, have 
emphasized PSMA as both a diagnostic and therapeutic target. Similar to prostate−specific antigen 
(PSA), PSMA is a highly expressed, prostate−specific biomarker. While PSMA is not a novel 
discovery, it remains a highly relevant target with the knowledge that attenuated AR signaling 
even prior to hormonal therapy is the hallmark of lethal PC and recent studies have confirmed the 
reciprocal relationship between PSMA and AR signaling in the era of highly potent AR−directed 
therapy(26, 88-92). 
 
2.8 Rationale for the appropriate radioisotope: 
 
Radionuclides that emit alpha particles (helium nucleus consisting of 2 protons and 2 neutrons) 
deliver about 4,000−fold the energy of a beta particle (composed of an electron or positron). While 
thousands of beta particle hits are required to kill a cell, a single alpha hit is sufficient to kill by 
causing irreparable double strand DNA breaks. In addition to their high energy, the range of 
emission is only 50−100µ leading to less potential for toxicity to bystander cells.  Based upon 
strong early studies, an international phase 3 study led by co−investigator Dr. Sartor demonstrated 
an overall survival benefit in addition to an improvement in patient reported outcomes, leading to 
FDA approval (13, 43). Importantly, as predicted based upon the short path length, the toxicity 
profile of 223Ra (Radium−223) is favorable with only mild myelosuppression and gastrointestinal 
adverse events.  Very clearly, this established α−emitting radiopharmaceutical in the clinic. 
However, 223Ra is “targeted” simply because it chemically resembles calcium and is, therefore, 
preferentially deposited in sites of active bone formation. Because the bone−targeting 
radiopharmaceutical anti−tumor effect derives from accumulation in proximity to malignant cells 
and/or stroma, these agents entirely ignore soft tissue and extra−osseous visceral metastases. As 
such, a method of delivering an α−emitting particle directly to tumor cells would be a significant 
advance. 
 
Converting indirect bone targeting to direct tumor cell targeting via a PSMA−specific mAb will 
result in the alpha particle being internalized and deposited adjacent to the nucleus. Such proximity 
to the nucleus (and the DNA) yields even greater potency. In addition, unlike the 223Ra indirect 
approach, direct tumor targeting would enable treatment of PC outside the bone (e.g., in the soft 
tissue and circulation) and allow killing of bone marrow micro−metastases before they induce the 
increased bone turnover necessary for successful use of 223Ra. We expect that by targeting macro− 
and microscopic metastatic tumor sites with PSMA−targeted alpha particles, we will be able to 

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20 
 
demonstrate even greater efficacy than seen with β−emitters, potentially with less toxicity. There 
have been anecdotal reports of PSMA−targeted α−particles utilizing actinium−225 (225Ac) in 
Europe, including a recent publication with impressive results(44). In addition, there are 
unpublished reports of “success” with PSA declines and scan improvements, with issues of 
impaired quality of life due to salivary gland toxicity. However, like the experience with 
PSMA−targeted β−radiation, there are no prospective trials. Based upon the high potency of 
α−particles, it may be even more important to target tumor rather than the other sites of low−levels 
of PSMA expression such as proximal renal tubules, salivary glands, and small bowel. In fact, a 
recent published report demonstrated significant proximal renal tubule uptake and late radiation 
nephropathy in mice models(45). Therefore, mAb−based α−particle delivery should be 
advantageous with less expected myelosuppression than seen with β−emitters. 
 
 
 
2.9 
Risk/Benefit Assessment  
 
 
This is a phase I clinical trial with the primary endpoints to find DLT and MTD. Based on 
pre−clinical findings by our group combined with our prior human experience with 90Y−J591 and 
177Lu−J591 the dose−limiting organs/tissue is expected to be red marrow. The expected toxicities 
can be leukopenia, thrombocytopenia, anemia, fatigue, renal failure, and transaminitis. 
 
 
2.10  Correlative Studies Background 
 
i. Archival tissue and cell−free plasma DNA to assess genomic alterations: 
PC is a clinically and molecularly heterogeneous disease with marked variability in patient 
outcomes. Defining the genomic alterations in PC has improved classification of tumors: for 
instance, 50% harbor TMPRSS2-ERG gene fusion, 10% SPOP mutation, and germline or 
somatic alterations involving DNA repair pathways (eg., BRCA2, ATM, MMR defects) occur 
in 20% of CRPC. Based on recent data from our group and others, we predict that these 
genomic alterations may help identify patients most likely to respond to DNA damaging 
therapy with 225Ac-J591. In PC models, ERG expression results in relative resistance to 
ionizing radiation.  Conversely, SPOP mutant prostate cancers and/or those with CHD1 loss 
show increased genomic instability, play a role in double strand DNA break repair, and result 
in increased sensitivity to DNA damage. Germline or somatic alterations involving DNA 
damage repair genes (such as BRCA2 and ATM) have also been shown to be preferentially 
sensitive to DNA damaging therapy including PARP inhibitors and platinum chemotherapy. 
We therefore hypothesize that distinct molecular phenotypes of prostate cancer may have 
predictable and exploitable differences in sensitivity to DNA damaging agents such as 
actinium-225. We and others have also described prostate cancer subtypes based upon AR 
signaling and neuroendocrine differentiation. We hypothesize that the NEPC / AR low tumors 
would express low PSMA and respond less well to PSMA-targeted therapy.  We will test these 
hypotheses using tissue and ctDNA collected from our prospective cohorts. 

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21 
 
We will evaluate archival tumor tissue (preferentially from metastatic biopsies) with the 
plan for utilization of our CLIA-approved targeted platform covering DNA (for mutation and 
copy number) and RNA (for fusion analysis) of 150 cancer related genes including AR, SPOP, 
CHD1, DNA repair, ERG fusion, and other CRPC-relevant alterations. Gene expression of 
androgen signaling genes and other relevant pathways will be assessed using a custom panel 
Nanostring platform developed at WCM, involving 350 genes including the AR signaling 
signature genes (n=30), the AR V7 splice variant, neuroendocrine prostate cancer genes, 
epithelial mesenchymal transition, cell cycle- genes, TMPRSS2-ERG fusion transcript, and 
control/housekeeper genes. In addition, we will collect plasma samples for ctDNA analysis 
prior to treatment, at 3-months, and at progression using the prostate cancer specific PCF 
SELECT platform developed in collaboration with others as part of a PCF Challenge Award. 
As discussed above, we will describe findings from this exploratory endpoint in each study 
with the plan to analyze these findings with relationship to efficacy and toxicity across studies, 
in particular at doses found to have efficacy. 
 
ii. 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 (93). 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 (94) and in a large analysis of 5 phase III trials, conversion from unfavorable to 
favorable as well as undetectable CTC count at 12 weeks is strongly associated with overall 
survival. 
 
iii.   Immune correlates: 
 
We and others have observed some durable responses following radiolabeled-PSMA therapy. 
Radiation may lead to an induction of or increase in immune responses to locally expressed 
antigens, but unlike external beam radiation, PSMA-targeting generally delivers radiation to 
all sites of disease (by imaging) and therefore observing an abscopal response is not possible. 
We plan to assess this by analyzing serological changes pre- and post-treatment and will also 
explore induction of immunogenic cell death by assessment of HMGB1 and calreticulin. 
 
iv. 
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 
 

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22 
 
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: 
 
i. PSA progression 
ii. Objective radiographic progression in soft tissue 
iii. 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 analogue (agonist/antagonist) if they have not 
undergone bilateral orchiectomy.   
 
5. Have previously been treated with at least one of the following: 
 
• Androgen receptor signaling inhibitor (such as enzalutamide) 
• CYP 17 inhibitor (such as abiraterone acetate) 
6. Have previously received taxane chemotherapy, been determined to be ineligible 
for taxane chemotherapy by their physician, or refused taxane chemotherapy. 
 
7. Age > 18 years 
 
8. Patients must have normal organ and marrow function as defined below:  
 
 
Absolute neutrophil count >2,000 cells/mm3 
 
Hemoglobin ≥9 g/dL  
 
Platelet count >150,000 x 109/µL  
 
Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance ≥ 60 mL/min/1.73 m2 by Cockcroft−Gault 
 
Serum total bilirubin <1.5 x ULN (unless due to Gilbert’s syndrome in which 
case direct bilirubin must be normal 
Serum AST and ALT <3 x ULN in absence of liver metastases; <5x ULN if  

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23 
 
     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 Cycle 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 (e.g. Sm-153, Sr-89) 
 
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 
 
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 
 

Protocol # 5 
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24 
 
4. 
OVERVIEW OF STUDY DESIGN AND METHODOLOGY 
4.1 Study Design 
This is an open−label, single−center Phase I dose escalation study designed to determine the 
dose−limiting toxicity (DLT) and the maximum tolerated dose (MTD) of 225Ac−J591 in a single 
dose regimen. The dose escalation will start at 13.3 KBq/Kg (0.36 µCi/Kg) and escalate in 
increments of 13.3 KBq/Kg (0.36 µCi/Kg) for each dose to a maximum of 93.3 KBq/Kg (2.52 
µCi/Kg).  
 
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). 
 
A single dose of 225Ac−J591 will be given to subjects with documented progressive metastatic 
CRPC. The 225Ac dose (13.3 KBq/Kg – 93.3 KBq/Kg or 0.36 µCi/Kg – 2.52 µCi/Kg) will be 
escalated in up to 7 different dose levels (utilizing an accelerated dose−escalation study design).  
Initially single subject cohorts will be enrolled in Cohort 1 (13.3 KBq/Kg or 0.36 µCi/Kg). 
Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2 weeks for one 
month, at 8 and 12 weeks, then every 4 weeks for next 3 months and then every 6 months for 
upto 3 years as described in Table :4). If a subject at a specific dose−level does not experience 
any grade >1 attributable toxicity (or increase by more than 1 grade for pre-existing AE), the 
next subject will be enrolled in the next cohort.  Once any subject at any dose level experiences 
attributable Gr >1 toxicity OR enrollment begins at dose-level 5, transition to modified 3+3 
dose−escalation study design will occur.  Any grade ≥3 non-hematological toxicity or any grade 
4 hematological toxicity with additional complications (grade 4 neutropenia [ANC <500/mm3] 
lasting greater than 7 days or of any duration associated with fever (i.e. febrile neutropenia); 
severe grade 4 thrombocytopenia (platelet count < 15,000) lasting greater than 7 days, associated 
with hemorrhage, and/or requirement of > 3 platelet transfusions in a 30-day period) at the a 
specific 225Ac−J591 dose will determine DLT and MTD. The enrollment ceiling of the dose 
escalation portion of the study is up to 52 study participants (up to 7 groups of up to 6 subjects 
each + 10 subjects in the expansion cohort).  
 
Upon completion of investigational treatment with single dose of 225Ac−J591, 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 3: Treatment Plan with 225Ac−J591 

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25 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
Rationale for Dose−Escalation Strategy: 
 
This study will use an accelerated dose−escalation design, transitioning to a 3+3 dose−escalation 
study design upon the occurrence of grade > 1 attributable toxicity or reaching Cohort 5, with the 
planned initial and subsequent cohorts described in Table 3. 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 with details provided in Section 
12.1.  
 
5. 
REGISTRATION PROCEDURES 
 
5.1 
Identification of subjects: 
 
Patients diagnosed with documented progressive metastatic CRPC disease who 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. 
 
BCohort 
BTreatment Dose 
n 
 
BKBq/Kg 
BµCi/Kg 
 
B1 
B13.3 
B0.36 
B1−6 
B2 
26.7 
B0.72 
B1−6 
3 
B40.0 
B1.08 
B1−6 
B4 
53.3 
B1.44 
B1−6 
5 
B66.7 
B1.80 
B3−6 
B6 
B80.0 
2.16 
B3−6 
B7 
93.3 
2.52 
B3−6 

Protocol # 5 
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26 
 
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:  
 
a. WCM Patient registration form 
b. First and last page of the fully executed informed consent form (including HIPPA), 
plus additional pages if checkboxes for correlative studies are required. 
c. Eligibility checklist signed and dated by investigator and research nurse 
d. Documentation of any eligibility waivers granted  
e. 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. 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 enrolled subject(s), screening and study related treatment 
procedures will be performed as outlined in Table 4 and described in detail in Section 6.1. 
 

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6.1 
Schedule of Evaluations 
 
Table 4: Schedule of trial events 
 
Screening 
Treatment 
Visit 
F/U 
Visit 1 
F/U 
Visit 
2 
F/U 
Visit 
3 
F/U 
Visit 
4 
F/U 
Visit 
5 
F/U 
Visit 
6 
Scan / 
Efficacy 
Visit 
Short 
Term 
F/Uj 
Long 
Term 
F/U 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
Physical Exam 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
Performance Status 
x 
x 
 
 
 
x 
 
x 
x 
x 
 
Vital Signsa 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
PROb 
x 
x 
x 
 
 
x 
 
x 
x 
 
 
CBC with diff, pltsc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xk 
Serum Chemistryd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xk 
PSA 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
LDH 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Testosterone 
x 
 
 
 
 
 
 
 
x 
 
 
CTC Counte 
x 
xe 
 
 
 
 
 
 
x 
 
 
Cell−Free DNA 
Research samplef 
x 
xf 
 
 
 
 
 
 
     x 
xf 
 
Seromics Research  
samplef 
x 
xf 
 
 
 
 
 
 
     x 
 
 
CTC Research 
sample 
x 
xf 
 
 
 
 
 
 
x 
 
 
68Ga−PSMA 
infusion & PET CTg 
xg 
 
 
 
 
 
 
 
x 
 
 
Radiographic 
evaluationh 
x 
 
 
 
 
 
 
 
x 
xh 
xh 
225Ac−J591 infusion 
 
x 
 
 
 
 
 
 
 
 
 
Archival Tissue 
x 
 
 
 
 
 
 
 
 
 
 
Stool 
x 
xf 
 
 
 
 
 
 
 
 
 
Adverse Event 
Monitoring 
x 
x 
x 
 
 
x 
 
x 
x 
x 
xk 
Concurrent 
Medications 
x 
x 
x 
 
 
x 
 
x 
x 
x 
 
Survival 
Assessmenti 
 
 
 
 
 
 
 
 
 
 
x 

Protocol # 5 
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28 
 
 
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 (except PSMA PET and research samples, which may be 
performed just prior to treatment if necessary due to scheduling issues). 
 
• 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 
• Patient reported outcomes: BPI−SF and FACT−P 
• 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 visit, do not 
need to repeat if has known result within 1 month of C1D1) 
• Research blood collect blood collection (plasma DNA, serum, CTC) - may be collected 
any time 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 
a: Vital signs will include height and weight during screening and at least weight thereafter 
b: PRO = patient reported outcomes = BPI−SF and FACT−P 
c: Any subject with grade 4 neutropenia or thrombocytopenia at any time point will be required to have CBC with differential at least twice per week 
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 C1D1 
f:  Blood/stool samples for research may be obtained during screening or prior to treatment C1D1, within 2 weeks of scan/efficacy visit, and 
progression 
g: 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 6-48 hours later to treatment in consenting subjects. 
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: Survival assessment and relevant medical history to be collected until death 
j: Short−term follow up to be completed q4 weeks following the scan visit until 6 months from the 1st treatment visit 
k: Long-term follow up to be completed q6 months for up to 3 years following the initial 6-month assessment; should include CBC with differential 
and CMP (in any CLIA certified lab) and long-term AE assessment (defined as either physician history and physical or phone assessment by member 
of the study team plus review of any additional medical records if deemed necessary to assess attribution of adverse event).  

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• 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) 
• 
68Ga−PSMA−HBED−CC (5±2mCi or 185±74MBq) injection followed by PET/CT 
• Optional repeat 68Ga−PSMA−HBED−CC injection and PET/CT 6-48 hours after initial 
injection/scan in consenting subjects for research purposes 
• Archival tissue collection for research 
• Stool collection for research – may be collected any time following consent prior to 
treament on C1D1 
 
Screening (except required 68Ga−PSMA−HBED−CC PET/CT scan) and treatment visit 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. The optional 2nd 68Ga−PSMA−HBED−CC PET/CT scan may occur prior to treatment 
on Day 1. 
 
6.1.1.1 Re–screening 
 
Subjects who are unable to complete the initial screening or are not initially eligible will be 
permitted to undergo repeat screening (following repeat written informed consent).  
 
6.1.2 Treatment Phase 
 
 
 
 
 
The treatment and early monitoring phase comprises of 7 visits spanning over approximately 
8−weeks.  Based upon 3 prior studies of single-dose radiolabeled J591 with nearly all toxicity 
occurring from 3-5 weeks following dosing (and blood count nadirs at days 28-31), subjects will 
be monitored most closely (at least weekly) during this time. 
 
Neutrophil count, platelet count, bilirubin, transaminases, and serum creatinine must be performed 
with results available and within range of eligibility criteria within 1 week prior to treatment visit. 
 
Details for each visit are listed below: 
 
 
 
 
 
 
6.1.2.1 225Ac−J591 infusion (Treatment Visit, Day 1) 
 
The following procedures must be completed on the day of treatment with 225Ac−J591: 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT−P 
• ECOG Performance Status 
• CBC with differential and platelet count 

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30 
 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA 
• LDH  
• Research blood collection (plasma DNA, serum, CTC) – if not done during screening 
• Single intravenous dose of 225Ac−J591 with at least 1 liter normal saline (Dose based on 
the Cohort in which the subject is enrolled) 
• Adverse event evaluation 
• Concomitant medications 
• Concomitant procedures 
 
As stated above, blood counts, bilirubin, transaminases, and renal function assessment must be 
available within 1 week prior to treatment visit and meet eligibility criteria.  
 
 
6.1.2.2 Follow−up visits: Follow up Visit 1 (Day 8 ±1), Visit 2 (Day 15 +/-2), Follow up Visit 
4 (Day 29 ±2), Follow up Visit 6 (Day 57 ±2) 
 
• Targeted Physical Examination with vital signs and weight 
• Medical History 
• Brief Pain Inventory, FACT−P (except Follow Up Visit 2) 
• ECOG Performance Status (except Follow Up Visit 2) 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
• PSA (Follow up visit 2 and 4) 
• LDH (Follow up visit 2 and 4) 
• Adverse event evaluation 
• Concomitant medications 
 
 
6.1.2.3 Follow−up lab visits: Follow up Visit 3 (Day 22 ±2), Visit 5 (Day 43 ±3) 
 
• CBC with differential and platelet count 
• CMP (with direct bilirubin with known Gilbert’s syndrome) 
Lab visits 3 and 5 may be performed at any CLIA certified lab 
 
In addition, should there be any period of grade 4 neutropenia or thrombocytopenia, then 
CBC with differential is required at least twice per week (defined as a 7-day period) 
 

Protocol # 5 
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31 
 
6.1.3 Efficacy Evaluation (scan) Visit (Day 85 ± 7) 
 
The following procedures must be completed during the end of study visit (likely occurring on at 
least 2 separate days): 
 
• 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 
• Research blood collection (plasma DNA, serum, CTC) 
• 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) followed by PET/CT  
• 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 until radiographic progression occurs: 
 
• 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) 
• PSA 
• LDH 
• At progression:  Above procedures plus plasma DNA collection for research 
 

Protocol # 5 
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32 
 
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 (which will occur after 
radiographic progression per PCWG3 recommendations). 
 
6.1.5 Long Term Follow Up 
 
Long-term follow up to be completed q6 months for up to 3 years following the initial 6-month 
assessment (may be included during short term follow up); should include CBC with differential 
and CMP (in any CLIA certified lab) and long-term AE assessment (defined as either physician 
history and physical or phone assessment by member of the study team plus review of any 
additional medical records if deemed necessary to assess attribution of adverse event). Survival 
assessment and relevant medical history to be collected until death.  Information may be collected 
from external providers. Should a subject withdraw from short-term follow up per protocol (i.e. 
completing study procedures including imaging and visits to the WCM site every 12 weeks until 
radiographic progression), per PCWG3 we recommend follow up CT and bone scans every 12 
weeks per clinical standard of care until radiographic progression. 
 
 
6.2 
Treatment Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 13.   
 
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 
 
A. 
225Ac−J591 
The humanized monoclonal antibody−huJ591 is provided by Dr. Neil Bander. Radionuclide 
conjugation will be done at the Division of Nuclear Medicine, Department of Radiology, Weill 
Cornell Medicine. 225Ac nitrate residue, 37 MBq (1.0 mCi) is supplied in a 2mL glass vial (by 
Department of Energy, Oak Ridge Laboratory), a radiochemical grade preparation. 
225Ac−DOTA−huJ591 mAb injection is manufactured by reacting 225Ac chloride with 
DOTA−huJ591 (3.0 mg) aseptically withdrawn from the packaged drug substance vial and 
allowing the DOTA chelator to chelate 225Ac in tetramethylammonium acetate buffer (TMAA). 

Protocol # 5 
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33 
 
Following the reaction, the 225Ac−DOTA−J591 is challenged with an excess of the chelator DTPA 
to remove any free or loosely bound Ac−225. 225Ac−DOTA−huJ591 is then separated from 
225Ac−DTPA by gel filtration (Biogel P−6 column, Biorad, CA) using sterile saline solution 
containing 2% Human Serum Albumin as an eluent. The eluent fraction (4−8 mL) containing 
225Ac−DOTA−huJ591 is then sterilized by membrane filtration into a final drug product vial. QC 
Samples are removed for Quality Control. The specific activity of the 225Ac−DOTA−huJ591 
injection is estimated based on dose calibrator measurement of total 225Ac activity (50 – 300µCi) 
and the total DOTA−huJ591 (3 mg) precursor used. Expected SA is 16.6 – 100 µCi/mg. Labeling 
efficiency and radiochemical purity will be determined using ITLC. Immunoreactivity of 
radiolabeled J591 mAb preparations will be determined using PSMA+ LNCaP tumor cells. 
 
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 (225Ac−J591, IND# 135267). 
 
 
B. 
68Ga−PSMA−HBED−CC 
 produces PSMA−HBED−CC. 
Upon purchase and shipment to Weill Cornell Medicine, they will be labeled with 68Ga with final 
product being 68Ga−PSMA−HBED−CC. 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). 
 
6.2.3 Route of Administration 
 
225Ac−J591 and 68Ga−PSMA−HBED−CC will be administered intravenously. 
 
6.2.4 Dose levels for 225Ac−J591 
 
Subject(s) enrollment will be done in an accelerated dose−escalation study design at each dose 
level (13.3 KBq/Kg or 0.36 µCi/Kg). The enrollment ceiling of the dose escalation portion of the 
study is up to 42 study participants (up to seven groups, up to 6 at each dose level). Each patient 
would receive single dose of the investigational agent. The total dose received by a subject will 
vary from 13.3 KBq/Kg to 93.3 KBq/Kg or (0.36 µCi/Kg – 2.52 µCi/Kg). 
 
6.2.5 Dose levels for 68Ga−PSMA−HBED−CC 
 

Protocol # 5 
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34 
 
All subjected enrolled will receive 5 ±2mCi or 185 ±74MBq of 68Ga−PSMA−HBED−CC during 
the screening visit and scan/efficacy visit. 
 
6.2.6 Study drug premedication 
 
No pre−medication is required, but recommended pre−medication for 225Ac−J591 will be H1 
blocker (recommended 25−50 mg diphenhydramine) and acetaminophen (recommended 325−620 
mg). No pre−medications will be administered for 68Ga−PSMA−HBED−CC. 
 
6.2.7 Study drug administration 
 
Intravenous access (peripheral or central) 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 225Ac−J591 or 68Ga−PSMA−HBED−CC.  225Ac−J591 will be infused at a rate of no 
faster than 5 mg/minute. 68Ga−PSMA−HBED−CC may be administered as slow IV push.  In 
addition, a minimum of 1 liter of normal saline will be administered prior to or following 
225Ac−J591 infusion and subjects should be instructed to increase oral hydration for the week 
following treatment. 
  
6.2.8. Monitoring Vital signs pre/post 225Ac−J591 and 68Ga−PSMA−HBED−CC 
 
The infusion of 225Ac−J591 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 minutes), at 90 ±10 minutes, and 
120 ±10 minutes following start of 225Ac−J591 infusion. If any subject has any infusion-related 
adverse reaction within 120 minutes for 225Ac−J591, they will stay longer until it is resolved. 
 
 
 
 
 
6.2.9. Imaging Plan 
 

Protocol # 5 
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35 
 
68Ga−PSMA−HBED−CC PET/CT Scan 
 
Patient preparation should be according to the policies and procedures of the local imaging site 
(CBIC). 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 
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.  
 
6.2.10 Managing toxicity 
 
NCI CTCAE version 4.0 is used to grade all adverse events. 
 
Dose−limiting toxicity (DLT) for both single-subject and 3+3 dose-escalation cohorts is 
defined as: 
 
• 
Grade 4 neutropenia lasting longer than 1 week or any occurrence of febrile neutropenia 
• 
Grade 4 thrombocytopenia lasting longer than 1 week, requiring more than 2 platelet 
transfusions in a 30-day period, or resulting in major bleeding 
• 
Any grade > 2 non−hematologic toxicity deemed to be at least possibly related to 225Ac−J591 
will be termed as 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 usually relies on the sample, as MTD 
is defined as the dose level at which no more than two patients out of 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 225Ac−J591 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. 

Protocol # 5 
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36 
 
 
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 225Ac−J591 
• Previous anaphylactic reaction to any J591 product 
 
The investigators or physicians may stop the protocol or terminate a subject’s participation in the 
protocol at any time should they judge: 
 
• 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. 
 

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7. 
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 single dose of 225Ac−J591 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 the treatment window).  
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with Investigational Agent can be found 
in Section 13.  
 
8.1. 
Investigational Agent   
 
A. 225Ac−J591: 
The humanized monoclonal antibody−huJ591 is provided by Dr. Neil Bander. Radionuclide 
conjugation will be done at the Division of Nuclear Medicine, Department of Radiology, Weill 
Cornell Medicine. 225Ac nitrate residue, 37 MBq (1.0 mCi) is supplied in a 2mL glass vial (by 
Department of Energy, Oak Ridge Laboratory), a radiochemical grade preparation. 
225Ac−DOTA−huJ591 mAb injection is manufactured by reacting 225Ac chloride with 
DOTA−huJ591 (3.0 mg) aseptically withdrawn from the packaged drug substance vial and 
allowing the DOTA chelator to chelate 225Ac in tetramethylammonium acetate buffer (TMAA). 
Following the reaction, the 225Ac−DOTA−J591 is challenged with an excess of the chelator DTPA 
to remove any free or loosely bound Ac−225. 225Ac−DOTA−huJ591 is then separated from 
225Ac−DTPA by gel filtration (Biogel P−6 column, Biorad, CA) using sterile saline solution 
containing 2% Human Serum Albumin as an eluent. The eluent fraction (4−8 mL) containing 
225Ac−DOTA−huJ591 is then sterilized by membrane filtration into a final drug product vial. QC 
Samples are removed for Quality Control. The specific activity of the 225Ac−DOTA−huJ591 
injection is estimated based on dose calibrator measurement of total 225Ac activity (50 – 300µCi) 
and the total DOTA−huJ591 (3 mg) precursor used. Expected SA is 16.6 – 100 µCi/mg. Labeling 
efficiency and radiochemical purity will be determined using ITLC. Immunoreactivity of 
radiolabeled J591 mAb preparations will be determined using PSMA+ LNCaP tumor cells. 
 
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 (225Ac−J591, IND# 135267). 
 

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B. 68Ga−PSMA−HBED−CC: 
PSMA−HBED−CC will be purchased from 
 
 and 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 
Gallium−68. 
 
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. 
 
8.2. 
Availability 
 
225Ac−J591 (IND# 135267) and 68Ga−PSMA−HBED−CC (IND# 124495) are investigational 
agents supplied to investigators by Weill Cornell Medicine. 
 
8.3. 
Agent Ordering 
 
 
 
 
Upon enrollment of the subject, the WCM Study Coordinator will be notified about the 225Ac−J591 
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.  
 
8.4. 
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  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.  We will also analyze the proportion with undetectable CTC count 
at 12 weeks and % changes from baseline to 12 weeks. 
 

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9.1.2 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 or treatment,efficacy visit, and progression). A single sample for 
germline control will be collected in EDTA.  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, including the identification of DNA repair alterations. 
 
9.1.3 Archival tissue: 
 
Archival tissue will be requested during the screening visit. Fifteen unstained slides containing 
tumor material from archival paraffin−embedded tissue should be obtained. If available, metastatic 
tissue is preferred to prostate biopsy/prostatectomy specimens.   The tissue will be analyzed for 
PSMA expression and targeted next-generation DNA and RNA sequencing, including assessment 
of DNA damage repair and AR pathways. Results will be for research purposes only. 
 
9.1.4 Immune correlates: 
 
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. We will utilize seromics to 
assess changes in antigen recognition before and after 225Ac−J591 and will also explore the 
induction of immunogenic cell death with HMGB1 (serum) and calreticulin (CTC). Stool will 
be collected prior to treatment to assess microbiome. Results of these assays will not be billed 
to the patient and are for research purposes only. 
 
9.2. 
Imaging Studies 
 
Conventional Imaging studies as well as 68Ga−PSMA−HBED−CC PET/CT 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. 
 
As an optional study in consenting subjects, will undergo two scans with 68Ga-PSMA (with a 
minimum time of 6 h and maximum time 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 
 

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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 be 
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 as well as undetectable CTC count at 12 weeks has been associated with overall survival. 
We will report the proportion of subjects who have CTC count <5 and normal LDH at the efficacy 
(scan) 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% and 50% 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  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. 
 
10.5  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. 
 
 
 

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10.6  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. 
 
10.7  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 optional but recommended 
investigational images (68Ga−PSMA−HBED−CC PET/CT imaging) 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 be offered optional but recommended baseline and subsequent 
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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  Calreticulin Expression on CTCs 
 
We will analyze for associations between calreticulin expression and response to treatment and 
survival using chi−square tests/Fisher’s exact tests and log−rank tests, respectively. We plan to 
report data for each individual study as well as across the studies. 
 
10.10  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 BPI−SF and 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 
 

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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 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 (and 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 (accelerated dose−escalation followed by 3+3 Fibonacci 
escalation).  Definitions of DLT and determination of MTD are defined above (Section 6.2.10).   
In the initial accelerated dose−escalation portion, cohorts will consist of single−subjects.  If no > 
grade 1 at least possibly related AE (or >1 grade increase for pre-existing AE) occurs within 8 
weeks as judged by the investigator, AE grading and attribution will be reviewed by the study 
chair (and discussed with the medical monitor if there are questions about severity or attribution) 
and treatment in the next cohort will begin.  In the event of any grade > 2 attributable toxicity 
(excluding infusion reactions) OR enrollment in Cohort 5 (whichever is first), the study will 
transition to modified 3+3 dose escalation cohorts. In addition to determination of MTD, we wish 
to gain additional information at lower doses that appear to be efficacious and safe. The rationale 
is to better evaluate a recommended phase 2 dose based upon combination of efficacy and toxicity 
information (rather than just highest tolerable dose per DLT and 3+3 definition) and to also have 
additional information at lower doses that appear to have some efficacy that might be used in future 
combination studies.  Therefore, we will “backfill” cohorts that have met both of the following 
criteria: i) 0 of 3 subjects with DLT and ii) at least 1 of 3 subjects with >30% PSA decline and/or 
measurable disease response.  Cohorts of single-subjects are not eligible for expansion. 
 
The overall design is constructed to reduce exposure to subtherapeutic doses of study drug. The 
design of the 3+3 dose-escalation stage is 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. 
 

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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 
Sample Size/Accrual Rate 
 
The planned sample size for this dose escalation Phase I study is 2−52 treated subjects and accrual 
rate will be 1 subject every 2−3 months during the accelerated dose−titration portion, then 1−2 
patients/month during modified 3+3 dose−escalation and expansion cohorts. 
 
Sample size determination for the dose-escalation portion of the study is as described above. 
Sample size determination for the expansion cohort is as follows.  We will enroll up to 16 
subjects into the expansion cohort (including the 3-6 used for establishing the MTD and 10 
others for additional safety information).  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 Simons 
two-stage minimax design.  We project a 30% PSA decline proportion of 20%, below which 
the regimen will be unacceptable and a 30% PSA decline proportion of 40%, 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 20% will be tested against the alternative 
hypothesis that the 30% PSA decline proportion is greater than or equal to 40%. 
 
The sample size computations were performed assuming a 10% level of significance and 80% 
power.  If 1 or fewer of the first 9 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 2 or more 
patients out of the first 9 evaluable patients experience a 30% decline in PSA, ongoing accrual 
will proceed to the target sample size of 16 patients (stage 2).  The new regimen will be 
declared effective and worthy of further testing if 5 or more patients experience a 30% PSA 
decline among the 16 patients entered.  This two-stage design yields a 0.80 probability of a 
positive result if the true 30% PSA decline proportion is 40%.  It yields a 0.90 probability of a 
negative result if the true 30% PSA decline proportion is 15%. 
 
 
12.3 
Stratification Factors 
 
There are no planned stratification factors.  Descriptive statistics will be utilized. Stopping rules 
for futility are in place as per Section 4.2. 
 
12.4 
Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 

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The primary endpoint will be the proportion of subjects with DLT from Visit 1 through End of 
Study 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. 
 
12.4.2 Analysis of Secondary Endpoints 
 
For PSA response, CTC response and Imaging response, Descriptive analysis will be done. For 
imaging response RECIST criteria with PCWG3 modifications will be applied. 
 
12.5 
Interim Analysis  
 
No interim analysis is planned (though safety analyses will occur in real−time and prior to each 
dose−escalation). 
 
12.6 
Reporting and Exclusions 
 
12.6.1 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 treatment single dose of with 
225Ac−J591. 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.  
 
12.6.2 Evaluation of response 
 
Subjects who complete 225Ac−J591 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. 
 

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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 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 225Ac−J591. 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 225Ac−J591 include: infusion reaction (fever, chills, rash, hypotension, and/or 
hypertension after injection), hematological/bone marrow toxicity (thrombocytopenia, 
neutropenia), pain,and transient hepatic enzyme elevations. In addition, allergic reactions 
including anaphylaxis, renal failure, and CNS toxicity are a possibility. Based upon experience 
with another 225Ac radiolabeled antibody (for leukemia), we will administer saline and instruct 
subjects to increase oral hydration for the week following treatment to reduce the risk of non-
specific renal toxicity from daughter radionuclides. 
 
Precautions/monitoring: 
 
The infusion of 68Ga−PSMA−HBED−CC or 225Ac−J591 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. A minimum of 1 liter 
normal saline will be administered before/during/after 225Ac−J591 infusion. Vital signs will be 
monitored before/after the 68Ga−PSMA−HBED−CC or 225Ac−J591 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 225Ac−J591 infusion, and within 30 minutes, 
60 (+/− 10) minutes, 90 (+/− 10) minutes, and 120 +/− 10 minutes after the225Ac−J591 infusion. 
If any subject has any adverse reaction within 120 minutes for 225Ac−J591, 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 

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intervals during the year, and carries out ongoing review of protocols submitted throughout the 
year.  Once a protocol has been submitted and approved by the Institutional Review Board (IRB) 
and is recommended for oversight by the DSMB, the Board determines if the protocol will be 
reviewed quarterly, semi−annually, or annually. 
 
The DSMB evaluates the accumulated data from the study in order to monitor the 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: 
 
• Completed DSMB Periodic Review Form. 
• Synopsis of the study to date. 
• IRB approved consent form. 
• IRB current protocol. 
• Summary table of study results. 
• Adverse event table. 
• 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. 
 

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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. 
 
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 the 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 this study, and will monitor the subjects 
during the conduct of the study. 
 
Ashish Saxena, MD will serve as the Medical Monitor for this study. 
 
 
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APPENDICES 
 
APPENDIX A 
Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 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