Clinical trial NCT03545165
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University
Start date: 2018-04-18; Completion date: 2020-07-15
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase I dose escalation study with combination of 177Lu-J591 and 177Lu-PSMA-617 using a dose-fractionated regimen will be performed in patients with documented progressive metastatic CRPC. The cumulative 177Lu-J591 dose for each subject will be 2.7 GBq/m2 (73 mCi/m2) of 177Lu with 20 mg J591 and the cumulative 177Lu-PSMA-617 dose for each subject will vary (depending on the Cohort) from 3.7 GBq (100 mCi) to 18.5 GBq (500 mCi). The 177Lu-PSMA-617 dose will be escalated in up to 6 different dose levels (3+3 dose-escalation study / de-escalation design). For the phase II portion, a minimum number of 14 patients will be enrolled at MTD (including those enrolled at MTD in Phase I) and a maximum of 24.

Detailed description:
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 combination of 177Lu-J591 and 177Lu-PSMA-617 in a two-week dose-fractionation regimen. 177Lu-J591 will be given at a moderate dose previously demonstrated to be safe x2 infusions two weeks apart. For 177Lu-PSMA-617 the dose escalation will start at 3.7 GBq (100 mCi) and escalate in increments of 1.85 GBq (50 mCi) for each dose to a planned maximum of 9.25 GBq (250 mCi) x2 doses, 2 weeks apart. Should there be unacceptable toxicity at the initial dose level, we will de-escalate to dose level -1 (1.85 GBq / 50 mCi per dose). After the phase I study has established a MTD, the Phase II, single-arm trial will start.

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).

Subjects will have Lutetium-177 Planar/SPECT Imaging on Day 8 (±1 day) after the first dose of 177Lu-J591 + 177Lu-PSMA-617. Optimal images will be performed on selected consenting subjects between the initial treatment visit #1 on Day 1 and Day 4 and prior to treatment visit #2 on D15 ±1. Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2 weeks for one month, at 8 and 12 weeks, and then every 4 weeks for next 3 months).

Upon completion of investigational treatment with dose-fractionation regimen of the combination of 177Lu-J591 + 177Lu-PSMA-617, subjects will undergo 68Ga-PSMA-HBED-CC injection and same day PET/CT at the end of study visit to document treatment response. Subsequently survival data and additional treatment(s) information will be captured from their routine Standard of care (SOC) visits.

.

Arms: arm 1: 177Lu-PSMA-617 \[1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)\] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration

177Lu-J591 \[1.35 GBq/m2 or 36.5 mCi/m2\] x2 doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration

68Ga-PSMA-HBED-CC \[185 ±74 MBq or 5 ±2 mCi\] intravenous during screening and at 12 weeks (±1 week) with standard imaging
Interventions: intervention 1: 177Lu-PSMA-617 intervention 2: 177Lu-J591 intervention 3: 68Ga-PSMA-HBED-CC
Intervention descriptions: intervention 1: \[1.85 GBq (50 mCi) - 9.25 GBq (250 mCi)\] intervention 2: \[1.35 GBq/m2 or 36.5 mCi/m2\] intervention 3: \[185 ±74MBq or 5 ±2 mCi\]

Protocol documents:
Prot_SAP_000.pdf: 


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E−mail: 
 
 
Participating Sites:  Weill Cornell Medicine, Dana Farber Cancer Institute, Tulane Cancer Center 


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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 
 
ADT 
AE 
AR 
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  
UAP 
Unanticipated Problem 
WCM 
Weill Cornell Medicine 


 
 
  
1 
 
Protocol Summary 
 
Full Title: 
Phase I/II dose-escalation trial of combination fractionated dose 
177Lu−J591 and 
177Lu−PSMA−617 in patients with metastatic 
castration−resistant prostate cancer 
Short Title: 
177Lu−J591 and 177Lu−PSMA−617 combination for mCRPC 
Clinical Phase: 
Phase I 
Principal Investigator:     Scott T. Tagawa, MD, MS  
Sample Size: 
N = 6 − 57 (Phase I: 3 + 3 dose−escalation study design up to 6 
dose−escalation / de-escalation cohorts for minimum of 6 and 
maximum of 30; Phase II minimum of 16 and maximum of 27) 
Accrual Ceiling: 
This study will enroll up to 57 subjects who receive treatment. 
Study Population: 
Adult male patients of >18 years with documented progressive 
metastatic CRPC 
Accrual Period: 
3 years (approximately 1−2 patients per month with gaps between 
dose-escalation cohorts and between stage 1 and 2 of the phase II 
portion).  
Study Design: 
Phase I dose escalation study with combination of 177Lu−J591 and 
177Lu−PSMA−617 using a dose-fractionated regimen will be 
performed in patients with documented progressive metastatic CRPC. 
The cumulative 177Lu−J591 dose for each subject will be 2.7 GBq/m2 
(73 mCi/m2) of 177Lu with 20 mg J591 and the cumulative 
177Lu−PSMA−617 dose for each subject will vary (depending on the 
Cohort) from 3.7 GBq (100 mCi) to 18.5 GBq (500 mCi). The 
177Lu−PSMA−617 dose will be escalated in up to 6 different dose 
levels (3+3 dose−escalation study / de-escalation design). For the phase 
II portion, a minimum number of 14 patients will be enrolled at MTD 
(including those enrolled at MTD in Phase I) and a maximum of 24.  
Study Duration: 
Approximately 3 months after enrollment, then transition to long−term 
follow up 
Study Agent: 
1) 177Lu−PSMA−617 [1.85 GBq (50 mCi) – 9.25 GBq (250 mCi)] x2 
doses, 2 weeks apart (Treatment Visit #1 and #2), IV administration 
 
2)  177Lu−J591 [1.35 GBq/m2 or 36.5 mCi/m2] x2 doses, 2 weeks apart 
(Treatment Visit #1 and #2), IV administration 
 
3) 68Ga−PSMA−HBED−CC [185 ±74 MBq or 5 ±2 mCi] intravenous 
during screening and at 12 weeks (±1 week) with standard imaging 
Primary Objectives: 
• (Phase I) Determine the dose limiting toxicity (DLT) of 
dose−fractionated combination therapy with 
177Lu−J591 and 
177Lu−PSMA−617 


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• (Phase I) Determine the maximum tolerated dose (MTD) and 
recommended phase II dose (RP2D) of dose−fractionated 
combination therapy with 177Lu−J591 and 177Lu−PSMA−617 
• (Phase II) To assess the proportion with PSA decline following the 
dose−fractionated combination therapy with 
177Lu−J591 and 
177Lu−PSMA−617 
Secondary Objectives: 
• To assess radiographic response rate by RECIST 1.1 with PCWG3 
modifications 
• To assess biochemical and radiographic progression−free survival by 
PCWG3 criteria 
• To assess overall survival following the dose−fractionated 
combination therapy with 177Lu−J591 and 177Lu−PSMA−617 
• To assess safety of dose−fractionated combination therapy with 
177Lu−J591 and 177Lu−PSMA−617 as assessed by CTCAE 4.0 
• To assess changes in CTC count as measured by CellSearch and the 
rate of favorable CTC count and LDH at 12 weeks following 
dose−fractionated combination therapy with 
177Lu−J591 and 
177Lu−PSMA−617 
• 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 immune effects of PSMA−targeted radionuclide therapy  
 
• To assess genomic alterations in relationship to outcome following 
dose−fractionated combination therapy with 
177Lu−J591 and 
177Lu−PSMA−617 
• To estimate whole body distribution and radiation dosimetry of 
177Lu−J591 and 177Lu−PSMA−617  
Endpoints: 
Dose limiting toxicity (DLT), adverse event rate, Maximum tolerated 
dose (MTD), recommended phase II dose (RP2D), PSA decline rate, 
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  
Follow up 
Treatment Visit 1 (Day 1): Injection of 1st dose of 177Lu–J591 + 177Lu–PSMA–617 
Treatment Visit 2 (Day 15): Injection of 1st dose of 177Lu–J591 + 177Lu–PSMA–617 
Imaging visit (Day 8): Adverse events, concomitant medication, Lutetium-177 Planar/SPECT Imaging 
(Optional additional imaging time points) 
Follow up Visit 1 (Day 22), Follow up Visit 2 (Day 29), Follow up Visit 4 (Day 57): Adverse events, 
concomitant medication 
Efficacy (scan) Visit (Day 85): Adverse events, concomitant medication, CT/MRI, bone scan, 
PSMA−ligand based PET/CT imaging 


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Table of Contents 
1. 
STUDY OBJECTIVES ........................................................................................................... 6 
1.1 
Primary Objectives .......................................................... Error! Bookmark not defined. 
1.2 
Secondary Objectives ....................................................................................................... 6 
1.3 
Exploratory Objectives ..................................................................................................... 6 
2. 
BACKGROUND .................................................................................................................... 7 
2.1 
Disease ............................................................................................................................. 7 
2.2 
PSMA ............................................................................................................................. 20 
2.3 
Anti−PSMA Monoclonal humanized anitbody (J591) .................................................... 7 
2.4 
Risk/Benefit Assessment ................................................................................................ 11 
2.5 
Radionuclinde−chelating PSMA ligand ......................................................................... 14 
2.6 
Investigational Agent ..................................................................................................... 17 
2.7 
Rationale......................................................................................................................... 18 
2.8 
Rationale for the appropriate radioisotope ..................................................................... 19 
2.9 
Risk/Benefit Assessment ................................................................................................ 20 
2.4 
Risk/Benefit Assessment ................................................................................................ 11 
2.10 Correlative Studies Background..................................................................................... 20 
3. 
SUBJECT SELECTION ....................................................................................................... 44 
3.1 
Study Population ............................................................................................................ 23 
3.2 
Inclusion Criteria ............................................................................................................ 45 
3.3      Exclusion Criteria .......................................................................................................... 46 
4. 
OVERVIEW OF STUDY DESIGN AND METHODOLOGY ........................................... 23 
4.1 
Study Design .................................................................................................................. 11 
4.2 
Rationale for Dose−Escalation Strategy ........................................................................ 24 
5. 
REGISTRATION PROCEDURES ...................................................................................... 47 
5.1 
Identification of subjects ................................................................................................ 25 
5.2 
Consent process .............................................................................................................. 25 
5.3 
Central Patient Registration ........................................................................................... 25 
6. 
STUDY PROCEDURES ...................................................................................................... 47 
6.1 
Schedule of Evaluations ................................................................................................. 27 
6.2 
Treatment Administration .................................................................................................. 25 
6.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 35 
6.4 
Duration of Therapy and Criteria for Removal from Study ........................................... 35 
6.5 
Duration of Follow Up ................................................................................................... 36 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ERROR! BOOKMARK NOT DEFINED. 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 36 
8.1 
Investigational Agent ..................................................................................................... 36 


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8.2 
Availability ...................................................................... Error! Bookmark not defined. 
8.3 
Agent Ordering ............................................................................................................... 37 
8.4 
Agent Accountability ..................................................................................................... 38 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 38 
9.1 
Laboratory Correlative Studies ...................................................................................... 38 
9.2 
Special Studies ............................................................................................................... 38 
10. MEASUREMENT OF EFFECT........................................................................................... 38 
10.1 CTC count response ....................................................................................................... 39 
10.2 Biochemical (PSA) response .......................................................................................... 39 
10.3 Duration of PSA response .............................................................................................. 39 
10.4 Duration of CTC response.............................................................................................. 39 
10.5 PSA Progression ............................................................................................................. 39 
10.6 PSA Stabilization ........................................................................................................... 39 
10.7 Time to PSA Progression .................................................................................................. 40 
10.8 Change in lesion size ...................................................................................................... 40 
10.9 PSMA Expression on CTCs ........................................................................................... 41 
9.2 
Special Studies ............................................................................................................... 41 
11. DATA REPORTING / REGULATORY CONSIDERATIONS .......................................... 41 
11.1 Data Collection ................................................................................................................. 41 
11.2 Regulatory Considerations ................................................................................................ 42 
12. STATISTICAL CONSIDERATIONS.................................................................................. 42 
12.1 Study Design/Endpoints.................................................................................................... 42 
12.2 Sample Size/Accrual Rate................................................................................................. 42 
12.3 Stratification Factors ......................................................................................................... 43 
12.4 Analysis of Endpoints ....................................................................................................... 43 
12.5 Interim Analysis ................................................................................................................ 44 
12.6 Reporting and Exclusions ................................................................................................. 44 
REFERENCES ............................................................................................................................. 24 
APPENDIX  .................................................................................................................................. 57 
 
 
 


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1. 
STUDY OBJECTIVES 
 
 
The objectives of this clinical trial are as follows: 
 
1.1 
Primary Objectives  
 (Phase I) Determine the dose limiting toxicity (DLT) of the combination of 177Lu−J591 and 
177Lu−PSMA−617 in a 2−week dose−fractionation regimen 
 (Phase I) Determine the cumulative maximum tolerated dose (MTD) and/or recommended 
phase II dose (RP2D) of the combination of 177Lu−J591 and 177Lu−PSMA−617 in a 
2−week dose−fractionation regimen 
 (Phase II) To assess the proportion with PSA decline following treatment with the 
combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation 
regimen 
 
1.2 
Secondary Objectives 
 
 To assess radiographic response rate by RECIST 1.1 with PCWG3 modifications 
 To assess biochemical and radiographic progression−free survival by PCWG3 criteria 
 To assess overall survival following treatment with the combination of 177Lu−J591 and 
177Lu−PSMA−617 in a 2−week dose−fractionation regimen 
 To assess safety of treatment with the combination of 177Lu−J591 and 177Lu−PSMA−617 
in a 2−week dose−fractionation regimen as assessed by CTCAE 4.0 
 To assess changes in CTC count as measured by CellSearch and the rate of favorable CTC 
count and LDH at 12 weeks following treatment with the combination of 177Lu−J591 and 
177Lu−PSMA−617 in a 2−week dose−fractionation regimen 
 
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 immune effects of PSMA−targeted radionuclide therapy  
 To assess genomic alterations in relationship to outcome following treatment with the 
combination of 177Lu−J591 and 177Lu−PSMA−617 in a 2−week dose−fractionation 
regimen 
 To estimate whole body distribution and radiation dosimetry of 177Lu−J591 and 
177Lu−PSMA−617 
 
 
 


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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 
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 immuno therapy with sipuleucel−T, and the 
bone−seeking α−emitter 223Ra have shown improved overall survival (OS) and most have 
demostrated quality of life advantages as well (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 


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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 
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 – 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 


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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 
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 75mCi/m2, and the 70mCi/m2 dose level was determined to be the single−dose MTD. 
Repeat dosing at 45 to 60mCi/m2 was associated with dose−limiting myelosuppression; however, 
up to three doses of 30mCi/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 70mCi/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 
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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 
survival (OS); as well as CTC count (CellSearch) changes in the expansion cohorts. 49 patients, 
with median age 74.1 years (range 55−95), median PSA of 44.9 ng/mL (1.9−766.5); 83.7% with 
bone, 61.2% with lymph node, 40.8% with visceral metastasis. 8.2% were CALGB (Halabi) low, 
34.7% were intermediate, 57.1% were in high−risk group. RP2D’s of fractionated 177Lu−J591 
were 40 mCi/m2 x2 or 45 mCi/m2 x2 with option for GCSF. PSA changes for the low dose group 
were reported as 6.3% showing >50% PSA decline, 12.5% reporting >30% PSA decline, and 
37.5% with any PSA decline. within RP2D group 21.2% showing >50% PSA decline, 42.4% 
reporting >30% PSA decline, and 66.7% with any PSA decline. The median overall survival for 
low dose group was 14.6 months and for RP2D group was 27.7 months. Accurate targeting of 
177Lu−J591 was seen in 79.6%. Patients with lower PSMA expression by imaging were less likely 
to respond (p=0.07). Of 25 with CTC counts, 14 declined, 8 stably favorable, and 3 increased. 
RP2D was associated with more PSA declines (p=0.036) and longer OS (p=0.004), even after 
controlling for CALGB prognostic grouping (adjusted HR 0.42 [95% CI 0.21, 0.84] p=0.01). 
Predictable, reversible myelosuppression was seen. 36 (73.5%) patients had grade 3/4 heme 
toxicities; 19 (57.6%) had Grade 4 heme toxicities in RP2D cohorts with 45.4% receiving 
prophylactic platelet transfusions (median 1, range 1−4) and 6 GCSF. 14 (28.6%) had infusion 
reactions (without pre−meds), with 1 patient having Grade 2 infusion reaction leading to 
withdrawing from the study prior to his 2nd dose. 5 (10.2%) had transient Gr 1/2 AST/ALT. This 
study concluded that fractionated 177Lu−J591 is well tolerated with predictable, reversible 
myelosuppression and PSA and CTC declines. Additionally, with dose−fractionation, the 
cumulative dose MTD is 14−28% higher than single dose MTD with similar toxicity. 
 
Table 1: Toxicities data from Phase 2 single dose 177Lu−J591 Study and Phase 1 
fractionated 177Lu−J591 study: 
 
Single Dose 
Fractionated Dose 


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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): 
 
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%. 
 
 
 
 
 
 
 
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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2.4 
Radionuclide−chelating PSMA ligand 
 
Targeted radionuclide therapy (both monoclonal antibody and/or urea based peptides) is a state 
of the art and rapidly developing therapy option for different cancer types. The potential 
advantage of targeted radionuclide therapy is saving the normal tissue while giving a high 
radiation dose to the tumor. 
 
After rather unsuccessful therapy with 90Y−CYT−356 monoclonal antibody (mAb) that binds 
to the intracellular domain of PSMA(43), phases 1 and 2 clinical trials utilizing the PSMA 
mAb J591, radiolabeled with 90Y (Yetrium−90) or 177Lu (Lutetium−177), have shown 
promising results(28, 34, 35, 39). 
 
Also, PSMA has recently been discovered as a promising target for radioisotope based 
approaches, both for therapy, for example, using ligands labeled with either β− or α−emitting 
nuclides such as 131I (Iodine−131), 177Lu (Lutetium−177), and 225Ac (Actinium−225), and for 
PET imaging, for example, using 68Ga−labeled PSMA ligands. Despite encouraging early 
results, data about intended and unintended effects of PSMA−based radioligand therapies 
(RLTs) are still scarce. 
 
Results from selective clinical trials using radiolabled PSMA ligand for therapy and diagnosis 
of prostate cancer are reported here under: 
 
2.4.1 
177Lu−PSMA−617 
 
a) 177Lu−DKFZ−PSMA−617 therapy in metastatic castration resistant prostate cancer (44): 
 
Thirty−one mCRPC patients with progressive disease despite second−line hormonal therapy 
and/or 
docetaxel 
chemotherapy 
were 
recruited 
for 
the 
study. 
All 
underwent 
68Ga−PSMA−HBED−CC PET/CT, prior to therapy with 177Lu−DKFZ−PSMA−617. The mean 
activity administered was 5.07 ± 1.85 GBq ranging over one to four cycles. Study reported decline 
in PSA from baseline. Based on biochemical response criteria, 25/31 had either complete response, 
partial response or stable disease while 6 continued to have disease progression. The mean ECOG 
performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I 
and grade II hemoglobin toxicity each, while none experienced nephrotoxicity or hepatotoxicity. 
 
b) 177Lu−PSMA−617 as A Novel Therapeutic Option in Patients With Metastatic Castration 
Resistant Prostate Cancer (45): 
 
28 consecutive patients with mCRPC who have exhausted conventional therapeutic options were 
treated with 1 or 2 cycles of 177Lu−PSMA−617. Mean administered activity at first therapy was 






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f) 
German collaborative publication 
 
The largest published experience is a retrospective case series of 145 patients with mCRPC treated 
at 12 centers in Germany between February, 2014 and July, 2015(49). While not a prospective 
research study, in general the patients included men who had tumor progression despite abiraterone 
(64%) and/or enzalutamide (52%) and had either received chemotherapy (54%) or were 
unfit/refused chemotherapy. Patients also received radium−223 if able/eligible (17%). Treatment 
was administered only if PSMA uptake was demonstrated on PSMA imaging. On average, 5.9 
GBq was administered per dose (range 2−8 GBq).  Retreatment was allowed at physician 
discretion.  Of assessable patients (n=99), 60% had PSA decline after initial treatment, with at least 
50% PSA decline occurring in 40%.  Safety was assessed by retrospective chart review with charts 
available in all 145 and labs available in 121 (83.4%).  Grade >2 hematologic AEs occurred in 
12% (grade 3/4 anemia in 10%, grade 3/4 leukopenia in 3%, and grade 3/4 thrombocytopenia in 
4%). Other AEs of any grade that occurred >4% include AST elevation 19%, fatigue 13%, renal 
failure 12%, ALT elevation 8%, xerostomia 8%, nausea 6%, dysgeusia 4%.  While retrospective 
in nature, this represents the largest published series and demonstrates some biochemical 
anti−tumor activity without a high occurrence of high−grade adverse events. 
 
g) 
Preliminary data from Australian prospective phase II study 
Preliminary results of the first prospective study utilizing 177Lu-PSMA-617 were reported at the 
2017 ESMO annual meeting.  46 Australian investigators enrolled 43 men with mCRPC and treated 
30 (7 excluded due to imaging results, 6 others for eligibility issues). Following PSMA and FDG 
PET/CT, subjects received 4-8 GBq of 177Lu-PSMA-617 and were planned to receive 4 doses 
every 6 weeks. Seventeen (57%) had at >50% PSA decline with median PFS 6.3 and OS 12.7 
months.  Toxicity was deemed acceptable. In this prospective study, but adverse events were more 
common than previously reported in retrospective studies. Xerostomia (grade 1-2) was common 
at 63%, nausea 50%, vomiting 20%, and fatigue 17%. All cause grade 3/4 anemia occurred in 
23%, neutropenia 10%, thrombocytopenia 27%, though attributable grade 3/4 anemia occurred in 
7%, neutropenia 7%, and thrombocytopenia 13%. 
 
Additional therapeutic studies using different radiolabled PSMA ligands are summarized in the 
table below: 
 
 
 
 


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Table 4: 117Lu−PSMA−617: Pilot studies of targeted radionuclide therapy: 
 
 
Radioligand Therapy 
N 
Dose 
(GBq) 
Total doses 
Reference 
1. 
177Lu−DKFZ−PSMA−617 
1 
7.4 
1 dose 
Kratochwil et al. 2015 
2. 
177Lu−DKFZ−PSMA−617 
10 
4.1 – 6.1 
1 dose 
Ahmadzedehfar et al. 2015 
3. 
177Lu−PSMA−617 
7 
0.19 – 0.21 
1 dose 
Kabasakal et al. 2015 
4. 
177Lu−PSMA I&T 
2 
5.7 – 8 
1 dose 
Weineisen et al. 2015 
5. 
177Lu−DKFZ−PSMA−617 
5 
3.4 – 3.9 
2 doses, 
10 weeks apart 
Delker et al. 2016 
6. 
177Lu−PSMA−617 
30 
3.7 – 6 
1 – 3 dose(s), 
2 months apart 
Kratochwil et al. 2016 
7. 
177Lu−PSMA−617 
9 
5.28 – 5.77 
1 dose 
Hohberg et al. 2016 
8. 
177Lu−PSMA−617 
7 
5.5 – 7.4 
1 dose 
Das et al. 2016 
9. 
177Lu−PSMA−617 
23 
7.4 
1 dose 
Demir et al. 2016 
10. 
177Lu−PSMA−617 
28 
5.13 – 6.59 
1 – 2 dose(s), 
2 months apart 
Rahbar et al. 2016 
11. 
177Lu−PSMA−617 
82 
5.4 – 6.4) 
1 dose 
Rahbar et al. 2016 
12. 
177Lu−PSMA−617 
31 
1.1 – 5.5 
1 – 4 dose(s) 
Yadav et al.  2016 
13. 
177Lu−PSMA−617 
1 
NA 
3 doses, 
8 weeks apart 
Schlenkhoff et al. 2016 
14. 
177Lu−PSMA−617 
43 
6 
1 – 4 dose(s) 
Zimbelmann et al. 2016 
15. 
177Lu−PSMA−617 
5 
5.8 – 7.4 
1 dose 
Chakraborty et al. 2016 
16. 
177Lu−PSMA−617 + 
177Lu−EDTMP 
1 
1.85 + 1.3 
1 dose each 
Bal et al. 2016 
17. 
177Lu−PSMA I&T 
22 
3.4 – 7.4 
1 – 4 dose(s), 
2 weeks apart 
Heck et al. 2016 
18. 
177Lu−PSMA I&T 
56 
3.6 – 8.7 
1 – 5 dose(s) 
Baum et al. 2016 
19. 
177Lu−PSMA I&T 
18 
7.4 
1– 4 dose(s) 
Okamoto et al. 2017 
20. 
177Lu−PSMA−617 
15 
3.7 – 6 
2 doses 
Fendler et al. 2017 
21. 
131I−MIP−1095 
36 
1.5 – 7.2 
1 – 3 dose(s) 
Afshar–Oromeih et al. 2017 
22. 
177Lu−PSMA−617 
1 
5.9 – 6.4 
4 doses 
Roll et al. 2017 
 
h. 
Fractionated dose 177Lu-PSMA-617 
 
Based upon our prior experience with radiolabeled J591 (demonstrating dose and toxicity response 
with improved safety with dose fractionation) and the worldwide experience of radiolabeled small 
molecules, we initiated a dose-escalation study of fractionated dose 177Lu-PSMA-617 in January, 
2018.  As of the time of current protocol writing, 4 cohorts have been treated with safety follow 
up (and the 5th / final planned cohort is enrolled), with administered/planned dose levels described 
in the Table below.  As predicted based upon dosimetry estimations, no dose-liming toxicity has 
been observed to date, including all potential dose-levels to be utilized in this protocol. 
 


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Table:  Dose-escalation strategy of fractionated dose 177Lu-PSMA-617 protocol 
Cohort 
Treatment Dose mCi (GBq) 
Total dose 
# Subjects 
 
Day 1 
Day 15 
mCi (GBq) 
(n) 
-1 
50 (1.85) 
50 (1.85) 
100 (3.7) 
0 
1 
100 (3.7) 
100 (3.7) 
200 (7.4) 
6 
2 
150 (5.55) 
150 (5.55) 
300 (11.1) 
6 
3 
200 (7.4) 
200 (7.4) 
400 (14.8) 
5 
4 
250 (9.25) 
250 (9.25) 
500 (18.5) 
6 
5 
300 (11.1) 
300 (11.1) 
600 (22.2) 
pending 
 
 
2.4.2 
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(50-55). 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(56, 
57). 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(58, 59). PET/CT−imaging with 68Ga−PSMA−11 has demonstrated this novel 
method as an important imaging modality for diagnosing recurrent PCa (50, 60-62). 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(63). 
 
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(61): 
 


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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 
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 (64): 
 
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 


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cancer: Comparison with 18F−FECH (52): 
 
This study was also published by the Heidelberg group, compared 68Ga−PSMA− HBED−CC 
PET/CT imaging to standard choline−based PET/CT. Thirty−seven patients with biochemical 
relapse of prostate cancer [mean prostate−specific antigen (PSA) 11.1 ± 24.1 ng/ml, range 
0.01−116] were retrospectively analyzed after 18F− fluoromethylcholine and 68Ga−PSMA PET/CT 
within a time window of 30 days. Radiotracer uptake that was visually considered as prostate 
cancer was semi− quantitatively analyzed by measuring the maximum standardized uptake values 
(SUVmax) of the scans acquired 1−hour after injection of 68Ga−PSMA complex solution (median 
132 MBq, range 59−263 MBq) and 18F−fluoromethylcholine (median 237 MBq, range 114−374 
MBq), respectively. In addition, tumor to background ratios were calculated. 
 
The results showed a total of 78 lesions characteristic for prostate cancer that were detected in 32 
patients using 68Ga−PSMA−HBED−CC PET/CT imaging and 56 lesions were detected in 26 
patients using choline PET/CT. The higher detection rate in 68Ga−PSMA−HBED−CC PET/CT 
imaging was statistically significant (p=0.04). In five patients, no lesion was found with both 
methods. All lesions detected by 18F−fluoromethylcholine PET/CT were also seen by 
68Ga−PSMA−HBED−CC PET/CT imaging. In 68Ga−PSMA−HBED−CC PET/CT imaging 
SUVmax was clearly (>10 %) higher in 62 of 78 lesions (79.1 %) and the tumor to background 
ratio was clearly (>10 %) 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 (60): 
 
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 


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compared with differences in SUVs between PET/CT 1−hour and 3−hours after injection in 
another patient cohort. This cohort was investigated using the same PET/CT system.  With 
PET/MRI, different diagnostic sequences, higher contrast of lesions and higher resolution of MRI 
enabled a subjectively easier evaluation of the images. In addition, four unclear findings on 
PET/CT could be clarified as characteristic of prostate cancer metastases by PET/MRI. However, 
in PET images of the PET/MRI, a reduced signal was observed at the level of the kidneys (in 11 
patients) and around the urinary bladder (in 15 patients). This led to reduced SUVs in six lesions. 
SUVmean values provided by the PET/MRI system were different in muscles, blood pool, liver 
and spleen. 
The authors concluded that prostate cancer was detected more easily and more accurately with 
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 
 
 
177Lu−J591 (IND #11613) 
 
i. 
J591 
The J591 Mab is a deimmunized monoclonal antibody directed at the extracellular domain of 
human PSMA.  J591 was derived from murine J591 using Biovation’s (Aberdeen, Scotland) 
Deimmunisation technology in which individual amino acids in predicted B and T cell epitopes 
were replaced with other amino acids such that the epitope would no longer be recognized by the 
human immune system, thereby decreasing the likelihood of the development of an anti–mAb 
antibody response in humans (65). This results in a potentially non–immunogenic antibody, which 
can be administered to patients on multiple occasions over long periods without inducing an 
immune response. Furthermore, the deimmunized Mab additionally has been engineered to possess 
the effect of inducing antibody dependent cellular cytotoxicity (ADCC) with human immune 
effector cells. J591 is produced from NS0 cells by Lonza Biologics (Slough, UK).  The molecular 
weight of J591 is approximately 147,000 daltons as determined by Matrix Assisted Laser 
Desorption Mass Spectrometry (MALDI–TOF).  The naked antibody is formulated in a 50 mM 
sodium phosphate, pH 5.5, containing 100 mM sodium chloride and 2 mM EDTA at a nominal 
concentration of 5 mg/mL. 
 


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ii. 
DOTA–J591 
In order to radiolabel J591 with – emitting radionuclides such as 177Lu, the J591 antibody 
molecule is first conjugated to a macrocyclic chelating agent, 1,4,7,10–tetraazacyclododecane– 
N,N’,N’’,N’’’–tetraacetic acid (DOTA) by direct coupling of one of the four carboxylic acid 
groups of DOTA to the primary amines present in the protein structure. The DOTA conjugated 
antibody is formulated in 0.3 M ammonium acetate, pH 7.0 at a nominal concentration of 8 mg/mL. 
 
iii. 
Radiolabeled J591 (177Lu−J591) 
The DOTA–J591 antibody molecule is labeled with radiometal 177Lu in 1.0 M ammonium acetate 
buffer at pH 7.0. The radiolabeled J591 complex is then purified using size–exclusion column 
chromatography. To avoid the effects of autoradiolysis on the antibody, reaction time is minimized 
and the radiolabeled antibody preparations are formulated in phosphate buffered saline containing 
not more than 1% Human Serum Albumin (HSA). All reagents used in the conjugation and 
purification of J591 are made with pyrogen–free water.  Radiolabeled J591 is periodically tested 
for sterility and pyrogenicity. 
 
Each patient dose will be supplied to the study site on the day of or day before treatment by the 
central radiopharmacy. The J591 mAb is a deimmunized monoclonal antibody directed at the 
extracellular domain of human PSMA.  For additional details, see Section 1 and/or Investigator 
Brochure. Radiolabeled antibody preparations are formulated in phosphate buffered saline 
containing not more than 1% Human Serum Albumin (HSA).In order to radiolabel J591 with – 
emitting radionuclides, the antibody molecule is first conjugated to a macrocyclic chelating agent, 
1,4,7,10–tetraazacyclododecane– N,N’,N’’,N’’’–tetraacetic acid (DOTA) by direct coupling of 
one of the four carboxylic acid groups of DOTA to the primary amines present in the protein 
structure.The radiolabeling of J591 with 177Lu is achieved by adding the radionuclide to the 
ammonium acetate buffered J591.  To avoid the effects of autoradiolysis on the antibody, reaction 
time is minimized and the reaction mixture is purified with a size exclusion column prior to 
administration. All reagents used in the conjugation and purification of J591 are made from 
pyrogen–free water.  Radiolabeled J591 is tested periodically for sterility and pyrogenicity. 
 
iv. 
Pharmacokinetics 
The pharmacokinetics of J591 antibody was studied in patients with prostate cancer using 111In–
J591 as a radiotracer. In a Phase 1 dose escalation study (see above) 4 groups of patients received 
different amounts of J591 antibody (25, 50, 100, 200 mg/m2) mixed with a trace amount of 111In–
J591 (5 mCi/1–2 mg). In a different Phase 1 dose–escalation study using 90Y–J591 (see above), a 
group of patients received 20 mg of total J591 antibody mixed with a trace amount of 111In–J591 
(5 mCi/1–2 mg) for imaging studies prior to 90Y treatment dose. These studies demonstrated that 
the plasma clearance kinetics of 111In– J591 antibody is dose–dependent at low doses (<50 mg/m2).  
It should be noted that, in these studies, plasma clearance kinetics was determined based on the 
measurement of radioactivity in the plasma over time. The actual J591 antibody levels have not 
been measured; there is an assumption that the clearance of radiolabeled antibody does indeed 


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reflect the J591 antibody clearance.  The plasma clearance kinetics, based on bi–exponential fitting 
of plasma–time activity curves indicate that the terminal half–life (T1/2) is about 44.2 ± 13.9 hrs 
at 11 mg/m2 antibody dose and 59.3±16.6 hrs at 25 mg/m2 antibody dose.  At higher doses of 
antibody mass, the plasma clearance is relatively slower, but stable.  In summary, the plasma 
clearance of antibody increases at lower doses of antibody (<25 mg/m2).  In addition, repeat 
administration of J591 antibody over a 4–week period does not affect plasma clearance of 
radiolabeled J591 in patients with prostate cancer (data not shown).  In a Phase 1 dose–escalation 
study using 177Lu–J591 (see above), a group of patients received J591 antibody mixed with a 
177Lu–J591 (10–70 mCi/m2 and total J591 10mg/m2). The plasma clearance kinetics (shown in 
Table–5) demonstrate that there is no difference between 177Lu and 111In labeled J591 antibody. 
 
Table–5: 
177Lu–J591 Vs. 111In–J591:  Plasma Clearance Kinetics: 
 
 
 
Pts. 
mg/m2 T½  (hr) 
T½  (hr) 
Vd at T0 
Clearance   
n=18# 
   10 
3.615.70 46.812 
39491067 7234 
 
 
 
 
 
 
 
 
n=16* 
11 
2.37±1.94 44.2±14 
4042±863 
94±34 
 
  
 
 
 
 
 
 
n=3$ 
25 
3.36±2.17 59.3±17 
3698±224 
56±16 
 
  
 
 
 
 
 
 
n=3$ 
50 
7.83±9.5 
99.7±32 
4156±256 
47±6.7 
 
  
 
 
 
 
 
 
n=3$ 
100 
5.7±7.5 
105±38 
4373±566 
40±13 
 
  
  
  
  
  
  
  
 
# = In a Phase 1 Dose escalation protocol, 18 patients were treated with 177Lu–J591 
* = In a Phase 1 Dose escalation protocol, 16 Patients were treated with 90Y–J591 and one week 
prior to treatment, 111In–J591 kinetics were studied.  
$ = In a Phase 1 Dose escalation protocol with huJ591 cold antibody treatment, 3 patients in each 
group received different amounts of cold huJ591 mixed with 111In–J591. 
 
v. 
Biodistribution 
The imaging studies with 111In–J591 in patients with prostate cancer showed that liver is the 
principal organ with significant uptake of radiolabeled antibody. The liver uptake of J591 is a 
function of J591 antibody mass administered (Table–6):  the higher the antibody mass, the lower 
the relative proportional uptake of radiolabeled antibody by the liver. In addition, at 20 mg of J591 
administered in Phase 1 dose escalation trials with 111In–DOTA–J591, the liver uptake increases 
with time and is at a maximum by day 6 (27.0 ± 1.7 % of injected dose).  No significant localization 
was seen in other major organs, such as spleen and kidneys.  
 
 
Biodistribution:  111In–J591 vs. 177Lu–J591. The imaging studies were done 5 times over a period 
of one week with 111In and 2 weeks with 177Lu.  The uptake of radioactivity in various source 


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23 
 
organs (% injected dose/organ) was determined. The imaging studies clearly document that the in 
vivo distribution of radiolabeled J591 during the first week is quite similar with both 111In and 
177Lu radionuclides (Table–7).  
 
Table–6: 111In–J591:  Liver Uptake (% injected dose) as a Function of J591 Antibody Mass: 
 
Time 
11 mg/m2 
25 mg/m2 
50 mg/m2  
1 
13.1 ± 2.5 
9.6 ± 1.0 
7.9 ± 0.8 
24 
19.0  ± 3.2 
12.9 ± 2.1 
11.2 ± 1.2 
48 
20.8  ± 2.8 
ND 
11.0 ± 0.4 
72 
22.5 ± 2.4 
14.5  ± 1.2 
12.1 ± 1.0 
120 
24.6 ± 2.8 
ND 
ND 
144 
27.0 ± 1.7 
17.1  ± 3.2 
13.9 ± 1.0 
 
Table–7: Biodistribution of Radiolabeled J591 Antibody: 
 
 
 
 
 
 
 
 
 
 
 
 
 
111In–J591 
 
 
177Lu–J591 
Organ 
DAY 0 
  DAY 6 
  DAY 0 
  DAY 7 
  
  
  
  
   
   
  
  
 
  
Whole Body 
100.0 
± 0.0  66.1 ± 18.4  100.0 
± 0.0  69.8 
± 9.5 
Remainder 
52.3 
± 5.7  24.9 ± 16.8  57.5 
± 6.4  34.7 
± 6.9 
Heart Contents 8.9 
± 2.3  3.4 
± 1.2 
 8.8 
± 2.2  3.1 
± 0.9 
Kidneys 
2.4 
± 0.8  2.5 
± 0.7 
 2.2 
± 0.5  2.5 
± 0.5 
Liver 
14.7 
± 3.2  28.0 ± 7.8 
 15.0 
± 3.8  23.7 
± 7.0 
Lungs 
9.0 
± 2.0  4.4 
± 1.7 
 6.9 
± 1.9  3.1 
± 0.7 
Red Marrow 
10.9 
± 5.0  1.2 
± 1.1 
 7.4 
± 2.4  0.6 
± 0.4 
Spleen 
1.8 
± 0.6   1.7 
± 0.8 
  2.2 
± 1.0   2.1 
± 0.8 
 
 
vi. 
Radiation Dosimetry: 177Lu–J591 
Based on imaging studies and plasma clearance with 177Lu–J591, the residence times () of 
radioactivity in various source organs (as shown in Table–7) were calculated.  Using “S” factors 
from MIRD tables, radiation dosimetry (cGy/mCi) for 177Lu–J591 was estimated (Table–8).  
Following administration of 177Lu–J591, the liver is the critical organ, receiving 7.77± 2.23 
rads/mCi, and the kidneys and spleen receive <7 rads/mCi.  The bone marrow dose was estimated 
to be 1.17 0.37 rads/mCi based on the assumption that 36% of bone marrow volume represents 
plasma volume. Hematopoietic toxicity is usually the dose–limiting factor in RIT(66).  Radiation 
dose of 9.0 Gy to the bone marrow is generally regarded as an “organ injury dose” and the tolerable 




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 
68Ga−PSMA−HBED−CC (IND # 124495) 
PSMA has recently been discovered as a promising target for radioisotope based approaches for 
PET imaging, for example, using 68Ga−labeled PSMA ligands(50-55). 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(56, 
57). 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(58, 59). PET/CT−imaging with 68Ga−PSMA−11 has demonstrated this novel 
method as an important imaging modality for diagnosing recurrent PCa(50, 60-62). 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(63). 
 
ABX Advanced Biochemical Compounds, Radeberg, Germany 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). 
 
i. 
Radiation Dosimetry: 68Ga−PSMA−HBED−CC 
Radiation dose estimates were provided by Professor Marcus Schwaiger of Technische Universitat 
Miinchen (TUM), Munich, Germany. Balb1−c mice were used to determine the biodistribution at 
4 time points after administration. Tissues were dissected after sacrifice and the percent of the 
administered dose was determined per organ and per gram of organ weight. The data of the 
biodistribution were extrapolated from mouse to man using OLINDA/EXM 1.0 Dosimetry 
Software (64; Stabin MG, et al. J Nucl Med. 2005 Jun;46(6):1023−7.). 
 
 
 


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Table 9: Radiation dose estimates for Humans administered 148 or 185 MBq (4 or 5 mCi) of 
68Ga−PSMA−HBED−CC: 
 
Administered 
ddose (Mbq) 
150 +/−−20 
185 +/−−20 
Administered dose 
(mCi) 
(4.0) 
(5.0) 
organ 
[mSv] per organ 
[mSv] per organ 
Brain 
1.64E−01 
2.05E−01 
Lung 
8.17E−01 
1.02E+00 
Liver 
1.30E+00 
1.63E+00 
Kidneys 
1.11E+02 
1.39E+02 
Stomach Wall 
3.32E+00 
4.15E+00 
Spleen 
7.96E+00 
9.95E+00 
Pancreas 
2.80E+00 
3.50E+00 
Red Bone Marrow 
1.35E+00 
1.69E+00 
Bladder Wall 
1.41E+00 
1.76E+00 
Effective Dose 
1.94E+00 
2.43E+00 
 
For comparison purposes, the average per capita annual exposure from natural background in the 
continental USA is 3.0 mSv. (Ionizing radiation exposure of the population of the United States. 
Bethesda, Md.: National Council on Radiation Protection and Measurements. 2009. ISBN 
978−0−929600−98−7. NCRP No. 160.) 
 
 
 
177Lu−PSMA−617 (IND # 131966) 
Modifications of PSMA−11 have resulted in the development of another novel small molecule 
PSMA−ligand, PSMA−617. In preclinical studies, this ligand showed a significantly improved 
binding affinity to PSMA as well as a highly efficient internalization into PCa cells(69). 


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PSMA−617 can be labeled with radionuclides like 68Ga(Gallium−68), 177Lu(Lutetium−177), 
111In(Indium−111), and 90Y(Yetrium−90) and, therefore, be used for PET−imaging as well as for 
radioligand−based therapy. Preclinical assays of PSMA−617 showed Ki values of 2.3 ± 2.9 nM, 
demonstrating a significant improvement compared to PSMA−11 (12.0 ± 2.8 nM). Based on these 
results, PSMA−617 has one of the highest binding affinities to the PSMA receptor, which have 
been published, so far. In preclinical studies, tumor−to−background ratios of up to 1,058 were 
observed at 24h post infusion. In addition, the internalization of the PSMA−617 into the PCa cells 
is highly effective: Internalized fraction: 17.67 ± 4.34 % IA/106 LNCaP cells (PSMA−11: 9.47 ± 
2.56 % IA/106 LNCaP cells)(59, 69). Since 2013, 177Lu−PSMA−617 has been increasingly used 
for radioligand therapy of metastatic PCa patients in several centers (Bad Homburg, Bonn, 
Cologne, Freiburg, Heidelberg, Istanbul, Melbourne, LMU Munich, Münster)(70). 
 
Radiation dosimetry and organ specific dosage details are described in section 2.4.1 and Table 2 
& 3 above. Toxicity data from various studies on 177Lu−PSMA−617 is described in section 2.7 
Table 12. 
 
Diagnostic evaluation with 68Ga−PSMA−HBED−CC followed by therapy with 177Lu−PSMA−617 
is thus opening a new theranostic potential of nuclear medicine. Initial studies in patients have 
demonstrated the utility of 177Lu−PSMA−617 for the treatment of disseminated prostate cancer(70, 
71). Dosimetric evaluation has shown that the critical organs are the parotid glands, and that up to 
27 GBq (~700 mCi) of 177Lu−PSMA−617 can be administered without crossing the 30 Gy critical 
dose threshold to the parotid glands(47). 
 
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 (72). However, even after surgical treatment, high risk PC is prone to recur and often 
becomes resistant to conventional hormonal therapy (73). For this reason, efforts have been made 
to optimize patient outcome in the adjuvant and neoadjuvant settings (74-76). Thus far, 
neoadjuvant therapies have yet to demonstrate a survival benefit (77). 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 (78). 
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 (79), 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 
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, 80, 81). 
 
Based on the knowledge that certain tumor types express significant amounts of one or several 


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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 (82). Another clinically validated 
target is human epidermal growth factor receptor 2 (HER2), which in breast cancer is targeted by 
trastuzumab (83). 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, 84-88). 
 
A. Rationale for the appropriate radioisotope: 
 
As described earlier, targeted radionuclide therapy as a treatment choice for mCRPC patients is 
being actively studied at various centers in the world (especially Europe and Australia). When 
compared to monoclonal antibodies, the low molecular weight compounds have a higher 
permeability into solid tumors, offer a significant advantage in achieving higher tumor uptake as 
well as a high percentage of specific binding. Additionally, small molecules display more rapid 
tissue distribution and faster blood clearance compared with intact immunoglobulins. These 
properties often lead to an enhanced target to non−target tissue ratio, which is important not just 
for imaging but also for successful application of therapeutic absorbed doses.  
 
Following tumor localization, the radiometal is trapped within the cell, leading to higher accretion 
of radionuclide by the tumor. 131I has lower energy  particles and longer physical half−life (max 
− 0.61 MeV; T½ = 8.04 d) compared to that with 90Y(max − 2.28 MeV; T½ = 2.67 d). Because 
of its higher energy, 90Y may be appropriate for larger tumors while 131I may be more cytotoxic 
for smaller, micro−metastatic lesions. Since 90Y does not emit any  photons, the corresponding 
111In labeled antibodies are generally used as chemical and biological surrogates to study 
biodistribution and estimate radiation dosimetry of 90Y labeled antibodies. In addition to 90Y, the 
lanthanide radiometal, 177Lu (max − 0.497 MeV; T½ = 6.74 d) is potentially useful for RIT. Also, 
177Lu has useful gamma photons ( = 0.21 MeV) for biodistribution and dosimetry studies. 
Therefore, 177Lu may have the advantages of both 131I and 90Y and may be the most appropriate 
radionuclide for therapy. Type of radiation and energy associated with some of the prevalent 
radioisotopes is summarized in the table hereunder: 
 
 
 


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Table 10: Radionuclides for Therapy: 
 
 
 
B. Rationale for Dose−Fractionated regimen: 
 
 
Pre−clinical models do not always predict toxicity in humans, but based upon the available data, 
the pre−clinical models combined with animal and human dosimetry data have predicted the 
toxicity seen with anti−PSMA radioimmunotherapy (i.e. radiolabeled monoclonal antibody) and 
anti−PSMA radioligand therapy (i.e. radiolabeled peptides). 
 
With radioimmunotherapy, one would predict that the dose−limiting organ is bone marrow, based 
upon the kinetics / circulation time and exposure of the bone marrow to circulating radiolabeled 
antibody before it gets into tumors days later.  With radioligand therapy, one would predict that 
there is comparatively very little bone marrow exposure, but there would be more exposure to sites 
of PSMA expression that are not exposed to (bulky) full−length antibodies.  Based upon the 
available data, this has been born out in human subjects (for radioimmunotherapy) and human 
patients (for radioligand therapy). 
 
We have conducted a series of overlapping, but sequential phase I and II clinical trials evaluating 
radiolabeled anti−PSMA monoclonal antibody J591.  These studies are summarized immediately 
below with additional details about dose−fractionation (as requested) following the summary. 
 
 Initial (1st in human) studies of trace−labeled 111In−DOTA−J591: demonstrated safety and 
targeting of J591 in men with mCRPC(32, 89, 90) 
 Phase I (single−dose) 90Y−J591: demonstrated safety, targeting, and preliminary efficacy in 
mCRPC(31) 
 Phase I (single−dose) 177Lu−J591: demonstrated safety, targeting, and preliminary efficacy in 


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mCRPC(28) 
 Phase II (single dose) 177Lu−J591: demonstrated efficacy in initial 32 subjects, subsequent 
analysis with significant dose−response and preliminary biomarkers(91) 
 Phase I fractionated−dose 177Lu−J591 dose−escalation study: demonstrated safety, confirming 
hypothesis that higher cumulative doses could be adminsterd as a split dose(92) 
 Phase II (single dose) 177Lu−J591 expansion phase: confirmed efficacy and dose−response 
with exploratory biomarkers(39) 
 Phase I fractionated−dose 177Lu−J591 plus docetaxel: demonstrated the ability to safely 
combine fractionated 177Lu−J591 with docetaxel 75 mg/m2 in men with mCRPC(93) 
 Phase I fractionated−dose 177Lu−J591 expansion phase: provided efficacy data, confirmed 
dose−response, continued analysis of exploratory biomarkers(41) 
 
Taken together, with >250 patients treated on these sequential clinical trials, we have drawn 
the following conclusions: (i) there is a clear dose−response with more responses and longer 
survival at higher doses; (ii) there is clear dose−toxicity response in terms of 
myelosuppression (which is both predictable and reversible); (iii) dose−fractionation allows 
higher cumulative dose with comparatively less toxicity (including allowing concurrent 
chemotherapy); and (iv) without pre−selection for PSMA expression, approximately 90% 
have accurate tumor targeting, though the small minority with low/no PSMA expression by 
imaging have a lower likelihood of response. While 177Lu−J591 mAb demonstrated 
significant efficacy, the major limitation in the optimization of therapeutic dose is the 
hematological toxicity (described in greater detail below).  
 
With a single−dose, 70 mCi/m2 of 
177Lu−J591 was the MTD, with dose−limiting 
myelosuppression in those receiving 75 mCi/m2 (with 2 of 3 with dose−limiting hematologic 
toxicity)(28). In the phase II study, this was confirmed with 70 mCi/m2 of 177Lu−J591 being 
tolerable with reversible myelosuppression, but with a significant amount of manageable grade 4 
myelosuppression (including approximately 40% platelet transfusion)(39). 
 
In radiotherapy, the anti−tumor response has been thought to be primarily due to induction of 
apoptosis by radiation(94-97). However, the degree of anti−tumor response following the 
administration of targeted radionuclides depends on several variables, especially total (cumulative) 
radiation dose to the tumor, dose−rate and tumor radiosensitivity. Single−agent RIT, although 
potentially useful for slowing solid tumor growth, has not been effective in controlling aggressive 
tumors, which often have p53 and other mutations and are less susceptible to apoptosis, the 
apparent mechanism of cell death from low dose−rate radiation(98). Bone marrow is the 
dose−limiting organ in RIT in the absence of marrow reconstitution(99, 100). Dose−fractionation 
is a practical strategy to decrease the dose to bone marrow while increasing the cumulative 
radiation dose to the tumor at an optimal dose−rate(97, 101, 102). The main reason for using dose 
fractionation is to take advantage of the difference between early−responding and late−responding 
tissues. The radiation effect on early−responding tissue can be reduced by prolonging the treatment 
time and dose fractionation. The radiation effect on late−responding tissues will not be changed 
significantly if the total dose is not changed(97, 102). Preclinical data have shown that dose 
fractionation or multiple low dose treatments can decrease toxicity while increasing the 


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efficacy(96, 103, 104). Similarly, there is some clinical evidence that bone marrow toxicity can be 
reduced with some modest increase in the cumulative maximum tolerated dose(105-107).  
 
Based upon these data, we performed two sequential studies of fractionated dose 177Lu−J591. 
 
As described in in the paragraph above, dose−fractionation of external−beam radiation as well as 
radioimmunotherapy has been demonstrated to have less toxicity and might be more efficacious 
by delivering active radiation over a more prolonged period of time to tumor cells.  Based upon 
the half−life of 177Lu−J591 combined with the kinetics of radiolabeled intact monoclonal antibody, 
we chose a 2−week interval between 177Lu−J591 doses: 
 
i) 
Phase I trial of fractionated dose 
177Lu−J591 in men with metastatic 
castration−resistant prostate cancer(41, 92) 
 
Men with progressive metastatic CRPC received 2 fractionated doses two weeks apart. Initially, 6 
cohorts of 3−6 pts got 2 doses of 177Lu−J591 2 weeks apart (20 mCi/m2, escalating to 45 mCi/m2 
x2). Subsequently, pts enrolled in 2 expansion cohorts at the recommended phase 2 doses (RP2D). 
Planar 177Lu−J591 imaging was semi−quantitatively scored. The endpoints were PSA changes and 
survival (OS); as well as CTC count (CellSearch) changes in the expansion cohorts. 49 patients, 
with median age 74.1 years (range 55−95), median PSA of 44.9 ng/mL (1.9−766.5); 83.7% with 
bone, 61.2% with lymph node, 40.8% with visceral metastasis. 8.2% were CALGB (Halabi) low, 
34.7% were intermediate, 57.1% were in high−risk group. RP2D’s of fractionated 177Lu−J591 
were 40 mCi/m2 x2 or 45 mCi/m2 x2 with option for GCSF. PSA changes for the low dose group 
were reported as 6.3% showing >50% PSA decline, 12.5% reporting >30% PSA decline, and 
37.5% with any PSA decline. within RP2D group 21.2% showing >50% PSA decline, 42.4% 
reporting >30% PSA decline, and 66.7% with any PSA decline. The median overall survival for 
low dose group was 14.6 months and for RP2D group was 27.7 months. Accurate targeting of 
177Lu−J591 was seen in 79.6%. Patients with lower PSMA expression by imaging were less likely 
to respond (p=0.07). Of 25 with CTC counts, 14 declined, 8 stably favorable, and 3 increased. 
RP2D was associated with more PSA declines (p=0.036) and longer OS (p=0.004), even after 
controlling for CALGB prognostic grouping (adjusted HR 0.42 [95% CI 0.21, 0.84] p=0.01). 
Predictable, reversible myelosuppression was seen. 36 (73.5%) patients had grade 3/4 heme 
toxicities; 19 (57.6%) had Grade 4 heme toxicities in RP2D cohorts with 45.4% receiving 
prophylactic platelet transfusions (median 1, range 1−4) and 6 GCSF. 14 (28.6%) had infusion 
reactions (without pre−meds), with 1 patient having Grade 2 infusion reaction leading to 
withdrawing from the study prior to his 2nd dose. 5 (10.2%) had transient Gr 1/2 AST/ALT. This 
study concluded that fractionated 177Lu−J591 is well tolerated with predictable, reversible 
myelosuppression and PSA and CTC declines. Additionally, with dose−fractionation, the 
cumulative dose MTD is 14−28% higher than single dose MTD with similar toxicity. 
 
 
 
 


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Table 11: Toxicities data from Phase 2 single dose 177Lu−J591 Study and Phase 1 fractionated 
177Lu−J591 study: 
 
 
 
Single Dose 
Fractionated Dose 
Cumulative 
Dose (mCi/m2) 
65 
70 
70 
(35 + 35) 
80 
(40 + 40) 
90 
(45 + 45) 
Platelets Grade 
4 
27% 
56.3% 
40% 
50% 
58.8% 
Platelet 
Transfusion 
7% 
41% 
0% 
31.3% 
52.9% 
Neutropenia 
Grade 4 
0% 
37.5% 
0% 
31.3% 
29.4% 
Febrile 
Neutropenia 
0% 
2.1% 
0% 
0% 
5.8% 
 
In addition, fractionated dosing allowed concurrent dosing with myelosuppressive chemotherapy: 
 
ii) 
Phase I trial of fractionated dose 177Lu−J591 plus docetaxel/prednisone in men with 
metastatic castration−resistant prostate cancer (42): 
 
Following progression on primary hormonal therapy, chemotherapy can offer symptomatic 
improvement as well as incremental survival benefit.  However, responses are transient and all 
men eventually suffer from progression of disease as described above with single−agent 
anti−PSMA based radioimmunotherapy. The combination of taxane chemotherapy with 
radiotherapy has been used in several diseases because of the radiosensitizing effects of 
taxane−based chemotherapy. In addition to favorable results from fractionated RIT and the 
radiosensitizing effects of taxane−based chemotherapy, it is hypothesized that the additional 
debulking by chemotherapy will overcome some of the limits imposed by the physical 
characteristics of 177Lu.  Based upon this theory, a phase I trial of docetaxel and prednisone with 
escalating doses of fractionated 177Lu−J591 was initiated. 15 men with median age 69.1 
(49.3−80.8) were enrolled.  The MTD/RP2D of 177Lu−J591 was 40 mCi/m2x2 doses (delivered 
with cycle 3 of docetaxel), with 73.3% showing >50% PSA decline, 80.0% reporting >30% PSA 
decline, and 86.7% with any PSA decline. Predictable, reversible myelosuppression was seen. 
Even at the highest dose level, no dose limiting toxicity was observed, with short−term / reversible 
grade 4 neutropenia in 33% and grade 4 thrombocytopenia in 13%. 
 
 
Aside from the overall rates of dose limiting toxicity, the combined studies have also consistently 
demonstrated the kinetics of myelosuppression, with nadir neutrophil and platelet counts 28−32 
days following the last administered dose of 177Lu−J591. 
 
With small−molecule radioligand therapy, both the predicted and reported toxicities are much 
different.  One would predict very little myelosuppression, but if it were to occur, it would be 


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expected to have kinetics similar to (or more quickly than) typical cytotoxic chemotherapy, as the 
clearance of the myelotoxic drug is quick (minutes to hours rather than days to weeks for 
antibodies).  In fact (with the known caveats of retrospective studies), this is the reported human 
experience.  Essentially no grade 4 neutropenia or thrombocytopenia has been reported within 
months of exposure to 177Lu−PSMA radioligands (see details below). 
 
While we have published on the long−term follow up with 177Lu−J591 with no cases of attributable 
permanent myelosuppression and/or myelodysplasia/leukemia, results are unknown with 
177Lu−PSMA RLT.  The available data with up to 6 months of reported post−treatment follow up 
are: 
1) no attributable grade 4 hematologic (or other) toxicity has been reported at any time (the one 
case of grade 4 thrombocytopenia is reported with a patient with grade 4 platelet count at 
pre−treatment baseline)  
2) repeat dosing has been performed in many patients at 8−12 weeks after initial dosing and in all 
cases, white blood cell count and platelet counts were acceptable prior to subsequent doses (up to 
5 doses, with dose #5 approximately 40 weeks after dose #1) 
 
The Table below is a summary of the prior summary anti−PSMA RLT Table which includes the 
severe leukocyte/neutrophil and platelet count rates following 177Lu−radiolabeled anti−PSMA 
peptides.  In addition to the Table below, a multicenter review of 177Lu−PSMA−617 data of 82 
patients receiving a single dose (mean 5.9 GBq) revealed no grade 4 hematologic or 
non−hematologic toxicity(108). 
 
 
 


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Table 12: Toxicities data following anti−PSMA radioligand therapy: 
 
*One patient had pre−treatment baseline platelet count of grade 4 
NR = not reported 
 
 
A dose fractionated regimen provides the theoretic benefit of higher cumulative radiation dose to 
the target tissue/organ while limiting toxicities secondary to non−specific binding of the 
radiolabeled ligand.  In addition to the toxicity data provide above, our group has consistently seen 
evidence of dose−response (see Table below), justifying a dose−escalation study. 
 
 
 
Radioligand Therapy 
N 
Dose 
(GBq), 
Range 
Total 
doses 
Grade 
4 
neutropenia 
Grade 4 
platelets 
Reference 
177Lu−PSMA−617 
30 
3.7 – 6 
1−3 
0 
0* 
Kratochwil et al 
2015 
177Lu−PSMA I&T 
56 
3.6 – 8.7 
1−5 
0 
0 
Baum et al 2016  
177Lu−PSMA−617 
9 
5.28 
– 
5.77 
1 
NR 
NR 
Hohberg et al 
2016  
177Lu−DKFZ−PSMA−617 5 
3.4 – 3.9 
2 
NR 
NR 
Delker 
et 
al 
2015  
177Lu−DKFZ−PSMA−617 10 
4.1− 6.1 
1 
0 
0 
Ahmadzedehfar 
et al 2016  
177Lu−PSMA−617 
7 
5.5 − 7.4 
1 
NR 
NR 
Das et al 2016  
177Lu−PSMA−617 
23 
7.4 
1 
NR 
NR 
Demir et al 2016  
177Lu−PSMA−617 
28 
6 
1−2 
0 
0 
Rahbar 
et 
al 
2016  
177Lu−PSMA−617 
31 
1.1− 5.5 
1−4 
0 
0 
Yadav et al 2016  
177Lu−PSMA I&T 
2 
5.7 − 8 
1 
0 
0 
Weineisen et al 
2015  
177Lu−PSMA I&T 
22 
3.4 – 7.4 
1−4 
0 
0 
Heck et al 2016  
177Lu−PSMA−617 
43 
6 
1−4 
0 
0 
Zimbelmann et 
al 2016  
177Lu−PSMA−617 
5 
5.8 – 7.4 
1 
0 
0 
Chakraborty et 
al 2016  










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Summary: 
 
Taken together, these data show that co−administering 2 agents that bind different sites of a target 
molecule (e.g., a cell surface receptor molecule) present on a population of cells results in additive 
binding of those agents. Where the target molecule/receptor is internalized, additive amounts of 
the 2 agents will, therefore, be internalized. Furthermore, if the 2 targeting agents have different 
properties (e.g., molecular mass, charge, hydrophilicity/hydrophobicity, pharmacokinetics, 
bio−distribution, etc.) such that their respective side effects differ, and are non−overlapping, the 2 
agents can be co−administered to result in additive binding/uptake by the targeted cells without 
causing any added toxicity. It is clear across our prior PSMA-targeted radionuclide therapy studies 
that higher administered doses lead to more responses and longer survival, but also increased 
toxicity. As a corollary, the dose of each agent can be modestly reduced (by 5−50%) below its 


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40 
 
respective maximum tolerated dose whereby the co−administration of the 2 targeting agents still 
provides an additive dose to the target cells but can substantially or completely reduce the toxicity 
experienced by the subject. 
 
 
2.8 
Risk/Benefit Assessment  
 
 
This is a phase I clinical trial with the primary endpoints to find DLT and MTD. Based on the prior 
clinical studies using 177Lu−J591 by our group the dose−limiting organs/tissue is expected to be 
red marrow. The expected toxicities can be leukopenia, thrombocytopenia, anemia, fatigue, renal 
failure, and transaminitis. All these toxicities have been transient and reversible. mCRPC patients 
treated with RIT using 177Lu−J591 have shown improved survival compared to historical controls. 
 
Based on findings by retrospective publications, the most common side effects and/or toxicities 
reported for 177Lu−PSMA−617 or 68Ga−PSMA−HBED−CC are fatigue, renal failure, xerostomia, 
leukopenia, anemia, thrombocytopenia (so far none of the published studies have reported any 
significant hematological toxicities) and transaminitis. All of these toxicities are reportedly mild 
and transient. mCRPC patients treated with RLT have higher response rates than any available 
standard drug in the refractory setting by historical standards.  
 
 
2.9  
Correlative Studies Background 
 
i. Archival tissue and cell−free plasma DNA to assess genomic alterations: 
We will incorporate tissue-based and circulating tumor DNA (ctDNA) approaches to assess 
prostate cancer pathway changes including AR signaling pathway activation (mRNA) and 
genomic alterations including DNA repair pathways and will correlate with PSMA heterogeneity 
on imaging. We will evaluate the association of molecular biomarkers with imaging and treatment 
response. Mechanisms of resistance will be assessed in a subset of patients enrolled at WCM 
through integrative genome-wide analysis of pre-treatment and progression tumor biopsies. At the 
end of this Aim, we will have defined the molecular landscape of CRPC patients enrolled on 
prospective trials of PSMA-targeted radionuclide therapy and will have identified biomarkers 
associated with outcome to be evaluated in a larger study to determine whether they are predictive 
or prognostic.  
 
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 PSMA-targeted 
radionuclide therapy. 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 


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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 177Lu. 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. 
 
We will evaluate archival tumor tissue (preferentially from metastatic biopsies) with the plan for 
utilization of our prostate cancer specific targeted platform covering DNA (for mutation and copy 
number) of 74 genes/regions commonly aberrant in prostate cancer and 42 control genes. Prostate 
cancer genes including AR, SPOP, CHD1, DNA repair, ERG fusion, and other CRPC-relevant 
alterations. We will also collect a single-sample of blood for germline analysis of DNA repair 
defects. 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. The panel is also being used for other 
prospective therapeutic trials which will allow for cross-comparison of data. 
 
Gene expression of androgen signaling genes and other relevant pathways will be assessed using 
a custom panel Nanostring platform developed and validated by Dr. Beltran’s lab. This panel 
includes 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. As discussed above, we will 
describe findings from this exploratory endpoint in each study with the plan to analyze identified 
biomarkers to determine their association with efficacy and toxicity across studies, in particular at 
doses found to have efficacy. 
 
 
ii. CTC Count: 
Circulating tumor cell (CTC) counts via the FDA-cleared, standard of care 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 (109). 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 
(110) 
 
iii. 
Immune Assays: 


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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. In 
prostate cancer, humoral immune response has already been documented with immunotherapy. 
We hypothesize that prostate cancer is immunogenic following PSMA-targeted radiation, and that 
the serological repertoire in patients may be useful as a pharmacodynamic, prognostic, or even 
predictive tool.  
 
We propose to test the hypothesis that radiolabeled anti-PSMA treatment of advanced prostate 
tumors leads to induction or increase in immune responses to locally expressed antigens by 
assessing serological changes pre- and post-treatment. Indeed, one surrogate to test whether these 
tumors become more immunogenic is to measure naturally occurring antibodies in the serum or 
plasma of patients. Autologous serotyping, i.e., serum antibody recognizing tumor-derived 
antigens, have resulted in a growing list of human cancer antigens that are immunogenic in the 
host of origin. With regard to cancer antigens recognized by the humoral immune system, over 
2700 sequences have been identified by SEREX analysis of sera from patients with a wide range 
of cancers; these antigens include mutational, overexpressed, oncogenic viral, differentiation, 
and cancer-testis (CT) antigens. These can be rapidly tested in high-throughput ELISA using 
recombinant antigens (Grand Serology). In some cases, such as the cancer/testis antigen NY-
ESO-1, serum antibodies are associated with spontaneous T cell responses measurable from 
peripheral blood. It should be noted that most of the antigens defined as targets of autoantibodies 
are intracellular, rather than surface antigens, and reflect the capacity of the immune system to 
detect abnormalities associated with neoplasia. The prevalent hypothesis is that antibodies are 
generated as antigens are released from dying tumor cells, either because of spontaneous necrosis 
or because of external treatments. The presence of antibodies to intracellular targets can be used 
as a marker of tumor existence or progression, but can also have a functional role to help 
generating T cell responses through the formation of immune complexes with their cognate 
antigen. Today, protein microarrays allow for the detection of specific serum antibodies against a 
very large number of targets simultaneously. Arrays can be used to determine patterns of 
antigens recognized by autoantibodies during the course of diseases. These tools are also useful 
to measure changes in antibody responses with treatment such as immunotherapies. The 
opportunity to define “seromic” changes in these prostate cancers, i.e., the scope of antigens 
recognized with increased specificity and frequency by post-treatment patient sera vs. baseline, is 
now within reach, provided adequate analyses of the vast amount of data generated by these 
microarray can be properly interpreted.  
 
Grand serology:  A series of known tumor antigens will be assessed in a hypothesis-driven 
manner for their capacity to elicit autoantibodies in advanced prostate cancer patients, at baseline 
and after treatment with PSMA-TRT. Using ELISA as previously described, we propose to test a 
series of 20-25 tumor antigens, including mutational, stem-cell, endogenous retroviral, and 
cancer-testis antigens such as TP53, NY-ESO-1, GAG-HERV-K, SOX2, PRAME, WT1, 
MAGE-A3, SSX2, CT45, etc., most of which already have demonstrated spontaneous 
immunogenicity various solid tumors, including advanced prostate cancer. Briefly, sera will be 


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tested in 4x serial dilutions, starting from 1/100, for IgG reactivity against full-length E. coli- or 
yeast-produced proteins of tumor and control antigens to assess specificity. Positive and negative 
control sera with known reactivity will be used on each plate to validate the assays. Reciprocal 
titers will be extrapolated and considered significant if >100. In samples with multiple serum 
collection time points available, significant changes in humoral response will be defined as 
antigen-specific antibody going from undetectable (titer <100) to detectable (titer >100), or with 
titers at least 4-fold different between time points. For antigens showing humoral reactivity, 
mapping of linear epitopes may be assessed using overlapping peptide series covering the 
sequence of the antigen, to assess polyclonality and potential spreading over time. In a subset of 
patients, other immunoglobulin isotype or subclass usage may be assessed as well. We propose 
that systemic tumor antigen-specific antibody responses in plasma or serum may be useful as 
a marker of immunological response to radiolabeled anti-PSMA treatment in advanced prostate 
cancer patients, and that increases or induction in immune responses will occur with treatment in 
comparison to baseline. These experiments are expected to shed light on both mechanisms of 
action of the drug, including occurrence of antigen spreading, and on potential predictive 
biomarkers. 
 
Seromics:  While Grand Serology offers a high-throughput way to quickly assess changes of 
antibody specificity in serum or plasma sample to known tumor antigens, it is limited by the 
small number of tumor targets identified to date, especially in prostate cancer. To circumvent this 
limitation, an alternative is to use a broader array of self-antigens instead as potential targets of 
immune responses generated by immunotherapy.  
 
Seromics is an exploratory, non-biased, hypothesis-generating platform that allows the testing of 
thousands of human proteins simultaneously as potential targets of autoantibodies from patient 
serum or plasma. The method only requires a few microliters of material, and may be customized 
for applications other than IgG antibody detection. The seromic platform can be used to define 
biomarkers or sets of antigens present at baseline in specific patient populations, and that could 
be used as prognostic or predictive markers.  It has been previously described that prostate 
cancer spontaneously elicits humoral responses to a small subset of autoantigens that are not 
immunogenic in healthy donors. Accordingly, seromics is suited to comprehensively look for 
serum antibody changes in prostate cancer patients at the antigen-specific level between 
consecutive time points, before and after treatment with radiolabeled anti-PSMA therapy. We 
plan to use either ProtoArrays (Invitrogen) or HuProt (CDI), protein microarrays spotted with 
9000 to 20000 cancer- and non-cancer associated proteins and controls, to define serum 
autoantibody changes in a subset of proposed treated patients (pre-post) with favorable 
outcomes, and compare them to changes in age-matched patients with no response.  
 
Immunogenic cell death: we hypothesize that the PSMA TRT will lead to generation of an 
immune response that will induce immunogenic cell death.  
High mobility group box 1 (HMGB1) is an important mediator of immunogenic cell death, and it 
has been shown that it is released by dying tumor cells following radiation. HMGB1 may promote 
dendritic cell activation and migration and antigen presentation; following certain anti-neoplastic 
therapy (such as radiation) higher levels of HMGB1 have been associated with improved 


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outcomes. We will assess HMBG1 via ELISA in serum obtained pre-and post-treatment with 
PSMA-TRT and analyze for associations with response, progression-free survival, and overall 
survival outcomes. We have stored serum (previously collected for HAHA assessment) from prior 
studies with long-term outcome data and continue to prospectively collect serum from patients 
being enrolled in current PSMA-TRT studies. 
 
Among the several markers of immunogenic cell death, calreticulin is one of the most investigated. 
Calreticulin exposure on tumor cell surface is widely accepted as an “eat-me” signal, which is 
required for phagocytosis of dying tumor cells.  Mainly an endoplasmic reticulum (ER)-associated 
chaperone protein, CTR translocation to the plasma membrane is triggered by reactive oxygen 
species (ROS)-induced ER stress, dictating the immunogenic cell death. We hypothesize that 
calreticulin tumor cell expression and cellular localization is associated with tumor response to the 
immunogenic response-inducing PSMA TRT. Unfortunately, the availability of pre- and post-
treatment tumor tissue is often a logistical problem in patients with prostate cancer. We expect to 
have a subset with pre- and post-treatment tumor tissue available and we will assess membrane 
expression of CRT in that subset. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
3. 
SUBJECT SELECTION 
 
3.1 
Study Population 
 


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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/GnRH 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/L  
 
Serum creatinine 
<1.5 x upper limit of normal (ULN) or 
 
calculated 
creatinine 
clearance 
≥ 
60 
 
mL/min/1.73 m2 by Cockcroft−Gault 


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46 
 
 
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 
<1.5 x ULN in the absence of liver 
 
metastases; <3 x ULN if due to liver 
 
metastases (in both circumstances bilirubin 
 
must meet entry criteria) 
 
9. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.3 
Exclusion Criteria 
 
1. Implantation of investigational medical device ≤4 weeks of Treatment visit #1 
(Day 1) or current enrollment in oncologic investigational drug or device study 
 
2. Use of investigational drugs ≤4 weeks or <5 half−lives of Treatment visit # 1(Day 
1) or current enrollment in investigational oncology drug or device study 
 
3. Prior systemic beta−emitting bone−seeking radioisotopes 
 
4. Known active brain metastases or leptomeningeal disease  
 
5. History of deep vein thrombosis and/or pulmonary embolus within 1 month of 
Treatment visit #1  
 
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 Treatment visit #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 


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10. Currently active other malignancy other than non−melanoma skin cancer.  Patients 
are considered not to have “currently active” malignancy if they have completed 
any necessary therapy and are considered by their physician to be at less than 30% 
risk of relapse. 
 
11. Known history of known myelodysplastic syndrome 
 
 
4. 
OVERVIEW OF STUDY DESIGN AND METHODOLOGY 
 
 
4.1 
Study Design 
 
This is an open−label, single−center Phase I dose−escalation study designed to determine the 
dose−limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combination of 
177Lu−J591 and 177Lu−PSMA−617 in a two−week dose−fractionation regimen. 177Lu−J591 will 
be given at a moderate dose previously demonstrated to be safe x2 infusions two weeks apart. For 
177Lu−PSMA−617 the dose escalation will start at 3.7 GBq (100 mCi) and escalate in increments 
of 1.85 GBq (50 mCi) for each dose to a planned maximum of 9.25 GBq (250 mCi) x2 doses, 2 
weeks apart. Should there be unacceptable toxicity at the initial dose level, we will de-escalate to 
dose level -1 (1.85 GBq / 50 mCi per dose). After the phase I study has established a MTD, the 
Phase II, single-arm trial will start. 
 
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). 
 
Subjects will have Lutetium−177 Planar/SPECT Imaging on Day 8 (±1 day) after the first dose of 
177Lu−J591 + 177Lu−PSMA−617. Optimal images will be performed on selected consenting 
subjects between the initial treatment visit #1 on Day 1 and Day 4 and prior to treatment visit #2 
on D15 ±1. Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2 weeks for 
one month, at 8 and 12 weeks, and then every 4 weeks for next 3 months).  
 
Upon completion of investigational treatment with dose−fractionation regimen of the combination 
of 177Lu−J591 + 177Lu−PSMA−617, subjects will undergo 68Ga−PSMA−HBED−CC injection and 
same day PET/CT at the end of study visit to document treatment response. Subsequently survival 
data and additional treatment(s) information will be captured from their routine Standard of care 
(SOC) visits. 
 
Table 14: Phase I dose-escalation plan for combination of 177Lu−J591 + 177Lu−PSMA−617: 


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48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Note: BSA will be capped at 2 for 177Lu-J591 dosing. 
 
Rationale for dosing amendment: 
Prior studies of 177Lu- and 90Y-J591 have utilized individualize dosing per body surface area 
(BSA).  As a single agent, 177Lu-J591 when delivered in a 2-dose fractionated regimen is 
suggested to be dosed at 45 mCi/m2 x2 (or 40 mCi/m2 x2with less toxicity and less efficacy).  
The dose in combination with docetaxel is 40 mCi/m2 x2).  In the initial version of the protocol, 
an estimate for fixed dosing based upon prior safe dose levels and average BSA was utilized.  
One subject in the initial cohort had prolonged myelosuppression and on analysis, had a low 
BSA.  Therefore based upon the wealth of prior safety data with BSA dosing and the wish to 
primarily assess one rather than 2 dosing variables, the dosing amendment will revert to BSA 
dosing.  In addition, we will cap BSA at 2 m2 with the intent of minimizing myelosuppression 
from the RIT. 
 
4.2 
Phase I: 
 
The Phase I portion will use a 3+3 dose-escalation study design, with the planned initial 
and subsequent cohorts described in Table 14. This study design is well-described and 
accepted by the clinical and scientific community, so we will not provide complete details 
here. Briefly, this design is constructed to reduce the chance of escalating the dose when 
the probability of DLT is high, and increase the chance of escalating the dose when the 
probability of DLT is low. The MTD is defined as the highest dose level with an observed 
incidence of DLT in no more than one out of six patients treated at a particular dose level. 
The dose escalation scheme provides the following probabilities of escalation based on the 
true chances of DLT at a specific dose level. One can see that the probability of escalation 
is high if the toxicity risks are low: 
 
True Probability of Toxicity: .05 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of Escalation: 
.97 
.91 
.71 
.49 
.31 
.17 
.08 
 
177Lu−J591 + 177Lu−PSMA−617: Dose escalation (per dose) 
                         177Lu−J591* 
177Lu−PSMA−617 
                       Dose: GBq (mCi) / m2 
Dose: GBq (mCi) 
Cohort 
 
-1 
2.22 (60) 
1.85 (50) 
1 
2.22 (60) 
3.7 (100) 
1a 
1.35 (36.5) 
3.7 (100) 
2 
1.35 (36.5) 
5.55 (150) 
3 
1.35 (36.5) 
7.4 (200) 
4 
1.35 (36.5) 
9.25 (250) 


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49 
 
As there is a reasonably large pool of short- and long-term experience with PSMA-directed 
177Lu, a phase II trial using the MTD to will be launched to obtain preliminary efficacy 
data.  
 
4.3 
Phase II: 
We will enroll up to 27 subjects in the Phase II trial utilizing a Simon two-stage design 
(including the 3-6 patients used for establishing the MTD ). For the phase II portion, we 
will define evaluable patients as those who met eligibility requirements, have initiated 
therapy, and were not removed from  the study for non-compliance or withdrawal.  Sample 
size recommendations for the two-stage design are determined according to Simons two-
stage minimax design.  The first stage will accrue a total of 16 patients (including those 
who were treated at the MTD in the phase I portion), if 6 or fewer of the first 16 evaluable 
patients do not experience a 30% decline in PSA, the study will be terminated and declared 
to have a negative result.  If 7 or more patients out of the first 16 evaluable patients 
experience a 30% decline in PSA, 9 more patients will be accrued in Stage 2 (total sample 
size of 27).  The new regimen will be declared to have activity and be worthy of further 
testing if 13 or more patients experience a 30% PSA decline among the 27 patients who 
are part of the phase II trial.    
 
 
5. 
REGISTRATION PROCEDURES 
 
5.1 
Identification of subjects: 
 
Patients diagnosed with documented progressive metastatic CRPC disease who are visiting 
Oncology Clinic at NYPH−Cornell Campus for their standard of care visit, will be approached for 
recruitment for this study. Investigators or delegates under their direct supervision may perform 
pre–screening of these potential subjects. 
 
5.2 
Consent process 
 
Potential subjects will have a discussion with the investigator/delegate including the rationale for 
the study, investigational nature of the protocol and study drug and the voluntary nature of 
participation, potential risks and benefits, alternatives to participation, and study procedures.  
Individuals will have the opportunity to read the written informed consent document at their leisure 
(preferably outside of the clinical area for > 1 day) and the opportunity to have questions answered 
in a private location with the understanding that should they decide not to participate, they will 
still be able to receive any available standard of care therapy.  Potential subjects will also have the 
opportunity to obtain the advice of their treating physician.  Investigators or delegates under their 
direct supervision will verify the subject’s understanding of the investigational and voluntary 
nature of the study, the potential risks and benefits, study procedures, and alternatives prior to 
signing of the written informed consent. 
 
5.3 
Central Patient Registration 


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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 15 and described in detail in Section 6.1.


 
 
  
0 
 
6.1 
Schedule of Evaluations 
 
Table 15: Schedule of trial events: 
 
Screening 
Treatment 
Visit 1 
Imaging 
visit 
Treatment 
Visit 2 
F/U 
Visit 1 
F/U 
Visit 2 
F/U 
Visit 3 
F/U 
Visit 4 
F/U 
Visit 5 
Scan / 
Efficacy 
Visit 
Short-
Term 
F/Uk 
Long-
Term 
F/U 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
Physical Exam 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
Performance Status 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
Vital Signsa 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
PROl 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
xl 
 
CBC with diff, pltsb 
x 
x 
x 
xc 
x 
x 
x 
x 
x 
x 
x 
 
Serum Chemistryd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
PSA 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
LDH 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
Testosterone 
x 
 
 
 
 
 
 
 
 
x 
 
 
CTC Counte 
x 
xe 
 
 
 
 
 
 
 
x 
 
 
CTC for Researchf 
x 
xf 
 
 
 
 
 
 
 
x 
 
 
Cell-Free DNA 
Research sampleg 
x 
xg 
 
 
 
 
 
 
 
     x 
 
 
Immune research 
samplem 
x 
xm 
 
 
 
 
 
 
 
x 
 
 
68Ga-PSMA 
infusion & PET CT 
x 
 
 
 
 
 
 
 
 
x 
 
 
Radiographic 
evaluationh 
x 
 
 
 
 
 
 
 
 
x 
xh 
xh 
177Lu-J591 infusion 
 
x 
 
x 
 
 
 
 
 
 
 
 
177Lu-PSMA-617 
infusion 
 
x 
 
x 
 
 
 
 
 
 
 
 


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1 
 
177Lu- 
Planar/SPECT 
imagingi 
 
 
xi 
xi 
 
 
 
 
 
 
 
 
Archival Tissue 
x 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Monitoring 
 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
Concurrent 
Medications 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
 
Survival 
Assessmentj 
 
 
 
 
 
 
 
 
 
 
 
x 
a: Vital signs will include height and weight during screening and at least weight thereafter 
b: Any subject with grade >2 neutropenia or thrombocytopenia at any time point will be followed at least weekly until resolution to grade 1 
c: Any subject with grade ≥2 neutropenia or thrombocytopenia at Treatment 2 will initially not be eligible to receive the second 177Lu-J591 / 177Lu-PSMA-617 infusions. The 
dose will be held until the toxicity has resolved to grade 1 for a maximum of 2 weeks. If the toxicity has not resolved after 2 weeks, the dose will be discontinued. 
d: CMP (with direct bilirubin in subjects with known Gilbert’s syndrome) 
e:  CTC enumeration via CellSearch methodology may be obtained during screening or prior to treatment C1D1 
f:  CTC collection for research purposes may be performed during screening or prior to treatment C1D1: two 2.3% sodium citrate “light blue top” tubes  
g:  Cell-Free DNA BCT®  may be obtained during screening or prior to treatment C1D1 and will be whole blood collection in a tube intended for collection, stabilization and 
transportation of cell-free plasma DNA. 10 mL tube will be used for collecting whole blood for research purposes 
h: Radiographic evaluation will include bone scan, CT/MRI of abdomen/pelvis, and Chest x-ray (CXR waived if CT/MRI includes chest). Following mandatory repeat 
imaging with Scan/Efficacy visit, continued repeat imaging is recommended approximately 12 weeks until radiographic progression as part of standard care. 
i: Planar/SPECT imaging one week after the 177Lu-PSMA-617 1st dose infusion in all subjects.  Optional imaging will be performed on consenting subjects between D1-D4 
and/or prior to treatment #2 on D15. 
j: Survival assessment and relevant medical history to be collected until death 
k: Short-term follow up to be completed q4 weeks following the scan visit until 6 months from the 1st treatment visit.  Subjects who are progression-free at 6 months will 
continue with q4-week labs and q12-week standard imaging per guidelines (as in h above). 
l: PRO = patient reported outcomes = BPI-SF and FACT-P; to be performed at time points specified during treatment phase, then q12 weeks (at imaging time points) during 
short-term follow up until radiographic progression 
m: serum for immune assays; 1 sample to be collected at any time during screening prior to treatment #1, then again during scan/efficacy visit 


 
 
  
0 
 
 
6.1.1. Screening Visit 
 
The following procedures must be completed no more than 1 month prior to 
enrollment and no more than 4 weeks following enrollment. 
 
 Informed Consent 
 Demographics 
 Medical History 
 Previous therapy 
 Surgical report will include date and type of surgery +/- lymphadenectomy 
 Radiotherapy report will include modality of therapy with prescribed dose and 
field and dates of therapy 
 Previous systemic (hormonal, chemo, other) therapy – drugs, doses, dates of 
therapy 
 Complete Physical Exam including height and weight 
 Brief Pain Inventory 
 Vital Signs 
 ECOG Performance Status 
 CBC with differential and platelet count 
 CMP (with direct bilirubin with known Gilbert’s syndrome) 
 PSA 
 Testosterone 
 CTC count via CellSearch methodology (may be collected prior to treatment 
C1D1, do not need to repeat if has known result within 1 month of C1D1) 
 CTC for Research (may be collected prior to treatment C1D1) 
 Cell-Free DNA BCT® Research blood sample (may be collected prior to treatment 
C1D1) 
 Immune research blood sample (may be collected prior to treatment C1D1) 
 CT or MRI (abdomen-pelvis), up to 1 month prior to enrollment 
 Bone scan, up to 1 month prior to enrollment 
 Any confirmatory tests to assess equivocal results of bone scan should also be 
completed within a month of enrollment 
 CXR, up to 1 month prior to enrollment (CXR waived if CT chest performed) 
 Single intravenous dose of 68Ga-PSMA-HBED-CC (5±2mCi or 185±74MBq) at least 
1 week prior to 177Lu-PSMA-617 infusion 
 
68Ga-PSMA-HBED-CC PET/CT scan to confirm the PSMA expression at the 
tumor site(s). PET/CT scans will be obtained 1 to 3 hours after the infusion of 
68Ga-PSMA-HBED-CC 
 Archival tissue for PSMA expression and genomic studies to identify DNA 
damage 
 


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Screening (except 68Ga-PSMA-HBED-CC PET/CT scan) and visit #1 may occur on 
the same day provided results are available, all entry criteria are met, and the subject is 
registered on the study prior to dosing. In this instance, duplicate procedures do not 
need to be performed. 
 
6.1.1.1. Re–screening 
 
Subjects who are unable to complete the initial screening or are not initially eligible 
will be permitted undergo repeat screening (with repeat written informed consent).  
 
6.1.2. Treatment Phase 
 
 
 
 
 
The treatment and early monitoring phase comprises of 8 visits spanning over 
approximately 12 weeks.  
Absolute neutrophil counts, platelet counts, bilirubin, transaminases, and serum 
creatinine must be performed with results available and within range of eligibility 
criteria within 1 week prior to treatment initiation on C1D1. 
Details for each visit are listed below: 
 
 
 
 
 
 
6.1.2.1 
177Lu-J591 and 177Lu-PSMA-617 infusion (Treatment 1 Day 1) and (Treatment 
2 Day 15 ±1 day) 
 
The following procedures must be completed on the day of treatment: 
 
 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  
 Intravenous dose of 177Lu-PSMA-617 (Dose based on the Cohort in which the 
subject is enrolled) and 177Lu-J591 
 Adverse event evaluation 
 Concomitant medications 
 Concomitant procedures 
 Planar/SPECT imaging (on D15 prior to treatment in consenting subjects) 
 
As stated above, Absolute neutrophil counts, platelet counts, bilirubin, transaminases, 
and renal function assessment must be available within 1 week prior to treatment on 
D1 and meet eligibility criteria.   


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For treatment #2 (D15), grade ≥ 2 thrombocytopenia or neutropenia within 24 hours of 
the second dose of 177Lu-PSMA products (Visit 3) requires a subject’s treatment to be 
held until the toxicity has resolved to least grade 1. If the toxicity has not resolved after 
2 weeks of monitoring, the subject’s 177Lu-PSMA product treatment will be 
permanently discontinued and will be termed dose-limiting toxicity 
 
6.1.2.2 Imaging visit (Day 8 ±1) [optional D1, D4, D15 in consenting subjects] 
 
 Planar/SPECT imaging 
 Targeted Physical Examination with vital signs and weight 
 Medical History 
 Brief Pain Inventory, FACT-P 
 ECOG Performance Status 
 CBC with differential and platelet count 
 CMP (with direct bilirubin with known Gilbert’s syndrome) 
 Adverse event evaluation 
 Concomitant medications 
 
6.1.2.2 Follow-up visits: Follow up Visit 1 (Day 22 ±3), Follow up Visit 2 (Day 29 ±3), 
Follow up Visit 4 (Day 57 ±3) 
 
 Targeted Physical Examination with vital signs and weight 
 Medical History 
 Brief Pain Inventory, FACT-P 
 ECOG Performance Status 
 CBC with differential and platelet count 
 CMP (with direct bilirubin with known Gilbert’s syndrome) 
 PSA (Follow up visits 2 & 4) 
 LDH (Follow up visits 2 & 4) 
 Adverse event evaluation 
 Concomitant medications 
 
 
6.1.2.3 Follow-up lab visits: Follow up Visit 3 (Day 43 ±3); Follow up Visit 5 (Day 71 
±3) 
 
 CBC with differential and platelet count 
 CMP (with direct bilirubin with known Gilbert’s syndrome) 
 PSA 
 LDH 
 
Lab visits may be performed at any CLIA certified lab 
 


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


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These q4-week lab/clinic 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.  Visits associated with repeat CT and bone scan (q12 weeks until 
radiographic progression) should be performed at the WCM investigative site. 
 
6.1.5 Long Term Follow Up 
 
Following cancer progression, survival assessment and relevant medical history to be 
collected until death.  Information may be collected from external providers. 
Information will be updated at least every 6 months following disease 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. 
177Lu−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. 
 
The DOTA–J591 antibody molecule is labeled with radiometal 177Lu in 1.0 M ammonium acetate 
buffer at pH 7.0. The radiolabeled J591 complex is then purified using size–exclusion column 
chromatography. To avoid the effects of autoradiolysis on the antibody, reaction time is minimized 
and the radiolabeled antibody preparations are formulated in phosphate buffered saline containing 
not more than 1% Human Serum Albumin (HSA). All reagents used in the conjugation and 
purification of J591 are made with pyrogen–free water.  Radiolabeled J591 is periodically tested 
for sterility and pyrogenicity. 
 
Each patient dose will be supplied to the study site on the day of or day before treatment by the 
central radiopharmacy. The J591 mAb is a deimmunized monoclonal antibody directed at the 


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6 
 
extracellular domain of human PSMA.  For additional details, see Section 1. Radiolabeled 
antibody preparations are formulated in phosphate buffered saline containing not more than 1% 
Human Serum Albumin (HSA).In order to radiolabel J591 with – emitting radionuclides, the 
antibody molecule is first conjugated to a macrocyclic chelating agent, 1,4,7,10–
tetraazacyclododecane– N,N’,N’’,N’’’–tetraacetic acid (DOTA) by direct coupling of one of the 
four carboxylic acid groups of DOTA to the primary amines present in the protein structure.The 
radiolabeling of J591 with 177Lu is achieved by adding the radionuclide to the ammonium acetate 
buffered J591.  To avoid the effects of autoradiolysis on the antibody, reaction time is minimized 
and the reaction mixture is purified with a size exclusion column prior to administration. All 
reagents used in the conjugation and purification of J591 are made from pyrogen–free water.  
Radiolabeled J591 is tested periodically for sterility and pyrogenicity. 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 (177Lu−J591, IND# 11613). 
 
 
B. 
177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC 
ABX Advanced Biochemical Compounds, Radeberg, Germany produces both peptides/ligands, 
PSMA−617 and PSMA−HBED−CC, with PSMA-617 licensed to Endocyte (West Lafayette, LA). 
Upon purchase and shipment to Weill Cornell Medicine, they will be labeled with either 177Lu or 
68Ga with final product being 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC, respectively. 
Radionuclide conjugation will be done at the Division of Nuclear Medicine, Department of 
Radiology, Weill Cornell Medicine.  
 
The material produced are subjected to quality assurance testing as outlined in the Food and Drug 
Administration “Points to Consider”. All production data and supporting documents, together with 
the results of all quality assurance testing, have been provided to and reviewed by the Food and 
Drug Administration (177Lu−PSMA−617, IND # 131966 and 68Ga−PSMA−HBED−CC, IND# 
124495). 
 
6.2.3 Route of Administration 
 
177Lu−J591, 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC will be administered intravenously. 
 
6.2.4 Dose levels for 177Lu−J591 + 177Lu−PSMA−617 
 
Subject(s) enrollment will be done as 3+3 study design at each dose level. Initially at least 3 
subject(s) will be enrolled in Cohort 1 and will receive 177Lu−PSMA−617 (2 GBq or 54 mCi x2 
doses 2 weeks apart) with dose escalation as described above in Section 4.1 (Table 14). 


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Simultaneously, all subjects will receive in combination a fixed dose of 177Lu−J591 (1.35 GBq/m2 
or 36.5 mCi/m2 capped at BSA of 2) x2 doses, 2 weeks apart. The enrollment ceiling of the dose 
escalation portion of the study is up to 30 treated study participants (up to five groups, up to 6 at 
each dose level). Each patient would receive two doses of both investigational agents (177Lu−J591 
and 177Lu−PSMA−617) in combination 2 weeks apart. The total dose received by a subject will 
vary from 4 GBq/m2 (108 mCi/m2) to 20 GBq/m2 (540 mCi/m2) for 177Lu−PSMA−617. The 
total dose received by a subject for 177Lu−J591 will be 2.7 GBq/m2 (73 mCi/m2), with BSA 
capped at 2. 
 
6.2.5 Dose levels for 68Ga−PSMA−HBED−CC 
 
All subjected enrolled will receive 5 ±2mCi or 185 ±74MBq of 68Ga−PSMA−HBED−CC during 
the screening visit and scan/efficacy visit. 
 
6.2.6 Study drug premedication 
 
No pre−medication is required, but is recommended prior to J591 dosing. Individual subjects may 
receive pre−medication at the discretion of their treating physician provided that they are not 
prohibited medications per study. The recommended pre−medication for 177Lu−J591 is a H1 
blocker (recommended 25−50 mg diphenhydramine) and acetaminophen (recommended 325−650 
mg). No pre−medications will be administered for 68Ga−PSMA−HBED−CC. 
 
6.2.7 Study drug administration 
 
Intravenous access must be well established prior to initiating infusion.  At the time of dosing, the 
IV line will be connected to an infusion container containing the prepared volume of 177Lu−J591, 
177Lu−PSMA−617 or 68Ga−PSMA−HBED−CC.  177Lu−J591 will be infused at a rate of no faster 
than 5 mg/minute. 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC may be administered as slow 
IV push. 
 
6.2.8. Monitoring 
Vital 
signs 
pre/post 
177Lu−J591 
+ 
177Lu−PSMA−617 
and 
68Ga−PSMA−HBED−CC 
 
The infusion of 177Lu−J591, 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC 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 


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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) [additionally, at 90 10 minutes and 120 10 minutes 
for 177Lu−J591 + 177Lu−PSMA−617] after the infusion. If any subject has any adverse reaction at 
60 minutes for 68Ga−PSMA−HBED−CC and at 120 minutes for 177Lu−J591 + 177Lu−PSMA−617, 
they will stay longer until it is resolved. 
 
6.2.9. Imaging Plan 
 
A. 68Ga−PSMA−HBED−CC PET/CT Scan 
Patient preparation should be according to the policies and procedures of the local imaging site 
(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(efficacy/scan visit). The 
images are acquired between 1 and 3 hours after the 68Ga−PSMA−HBED−CC infusion. Image 
acquisition will be from vertex of skull to mid thighs. 
 
B. Lutetium−177 Planar/SPECT imaging 
 
Patient preparation should be according to the policies and procedures of the local imaging site. 
The patient does not need to be fasting for either the infusion or the scans. The use of intravenous 
or oral contrast will not be permitted. Specifications for acquiring the 177Lu−PSMA−617 
planar/SPECT images will be provided in study specific documentation by the study chair or the 
co−investigators from the Division of Nuclear Medicine. Planar/SPECT images should be 
obtained during the Imaging Visit (Day 8 ±1) on all subjects after the 177Lu−J591 + 
177Lu−PSMA−617 infusion. Image acquisition will be from vertex of skull to mid thighs.  Optional 
images will be performed on selected consenting subjects between initial Treatment Visit (between 
D1 − D4) and prior to Treatment Visit 2 (Day 15 ±1). 
 
 
6.2.10 Managing toxicity 
 
NCI CTCAE version 4.0 is used to grade all adverse events. 
 
• 
Grade ≥ 2 thrombocytopenia or neutropenia within 24 hours of the second dose of 177Lu−J591 
+ 177Lu−PSMA−617 (Treatment Visit #2) requires a subject’s treatment to be held until the 
toxicity has resolved to least grade 1. If the toxicity has not resolved after 2 weeks of 
monitoring, the subject’s 177Lu−J591 + 177Lu−PSMA−617 treatment will be permanently 
discontinued and will be termed dose−limiting toxicity. 


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Dose−limiting toxicity (DLT) is defined as: 
 
• 
Grade 4 hematologic toxicity that is deemed at least possibly related to 177Lu−J591 and/or 
177Lu−PSMA−617 will be termed dose−limiting toxicity 
• 
Any grade > 2 non−hematologic toxicity deemed to be at least possibly related to 177Lu−J591 
and/or 177Lu−PSMA−617 will require a subject’s 177Lu−J591 + 177Lu−PSMA−617 treatment 
to be permanently discontinued and will be termed dose−limiting toxicity.   
 A 1-grade increase in a pre-existing from grade 2 to grade 3 will only be considered a 
DLT if probably or definitely related to study drug 
 
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 
177Lu−J591, 177Lu−PSMA−617 or 68Ga−PSMA−HBED−CC as judged by the investigator (see 
note above re: 1-grade increases in which case only probably/definitely related toxicities will be 
deemed DLT).  Attribution will be reviewed by the study chair and discussed with the medical 
monitor if there are questions about severity or attribution. 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
All medications that are administered during the study must be recorded in the patient’s CRF and 
in the source documents.  Concomitant medications for other medical conditions are permitted as 
clinically indicated subject to approval by the study chair. 
 
Subjects will be advised to use contraceptive precautions to avoid pregnancy during the treatment 
phase since the effects of investigational agents on sperms and embryos are unknown. 
 
6.4 
Duration of Therapy and Criteria for Removal from Study 
 
Duration of treatment portion of the study (excluding screening time) will be approximately 85 
Days (±7 days). By signing the informed consent form and agreeing to participate in this study, 
the subjects are required to participate in entirety up to the completion of all scheduled visits and 
study procedures, or until one of the following criteria applies: 
 
 A protocol violation occurs 
 Disease progression occurs 


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 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 177Lu−J591 or 177Lu−PSMA−617 
 Previous anaphylactic reaction to any J591 product or PSMA peptides/ligands 
 
The investigators or physicians may stop the protocol or terminate a subject’s participation in the 
protocol at any time should they judge: 
 
 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. 
 
 
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 177Lu−J591 + 177Lu−PSMA−617 x 2 doses, 2−weeks apart 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).  


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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. 177Lu−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. 
 
The DOTA–J591 antibody molecule is labeled with radiometal 177Lu in 1.0 M ammonium acetate 
buffer at pH 7.0. The radiolabeled J591 complex is then purified using size–exclusion column 
chromatography. To avoid the effects of autoradiolysis on the antibody, reaction time is minimized 
and the radiolabeled antibody preparations are formulated in phosphate buffered saline containing 
not more than 1% Human Serum Albumin (HSA). All reagents used in the conjugation and 
purification of J591 are made with pyrogen–free water.  Radiolabeled J591 is periodically tested 
for sterility and pyrogenicity. 
 
Each patient dose will be supplied to the study site on the day of or day before treatment by the 
central radiopharmacy. The J591 mAb is a deimmunized monoclonal antibody directed at the 
extracellular domain of human PSMA.  For additional details, see Section 1. Radiolabeled 
antibody preparations are formulated in phosphate buffered saline containing not more than 1% 
Human Serum Albumin (HSA).In order to radiolabel J591 with – emitting radionuclides, the 
antibody molecule is first conjugated to a macrocyclic chelating agent, 1,4,7,10–
tetraazacyclododecane– N,N’,N’’,N’’’–tetraacetic acid (DOTA) by direct coupling of one of the 
four carboxylic acid groups of DOTA to the primary amines present in the protein structure.The 
radiolabeling of J591 with 177Lu is achieved by adding the radionuclide to the ammonium acetate 
buffered J591.  To avoid the effects of autoradiolysis on the antibody, reaction time is minimized 
and the reaction mixture is purified with a size exclusion column prior to administration. All 
reagents used in the conjugation and purification of J591 are made from pyrogen–free water.  
Radiolabeled J591 is tested periodically for sterility and pyrogenicity. 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 (177Lu−J591, IND# 11613). 


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B. 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC: 
PSMA−617 will be obtained from Endocyte (West Lafayette, LA) and PSMA−HBED−CC will be 
obtained from ABX Advanced Biochemical Compounds, Radeberg, Germany 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 Lutetium−177 or 
Gallium−68, respectively. 
 
The material produced are subjected to quality assurance testing as outlined in the Food and Drug 
Administration “Points to Consider”. All production data and supporting documents, together with 
the results of all quality assurance testing, have been provided to and reviewed by the Food and 
Drug Administration (177Lu−PSMA−617, IND # 131966 and 68Ga−PSMA−HBED−CC, IND# 
124495). 
 
8.2. 
Availability 
 
177Lu−J591 (IND# 11613), 177Lu−PSMA−617 (IND# 131966) 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 
177Lu−J591, 177Lu−PSMA−617 and 68Ga−PSMA−HBED−CC infusion dates. The WCM Study 
Coordinator will arrange with the staff of Nuclear Medicine Division at WCM for the timely 
labeling and delivery of the radiolabeled PSMA peptides to the site of infusion. The dates for study 
visits will be confirmed with the subject, site of infusion, and site of imaging.  
 
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 immune analysis: 
 


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Whole blood samples (2.7 mL in each vial) in two 4.5 mL 2.3% sodium citrate tubes (light blue 
top tube) will be collected for research analysis at specified time points (Screening/baseline and 
efficacy visit). These samples are collected for research purposes only and will not be billed to the 
subject. CTC will be stained for calreticulin analyzed for research purposes only. 
 
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 pre-treatment and efficacy visit). These samples are collected 
for research purposes only and will not be billed to the subject. The cell−free plasma DNA will be 
analyzed for genomic studies and to identify DNA repair and AR-pathway alterations. 
 
9.1.3 Immune Assay: 
 
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. Results of these assays will not be 
billed to the patient and are for research purposes only. 
 
9.1.4 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 DNA damage repair pathways for research purposes only. 
 
9.2. 
Special Studies 
 
Conventional Imaging studies as well as 68Ga−PSMA−HBED−CC PET/CT imaging and 
Lutetium−177 Planar/SPECT imaging will be performed as described in schedule as well as 
clinically indicated to assess disease response. In subjects enrolled in this study, the measurable 
disease response will be calculated using Response Evaluation Criteria in Solid Tumors (RECIST 
Version 1.1) with PCWG3 modifications. 
 
 
10. 
MEASUREMENT OF EFFECT 
 
 
10.1  CTC count response 
 
All subjects in this study will get blood samples drawn (at screening and EOS visit) for CTC 
enumeration by CellSearch methodology.  Our primary analysis will assess those whose CTC 
counts drop to less than 5 or stay below 5 (responders) vs. those who remain at least 5 or above 
(non−responders) at EOS visit. 
 


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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 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% confirmed by a second PSA value  2 weeks later, will be 
reported. Subjects must not demonstrate clinical or radiographic (CT and/or MR) evidence of 
disease progression during this time period. 
 
10.3  Duration of PSA response 
 
Duration of PSA response is defined as the time from the first 25% PSA decline until the PSA 
value is confirmed to increase by 25% above the nadir, provided that the increase is at least 2 
ng/mL above the nadir. 
 
10.4  Duration of CTC response 
 
Duration of CTC response is defined from the first CTC count drop to <5 (or <50% of baseline) 
to the time CTC count increases to >5 (or >25% increase from nadir). 
 
10.5  PSA Progression 
 
PSA progression will be defined as a rise of > 25% above either the pretreatment level or the nadir 
PSA level (whichever is lowest). PSA must increase by > 2 ng/ml to be considered progression. 
Confirmation requires a second consecutive rising PSA at least 2 weeks apart. 
 
10.6  PSA Stabilization 
 
PSA stabilization is referred to as any set of PSA values that do not meet the criteria for PSA 
response or PSA progression. 
 
10.7  Time to PSA Progression 
 
Time to PSA progression is defined as the interval between initiating treatment until the PSA rises 
25% above nadir provided that the increase is at least 2 ng/mL. 
 
10.8  Change in lesion size  


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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 and Lutetium−177 
Planar/SPECT 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 treatment 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 
68Ga−PSMA−HBED−CC PET/CT, and those treated with 177Lu−labeled products will undergo 
Planar/SPECT imaging. We will analyze the data for associations with response to treatment as 
well as survival by chi−square tests/Fisher’s exact tests and log−rank tests, respectively. For 
pre/post imaging comparisons, McNemar’s chi−square test and paired t−tests/Wilcoxon 
signed−rank tests will be used, as appropriate. We plan to report data for each individual study as 
well as across the studies. 


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10.9  Calreticulin Expression on CTCs (immune measure) 
 
We will analyze for associations between calreticulin expression as a categorical variable 
(membrane vs cytoplasmic vs mixed vs no 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 PSMA 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 
 
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 


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and approve the changes prior to submission of these changes to the local IRB and distribution to 
participating sites. 
 
 
12. 
STATISTICAL CONSIDERATIONS 
 
 
12.1 
Phase I Study Design/Endpoints 
 
The phase I portion is a study of subjects with documented progressive metastatic CRPC with 
the primary endpoint of determination of MTD (or recommended phase II dose).   In general, 
if there are sufficient numbers of subjects, descriptive statistics (e.g., number of observations, 
means, standard deviations, medians, and ranges) will be used to summarize data and selected 
endpoints may be summarized by dosing regimen. Otherwise, subject listings will be provided. 
No formal hypothesis testing is planned. 
 
The dose-escalation schedule (using 3+3 modified Fibonacci escalation), definitions of DLT, 
and determination of MTD are defined above (Section 6.2.10).  The design is constructed to 
reduce the chance of escalating the dose when the probability of DLT is high, and increase the 
chance of escalating the dose when the probability of DLT is low. The maximum tolerated 
dose is defined as the highest dose level with an observed incidence of DLT in no more than 
one out of six patients treated at a particular dose level. The dose escalation scheme provides 
the following probabilities of escalation based on the true chances of DLT at a specific dose 
level. One can see that the probability of escalation is high if the toxicity risks are low. 
 
True Probability of Toxicity 
0.05 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
Probability of Escalation 
0.97 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
 
12.2. 
Phase II Study Design/Endpoints 
 
We will enroll up to 27 subjects into the Phase II portion (including the 3-6 used for 
establishing the MTD).  We will define evaluable patients as patients who met eligibility 
requirements, have initiated therapy, and were not removed from the study for non-compliance 
or patient withdrawal.   
 
Sample size recommendations for the two-stage design are determined according to Simon’s 
two-stage minimax design.  We project a 30% PSA decline proportion of 35%, below which 
the regimen will be unacceptable and a 30% PSA decline proportion of 60%, above which the 
regimen will be considered worthy of further exploration.  The null hypothesis that the 30% 
PSA decline proportion is less than or equal to 35% will be tested against the alternative 
hypothesis that the 30% PSA decline proportion is greater than or equal to 60%. 
 
The sample size computations were performed assuming a 0.10 one-sided level of significance 
and 90% power assuming a historical control value for PSA decline of 35% and the alternative 


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hypothesis of 60%.  If 6 or fewer of the first 16 evaluable patients do not experience a 30% 
decline in PSA (stage 1), the study will be terminated and declared to have a negative result.  If 
7 or more patients out of the first 16 evaluable patients experience a 30% decline in PSA, 
ongoing accrual will proceed to the target sample size of 27 patients (stage 2).  The new 
regimen will be declared active in this patient population and worthy of further testing if 13 or 
more patients experience a 30% PSA decline among the 27 patients entered.  This two-stage 
design yields a 0.90 probability of a positive result if the true 30% PSA decline proportion is 
60%.  It yields a 0.90 probability of a negative result if the true 30% PSA decline proportion 
is 35%. An exact 95% binomial confidence interval will be constructed for the proportion of 
patients with PSA decline. 
 
 
12.3 
Sample Size/Accrual Rate 
 
The planned sample size for this dose escalation Phase I study is between 6 and 24 total patients 
and the accrual for phase II will be between 16 and 27 patients and will include patients treated at 
the MTD from the phase I portion. The accrual rate is anticipated to be 1−2 subjects every month 
on average (with expected pauses in enrollment between dose-escalation cohorts and between the 
stage 1 and stage 2 of the phase II trial). 
 
12.4 
Stratification Factors 
 
This is not a randomized trial and so there are no stratification factors.   
 
12.5 
Analysis of Endpoints 
 
12.5.1 Analysis of Primary Endpoints 
 
The primary endpoint will be the proportion of subjects with DLT from Treatment Visit #1 through 
End of Study (Efficacy/scan) Visit. The MTD is the highest dose amongst the different dose−level 
cohorts in this study at which no more than 1 out of 6 subjects in a cohort experience DLT. 
 
12.5.2 Analysis of Secondary Endpoints 
 
For PSA response, CTC response and imaging response, descriptive analysis will be done. For 
imaging response RECIST (Version 1.1) criteria with PCWG3 modifications will be applied. 
Biomarker and patient reported outcome data will be analyzed within this study as well as across 
additional radiolabeled−PSMA studies. 
 
12.6 
Interim Analysis  
 
No interim analysis is planned for the phase I portion (though safety analyses will occur in 
real−time and prior to each dose−escalation). For the phase II portion, accrual will be suspended 


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after 16 patients have been enrolled in stage 1. If at least 7 patients out of the 16 patients 
experienced a PSA decline > 30%, 9 more patients will be accrued as part of stage 2. 
 
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 first treatment with 177Lu−J591 + 
177Lu−PSMA−617 and up to 30 days after there last treatment. 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 177Lu−J591 + 177Lu−PSMA−617 treatment combination (2 doses of each 
investigational agents) and at least 12 weeks of subsequent follow−up evaluations (as described in 
the Schedule Calendar−Section 6.1) will be considered evaluable (consistent with PCWG3 
guidelines). As the timing of response is not known, should the anticipated time to response be 
determined to be earlier than with other therapies using alternative markers of response, we may 
not replace subjects who are not evaluable through week 12 on study. 
 
 
13.  
ADVERSE EVENT REPORTING REQUIREMENTS 
 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe use 
of the drug or device under investigation.  Safety will be monitored by evaluation of adverse events 
reported by patients or observed by investigators or research staff, as well as by other investigations 
such as clinical laboratory tests, x−rays, electrocardiographs, etc. 
 
13.1 
Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, and does not imply any judgment about 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  
 


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There 
are 
no 
known 
contraindications 
for 
177Lu−J591, 
177Lu−PSMA−617 
or 
68Ga−PSMA−HBED−CC. Because of the potential for infusion or allergic reaction, the subject 
should be monitored for safety for one to two hours following the infusion. 
 
Based on prior studies, the known side effects, risks, and hazards associated with the 
administration of 177Lu−J591, 177Lu−PSMA−617 or 68Ga−PSMA−HBED−CC include: infusion 
reaction (fever, chills, rash, hypotension, and/or hypertension after injection), xerostomia, renal 
insufficiency, hematological/bone marrow toxicity (thrombocytopenia, neutropenia) and transient 
hepatic enzyme elevations. In addition, allergic reactions including anaphylaxis, hypotension, 
hypertension, difficulty breathing, rash, human anti−humanized antibody (HAHA) response and 
CNS toxicity are a rare possibility. 
 
 
Precautions/monitoring: 
 
The infusion of 177Lu−J591, 177Lu−PSMA−617 or 68Ga−PSMA−HBED−CC and subsequent 
monitoring will occur in a facility that is equipped for cardio–pulmonary resuscitation. The 
dispensed dose will be infused under the supervision of nuclear medicine physician or designee 
under the supervision of a nuclear medicine physician. Infusion–related reactions (fever, rigors) 
will be treated with acetaminophen, meperidine and diphenhydramine hydrochloride as clinically 
appropriate. Vital signs will be monitored before/after the 177Lu−J591 + 177Lu−PSMA−617 or  
68Ga−PSMA−HBED−CC infusion. Systolic and diastolic blood pressure (mm Hg), temperature, 
pulse rate (beats/minute), and respiratory rate (breaths/minute), will be recorded with the patient 
in sitting position. Any clinically significant change in the vital signs will be recorded as AEs. 
Serial vital signs including temperature, BP, and heart rate will be monitored within 30 minutes of 
the infusion, and within 30 minutes and 60 minutes (+/− 10) after the infusion (also, 90 +/− 10 
minutes and 120 +/− 10 minutes for 177Lu−J591 + 177Lu−PSMA−617). If any subject has any 
adverse reaction at 60 minutes for 68Ga−PSMA−HBED−CC and 120 minutes for 177Lu−J591 + 
177Lu−PSMA−617, they will stay longer until it is resolved. 
 
13.1.2. Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment.  A reaction that follows a plausible 
temporal sequence from administration of the study drug and follows a known response pattern to 
the suspected study drug. The reaction can be confirmed with a positive re–challenge test or 
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Probable – The AE is likely related to the study treatment.  A reaction that follows a plausible 
temporal sequence from administration of the study drug and follows a known response pattern to 
the suspected study drug.  The reaction cannot be reasonably explained by the known 
characteristics of the patient’s clinical state or other modes of therapy administered to the patient. 
 
Possible – The AE may be related to the study treatment.  A reaction that follows a plausible 
temporal sequence from administration of the study drug and follows a known response pattern to 
the suspected study drug.  The reaction might have been produced by the patient’s clinical state or 
other modes of therapy administered to the patient. 
 
Unlikely – The AE is doubtfully related to the study treatment.  The current state of knowledge 
indicates that a relationship is unlikely. 
 
Unrelated – The AE is clearly NOT related to the study treatment.  No relationship between the 
experience and the administration of study drug; related to other etiologies such as concomitant 
medications or patient’s clinical state. 
 
 
 
13.1.3. Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be maintained 
by the research staff and kept in the patient’s research chart.    
 
 
13.1.4. Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link: 
 
http://researchintegrity.weill.cornell.edu/forms and policies/forms/Immediate Reporting Policy
.pdf 
 
13.2. Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other serious 
events that may jeopardize the subject or require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 
 
13.2.1. Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:   
 


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http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy
.pdf 
 
13.2.2. Reporting of SAE to FDA 
 
If an SAE occurs on this study, the event will be filed on a MedWatch form with the FDA. The 
investigator must notify the FDA of any SAE’s as soon as possible but no later than 7 calendar 
days after the initial receipt of the information 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Central Document Room 
5901−B Ammendale Road  
Beltsville, MD 20705−1266   
 
13.3. AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow−up is required. This 
requirement indicates that follow−up may be required for some events after the patient 
discontinues participation from the study. 
 
 
14.  
DATA AND SAFETY MONITORING PLAN (DSMP) 
 
 
This study will utilize the Weill Cornell Medicine (WCM) Institutional Data Safety Monitoring 
Board (DSMB) and follow its policies and procedures for monitoring this study for safety 
concerns, with ongoing updates from the Study Chair on a continuous basis. 
  
The Weill Cornell’s DSMB is comprised of medical specialists and advisors on human rights 
issues in human subjects research.  The DSMB currently has 9 members, meets at quarterly 
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: 
 


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 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. 
 
For this study, the DSMB will be notified after each cohort has been completed prior to dose 
escalation to the next cohort and prior to transition from phase I to phase II.  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 


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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. 
 
Sarah Rutherford, MD will serve as the Medical Monitor for this study. 
 
 
15. 
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Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha emitter 
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Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and 
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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 
20 
Very sick, hospitalization indicated. 
Death not imminent. 


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confined to bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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APPENDIX B 
  
WCMC IRB SAE Reporting Forms 
  
http://researchintegrity.weill.cornell.edu/institutional review board/irb adv.html