A Randomized Phase 2 Trial of 177Lu Radiolabeled Monoclonal Antibody HuJ591 (177Lu-J591) and Ketoconazole in Patients With High-Risk Castrate Biochemically Relapsed Prostate Cancer After Local Therapy
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Weill Medical College of Cornell University

Protocol and Statistical Analysis Cover Page  
Note: This cover page is separate from IRB-approved protocol. 
A Randomized Phase 2 Trial of 177Lu Radiolabeled Monoclonal 
Antibody HuJ591 (177Lu-J591) and Ketoconazole in Patients with 
High-Risk Castrate Biochemically Relapsed Prostate Cancer After 
Local Therapy 
PI: Scott T. Tagawa, M.D. 
NCT #: NCT00859781 
WCM Protocol #: 0810010067 
Version Date: August 30, 2021 

IRB Protocol Number: 0810010067 
Randomized Phase II: LuJ591+Ketoconazole 
Protocol Version 10 Dated: 30 August 2021 
A Randomized Phase 2 Trial of 177Lu Radiolabeled Monoclonal 
Antibody HuJ591 (177Lu-J591) and Ketoconazole in Patients with 
High-Risk Castrate Biochemically Relapsed Prostate Cancer After 
Local Therapy 
Study Chair: 
Scott T. Tagawa, M.D. 
Division of Hematology/Medical Oncology 
Weill Cornell Medical College 
525 East 68th Street,  
New York, NY 10065 
Tel: 646-962-2072 
Fax: 646-962-1603 
stt2007@med.cornell.edu 
Protocol Version 1 Dated: September 08, 2008 
Protocol Version 2 Dated: October 28, 2009 
Protocol Version 3 Dated: January 15, 2010 
Protocol Version 4 Dated: May 25, 2010 
Protocol Version 5 Dated:  June 01, 2011 
Protocol Version 6 Dated:  July 02, 2012 
Protocol Version 7 Dated: October 31, 2013 
Protocol Version 8 Dated: May 4, 2015 
Protocol Version 9 Dated: January 26, 2016 
Protocol Version 10 Dated: August 30, 2021 

ii 
 
 
 
Statistician: 
 
 
 
       Paul Christos, DrPH 
       Weill Cornell Medical College 
       Division of Biostatistics and Epidemiology 
       pac2001@med.cornell.edu 
 
 
 
 
 
 
 Study email address:  
guonc@med.cornell.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

iii 
 
 
 
 
INVESTIGATOR AGREEMENT 
 
 
Protocol Version 10.0 Dated:  30 August 2021 
 
I have read the protocol entitled “A Randomized Phase 2 Trial of 177Lu Radiolabeled 
Monoclonal Antibody  HuJ591 (177Lu-J591) and Ketoconazole in Patients with High-Risk 
Castrate Biochemically Relapsed Prostate Cancer After Local Therapy.” 
 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for 
Good Clinical Practice and applicable regulatory requirements and to inform all who assist 
me in the conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
Principal investigator printed name 
 
 
 
 
 
 
 
Principal investigator signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
Investigational site or name of institution and 
location (printed) 
 

iv 
 
 
 
SCHEMA 
 
 
 
 
                                                               
 
 
                                                                    
 
 
 
 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
           
 
 
 
 
 
Informed Consent 
Screening 
Labs (CBC, chemistry, PSA, testosterone), CT/MRI abd/pelvis, bone scan, CXR 
Randomization 
2:1 
Group 2 
Ketoconazole 400 mg TID plus 
hydrocortisone 20 mg AM, 10 mg 
PM x 4 weeks 
High risk biochemically progressive non-
metastatic castrate resistant prostate cancer 
Group 1 
Ketoconazole 400 mg TID plus 
hydrocortisone 20 mg AM, 10 mg 
PM x 4 weeks 
Infusion of trace-labeled 111In-J591, 
continue ketoconazole, J591 scan 
Infusion of 177Lu-J591 x1, continue 
ketoconazole, J591 scan 
CT/MRI abd/pelvis, bone scan, 
CXR q 6 months 
(q3 months after PSA progression) 
CT/MRI abd/pelvis, bone scan, 
CXR q 6 months 
(q3 months after PSA progression) 

v 
 
PROTOCOL SUMMARY 
Study Title:   
A Randomized Phase 2 Trial of 177Lu Radiolabeled Monoclonal Antibody 
HuJ591 (177Lu-J591) with Ketoconazole in Patients with High Risk 
Castrate Biochemically Relapsed Prostate Cancer after Local Therapy 
Principal 
Investigator:   
Scott T. Tagawa, MD (New York Presbyterian Hospital-Weill Cornell Medical 
College) 
Number of Study 
Centers Planned: 
 
10-16 
Clinical Phase: 
Phase 2 (Randomized) 
Study Rationale: 
To determine the clinical activity of 177Lu -J591 with ketoconazole for the 
treatment of patients with castrate resistant biochemically progressive prostate 
cancer 
Study 
Objectives:  
Primary Objective 
Compare the rate of progression to radiographically apparent metastatic 
disease at 18 months with 177Lu -J591 plus ketoconazole versus 
ketoconazole plus trace-labeled 111In-J591 (placebo) 
 
Secondary & Exploratory Objectives 
• 
Compare progression free and metastasis free survival 
• 
Define the PSA response rate (50% reduction, with 30% reduction 
exploratory analysis). 
• 
Define the duration of PSA response 
• 
Define the toxicity of 177Lu-J591 given as single dose plus ketoconazole 
in men with castrate resistant biochemical disease. 
• 
Assess the overall and prostate cancer specific survival rate of patients 
following treatment.  
• 
Assess the prognostic implications of baseline adrenal hormone levels in 
men with castrate resistant non-metastatic prostate cancer receiving 
ketoconazole 
• 
Define the toxicity and need for dose modifications  with “high dose” 
ketoconazole in men with biochemically progressive castrate resistant 
prostate cancer 
• 
To explore the ability of 177Lu-J591 or 111In-J591 to image metastatic 
sites in patients who are NED on bone scan CT/MRI of abdomen/pelvis 
and CXR (selected sites) 
• To assess the prognostic implications of baseline circulating tumor cell 
(CTC) counts in men with castrate resistant non-metastatic prostate 
cancer receiving ketoconazole and to explore the implications of serial 

vi 
 
changes in CTC counts (centrally assessed, optional) 
• To explore the feasibility of quantitative assessment of PSMA 
expression in CTCs and explore prognostic and predictive implications 
of PSMA expression in circulating tumor cells prior to therapy with Lu-
J591 (centrally assessed, optional) 
• 
To assess the implications and changes with therapy of plasma markers 
of hemostasis, fibrinolysis, and angiogenesis in biochemically 
progressive castrate resistant prostate cancer (centrally assessed, 
optional. 
• 
To describe reasons for lack of participation in study treatment 
• 
To assess patient reported outcomes in the setting of non-metastatic 
CRPC and with the development of metastases 
Methodology: 
Subjects will be randomized in a 2:1 fashion to receive ketoconazole with 70 
mCi/m2 of 177Lu-J591 or trace-labeled 111In-J591.  Subjects will be stratified by 
site and method of primary therapy (surgery vs radiation).  All subjects will 
receive ketoconazole (400 mg po TID) plus hydrocortisone (20 mg am, 10 mg 
pm) for 4 weeks followed by a single infusion of 177Lu-J591 or trace-labeled 
111In-J591, then continue ketoconazole/hydrocortisone until 
progression/toxicity.  Patients will be followed for response (biochemical), 
disease progression, and toxicity with the primary endpoint of time to 
radiographically apparent metastatic disease 
Number of 
Patients Planned: 
  
55 
Statistical 
Methods 
Based upon entry criteria, we expect 50% of patients to have developed 
metastasis at 18 months with ketoconazole + 111In-J591.  With a sample size of 
50 (2:1 randomization), the study will have ≥80% power, with a pre-set one 
sided alpha of 10%, to determine an absolute difference in the 18-month 
metastasis-free survival (MFS) between groups of 30% (e.g., 80% vs 50%). An 
additional 10% will be enrolled to account for unevaluable subjects and loss to 
follow-up, resulting in a planned final n = 55. 

vii 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ...................................................................................................................................... iv 
PROTOCOL SUMMARY  ...........................................................................................................v 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objectives ......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
1.3 
Exploratory Objectives ...............................................................................................1 
 
2. BACKGROUND ......................................................................................................................2 
2.1 
Disease ..........................................................................................................................2 
2.2 
Investigational Agent ...................................................................................................7 
2.3 
Rationale .....................................................................................................................13 
2.4 
Correlative Studies Background .. ...........................................................................13 
 
3. PATIENT SELECTION........................................................................................................18 
3.1 
Inclusion Criteria  ......................................................................................................18 
3.2 
Exclusion Criteria ......................................................................................................19 
 
4. ENROLLMENT & REGISTRATION PROCEDURES ....................................................21 
 
4.1  
Enrollment Procedures  .............................................................................................21 
4.2  
Central Patient Registration .....................................................................................22 
 
5. TREATMENT PLAN ............................................................................................................23 
5.1 
Agent Administration ................................................................................................23 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................24 
5.3 
Duration of Therapy and Criteria for Removal from Study .................................26 
5.4 
Duration of Follow Up ...............................................................................................26 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................26 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................27 
7.1  
Comprehensive Adverse Events and Potential Risks List (CAEPR) ....................27 
7.2  
Adverse Event Characteristics..................................................................................28 
7.3  
Recording of Adverse Events ....................................................................................29 
7.4  
Serious Adverse Event Reporting.............................................................................29 
7.5 
Secondary AML/MDS ...............................................................................................30 
 
8. AGENT INFORMATION .....................................................................................................31 
8.1 
Investigational Agent (IND#11,613):  J591 ..............................................................31 
8.2 
Agent Ordering ..........................................................................................................31 
8.3 
Drug Accountability...................................................................................................31 
 
9. CORRELATIVE/SPECIAL STUDIES ...............................................................................32 
9.1 
Laboratory Correlative Studies ................................................................................32 
9.2 
Special Studies ............................................................................................................34 

viii 
 
 
10. STUDY CALENDAR ............................................................................................................35 
10.1     Study Procedures .......................................................................................................37 
 
11. MEASUREMENT OF EFFECT ..........................................................................................46 
11.1 
Metastasis-Free Proportion ......................................................................................46 
11.2 
Response Criteria ......................................................................................................46 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS ........................................47 
12.1 
Data Collection ...........................................................................................................47 
12.2 
Regulatory Considerations ........................................................................................47 
12.3 
DSMB ………………. ................................................................................................48 
12.4 
Initial Safety Review ..................................................................................................49 
12.5 
Analysis and Reporting  ............................................................................................49 
 
13. STATISTICAL CONSIDERATIONS .................................................................................49 
 
14. INCLUSION OF WOMEN AND MINORITIES ...............................................................52 
 
15. STUDY PERSONNEL...........................................................................................................52 
 
16. FUNDING ...............................................................................................................................54 
 
17. ADDITIONAL STUDY SITES .............................................................................................55 
 
REFERENCES .............................................................................................................................56 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ...............................................................................................64 
 
APPENDIX B 
Stopping Rules ...................................................................................................................65 
       
      APPENDIX C 
            % Skeleton for Radiotherapy .............................................................................................66 
 
      APPENDIX D 
           Department of Defense Language ......................................................................................67 
 
      APPENDIX E 
           Radiographic Guidelines .....................................................................................................70 
 
      APPENDIX F 
           Ketoconazole substitution (ex-U.S.) ...................................................................................71 
 
APPENDIX G 

ix 
 
           FACT-P ...............................................................................................................................72 
 
APPENDIX H 
           PIRADS v2  ............................................................................................................................ 
 
    

1 
 
1. OBJECTIVES 
 
1.1. 
Primary Objectives  
 
To compare the rate of progression to radiographically apparent metastatic disease at 18 
months with 177Lu -J591 plus ketoconazole versus trace-labeled 111In-J591 plus 
ketoconazole. 
 
1.2. 
Secondary Objectives 
 
 
To define the PSA response rate (50% reduction, with 30% reduction exploratory 
analysis). 
To define the duration of PSA response 
To define the toxicity of 177Lu-J591 given as single dose plus ketoconazole in men with 
castrate resistant biochemical disease. 
To assess the overall and prostate cancer specific survival rate of patients following 
treatment.  
To define the toxicity and need for dose modifications with “high dose” ketoconazole in 
men with biochemically progressive castrate resistant prostate cancer 
To assess the prognostic implications of baseline adrenal hormone levels in men with 
castrate resistant non-metastatic prostate cancer receiving ketoconazole 
To explore the ability of 177Lu-J591 to image metastatic sites in patients who are NED on 
bone scan CT/MRI of abdomen/pelvis and CXR (selected study sites) 
To assess the changes with therapy and implications of plasma markers of hemostasis, 
fibrinolysis, and angiogenesis in biochemically progressive castrate resistant prostate 
cancer (optional) 
To assess patient reported outcomes with high-risk, non-metastatic CRPC and with the 
development of metastases 
     1.3 
Exploratory Objectives 
To assess the prognostic implications of baseline circulating tumor cell (CTC) counts in 
men with castrate resistant non-metastatic prostate cancer receiving ketoconazole and to 
explore the implications of serial changes in CTC counts 
To explore the prognostic and predictive implications of PSMA expression in circulating 
tumor cells 
To explore the prognostic and predictive implications of PSMA expression in archival 
surgical or biopsy material in subjects being treated with anti-PSMA RIT 

2 
 
To describe reasons for lack of participation in study treatment (i.e. reasons for pre-
screen and screen failures) 
 
2. BACKGROUND 
 
2.1  
Disease 
 
Prostate cancer is the leading cause of noncutaneous cancer in men in the United States, 
accounting for 29% of all cancers with 218,890 estimated new cases in 2007 (1).  It is the second 
leading cause of cancer-related death, with 27,050 US men estimated to die from this disease in 
2007(1).  Clinically localized adenocarcinoma of the prostate is treated primarily with surgery or 
radiation therapy, with or without hormonal or chemotherapy, although another option for some 
men with newly diagnosed prostatic adenocarcinoma is active surveillance or observation, since 
some men will continue to be asymptomatic until death from another cause (2, 3).  Although 
therapy for localized disease may be successful at eradicating the disease, some patients suffer 
recurrence or present with advanced disease.  First line therapy for advanced adenocarcinoma of 
the prostate usually includes androgen deprivation with a mean duration of efficacy of 12-18 
months (4), although there is a wide variation in response in this heterogeneous disease. 
 
Unfortunately, after primary therapy with surgery or radiotherapy, some men suffer relapsed 
disease.  In the current PSA era, the majority of these relapses are initially “biochemical” only, 
i.e. with a rising PSA despite no evidence of cancer on scans (5, 6), affecting approximately 
50,000 or more men per year in the U.S. alone.  Some of these men may be “salvaged” with 
appropriate therapy for local relapse (radiation for those that had surgery first, and surgery or 
cryotherapy for those with locally relapsed disease after radiotherapy) (6).  Although there is no 
proven overall survival benefit in a prospective randomized trial, radiotherapy as a salvage 
regimen after radical prostatectomy can lead to long-term survival in selected individuals (7-10). 
 However, most patients who receive local or regional radiotherapy with the hopes of cure after 
biochemical relapse following surgery subsequently suffer systemic progression.  We have 
demonstrated J591-based therapy’s ability to successfully target known sites of disease and have 
positive signals of 177Lu-J591’s efficacy in the advanced setting (see below).  Since forms of 
radiotherapy have been validated in the clinically localized as well as salvage setting, “targeted 
radiotherapy” in the form of radioimmunotherapy is at least theoretically an attractive option 
with the possibility of even greater efficacy in the minimal disease (biochemical only) setting.  
The most studied form of radioimmunotherapy to date uses targeting of the CD20 antigen (I131 
tositumomab and Y90 ibritumomab tiuxetan) in non-Hodgkin’s lymphoma.  While approved in 
the relapsed setting, it appears that these therapies have their greatest impact in the minimal 
disease setting (11-16).  In addition, the decay characteristics of 177Lu with its relatively short 
range beta emission is preferably suited for small volume, rather than bulky, disease sites. 
 
Prostate specific membrane antigen 
Prostate specific membrane antigen (PSMA) is the single, most well-established, highly 
restricted prostate epithelial cell membrane antigen known (17-22).  The PSMA gene has been 
cloned, sequenced, and mapped to chromosome 11p (18, 23). Although first thought to be 
entirely prostate-specific (17-19), subsequent studies demonstrated that PSMA is also expressed 
by cells of the small intestine, proximal renal tubules and salivary glands (21).  However, the 
level of expression in these non-prostate tissues is 100-1000-fold less than in prostate tissue (22), 

3 
 
and the site of PSMA expression in these normal cells (brush border/luminal location) are not 
typically exposed to circulating Ab.  In contrast to other well known prostate-restricted 
molecules such as PSA and prostatic acid phosphatase (PAP) that are secretory proteins, PSMA 
is a type II integral cell-surface membrane protein that is not secreted, thereby making PSMA an 
ideal target for mAb therapy.  Pathology studies indicate that PSMA is expressed by virtually all 
prostate cancers (23). Moreover, PSMA expression increases progressively in higher grade 
cancers, metastatic disease and hormone-refractory prostate cancer (19, 20, 24, 25). 
 
PSMA has been found to have folate hydrolase and neurocarboxypeptidase activity (26). 
Although its role in PC biology is unknown, the consistent finding of PSMA upregulation 
correlating with increased aggressiveness of the cancer implies that PSMA has a functional role 
in PC progression.  Inhibition of enzymatic activity in vitro or in xenograft models has not 
demonstrated significant growth inhibitory effect (27). Nevertheless, the expression pattern of 
PSMA makes it an excellent target for mAb based targeted therapy of prostate cancer. 
 
PSMA as a target in prostate cancer 
Use of capromab penditide (Prostascint ®) has validated PSMA as an in vivo target for 
imaging (28, 29), although clinical treatment studies with capromab have been disappointing (30, 
31).  Molecular mapping revealed that capromab targets a portion of the PSMA molecule that is 
within the cell’s interior and not exposed on the outer cell surface (32-34) and cannot bind to viable 
cells (17, 34).  Recognition of these features led Neil Bander at WCMC and others to propose that 
mAbs to the exposed, extracellular domain of PSMA had the potential to significantly improve in 
vivo targeting likely resulting in enhanced imaging and therapeutic benefit (34, 35).  These 
antibodies (J591, J415, J533 and E99) demonstrate high affinity binding to viable PSMA-expressing 
LNCaP cells in tissue culture and are rapidly internalized (34, 36).   
 
Pre-clinical experience with J591 
Murine monoclonal Ab J591 (muJ591) was chosen for clinical development and has been 
extensively studied in pre-clinical models (37-39).  The affinity of J591 is 1 nm which other studies 
have shown to be the optimal affinity in therapeutic models, lower affinity providing less binding 
and higher affinity interfering with antibody penetration into tumor masses (40). 
 
Immunohistochemistry studies with mAbs to PSMAext confirmed the highly restricted 
expression pattern of PSMA with binding to prostate epithelial cells and weak binding to the brush 
border of renal proximal tubular and small bowel epithelium. Unexpectedly, immunohistochemical 
studies of a variety of malignant tissues found that tumor vascular endothelium of all solid tumors, 
but not normal vascular endothelium, bound anti-PSMA antibodies (34).  This further raised the 
interest in anti-PSMA antibodies as a potential way to specifically target not just prostate cancer but 
all solid tumors using a vascular targeting approach. 
 
Animal studies utilized nude mice implanted subcutaneously with PSMA-expressing 
LNCaP cells.  After allowing the tumors to establish and reach a diameter of 7-10 mm, the 
animals were treated with J591 radiolabeled with different isotopes, including 131Iodine (131I-
J591), 177Lutetium (177Lu-J591) and 90Yttrium (90Y-J591).  These studies showed that 90Y and 
177Lu provide better dosimetry due to their longer intracellular half-lives and radioiodine’s 
relatively rapid clearance and that anti-tumor responses were seen with all radionuclides with an 
apparent dose response relationship.  Higher cumulative doses of either 90Y or 177Lu could be 

4 
 
delivered using fractionated dosing (multiple sub-MTD doses rather than a single MTD dose).  
Median survival of the animals improved by 300% for fractionated 90Y-J591 therapy (150 days 
vs. 52 days (control).  With fractionated dose 177Lu-J591, >80% of the mice were cured (39).  A 
major limitation of using a mouse mAb in patients is the development of a human anti-mouse 
antibody (HAMA) response that precludes repetitive dosing.  Therefore, mAb J591 was de-
immunized by using a next generation approach to humanization developed by Biovation, Ltd. 
(Aberdeen, UK) into a humanized form (huJ591). 
 
Clinical experience with J591 
Initial phase I studies using huJ591 trace-labeled with 111In using a DOTA chelate showed 
that repetitive dosing was well tolerated with total doses of up to 500 mg/m2 without the 
development of a human anti-humanized (de-immunized) antibody (HAHA) response (41, 42). No 
dose limiting toxicity occurred and the maximum tolerated dose was not reached. 
 
After the first dose, total body gamma camera images were obtained within one hour 
post-infusion (day 0) and on 3 more occasions in the following week.  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.  Per-cent injected dose in the liver diminished with increasing dose of antibody, and 
higher doses were associated with longer plasma clearance times (43-45).  
 
Choice of Radionuclide 
For targeted radionuclide therapy, monoclonal antibodies and peptides can be labeled efficiently 
with several radionuclides emitting beta particles (Table 1-1). The higher beta energy particles of 
90Y may be good for bulky tumors, but it may not be necessary or even sub-optimal, for small 
tumors and especially bone or bone marrow metastases. The relatively low energy beta particles 
of 131I are ideal, but in vivo dehalogenation of radioiodinated molecules is a major disadvantage 
for internalizing antibody and peptide molecules.  In contrast, 177Lu has low energy beta particle 
with only 0.2-0.3 mm range and delivers much lower radiation dose to bone marrow compared 
to 90Y. In addition, due to longer physical half-life (compared to 90Y), the tumor residence times 
are higher. As a result, higher activities (more mCi amounts) of 177Lu labeled agents can be 
administered with comparatively less radiation dose to marrow. 

5 
 
 
Table 1-1: Beta Emitting Radionuclides For Therapy 
 
 
 
 
 
 
 
131I 
 
90Y 
 
177Lu  
 
 
Physical half-life (days) 
 
 
8.05 
 
2.67 
 
6.7 
 
β- particles (MeV) 
Max 
 
 
0.61 
 
2.280  
0.497  
Average 
 
0.20 
 
0.935  
0.149  
 
 
        
  
Range in tissue (mm) Max 
 
 
2.4 
 
12.0 
 
2.20 
 
 
 
Average 
 
0.4 
 
  2.7 
 
0.25 
 
 
 
Gamma emission (MeV) 
 
0.364 (81%)  
None  
0.113 (7%) 
0.208 (11%) 
Equilibrium Dose Constant 
rad.g/hr.   for β- radiation  
 
 
0.389  
1.9886  
0.314 
gamma 
 
 
 
 
0.815          
No 
 
0.075 
________________________________________________________________________ 
 
 
Phase I Trials of Radiolabeled J591. 
Two independent phase I clinical trials have been performed at WCMC using 90Y or 
177Lu linked via a DOTA chelate to huJ591 in patients with hormone-refractory prostate cancer 
(46, 47).  Briefly, the primary objectives of these trials were to define the MTDs of the isotopes 
as well as to further define dosimetry, PK, 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 patients 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 (23), no determination of PSMA expression was done.  Patients were required to 
have an absolute neutrophil count (ANC) ≥ 2.0 x 109/L, platelet count ≥ 150 x 109/L.  Prior 
radiation therapy encompassing > 25% of the skeleton or prior treatment with 89Strontium or 
153Samarium were not permitted.  Other standard laboratory exclusion criteria applied as well 
(46, 47).  Dose limiting toxicity in the 2 trials was defined as:  Hematologic toxicity consisting of 
grade 4 thrombocytopenia (platelet < 10 x 109/L) and/or grade 4 neutropenia (ANC < 0.5 x 109) 
for greater than 5 days; and other toxicity consisting of grade ≥ 3 non-hematologic toxicity 
attributable to radiolabeled J591. 
 
90Y-J591 phase I trial:(46)  Twenty nine subjects initially received 5 mCi of 111In linked 
via a DOTA chelate to 20 mg of mAb J591 for pharmacokinetic and biodistribution 
determinations.  One week later, they received 90Y -DOTA-J591.  All patients received 20 mg of 
mAb J591 with the 90Y dose escalated in cohorts of 3 or more patients at the following planned 
dose levels: 5, 10, 15, and 20 mCi/m2.  A fifth dose level of 17.5 mCi/m2 was added to more 
precisely define the MTD. Toxicity was dose-related and limited to reversible myelosuppression, 
predominantly thrombocytopenia.  The 17.5 mCi/m2 dose level was determined to be the MTD.  

6 
 
Four eligible patients were re-treated with none experiencing irreversible myelosuppression (no 
DLTs).   J591 imaging of known sites of both bone and soft tissue metastases were seen in 90% 
of patients. Two patients at the 20 mCi/m2 dose level (MTD + 1 level) experienced 85% and 
70% declines in PSA lasting 8 and 8.6 months, respectively as well as objective measurable 
disease responses.  An additional 6 patients (21%) experienced PSA stabilization.  No HAHA 
response was detected. 
 
 
177Lu-J591 phase I trial:(47)  In the 177Lu trial, 35 subjects received a total of 10 mg/m2 of 
J591 with escalating doses of 177Lu ranging from 10 mCi/m2-75 mCi/m2.  Since 177Lu can be 
directly imaged and has a longer physical t1/2 than 111In, imaging took place during the 2 weeks 
following dosing.  Patients received 10 mg/m2 J591 with doses of 177Lu ranging from 10 
mCi/m2-75 mCi/m2.  Imaging demonstrated successful targeting of metastatic sites in 100% of 
the 30 patients with radiographic evidence of disease. The 70 mCi/m2 dose was defined as the 
single-dose MTD with grade 4 thrombocytopenia as the DLT.  Repeat dosing at 45 to 60 mCi/m2 
resulted in dose-limiting myelosuppression; up to 3 doses of 30 mCi/m2 could be safely 
administered.  PSA declines of ≥ 50% were seen in 4 patients lasting 3+ to 8 months.  An 
additional 16 subjects (46%) experienced PSA stabilization for a median of 60 days (1 – 21+ 
months).  No HAHA responses were detected.   
 
Cytotoxin conjugated J591.  
MLN2704 is a antibody-chemotherapy conjugate designed to target PSMA.  J591 is 
conjugated to maytansinoid 1 (DM1), which is a potent microtubule-depolymerizing compound. 
 Pre-clinical activity was demonstrated (48), leading to a phase I trial designed to explore single 
ascending doses of the conjugate to define DLT, MTD and PK (49).  Twenty three subjects with 
progressive castrate metastatic prostate cancer received MLN2704 at doses ranging from 18 – 
343 mg/m2 in an accelerated dose escalation scheme; 18 received at least 3 doses.  Grade > 3 
toxicities occurred in 2 subjects, including 1 episode of uncomplicated febrile neutropenia and 
transient grade 3 elevation of transaminases.  One subject (treated at 343 mg/m2) achieved a 
>50% decline in PSA, and another (treated at 264 343 mg/m2) experienced a PR by RECIST 
along with a >50% decline in PSA. 
 
A subsequent multicenter phase I/II study was initiated based upon the above results (50). 
 Sixty two subjects received multiple doses of MLN2704.  Because of neurotoxicity at every 1 or 
2 week doses, the study was amended to include every 3 week dosing and dosing on days 1 and 
15 of 42-day cycles.  Of the 4 schedules tested, PSA declines were most frequent at 330 mg/m2 
every 2 weeks (2/6 had PSA decrease >50%, 2/6 had PSA stabilization).  However, grade 2-3 
neuropathy was dose-limiting, and could not be predicted by prior taxane-based chemotherapy, 
diabetes, or prior neuropathy.  Although response was modest, and treatment was limited by 
toxicity, this trial demonstrated proof of principle that an immunoconjugate utilizing a PSMA 
antibody has therapeutic potential. 
 
Phase II trial of 177Lu-J591 in metastatic castrate resistant prostate cancer 
 
Based upon the phase I results described above (47), a phase II trial has completed 
enrollment.  In this investigator-initiated study, subjects with progressive metastatic CRPC 
received one dose of 177Lu -J591 in two-cohorts. Cohort 1 (65mCi/m2), 15 pts; Cohort 2: 
(70mCi/m2), 17 pts. The primary endpoint is PSA and/or measurable disease response; the 
secondary endpoint is toxicity. A 177Lu-J591 imaging study was done to confirm tumor targeting. 

7 
 
 All of the initially planned 32 pts (14 chemo-naïve) have been treated.  Preliminary analysis 
reveals the following (51): 
 
Median age is 71 (range 51 – 88), median baseline PSA 77.92 (range 3.31 – 2184.6).  
Three pts achieved PSA declines of >50%. Another more preliminary analysis has been 
performed based upon retrospective analyses in patients on prospective chemotherapy trials 
demonstrating that 30% declines in PSA are most associated with survival benefits (52, 53).  Of 
the 15 subjects receiving 65mCi/m2, 2 of 15 (13%) achieved a 30% PSA decline.  Of the 17 
subjects receiving 70mCi/m2, 7 (47%) experienced at least a 30% decrease in PSA. 
 
Platelet nadir <25 x 109/L occurred in 42% of pts, 9 of whom required 1 – 4 platelet 
transfusions (median = 2). 29/32 pts recovered normal platelet counts; the remaining 3 pts had 
rapidly progressive disease with bone marrow involvement. Neutropenia ≤ 0.5 x 109/L occurred 
in 27% of pts, 6 of whom received brief therapy with growth factors. All 32 pts had normal 
neutrophil recovery and no pt experienced neutropenic fever. No significant drug-related non-
hematologic toxicity has occurred. Excellent targeting of known sites of PC metastases has been 
observed in 31/32 (97%) of pts.  
 
In summary, single dose 177Lu-J591 demonstrates anti-tumor activity in pts with 
progressive CRPC with reversible myelosuppression.  32 of the initially planned 32 subjects 
have been treated to date and follow up is ongoing.  Because of an FDA mandate, treatment was 
begun at a lower dose than the phase I MTD.  Since there appears to be a dose response 
relationship (13 vs 47% with >30% PSA decline, 46 vs 71% with any PSA decline), an 
expansion protocol at the MTD is planned to tighten the confidence intervals for response at the 
MTD.  Based upon acceptable toxicity in both groups and signals for increased efficacy at the 
higher dose (the MTD based upon the phase I trial), we are proceeding with the current trial. 
 
2.2  
Investigational Agent 
 
2.2.1 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 
(Biovation , Aberdeen , Scotland, UK) 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.28 This results in a potentially non-immunogenic antibody, which might be 
administered to patients on multiple occasions over long periods without inducing an 
immune response (see Clinical Experience). 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 (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. 

8 
 
 
2.2.2 DOTA-J591 
In order to radiolabel J591 with β- 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. 
 
2.2.3 Radiolabeled J591 
The DOTA-J591 antibody molecule is labeled with radiometal 177Lu or 111In 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 β- 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. 
Refer to the Investigator Brochure for further details. 
 

9 
 
 
2.2.4 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 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 (T1/2β) 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 1-2) demonstrate that there is no 
difference between 177Lu and 111In labeled J591 antibody.  
 
 
Table 1-2: 
177Lu-J591 Vs. 111In-hJ591:  Plasma Clearance Kinetics 
 
 
Pts. 
mg/m2 T½ α (hr) 
T½ β (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. 
 

10 
 
2.2.5 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 1-3):  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 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 1-4).  
Table 1-3: 
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 
 

11 
 
Table 1-4: 
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 
 
2.2.6 Radiation Dosimetry 
Based on imaging studies and plasma clearance with 177Lu-J591, the residence times (τ) 
of radioactivity in various source organs (as shown in Table 1-4) were calculated.  Using 
“S” factors from MIRD tables, radiation dosimetry (cGy/mCi) for 177Lu-J591 was 
estimated (Table 1-5).  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 (54).  Radiation dose of 
9.0 Gy to the bone marrow is generally regarded as an “organ injury dose” and the 
tolerable absorbed doses were usually estimated to be 65% of LD50 (50%) organ injury 
dose. Therefore, the tolerable absorbed dose for bone marrow is about 3.0 Gy (330 rads). 
The maximum tolerable radiation doses to kidneys, liver and spleen are approximately 
20-25 Gy (2000-2500 rads).  Dosimetric studies using radiolabeled antibodies have been 
effectively used by many investigators to determine patient-specific radiation dosimetry 
of radiolabeled antibody treatment (55, 56).  Based on the dosimetry data shown in Table 
1-5, the maximum bone marrow dose following administration of 70mCi/m2 of 177Lu-
J591 would deliver 164 rads to an average person with a BSA of 2.0 m2. The maximum 
dose the liver would be about 1100 rads, well below the maximum tolerable liver dose.  

12 
 
Table 1-5: 
Radiation Dosimetry (rads/mCi) of 177Lu-J591 in Patients with Prostate 
Cancer 
Organ 
  
Mean 
  
S.D. 
Adrenals 
 
0.52 
± 
0.08 
Brain 
 
0.40 
± 
0.07 
Gall Bladder 
 
0.55 
± 
0.08 
LLI Wall 
 
0.42 
± 
0.07 
Small Intestine 
 
0.43 
± 
0.07 
Stomach 
 
0.45 
± 
0.07 
ULI Wall 
 
0.44 
± 
0.07 
Heart Wall 
 
3.50 
± 
0.70 
Kidneys 
 
5.20 
± 
1.29 
Liver 
  
7.77 
± 
2.23 
Lungs 
 
2.79 
± 
0.80 
Muscle 
 
0.42 
± 
0.07 
Pancreas 
 
0.52 
± 
0.08 
Red Marrow 
  
1.17 
± 
0.37 
Bone Surfaces 
 
0.70 
± 
0.14 
Skin 
 
0.42 
± 
0.07 
Spleen 
 
7.28 
± 
3.41 
Testes 
 
0.36 
± 
0.13 
Thymus 
 
0.44 
± 
0.07 
Thyroid 
 
0.41 
± 
0.07 
Urin. Bladder Wall 
 
0.97 
± 
0.22 
  
 
 
 
  
Total Body 
 
0.71 
± 
0.10 
Effective Dose Equiv.  
2.14 
± 
0.35 
Effective Dose 
  
1.33 
± 
0.19 
 
 

13 
 
 
2.3  
Rationale 
 
As stated above, we have validated that J591 can target known sites of disease and have 
preliminary evidence that there is anti-tumor effect of radiolabeled J591.  Since forms of 
radiotherapy have been validated in the clinically localized as well as salvage setting, 
“targeted radiotherapy” in the form of radioimmunotherapy is at least theoretically an 
attractive option with the possibility being a higher yield therapy in the minimal disease 
(biochemical only) setting [see information on anti-CD20 based radioimmunotherapy 
above].   
 
The objective of this study is to determine the efficacy of the addition of 177Lu -J591 to 
ketoconazole in men with progressive biochemical (PSA) prostate cancer despite medical 
or surgical castration.  All subjects will receive ketoconazole (400 mg p.o. TID) plus 
replacement doses of hydrocortisone (20 mg am, 10 mg pm).  Subjects will be 
randomized to receive a single dose of 70 mCi/m2 177Lu -J591 or trace-labeled 111In-J591 
(i.e. placebo).  Subjects will be followed for response, disease progression, safety and 
toxicity.  The treatment phase will last until progression of disease or toxicity 
necessitating discontinuation of therapy.  Subjects will be followed until the primary 
endpoint, which is the development of radiographically apparent metastatic disease.  
 
2.4 
Correlative Studies Background 
 
2.4.1 
Adrenal androgen levels 
 
Although androgen deprivation therapy with LHRH agonists are successful in 
suppressing testosterone levels in the majority of cases, adrenal androgen levels are not 
typically suppressed by significant amounts (57).  In addition, some evidence exists that 
targeting adrenal androgens may play a role in the management of prostate cancer (58, 
59), leading to the common use of ketoconazole for this purpose.  CALGB 9583 was a 
randomized trial of antiandrogen withdrawal with or without ketoconazole (60).  As part 
of the correlative sciences portion of this trial (secondary endpoint), adrenal androgen 
level were prospectively collected.  Baseline adrenal androgen levels in men with 
metastatic castrate resistant prostate cancer were associated with PSA response and 
overall survival (61).  Based upon these data, we plan to prospective assess and validate 
these results in men with biochemically progressive castrate resistant prostate cancer.  As 
published we will compare the median baseline androgen levels in those with a PSA 
response vs those without.  In addition, we will categorically analyze subsets of baseline 
adrenal androgen levels and correlate them with time to development of radiographically 
apparent metastatic disease and overall survival.  As the published analysis did not 
prospectively identify categorical values for analysis (median levels were used), we will 
also use prospective determined levels based upon the published studies and categorize 
subsets for analysis. 
 

14 
 
2.4.2 
Plasma markers of hemostatic activation, fibrinolysis, and angiogenesis 
 
Trousseau first published the link between malignancy and thrombosis in 1865 (62).  
Since then, various physicians and scientists have studied this association in terms of 
thrombotic mechanisms, determinants of cancer prognosis, and treatment outcomes.  
Data from the MEGA study, a large population-based, case-control study, revealed that 
cancer increases the risk of venous thromboembolism 7-fold overall, with a higher risk 
near the time of diagnosis and with advanced rather than localized disease (63).  The 
presence of a malignancy also increases the risk for recurrent venous thromboembolism 
(64, 65).  In addition, both the Levitan study (64) and data from the Danish registries (66) 
found that thrombosis in the cancer patient predicts for worse prognosis and a shorter 
survival.   
 
Even in the absence of clinical thromboembolic disease, abnormalities in coagulation 
tests in patients with malignancy are common.  Elevation of coagulation factor levels, 
fibrin degradation products, and platelet counts are common (67).  Other more specific 
parameters demonstrative of activation of hemostasis, including thrombin-antithrombin 
(TAT) complexes, fibrinopeptide A, D-dimers and prothrombin fragment F1+2, are also 
elevated. The hemostatic activation observed in many cancer patients may be the result of 
direct activation by the malignant cell or an indirect effect mediated through activated 
endothelium or monocytes (68, 69).  
 
The link between early activation of hemostasis and cancer prognosis has also been 
demonstrated in clinical studies. D-dimers are a marker of fibrin formation and 
degradation by both thrombin and plasmin. The levels of D-dimers are elevated in a 
variety of clinical situations associated with increased thrombin generation such as 
disseminated intravascular coagulation and thromboembolic events.  Clinical studies have 
shown that D-dimer levels are significantly elevated in many patients with both 
disseminated and limited malignancies without evidence of clinical thromboembolism 
(67).  Quantitative measurements of D-dimers, using sensitive immunoassays, have been 
reported to have prognostic significance.  The plasma level of D-dimers predicts survival 
in patients with both limited and disseminated lung cancer (70-72).  Similarly, in women 
with breast cancer, levels of D-dimers have correlated with malignant versus benign 
breast lesions (73), the presence of lymph node metastases on surgical pathology (73), 
and with volume of disease, time to progression, and overall survival in metastatic 
disease (74).  Quantitative D-dimer levels also correlate with levels of IL-6 and VEGF 
(74).  In patients with colorectal cancer, pre-operative levels of D-dimer have been 
correlated with stage of disease, tumor size and or depth of invasion, lymph node 
metastases, and distant metastases (75).  Levels of D-dimers have also correlated with 
FIGO stage in women with ovarian cancer (76). Pre-operative levels of plasma TAT 
complexes, an assay more reflective of immediate thrombin generation, have been 
correlated with risk of venous thrombosis in patients with cancer undergoing surgery 
(77).  Plasma TAT levels have also been shown to correlate with response to therapy and 
prognosis in patients treated for lung cancer (78).  In addition, there is evidence that 
inhibitors of coagulation may decrease tumor growth, limit metastases, and improve 
survival in cancer models (79-82). 

15 
 
Like many other cancers (as discussed above), prostate cancer is linked to thrombosis. 
 In a review of patients with thrombosis with or without cancer using Medicare claims 
data, prostate cancer was the third most common type of malignancy to be associated 
with a thrombosis (64).  Activation of both the coagulation and fibrinolytic systems has 
been demonstrated in prostate cancer (83).  Clinically, men with carcinoma of the 
prostate are at increased risk of thromboembolic disease, but may also have increased risk 
of bleeding (84).  The interaction of tumor cells with the coagulation and fibrinolytic 
systems is likely be important in tumor growth and spread.  Markers of activation of 
coagulation, including D-dimers, TAT, and prothrombin fragment F1+2, are elevated in 
men with advanced prostate cancer compared to age-matched controls (85).  TF 
expression (using immunohistochemistry) has also been correlated with angiogenesis and 
PSA level (86).  In metastatic disease, immunohistochemical assessment of biopsy 
specimens for TF correlated with prognosis with androgen deprivation therapy (87).  
Preoperative levels of IL-6 and its receptor are associated with recurrence and 
progression in localized prostate cancer (88, 89).  Increased VEGF expression correlates 
with Gleason score and pathologic stage in localized prostate cancer (90).  However, in 
prostate cancer as in other cancers, it is unclear if expression of angiogenic markers in 
tumor tissue or neighboring normal tissue or stroma is more important prognostically (91-
93). 
 
On our own preliminary data set, we have shown that subclinical hemostatic 
activation is common in men with untreated clinically localized prostate cancer and 
correlates with objective measures of surgical blood loss with prostatectomy (94). We 
have confirmed others’ observations that trends of several markers increase with age 
(fibrinogen, p=0.005; TAT, p=0.088; D-dimer, p<0.001; IL-6, p<0.001; IL-8, p=0.059) 
(95).  We also noted trends for correlations amongst several markers (TAT and D-dimer, 
p<0.001; TAT and IL-6, p=0.009; D-dimer and IL-6, p<0.001, fibrinogen and D-dimer, 
p<0.001; fibrinogen and IL-6, p<0.001; fibrinogen and IL-8, p=0.076) (95).  In addition, 
we found a correlation between pre-operative IL-6 levels and pre-operative PSA and a 
validated post-operative prognostic nomogram-derived score (p=0.038) which predicts 
prostate cancer recurrence at 10 years after radical prostatectomy using pre- and post-
operative variables (96)(95).  Preliminary data from a pilot study in men with advanced, 
untreated prostate cancer examining the effect of androgen deprivation on markers of 
hemostatic activation, fibrinolysis, and angiogenesis, data from the first 3 subjects reveals 
that levels of markers decrease significantly after only one month of therapy (mean 
decreases in TAT by 60.9%, IL-8 by 24.9%, IL-6 by 60.5%, and D-dimers by 72.1%).  In 
addition, the reverse has been observed anecdotally in one pt with markers drawn pre-
operatively and again upon recurrence (increase in TAT by 316%, IL-8 by 259%, IL-6 by 
307%, and D-dimer by 2226%).  Our hypothesis is that further hormonal therapy with 
ketoconazole will affect these markers as well.  We will assess baseline values and 
compare values at 1 month and 6 months after therapy.  In addition to assessing changes 
with therapy, we will perform exploratory analyses examining the use of baseline values 
as well as percent change in predicting response to ketoconazole. 

16 
 
 
2.4.3 
Circulating tumor cells (CTCs) 
 
Assays to detect CTCs in the peripheral blood of cancer patients have been used clinically to 
provide prognostic information and to test for minimal residual disease. Typical methods to 
detect these CTCs are either antibody-based (immunocytochemistry or flow cytometry) or 
RT-PCR; each has its specific advantages and limitations. For example, RT-PCR can be very 
sensitive and highly specific when the expression of the target mRNA is limited to malignant 
tumor cells. Flow cytometry, on the other hand, has been used to detect and authenticate cells 
as CTCs, but it does not allow visual confirmation of cell morphology or discrimination of 
changes at the subcellular level (97). The challenges in CTC detection relate to the need for 
high sensitivity combined with high specificity. Important progress in this field has recently 
arisen with the development of a semi automated enrichment system, the CellSearch 
(Veridex LLC, Warren, NJ) that uses an antibody-based immunomagnetic-capture and 
automated staining methodology (98). The immunomagnetic capture is achieved with the use 
of a ferrofluid-coated antibody specific for the epithelial cell adhesion molecule EpCAM 
(99), a 40 KD, transmembrane glycoprotein that consists of two epidermal growth factor-like 
extracellular domains. EpCAM, encoded by the GA733-2 gene located on the long arm of 
chromosome 4 (100), has been described under various names, mostly associated with 
monoclonal antibodies specific for cell surface antigen (MH99, AUA1, MOC31, 323/A3, 
KS1/4, GA733, and HEA125 (used in this assay). Litvinov et al. first suggested the name 
EpCAM, which more precisely reflects the molecule’s function and tissue specificity. 
EpCAM is detected at the basolateral membrane of the majority of epithelial tissues, and is 
overexpressed by the majority of human epithelial carcinomas, including colorectal, breast, 
prostate, and head and neck carcinomas (101). Thus, use of antibodies to EpCAM allows for 
circulating epithelial-derived tumor cells to be isolated and concentrated from peripheral 
blood so they can be further inspected by microscopy. However, as EpCAM, can also be 
expressed in leucocytes, the specificity of this antibody-based assay to detect CTCs is 
lowered to 80%. To increase the specificity of detection for epithelial tumor-derived cells, 
CellSearch technology uses three additional immunostains: an antibody against CD45 
conjugated with allophycocyanin to identify white blood cells (WBC), the nuclear dye [4,6-
diamidino-2-phenylindole (DAPI)] to fluorescently label the cells’ nuclei, and two 
phycoerythrin-conjugated 
anti-cytokeratin 
antibodies 
recognizing 
cytokeratins 
(predominantly cytokeratins 8, 18, and 19) to more specifically identify epithelial cells as 
such. Stained cells are analyzed on a fluorescence microscope using the Cell Track Analyzer 
II. Automatically selected images are then reviewed by the operator for the identification and 
counting of CTCs. The criteria for an object to be defined as a CTC include: round-to oval 
morphology, a visible nucleus (DAPI staining), positive staining for cytokeratins, and being 
negative for CD45. In addition, the consensus pathognomonic features of epithelial tumor 
cells, such as a clearly enlarged nucleus, high nucleus/cytoplasmic ratio and/or clusters of 
two or more immunopositive cells are also part of the CTC definition criteria, further 
attesting to the epithelial-tumor specificity developed in the CellSearch method (for review 
see (102)). The accuracy, sensitivity and linearity of CTC detection by this method has been 
previously established (98). 
 

17 
 
PSMA staining in CTCs isolated from the blood of a CRPC patient. The EpCAM-enriched 
cells were isolated from the blood of CRPC patients and were further immunostained for PSMA 
(J591) and DAPI. Left Panel: Phase image of the ferrobead captured cells, showing the ferrobead 
loacation and the overall cell integrity. Middle Panel: PSMA immunostaining shows a distinct cell-
membrane localization. Right Panel: Merged image of PSMA and DAPI staining. The diameter of 
the depicted cells is approximately 15 um.  
Clinical studies of CTCs in humans with cancer: Using this system, Cristofanilli et al. 
show in a prospective study, that CTC detection provides significant prognostic information 
for patients with metastatic breast cancer (103). In this pivotal study, the detection of >5 
CTCs per 7.5 mL of blood at the start of chemotherapy and after each cycle of therapy was 
associated with shorter progression-free and overall survival for patients with metastatic 
breast cancer. Another related study in metastatic breast cancer revealed that CTC counts are 
more predictive of outcomes than the standard clinical parameters (104). The CellSearch 
system and reagents have now been Food and Drug Administration–cleared for routine 
clinical use in metastatic breast, colorectal, and prostate cancer. Recent studies using this 
technology in prostate cancer also show that a count of >5 CTCs per 7.5 mL of blood is 
associated with poor overall survival, in this case in patients with metastatic PC (105, 106). 
Furthermore, in a subset of CRPC patients, the presence of CTCs was shown to be the most 
significant parameter predictive of survival in both univariate and multivariate analyses 
(105).  These single institution findings have been confirmed with a multi-centered study 
(Moreno et al., American Society of Clinical Oncology 2007Annual Meeting), leading to an 
application for FDA approval in prostate cancer.  Finally, it has been demonstrated that 
CTC’s isolated using this technology can be analyzed with immunohistochemistry, 
immunofluorescence, and  FISH analysis, which has confirmed the neoplastic nature of these 
cells and demonstrated amplification of the androgen receptor (107). For these reasons, we 
believe this technology is the most advanced, sensitive, and appropriate for our CTC study.  
We will perform cell counting on 7.5 mL samples at baseline, 1 month (pre-J591 for that 
arm), 2 months, and at 6 months.  We will analyze baseline levels (< 5 CTCs/7.5 mL blood 
vs >5) as well as changes with treatment for associations with PSA response and time to 
development of radiographically evident metastatic disease. 
 
WCMC studies using CTCs in prostate cancer:  We have been using the CellSearch system 
to count CTCs.  However, using this methodology the enumerated CTCs cannot be retrieved 
for any further molecular analysis. Thus, we have collected an additional sample of blood 
which is subjected to automated immunomagnetic selection using the CellSearch profile kit 
allowing us to selectively collect the EpCAM-positive cells without any additional staining. 
Following isolation, isolated tumor cells may be assessed using a variety of methods.  Since 
PSMA expression is universal, there has not been any selection of patients treated on any of 
our clinical trials utilizing J591.  We will explore the utility of assessment of PSMA 
expression by immunohistochemistry (scored in quantitiative fashion) of pre-treatment CTCs 
with relationship to response to Lu-J591. 
 
 
 
 
 
 
 
 
 

18 
 
2.4.4 
Patient Reported Outcomes 
Quality of life has not been well-described in men with non-radiographically evident 
CRPC.  In addition, while the appearance of radiographically-evident metastatic 
disease is generally agreed to be a negative prognostic event, studies assessing the 
initial appearance of metastases have only sub-optimally examined patient 
symptoms. 
The Functional Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire is 
a validated tool to assess both global and prostate cancer specific symptoms and 
quality of life.  The FACT-P (version 4) questionnaire will be completed by subjects 
at baseline and at each radiographic assessment timepoint (prior to results). 
 
3. PATIENT SELECTION 
 
3.1  
Inclusion Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed adenocarcinoma 
of the prostate. 
 
3.1.2 Biochemical progression (rising PSA) after medical or surgical castration 
o Subjects who have received antiandrogens (such as bicalutamide) and 
have experienced PSA decline must have biochemically (PSA) progressed 
following discontinuation of anti-androgen therapy.  
o PSA:  An increase in PSA determined by two separate measurements taken 
at least one week apart and confirmed by a third, and if necessary, a fourth 
measurement.  If the third measurement is not greater than the second 
measurement, then a fourth measurement must be taken; the fourth 
measurement must be greater than the second measurement for the patient to 
be eligible for enrollment in the study.  Furthermore, the confirmatory PSA 
measurement (i.e., the third or, if applicable, fourth PSA measurement) must 
be ≥ 1 ng/mL with prior prostatectomy or > 2 ng/mL without prostatectomy 
and ≥ 25% above the previous nadir. 
 
3.1.3 High risk of systemic progression defined as: 
 
o Rising PSA as defined above and either: 
o Absolute PSA > 20 ng/mL 
      AND/OR 
o PSA DT < 8 months 
PSA doubling time (PSA-DT) will be calculated using a linear regression 
model. In the model, the logarithm of PSA will be modeled as a linear 
function of time. The PSA-DT will be calculated as the product of log 2 
multiplied by the reciprocal of the slope of the regression equation, for 
which the logarithm is the natural log function. For standardization 
purposes across sites, a web-based PSA doubling time calculator 
developed by Memorial Sloan Kettering, is available at 
http://www.mskcc.org/mskcc/html/10088.cfm 

19 
 
The minimum PSA value for eligibility will be greater than or equal to 1 
with prior prostatectomy or at least 2 ng/mL without prostatectomy. All 
PSA values of at least 0.1 ng/mL over the past 6 months must go into the 
equation.  A minimum of 3 PSA values with a minimum of 2 weeks 
between assessments is required (the screening PSA may be used for the 
3rd value if necessary). 
 
3.1.4 No evidence of local recurrence or distant metastases within 1 month of 
enrollment (or following enrollment as part of screening) including: 
 Radionuclide bone scan without evidence of metastatic disease 
• In the event of an equivocal bone scan, confirmation is needed 
with Xray, CT scan, or MRI 
 CT or MRI of abdomen/pelvis without evidence of metastatic disease or 
recurrent disease in the prostate or prostate bed 
 If no prior prostatectomy or radiation to the prostate, multiparametric MRI 
(mpMRI) of the prostate must have been performed and scored with 
PIRADS v2. The PIRADS score must be <3. (Appendix H: Summary of 
PIRADS V2 Scoring). mpMRI must be performed within 30 days prior to 
randomization. 
 Chest Xray or CT of chest without evidence of metastatic disease 
 Digital rectal exam (DRE) without clinical suspicion of 
recurrent/persistent prostate cancer 
 
3.1.5 Age >18 years. 
 
3.1.6  Serum testosterone < 50 ng/ml 
  
3.1.7 The effects of J591 on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason, patients capable of fathering 
children must agree to use an effective method of contraception for the 
duration of the trial. 
 
3.1.8 Subjects on bisphosphonate therapy or denosumab must be on a stable dose and 
must have started therapy > 4 weeks prior to protocol therapy.  Initiation of 
bisphosphonate therapy or denosumab is not allowed during the treatment 
phase. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria  
 

20 
 
3.2.1 
Use of red blood cell or platelet transfusions within 4 weeks of treatment 
 
3.2.2 
Use of hematopoietic growth factors within 4 weeks of treatment 
 
3.2.3 
Prior cytotoxic chemotherapy and/or radiation therapy within 4 weeks of 
treatment 
 
3.2.4 
Prior radiation therapy encompassing >25% of skeleton (see Appendix C) 
 
3.2.5 
Prior treatment with 89Strontium or 153Samarium containing compounds (e.g. 
Metastron®, Quadramet®) 
 
3.2.6 
Platelet count <150,000/mm3 or known primary qualitative platelet disorder 
 
3.2.7 
Absolute neutrophil count (ANC) <2,000/mm3  
 
3.2.8 
Hematocrit <30 percent and Hemoglobin < 10 g/dL 
 
3.2.9 
Abnormal coagulation profile (PT or INR, PTT > 1.3x ULN) unless on 
therapeutic anticoagulation – see concomitant meds section 
 
3.2.10 Serum creatinine >2.5 mg/dL 
 
3.2.11 AST (SGOT) >2x ULN 
 
3.2.12 Bilirubin (total) >1.5x ULN; subjects with Gilbert’s syndrome will be allowed 
if direct bilirubin is within institutional normal limits 
 
3.2.13 Active serious infection  
 
3.2.14 Active angina pectoris or NY Heart Association Class III-IV 
 
3.2.15 ECOG Performance Status  > 2 
 
3.2.16 Life expectancy <12 months 
 
3.2.17 History of deep vein thrombosis and/or pulmonary embolus within 1 month of 
study entry 
 
3.2.18 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 
 
3.2.19 Prior investigational therapy (medications or devices) within 4 weeks of 
treatment. Furthermore, other investigational therapy is not permitted during 
the treatment phase. 

21 
 
 
3.2.20 Prior use of ketoconazole for the purposes of prostate cancer therapy for 
greater than 1 month 
 
3.2.21 Known history of HIV.   
 
 
The effects of J591 are unknown in this population.  Furthermore, 
ketoconazole has many well-described drug-drug interactions which could 
affect antiviral therapy.  If necessary, this population will be studied 
separately. 
 
3.2.22  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. 
 Known history of known myelodysplastic syndrome 
  
 
 
3.2.23 Adrenal hormone inhibitors (other than ketoconazole) within 4 weeks prior to 
study enrollment. 
 
  
 
 
3.2.24  Finasteride (Propecia® or Proscar®) or dutasteride (Avodart®) within 4 
weeks of enrollment. 
 
  
 
 
3.2.25   Patients on corticosteroids prior to enrollment must have either discontinued 
and shown biochemical progression or have biochemical progression on a 
stable dose 
 
4. ENROLLMENT AND REGISTRATION PROCEDURES 
 
4.1   Enrollment Procedures 
 
 
4.1.1  Identification of subjects 
Potential subjects will be recruited from the oncology, urology, and radiation 
oncology practices of participating institutions and affiliates.  Public advertisements 
will be allowed if approved by WCMC and the local IRB.  Pre-screening of potential 
subjects may be performed by investigators or delegates under their direct 
supervision.  Investigational sites may elect to obtain waiver of HIPAA for pre-
screening purposes. 
 
4.1.2  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 therapy off-trial.  Potential subjects will also have the 

22 
 
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.   
 
Documentation of the consent process and that written consent was conducted must 
be documented in the subject’s medical record. 
 
4.2   Central Patient Registration 
 
Patients will be centrally registered with the Weill Cornell Medical College (WCMC), Division 
of Hematology and Medical Oncology Clinical Research Office.  To register a patient, upload 
the following documents into a pdf file(s) and email to guonc@med.cornell.edu (note that this 
email address will not accept emails larger than 4.5 MB in size, so large size files may need to be 
split).  If scan/email is not readily available, fax to the Clinical Research Office at 646-962-1611. 
Fax should be followed by phone call or email to ensure receipt. 
 
● 
WCMC Patient Enrollment Form 
• 
First and last page of the fully executed informed consent form, plus 
additional pages if checkboxes for correlative studies are required. 
• 
Fully executed HIPAA research authorization form (if separate from the 
consent document) 
• 
Eligibility checklist signed and dated by investigator and research nurse 
• 
Source documents verifying eligibility including 
i. 
Pathology report confirming diagnosis 
ii. 
Laboratory reports confirming PSA progression 
iii. 
Radiology reports, bone scan, CT/MRI scan of abdomen/pelvis and 
Chest x-ray or CT scan 
iv. 
Laboratory reports confirming all required eligibility criteria have been 
met 
v. 
On-study visit note documenting PS and consenting process 
• 
Documentation of any eligibility waivers granted  
 
Central registration information is reviewed and entered into the HemOnc centralized research 
database. These documents should be emailed (or faxed if email is not feasible) Monday to 
Friday from 9:00 AM to 4:45 PM EST.  Patients will be assigned a sequence number for the 
protocol.  The registering institution will then be faxed a copy of the sequence number as 
confirmation of a completed registration.   
 
Registration of patients cannot occur until the Coordinating Center has received proper 
documentation from the registering institution of IRB approval, including a copy of the current 
approval letter, stamped consent and signed FDA-1572 form.  These documents may be emailed 
to guonc@med.cornell.edu or faxed to the Coordinating Center at 646-962-1611.  
 
 
5. TREATMENT PLAN 

23 
 
 
5.1  
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications for   
ketoconazole and hydrocortisone are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. 
 
 
 
5.1.1 
Ketoconazole (all subjects) 
Ketoconazole (Nizoral) will be prescribed at a dose of 400 mg (two 200 mg tabs) to be 
taken orally (preferably on an empty stomach) three times per day (total daily dose of 
1200 mg).  For subjects on chronic gastric acid suppressive therapy (chronic 
administration of proton pump inhibitors or H2 blockers), ketoconazole should be taken 
with cola or orange juice.  The cost of the drug will be billed to the subject’s insurance 
company. 
 
 
 
5.1.2 
Hydrocortisone (all subjects) 
Hydrocortisone (Cortef) will be prescribed at a dose of 20 mg orally each morning, 10 
mg orally each evening (total daily dose of 30 mg).  The cost of the drug will be billed to 
the subject’s insurance company. 
 
5.1.3  Radiolabeled J591 
Eligible patients will receive a single dose of 177Lu-J591 (70 mCi/m2) or 111In-J591 (5 
mCi) on a Thursday or Friday approximately 4 weeks after cycle 1, day 1 consisting of 
J591 chelated at a specific activity of 12-15 mCi of 177Lu per mg of antibody plus 
sufficient non-radiolabeled, non-DOTA-conjugated (“naked”) J591 to achieve a total 
antibody dose of 20 mg.  Each dose will be administered by an IV infusion at a rate not to 
exceed 5 mg/min. 
 
5.1.3.1 Radiolabeled-J591 pre-medications 
It is suggested that subjects receive pre-medications prior to J591 infusion with 
diphenhydramine 25 – 50 mg p.o. or IV and acetaminophen 325 – 650 mg p.o. 
 
5.1.3.2  Monitoring post- radiolabeled-J591 infusion 
During and after infusion, patients will be monitored for possible allergic reaction.  
Allergic events will be managed as follows: rash, pruritis, 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.  Patients will be 
treated in a facility that is equipped for cardiopulmonary resuscitation.  Infusion-
related reactions (fever, rigors) will be treated with acetaminophen, meperidine and 
diphenhydramine hydrochloride as clinically appropriate. 
 
5.1.3.3  Vital signs pre/post radiolabeled J591 infusion 
Vital signs (temperature, heart rate, blood pressure, respiratory rate) should be 
documented 0-30 min prior to infusion.  12-18 minutes following infusion of study 

24 
 
drug, temperature, heart rate and blood pressure should be documented.  Heart rate, 
blood pressure, and respiratory rate should then be documented at least every 15 
minutes x3, then every 30 minutes x2.  In addition to baseline and at 15 min, 
temperature should be documented at least hourly x2 following infusion of study 
drug.  Subjects experiencing Gr > 0 infusion reactions at 2 hours post-infusion should 
be monitored for an additional hour.  Additional vital signs may be performed at the 
discretion of the study team.  Detailed instructions for vital signs are as follows: 
Pre-infusion (0-30 min before infusion):  temperature, HR, BP, RR 
    [Infusion will last a minimum of 4 minutes] 
Post infusion #1 (15 min +/-3 following end of infusion):  temperature, HR, BP, RR 
Post infusion #2 (30 min +/-3 following end of infusion):  HR, BP, RR  
Post infusion #3 (45 min +/-3 following end of infusion):  HR, BP, RR 
Post infusion #4 (60 min +/-5 following end of infusion):  temperature, HR, BP, RR 
Post infusion #5 (90 min +/-5 following end of infusion):  HR, BP, RR 
Post infusion #6 (120 min +/-10 following end of infusion):  temperature, HR, BP, 
RR 
 
 
 
5.1.4  Castration 
All subjects who have not been surgically castrated will continue to receive LHRH 
agonist/antagonists to maintain chemically castrated state (goal testosterone < 50) as part 
of standard care.  Examples of acceptable medications include leuprolide and goserelin. 
 
5.2  
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 specific protocol requirements outlined below. 
 
5.2.1 Excluded medications  
o Aspirin and/or non-steroidal anti-inflammatory agents possessing anti-platelet 
activity must be discontinued if the platelet count drops below 150,000.  
These medicines may be re-initiated at the discretion of the treating physician 
after confirmed recovery from any thrombocytopenia (after 2 consecutive 
rises with 2nd > 100,000). 
o Anti-platelet medications including, but not limited to, abciximab, cilostazol, 
clopidogrel, dipyridamole and ticlopidine HCL should be discontinued be 
discontinued if the platelet count drops below 150,000.  These medicines may 
be re-initiated at the discretion of the treating physician after confirmed 
recovery from any thrombocytopenia (after 2 consecutive rises with 2nd > 
100,000). 
o Anti-coagulant medications including, but not limited to, heparins 
(unfractionated and low molecular weight forms), coumarins (including 
warfarin sodium), anti-Xa inhibitors (including fondaparinux and abixaban), 
and direct thrombin inhibitors (including rivaroxaban) at therapeutic doses 
when platelet count <50,000/mm3.  These medications may be re-initiated 

25 
 
upon confirmed recovery of thrombocytopenia (after 2 consecutive rises with 
the 2nd above 75,000) 
o Any investigational mAb based therapy not covered in this protocol.  Note 
that “approved” monoclonal antibody therapy such as denosumab is allowed 
provided that subjects have initiated therapy and are on a stable dose/schedule 
at least 1 month prior to enrollment. 
o Medication to support platelet count (such as oprelvekin (Neumega®), 
romiplostim (Nplate), eltrombopag (Promacta)). 
o Patients on drugs known to be metabolized by the cytochrome P450 system 
(specifically CYP 3A4) should be cautioned about potential interactions with 
ketoconazole.  Specifically, cisapride, terfanadine and astemizole are 
contraindicated (see black box warning in product’s label).  Any such 
interactions should be discussed with the patient’s treating physician. 
 
 
 
5.2.2 
Myelosuppression guidelines 
 
 
 
 
5.2.2.1  Thrombocytopenia – monitoring guidelines 
 
• Based upon previous studies, the expected time of platelet nadir is expected to 
be 4-5 weeks after Lu-J591 infusion.  Physicians should search for additional 
causes of thrombocytopenia when suspected, especially if the platelet count 
falls < 3 weeks before or > 8 weeks after Lu-J591 infusion. 
 
• During periods of time when the platelet count is < 25,000/mm3, platelet 
counts must be monitored at least twice per week. 
 
 
 
 
5.2.2.2  Thrombocytopenia – transfusion guidelines 
 
• Per ASCO guidelines (108), prophylactic platelet transfusion is recommended 
at a threshold platelet count of 10,000/mm3. 
 
• Physicians should use their clinical judgment in determining the need for 
platelet transfusions for the non-bleeding subject with a platelet count > 
10,000/mm3, including factors such as platelet kinetics or factors that might 
alter platelet kinetics such as fever. 
 
 
 
 
5.2.2.3  
Neutropenia – growth factor guidelines 
 
• Per ASCO guidelines (109), WBC growth factors are not recommended for 
afebrile neutropenia.  However physicians may consider prophylaxis with 
filgrastim or pegfilgrastim for those subjects with severe neutropenia and 
known risk factors for neutropenic complications, including age > 65.  
Sargramostim (GM-CSF) should not be used because of its effect against 

26 
 
prostate cancer (110-114), including in combination with ketoconazole in this 
patient population (115). 
 
5.3  
Duration of Therapy and Criteria for Removal From Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
o Development of metastatic disease / Disease progression*, 
 
o Intercurrent illness that prevents further administration of treatment, 
 
o Unacceptable adverse event(s), 
 
o Subject decides to discontinue treatment,  
 
o Subject decides to withdraw from the study, or 
 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 * Subjects with biochemical progression only (rising PSA) should be encouraged to   
remain on study as long as there is no medical contraindication. Subjects who receive 
subsequent anti-cancer therapies prior to development of radiographic metastases 
should continue protocol follow up every 3 months (including scans).  Subjects who 
withdraw from treatment to receive investigational agents should be encouraged to 
allow reporting of follow up of the primary and secondary endpoints such as 
development of metastatic disease and death.  Subsequent anti-cancer therapies will 
be documented. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for 3 years after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
 
6.1 Ketoconazole 
Subjects experiencing grade 3 or 4 non-hematologic toxicities will have ketoconazole held 
until resolution to < grade 1 (The toxicity should be at least probably related to ketoconazole 
and does not need to be held if toxicity is unrelated).  Subjects experiencing > grade 3 non-
hematologic toxicity that does not resolve to < grade 1 within 4 weeks will be removed from 
ketoconazole therapy.  Subjects experiencing resolution to < grade 1 may resume 
ketoconazole at a lower dose (dose level -1).  Further grade > 3 toxicities will result in 
permanent discontinuation of ketoconazole.  Dose reduction or discontinuation of 
ketoconazole for other reasons should be discussed with the study chair. 

27 
 
 
Dose Level 
Agent / Dose 
-1* 
Ketoconazole 200 mg tabs 
1 tab p.o. TID 
0 
Ketoconazole 200 mg tabs 
2 tabs p.o. TID 
 
*Subjects who require dose reduction of ketoconazole will have hydrocortisone continued 
or discontinued at the discretion of the investigator.  Should subjects discontinue 
hydrocortisone, the dose should be tapered (suggestion: taper by 5 mg every three days). 
 
 
7. 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 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. 
 
7.1  Investigational Agent Risks 
 
7.1.1 177Lu-J591 (No additional risks expected from 111In-J591) 
Radiolabeled J591 is likely to cause thrombocytopenia and/or neutropenia as well as 
anemia.  Mild to moderate infusion reactions (fever, chills, rigors) are occasionally seen 
after administration. The following risks are possible after treatment with this 
experimental drug:  allergic reactions, rash, hypotension, hypertension, renal 
insufficiency, liver enzyme elevations (ALT and/or AST), difficulty breathing and human 
anti-humanized antibody (HAHA) response.  
 
Precautions/monitoring: 
Subjects should receive pre-medication prior to Lu-J591 infusion as described in Section 
5.2.3.1.  During and after infusion, patients will be monitored for possible allergic 
reaction.  Allergic events will be managed as follows: rash, pruritis, urticaria and 
wheezing will be treated with diphenhydramine hydrochloride, demerol and/or steroids as 
clinically appropriate.  Anaphylaxis or anaphylactoid signs or symptoms will be treated 
with steroids and/or epinephrine as clinically indicated.  Patients will be treated in a 
facility that is equipped for cardiopulmonary resuscitation.  Infusion-related reactions 
(fever, rigors) will be treated with acetaminophen, meperedine and diphenhydramine 
hydrochloride as clinically appropriate. 
 
7.1.2  Ketoconazole  
The most common side effects are weakness or lack of strength, gastrointestinal 
complaints such as nausea or vomiting, liver toxicity, skin reactions, and a potential risk 
of adrenal suppression. 
 

28 
 
Precautions/monitoring: 
Subjects should take ketoconazole as described in Section 5.2.1.  .  Regular monitoring of 
liver enzymes is required.  Ketoconazole is metabolized by the cytochrome P450 system 
and is a 3A4 substrate/inhibitor.  Caution should be used with subjects on other 
medications metabolized by this system.  Fatal arrhythmias have been reported in patients 
taking ketoconazole in combination with certain medications.  See excluded medications 
in Section 5.2.1.  
 
 
7.1.3  Hydrocortisone 
Side effects of hydrocortisone include fluid retention (swelling), electrolyte imbalances 
(sodium and potassium), elevated glucose, elevated blood pressure, muscle weakness, 
bone loss, and skin changes. 
 
7.2 
Adverse Event Characteristics  
 
• 
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 supporting 
laboratory data. 
• 
Probable – The AE is likely related to the study treatment.  A reaction that 
follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  The 
reaction cannot be reasonably explained by the known characteristics of the 
patient’s clinical state or other modes of therapy administered to the patient. 
• 
Possible – The AE may be related to the study treatment.  A reaction that 
follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  The 
reaction might have been produced by the patient’s clinical state or other 
modes of therapy administered to the patient. 
• 
Unlikely – The AE is doubtfully related to the study treatment.  The current 
state of knowledge indicates that a relationship is unlikely. 
• 
Unrelated – The AE is clearly NOT related to the study treatment.  No 
relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or patient’s 
clinical state. 
 
7.3 Recording of Adverse Events 
 

29 
 
All adverse events will be recorded on a patient specific adverse event log.  The AE 
log will be maintained by the research staff and kept in the patient’s research chart.     
 
7.4   Serious Adverse Event (SAE) Reporting 
 
7.4.1. Definition of SAE 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered AEs if the illness or 
disease existed before the patient was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definitions for SAEs.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
Clarification should be made between the terms “serious” and “severe” since they 
ARE NOT synonymous.  The term “severe” is often used to describe the intensity 
(severity) of a specific event (as in mild, moderate, or severe myocardial infarction); 
the event itself, however, may be of relatively minor medical significance (such as a 
severe headache).  This is NOT the same as “serious,” which is based on patient/event 
outcome or action criteria described above and are usually associated with events that 
pose a threat to a patient’s life or functioning.  A severe adverse event does not 
necessarily need to be considered serious.  For example, persistent nausea of several 
hours duration may be considered severe nausea but not an SAE.  On the other hand, 
a stroke resulting in only a minor degree of disability may be considered mild, but 

30 
 
would be defined as an SAE based on the above noted criteria. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
 
 
7.4.2. Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the 
policies of the local IRB.    For WCMC patients, reportable SAEs will be 
reported on the institutional SAE reporting form and comprehensive AE & 
IND Reporting table.  These forms may be downloaded at  
 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 
 
For all other institutions: SAE’s will be reported to the local IRB per the 
institutional guidelines. 
 
7.4.3. Reporting of SAE to Weill Cornell Medical College 
 
Institution will notify Weill Cornell Medical College of all serious adverse 
events that occur within 24 hours of investigator notification by contacting 
Dr. Scott Tagawa’s office at 646-962-2072.  A written SAE report should be 
filed with the local IRB in accordance with the institutional guidelines.  The 
following forms must be emailed to guonc@med.cornell.edu and/or faxed to 
Weill Cornell Medical College Clinical Trials Office at 646-962-1611 within 
five (5) business days of investigator notification: 
• 
Completed MedWatch Form 
• 
Completed WCMC SAE Cover Sheet 
 
Note that specified AE/SAE’s such as thrombocytopenia or bleeding are 
required to be reported within 24 hours.  The Principal Investigator and 
Medical Monitor will review all SAEs and copies of all SAEs will be 
electronically distributed to all participating site for submission to the local 
IRB. 
 
7.4.4. Reporting of SAE to FDA  
 
If an SAE occurs on this study, the event will be filed on a MedWatch form 
with the FDA.  All completed MedWatch forms will be sent to WCMC for 
submission to the FDA. 
 
 
7.5 
Secondary AML/MDS 
Myelodysplastic syndrome and acute myeloid leukemia has been reported in patients previously 
treated with anti-CD20 based RIT for non-hodgkin’s lymphoma.  Some case reports and small 
series have raised concern for this phenomenon after RIT (116).  However, given the increased 
incidence of MDS/AML in this population, either because of their underlying illness or of their 
exposure to previous cytotoxic therapy (especially alkylating agents), there is no good evidence 

31 
 
to suggest that there is a significantly increased risk than of a similar population of patients not 
receiving RIT (117, 118).  However, based upon the theoretical increased risk, the incidence of 
MDS/AML during follow up will be noted and used to increase the investigators’ experience and 
knowledge.  Any suspected potential increased risk of MDS/AML will be reported to the IRB 
and DSMB. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with radiolabeled J591 can be 
found in Section 7.1.   
 
8.1 Investigational Agent (IND#11,613)   
 
Radiolabeled J591 (177Lu -J591 and 111In-J591) are an investigational agents supplied to 
investigators by Weill Cornell Medical College.  Ketoconazole and hydrocortisone are 
commercially available and should be prescribed as indicated above (see Section 5.1). 
 
8.2 Radiolabeled J591 Ordering 
 
 
 
Upon enrollment, sites will notify the WCMC Study Coordinator of the proposed D29 
radiolabeled J591 infusion date.  The WCMC Study Coordinator will arrange for 
shipment of the radiolabeled antibody to the treatment site.  After confirmation of the 
date of infusion at the D15 telephone follow up, the site will confirm treatment date with 
the WCMC Study Coordinator and shipment to the site’s nuclear medicine department 
will be confirmed. 
 
8.3 Drug Accountability 
 
The case report forms relating to the preparation, quality control and drug accountability 
will be completed by the radiochemists in nuclear medicine. 
 
Test articles: 
a) mAb HuJ591, 5 mg/ml (non-radioactive, non-DOTA conjugated naked antibody),  
b) DOTA-HuJ591-GS, 8.0 mg/ml (non- radioactive antibody for labeling with 177Lu)  
 
Storage:  The primary inventory of test articles is stored at Goodwin Biotech, Plantation, 
FL, a cGMP, FDA-approved facility.  This storage facility is monitored around the clock 
and is equipped with back-up power generators in the event of a power outage. 
Periodically, as needed, vials of the test articles are shipped to WMC Urologic Oncology 
where they are stored in a locked, monitored, centrally alarmed refrigerator. Access to the 
storage area in WMC Urologic Oncology is limited by ID card-required access and a 
locked refrigerator with a key controlled by the WMC Urologic Oncology Lab 
administrator (Lana Winter). 
 
Inventory:  An official inventory record is kept and updated in real time. On the day of 
radiolabeling and dose administration to the patient, the radiochemists remove the test 
articles from the refrigerator and record the number of vials removed from the inventory 

32 
 
and the number remaining in the official inventory record. These records are kept in 
WMC Urologic Oncology.  
 
The “test article”, 177Lu-J591, is prepared by the radiochemists in the Nuclear Medicine 
laboratory. The radionuclides are received and stored in the nuclear medicine department 
according to the procedures established by the Institutional Radiation Safety Office. The 
radiolabeling and quality control data on radiochemical purity, immunoreactivity, sterility 
and pyrogenicity tests are kept in nuclear medicine. Radiolabeled antibody preparations 
are kept refrigerated until use. 
 
Disposal:  Unused radiolabeled antibody preparations are stored in lead containers for 
decay and subsequently disposed of according to standard radiation safety guidelines.  
Unused non-radioactive antibody vials and partially used vials (test articles) are 
destroyed or recycled to the WMC Urologic Oncology research lab for non-clinical 
research purposes.  
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
 
 
Additional Correlative Tests will be performed during the trial and will be centrally 
analyzed. 
 
 
 
Only the materials (tubes, shipping box, FedEx airbill) for CTC counts via CellSearch 
methodology will be provided to the site following site activation. Additional 
materials should be requested directly by emailing GUONC@med.cornell.edu. The 
site should use their own supplies for the remainder of the tests. 
 
 
A unique ID (number) for the Adrenal Androgen, CTC, Plasma markers, Archival 
Tumor, and HAHA samples will be provided by WCMC via email. Please contact 
GUONC@med.cornell.edu prior to the date of sample collection (if possible) for the 
unique ID. Please use the number provided to write it on the label and the lab 
requisition. The material shipment for these samples should be provided by site. 
 
 
Please notify GUONC@med.cornell.edu when shipping samples, and provide the 
tracking number. A Requisition form should be completed (as described in the Lab 
Manual) detailing the samples that are being shipped for all samples except the CTC 
counts via CellSearch methodology. 
 
 
Note: Plasma markers (9.1.2) are the only tests that are optional.  All other correlative 
samples are required.  The collection of archival tissue may be waived if no tissue is 
available. 
 
9.1.1 Adrenal Androgen Levels 
 
Serum levels of adrenal androgen levels will be obtained at screening (any time 
following consent and prior to therapy initiation on C1D1), Cycle 2 Day 1, and at the 

33 
 
time of PSA progression. Collect 10 mL of peripheral blood in a yellow (SST) or red 
top tube. Label samples with the unique sample number that will be provided by the 
Weill Cornell Medical College study coordinator to ensure that laboratory personnel 
will be blinded to subject and clinical data.  
 
Please refer to the Lab Manual for further details on collecting, handling and shipping 
of adrenal androgen samples. 
 
 
9.1.2 Plasma markers of hemostatic activation, fibrinolysis, and angiogenesis (optional) 
 
Plasma samples will be collected on C1D1 prior to therapy (may be collected as part 
of screening within 1 week of C1D1), Cycle 2 Day 1 (prior to J591 administration), 
Cycle 3 Day 1, at PSA progression, and at end of study. Refer to the Lab Manual for 
further details on collecting blood samples for plasma markers. Samples will be 
labeled with a unique sample ID number to ensure that laboratory personnel will be 
blinded to subject and clinical data. 
 
Refer to the Lab Manual for details on handling and shipping of blood samples for 
plasma markers.  
 
* Plasma markers are the only tests that are optional. 
 
9.1.3  Circulating tumor cells 
 
 
 
Circulating tumor cells (CTCs) will be assessed in the following manner: 
 
- CTC counts via CellSearch methodology 
 
- CTC analysis for research 
  
 
9.1.3.1  Collection of specimens for CTC counts (enumeration) via CellSearch 
 
 
 
 Methodology: 
 
Kits (including requisition and FedEx airbill) will be provided for CTC samples for 
counts via CellSearch methodology. At specified time points [baseline C1D1 prior to 
ketoconazole, C2D1 (prior to Lu-J591), C3D1, at the time of PSA progression, and at 
end of study] samples for CTC count via CellSearch methodology will be collected. 
Use the label from the requisition and place it on the tube to ensure that laboratory 
personnel will be blinded to subject and clinical data. The name should be the unique 
ID provided by WCMC coordinator (NOT the patient name). Refer to the Lab 
Manual for further details on collecting, handling and shipping of blood samples for 
CTC counts via CellSearch methodology. 
 
9.1.3.2  Collection of specimens for CTC analysis for research: 
 
At specified time points (screening/baseline at C1D1 prior to treatment and at end of 
study), blood samples will be collected as described in the Lab Manual. No Kit will 
be provided for this test, sites should use their own materials. Samples will be labeled 

34 
 
with a unique sample ID number to ensure that laboratory personnel will be blinded 
to subject and clinical data. 
Refer to the Lab Manual for further details on handling and shipping of blood 
samples for CTC analysis for research. 
 
9.1.3  Human Anti-Humanized Antibody (HAHA) specimen: 
 
Blood samples will be collected at screening and EOS. Refer to the Lab Manual for 
further details on collecting, handling and shipping of blood samples for HAHA. 
 
 
9.1.4  Archival Tumor PSMA expression 
 
9.1.4.1 Specimens 
At the screening visit, paraffin-embedded tumor blocks or 10 unstained slides with 
representative tumor tissue will be collected as described in the Lab Manual.  
Samples will be labeled with a unique sample ID number to ensure that laboratory 
personnel will be blinded to subject and clinical data. 
 
 
For shipping instructions, please refer to the Lab Manual. 
 
 
 
 
9.2 
Special Studies 
 
9.2.1 Radiolabeled-J591 Imaging 
 
9.2.1.1 Assessment 
 
 
9.2.1.1.1 Method of Assessment:   
 
 
 
Planar imaging will be performed 2-8 days after radiolabeled-J591 administration 
(scan window will be assigned at randomization). In the case of a suspicious 
lesion, SPECT of the area may be performed at the nuclear med physician’s 
discretion. In addition a CT/MRI may be obtained for possible confirmation. 
Identified sites will be followed on subsequent imaging modalities (bone scan, CT 
or MRI) to define the interval between identification of the lesion/s by 
radiolabeled-J591 versus other modalities.  Images will be captured as specified in 
the Imaging Manual and provided to WCMC on disc in dicom format. 
 
 
9.2.1.1.2 Timing of Assessment 
 J591 scanning will be performed approximately 2-3 or 6-8 days after J591 
 administration (scan date will be assigned with randomization).  Scans will be 
assessed centrally at WCMC. 
 
 

 
 
10. STUDY CALENDAR 
 
The study flow chart, including all procedures to be performed during the study, is presented below.  Prior to engaging in any study 
procedure, each patient must sign and date an informed consent form. 
 
Baseline evaluations are to be conducted within 1 week prior to administration of protocol therapy.  Scans and x-rays must be done within one 
month of enrollment (or following enrollment as part of screening).   
 
Study Procedure 
Screening 
Period 
 
V1 
V2 
V38 
V4 
± 
V5 
V6 
V7 
V8 
V9 
F/U14 
PSA 
progression 
EOS11 
Day 
-28 to -1 
C1D1 
C2D1 
C2 
D3-9 
C2D22 
C3D1 
C3D8 
C3D15 
C3D22 
C4D1 
Every 4 
weeks 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
X++ 
X++ 
 
 
X++ 
 
 
 
X++ 
X++ 
X++ 
X++ 
Physical Exam (PE)-
Complete 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
PE – Targeted9 
 
X 
X 
 
 
X 
 
 
 
X 
X 
 
 
Vital Signs10 
X 
X 
X+ 
 
 
X 
 
 
 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous Therapy Report 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Height, weight 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
CBC with differential + 
platelet count2,3 
X 
X 
X 
 
± 
X 
X3 
X3 
X3 
X 
X 
X 
X 
PT or INR, PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrolytes, BUN, 
Creatinine 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Total protein, albumin, 
calcium 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
total bilirubin, AST 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
ALT, LDH, Alk Phos 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
PSA4 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 

36 
 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Human anti-J591antibody  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI (abdomen-
pelvis)1 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Bone Scan1 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
CXR1 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
J591 scan 
 
 
 
X* 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
FACT-P13 
 
X13 
 
 
 
 
 
 
 
 
X12 
X12 
X12 
Concomitant Medications 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Concomitant Procedures 
 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
111In/177Lu-J591 
Administration 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Ketoconazole/ 
Hydrocrotisone7 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Plasma Markers 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Circulating Tumor Cells5 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Adrenal Hormones 
 
X6 
X6 
 
 
 
 
 
 
 
 
X6 
 
Archival Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
A phone assessment will be performed on D15 +/- 3 days to assess compliance and toxicity of ketoconazole/hydrocortisone. 
± CBC on D50 +/- 2 days is required for pts on anticoagulation or NSAIDS, suggested in pts with baseline plt count < 200 
 
*J591 scan may be done 2-8 days after infusion (date will be assigned upon randomization).  SPECT studies of sites of disease will be obtained in selected patients as necessary.  
+ vital signs to be taken prior to infusion and post-infusion as per Section 5.1.3.3 
++ interval medical history 
1 Baseline radiographic evaluation should be performed within one month of enrollment (or following enrollment as part of screening).  Subsequent scans (CT/MRI abd/pelvis, 
CXR (or CT chest), and bone scan) should be performed every 6 months until PSA progression, then every three months thereafter unless clinically indicated sooner. 
2 CBC repeated twice a week when platelets <25,000/mm3 and/or ANC <500/mm3 
3 CBC’s not associated with study visits may be performed at any CLIA certified laboratory 
4 The same lab should be used for all study PSA’s if possible 
5 CTC counts  via CellSearch (using kit) at C1D1 prior to ketoconazole, C2D1 (prior to Lu-J591), C3D1, at the time of PSA progression, and at end of study. Additional blood 
samples for CTC analysis for research will be drawn.at C1D1 prior to treatment and at end of study 
6 Adrenal hormone levels should be drawn prior to starting treatment on Cycle 1, Day 1, 1 month, and at PSA progression 
7 Starting after C1D1 assessment and blood draw until toxicity, investigator, or patient decision as per Sections 5.2.1, 5.2.2, 6.1. Distribute medication diary at the beginning of 
each cycle.  
8 Visit 3 (C2D1): Targeted physical exams can be completed the day prior to the scheduled J591 infusion date.  

37 
 
9 All references to targeted physical exams throughout the protocol include a heart and lung examination, as well as evaluation of any abnormalities found during the complete 
physical exam performed at screening 
10 Vital signs include temperature, heart rate, blood pressure, and respiratory rate. 
11 The End of Study Visit occurs when patient shows evidence of metastatic disease.  Patient remains on trial until documented metastatic disease.  In addition to scans a biopsy 
can be performed to prove metastatic disease.  Patient can receive additional therapy prior to showing metastatic disease and still remain on trial.  Site will be asked for 
information regarding the additional therapy in the case report forms.  
12  In the event that the J591 infusion is delayed, cycle 1 will be extended until the date of the J591 infusion.  The date of the J591 infusion will be considered Cycle 2, Day 1.  
13  The FACT-P questionnaire should be completed after enrollment, but prior to therapy (on C1D1 prior to ketoconazole).  Questionnaires should also be completed at each  
radiographic assessment point (q6 months prior to PSA progression, q3 months after PSA progression) – may be performed just prior to scan, on day of scan, or after scan, but 
BEFORE results of scans are discussed.  In addition, FACT-P will be completed at PSA progression and EOS 
14 Follow up is at least every 4 weeks while on ketoconazole and until study drug toxicities have resolved (with the exception of anemia).  Following discontinuation of  
ketoconazole, follow up is at least every 12 weeks (or 3 months)

37 
 
10. 1  STUDY PROCEDURES:  Schedule of Events  
 
The assessments to be performed during the study are outlined below by study period, visit and 
day.  Study assessments through Visit 9 (Day 85) will be completed within ±3 days of the 
specified day for the visit, except where noted.  Visits after Day 169 will be performed within ±7 
days of the scheduled visit. 
 
Screening Period (Visit 1, Days -28 to -1) – All subjects 
The procedures outlined for Visit 1 must be completed prior to the patient receiving study drug.  
The following procedures will be conducted at Visit 1: 
• Informed Consent 
• Medical History 
• Concurrent medications 
• Complete Physical Exam 
• Vital Signs 
• Demographics 
• Previous therapy 
o Surgical report will include date and type of surgery +/- lymphadenectomy 
o Radiotherapy report will include modality of therapy with prescribed dose and 
field and dates of therapy 
o Previous hormonal therapy – drugs, doses, dates of therapy 
 Continuous vs intermittent therapy 
• ECOG Performance Status  
• Height, Weight 
• CBC with differential and platelet count. 
• PT or INR, PTT 
• Electrolytes, BUN, Creatinine 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• PSA 
• PSA DT Calculation 

38 
 
• Alkaline phosphatase 
• Testosterone 
• Human anti-J591 antibody sample  (may also be drawn C1D1 prior to initiation of 
study drugs) 
• Urinalysis 
• Archival Tissue (section 9.1.4) - Paraffin-embedded tumor blocks or 5 unstained 
slides with representative tumor tissue 
• EKG, up to 1 month prior to treatment 
• CT or MRI (abdomen-pelvis), up to 4 weeks prior to enrollment 
• Bone scan, up to 4 weeks prior to enrollment 
o Any confirmatory tests to assess equivocal results of bone scan should also be 
completed within 4 weeks of enrollment 
o CXR, up to 4 weeks prior to enrollment (if CT chest has been performed within 4 
weeks of enrollment, this procedure is waived) 
Evaluations and procedures at Visit 2 (C1D1) – All subjects 
Following screening procedures, eligible patients will be dosed with ketoconazole and 
hydrocortisone.  See Section 5.1 for details on the dose and administration. 
The following assessments are to be collected prior to drug administration unless otherwise 
noted: 
• Interval medical history 
• Targeted Physical Examination with vital signs 
• ECOG PS 
• CBC with differential and platelet count* 
• Electrolytes, BUN, Creatinine* 
• PSA* 
• Adrenal hormone levels 
• Plasma markers  
• CTC’s 
• Adverse Events 

39 
 
• Concomitant medications 
• Concomitant procedures 
• FACT-P questionnaire (prior to ketoconazole/hydrocortisone administration) 
• Ketoconazole/hydrocortisone administration instruction (re-inforcement) – 
prescriptions should have been filled prior to this visit, but no drugs should have been 
taken prior to blood draw D1 
o Distribute Medication Diary 
*Note that treatment day labs are used for baseline (not for assessment of eligibility), though 
subjects may be withdrawn from the study for safety concerns per the investigator’s discretion. 
Phone Assessment (Cycle 1, Day 15 +/- 2 days) – All subjects 
• Compliance 
• Toxicity screening 
• Next visit reminder (confirmation of date/time of next visit with J591 infusion should 
also be confirmed after delivery date of drug is confirmed) 
 
Evaluations and procedures at Visit 3 (C2D1) – All subjects 
Following assessment, eligible, randomized patients who have not come off trial for toxicity or 
noncompliance will be dosed with radiolabeled-J591.  See section 5.2.3 for details on the 
administration.   
Note: The J591 infusion days should be scheduled on a Thursday or Friday. If needed, visits can 
be scheduled on a Wednesday afternoon but the earliest the site will receive drug is Wednesday 
at noon. Because of the nature of study drug and shipping, dosing outside of specified window 
should be discussed with WCMC, but will not require a protocol exception provided the date has 
been pre-approved by WCMC. The exact date of the J591 infusion will be confirmed 2 weeks 
prior. The site is not responsible for ordering the J591. WCMC will handle ordering and shipping 
the drug.  The shipping material needs to be sent back to WCMC.  A return air bill will be 
included with the shipment. 
Note: In the event that the J591 infusion is delayed, cycle 1 will be extended. The date of the 
J591 infusion will be considered cycle 2, day 1. 
 
Patients will remain at the clinical site for a minimum of 2 hours after completion of 
radiolabeled-J591 administration to monitor vital signs. The patient should be considered 
clinically stable by the investigator prior to discharge. The following assessments are to be 
collected prior to drug administration unless otherwise noted: 
• Interval medical history 

40 
 
• Targeted Physical Examination 
• ECOG Performance Status 
• Vital Signs (pre-infusion, post infusion as per Section 5.1.3.3) 
• Verification of ketoconazole/hydrocortisone administration, Collection/Distribution 
of diary 
• CBC with differential and platelet count* 
• Electrolytes, BUN, Creatinine* 
• PSA* 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• Alkaline phosphatase 
• Plasma markers  
• Adrenal hormones 
• CTC’s  
• Concomitant medications 
• Concomitant/interval procedures 
• Adverse events (pre- and post- infusion) 
*Note that treatment day labs are used for radiolabeled-J591 baseline (not for assessment of 
eligibility) 
 
Evaluations and procedures at Visit 4/J591 Scan (C2D3-9) 
• Adverse Events 
• Concomitant medications 
• Concomitant/interval procedures 
• J591 imaging (2-8 days after infusion).   At selected study sites, whole body planar 
radionuclide images will be obtained between 2-8 days post-J591treatment.   The date of 
scan (3 or 4 days vs 6-8 days after J591 infusion) will be assigned at the time of 
randomization.  SPECT studies of sites of disease will be obtained in selected patients as 
appropriate. These will be used to assess the ability of radiolabeled J591 to image 

41 
 
metastatic sites that do not appear on conventional imaging modalities (bone scan, 
CT/MRI). 
 
Evaluations and procedures C2D22 (safety CBC for some subjects) 
For subjects on aspirin/NSAIDs with anti-platelet properties or anticoagulation, a CBC on 
approximately Day 50 is required (3 weeks +/- 2 days after radiolabeled J591 infusion).  For all 
other subjects, in particular subjects with baseline platelet counts < 200/mm3 a CBC at this 
timepoint is suggested, but not required.   
 
• CBC with differential † 
 
 
Evaluations and procedures C3D1 
• Interval medical history 
• Targeted Physical Examination 
• Vital Signs 
• ECOG Performance Status 
• Verification of ketoconazole/hydrocortisone administration, Collection/Distribution 
of diary 
• Adverse Events 
• Concomitant medications 
• Concomitant/interval procedures 
• CBC with differential and platelet count. 
• Electrolytes, BUN, Creatinine 
• Total protein, albumin, calcium 
• Total bilirubin, AST, ALT, alkaline phosphatase, LDH 
• PSA 
• Plasma markers 
• CTCs 

42 
 
 
Evaluations and procedures Cycle 3 D8 *† 
• CBC with differential and platelet count 
 
Evaluations and procedures Cycle 3 D15 *† 
• CBC with differential and platelet count† 
 
Evaluations and procedures Cycle 3 D22 *† 
• CBC with differential and platelet count† 
All CBC results during cycle 3 must be either entered into the REDCap eCRF database or 
emailed to guonc@med.cornell.edu within 24 hours of testing. 
*Lu-J591 subjects with platelets < 25,000 and/or ANC < 500 are required to have CBC’s 
performed at least twice per week until recovery to platelets > 25,000 and ANC > 500 
† Lu-J591 CBC evaluations may be performed at approved CLIA certified local 
laboratories with PI’s pre-approval 
 
Evaluations and procedures C4D1 – ALL PTS 
• Adverse events 
• Concomitant medications 
• Concomitant/interval procedures 
• Verification of ketoconazole/hydrocortisone administration, Collection/Distribution 
of diary 
• Interval Medical History 
• Targeted Physical Exam 
• Vital Signs 
• ECOG Performance Status  
• Weight 
• CBC with differential and platelet count. 
• Electrolytes, BUN, Creatinine 

43 
 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• PSA 
• Alkaline phosphatase 
 
J591 subjects who have not yet recovered ANC > 1.5 and/or platelet counts > 150 by Visit 9 
(Cycle 4 D1) will continue to have CBC’s checked weekly until these criteria satisfied or 
until permission is granted by the Study Chair 
 
Evaluations and procedures q4 weeks while on ketoconazole and until resolution of study 
drug toxicities with the exception of anemia until EOS 
• Adverse events 
• Concomitant medications 
• Concomitant/interval procedures 
• Verification of ketoconazole/hydrocortisone administration, Collection/Distribution 
of diary 
• Interval Medical History 
• Targeted Physical Exam 
• Vital Signs 
• ECOG Performance Status  
• Weight 
• CBC with differential and platelet count. 
• Electrolytes, BUN, Creatinine 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• PSA 
• Alkaline phosphatase 
• Other laboratory assessments and procedures as clinically indicated. 
NOTE:  For individual subjects deemed to be tolerating ketoconazole well, following 6 
months on study (after scans) study evaluations need to be performed by official study 
investigators at official study sites only every 12 weeks.  For those subjects who are 

44 
 
tolerating study drug well (in the opinion of the investigator) and for whom travel is a 
burden, the other two q4 week evaluations may be performed by a local lab with either 
local physician and/or phone assessment for adverse events (i.e. at least every third visit 
must be done on site by official study investigators).  In this case, source documents 
should be collected and drug diaries may be collected by fax/mail/email.  Subjects who 
discontinue ketoconazole for any reason may be followed every 12 weeks following 
resolution of ketoconazole and study drug toxicities (except anemia). 
Radiographic Evaluation and Patient Reported Outcome Evaluation 
• Bone scan, CT/MRI abdomen/pelvis, and CXR + FACT-P# at baseline 
• Bone scan*, CT/MRI of abdomen/pelvis, and CXR + FACT-P# will be repeated 
every 6 months in the absence of biochemical or clinical progression 
• Bone scan*, CT/MRI of abdomen/pelvis, and CXR + FACT-P# will be repeated 
every 3 months subsequent to biochemical or clinical progression 
• In addition, a bone scan will be performed for subjects with clinical signs or 
symptoms of bone metastases at the investigators discretion 
*During the first 6 months, bone scan progression requires confirmation by a 2nd bone scan.  The 
date of progression is defined as the date of the 1st scan that is subsequently confirmed to be 
positive. 
#FACT-P to be administered either prior to imaging or following imaging, but before results of 
scans are disclosed to subject. 
 
Evaluations and procedures at PSA progression 
Note:  subjects may remain on ketoconazole/hydrocortisone beyond PSA progression at the 
discretion of the investigator and/or their treating physician 
• Adverse events 
• Concomitant medications 
• Concomitant/interval procedures 
• Verification of ketoconazole/hydrocortisone administration, Collection of diary 
• Interval Medical History 
• Complete Physical Exam 
• Vital Signs 
• ECOG Performance Status  

45 
 
• Weight 
• CBC with differential and platelet count. 
• Electrolytes, BUN, Creatinine 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• Alkaline phosphatase 
• PSA 
• Testosterone 
• Plasma markers 
• CTC’s 
• Adrenal hormones 
• Other laboratory assessments and procedures as clinically indicated. 
• FACT-P 
 
Evaluations and procedures at End of Study (EOS = development of metastatic disease on 
scans) 
Note:  subjects may remain on protocol past initial scans with evidence of metastatic disease if 
confirmatory scans are warranted 
• Adverse events 
• Concomitant medications 
• Concomitant/interval procedures 
• Verification of keto/hydrocortisone administration, Collection of diary (if relevant) 
• Interval Medical History 
• Complete Physical Exam 
• Vital Signs 
• ECOG Performance Status  
• Weight 

46 
 
• CBC with differential and platelet count. 
• Electrolytes, BUN, Creatinine 
• Total protein, albumin, calcium, total bilirubin, AST, ALT, LDH 
• Alkaline phosphatase 
• PSA 
• Testosterone 
• Plasma markers 
• CTC’s 
• Human anti-J591 antibody sample   
• Other laboratory assessments and procedures as clinically indicated. 
• FACT-P 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Primary Endpoint:  Proportion free of radiographically evident metastases at 18 
months.  Bone scans with <3 metastatic lesions should be confirmed with CT/MRI or a 
repeat scan >4 weeks after the initial scan.  Should a subject require confirmatory scans, 
the date of radiographic progression will be the date of the initial scan showing suspicion 
of metastasis. 
 
 
11.1.1 Metastasis-free survival 
Time to development of metastatic disease will be calculated from the date of treatment 
to the date of the first radiographic evidence of metastatic disease.  Bone scans with <3 
metastatic lesions should be confirmed with CT/MRI or a repeat scan >4 weeks after the 
initial scan.  Should a subject require confirmatory scans, the date of radiographic 
progression will be the date of the initial scan showing suspicion of metastasis. 
 
 
11.2 
Response Criteria 
 
11.2.1  Biochemical (PSA) response 
A PSA decline of ≥50% has been demonstrated to correlate with improved survival in 
advanced castrate disease (119). In addition, Scher, et al have demonstrated that a PSA 
which either declines or shows no increase from baseline at either 8 or 12 weeks after 
initiating therapy correlates with improved survival compared to patients whose PSA 
rises despite therapy (120). Both of these criteria (≥ 50% PSA decline and no increase 
from baseline) will be recorded. 

47 
 
PSA response will be determined by comparing the PSA levels after therapy to the 
baseline, pre-treatment PSA. A decline of ≥ 50%, confirmed by a second PSA value ≥ 2 
weeks later, should be reported. Patients must not demonstrate clinical or radiographic 
(CT and/or MR) evidence of disease progression during this time period. 
Analyses of phase III trials of docetaxel versus mitoxantrone chemotherapy in men with 
metastatic androgen independent prostate cancer have shown that a 30% decrease in PSA 
levels is most strongly associated with a treatment effect on overall survival (52, 53).  A 
PSA decline of > 30% will be assessed and used for exploratory analysis in the prediction 
of time to metastatic disease and overall survival. 
 
11.2.2 Duration of PSA response 
Duration of PSA response is defined as the time from the first 50% (or 30%)  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 nadir. 
 
11.2.3 Progression (see also 11.1) 
 
11.2.3.1 Biochemical progression 
Biochemical (PSA) progression is defined as a PSA measured ≥ 12 weeks after treatment 
which is confirmed (by a repeat assay) to rise ≥ 25% above the baseline, pre-treatment 
value AND ≥ 2 ng/mL. In the case of a patient whose PSA declines after therapy, PSA 
progression is defined as a rise in PSA ≥ 25% above the nadir value AND ≥ 2 ng/mL. 
The time of progression is determined using the date of the 1st (subsequently confirmed) 
PSA ≥ 25% above baseline or nadir.  PSA rise < 12 weeks of initiating treatment is not 
considered to be progression. 
 
11.2.3.2 Time to biochemical 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 
 
11.2.3.3 Time to PSA progression above baseline 
Time to PSA progression above baseline will also be recorded. Time to PSA progression 
above baseline will be defined as the interval between initiating treatment until the PSA 
rises above the pre-treatment baseline by at least 2 mg/mL.  PSA rise < 12 weeks of 
initiating treatment is not considered to be progression. 
 
 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
12.1 
Data Collection and Monitoring 
 
The data collection plan for this study is to utilize a user ID/password protected 
encrypted database created by the WCMC CTSC to capture all treatment, toxicity, 
and efficacy data for all enrolled patients.  Electronic CRF’s (case report forms) 
utilizing unique study ID numbers to minimize potential exposure of PHI will be 
completed on an ongoing basis by all sites. 
 

48 
 
The study will be monitored by Weill Cornell Medical College.  Data integrity will 
occur via electronic and fax queries.  A review of the majority of source documents to 
verify CRF integrity is planned for the initial subject treated at each site.  Further 
electronically collected data will be reviewed in real time and electronic queries will 
be sent.  Weill Cornell reserves the right to site audits as necessary.  In the event this 
will occur, the site will be given ample notice prior to the visit. 
 
 
12.2     Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Study 
Chair.  Weill Cornell will have the opportunity to review and approve the changes 
prior to submission of these changes to the Weill Cornell IRB and distribution to 
participating sites. 
 
12.3     Data Safety Monitoring Board 
This study will utilize the Weill Cornell Medical College (WCMC) Institutional Data 
Safety Monitoring Board (DSMB) and follow its policies and procedures for 
monitoring this double-blinded study for safety concerns, with ongoing updates from 
the Study Chair on an ongoing basis.  The interim analysis will be performed by the 
DSMB and the decision to proceed or stop the trial will be provided to the Study 
Chair. 
 
The Weill Cornell 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: 
1.  Completed DSMB Periodic Review Form. 
2.  Synopsis of the study to date. 
3.  IRB approved consent form. 
4.  IRB current protocol. 
5.  Summary table of study results. 
 
 
 
6.  Adverse event table. 
 
 
 
7.  Data safety monitoring plan. 
 
Safety monitoring is carried out to ensure and maintain the scientific integrity of 
human subject research projects and to protect the safety of human subjects.  Safety 

49 
 
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 palce 
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, the monitoring is usually performed by a statistician in 
conjunction with a Safety Officer.  For those single-site, high risk trials, a DSMB 
may be appropriate.  For larger, single or multi-site studies, the monitoring is usually 
performed by a committee, often called a Data Safety Monitoring Board (DSMB).  
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 Medical College 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. 
 
 
 
12.4  Initial Safety Review 
177Lu-J591 has been shown to be safe at a dose of 70 mCi/m2 in a phase I dose-
escalation trial and a multicentered phase II trial.  Because the major toxicity 
(myelosuppression) is at least in part due to the location of metastases (cortical bone 
and bone marrow), it is expected that the toxicity in this study population will not 
exceed that seen in the trials in metastatic CRPC.  However, safety data will be 
monitored on a real-time basis by the Study Chair and shared with the core study 
investigators.  Should there be > 1 subject experiencing a stopping rule as defined by 
agreement with the FDA during the conduct of the phase II trial in metastatic CRPC 
(see Appendix B) within the initial 9 subjects (approximately 6 subjects receiving 
177Lu-J591), enrollment will be halted pending DSMB review.  Enrollment will 
continue without a pause during the ongoing safety analysis.  Completion of initial 
safety review is anticipated to be completed in summer, 2011. 
 
12.5     Analysis and Data Reporting 
Secondary endpoints examining the patient population or treatment with 
ketoconazole/hydrocortisone without regard to the study drug (radiolabeled J591) 
may be analyzed without breaking the blinding procedures on an ongoing basis and 
may be reported during the conduct of the study. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 

50 
 
 
 
 
  
The study is a randomized phase 2 study with a 2:1 ratio favoring 177Lu-J591, with 
stratification by investigational site and mode of primary therapy (radiation vs surgery).  
Randomization will be performed by using a series of randomized blocks of 6 within 
each participating site/primary therapy stratum (with a 2:1 allocation ratio). This will 
provide assurance that after six patients are enrolled in any given participating 
site/primary therapy stratum, there will be four patients assigned to the combination 
regimen (Group 1) and two patients assigned to the single regimen (Group 2). This 
procedure will allow for each site to contribute similar numbers of 177Lu-
J591/ketoconazole patients and 111In-J591 (placebo)/ketoconazole patients within the 
defined participating site/primary therapy strata.  
 
 
The primary endpoint is the proportion free of metastases in each group at 18 months.  
Ninety-five percent confidence intervals (95% CI) will be estimated for the 18-month 
MFS proportion in both groups via binomial proportions.  The MFS proportion will also 
be descriptively evaluated at 12, 24, 30, and 36 months in each group. 
 
MFS will be measured from the start of the treatment to the date of either documentation 
of metastatic disease or death.  All treated patients will be observed for a minimum of 18 
months.  The 18-month MFS proportion with ketoconazole + 111In-J591 has been 
estimated to be 50% {521 Smith, M.R. 2005}; therefore, the target 18-month MFS 
proportion for the combination of ketoconazole + 177Lu-J591 regimen is hypothesized to 
be 80%.  An intent to treat analysis will include all randomized subjects.  However, we 
will also analyze subjects who received study-drug.  This subset will be those subjects 
who met eligibility requirements, have initiated therapy, and were not removed from the 
study for non-compliance or patient withdrawal within the first 4 weeks, and received 
infusion of study drug. 
 
With approximately 34 patients in the ketoconazole+J591 arm and 17 patients in the 
ketoconazole monotherapy arm (2:1 allocation), this design will allow for the detection of 
a 30% absolute difference in the 18-month MFS proportion between the 
ketoconazole+J591 arm and the ketoconazole monotherapy arm (80% vs. 50%, 
respectively) with ≥80% power and a one-sided alpha level of 10%.  An additional 10% 
will be enrolled to account for loss to follow up (total projected number of subjects to be 
randomized = 55).  A 95% CI for the difference in the 18-month MFS proportion 
between the two treatment arms can be constructed to be within ± 18% of the true 
difference in 18-month MFS proportions. 
 
 
 
13.1.1 111In-J591 as placebo 
We have chosen to infuse 111In-J591 as a placebo in this double-blind study.  The 
infusion procedures and characteristics of this compound are similar to 177Lu-J591.  In 
addition, 111In-J591 will allow imaging studies to be performed.  Because 111In is a pure 
gamma-emitter, there will be no treatment effect as in the beta emission with 177Lu.  It is 
theoretically possible that by infusing 111In-J591, there will be a treatment effect by 
ADCC, thereby diluting the proportional effect of 177Lu-J591 in the experimental arm.  
However, clinically meaningful ADCC is not expected, as it has been demonstrated at 

51 
 
much higher doses of the J591 antibody (122), and by giving equal antibody doses in 
each study arm, we will be able to truly evaluate the effect of 177Lu radioimmunotherapy. 
 
13.2 
Sample Size/Accrual Rate 
 
The planned sample size is 55 subjects (50 + 10% for in-evaluable / loss to follow-up = 
55). Subjects who come off protocol prior to day 29 of treatment (i.e. prior to infusion of 
study drug) will be replaced.  It is anticipated that the average site will pre-screen several 
subjects per month and enroll approximately 3 subjects per year. 
 
13.3 
Stratification Factors 
 
Patients will be stratified by treating institution and delivery of primary therapy (surgery 
and/or radiotherapy vs no primary therapy to the prostate). 
 
13.4 
Analysis of Secondary & Exploratory Endpoints 
 
Secondary endpoints include biochemical (PSA) response rate, duration of PSA response, 
biochemical (PSA) progression, time to biochemical (PSA) progression, time to 
biochemical (PSA) progression above baseline, overall survival, and toxicity.  We 
anticipate that the 95% confidence interval around the PSA response rate will be within 
±9% of the true value for Arm 1 and within ±15% of the true value for Arm 2.  Time to 
biochemical (PSA) progression, time to biochemical (PSA) progression above baseline, 
median MFS-time, and overall survival will be estimated using the Kaplan-Meier 
method, and 95% confidence intervals will be calculated using Greenwood’s formula. 
 
 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be 
assessed and graded according to CTCAE v. 4.0 terminology.  Exact 95% confidence 
intervals around the toxicity proportions will be calculated to assess the precision of the 
obtained estimates. 
 
 
Imaging studies:  The possibility of identifying sites of metastatic disease not apparent on 
conventional imaging (CT/MRI abdomen/pelvis, bone scan, and CXR) will be confirmed 
with serial imaging.  Any potential metastatic site on J591 imaging will be followed over 
time by conventional imaging.  Sites of disease appearing on J591 scan and subsequently 
confirmed by conventional imaging will be labeled as positive.  Any site apparent on 
J591 scan that is subsequently biopsied as part of standard care and confirmed to be 
metastatic prostate cancer will be labeled as definite.  Sites of disease appearing on J591 
scan without any corroborating evidence (conventional imaging or biopsy) will be 
labeled as possible. 
 
Adrenal hormonal levels:  Baseline adrenal hormonal levels will be categorized by 
median baseline levels found in CALGB 9583 (60, 61).  In addition, as this may be a 
different patient population, we will analyze by median as well as quartiles.  We will 
correlate levels with time to radiographic metastatic disease as well as PSA response and 
overall survival.  Changes in adrenal hormone levels will be analyzed with time 
(baseline, 1 month, 6 months, at progression). 

52 
 
 
Plasma markers of hemostasis/fibrinolysis/angiogenesis:  Baseline levels will be 
categorically analyzed by median as well as in quartiles and will be correlated with 
clinical endpoints (time to mets, survival, PSA response).  We will also perform 
exploratory analyses using these values as continuous variables.  In addition, a 
description of changes in levels of these markers with time/treatment will be reported.  
We will explore changes (decreases) by 50% (and median decrease) in correlation with 
outcome/response. 
 
CTC’s:  Change in CTC counts will be summarized descriptively.  Baseline counts > 5 
CTCs vs < 5 (per 7.5 mL) will be analyzed for time to metastatic disease in the overall 
population.  We will also analyze changes with therapy:  Decrease from > 5 to < 5, 
increase from < 5 to > 5, and stable categorical counts with respect to primary and 
secondary efficacy endpoints. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment on study.  Toxicity of radiolabeled J591 in this 
population will be evaluated from the time of J591 administration. 
 
13.5.2 Evaluation of response.  All patients included in the study will be assessed 
for response to treatment if they have received at least 4 weeks of therapy with 
ketoconazole and received radiolabeled J591.  Subjects dropping out of the 
study prior to J591 administration will be replaced.   
 
14 Inclusion of Women and Minorities 
 
Women are excluded from the protocol because prostate cancer is a disease of men.  No 
exclusion based upon race/ethnicity will occur. 
 
15.  Study Personnel 
 
Study Chair (Scott T. Tagawa, MD):  Responsible for patient recruitment and over-all 
clinical management, protocol design and coordination, assessment of adverse events, safety, 
toxicity, and effect of treatment.  Will communicate with principal investigators and study 
personnel at all sites and run monthly study teleconferences with the Study Coordinator.  
Will oversee any changes to the protocol and will be responsible for submitting amendments 
to the appropriate regulatory agencies (such as IRB, DSMB, sponsors, FDA, etc.). [See also 
Appendix D] 
 
WCMC Co-Investigators (David M. Nanus, MD, Caryn Ecker, NP, Himisha Beltran, MD, 
Yuliya Jhanwar, MD, Ana Molina, MD, Meghan Moran NP, Trisha Youn, MD):  
Responsible for patient recruitment, overall clinical management, assessment of adverse 
events, safety, toxicity, and effect of treatment.  Will assist with protocol design, 
coordination, and interpretation of scans. 
 

53 
 
Nuclear Medicine Chairs (Stanley Goldsmith, MD, Shankar Vallabhajosula, PhD): 
Responsible for administration of IND agents (radiolabeled J591 antibodies) for diagnostic 
and therapeutic studies, will oversee evaluation and quantitation of radiolabeled J591 scans. 
Will oversee quality control of radiolabeled antibody. 
 
Statistician (Paul Christos, MS, Dr.PH):  Assist with study design, data analysis and 
interpretation, assist with protocol amendments. 
 
Research Nurse Assist with patient recruitment, study drug administration, documentation 
of adverse events. 
 
Study Coordinator Assist with pre-screening and screening of subjects at WCMC; 
communicate with DOD; coordinate potential and enrolled subjects at all sites; optimize 
accurate data collection and entry by communicating frequently with other sites; prepare data 
for analysis.  Will run monthly study teleconferences with principal investigators and other 
study team members at other sites in conjunction with the Study Chair.  Will assist the Study 
Chair in providing continuing review documents for appropriate regulatory agencies (such as 
IRB, DSMB, sponsors). 
 
Research Monitor John Leonard, M.D. is responsible to oversee the safety of the research 
and report observations/findings to the IRB of Record or a designated official.  The Research 
Monitor will review all unanticipated problems involving risk to volunteers or others 
associated with the protocol and provide an unbiased written report of the event to the IRB of 
Record. The Research Monitor may discuss the research protocol with the investigators, 
interview human subjects, and consult with others outside of the study about the research.  
The Research Monitor shall have authority to stop the research protocol in progress, remove 
individual human subjects from the study, and take whatever steps are necessary to protect 
the safety and well-being of human subjects until the IRB can assess the monitor’s report.  
The Research Monitor is responsible for promptly reporting their observations and findings 
to the IRB. [See also Appendix D] 
 
Consultant (Neil H. Bander, MD):  Will provide insight and guidance in overall study 
design, use of antibody, and correlative studies examining PSMA expression.  [see also 
Section 15.1] 
 
15.1 
Conflicts of Interest 
 
Neil H. Bander, MD will serve as an unpaid consultant on the study.  He holds the patent 
rights to J591 and has served as a paid consultant to BZL Biologics (company that has 
assisted in the production of the J591 monoclonal antibody).  He will have no access to any 
of the study data other than the blinded material (circulating tumor cells and archived tissue 
slides) on which some of his lab personnel may perform PSMA staining.  He will have no 
role in screening of subjects, obtaining informed consent, treatment of the subjects, or 
analysis and reporting of the data. 
 
 
16. Funding 

54 
 
 
This protocol has been initiated with WCMC funding as well as funding via the WCMC 
CTSC.  Funds from WCMC have been and will be supplemented through past grants from 
the Cancer Research Institute, the David H. Kock Foundation, and the National Cancer 
Institute.  Part of the Study Chair’s funding through a K12 mechanism (KL2 RR024997-01 
(PI: Imperato-McGinley) K12 Clinical & Translational Research Training Scholars Award) 
and Prostate Cancer Foundation Young Investigator’s award will cover his time and effort in 
the development of the protocol.  The study will be performed at the WCMC CTSC through 
funds via the WCMC CTSA (UL1 RR024996).  Additional study sites have preferentially 
been chosen because of available CTSA funding.  Some of the correlative studies (adrenal 
androgen levels, plasma markers of hemostasis, fibrinolysis, and angiogenesis) will be 
performed in the WCMC CTSC core lab and will be funded via the CTSA. The user 
ID/password protected/encrypted web-based database will also be built and run by WCMC 
CTSC personnel funded via the CTSA. 
 
Additional funding for the WCMC site will be obtained through the Department of Defense 
(via a DOD Prostate Cancer Research Program Clinical Trial Award (Funding Opportunity 
Number W81XWH-08-PCRP-CTA, PC081664).   There will be strict non-overlapping 
budgets, as funds are available from multiple sources.  Other sites will be funded via their 
CTSA and supplemented by the WCMC Urologic Oncology Research Fund. 

55 
 
 
17.  Additional Study Sites 
 
The study protocol has been developed by WCMC investigators.  However, the Study Chair 
and other WCMC investigators have incorporated changes to the study design based upon 
input from a core group of investigators at additional sites provided via email, 
teleconferences, and an investigator meeting at the 2008 ASCO Annual Meeting.  The core 
group of study investigators who provided input on study design will be included in initial 
safety review.   
 
The below additional study sites (and principal investigators) are collaborators on this study 
protocol: 
 
 
University of Southern California (David Quinn) 
Indiana University (Costantine Albany) 
University of Iowa (Dan Vaena) 
Emory University (Omer Kucuk, David Schuster) 
University of Pittsburgh (Leonard Appleman) 
Cedars Sinai (Edwin Posadas) 
University of Utah (Neeraj Agarwal) 
Georgetown University (George Phillips) 
University of Kansas (Peter Van Veldhuizen) 
University of Arizona (Parminder Singh) 
UF Health – Orlando (Julio Hajdenberg) 
 
 
 

56 
 
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63 
 
 
 
APPENDICIES 
 
 
 
• Appendix A - Performance Status Criteria 
• Appendix B – Stopping Rules from prior phase II study 
• Appendix C - % Skeleton for Radiotherapy 
• Appendix D – Department of Defense Information 
• Appendix E – Radiographic guidelines 
• Appendix F – Substitution for ketoconazole (selected countries outside of U.S.) 
• Appendix G – Functional Assessment of Cancer Therapy – Prostate (FACT-P) 
• Appendix H – PIRADS v2 

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

65 
 
APPENDIX B 
 
 
Stopping Rules (from phase 2 single-dose study, to be used as a guideline for DSMB 
reporting) 
 
In the initial portion of the single-dose phase II study of 177Lu-J591 for men with metastatic 
CRPC, the FDA required notification with a hold on further enrollment pending review if any of 
the below criteria were met.  For the current study, the DSMB must be notified when any of the 
below stopping rules occur.  Should >1 subject within the initial 9 experience any of the 
following, further enrollment will be held until DSMB review and FDA permission for 
continuation is given. 
 
Hematologic 
• 
Grade 4 thrombocytopenia that persists for ≥ 14 days after therapy  
• 
Grade 4 thrombocytopenia that requires > 2 platelet transfusions over a 14 day 
period (note that multiple units of platelet products given together are considered a 
single transfusion) 
• 
Grade 3 thrombocytopenia persisting > 30 days 
• 
Grade 4 neutropenia that requires growth factor support for more than 14 days 
• 
Grade 3 neutropenia that persists > 30 days 
• 
Febrile neutropenia 
Non-hematologic 
• Any ≥ Grade 3 non-hematologic toxicity considered by the investigator to be related 
to study drug (radiolabeled J591) 
The NCI Common Toxicity Criteria for adverse events (CTCAE) version 4.0 will be utilized. 

66 
 
Appendix C Calculation of % Skeleton Involvement* 
 
 
*International Commission on Radiological Protection: Task Group on Reference Man. Report of 
the task Group on Reference Man: a report prepared by a task group of Committee 2 of the 
International Commission on Radiological Protection. Oxford; New York: Pergamon Press, 
1975 
 
 

67 
 
Appendix D 
 
Protocol Addendum 
 
A Randomized Phase 2 Trial of 177Lu Radiolabeled Monoclonal Antibody HuJ591 (177Lu-J591) 
and Ketoconazole in Patients with High-Risk Castrate Biochemically Relapsed Prostate Cancer 
After Local Therapy  
IRB # 0810010067  
HRPO Log Number A-15378 
 
 
The following are reporting requirements and responsibilities of the Principal Investigator 
to the United States Army Medical Research and Materiel Command’s (USAMRMC) 
Office of Research Protections (ORP), Human Research Protection Office (HRPO). 
 
        (1)  The protocol will be conducted in accordance with the protocol submitted to and 
approved by the USAMRMC ORP HRPO and will not be initiated until written 
notification of approval of the research project is issued by the USAMRMC ORP HRPO.   
 
        (2)  Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command as a part of 
their responsibility to protect human subjects in research.  Research records will be stored 
in a confidential manner so as to protect the confidentiality of subject information.   
 
        (3)  All unanticipated problems involving risk to subjects or others, serious adverse 
events related to participation in the study and subject deaths related to participation in 
the study will be promptly reported by phone (301-619-2165), by email 
(hsrrb@.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office of 
Research Protections, Human Research Protection Office.  A complete written report will 
follow the initial notification.  In addition to the methods above, the complete report will be 
sent to the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-RP, 504 
Scott Street, Fort Detrick, Maryland 21702-5012.   
 
        (4)  Suspensions, clinical holds (voluntary or involuntary), or terminations of this 
research by the IRB, the institution, the Sponsor, or regulatory agencies will be promptly 
reported to the USAMRMC ORP HRPO. 
 
        (5)  Any deviation to the protocol that may have an adverse effect on the safety or 
rights of the subject or the integrity of the study will be reported to the USAMRMC ORP 
HRPO as soon as the deviation is identified.   
 
        (6)  Major modifications to the research protocol and any modifications that could 
potentially increase risk to subjects will be submitted to the USAMRMC ORP HRPO for 
approval prior to implementation.  All other amendments will be submitted with the 
continuing review report to the USAMRMC ORP HRPO for acceptance. 
 

68 
 
        (7)  A copy of the approved continuing review report and the local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these documents 
become available.  A copy of the approved final study report and local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these documents 
become available.   
 
        (8)  The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or 
other government agency concerning this clinical investigation or research, the issuance of 
Inspection Reports, FDA Form 483, warning letters or actions taken by any Regulatory 
Agencies including legal or medical actions and any instances of serious or continuing 
noncompliance with the regulations or requirements that relate to this clinical investigation 
or research will be reported immediately to USAMRMC ORP HRPO.   
 
 
Guidance for the Requirement of a Medical Monitor 
 
    Per DoD Directive 3216.02, all greater than minimal risk studies require a Medical 
Monitor.  The USAMRMC ORP HRPO also reserves the authority to require assignment 
of a Medical Monitor for those protocols assessed as presenting no greater than minimal 
risk to the subjects participating in the study.   
 
 
Responsibilities of the Medical Monitor 
 
The medical monitor is required to review all unanticipated problems involving risk to 
subjects or others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event.  At a minimum, the medical 
monitor must comment on the outcomes of the event or problem and in case of a serious 
adverse event or death, comment on the relationship to participation in the study.  The 
medical monitor must also indicate whether he/she concurs with the details of the report 
provided by the principal investigator.  Reports for events determined by either the 
investigator or medical monitor to be possibly or definitely related to participation and 
reports of events resulting in death must be promptly forwarded to the USAMRMC ORP 
HRPO. 
 
 
 
Please indicate the name of the medical monitor and the role they will have in this research 
study.  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. 
 
 
Research  Monitor:  John Leonard, MD 
 
 

69 
 
Describe the specific role of the Research Monitor in this research study:   
 
The Research Monitor is responsible to oversee the safety of the research and report observations/findings to 
the IRB of Record or a designated official.  The Research Monitor will review all unanticipated problems 
involving risk to volunteers or others associated with the protocol and provide an unbiased written report of 
the event to the IRB of Record. The Research Monitor may discuss the research protocol with the 
investigators, interview human subjects, and consult with others outside of the study about the research.  The 
Research Monitor shall have authority to stop the research protocol in progress, remove individual human 
subjects from the study, and take whatever steps are necessary to protect the safety and well-being of human 
subjects until the IRB can assess the monitor’s report.  The Research Monitor is responsible for promptly 
reporting their observations and findings to the IRB. 

70 
 
Appendix E 
 
Radiographic Guidelines 
 
This study is designed to include men without radiographic evidence of metastases with the 
primary endpoint of various measures of time to the development of radiographic appearance of 
metastatic disease.  It is understood that there may be instances when the determination of lack 
of radiographic evidence of metastases may be equivocal.  The following general guidelines 
should be followed: 
 
Equivocal bony lesions on bone scan should be evaluated by X-ray, CT, or MRI.  If the etiology 
of the bone scan lesion may be explained by another cause (e.g. fracture), the lesion will not be 
considered evidence of osseous metastatic disease. 
 
In the case of borderline lymphadenopathy, every attempt should be made to obtain historical 
scans.  Should the lesion be present and stable over time and unchanged despite biochemical 
progression and in the opinion of the investigator does not represent metastatic disease from 
prostate cancer, the lesion will not be considered evidence of metastatic soft tissue disease. 
 
Equivocal lesions suspicious for metastatic disease should be biopsied if feasible. 
 
Keeping the guidelines in mind, any equivocal lesion should be assessed by the PI and may be 
discussed with the study chair.  Images may also be sent for central review (assuming written 
informed consent has been provided). 
 
 

71 
 
Appendix F 
 
Substitution for ketoconazole 
 
In countries outside of the U.S. where the administration of ketoconazole for prostate cancer is 
prohibited, substitution of an alternative form of secondary hormonal therapy (or continuation of 
LHRH agonist/antagonist alone) with approval of the study chair will be allowed. 
 

72 
 
Appendix G 
Functional Assessment of Cancer Therapy – Prostate (FACT-P), version 4 

73 
 
Appendix H 
Summary of PIRADS V2 Scoring 
 
Magnetic resonance imaging (MRI) is the reference standard imaging test for the local staging of 
prostatic carcinoma. Prostate cancer staging is according to the tumor nodes metastases (TNM) 
criteria established by the American Joint Committee on Cancer. 
 
To overcome variation in the performance, interpretation, and reporting of prostate MRI exams, the 
European Society of Urogenital Radiology (ESUR) drafted guidelines for the MR imaging and MR 
reporting of prostate cancer with a specific radiology lexicon referred to as the PI−RADS system. 
Ever since then the use of PI−RADS version 1 (PI−RADS v1) for the identification and grading of 
tumor foci with MRI has garnered tremendous interest. However, experience from working with 
PI−RADS v1 has also revealed several limitations, in part due to rapid progress in the field. In an 
effort to make PI−RADS standardization more globally acceptable, the American College of 
Radiology (ACR), ESUR and the AdMeTech Foundation established a Steering Committee to build 
upon, update and improve upon the foundation of PI−RADS v1. This effort resulted in the 
development of PI−RADS v2. 
 
Assignment of a PI−RADS v2 Assessment Category is based on multi−parametric MRI (mpMRI) 
findings only and does not incorporate other factors such as serum prostate specific antigen (PSA), 
digital rectal exam, clinical history, or the choice of treatment. A sector map (adapted from a 
European Consensus Meeting and the ESUR Prostate MRI Guidelines 2012) employing thirty‐nine 
sectors/regions: thirty‐six for the prostate, two for the seminal vesicles and one for the external 
urethral sphincter is used for standardized reporting and interpretation. 
 
PI−RADS v2 Assessment Categories: 
 
PIRADS 1− Very low (clinically significant cancer is highly unlikely to be present) 
PIRADS 2− Low (clinically significant cancer is unlikely to be present) 
PIRADS 3− Intermediate (the presence of clinically significant cancer is equivocal) 
PIRADS 4− High (clinically significant cancer is likely to be present) 
PIRADS 5− Very high (clinically significant cancer is highly likely to be present) 
 
When assessing the peripheral zone lesions, diffusion−weighted imaging (DWI) component of the 
mpMRI is the primary determining sequence (dominant technique) for assigning the PIRADS score. 
 
When assessing the transition zone lesions, T2−weighted pulse sequence (T2W) of the mpMRI is the 
primary determining sequence (dominant technique) for assigning the PIRADS score. 
 
PI−RADS assessment for peripheral zone lesions: 
 
DWI  
T2W  
DCE  
PIRADS  
1 
Any 
Any 
1 
2 
Any 
Any 
2 
3 
Any 
− 
3 

74 
 
3 
Any 
+ 
4 
4 
Any 
Any 
4 
5 
Any 
Any 
5 
 
PI−RADS assessment for transition zone lesions: 
 
T2W 
DWI 
DCE  
PIRADS  
1 
Any 
Any 
1 
2 
Any 
Any 
2 
3 
≤4 
Any 
3 
3 
5 
Any 
4 
4 
Any 
Any 
4 
5 
Any 
Any 
5 
 
PI−RADS scoring for DWI: 
 
Score  Peripheral Zone (PZ) or Transition Zone (TZ)  
1  
No abnormality (i.e. normal) on ADC and high b‐value DWI  
2  
Indistinct hypointense on ADC  
3  
Focal mildly/moderately hypointense on ADC and isointense/mildly hyperintense 
on high b‐value DWI.  
4  
Focal markedly hypontense on ADC and markedly hyperintense on high b‐value 
DWI; <1.5cm in greatest dimension  
5  
Same as 4 but ≥1.5cm in greatest dimension or definite extraprostatic 
extension/invasive behavior  
 
 
PI−RADS scoring for T2W: 
 
Score  
Peripheral Zone (PZ)  
1 
Uniform hyperintense signal intensity (normal)  
2 
Linear or wedge‐shaped hypointensity or diffuse mild hypointensity, usually 
indistinct margin 
3 
Heterogeneous signal intensity or non‐circumscribed, rounded, moderate 
hypointensity. Includes others that do not qualify as 2, 4, or 5 
4 
Circumscribed, homogenous moderate hypointense focus/mass confined to prostate 
and <1.5 cm in greatest dimension 
5 
Same as 4 but ≥1.5cm in greatest dimension or definite extraprostatic 
extension/invasive behavior 
 
PI−RADS scoring for T2W: 
 
Score  
Transition Zone (TZ)  
1 
Homogeneous intermediate signal intensity (normal) 
2 
Circumscribed hypointense or heterogeneous encapsulated nodule(s) (BPH) 
3 
Heterogeneous signal intensity with obscured margins. Includes others that do not 

75 
 
qualify as 2, 4 or 5 
4 
Lenticlular or non‐circumscribed, homogeneous, moderately hypointense, and <1.5 
cm in greatest dimension 
5 
Same as 4 but ≥1.5cm in greatest dimension or definite extraprostatic 
extension/invasive behavior 
 
PI−RADS scoring for DCE: 
 
Score  Peripheral Zone (PZ) or Transition Zone (TZ)  
(−) 
No early enhancement, or diffuse enhancement not corresponding to a focal finding 
on T2W and/or DWI or focal enhancement corresponding to a lesion demonstrating 
features of BPH on T2W  
(+) 
Focal, and; earlier than or contemporaneously with enhancement of adjacent normal 
prostatic tissues, and; corresponds to suspicious finding on T2W and/or DWI  
 
 
Patients diagnosed with PCa who have been treated earlier with hormonal therapy and are now 
progressed to castration resistant prostate cancer (CRPC) without any evidence of frank metastasis 
on conventional imaging modalities (CT scan, Bone scan, CXR) will be required to undergo 3−Tesla 
mpMRI. If their PI−RADS score is 3 or below, they will be included in the study since they are 
unlikely to have local disease progression. 
 
EPE Scoring: 
 
Standardized criteria used for assessment of extra-prostatic extension (EPE) at MRI proposed by 
the European Society of Uroradiology [1]. 
 
EPE 
Score 
Original 
PI-RADS 
criteria 
Modified PI-RADS criteria 
1 
Abutment 
Clearly confined, intervening normal tissue between 
tumor and intact prostate capsule 
2 
Not specified 
Abutment, tumor abuts but does not deform capsule 
3 
Irregularity 
Irregularity, tumor abuts capsule causing capsular 
irregularity 
4 
Bulge, loss of capsule, 
neurovascular 
bundle 
thickening 
Tumor bulges, deforms or obscures (loss of) 
capsule with or without neurovascular bundle 
thickening 
5 
Measurable extracapsular 
disease 
Gross/measurable extracapsular disease 
 
 
Note: 1) For PI‐RADS v2 clinically significant cancer is defined on pathology/histology as Gleason 
score > 7 (including 3+4 with prominent but not predominant Gleason 4 component), and/or volume 
> 0.5cc, and/or extraprostatic extension (EPE).  
2) PI-RADS score of 5 for DWI and/or T2W represents lesion of ≥1.5cm in greatest dimension [Ref: 
ESUR guidelines] 

76 
 
3) Higher tumor incidence correlates with higher PI-RADS score [1] 
4) Imaging features used to assess for EPE include asymmetry or invasion of the neurovascular 
bundles, a bulging prostatic contour, an irregular or spiculated margin, obliteration of the 
rectoprostatic angle, a tumor‐capsule interface of greater than 1.0 cm, breach of the capsule with 
evidence of direct tumor extension or bladder wall invasion. [Ref: ESUR guidelines] 
 
 
Ref: 
1. Schieda N, Quon J, Lim C, et al. Evaluation of the European Society of Urogenital 
Radiology (ESUR) PI-RADS scoring system for assessment of extra-prostatic extension 
in prostatic carcinoma, Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.06.016  
2. Junker D, Schäfer G, Edlinger M, et al. Evaluation of the PI-RADS Scoring System for 
Classifying mpMRI Findings in Men with Suspicion of Prostate Cancer. BioMed Research 
International. 2013;2013:252939. doi:10.1155/2013/252939.