Clinical trial NCT02410577
Conditions: Glioblastoma
Keywords: 89Zr-J591 15-002
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-04-01; Completion date: 2018-08-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test a new imaging agent called 89Zr-J591 (stands for humanized antibody called J591, that is attached to a radioactive material called Zirconium-89) in patients with glioblastoma multiforme.

Detailed description:

Arms: arm 1: Patients will not be required to fast prior to imaging with 89Zr-J591 injection or imaging. The total dose of humanized mAb J591 will be 20mg. Patients will first receive an injection of 18-19mg of unchelated J591 to reach the total administered dose of antibody (IND11407) followed by 5 mCi (+/- 10%) of 89Zr-J591 (1 to 2 mg). Administration of the cold antibody will be followed by the labeled compound.
Interventions: intervention 1: 89Zr-J591 intervention 2: PET/CT Scan intervention 3: MRI intervention 4: Blood draw
Intervention descriptions: intervention 1: The intervention is the administration of an injection of 18-19mg of unchelated J591 to reach the total administered dose of antibody followed by 5 mCi (+/- 10%) of 89Zr-J591 (1 to 2 mg) . After administration of the experimental tracer, the patient will undergo a Brain PET/CT scan 24 hours, 48 hours post injection and 3-8 days. The 48 hour scan is strongly suggested, but optional. intervention 2: None intervention 3: None intervention 4: Bloods samples will be drawn immediately before and approximately 30 minutes after 89Zr-J591 injection.

Protocol documents:
Prot_SAP_000.pdf: 
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A Pilot Study of 89Zr-J591 Anti-Prostate-Specific Membrane Antigen Monoclonal 
Antibody in Patients with Glioblastoma Multiforme 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal 
Investigator/Department: 
Joseph R. Osborne, MD,PhD 
Dept. of Radiology – Molecular 
Imaging and Therapy Service (MITS) 
Co-Principal 
Investigator(s)/Department: 
Philip H. Gutin, MD 
Christian Grommes, MD 
Dept. of Neurosurgery 
Dept. of Neurology 
Investigator(s)/Department: 
Steven Larson, MD 
Jorge Carrasquillo, MD 
Neeta Pandit-Taskar, MD 
Wolfgang Weber, MD 
Michelle Bradbury, MD/PhD 
Robert Young, MD 
Andrei Holodny, MD 
Sirish Kishore, MD 
John Humm, PhD 
Joe O’Donoghue, PhD 
Antonio Omuro, MD 
Lisa De Angelis, MD 
Craig Nolan, MD 
Igor Mellinghoff, MD 
Thomas Kaley, MD 
Elena Pentsova, MD 
Eli Diamond, MD 
Adrienne Biore, MD/PhD 
Mariza Daras, MD 
Mark Bilsky, MD 
Cameron Brennan, MD 
Ilya Laufer, MD 
Viviane Tabar, MD 
Marc Rosenblum, MD 
Kathryn Beal, MD 
Daniel Spratt, MD 
Mithat Gonen, PhD 
Dept. of Radiology – MITS 
Dept. of Radiology – MITS 
Dept. of Radiology – MITS 
Dept. of Radiology – MITS 
Dept. of Radiology 
Dept. of Radiology 
Dept. of Radiology 
Dept. of Radiology 
Dept. of Medical Physics 
Dept. of Medical Physics 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Pathology 
Dept. of Radiation Oncology 
Dept. of Radiation Oncology 
Dept. of Epi and Biostats 
Consenting 
Professional(s)/Department: 
Joseph Osborne, MD/PhD 
Steven Larson, MD 
Jorge Carrasquillo, MD 
Neeta Pandit-Taskar, MD 
Wolfgang Weber, MD 
Philip H. Gutin, MD 
Christian Grommes, MD 
Antonio Omuro, MD 
Lisa De Angelis, MD 
Dept of Radiology – MITS 
Dept of Radiology – MITS 
Dept of Radiology – MITS 
Dept of Radiology – MITS 
Dept of Radiology – MITS 
Dept. of Neurosurgery 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 


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Craig Nolan, MD Igor 
Mellinghoff, MD 
Thomas Kaley, MD 
Elena Pentsova, MD 
Eli Diamond, MD 
Adrienne Boire, MD/PhD 
Mariza Daras, MD 
Mark Bilsky, MD 
Cameron Brennan, MD 
Ilya Laufer, MD 
Viviane Tabar, MD 
Rupa Juthani, MD 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurology 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
Dept. of Neurosurgery 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Participating Institutions – If multicenter 
study coordinated by MSKCC: 
PI's Name 
Site's Role 
Weil Cornell Medical College 
Neil Bander, MD 
Data Analysis 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..............................................................................5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................................6 
 
3.0 
BACKGROUND AND RATIONALE ............................................................................................6 
 
J591 ................................................................................................................................................7 
 
DFO-J591........................................................................................................................................8 
 
Radiolabeled J591...........................................................................................................................9 
 
Anti-PSMA Monoclonal Antibodies ..................................................................................................9 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................................13 
 
4.1 
Design....................................................................................................................................13 
 
4.2 
Intervention ............................................................................................................................13 
 
5.0 
DIAGNOSTIC AGENTS ............................................................................................................14 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................................15 
 
6.1 
Subject Inclusion Criteria........................................................................................................15 
 
6.2 
Subject Exclusion Criteria.......................................................................................................15 
 
7.0 
RECRUITMENT PLAN ..............................................................................................................15 
 
8.0 
PRETREATMENT EVALUATION .............................................................................................16 
 
9.0 
TREATMENT/INTERVENTION PLAN .......................................................................................16 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION...........................................................18 
 
11.0 TOXICITIES/SIDE EFFECTS ....................................................................................................20 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..............................21 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..............................................................................21 
 
14.0 BIOSTATISTICS .......................................................................................................................21 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ........22 
 
15.1 Research Participant Registration ..........................................................................................22 
 
15.2 Randomization .......................................................................................................................22 
 
16.0 DATA MANAGEMENT ISSUES ................................................................................................22 
 
16.1 Quality Assurance ..................................................................................................................23 
 
16.2 Data and Safety Monitoring ....................................................................................................23 
 
17.0 PROTECTION OF HUMAN SUBJECTS ...................................................................................24 
 
17.1 Privacy ...................................................................................................................................24 
 
17.2 Serious Adverse Event (SAE) Reporting ................................................................................24 
 
17.2.1 ............................................................................................................................................25 


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18.0 INFORMED CONSENT PROCEDURES ...................................................................................25 
 
19.0 REFERENCES ..........................................................................................................................26 
 
20.0 APPENDICES ...........................................................................................................................27 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Immuno-PET with radiolabeled antibody 89Zr-J591 will assess quantitatively the tumor vasculature- 
specific expression of the prostate-specific antigen (PSMA) in patients with Glioblastoma Multiforme. 
Glioblastoma is a cerebral neoplasm with a uniformly poor prognosis—a disease for which targets 
for new treatments are constantly sought. One such target might be prostate-specific membrane 
antigen (PSMA), which is expressed in prostate carcinoma and, more importantly in this context, in 
the endothelium of vessels in most malignant solid tumors including glioblastoma [1]. The purpose of 
this experiment is to assess the binding of 89Zr-J591 in patients (n=10) with glioblastoma multiforme. 
An assessment of binding will ascertain whether this target is expressed at adequate levels for 
sustained radionuclide or antibody-drug conjugate targeting directed towards the vessels or cells 
within the perivascular niche. 
 
Schema 
 
 
Clinical diagnosis of Glioblastoma 
Eligibility for surgery (n = 10) 
 
 
 
Baseline Eligibility 
criteria Disease 
assessment 
Physical Exam 
Clinical labs; Vitals signs 
 
 
 
Day 0 
Blood sample collection pre and post injection 
5mCi (+/-10%) 89Zr-J591 per IND 114077 
Vitals and Adverse events 
 
 
 
 
Subsequent Imaging Days 1, 2 (optional), 3-8 
Pet scans may be obtained at each of the following time points: approximately 24 hours (Day 1) , 
48 (Day 2), and 3-8 days, Blood sample collection on each imaging day 
The 48 hour scan (day 2) is optional 
 
 
 
Day 3–  10 (Day of surgery) 
Blood sample collection, Quantitative autoradiography and 
specialized staining by the medical physics co-investigator  
team Standard-of-Care pathologic accessioning 


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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Endpoints 
 
1a To determine the binding of 89Zr-J591 for the vasculature of glioblastoma multiforme in 
human subjects. 
1b  To confirm that pre-surgical tumor localization of radiotracer is related to PSMA expression 
based on correlation with post-surgical histopathologic analysis. 
 
3.0 
BACKGROUND AND RATIONALE 
 
Glioblastoma multiforme (GBM) is the most common cancer arising from the brain. It is also the most 
aggressive subtype (WHO grade IV) among gliomas, a collection of tumors including 
oligodendrogliomas and astrocytomas. Malignant gliomas are diffusely infiltrative and hence all 
locally directed therapies such as surgery or radiotherapy are inherently palliative. Even with 
maximum treatment at initial diagnosis, malignant gliomas have a dismal prognosis with estimated 5- 
year survival rates of 10% [2]. Standard management is maximal surgical resection followed by 
involved field radiotherapy with concomitant temozolomide given daily at 75 mg/m2 and followed by 
monthly cycles of adjuvant temozolomide given at 150-200 mg/m2/d on days 1 to 5 for a total of 6 
cycles. However, GBMs are relentlessly progressive, and median survival with this treatment is only 
14 months [2]. 
 
The treatment of recurrent malignant gliomas represents a therapeutic challenge. The treatment 
options at recurrence remain currently limited [3]. There are currently few salvage treatment options 
that have consistently shown efficacy for recurrent GBMs [4]. A review of 225 GBM patients with 
recurrent GBM enrolled in 8 previous phase II studies, in which none of the treatments were 
considered particularly effective, showed a 6 month PFS of 15% for GBM [5]. Systemic 
administration of the DNA alkylator BCNU results in a 6mPFS (6 month progression free survival) 
rate of only 17.5% for recurrent GBM. Glioblastomas are highly hypoxic tumors with strong 
endogenous expression of HIF-1a and of VEGF and its receptors and a consequently vigorous 
angiogenic phenotype. Anti-angiogenic therapies with antibodies (bevacizumab) and tyrosine kinase 
inhibitors of the VEGF receptor (e.g. Enzastaurin, SU11248) are already demonstrating an important 
impact in glioblastoma treatment. Bevacizumab was approved by the FDA for the treatment of 
recurrent GBMs based on promising efficacy in a landmark Phase II trial [4, 6]. Tumor vascular 
targeting, exploiting the phenotypic and genotypic variations of tumor (versus normal) vessels, is 
another potentially valuable anti-angiogenic approach for glioblastoma. 
 
The endothelium of malignant brain tumors is a particularly attractive target for vascular-targeted 
radio-immunotherapy, because: 
 
1.  Glioblastomas are highly vascular, 
2.  Radiation-resistant glioma stem cells appear to reside, at least in part, in a perivascular niche 
sustained largely by endothelium [7] 
3.  Endothelium can be exposed to radiolabeled antibody much more readily than can the tumor 
substance, which is protected by the blood-brain barrier. 


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PSMA is expressed in prostate carcinoma and, more importantly in this context, in the endothelium 
of vessels in most malignant solid tumors [8, 9]. We have immuno-stained the blood vessels of 32 
paraffin-fixed glioblastoma specimens with the anti-PSMA mAb 3E6 and found positive PSMA 
staining in the endothelium in 100% of the cases [9, 10]. 
 
 
Table 1. Extent of Vascular Staining for PSMA 
 
Extent 
<5% 
6-25% 
26-50% 
51-75% 
75-100% 
No. of Tumors 
0 
8 
2 
15 
7 
 
 
 
Table 2. Intensity of Staining for PSMA 
 
Intensity 
0 
1+ 
2+ 
3+ 
 
No. Tumors 
0 
3 
15 
14 
 
 
 
J591 is an anti-PSMA antibody that binds with high affinity to the external domain of PSMA. There 
has been extensive clinical experience at Weill-Cornell and at MSKCC with the naked antibody and 
with 177lutetium-labeled antibody in the treatment of prostate cancer and, more recently, in the 
vascular-targeted therapy of a variety of other solid tumors. We are in the early stages of designing a 
radio-immunotherapy trial with radiolabeled J591as an anti-angiogenic agent for glioblastoma but 
before proceeding we desire to demonstrate physiologic binding of J591 to the tumor vessels. 89Zr- 
J591 PET has been used safely in patients with prostate cancer both primary disease and metastatic 
castration resistant disease [11]. Our plan is to demonstrate binding of J591 with 89Zr-J591 PET and 
also optimize 89Zr-J591 PET in glioblastoma patients for the possibility of measuring response to 
radiolabeled J591 and other anti-angiogenic agents. 
 
J591 
 
The J591 mAb is a humanized monoclonal antibody directed at the extracellular domain of human 
PSMA [12]. J591 was derived from murine J591 using Biovation’s (Biovation, Aberdeen, Scotland, 
UK) de-immunization 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. 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 humanized 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 


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Table 3. 89Zr-DFO-J591 Absorbed Doses in 70-kg Standard Man 
 
 
89Zr-DFO-huJ591 Patient Dosimetry 
 
# of 
Injections/CT 
scans 
Dose per 
CT 
scan/cGy 
CT 
Extent 
Activity of 89Zr-DFO- 
 
huJ591 
5 
mCi 
1 
 
Low dose WB CT scan 
80 
mA 
0 
0.90 
WB 
Low dose Head CT 
 
Head 
scan 
80 
mA 
3 
0.90 
only 
Ultra low dose WB CT 
 
scan 
10 
mA 
0 
0.11 
WB 
 
1 89Zr- 
DFO- 
Absorbed Dose 
 
TOTAL 
Absorbed 
huJ591 
CT 
cGy per 
Dose 
Target Organ 
cGy/mCi 
admin 
cGy 
cGy 
Adrenals 
2.03 
10.1 
0.00 
10.1 
Brain 
0.52 
2.6 
2.70 
5.3 
Breasts 
0.82 
4.1 
0.00 
4.1 
Gallbladder Wall 
2.76 
13.8 
0.00 
13.8 
LLI Wall 
0.81 
4.1 
0.00 
4.1 
Small Intestine 
1.09 
5.4 
0.00 
5.4 
Stomach Wall 
1.22 
6.1 
0.00 
6.1 
ULI Wall 
1.23 
6.2 
0.00 
6.2 
Heart Wall 
3.17 
15.8 
0.00 
15.8 
Kidneys 
3.53 
17.6 
0.00 
17.6 
Liver 
7.69 
38.4 
0.00 
38.4 
Lungs 
2.14 
10.7 
0.00 
10.7 
Muscle 
0.85 
4.2 
0.00 
4.2 
Ovaries 
0.90 
4.5 
0.00 
4.5 
Pancreas 
1.86 
9.3 
0.00 
9.3 
Red Marrow 
1.19 
5.9 
0.00 
5.9 
Osteogenic Cells 
1.16 
5.8 
0.00 
5.8 
Skin 
0.57 
2.9 
0.00 
2.9 
Spleen 
2.72 
13.6 
0.00 
13.6 
Testes 
0.58 
2.9 
0.00 
2.9 
Thymus 
1.16 
5.8 
0.00 
5.8 
Thyroid 
0.69 
3.4 
2.70 
6.1 
Urinary Bladder Wall 
0.77 
3.8 
0.00 
3.8 
Uterus 
0.87 
4.4 
0.00 
4.4 
Total Body 
1.06 
5.3 
0.00 
5.3 
 
Effective Dose Equivalent 
(rem/mCi) 
1.99 
9.96 
0.08 
10.05 
 
1 Pandit-Taskar et al, 89Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate 


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cancer. 
Eur J Nucl Med Mol Imaging, published online Aug, 2014: DOI 10.1007/s00259-014-2 
Dosimetry was performed in accordance with the methods recommended by the MIRD Committee of the 
Society of Nuclear Medicine and Molecular Imaging as implemented in the OLINDA/EXM software 
application 
 
 
DFO-J591 
 
In order to radiolabel J591 with + emitting radionuclides such as 89Zr, the J591 antibody molecule is 
first conjugated to a macrocyclic chelating agent, 1,4,7,10-tetraazacyclododecane- N, N’, N’’, N’’’- 
tetraacetic acid (DFO) by direct coupling of one of the four carboxylic acid groups of DFO to the 
primary amines present in the protein structure. The DFO conjugated antibody is formulated in 0.3 M 
ammonium acetate, pH 7.0 at a nominal concentration of 8 mg/mL. 
 
Radiolabeled J591 
 
The DFO-J591 antibody molecule is labeled with radio-metal 89Zr 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 auto-radiolysis 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. 
 
Anti-PSMA Monoclonal Antibodies 
 
The PSMA gene has been cloned, sequenced, and mapped to chromosome 11 [13]. PSMA is 
anchored to the cell membrane. Initial validation of PSMA as an in vivo target has been borne out by 
imaging trials with mAb 7E11/CYT-356 marketed as ProstaScint (Capromab) [14-17]. Molecular 
mapping, however, indicates that capromab targets a portion of the PSMA molecule that is within the 
cell’s interior and not exposed on the outer cell surface [10, 18]. In living cells, this internal binding 
site is not accessible to antibody. Successful imaging with capromab relates to targeting of 
dead/dying cells within tumor sites. It has been noted that a mAb to the extracellular domain of 
PSMA would provide benefits including improved localization in patients and enhanced imaging and 
therapy. At Weill Medical College, Liu et al have reported the development of 4 IgG mAb to the 
external domain of PSMA (PSMAext) [19]. These antibodies to PSMAext demonstrate high affinity 
binding to PCa cells in tissue culture, on tissue sections, and in animal models in vivo. Furthermore, 
unlike capromab, these mAb can bind to viable cells because the target-binding site is present on 
the exterior of the cell. In in vitro and in vivo animal models of prostate cancer, for which these 
antibodies were developed, 177Lu -J591 has demonstrated substantial anti-tumor activity. In these 
studies, immune-deficient ‘nude’ mice are implanted intramuscularly with PSMA-expressing human 
prostate cancer cells [18]. Cancers are allowed to ‘establish’ for a period of approximately 2 weeks 
during which time the cancer develops a blood supply allowing further growth. At the time of 
treatment initiation, the cancer implants average 1.0 cm in diameter (or approximately 5% of the 
animal’s body weight. Results demonstrate that 177Lu -J591 induces an average of >90% tumor 
reduction compared to control-treated mice (saline or non-radioactive antibody or 177Lu -irrelevant 


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antibody). A portion of the animals showed complete disappearance of tumor. These studies also 
demonstrate significant improvement in survival of the 177Lu -J591-treated animals, with a large 
proportion of cured animals. Cancers not expressing PSMA do not respond to treatment 
demonstrating the specificity of the treatment. Animals treated with multiple, low doses of 177Lu - 
J591, rather than single, larger doses of 177Lu -J591, appear to have better tumor reduction 
responses, better survival, and less toxicity. 
 
Prior studies/Preliminary results 
 
The first step in evaluating this hypothesis in human subject will be to evaluate 89Zr-J591 bio- 
distribution, dosimetry and tumor binding in patients with glioblastomas. 
 
CLINICAL EXPERIENCE: 
 
111Indium J591- (Cornell protocol 1099-905) 
 
Fourteen patients were entered in a Phase 1 study where patients received 4 
weekly doses of 111Indium labeled J591. One patient, at the highest dose level, 
developed an anaphylactic reaction associated with a too rapid infusion rate, 
and he received only a single dose. He recovered promptly and completely 
but, due to the reaction, was not given further doses. The infusion rate has 
since been limited to 5 mg/minute. Another patient received only a single dose 
due to rapid disease progression and loss of protocol eligibility. The remaining 
12 patients, who received total doses ranging from 62.5 mg/m2 to 500 mg/m2, 
demonstrated the following Grade 1 to 3 (CTCAE) hematological adverse 
events: neutropenia, lymphocytopenia, leukocytopenia, hemoglobinemia, and 
thrombocytopenia. 
 
Observed Adverse Events 
 
All of these hematological toxicities were transient in nature and returned to 
baseline levels during the course of the study. Imaging studies, done in all 
patients, demonstrated excellent antibody targeting to tumor sites without 
significant targeting to normal tissue sites. Results demonstrated no clinical or 
laboratory evidence of immunogenicity of the J591 antibody. 
 
90Yttrium J591- (Cornell 
protocol 0200-119) 
 
The objectives of this trial 
were to study the targeting, 
dosimetry, toxicity, 
pharmacokinetics and the 
immunogenicity of the 
humanized antibody (HAHA) 
as well as the preliminary 
therapeutic efficacy. Patients 
received an initial dose of 


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111In-DFO-J591-GS (20 mg, 5mCi) for pharmacokinetic and bio-distribution determinations, followed 
one-week later, with a dose of 90Y-DFO-J591-GS (20 mg). The dose schedule was selected to allow 
multiple imaging sessions prior to 111In decay as well as clearance of the J591 from the initial dose 
prior to delivering the 2nd dose. The 90Y dose was selected based on prior published experience with 
other antibodies. The first dose utilizes 4-5 mCi of 111In and allows imaging for approximately one 
week. Eligible subjects were hormone-refractory with progressing prostate cancer. Twenty-nine 
subjects were entered at the following dose levels: 5, 10, 15, 17.5 and 20 mCi/m2.  Patients were 
eligible for up to three re-treatments if platelet and neutrophil recovery were satisfactory.  Four 
patients were re-treated. Dose-limiting toxicity was seen at 20 mCi/m2 with two patients experiencing 
thrombocytopenia with non-life threatening bleeding episodes requiring platelet transfusions. The 
17.5 mCi/m2 dose level was determined to be the maximum tolerated dose.  No re-treated patients 
experienced dose-limiting toxicity.  Non-hematologic toxicity was not dose-limiting. Among the 29 
patients receiving 111In-DFO-J591-GS, 19 patients had bone lesions and 13 patients had soft tissue 
lesions. 17 of 19 (89%) patients with bone lesions and 9 of 13 (69%) with soft tissue lesions were 
accurately targeted resulting in an overall targeting sensitivity of 26 of 
32 (81%). Two patients treated at the 20 mCi/m2 dose level exhibited 85% and 70% declines in 
PSA lasting 8 and 8.6 months prior to returning to pre-treatment values. In addition, these two 
patients had objective measurable disease responses with 90% and 40% decrease in the size of 
pelvic and retroperitoneal lymphadenopathy. Both patients were hormone-refractory with lymph 
node-only disease and had not received prior chemotherapy. The second patient was re-treated 
with 90Y-DFO-J591-GS on day 119. An additional 6 patients experienced PSA stabilization by week 
12. 
 
 
 
 
177Lutetium J591- (protocol 1100-472) 
 
35 patients with androgen-independent prostate cancer were entered on a phase I trial of 177Lu- 
J591. Patients received 10 mg/m2 J591 with doses of 177Lu ranging from 10 mCi/m2 - 75 mCi/m2. 
Several patients were re-treated. Of the 3 patients at the 75 mCi/m2 dose level, one experienced 
dose-limiting (grade 4) thrombocytopenia while the remaining 2 patients experienced grade 3 
thrombocytopenia. All 3 of these patients experienced grade 4 neutropenia, one of which was dose- 
limiting neutropenia of 6 days duration. As 2 of 3 patients at this dose level experienced DLT, no 
additional patients were entered at this dose. At the prior dose level of 70mCi/m2, 6 patients were 
entered. 2 patients had transient grade 4 neutropenia not meeting the definition of DLT; 1 of these 
patients had grade 4 thrombocytopenia. As there was only 1 DLT in these 6 patients, the 70 mCi/m2 
dose level was determined to be the MTD. Among the 35 patients receiving 177Lu -J591, 30 (86%) 
had metastatic disease detected on screening imaging studies. Specifically, 21 (60%) patients had 
bone-only metastases, 6 (17%) had soft tissue-only metastases and 3 (9%) had both bone and soft 
tissue disease. In all of these 30 patients, known sites of metastatic disease were successfully 
imaged by 177Lu-J591 scintigraphy. 


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All 35 patients in this trial had abnormal, 
rising PSAs and 7 patients had 
measurable disease.  None of the 7 
patients with measurable disease had an 
objective tumor response nor a  50% 
PSA decline. Based on PSA, 14 
demonstrated progressive disease (PSA 
increase of ≥ 25%) after treatment while 
21 of the 35 patients had evidence of 
biologic activity. 4 patients had ≥ 50% 
PSA declines lasting 3+ to 8 months, and 
16 patients had PSA stabilization (< 25% 
increase from baseline) of ≥ 28 days. The 
median duration of PSA stabilization was 60 days with a range of 28-601+ days. 
Observed Adverse Events 
The observed adverse events of this therapeutic protocol were predicted by the prior Indium study. 
Please note: these prior studies were therapeutic and diagnostic nuclides like 89Zr are unlikely to 
have a similar effect on the bone marrow and with toxicity. 
 
 
 
89Zirconium J591 
 
Localized Prostate (Cornell protocol 1202012209): The objectives of this trial were to study the 
targeting, dosimetry, toxicity, pharmacokinetics 
and the immunogenicity of the humanized 
antibody 89Zr-J591under IND 115521. A total of 
eleven patients received an initial dose of 89Zr- 
J591 (20 mg, 5mCi) for pharmacokinetic and bio- 
distribution determinations. Patients were imaged 
5-6 days after injection with all patients 
undergoing whole body PET and a limited scan of 
the pelvis. Eleven Patients were injected and 
scanned. None of the patients experiences any 
adverse effects. Imaging studies, done in all 
patients, demonstrated excellent antibody 
targeting to tumor sites without significant 
targeting to normal tissue sites. Results 
demonstrated no clinical or laboratory evidence of 
immunogenicity of the J591 antibody. Results of 
this pilot trial were published in Journal of Urology 
in 2013. 


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Metastatic Prostate 
 
Currently over 50 patients have been successfully imaged with 89Zr-DFO- 
J591 for men with metastatic prostate cancer. These results have been 
published. An estimated 98% of lesions identified on standard imaging 
(including bone scan, FDG PET, and CT) were visualized by immuno-PET 
(personal communication).  Furthermore, there were a significant number of 
lesions (~10%) that were solely identified by immuno-PET. Biopsy samples 
were performed on a subset of patients, and an estimated 90% of patients 
who had positive J591 PET scans that were otherwise negative by standard 
imaging, were histopathologically confirmed to be prostate cancer. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
Patients with recurrent glioblastoma are eligible. Additionally, patients with a newly 
diagnosed biopsy-proven glioblastoma requiring re-resection prior to initiation of therapy are 
eligible. Patient with a newly diagnosed brain lesion identified on standard-of-care imaging 
modalities such as CT or MRI that show typical imaging characteristics of a glioblastoma are 
also eligible. The patients will undergo 89Zr-J591 PET imaging. Surgical resection will be 
carried out post completion of imaging and part of the resected tumor stained for PSMA and 
graded by percentage of cells stained and by staining intensity. 
 
Standard imaging procedures: 
 
● CT scan 
● MRI 
 
Investigational diagnostic imaging agent 
 
● 
89Zr-J591 
 
This study is not designed to confirm the imaging accuracy of 89Zr-J591 and thus, a truth 
standard has not been defined for the purpose of data analyses. Efficacy studies with an 
appropriate sample size to allow for the assessment of imaging accuracy against a truth 
standard will be conducted in the future as a Phase II study. At that time, more refined 
eligibility criteria are likely to be applied to study candidates. 
 
4.2 
Intervention 
 
The intervention is the administration of an injection of 18-19mg of unchelated J591 to reach 
the total administered dose of antibody (IND11407) followed by 5 mCi (+/- 10%) of 89Zr-J591 
(1 to 2 mg) . After administration of the experimental tracer, the patient will undergo a Brain 
PET/CT scan 24 hours, 48 hours post injection and 3-8 days. The 48 hour scan is strongly 
suggested, but optional. 
 
No clinical management decisions will be made based on 89Zr J591 imaging. 


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5.0 
DIAGNOSTIC AGENTS 
 
89Zr-J591 
 
J591 is a humanized antibody that targets the external domain of PSMA, and has been studied as 
therapy as an unconjugated (“cold”) antibody, and labeled with Yttrium-90, and Lutetium-177. 
Several experiments have shown that J591 is an excellent means of targeting the tumor 
neovasculature, particularly in glioblastoma multiforme. This protocol will extend these studies into 
the realm of imaging for diagnostic and, ultimately, potential therapeutic applications. The radio- 
antibody 89Zr-J591 has characteristics that have the potential to outperform other radiotracers in use 
for glioblastoma multiforme by targeting tumor-specific angiogenesis. 
 
1.  The antigen target, PSMA, is uniquely expressed in the tumor neovasculature for multiple 
solid tumors, particularly glioblastoma multiforme (Chang S, et al. Cancer Res, 1999). 
2.  The long half-life of the 89Zr makes it possible to image at late times after injection, when 
background activity has cleared from blood and soft-tissue. 
3.  89Zr is a Positron emitter, and PET imaging has much higher sensitivity and resolution 
characteristics compared to conventional nuclear medicine imaging procedures, such as 
SPECT. 
 
We will use Zirconium-89, a positron-emitting radionuclide, labeled to J591. The final drug product is 
89Zr-J591 in human serum albumin/ saline, sterile filtered in a sterile vial, sealed with rubber septa 
and closed with aluminum stopper. 89Zr is chelated by the DFO of the DFO-J591 conjugate. Human 
serum albumin is USP grade and has been adequately tested for HBV, HCV, and HIV-1. No other 
materials of animal origin are used in the manufacture of 89Zr-J591. Manufacture of first DFO-J591 
and then 89Zr-J591 is performed by the Radiochemistry & Molecular Imaging Probes core facility at 
MSKCC. J591 is provided under IND# 114077 from Dr. Neil Bander of Cornell, which we are cross- 
referencing for information regarding its chemistry, manufacturing and controls. Cold antibody will be 
administered separately according to the IND. 
 
Zr conjugation technique 
 
 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 Subject Inclusion Criteria 
 
1.  Patients age > 25 years old < 80 years old 
2.  Patients with reoccurrence of brain tumor 
• 
The principal investigator or co-PI must review MRI and CT findings based on the 
radiologic assessment provided they meet the following imaging criteria (as 
established in the clinical trial 09-177) 
OR 
Patients with newly diagnosed GBM, and one of the following options: 
• 
Eligible for surgery after the last research scan. 
• 
Significant residual disease after initial surgery 
o The principal investigator or co-PI must review MRI and CT findings and 
agree with the presence of significant residual disease 
• 
Treatment (non-surgical) naïve 
  
3.  Karnofsky Performance Score ≥ 70 
 
6.2 
Subject Exclusion Criteria 
 
1.  Laboratory values: 
 
o Serum creatinine >2.5 mg/dL. 
o AST (SGOT) >2.5x ULN. 
o Bilirubin (total) >1.5x ULN. 
o Serum calcium >11 mg/dL. 
 
2.  Pregnant or breastfeeding (if a female is of childbearing potential, and unsure of 
pregnancy status, a standard pregnancy test should be done). 
3.  If an initial biopsy demonstrates neoplasm other than GBM 
4.  Presence of any other co-existing condition which, in the judgment of the investigator, 
might increase the risk to the subject. 
5.  Presence of serious systemic illness, including: uncontrolled inter-current infection, 
uncontrolled malignancy, significant renal disease, or psychiatric/social situations, which 
might limit compliance with study requirements 
6.  Prior treatment. 
7.  Other serious illness (es), which might preclude completion of this, study or interfere with 
determination of causality of any adverse effects experienced in this study. 
 
7.0 
RECRUITMENT PLAN 
 
A member of the patient’s treatment team at hospital will identify potential research subject. He or she 
will screen their patient’s medical records for suitable research study participants and discuss the 
study and their potential for enrolling in the research study. Potential subjects contacted by their 


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treating physician will be referred to the investigator/research staff of the study. Adult patients with 
recurrence of GBM, or newly diagnosed GBM, based on MR scan confirmation (as defined by IRB 
approved protocol 09-117), will be eligible for this trial. Additional therapies to temozolomide and 
radiation are allowable. Should the concomitant agent be available through another clinical trial, the 
site will need to ensure treatment details (dose, time of administration, and any interruptions in 
therapy). 
 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Standard clinical imaging studies will be performed within 6 weeks prior to study entry. No 
intervening new therapy is allowed between conventional imaging studies and 89Zr-J591: 
 
• 
MRI  and/or CT 
 
Laboratory tests, as part of standard of care, will be obtained within 4 weeks prior to study entry. 
 
• 
Serum creatinine 
• 
AST (SGOT) 
• 
Bilirubin 
• 
Serum calcium 
• 
Pregnancy test if applicable (within 2 weeks of study entry) 
 
Pre-surgical planning: Preoperative MRI per routine and PET-CT imaging p.i.89Zr-J591 will be 
performed and co-registered for identification of potential biopsy target/s. The surgeon will 
prospectively delineate the planned resection volume (PRV) on pre-operative neuro-navigational 
MRI co-registered to the PET-CT (iPlan workstation, BrainLAB AG). Biopsy target regions will be 
identified on the basis of tracer uptake. Regions of tracer uptake are considered potential targets if 
(1) they are within the PRV and (2) are at least 1 cm3 in volume. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Injection details: 
 
Patients will not be required to fast prior to imaging with 89Zr-J591 injection or imaging. The total dose of 
humanized mAb J591 will be 20mg. Patients will first receive an injection of 18-19mg of unchelated J591 
to reach the total administered dose of antibody (IND11407) followed by 5 mCi (+/- 10%) of 89Zr-J591 (1 
to 2 mg). Administration of the cold antibody will be followed by the labeled compound. 
 
The adverse events to this injection protocol from IND 114077 are detailed in section 11.0. We have 
injected greater than 50 patients at MSKCC with this agent with no severe AEs. 
 
Blood Samples: 
 
Bloods samples will be drawn immediately before and approximately 30 minutes after 89Zr-J591 
injection. Blood samples will also be drawn on subsequent days of imaging and day of surgery. This 
data will be used to determine the blood clearance of radiotracer and will inform the accumulation of the 


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same in the target tissue. With these additional metrics, specific binding will be easier to determine and 
safety (particularly possible follow-up therapeutic protocols will be more easily determined. 
 
Radiation Dosimetry 
 
Method and Analysis: 
 
Normal-organ radiation absorbed doses and the effective dose for 89Zr-DFO-J591 in human were 
estimated based on based on MSKCC clinical study of 89Zr-DFO-J591 in 10 patients: dosimetry 
estimates by Joe O'Donoghue using the formalism of the Medical Internal Radionuclide Dosimetry 
(MIRD) Committee of the Society of Nuclear medicine (SNM). 
 
Assuming a 5 mCi administered activity of 89Zr-DFO-J591 and a low-dose head CT scan is to be 
performed, for 2-3 time points the predicted human radiation dosimetry for 89Zr-DFO-J591, total normal- 
organ absorbed doses and effective dose are tabulated below. 
 
The human normal-organ radiation doses thus derived were found to be comparable to those of other 
commonly used diagnostic radiotracers. In the radiation dosimetry analysis, the critical organ was 
determined to be the kidneys, receiving a dose-equivalent of 1.97 rem/mCi. In the trial proposed, a 5 
mCi injected-dose of 89Zr-DFO-J591 is to be administered initially. If needed to get adequate PET 
images, the radioactive compound dose could be increased. Based upon the predicted human 
dosimetry, even with an administered dose as high as 12 mCi, the total absorbed dose to the kidneys 
should be less than 28 rem. 
 
SCANNING DETAILS: 
Imaging session 
On Day 0 each patient would receive 20mg/5 mCi ±10% intravenous injection of the investigational 
agent followed by PET/CT imaging approximately 24 hours (day 1), 48 hours (day 2, optional) post 
injection, and 3-8 days. 
 
CT: 
 
• 
kVp 
80 
• 
Qual. Ref. mAs 30 
• 
Slice 3.0 mm Acq 16 x 1.2 mm 
• 
Pitch 1.5 
• 
Kernel B31f medium smooth + (H19sLowDose for ECT for AC CT) 
 
PET Acquisition: 
 
• 
No of beds: 2 
• 
Scan duration/bed: 3 min/bed 
• 
Field of view (FOV): Brain 
• 
Total scan time: ~20 minutes 
 
MRI: 


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Structural MRI, scans will be acquired on a 3.0 Tesla scanner (General Electric, Milwaukee, WI). High 
resolution T1 and T2-weighted images will be acquired prior to contrast injection.  DWI will be acquired 
using a spin-echo echo planar sequence with b = 1000 s/mm2. A 4-slice 1H-MRSI scan will be 
performed using the method of Duyn et al., with a 15 mm slice thickness, 3.5-mm interslice gap, TE/TR 
280/2300 ms, field-of-view (FOV) 240 mm, 24x24 matrix and 512 points with a scan time of 17 minutes 
producing 1.0 cm3 voxels (i). Unsuppressed water spectra will be acquired for reference allowing 
detection of individual metabolic variances with respect to water concentration independent of peak 
area ratios. Dynamic susceptibility contrast enhanced (DSC) perfusion weighted imaging will be 
performed using an injection of 0.2 mM/kg Gd-DTPA (Magnevist, Berlex, Wayne,NJ) and a GRE-EPI 
sequence with TE/TR 30/1500 ms to estimate rCBV. Post-contrast T1-weighted 3D GRE imaging will be 
acquired followed by T2-weighted Fast Spin Echo and Fluid Attenuated Inversion Recovery image sets. 
 
AUTORADIOGRAPHY: 
 
The major components of our quantitative autoradiography system include a digital cryostatic 
microtome (MICROM 500M) and our recently installed state-of the-art GE Typhoon 7000IPphosphor 
plate autoradiography system capable of spatial resolution as low as 25 μm. Following acquisition of 
autoradiographic images, sections may then be stained with either histo- or immuno-histochemical 
(IHC) techniques, and scanned digital images acquired at very high resolution (< 1 m/pixel). All image 
sets will then be registered using a combination of mutual information and external fiduciary markers 
placed on the sections. These techniques have previously been used at MSKCC in a similar mamnner 
to study 124I-A33 uptake and sub-tumoral distribution. 
 
Infusion reactions 
 
Infusion reactions with J591 are generally mild if they occur at all. In the even of fever, rigors, shortness 
of breath, or other evidence of infusion reaction, patients may receive diphenhydramine 25 mg IV and 
Tylenol 650 mg as felt to be clinically appropriate by the treating physician.  This has been the accepted 
protocol since MSKCC IRB 11-126 for the injection of 89Zr-J591. 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Primary Outcomes 
 
Positive lesions on 89Zr-J591 PET will be defined as those with higher activity than adjacent or contra 
lateral background that is deemed not to be physiologic. The gold standard of positive will consist of 
lesion identified on conventional imaging, (CT/MRI, bone scan) consistent with metastatic disease. 
Antibody scan will be read blinded from clinical history and conventional imaging modalities. Two 
different readers will visually analyze the scans, SUV max will be determined, and the results will be 
merged when the data are complete. A combined list will be generated that will then contain 
individual SUVmax measurements. 
 
Laboratory Safety Assessments: Hematology and blood chemistry assessments (CBC, serum 
BUN, creatinine, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and blood glucose levels) 
will be done at the time points described in Table 4. 


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Baseline 
(w ithin 4 
w eeks of 
study entry) 
Day 0 
Day 1 (24 
hours 
post 
injection) 
Day 2
2 
(48 hours 
post 
injection) 
Days 
3-8 
Day of 
Surgery
3 
Informed consent 
X 
Medical history 
X 
Physical examination 
X 
Routine clinical laboratory 
X 
Pregnancy test (if applicable) 
X 
Vital signs 
X 
X
4 
Concomitant medications 
X 
Adverse events 
X 
X 
X 
X 
X 
Standard imaging1 
X 
89Zr-J591 injection 
X 
89Zr-J591 PET/CT scans 
X 
X 
X 
Tissue sampling 
X 
Research Blood Draw 
X 
X 
X 
X 
X 
Performance Status: Performance status will be assessed using the Karnofsky Performance Status 
scale. 
 
Vital Signs: Blood pressure and heart rate will be obtained at the time points outlined in the flowchart. 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4: Study Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Standard imaging includes CT and/or MRI and can be completed w ithin 6 w eeks prior to study entry 
2 Day 2 (48 hours post injection) PET/CT scan is optional 
3 Surgery should occur after the completion of last PET/CT scan. 
4 Vitals on Day 0 w ill be done pre-injection and post-injection of 89Zr-J591. 
 
 
Tissue sampling for surgical patients 
 
Surgical resection with targeted tissue acquisition will take place per routine, with integrated 
frameless stereotactic tracking used to annotate sites of biopsies, and updated by intraoperative MRI 
(iMRI, 1.5T Siemens magnet). Tissue samples from several regions (from contrast enhanced portion 
of the tumor) will be collected within and around the tumor after adequate specimens have been 
obtained for diagnostic purposes, as determined by the attending neurosurgeon and pathologist. 
 
Samples will be obtained during surgery at various locations at the site of the lesion during a routine 
resection procedure. Each sample will be placed into separate preweighed 10% formalin-containing 
vials, reweighed, and immediately counted in a calibrated Wallac gamma spectrometer (located just 
outside of the operating room). Decay-corrected radioactivity of each sample (Bq/g tissue) will be 


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determined, and available samples ranging from high to low radioactivity (Bq/g tissue) will be 
submitted to pathology in a “blinded manner” for routine fixation and pathological scoring. In the 
event that the neurosurgeon requires a frozen section during the procedure, the resected sample will 
be divided: one portion for immediate frozen section analysis (which will include histological 
confirmation by MSKCC) and another for radioactivity measurement and processing as a study 
sample. If the surgeon judges the resected tissue sample to be too small or heterogenous to be 
divided without compromising diagnosis, the clinically relevant frozen section analysis will take 
precedence. An inservice from radiation safety will be conducted with the OR staff and neuro- 
surgeons involved prior to the first patient. 
 
Histopathology, molecular characterization, and digital autoradiography of excised specimens. 
Excised brain tumor biopsy specimens will be divided and a portion flash-frozen in liquid nitrogen, 
cryosectioned, and transferred for H&E staining and immunohistochemical staining for PSMA 
expression; remaining frozen material will be stored at -80°C. This excess frozen material at -80⁰ C 
for seven years or if consent is withdrawn, the tissue will be destroyed immediately. Unfrozen 
portions will be processed for autoradiography to visualize the distribution of this agent along the 
endothelium of tumor neovasculature. 
 
Processing of samples for molecular characterization and digital autoradiography will be carried out 
under the direct supervision of Dr. Sean Carlin, Assistant Attending in the Radiochemistry and 
Imaging Sciences Service. Specimens will be flash-frozen and mounted and sectioned immediately 
following receipt. Sections will be exposed to a storage phosphor plate for an appropriate length of 
time, and images subsequently acquired using a GE Typhoon 7000IP plate reader. Sequential 
sections will be stained manually to determine PSMA and CD34 expression, and digital microscopic 
images obtained using an Olympus BX60 microscope equipped with a computer-controlled stage 
and high-sensitivity CCD camera. 
 
PSMA assay and manual staining will be carried out in Dr. Carlin’s laboratory, Z1733 center 
laboratory, which if fully equipped to carry out these procedures 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Risks 
 
89Zr-J591 PET/CT Scans 
 
As part of this scan there is radiation delivered from the 89Zr and from the low dose CT scan that are 
performed as part of the CT for attenuation correction and co-registration. There is a low theoretical 
risk of developing a cancer at some point later in life as a result of the radiation exposure received in 
this study. This risk is particularly low for adults given the fact that the radiation from the scans will 
be over several weeks. Participants should not father a baby while on this study. Acceptable birth 
control methods include abstinence, double barrier method, surgically sterilized patient or partner. 
 
J591 
 
Potential risks associated with J591 are allergic reactions, characterized by fever, chills, and 
sometimes rashes or hives. Less likely shortness of breath can occur. Rare allergic reactions can 
present as infection, shock or death or swelling of the throat. Allergic reactions such as these have 


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not been seen with J591. However, some patients have developed the fever and chills and 
shortness of breath when J591 has been used in the past. Such reactions are usually addressed by 
stopping the administration of the drug, administering steroids, acetaminophen and/or 
diphenhydramine, and restarting the drug at a slower rate if the reaction is not severe. 
 
There is a very small risk of infection. This could cause itching or redness at the area on the patient’s 
arm where the IV was placed. 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Positive lesions on 89Zr-J591 will be defined visually as a focus of accumulation of radioactivity that 
is deemed to not be physiologic and is higher than adjacent or contra lateral background. Antibody 
scan will be read blinded from clinical history and conventional imaging modalities. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will remain on study until day of surgery. Participation in the study is voluntary. Patients 
have the right to withdraw from the study at any time. If a patient chooses to withdraw, he or she 
must inform the investigator immediately. In addition, the investigator has the right to terminate 
participation of any patient at any time if it is deemed in the patient’s best interest. The reason and 
circumstances for premature discontinuation will be documented in the patient’s medical records. 
Possible examples for reasons of premature study withdrawal include withdrawal of consent, SAE or 
intolerable AE, or any other medical illness at investigator’s discretion. 
 
For patients who are enrolled without prior histological confirmation of glioblastoma, if the surgery is 
found not to meet histological criteria for glioblastoma, the patient will be removed from the study 
and replaced until 10 evaluable patients complete the protocol. 
 
14.0 
BIOSTATISTICS 
 
Objective 1a of this study is to determine the binding of 89Zr-J591 for the vasculature of glioblastoma 
multiforme in human subjects. This will be measured by J591 uptake in PET scan. 
 
Two sets of analyses are planned for objective 1a. In the first set the unit of analysis is patient and 
the only planned analysis is to present the number of patients with any uptake (a binary variable as 
defined in Sections 10 and 12) at each time point along with a 95% exact confidence interval. If, for 
example, 8 of the 10 patients have an uptake the confidence interval for this proportion will be 0.44- 
0.97. 
 
The second set of analyses will use uptake as a continuous variable and primarily consist of 
summary statistics. Since some patients will have multiple lesions a lesion-based analysis with 
necessary corrections for the intra-patient correlation will be used. These analyses will be performed 
separately for each scan (time point). While it is also of interest to compare the uptake across time 
points using generalized estimating equations, this will be done with the understanding that 
statistical power will be limited. 


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Objective 1b (correlating PMSA expression with uptake) will be accomplished using lesion-based 
analysis where PSMA expression will be obtained from the surgical samples and uptake from the 
pre-operative scans. Since both variables are continuous we will use a random-coefficients 
regression if the number of lesions per patient is sufficient. If not, standard metrics of rank correlation 
will be estimated. This analysis will be based on surgically-sampled lesions. 
 
Sample size was determined based on logistics and availability of funding. 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
NA 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. 
The data collected for this study will be entered into a secure database. Source documentation will 
be available to support the computerized patient record. Study personnel will record clinical data in 
each patient’s source documents (i.e., the patient’s medical record). The investigator will maintain 
adequate and accurate records to enable the conduct of the study to be fully documented and the 
study data to be subsequently verified. After study closure, the investigator will maintain all source 
documents, study-related documents, and the data stored in the database used for data collection. 
 
Dr. Neil Bander is involved with the development of the tracer and therefore will be provided with the 
de-identified study results to contribute throughout the study. All data provided will be de-identified 
before being sent outside of MSKCC electronically. 


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16.1 
Quality Assurance 
 
Regularly scheduled registration reports will be generated to monitor patient accruals and the 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and the extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period, and potential 
problems will be brought to the attention of the principal investigator for discussion and 
action. 
 
The study team will conduct random-sample data quality and protocol compliance audits at 
least once a year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The data and safety monitoring (DSM) plans at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the policies set forth by the NCI in 
the document entitled Policy of the National Cancer Institute for Data and Safety Monitoring 
of Clinical Trials, which can be found at  http://cancertrials.nci.nih.gov/clinicaltrials. The DSM 
plans at MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC DSM plans can be found on the MSKCC Intranet at: 
http://mskweb5.mskcc.org/intranet/html/70775.cfm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research quality assurance) and departmental procedures for quality 
control, and there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the MSKCC Research Council and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, 
and the monitoring procedures will be established at the time of protocol activation. 
 
For this protocol, we will use the following patient safety monitoring plan and monitoring for 
adverse events, in terms of the test performed and their timing relative to injection (see Table 
1 and 2).  Patient will be observed closely during infusion and vital signs will be obtained pre- 
and post-injection of radiotracer. 
 
Safety reviews will be performed by the MSKCC-DSMC with yearly review by the IRB. 
 
Section 16.3 Regulatory Documentation 
Participating sites that are consulting and/or conducting specimen or data analysis should 
submit this protocol to their IRB according to local guidelines. Copies of any site IRB 
correspondence should be forwarded to MSK. 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonization, and the ethical standards set forth in the Declaration of 
Helsinki 2004 (available at:  www.laakariliitto.fi/e/ethics/helsinki.html). 
 
This protocol does not have therapeutic intent and does not offer patients therapeutic benefit. This 
will be clearly conveyed to patients when communicating the potential toxicities/side effects of 
participating in this trial. Participation in the trial is voluntary and there will be no financial benefit (or 
burden) for the patients. Participants will not be charged for 89Zr-J591 radiotracer and PET scans, 
and research testing on resected tumor tissue. 
 
17.1 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 


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For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
17.2.1 
 
NA 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 


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Page  26 of 27 
 
 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Liu, H., et al., Constitutive and antibody-induced internalization of prostate-specific 
membrane antigen. Cancer Research, 1998. 58(18): p. 4055-60. 
2. 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med, 2005. 352(10): p. 987-96. 
3. 
Hou, L.C., et al., Recurrent glioblastoma multiforme: a review of natural history and 
management options. Neurosurg Focus, 2006. 20(4): p. E5. 
4. 
Vredenburgh, J.J., et al., Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J 
Clin Oncol, 2007. 25(30): p. 4722-9. 
5. 
Wong, E.T., et al., Outcomes and prognostic factors in recurrent glioma patients enrolled 
onto phase II clinical trials. J Clin Oncol, 1999. 17(8): p. 2572-8. 
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Kreisl, T.N., et al., Phase II trial of single-agent bevacizumab followed by bevacizumab plus 
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7. 
Evers, P., et al., Irradiation of the potential cancer stem cell niches in the adult brain 
improves progression-free survival of patients with malignant glioma. BMC Cancer, 2010. 10: 
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Page  27 of 27 
 
 
8. 
Chang, S.S., et al., Five different anti-prostate-specific membrane antigen (PSMA) antibodies 
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Wernicke, A.G., et al., Prostate-specific membrane antigen as a potential novel vascular 
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Osborne, J.R., et al., A Prospective Pilot Study of Zr-J591/Prostate Specific Membrane 
Antigen Positron Emission Tomography in Men with Localized Prostate Cancer Undergoing 
Radical Prostatectomy. J Urol, 2013. 
12. 
Rice, S.L., et al., The next generation of positron emission tomography radiopharmaceuticals 
in oncology. Semin Nucl Med, 2011. 41(4): p. 265-82. 
13. 
Rinker-Schaeffer, C.W., et al., Localization and physical mapping of the prostate-specific 
membrane antigen (PSM) gene to human chromosome 11. Genomics, 1995. 30(1): p. 105-8. 
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Babaian, R.J., et al., Radioimmunoscintigraphy of pelvic lymph nodes with 111indium-labeled 
monoclonal antibody CYT-356. J Urol, 1994. 152(6 Pt 1): p. 1952-5. 
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Kahn, D., et al., Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts 
prostate cancer response to salvage radiotherapy after failed radical prostatectomy. J Clin 
Oncol, 1998. 16(1): p. 284-9. 
16. 
Kahn, D., et al., 111Indium-capromab pendetide in the evaluation of patients with residual or 
recurrent prostate cancer after radical prostatectomy. The ProstaScint Study Group. J Urol, 
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17. 
Kahn, D., et al., Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection 
of occult prostate cancer recurrence. J Urol, 1994. 152(5 Pt 1): p. 1490-5. 
18. 
Troyer, J.K., M.L. Beckett, and G.L. Wright, Jr., Location of prostate-specific membrane 
antigen in the LNCaP prostate carcinoma cell line. Prostate, 1997. 30(4): p. 232-42. 
19. 
Liu, H., et al., Constitutive and antibody-induced internalization of prostate-specific 
membrane antigen. Cancer Res, 1998. 58(18): p. 4055-60. 
20. 
Cristy M, E.K., SPECIFIC ABSORBED FRACTIONS OF ENERGY AT VARIOUS AGES 
FROM INTERNAL PHOTON SOURCES. VI. NEWBORN. ORNL/TM-8381, 1987. 6. 
21. 
Stabin, M.G., R.B. Sparks, and E. Crowe, OLINDA/EXM: the second-generation personal 
computer software for internal dose assessment in nuclear medicine. J Nucl Med, 2005. 
46(6): p. 1023-7. 
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Zanzonico, P.B., Internal radionuclide radiation dosimetry: a review of basic concepts and 
recent developments. J Nucl Med, 2000. 41(2): p. 297-308. 
 
23. 
Pandit-Taskar, N., et al., Zr-huJ591 immuno-PET imaging in patients with advanced 
metastatic prostate cancer. Eur J Nucl Med Mol Imaging, 2014. 
 
20.0 
APPENDICES 
 
NA