Clinical trial NCT03675451
Conditions: Prostate Cancer
Keywords: PET/CT Imaging Nuclear Medicine
Sponsor: Weill Medical College of Cornell University
Start date: 2017-02-08; Completion date: 2018-06-27
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The present study is a phase II, open label, single-center, non-randomized, single-dose study.

Twenty subjects in total will be enrolled at Weill Cornell Medical College (WCMC)/ NYPH.

The primary objective is to evaluate the ability of 89Zr-Df-IAB2M to detect localized, clinically significant (defined as: ≥ 0.5 cm3 with Gleason pattern ≥ 4) prostate cancer (PCa).

After the screening period (up to 28 days), each subject will be scheduled to receive 10 mg infusion of IAB2M conjugated with 2.5 mCi 89Zr-Df.

2 - 4 days post-infusion, subjects will undergo a 89Zr-Df-IAB2M PET/CT scan. Images read by a Nuc Med MD reporting: location, SUV and, if possible, size of all areas with abnormal uptake.

(they will also undergo a pelvic MRI if they have not obtained an MR image during the screening period or on day of infusion)

Optional but recommended 68Ga-PSMA-HBED-CC (5±2mCi) injection and PET/CT scan (1 to 3 hours after the injection) will also be performed prior to radical prostatectomy depending on subject's availability and compliance.

Patient will undergo radical prostatectomy after completion of above imaging procedures.

Detailed description:
The primary endpoint of this study is the proportion of subjects with PSMA-positive (identified by H\&E staining and immunohistochemistry) "dominant" PC lesion(s) greater than 5mm in diameter, whose lesion(s) have been successfully identified by 89Zr-Df-IAB2M imaging. Because this is an exploratory pilot study, no formal sample size/power calculation is required. However, with a sample size of 20 patients in the study, a two-sided 95% confidence interval for the proportion of patients successfully imaged by 89Zr-Df-IAB2M can be constructed to be within ± 19.0% of the observed proportion of patients with successful imaging by 89Zr-Df-IAB2M. This calculation assumes an 89Zr-Df-IAB2M imaging-success proportion of 75%. All estimates from the study will serve as preliminary data (i.e., hypothesis-generating) for future studies.

Arms: arm 1: Injection of study drug followed by PET/CT imaging.

Optional but recommended 68Ga-PSMA-HBED-CC (5±2mCi) injection and PET/CT scan (1 to 3 hours after the injection) will also be performed prior to radical prostatectomy depending on subject's availability and compliance.

Followed by prostatectomy
Interventions: intervention 1: 89ZR-DF-IAB2M intervention 2: 68Ga-PSMA-HBED-CC
Intervention descriptions: intervention 1: injection of 10 milligrams of radioactive 89Zr-Df-IAB2M followed by PET/CT scan intervention 2: Optional but recommended 68Ga-PSMA-HBED-CC (5±2mCi) injection and PET/CT scan (1 to 3 hours after the injection) will also be performed prior to radical prostatectomy depending on subject's availability and compliance.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
i
 
IRB Protocol Number: 1311014489 
Version 6 dated: May 31, 2017 
ClinicalTrials.gov ID: NCT03675451 
 
TITLE: PSMA Imaging of Localized Prostate Cancer 
 
Principal Investigator: 
 
Douglas Scherr, MD 
 
 
 
 
 
 
Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
Study Nurse: 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator: 
 
Study Coordinator: 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version Date:  
Original, Version 1, dated May 6, 2015 
Amendment1, Version 2, dated July 16, 2015 
Amendment 2, Version 3, dated May 14, 2016 
Amendment 3, Version 4, dated December 22, 2016 
Amendment 4, Version 5 dated January 27, 2017 
Amendment 5, Version 6 dated May 31, 2017 
 


 
 
ii 
 
SCHEMA 
 
 
RADICAL PROSTATECTOMY 
3-30 days after 89Zr-df-IAB2M PET/CT scan (preferably 1 week after the scan), depending on 
patient’s availability and compliance. 
HISTOPATHOLOGY 
 
Including individual lesion mapping, size determination, Gleason score and IHC findings. 
IMAGING 
After the screening period (up to 28 days), each subject will be scheduled to receive 10 mg 
injection of df-IAB2M conjugated with 2.5 mCi of 89Zr. 
 
Subjects will undergo 89Zr-df-IAB2M PET/CT scan 2-4 days after the injection of 89Zr-df-IAB2M 
depending on patient’s availability and compliance. Images read by a Nuclear Medicine Physician 
reporting: location, SUV and, if possible, size of all areas with abnormal uptake.  
Optional but recommended 68Ga-PSMA-HBED-CC (5±2mCi) injection and PET/CT scan (1 to 3 
hours after the injection) will also be performed prior to radical prostatectomy depending on 
subject’s availability and compliance. 
 
(subjects will also undergo a pelvic MRI if they have not obtained an MR image during the 
screening period or on day of infusion) 
RESULTS 
Histopathology lesion data correlated with imaging results. 
ENROLLMENT 
 
Twenty (20) subjects in total will be enrolled at Weill Cornell Medical College (WCMC)/ NYPH.   
 


 
 
iii 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................ i 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objectives ........................................................................................................ 
1.2 
Secondary Objectives .................................................................................................... 
 
2. BACKGROUND ......................................................................................................................1 
2.1 
Disease ..........................................................................................................................1 
2.2 
Investigational Agent ...................................................................................................2 
2.3 
Rationale .......................................................................................................................5 
2.4 
Correlative Studies Background ................................................................................9 
 
3. PATIENT SELECTION........................................................................................................10 
3.1 
Inclusion Criteria  ......................................................................................................10 
3.2 
Exclusion Criteria ......................................................................................................10 
 
4. REGISTRATION PROCEDURES ......................................................................................11 
 
5. INVESTIGATIONAL IMAGING PLAN ............................................................................11 
5.1 
Agent Administration ................................................................................................11 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....................11 
5.3 
Duration of Therapy and Criteria for Removal from Study .................................12 
5.4 
Duration of Follow Up ...............................................................................................12 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................13 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................13 
7.1  
89Zr-df-IAB2M Potential Risks .................................................................................13 
7.2  
68Ga-PSMA-HBED-CC Potential Risks………………………………………….. 15 
7.3  
Adverse Event Characteristics..................................................................................16 
7.4  
Recording Adverse Events ........................................................................................16 
7.5  
Serious Adverse Event Reporting.............................................................................16 
 
8. PHARMACEUTICAL INFORMATION ............................................................................17 
8.1 
89Zr-df-IAB2M (IND# 130768) .................................................................................17 
8.2 
Availability..................................................................................................................18 
8.3 
89Zr-df-IAB2M Accountability .................................................................................18 
8.4 
89Zr-df-IAB2M Infusion ............................................................................................18 
 
9. IMAGING AND SPECIAL STUDIES .................................................................................20 
9.1 
Imaging and Histopathology .....................................................................................20 
9.2 
Special Studies ............................................................................................................23 
 
10. STUDY CALENDAR ............................................................................................................24 


 
 
iv 
 
 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ........................................25 
11.1     Data Collection ...........................................................................................................25 
 
11.2 
Regulatory Considerations ........................................................................................25 
 
12. STATISTICAL CONSIDERATIONS .................................................................................25 
12.1 
Study Design/Endpoints ............................................................................................26 
12.2 
Sample Size/Accrual Rate .........................................................................................29 
12.3 
Stratification Factors .................................................................................................29 
 
REFERENCES .............................................................................................................................30 
 
INFORMED CONSENT TEMPLATE.......................................................................................... 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ................................................................................................... 
 
APPENDIX B 
WCMC SAE Reporting Forms ..............................................................................................


 
 
  
 
1. OBJECTIVES 
 
1.1. 
Primary Objectives  
 
 To evaluate the ability of 89Zr-df-IAB2M to detect localized, clinically significant (defined 
as: ≥ 0.5 cm3 with Gleason pattern ≥ 4) prostate cancer (PCa).  
 
1.2. 
Secondary Objectives 
 
 
 To determine the correlation of 89Zr-df-IAB2M PET/CT findings with pathological 
features (i.e. Gleason pattern, diameter and PSMA-positivity). 
 To compare the in vivo 89Zr-df-IAB2M PET/CT and 68Ga-PSMA-HBED-CC PET/CT to 
mpMRI. 
 To determine the sensitivity, specificity, positive predictive value (PPV), negative 
predictive value (NPV) of IAB2M to detect all pathologically identified PCa lesions that 
do not meet criteria for clinical significance (defined as: < 0.5 cm3 with Gleason pattern < 
4). 
 Determine the proportion of IAB2M positivity (as measured by SUV) versus lesion size, 
Gleason pattern, and PSA levels. 
 Determine ability of 89Zr-df-IAB2M PET/CT to identify extra-prostatic extension. 
 Determine ability of 89Zr-df-IAB2M PET/CT to identify lymph node or other extra-
prostatic involvement. 
 To determine the safety of 89Zr-df-IAB2M PET/CT and 68Ga-PSMA-HBED-CC PET/CT 
imaging. 
 
 
2. BACKGROUND 
 
2.1 
 
Disease 
 
Localized PCa is presently evaluated by serum prostate specific antigen (PSA) sampling and 
transrectal ultrasound (TRUS) and magnetic resonance (MR) imaging, both of the latter being 
anatomic approaches. As a secretory protein, PSA does not provide anatomic details nor does 
it distinguish between malignant or benign pathology. TRUS and MR imaging modalities are 
limited by their inability to identify and differentiate localized malignant tissue from common 
benign pathology, i.e., benign prostatic hyperplasia, inflammation, etc. Furthermore, the 
images created are poorly defined and subject to artifact. The present inability to clearly image 
and identify malignant tissue and to localize the site/s of disease leads to unnecessary biopsy 
of many patients [1,000,000 prostate biopsies per year in US] and an inability to direct the 
biopsy towards any suspicious site/s. As a direct result, the substantial majority of prostate 
biopsies are negative, suggesting that there was no need for the biopsy or that the biopsy failed 
to sample the lesion1,2. Nevertheless, the biopsied patients are subject to potentially significant 
morbidity and even mortality3,4.  
 
An imaging modality that is able to selectively identify malignant prostatic tissue within the 


 
 
2
 
gland, would allow for accurate, targeted biopsies of suspicious foci and would reduce 
unnecessary biopsies in patients with benign pathologies. The modality would also allow for 
improved clinical staging and risk stratification, improved monitoring of patients on active 
surveillance and improved targeting of focal therapy.  
 
Prostate Specific Membrane Antigen (PSMA) 
 
PSMA is the single, most well-established, highly restricted prostate epithelial cell membrane 
antigen known5-12.  Although first thought to be entirely prostate-specific5,13,14, subsequent 
studies demonstrated that PSMA is also expressed by some brain astrocytes and cells of the 
small intestine, proximal renal tubules and salivary glands9. However, the level of expression 
in these non-prostate tissues is between a hundred-fold to a thousand-fold less than in prostate 
tissue8 and the site of PSMA expression in these normal cells (brush border/luminal location) 
are not readily accessible to circulating antibodies because of the blood: brain barrier or, in the 
case of the epithelial locations, due to intervening cell layers, basement membrane and 
epithelial tight junctions.  
 
In contrast to other well-known prostate-restricted molecules such as PSA and prostatic acid 
phosphatase (PAP), which are secretory proteins, PSMA is a type II integral cell-surface 
membrane protein that is not secreted. Pathology studies indicate that PSMA is expressed by 
virtually all prostate cancers15 and PSMA expression increases progressively in higher grade 
cancers, metastatic disease, and hormone-refractory prostate cancer7,9,10. These qualities make 
PSMA an ideal target for monoclonal antibody (mAb) imaging and/or therapy. 
 
2.2 
 
Investigational Agent 
 
Humanized J591 (huJ591) 
 
The huJ591 mAb is a de-immunized monoclonal antibody directed at the extracellular domain 
of human PSMA. huJ591 was derived from murine J591 using Biovation’s DeImmunization 
technology (Biovation, Aberdeen, Scotland, UK). In this technology, individual amino acids 
in predicted B and T cell epitopes were replaced with alternative amino acids such that the 
murine epitopes are no longer immunogenic to the human immune system.16 The modification 
results in a non-immunogenic antibody that may be administered to patients on multiple 
occasions and over long periods without inducing an immune response. huJ591 is produced 
from NS0 cells by Lonza (Lonza Biologics, Slough, UK).  
 
The humanized version of J591 has provided promising results in imaging both localized PCa 
and metastatic disease. Initial phase I/II studies using huJ591 trace-labeled with 111Indium 
(111In) and 177Lutitium (177Lu) using a DOTA chelate showed that repetitive dosing was well 
tolerated without the development of a human anti-humanized antibody (HAHA) response17-
22. No dose limiting toxicity occurred at imaging doses of radionuclide conjugates and the 
maximum tolerated dose was not reached. Excellent tumor targeting could be detected at all 
dose levels of the mAb. No mAb targeting to sites other than those involved by PCa was 
observed although, as seen in other trials using radiometals, the liver is the primary site of 


 
 
3
 
radiometal metabolism. Percent injected dose in the liver diminished with increasing dose of 
cold huJ591, and higher doses were associated with longer plasma clearance times.23-25  
 
Humanized J591-Minibody (IAB2M)  
 
IAB2M is an engineered antibody fragment (derived from huJ591) that targets the extracellular 
domain of the PSMA. The intact parental huJ591 antibody demonstrated sufficient tumor 
uptake to be useful as an imaging and therapy agent17,26-29, however, the prolonged blood 
circulation time leads to increased background activity and radiation dose to normal organs 
thereby, somewhat limiting the imaging or therapeutic potential of these agents. Radiolabeled 
engineered antibody fragments have much faster clearance rates, providing improved tumor-
to-blood ratios30,31. However, fragments below 60 kDa are filtered through the glomerulus, 
leading to significant renal excretory activity32, which is an unfavorable characteristic for a 
PCa imaging agent as the radioactivity within the bladder interferes with imaging of the 
adjacent prostate. To address these issues, IAB2M was engineered by fusing VH-linker-VL-
CH3 gene segments, producing a single-chain protein that self-assembles into a small, stable, 
bivalent imaging agent with a molecular weight of approximately 80 kDa. The minibody 
format is half the size of complete, full-length antibodies, yet retains full bivalent binding to 
the target and is not excreted via the glomerulus. 
Previous studies with a radiolabeled minibody demonstrates rapid biodistribution, efficient 
target penetration, and rapid blood/background clearance due to the smaller size, allowing 
high-contrast images to be obtained within hours after injection33-35 compared to the current 
delay of several days to a week when intact antibodies are used for imaging36. The lack of CH2 
domain in the minibody format removes antibody effector functions, removes FcRn-mediated 
prolongation of plasma half-life, and the risk of an immunologic response such as complement-
dependent cytotoxicity is reduced to negligible. For functional imaging purposes, IAB2M is 
conjugated to desferrioxamine (Df) and radiometal labeled with 89Zr (T ½  78.41 hours).  The 
end product, 89Zr-df-IAB2M, is non-immunogenic, recognizes an extracellular target, is not 
excreted via the kidney, and exhibits rapid kinetics desirable for imaging. 
 
Engineering the IAB2M Minibody 
 
The DNA sequences of the heavy and light chains for the humanized anti-PSMA antibody 
huJ591 were provided by Dr. Neil H. Bander (Weill Cornell Medical College). ImaginAb, the 
creators and IND owners of IAB2M, re-humanized the DNA sequences using a later generation 
approach.  The variable genes from the heavy and light chain DNA were separately amplified 
and joined together by overlap PCR to form a single-chain Fv (scFv) with an 18 amino acid 
linker. This scFv fragment was subsequently fused to the human IgG1 CH3 domain via the 
human IgG1 hinge sequence by overlap PCR to form the complete minibody (scFv-CH3 
dimer) construct (see Figure 1).  




 
 
5
 
During the last two decades, many efforts have been undertaken to develop PSMA-
ligands43,44. One of these ligands, the small molecule Glu-NH-CO-NH-Lys-(Ahx)-
[68Ga(HBED-CC)], also known as PSMA-11®, PSMAHBED, Glu-CO-Lys(Ahx)-HBED-
CC, DKFZ-PSMA-11, PSMA-HBED- CC, PSMA-HBED, PSMA or ProstamedixTM, 
developed at the German Cancer Research Center Heidelberg (DKFZ), has become the 
most clinically used radiotracer. This compound shows a strong binding affinity to PSMA 
as well as a highly efficient internalization into PCa cells45,46. PET/CT-imaging with 68Ga-
PSMA-11 has demonstrated this novel method as an important imaging modality for 
diagnosing recurrent PCa37,47-49. Perera et al., did systematic review of 68Ga-PET articles 
and Sixteen articles involving 1309 patients were analyzed. On per-patient analysis, the 
summary sensitivity and specificity were both 86%. On per lesion analysis, the summary 
sensitivity and specificity were 80% and 97%, respectively50. 
 
ABX Advanced Biochemical Compounds, Radeberg, Germany produces PSMA-HBED-
CC for clinical use. Upon purchase and shipment to Weill Cornell Medicine, the peptide 
will be labeled with 68Ga with the final product being 68Ga-PSMA-HBED-CC. 
Radionuclide conjugation will be done at the Division of Nuclear Medicine, Department 
of Radiology, Weill Cornell Medicine.  
 
The material produced are subjected to quality assurance testing as outlined in the Food 
and Drug Administration “Points to Consider”. All production data and supporting 
documents, together with the results of all quality assurance testing, have been provided to 
and reviewed by the Food and Drug Administration (68Ga-PSMA-HBED-CC, IND# 
124495). 
 
 
2.3 
 
Rationale  
 
 
89Zr-df-IAB2M for PCa imaging/diagnosis  
 
An ad-hoc analysis of data from 18 subjects with metastatic PCa showed that the 
combination of conventional imaging (CT, bone scan, FDG PET) and 89Zr-df-IAB2M PET 
imaging identified a total of 168 lesions (152 bone lesions and 16 soft tissue lesions). 
Thirty-four of these 168 lesions (32 bone lesions and two soft tissues lesions) were 
identified by 89Zr-df-IAB2M PET but not by conventional imaging. A total of 13 biopsies 
in these 18 patients confirmed true-positive identification of lesions in 11 of 11 locations 
and true-negative identification in one of two locations using 89Zr-df-IAB2M compared 
with nine of 11 positive lesions and two of two negative lesions correctly identified by 
FDG PET. This improved sensitivity and specificity illustrates the potential of 89Zr-df-
IAB2M PET to provide clinicians with actionable information that may improve the 
accuracy of diagnosis, staging of the disease, risk stratification, and treatment decision-
making.   
 
Further review of 89Zr-df-IAB2M PET/CT by an independent third-party core lab was 
undertaken to determine the ideal unlabeled protein dose(10, 20 and 50 mg) and timing of 


 
 
6
 
optimal imaging for lesion detection. This un-blinded analysis revealed predominantly 
pelvic and lumbar spinal bone metastases and nodal metastases detection in the 18 subject 
cohort. Based on both estimated lesion detection rate, PET/CT activity and reader 
preference, the 48 hour imaging time point was determined to be the best time point for 
lesion detection and quantitation, while the time points from 24 hours through 96 hours 
demonstrated comparable qualitative and quantitative results to the 48 hour time point.  
Increasing unlabeled antibody affected the time course of detection of prostate metastases 
in all tissues examined, with the 10 mg cohort demonstrating the most sensitivity for lesion 
detection and quantitation. These results suggested that 89Zr-df-IAB2M can be an effective 
probe for the PCa marker PSMA and provide a robust imaging scan to better detect PCa 
tumor burden. 
 
Amendment v3 (01/27/17): 
68Ga-PSMA-HBED-CC for PCa imaging/diagnosis: 
Results from selective clinical trials using 68Ga-PSMA-HBED-CC to evaluate its diagnositic 
value are reported here under: 
 
a) Diagnostic value of 68Ga-PSMA-HBED-CC PET/CT imaging in the diagnosis 
of recurrent prostate cancer48: 
 
The study reports data from a retrospective analysis of 319 patients who underwent 
68Ga-PSMA-ligand PET/CT from 2011 to 2014. The 68Ga-PSMA-HBED-CC solution 
was applied to the respective patient via an intravenous bolus injection (mean of 172.4 
MBq ±70.9, range 40 – 400 MBq, median 161 MBq). A non-contrast-enhanced CT 
scan was performed 1-hour post tracer injection. Histological verification was 
performed in 42 patients after the 68Ga-PSMA-ligand PET/CT. Tracer uptake was 
measured in 901 representative tumor lesions. 82.8% of the patients had at least one 
lesion indicative of PCa was detected. Tumor-detection was positively associated with 
PSA level and Androgen deprivation therapy (ADT). Gelason Score and PSA 
doubling time (PSA-DT) were not associated with tumor-detection. The average 
maximum standardized uptake value (SUVmax) of tumor lesions was 13.3 ± 14.6 (0.7-
122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 
different patients, and all other lesions (n = 416) were true-positive or true-negative. 
A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV) and 
positive predictive value (PPV) revealed values of 76.6%, 100%, 91.4% and 100%. A 
patient-based analysis revealed a sensitivity of 88.1%. 
 
b)  PET imaging with a 68Ga-PSMA ligand for the diagnosis of prostate cancer: 
biodistribution in humans and first evaluation of tumor lesions 51: 
 
Initial clinical studies with the 68Ga-labeled PSMA-HBED-CC were conducted at 
Heidelberg University Hospital and the German Cancer Research Center to assess 


 
 
7
 
the biodistribution of 68Ga-PSMA-HBED-CC in normal tissues and tumor lesions. 
A total of 37 patients with prostate cancer and rising PSA levels were subjected to 
68Ga-PSMA-HBED-CC PET/CT imaging. Quantitative assessment of tracer 
uptake was performed 1 and 3 h post-injection by analysis of mean and maximum 
standardized uptake values (SUVmean/max) of several organs and 65 tumor 
lesions. Subsequently, tumor to background ratios were calculated. 
 
The 68Ga-PSMA-HBED-CC PET/CT images showed intense tracer uptake in both 
kidneys and salivary glands. Moderate uptake was seen in lacrimal glands, liver, 
spleen and in small and large bowel. Quantitative assessment revealed excellent 
contrast between tumor lesions and most normal tissues. Of 37 patients, 31 (83.8 
%) showed at least one lesion suspicious for cancer at a detection rate of 60 % at 
PSA <2.2 ng/ml and 100 % at PSA >2.2 ng/ml. Median tumor to background ratios 
were 18.8 (2.4-158.3) in early images and 28.3 (2.9-224.0) in late images. Within 
healthy organs, kidneys and salivary glands demonstrated the highest radiotracer 
uptake. Lesions suspicious for prostate cancer presented with excellent contrast as 
early as 1-hour after injection with high detection rates even at low PSA levels. 
 
c) 68Ga-labeled PSMA ligand as superior PET tracer for the diagnosis of 
prostate cancer: Comparison with 18F-FECH 39: 
 
This study was also published by the Heidelberg group, compared 68Ga-PSMA- 
HBED-CC PET/CT imaging to standard choline-based PET/CT. Thirty-seven 
patients with biochemical relapse of prostate cancer [mean prostate-specific 
antigen (PSA) 11.1 ± 24.1 ng/ml, range 0.01-116] were retrospectively analyzed 
after 18F- fluoromethylcholine and 68Ga-PSMA PET/CT within a time window of 
30 days. Radiotracer uptake that was visually considered as prostate cancer was 
semi- quantitatively analyzed by measuring the maximum standardized uptake 
values (SUVmax) of the scans acquired 1-hour after injection of 68Ga-PSMA 
complex solution (median 132 MBq, range 59-263 MBq) and 
18F-
fluoromethylcholine (median 237 MBq, range 114-374 MBq), respectively. In 
addition, tumor to background ratios were calculated. 
 
The results showed a total of 78 lesions characteristic for prostate cancer that were 
detected in 32 patients using 68Ga-PSMA-HBED-CC PET/CT imaging and 56 
lesions were detected in 26 patients using choline PET/CT. The higher detection 
rate in 68Ga-PSMA-HBED-CC PET/CT imaging was statistically significant 
(p=0.04). In five patients, no lesion was found with both methods. All lesions 
detected by 18F-fluoromethylcholine PET/CT were also seen by 68Ga-PSMA-
HBED-CC PET/CT imaging. In 68Ga-PSMA-HBED-CC PET/CT imaging 


 
 
8
 
SUVmax was clearly (>10 %) higher in 62 of 78 lesions (79.1 %) and the tumor 
to background ratio was clearly (>10 %) higher in 74 of 78 lesions (94.9 %) when 
compared to 18F-fluoromethylcholine PET/CT. 
 
The authors concluded that 68Ga-PSMA-HBED-CC PET/CT can detect lesions 
characteristic for prostate cancer with improved contrast when compared to 
standard 18F-fluoromethylcholine PET/CT, especially at low PSA levels. 
 
 
d) Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled 
PSMA ligand for the diagnosis of recurrent prostate cancer: initial experience 
47: 
 
In a more recent publication, the Heidelberg group evaluated the feasibility of 
PET/MRI imaging with 68Ga-PSMA-HBED-CC. Twenty patients underwent 
PET/CT 1-hour after injection of the 68Ga-PSMA-HBED-CC followed by 
PET/MRI 3-hours after injection. Data from the two investigations were first 
analyzed separately and then compared with respect to tumor detection rate and 
radiotracer uptake in various tissues. To evaluate the quantification accuracy of 
the PET/MRI system, differences in SUVs between PET/CT and corresponding 
PET/MRI were compared with differences in SUVs between PET/CT 1-hour and 
3-hours after injection in another patient cohort. This cohort was investigated 
using the same PET/CT system.  With PET/MRI, different diagnostic sequences, 
higher contrast of lesions and higher resolution of MRI enabled a subjectively 
easier evaluation of the images. In addition, four unclear findings on PET/CT 
could be clarified as characteristic of prostate cancer metastases by PET/MRI. 
However, in PET images of the PET/MRI, a reduced signal was observed at the 
level of the kidneys (in 11 patients) and around the urinary bladder (in 15 patients). 
This led to reduced SUVs in six lesions. SUVmean values provided by the 
PET/MRI system were different in muscles, blood pool, liver and spleen. 
 
The authors concluded that prostate cancer was detected more easily and more 
accurately with Ga-PSMA PET/MRI than with PET/CT and with lower radiation 
exposure. Consequently, this new technique could clarify unclear findings on 
PET/CT. However, scatter correction was challenging when the specific 68Ga-
PSMA-HBED-CC was used. Moreover, direct comparison of SUVs from PET/CT 
and PET/MR needs to be conducted carefully. 
These encouraging results suggest 68Ga-PSMA-HBED-CC to be an effective probe for 
the PCa marker “PSMA” in metastatic prostate cancer patients and that it can provide a 
robust imaging scan to better detect PCa tumor burden. We plan to utilize this probe to 


 
 
9
 
better understand its diagnostic role in prostate cancer patients with localized disease. 
 
 
2.4 
Correlative Studies Background 
 
 
Imaging Modalities for the evaluation of Prostate Cancer 
 
 
Cross-Sectional Imaging 
 
The cross-sectional imaging modalities that are used to evaluate PCa include CT and MRI. 
The utility of each of these modalities varies according to the stage of disease. At present, 
neither of these modalities can reliably distinguish viable PCa from necrotic or nonmalignant 
tissue. 
 
CT: Does not effectively evaluate disease that is confined to the prostate and adjacent area. 
It is not sensitive enough to detect microscopic nodal disease or tumor in non-enlarged lymph 
nodes. 
  
MRI: To provide the most accurate assessment of the extra-prostatic region, neurovascular 
bundles, and seminal vesicles, MRI is considered the modality of choice. However, MRI is 
limited by multiple sophisticated post-imaging processes and until recently has not been 
standardized52. MRI can detect soft tissue disease and is most useful to corroborate bone 
scintigraphy findings (particularly when the earliest involvement is thought to be present in 
the bone marrow). MRI is most sensitive in the axial skeleton and pelvis, and is less effective 
in the ribs, chest wall, and skull. Multiple studies have demonstrated the inability of current 
multi-parametric MRI to supplant the need for TRUS guided biopsy in the diagnostic or 
surveillance setting53-55. 
 
 
Functional imaging/Positron Emission Tomography (PET) 
 
PET has advantages over conventional imaging methods because it quantitatively assesses 
biologic processes in vivo and can assess different processes using specific radiotracers. 
Processes that can be analyzed include glucose and amino acid metabolism, proliferation, 
blood flow, and biomarker/receptor status (i.e., androgen receptor, PSMA, etc). Most studies, 
however, have focused on the accumulation of fluorodeoxyglucose (FDG). Functional 
imaging has not yet added significant value to the management of PCa. 
 
PET scanning with 89Zr-df-IAB2M: 89Zr is an attractive radiometal for use in immuno-
PET because of its physical half-life of 78.41 hours, which is well matched to the 
pharmacokinetics of the minibody. 89Zr is cyclotron produced, has favorable chemistry 
allowing linkage to Df-IAB2M with high yields, maintaining high radiochemical purity and 
stability without compromising minibody binding affinity.   
 
 
Amendment v3 (01/27/17): 


 
 
10 
 
 
PET scanning with 68Ga-PSMA-HBED-CC: A similar opportunity exists to bring 
clinically important PET tracer(s) into widespread clinical use readily and inexpensively, 
through the use of generator-produced Gallium-68 (Ga-68), a positron emitting radionuclide 
with a 68 minutes half-life. Due to the high cost of establishing and maintaining cyclotron 
and elaborate radiochemistry facilities, generator-produced positron-emitting radionuclides 
such as Ga-68 have become an attractive alternative to F-18 (Fluorine-18). Ga-68 has come 
to be a relevant radionuclide for routine clinical examinations, especially in Europe, due to 
the commercial availability of Germanium (Ge-68)/ Gallium-68 (Ga-68) generators (271 
days half-life) that allow obtaining Ga-68 on-site without the need for a cyclotron. The Ge-
68 /Ga-68 generator can be used for up to 1 year and the equilibrium between Ga-68 and Ge-
68 is rapidly re- established allowing multiple radiotracer preparations in a day from a single 
generator. 
 
3. PATIENT SELECTION 
 
3.1  
Inclusion Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed localized prostate 
cancer that are scheduled to undergo radical prostatectomy. 
 
3.1.2 Age >18 years. 
 
3.1.3 Patients must have laboratory values consistent with eligibility to undergo a 
radical prostatectomy:  
o creatinine 
1.5 X upper limit of normal 
o creatinine clearance 
> 60 mL/min 
 
3.1.4 The effects of 89Zr-df-IAB2M on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason, men must agree 
to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while her male 
partner is participating in this study, she should inform her treating physician 
immediately. 
 
3.1.5 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 Exclusion Criteria  
 
3.2.1 Treatment or plans for treatment with radiation therapy, surgery, chemotherapy, 
or investigational therapy between the time of conventional imaging, 89Zr-df-
IAB2M PET/CT and the surgical resection used for the study evaluation. 
 


 
 
11 
 
3.2.2 Transrectal prostate biopsy performed less than four weeks prior to 89Zr-df-
IAB2M administration. 
 
3.2.3 Uncontrolled illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.  
 
 
4. REGISTRATION PROCEDURES 
 
Patient Registration 
 
Eligibility will be confirmed as defined in the Section entitled Criteria for Patient/Subject 
Eligibility. Informed consent will be obtained by following procedures defined in the Section 
entitled Informed Consent Procedures. During the registration process registering individuals will 
be required to complete a protocol specific Eligibility Checklist. 
 
 
5. INVESTIGATIONAL IMAGING PLAN 
 
5.1  
Agent administration 
 
89Zr-df-IAB2M: 
89Zr-df-IAB2M will be administered under IND No. 130768. 89Zr-df-IAB2M will be 
administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 7.  No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the patient’s 
malignancy. 
 
68Ga-PSMA-HBED-CC: 
Single intravenous dose of 68Ga-PSMA-HBED-CC (5 2 mCi) will be administered 
under IND # 124495 on an outpatient basis. Intravenous access must be well 
established prior to initiating infusion.  The injection will be given by slow intravenous 
bolus.  Following completion of the 68Ga-PSMA-HBED-CC injection, a normal saline 
flush (approximately 10 mL) will ensure that all 68Ga-PSMA-HBED-CC remaining in 
the infusion line is injected. 
 
 
5.2  
General concomitant medication and supportive care guidelines 
 
Allergic events will be managed as follows: rash, pruritis, urticaria and wheezing will 
be treated with diphenhydramine or equivalent H1 blocker and/or steroids as clinically 
appropriate.  Anaphylaxis or anaphylactoid signs or symptoms will be treated with 
steroids and/or epinephrine as clinically indicated.  Infusion-related reactions (fever, 


 
 
12 
 
rigors) will be treated with acetaminophen, meperidine or other narcotics and 
diphenhydramine hydrochloride as clinically appropriate.  
 
5.3 
Monitoring vital signs pre/post 89Zr-df-IAB2M and 68Ga-PSMA-HBED-CC 
 
The injection of 89Zr-df-IAB2M and 68Ga-PSMA-HBED-CC, and subsequent 
monitoring will occur in a facility that is equipped for cardio–pulmonary resuscitation. 
The dispensed dose will be infused under the supervision of nuclear medicine physician 
or designee under the supervision of a nuclear medicine physician. Subjects will be 
offered/receive pre–medication prior to the investigational agent infusion.  Infusion–
related reactions (fever, rigors) will be treated with acetaminophen, meperidine and 
diphenhydramine hydrochloride as clinically appropriate. Other allergic events will be 
managed as follows: rash, pruritus, urticaria and wheezing will be treated with 
diphenhydramine hydrochloride, meperidine and/or steroids as clinically appropriate.  
Anaphylaxis or anaphylactoid signs or symptoms will be treated with steroids and/or 
epinephrine as clinically indicated.  Vital signs will be monitored during the infusion. 
Systolic and diastolic blood pressure (mm Hg), temperature, pulse rate (beats/minute), 
and respiratory rate (breaths/minute), will be recorded with the patient in sitting 
position. Any clinically significant change in the vital signs will be recorded as AEs. 
Serial vital signs including temperature, BP, and heart rate will be monitored before 
the infusion and 30 minutes and 60 minutes after the infusion. If any subject has any 
adverse reaction at 60 minutes, they will stay longer until it is resolved. 
 
 
5.4  
Duration of study participation and criteria for removal from study 
 
For completion of all scheduled visits and study procedures, a patient may participate 
for up to 11 weeks or until one of the following criteria applies: 
 
o Disease progression, 
 
o Intercurrent illness that prevents administration of 89Zr-df-IAB2M, 68Ga-
PSMA-HBED-CC or prostatectomy, 
 
o Unacceptable adverse event(s), 
 
o Patient decides to withdraw from the study, or 
 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further participation in the judgment of the investigator. 
 
5.5 
Duration of Follow Up 
 


 
 
13 
 
Patients will be followed for six to seven weeks after their radical prostatectomy.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Not applicable. 
 
 
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  89Zr-df-IAB2M Potential Risks  
 
There are no known contraindications for 89Zr-df-IAB2M.  No drug related adverse events 
were reported in the Phase I study.  Because of the potential for infusion or allergic reaction, 
the subject should be monitored for safety for one hour following the infusion. 
 
The 14 day sterility testing will not be completed at the time of 89Zr-df-IAB2M infusion. The 
89Zr-df-IAB2M dose will be released based on the controlled process along with a history of 
sterile lots. If a sterility test becomes positive any time during the 14-day period, the 
Investigator will be notified immediately.  The subject who received the 89Zr-df-IAB2M will 
be contacted and requested to have an office visit including blood cultures and, if clinically 
indicated, started on broad spectrum intravenous antibiotics (Vancomycin and Imipenem). 
 
Radiation Dosimetry:  89Zr and the CT component of the PET/CT study expose patients to 
ionizing radiation.  
In the phase I/IIa study 18 patients received a total of four PET scans. For each PET scan 
(considered discrete time points) the radioactivity levels in the brain, lungs, heart, liver, 
gallbladder, kidneys, intestines, urinary bladder and whole body were obtained and recorded.  
Time activity curves were generated, fit to an exponential model using the OLINDA/EXM 
software, and the number of disintegrations in the source organs were determined and used to 
estimate the organ radiation dose. The radiation doses estimates are shown in Table 1.  
The lower large intestinal wall received the largest estimated dose (2.0± 0.78mSv/MBq) 
followed by the liver (1.74± 0.68 mSv/MBq) and the kidneys (1.56± 0.48 mSv/MBq). The 
Effective Dose was 0.687 ± 0.141 mSv/MBq, thereby resulting in an estimated Effective Dose 
of 63.5 mSv for the anticipated 2.5 mCi injection in the present trial. 
 






 
 
16 
 
Stomach Wall 
3.32E+00 
4.15E+00 
Spleen 
7.96E+00 
9.95E+00 
Pancreas 
2.80E+00 
3.50E+00 
Red Bone Marrow 
1.35E+00 
1.69E+00 
Bladder Wall 
1.41E+00 
1.76E+00 
Effective Dose 
1.94E+00 
2.43E+00 
 
For comparison purposes, the average per capita annual exposure from natural background 
in the continental USA is 3.0 mSv57. 
 
7.3 
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. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
7.4 
Recording of Adverse Events 
 
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.     
 
7.5 
Serious Adverse Event (SAE) Reporting 
7.5.1. Definition of SAE 
 
SERIOUS ADVERSE EVENTS include death, life threatening adverse 
experiences, hospitalization or prolongation of hospitalization, disability or 
incapacitation, overdose, congenital anomalies and any other serious events 
that may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 
7.5.2. Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the 


 
 
17 
 
IRB policy.  The IRB requires immediate reporting of all unexpected and 
study-related (definite or probable) adverse events.  The following procedure 
will be followed for reporting SAE to the IRB: 
 
 
Complete the SAE Cover Sheet (See Appendix B) 
 
If the event is unexpected AND definitely or probably related to the 
study, complete the IRB Unexpected, Study-related Adverse Events, 
Incidents, and Information Reporting Form.  This form should be 
submitted within 24 hours of investigator notification of the event. 
 
If the event is expected OR possibly or unrelated to the study, only 
the SAE Cover Sheet must be completed.  These events will be 
reported to the IRB at the time of continuing renewal on the Adverse 
Event & IND Safety Reporting Cumulative Table. 
 
Forms 
may 
also 
be 
downloaded 
from 
the 
IRB 
website 
at: 
http://www.med.cornell.edu/research/for pol/ins rev boa.html 
 
7.5.3. Reporting of SAE to FDA   
 
If an SAE occurs on this study, the event will be filed on a MedWatch form 
with the FDA. 
 
CDER-only Biologic INDs:  
Food and Drug Administration  
Center for Drug Evaluation and Research  
Therapeutic Biologic Products Document Room  
5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
8. PHARMACEUTICAL INFORMATION 
 
A description of potential risks associated with 89Zr-df-IAB2M can be found in Section 7.1.   
 
8.1 89Zr-df-IAB2M (IND#:130768)   
 
8.1.1  Radiolabeling of 89Zr-df-IAB2M: 
 
89Zr-df-IAB2M is produced and will be administered under IND No. 130768. For this study, 
IAB2M is conjugated to desferrioxamine (Df) for labeling with 89Zr. The final investigational 
drug product is 89Zr-df-IAB2M and is supplied as a sterile filtered solution in a sterile vial 
sealed with rubber septa and closed with an aluminum stopper. 89Zr is chelated by the Df 
moiety of the Df-IAB2M conjugate. No materials of animal origin are used in the 
manufacturing of 89Zr-df-IAB2M. Manufacturing of Df-IAB2M has been performed and 


 
 
18 
 
overseen by ImaginAb, Inc. U.S.  df-IAB2M is provided by ImaginAb under IND# 118810.  
The labeling of df-IAB2M with 89Zr is performed at Weill Cornell Medicine by Shankar 
Vallabhajosula, 
Ph.D., 
Chief 
of 
Radiochemistry 
and 
the 
Professor 
of 
Radiochemistry/Radiopharmacy in Radiology. df-IAB2M is provided by ImaginAb, under 
IND# 118810. The process for the manufacture of the 89Zr-df-IAB2M has been submitted and 
reviewed as a part of the IND #130768. The radiochemistry staff at Weill Cornell Medicine 
will be responsible for QC testing and batch release of 89Zr-df-IAB2M for clinical use. 
The final study drug product is 2.5 (+/- 10%) mCi of 89Zr-df-IAB2M formulated in solution 
consisting of 5% human serum albumin solution USP, 4mg/mL gentisic acid and 0.2M sodium 
acetate solution, aseptically mixed with df-IAB2M to achieve a total protein dose of 10 mg. 
 
8.1.2 Radiopharmacy dispensation of 89Zr-df-IAB2M:  
The Nuclear Medicine Physician or designee is responsible for ensuring that the delivery of 
the investigational drug product from the Radiopharmacy to the facility site for patient infusion 
are correctly labeled, received, handled, and stored in accordance to ICH and applicable 
government regulations, local/state laws, and used in accordance with this protocol.   
The syringe will be shielded by secondary lead containers for radiation protection purposes. 
The exact radioactive dose administered must be determined by measuring the 89 Zr-activity in 
the syringe before infusion and after infusion by using a dose calibrator, with radioactivity 
decay correction for infusion time. Measured radioactivity values and times of measurement 
will be documented, as well as the total injected volume.  All unused study drug product must 
be returned to the Radiopharmacy or destroyed in accordance with institutional policies. 
 
8.1.3 
Availability 
 
df-IAB2M is an investigational agent supplied to investigators by ImaginAb. The process for 
the manufacture of the 89Zr-df-IAB2M by the Radiochemistry/Radiopharmacy Lab in the 
department of Radiology at Weill Cornell Medicine has been submitted and reviewed as a part 
of the IND # 130768.  
 
8.1.4 
89Zr-df-IAB2M Accountability 
 
89Zr-df-IAB2M Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents 
received from ImaginAb on a Drug Accountability Record Form (DARF). 
 
8.1.5 
89Zr-df-IAB2M Infusion 
 
89Zr-df-IAB2M will be administered under IND No. 130768. A 10 mg mass dose containing 
2.5 mCi 89Zr labeled to 2-3 mg of df-IAB2M and 7-8mg of cold (unlabeled) df-IAB2M will be 
injected intravenously. The dispensed dose will be infused under the direct supervision of a 
Nuclear Medicine Physician or designee. Patients will be monitored for safety during and up 
to one hour after the injection.  


 
 
19 
 
Regulatory agencies require accounting for the disposition of all investigational drugs received 
by each clinical site. Information on drug disposition required by law consists of: 1) date 
received; 2) date dispensed; 3) quantity dispensed, and 4) patient identification number to 
whom the drug was dispensed. The Investigator is responsible for accounting for all unused 
study drug and all used study drug.  
 
8.2 68Ga-PSMA-HBED-CC (IND #124495): 
8.2.1 
 
Radiolabeling of 68Ga-PSMA-HBED-CC: 
ABX Advanced Biochemical Compounds, Radeberg, Germany produces PSMA-HBED-CC. 
Upon purchase and shipment to Weill Cornell Medicine, it will be labeled with 68Ga with final 
product being 68Ga-PSMA-HBED-CC. Radionuclide conjugation will be done at the Division 
of Nuclear Medicine, Department of Radiology, Weill Cornell Medicine.  
 
The material produced is subjected to quality assurance testing as outlined in the Food and 
Drug Administration “Points to Consider”. All production data and supporting documents, 
together with the results of all quality assurance testing, have been provided to and reviewed 
by the Food and Drug Administration (68Ga-PSMA-HBED-CC, IND# 124495). 
 
8.2.2 Radiopharmacy dispensation of 68Ga-PSMA-HBED-CC: 
The Nuclear Medicine Physician or designee is responsible for ensuring that the delivery of 
the investigational drug product from the Radiopharmacy to the facility site for patient infusion 
and also to make sure that it is correctly labeled, received, handled, and stored in accordance 
to ICH and applicable government regulations, local/state laws, and used in accordance with 
this protocol.   
The syringe will be shielded by secondary lead containers for radiation protection purposes. 
The exact radioactive dose administered must be determined by measuring the 68Ga-activity in 
the syringe before infusion and after infusion by using a dose calibrator, with radioactivity 
decay correction for infusion time. Measured radioactivity values and times of measurement 
will be documented, as well as the total injected volume.  All unused study drug product must 
be returned to the Radiopharmacy or destroyed in accordance with institutional policies. 
8.2.3 Availability 
PSMA-HBED-CC is an investigational agent supplied to investigators by ABX Advanced 
Biochemical Compounds, Radeberg, Germany. The process for the manufacture of the 68Ga-
PSMA-HBED-CC by the Radiochemistry/Radiopharmacy Lab in the department of Radiology 
at Weill Cornell Medicine has been submitted and reviewed as a part of the IND # 124495. 
8.2.4 
68Ga-PSMA-HBED-CC Accountability 
 
68Ga-PSMA-HBED-CC Inventory Records – The investigator, or a responsible party 
designated by the investigator, will maintain a careful record of the inventory and disposition 
of all agents received from ABX Advanced Biochemical Compounds, Radeberg, Germany on 
a Drug Accountability Record Form (DARF). 
 
8.2.5 
68Ga-PSMA-HBED-CC Infusion 


 
 
20 
 
 
Single intravenous dose of 68Ga-PSMA-HBED-CC (5 2 mCi) will be administered under IND 
# 124495 on an outpatient basis. Intravenous access must be well established prior to initiating 
infusion.  The injection will be given by slow intravenous bolus.  Following completion of the 
68Ga-PSMA-HBED-CC injection, a normal saline flush (approximately 10 mL) will ensure 
that all 68Ga-PSMA-HBED-CC remaining in the infusion line is injected. 
 
 
9. IMAGING AND SPECIAL STUDIES 
 
9.1 
Imaging and histopathology 
 
9.1.1 3T multi-parametric pelvic MRI 
 
9.1.1.1 Method of Assessment 
 
 
 
3T mpMRI preoperative images will be read by GU radiologist reporting: location, size 
and features of lesions suspicious for PCa. Lesional criteria on MR are defined as being 
well-circumscribed with low signal intensity on T2 weighted images with associated 
diffusion restriction on ADC maps.  Dynamic contrast enhanced (DCE) MR imaging 
on preoperative images will also be evaluated subjectively for early and intense 
enhancement followed by rapid washout, findings that are all associated with prostate 
cancer.  The radiologist will have access to TRUS biopsy results.  
 
An MR /lesional analysis will be performed.  Lesional criteria on MR will be defined 
as well-circumsribed low signal intensity on T2 weighted images with associated 
diffusion restriction on ADC maps.  Dynamic contrast enhanced MR imaging on 
preoperative images will also be evaluated subjectively for early and intense 
enhancement followed by rapid washout, findings that are all characteristic of prostate 
cancer.   
 
 
 
9.1.1.2 Timing of Assessment 
 
Will be performed within six weeks prior to or on Visit 3. The investigators will 
attempt to schedule the mpMR as close to the date of the PET/CT so that the post-
TRUS biopsy changes do not confound the differences between the two imaging 
modalities.   
 
 
9.1.2 
89Zr-df-IAB2M PET/CT imaging 
 
9.1.2.1 Method of Assessment 
 
PET/CT will be read twice by a nuclear medicine physician. For the first interpretation, 
the physician will be blinded from clinical history, biopsy results and conventional 


 
 
21 
 
imaging modalities. After the initial reading, the nuclear medicine physician will be 
provided with both the TRUS biopsy results and previously read scans for the repeat 
PET/CT reading. During each interpretation, the physician will record all abnormal, 
suspicious areas with higher uptake than adjacent or contralateral background. Each 
abnormal area will be recorded on a map of the prostate along with maximum 
standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean).  
 
Subsequently, the accumulation of 89Zr-df-IAB2M will be compared to areas of known 
PCa foci on histopathology and mpMRI, as described in Section 13. After completion 
of the histopathology, the PET/CT findings will be compared to histopathology to 
perform a lesion by lesion analysis with histopathology serving as the reference gold 
standard.  This analysis will primarily include tumors ≥ 0.5 cm3 on histopathology, with 
a secondary assessment of any lesions <0.5 cm3. Similarly, areas of increased uptake 
identified on IAB2M, which had been read as suspicious for cancer will be compared 
to histopathology to determine the underlying pathology (e.g., inflammation, benign 
prostatic hyperplasia). 
 
9.1.2.2 Timing of Assessment 
 
Infusion of 89Zr-df-IAB2M will occur during Visit 2. Imaging will be performed 2-3 
days after the injection on Visit 3. Please refer to the Calendar of Events (Section10). 
 
9.1.3 
68Ga-PSMA-HBED-CC PET/CT imaging 
 
Patient preparation should be according to the policies and procedures of the local 
imaging site (CIBC). The patient does not need to be fasting for either the infusion or 
the scans. The use of intravenous or oral contrast will not be permitted. Specifications 
for acquiring the 68Ga-PSMA-HBED-CC PET/CT scans will be provided in study 
specific documentation by the study chair or the co-investigators from the Division of 
Nuclear Medicine. PET/CT images are acquired between 1 and 3 hours after the 68Ga-
PSMA-HBED-CC infusion. Image acquisition will be from vertex of skull to mid 
thighs. The subject will be scheduled for the injection and imaging between screening 
and prostatectomy depending on subjects’ availability and compliance. 
 
9.1.4 Histopathology 
 
9.1.4.1 Method of Assessment 
 
All patients will undergo radical prostatectomy and potential lymph node dissection. 
The prostate gland will be fixed in formalin for 12-24 hours at room temperature. After 
fixation, the gland will be processed according to standard institutional protocol, as 
follows: 
 
1) Weigh the prostate gland with attached seminal vesicles and vasa deferentia 
 
2) Measure the prostate, seminal vesicles, and vasa deferentia 


 
 
22 
 
 
3) Orient the gland. Note and describe any nodularities or asymmetry to the gland; 
tissue disruptions; defects; or surface irregularities; adherent tissues/organs, etc. 
 
4) Ink the entire specimen—green on the right side and black on the left. 
 
5) Amputate both seminal vesicles and vasa deferentia at their attachment to the 
prostate and submit the most proximal portion of each for histology (i.e., submit 
the portion of SV/VD nearest their juncture with the prostate). 
 
6) Amputate the most distal (apical) 5-7 mm of the gland. Place the broad cut 
surface of this “cone” of tissue onto the table and section perpendicularly to the 
midline (into ~3 mm strips). Submit the strips on “edge” for margin (ink) 
evaluation. When submitting, if the strips are not too long, leave the left and right 
sides connected and submit the anterior and posterior halves separately (e.g., A2-
anterior apex, A3-posterior apex). If the strips are too long to fit into a cassette, 
divide the strips into left and right halves. Maintain the separation of anterior and 
posterior halves and designate appropriately in the summary of sections (e.g., A2-
left anterior apex, A3-right anterior apex, A4-left posterior apex, A5- right posterior 
apex). 
 
7) Amputate the most proximal (basal) 5-7 mm of the gland, which should include 
the bladder neck margin, and process this “cone” of tissue in the same manner as 
the apex (Step 6). 
 
8) Section the remaining prostate perpendicular to the urethra into 4 mm thick 
slices, starting at the apex and continuing towards the base until completely 
sectioned. Designate the slices/levels as A, B, C, etc., starting from the apex. 
Generally, an average 35 gram prostate should be sectioned into at least five levels 
(A to E). 
 
Sections to submit for histology: Right and left seminal vesicle and vas deferens 
(1-2 cassettes total, depending on size); Bladder neck/base margin (2-4 cassettes, 
divided as above); Apical margin (2-4 cassettes, as above) 
 
Remaining prostate will be submitted as follows: 
Each slice/level is quadrisected into 1) left anterior 2) left posterior 3) right anterior 
and 4) right posterior, as with the apex and base margins. However, DO NOT cut 
the slices/levels into strips; submit as intact quadrant pieces and designate in the 
summary of sections (e.g., left anterior slice A should be "LAA", and left posterior 
slice A should be "LPA" and so forth). 
 
A pathologist, blinded to the imaging results, will independently review all slides. 
Cases will be reported according to standard pathologic procedures including the 
presence of tumor, Gleason score, extracapsular extension, and seminal vesicle 
invasion. In addition, using an anatomical map of the prostate, each individual tumor 


 
 
23 
 
focus will be outlined and annotated (location within the gland, tumor size, tumor stage, 
and Gleason score). Any other abnormal areas/findings within the specimen will also 
be annotated. Immunohistochemical assessment of PSMA expression and/or 
neuroendocrine features will be performed as specified in source documentation. A 
tabular list of all cancer lesions will be made for each patient based on size and/or stage 
of each tumor and listing Gleason score, stage, and location. This list will be used to 
review and correlate with imaging findings on IAB2M PET/CT and mpMRI. 
 
9.1.3.2 Timing of Assessment 
 
Histopathologic specimen assessment will occur after Visit 4, radical prostatectomy. 
Please refer to the Calendar of Events (Section10). 
 
9.2 
Special Studies 
 
9.2.1 Antigenicity Testing (HAHA)  
 
9.2.1.1 Method of Assessment 
 
5 mL of whole blood will be drawn by peripheral venipuncture in a yellow top STT 
tube (5 mL) for HAHA evaluation.  
 
9.2.1.2  
Timing of Assessment 
 
Blood draws for HAHA determinations will be obtained on Visit 2, prior to 89Zr-df-
IAB2M infusion and at Visit 5 (refer to Section 10). 
 
 
 
 


 
 
24 
 
10. 
STUDY CALENDAR 
 
Table 3: Schedule of Assessments  
Protocol 
Assessments 
Screeninga 
Visit 1 
Infusion 
Visit 2 
Imaging  
Visit 3 
Prostatectomy 
Visit 4 
HAHA 
Visit 5 
 
Day -28 to -1 
Day 0 
Day 2 - 4 
Within 3-30 days 
after visit 3 
(preferably 1 
week after scan) 
6 Weeks ±1 
week after 
Visit 4  
Informed 
consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
X 
 
 
 
Concomitant 
medicationsb 
X 
X 
X 
 
 
Physical exam 
X 
Xc 
 
 
 
Karnofsky 
Performance  
X 
 
 
 
 
Vital signsc 
X 
X 
X 
 
 
Blood lab 
samplesd  
X 
X 
X 
 
 
Radiographic 
studiese 
X 
Xe 
Xe 
Xe 
 
HAHA Blood 
 
 
Xf 
 
 
Xf 
89Zr-df-IAB2M 
tracer 
administration 
 
X 
 
 
 
68Ga-PSMA-
HBED-CC 
administration 
and PET/CT 
scan 
 
Xg 
 
 
 
89Zr-df-IAB2M 
PET/CT scan 
 
 
X 
 
 
Adverse events  
 
X 
X 
 
 
 
a  
Screening evaluation should be performed following informed consent and within 4 weeks before enrollment, 
except when noted otherwise. Evaluations performed as standard of care before informed consent but within the 
4-week window need not be repeated.   
b 
Concomitant medication refers to medication received by subjects from the point of signed informed consent 
through the end of Visit 6.   
c  
Vital signs include height, weight, temperature, blood pressure and heart rate. Height and weight are obtained 
only at Visit 1. During the Infusion Visit 2, serial vital signs will be monitored pre-infusion, then 30 minutes 


 
 
25 
 
and 60 minutes post-infusion (±5 minutes).  
d 
Laboratory samples collected include Chemistry panel, CBC (hematology), PSA (first blood draw only), and 
serum testosterone level (first blood draw only). All Screening laboratory samples are to be collected within 14 
days before enrollment or at Visit 2, Pre-infusion (serum testosterone level may be up to 4 weeks before 
enrollment or Visit 2, prior to 89Zr-df-IAB2M infusion) and again at Visit 3.  
e 
Radiographic evaluations include a modified (3T multiparametric) MRI of the pelvis, if clinically indicated. 
Radiographic studies are to be performed within 6 weeks before, or on Visit 3/Day 2, provided the patient has 
not received a new intervening anti-cancer treatment. 
f 
Blood sample will be drawn via venipuncture for HAHA  evaluation pre-infusion at Visit 3and repeat samples 
will be taken at Visit 5 (week 6, +/- 1 week).  
g 
68Ga-PSMA-HBED-CC administration followed by PET/CT scan 1 – 3 hours later must be done prior to 89Zr-
df-IAB2M tracer administration on Visit 2 otherwise the 68Ga-PSMA-HBED-CC administration and PET/CT 
scan can be done anytime between screening and prostatectomy visit. 
 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 
Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, and efficacy data for all enrolled patients.  
 
            11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool 
for the creation of customized, secure data management systems that include Web-
based data-entry forms, reporting tools, and a full array of security features including 
user and group based privileges, authentication using institution LDAP system, with a 
full audit trail of data manipulation and export procedures.  REDCap is maintained on 
CTSC-owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2  Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.  
 
12. STATISTICAL CONSIDERATIONS 
 
Data analysis and image interpretation will be performed in a manner similar to the strategy 
employed by Osborne et al. 58 and Turkbey B et al59, with both a lesion specific and sector-specific 
analysis.   For the sector-analysis, the prostate gland will be divided into segments as described in 
the START criteria58.  A lesion-based analysis will also be performed after review of 
histopathology. 


 
 
26 
 
 
Sectors of the prostate gland as described by the START criteria, Moore C, et al.   
 
12.1 
Study Design/Endpoints 
 
The present study is a phase II, open label, single-center, non-randomized, single-
dose study. 
 
Primary endpoints 
 
The primary endpoint of this study is the proportion of subjects with PSMA-positive 
(identified by H&E staining and immunohistochemistry) "dominant"  PC lesion(s) 
greater than 5mm in diameter, whose lesion(s) have been successfully identified by 
89Zr-df-IAB2M imaging. Because this is an exploratory pilot study, no formal sample 
size/power calculation is required.  However, with a sample size of 20 patients in the 
study, a two-sided 95% confidence interval for the proportion of patients successfully 
imaged by 89Zr-df-IAB2M can be constructed to be within ± 19.0% of the observed 
proportion of patients with successful imaging by 89Zr-df-IAB2M.  This calculation 
assumes an 89Zr-df-IAB2M imaging-success proportion of 75%.  All estimates from 
the study will serve as preliminary data (i.e., hypothesis-generating) for future studies.  
 
o Descriptive statistics will be calculated for the study cohort: 
 
 Median and inter-quartile range or mean and standard deviation for age, 
biopsy Gleason score (1o, 2o, Total), number of cores on biopsy, number 
of positive cores on biopsy, PSA, number of lesions on prostatectomy 
pathology (RP pathology), lesion size on RP pathology, Gleason score 
(1o, 2o, and total) on RP pathology. 
 
o Lesion-based analysis: 


 
 
27 
 
 
 SUVmax measurements of 89Zr-df-IAB2M PET/CT images obtained in 
tumor and non-tumor regions will be compared. To account for 
intrapatient correlation of multiple lesions, a linear mixed-effects model 
with a random intercept will be used to estimate and compare the mean 
SUVmax values in different regions. P<0.05 will be indicative of a 
significant difference as described by Turkbey B, et al.59 
 
 Positive and negative predictive values will be estimated by using 
generalized estimating equations (GEE) modeling, with logit link 
function and a working independence correlation structure. Robust 
variance estimation and the delta method will be used to calculate 
standard errors of the positive and negative predictive values. The Wald 
test with robust variance estimates will be used for statistical inference.  
Subgroup analyses will be performed for high, moderate, and low risk 
disease (see secondary endpoints).  
 
 Receiver operating curve characteristics (ROC) will be constructed to 
determine the predictive ability of SUV level on detection of any disease 
and disease severity as correlated to histopathology. 
 
Secondary endpoints 
 
 To determine the ability of in vivo 89Zr-df-IAb2M PET/CT to correlate with 
pathological features (i.e. Gleason pattern, diameter and PSMA-positivity): 
 
o The Wilcoxon rank sum test will be used to compare lesions that were and were 
not identified on in vivo PET with respect to lesion size, immunohistochemical 
PSMA staining, and Gleason score (demonstrated by histopathology).  This 
lesion based analysis will be performed in a similar fashion as described above. 
 
 To compare the in vivo 89Zr-df-IAb2M PET/CT and 68Ga-PSMA-HBED-CC PET/CT 
to in vivo mpMRI: 
 
o The diagnostic accuracy of 89Zr-df-IAB2M PET/CT and 68Ga-PSMA-HBED-
CC PET/CT imaging in patients with prostate cancer will be compared with that 
of mpMRI imaging by using sector-based analysis, as described by Turkbey B 
et al.59 The estimates of patient-specific sensitivity and specificity will be 
defined as the proportion of true-positive sectors and the proportion of true-
negative sectors in each patient. Overall sensitivity and specificity will then be 
estimated by calculating the mean (and standard error) of these individual-


 
 
28 
 
specific estimates across patients. Differences in sensitivity and specificity 
between modalities will then be evaluated by the Wilcoxon signed-rank test. 
 
 To determine the sensitivity, specificity, PPV, NPV of IAB2M to detect all 
pathologically identified PCa lesions that do not meet criteria for clinical significance 
(defined as: < 0.5 cm3 with Gleason pattern < 4): 
 
o As above, but for lesions considered not to be clinically significant. 
 
 To correlate IAB2M positivity (SUV) and lesion size: 
  
o The Spearman-rank correlation coefficient will be used to evaluate the 
association between SUV and size of the lesion (procedure for size 
measurements are defined in Section 9.1.3). 
 
 To correlate IAB2M positivity (SUV) and Gleason pattern (3, 4 and 5): 
 
o The Spearman-rank correlation coefficient will be used to evaluate the 
association between correlate SUV and the histopathologically defined Gleason 
pattern.  The Wilcoxon rank-sum test will also be used to compare 
SUVmax measurements between lesions with low Gleason score (3+4 or lower) 
and high Gleason score (4+3 or higher). 
 
 To correlate IAB2M positivity (SUV) and PSA: 
 
o The Spearman-rank correlation coefficient will be used to evaluate the 
association between SUV and serum PSA levels obtained during screening. 
 
 To determine the ability of in vivo 89Zr-df-IAB2M PET/CT to identify extra-prostatic 
extension: 
 
o The Wilcoxon rank-sum test will be used to compare SUVmax measurements of 
IAB2M-positive extra-prostatic sites between lesions with and without 
histopathologically confirmed extra-prostatic extension.  
 
 To determine the ability of in vivo 89Zr-df-IAB2M PET/CT to identify occult lymph 
node involvement: 
 


 
 
29 
 
o The Wilcoxon rank-sum test will be used to compare SUVmax measurements of 
IAb2M-positive 
lymph 
nodes 
between 
patients 
with 
and 
without 
histopathologically confirmed lymph node involvement.  
 
 To further evaluate the safety of 89ZR-DF-IAB2M PET/CT and 68Ga-PSMA-HBED-
CC imaging.  
 
o See section on Risks 
  
Additionally, we will assess whether there is improved sensitivity in detecting 
localized PCa by combining imaging results. This assessment will be done by 
estimating the PPV with different combinations of imaging modalities.  The 
incremental effect of an additional imaging modality on PPV will be tested with 
the Wald test, as described by Turkbey B, et al.59 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 
alpha level.  All analyses will be performed in SAS Version 9.4 (SAS Institute, Inc., 
Cary, NC) and Stata Version 13.0 (StataCorp, College Station, TX). 
 
12.2 
Sample Size/Accrual Rate 
 
The sample size for this study will be 20 patients. We anticipate an accrual rate of at 
least two patients per month.  With a sample size of 20 patients in the study, a two-
sided 95% confidence interval for the proportion of patients successfully imaged by 
89Zr-df-IAB2M can be constructed to be within ± 19.0% of the observed proportion of 
patients with successful imaging by 89Zr-df-IAB2M.  This calculation assumes an 89Zr-
df-IAB2M imaging-success proportion of 75%.  All estimates from the study will serve 
as preliminary data (i.e., hypothesis-generating) for future studies.” 
 
12.3 
Stratification Factors 
 
No stratification factors.  However, an interim analysis and efficacy determination 
based on the primary endpoint will be performed after the first 10 patients have 
completed Visit 4 and subsequent histopathological analysis has been performed on the 
prostate specimen. 
 
 
 
 
 
 
 


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


 
 
35 
 
 
APPENDIX B 
 
WCMC IRB SAE Reporting Forms 
 
http://researchintegrity.weill.cornell.edu/institutional review board/irb adv.html