Conditions: Prostate Cancer
Keywords: high-risk prostate cancer localized prostate cancer prior to prostatectomy neoadjuvant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a single-center, single arm, open-label phase II study evaluating the safety, anti-tumor effect, and immunogenicity of neoadjuvant Dupixent given prior to radical prostatectomy.

Detailed description:
This is a single-center, single arm, open-label phase II study evaluating the safety, anti-tumor effect, and immunogenicity of neoadjuvant Dupixent given prior to radical prostatectomy in men with high-risk localized prostate cancer (this trial will enroll men with at least high risk prostate cancer defined by NCCN Guidelines Version 2.2017 = clinical stage ≥T3a or PSA \>20 ng/mL or Gleason score ≥8).

Patients will be recruited from the outpatient Urology clinic. Men will be treated with dupilumab 600 mg subcutaneously (SQ) on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43. They will then undergo surgery on day 57. 14 days after the last dose of Dupixent, prostate glands will be harvested at the time of radical prostatectomy, and prostate tissue will be examined for the secondary endpoints.

Follow-up evaluation for adverse events will occur 30 days and 60 days after surgery. Patients will then be followed by their urologists according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-3.

Arms:
arm 1: Participants will be treated with dupilumab 600 mg SQ on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43. They will then undergo surgery on day 57. 14 days after the last dose of Dupixent, prostate glands will be harvested at the time of radical prostatectomy, and prostate tissue will be examined for the secondary endpoints.

Interventions: intervention 1: Dupilumab
Intervention descriptions: intervention 1: dupilumab 600 mg SQ on day 1, and then 300 mg SQ on days 8,15, 22, 29, 36, 43.

Protocol document:
Prot_SAP_000.pdf: 
Neoadjuvant Dupilumab in Localized High-Risk Prostate Cancer September 3, 2020 Version 3.0 
Johns Hopkins University 
 
 
 
 
 
Study # J18116  
 
 
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Neoadjuvant Dupilumab in Men with Localized High-Risk Prostate Cancer  
IRB #: IRB00182718 
NCT#  NCT03886493 
 
Johns Hopkins University 
 
Principal Investigator 
Kenneth J Pienta, MD  
Johns Hopkins Brady Urological Institute 
email: kpienta1@jhmi.edu 
 
Co-Principal Investigators 
Angelo De Marzo, MD 
Johns Hopkins Kimmel Cancer Center 
Email: ademarz@jhmi.edu 
 
Bruce Trock, PhD  
Johns Hopkins Brady Urological Institute 
Email: btrock@jhmi.edu 
 
Michael Gorin, MD 
Johns Hopkins Brady Urological Institute 
Mgorin1@jhmi.edu 
 
 
Research Nurse 
Carolyn Chapman, RN 
Johns Hopkins Kimmel Cancer Center 
Email: cchapma7@jhmi.edu 
 
Study Coordinator 
Alice Jordan 
Johns Hopkins Kimmel Cancer Center 
Email: ajorda30@jhmi.edu  
 
 
 
 
 
Protocol Type / Version # / Version Date:  
Protocol Version 2.0 Date: February 4, 2019
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related 
activities. 


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SYNOPSIS 
Title 
Neoadjuvant Dupilumab in Men with Localized High-Risk Prostate Cancer  
Institution 
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 
PI(s) 
Kenneth J Pienta MD (PI), Angelo De Marzo MD PhD (Co-PI), Michael Gorin, MD (Co-PI), 
Bruce Trock PhD (co-PI) 
Sponsor 
Johns Hopkins University 
Regeneron, Inc. 
 
IRB # 
IRB00182718 
Study 
agent 
Dupilumab 
 
Phase 
Phase II Study  
Indication 
Men with high-risk localized prostate cancer, prior to radical prostatectomy 
Target 
population 
Inclusion criteria 
 
Histologically confirmed prostate adenocarcinoma 
 
Clinical stage T1c–T3b, N0, M0 
 
Gleason sum 7-10 
 
At least 2 positive cores at biopsy 
 
Prior decision to undergo radical prostatectomy 
 
Adult male >18 years of age 
 
ECOG performance status 0-1, or Karnofsky score ≥ 70% 
 
Adequate kidney, liver, and bone marrow function 
 
Willingness to sign informed consent and adhere to study requirements 
Exclusion criteria: 
 
Presence of known lymph node involvement or distant metastases 
 
Prior radiation, hormones, biologics, or chemotherapy for prostate cancer 
 
Prior immunotherapy/vaccine therapy for prostate cancer 
 
Concomitant treatment with hormonal therapy or 5-reductase inhibitors 
 
Use of experimental agents for prostate cancer within the past 3 months 
 
History of autoimmune disease requiring systemic immunosuppression 
 
History of other lethal malignancy within 3 years 
 
Uncontrolled major infectious, cardiovascular, pulmonary, hematologic, or psychiatric 
illnesses that would make the patient a poor study candidate 
 
significant eye disease 
 
Start date/ 
Duration 
Initial patients are expected to be entered in July 2018. With an estimated enrollment rate 
of 2-3 patients per month, accrual is expected to last 8-10 months. 


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Sample 
size 
20 evaluable patients (i.e. those that undergo prostatectomy) 
Rationale 
Once prostate cancer (PCa) metastasizes it is incurable and advanced PCa continues to 
kill more than 27,000 men per year in the United States (1).  New supra-castration agents 
significantly extend life for men with metastatic castrate resistant prostate cancer 
(mCRPC) but progress has largely stalled in the last few years in the development of novel 
therapeutics.  In particular, mCRPC has been particularly resistant to the newer 
immunotherapeutic anti-CTLA4 and anti-checkpoint strategies. For the field to move 
forward we need to know why PCa appears to be immunologically silent. We have 
previously identified alternatively activated Tumor associated macrophages (M2-TAMs) as 
key regulators of PCa tumorigenesis (2-10). Polarization of undifferentiated monocytes inot 
fully functional M2-TaMs requires activation of the IL4 receptor. Suppression of M2-TAMs 
by blocking the IL4 receptor in preclinical models inhibits tumor growth but effective clinical 
strategies remain to be developed. Simultaneously, primary and metastatic PCa lesions 
demonstrate poor infiltration by cytotoxic T cells. We hypothesize that M2-TAMs act in the 
tumor microenvironment to promote tumor growth (e.g., secrete MMPs,VEGF) while 
inhibiting the host immune response (e.g., express PD-L1 and secrete immunosuppressive 
cytokines such as IL-10).  
We aim (Primary Outcome) to investigate whether inhibition of M2-TAMs via administration 
of  dupliumab, an IL4 receptor antagonist approved for use in topic dermatitis,  will inhibit 
the infiltration of M2-TAMs in primary prostate cancers in the neoadjuvant setting for men 
with localized high-risk prostate cancer (11, 12). This will be accomplished by a 
comparison of pre-dupilumab M2-TAM infiltration in the biopsy vs. post-dupilumab M2-
TAM infiltration in the RP specimen.  Secondary outcomes will include: 1)  confirmation of 
the safety and feasibility of Dupilumab administered using a standard dose / schedule in 
the neo-adjuvant setting; 2) Quantify the extent of CD8+ T cell infiltration into the prostate 
from harvested prostate glands of treated patients;  3) Quantify the extent of CD4+ T cell 
and Treg infiltration into the prostate in prostate specimens of treated patients; 4) Quantify 
markers of apoptosis in prostate tumor specimens of treated patients using TUNEL 
staining and expressed as the mean staining percentage in tumor tissue; 5) Quantify 
markers of cell proliferation in prostate tumor specimens of treated patients using Ki-67 
staining and expressed by the mean staining percentage in tumor; 6) Evaluate the 
proportion of pathological complete responses in prostate tumor specimens of treated 
patients; 7) Evaluate PSA response rates defined as the proportion of patients who 
achieve an undetectable PSA (<0.1 ng/mL) by 3 months after prostatectomy. We 
hypothesize that neoadjuvant Dupilumab will be feasible and safe (i.e. will not interfere 
with subsequent prostatectomy), and will produce a measurable decrease in M2-TAM 
infiltration into the primary tumor microenvironment.   
If this study shows significant reduction in M2-TAM infiltration and administration of the 
study drug is feasible and safe, then future studies would aim to use Dupilumab in the 
mCRPC setting as an adjunct to cytotoxic and immunologic therapies.  
 
Objectives Primary: 
 
Evaluate the ability of dupilumab to inhibit M2-TAMs infiltration of prostate cancer 
by comparison of pre-dupilumab M2-TAM infiltration in the biopsy vs. post-


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dupilumab M2-TAM infiltration in the RP specimen.  
Secondary: 
 
 To confirm the safety and feasibility of Dupilumab administered using a standard 
dose / schedule in the neo-adjuvant setting 
 
Quantify the extent of CD8+ T cell infiltration into the prostate from harvested 
prostate glands of treated patients 
 
Quantify the extent of CD4+ T cell and Treg infiltration into the prostate in prostate 
specimens of treated patients 
 
Quantify markers of apoptosis in prostate tumor specimens of treated patients 
using TUNEL staining and expressed as the mean staining percentage in tumor 
tissue 
 
Quantify markers of cell proliferation in prostate tumor specimens of treated 
patients using Ki-67 staining and expressed by the mean staining percentage in 
tumor 
 
Evaluate the proportion of pathological complete responses in prostate tumor 
specimens of treated patients 
 
Evaluate PSA response rates defined as the proportion of patients who achieve an 
undetectable PSA (<0.1 ng/mL) by 2 months after prostatectomy. 
 
Study 
design 
This is a single-center, single arm, open-label phase II  study evaluating the safety, anti-
tumor effect, and immunogenicity of neoadjuvant Dupilumab given prior to radical 
prostatectomy in men with high-risk localized prostate cancer (this trial will enroll men with 
at least high risk prostate cancer defined by NCCN Guidelines Version 2.2017 = clinical 
stage ≥T3a or PSA >20 ng/mL or Gleason score ≥8).  Patients will be recruited from the 
outpatient Urology clinic. Men will be treated with dupilumab 600 mg s.q. on day 1, and 
then 300 mg s.q. on days 8,15, 22, 29, 36, 43.  They will then undergo surgery on day 57.  
14 days after the last dose of Dupilumab, prostate glands will be harvested at the time of 
radical prostatectomy, and prostate tissue will be examined for the secondary endpoints.  
Follow-up evaluation for adverse events will occur 30 days and 60 days after surgery. 
Patients will then be followed by their urologists according to standard institutional 
practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 
(±2) months during years 2-3. 
        Study Schema: 
.  
 
Baseline evaluations: 
 
Informed consent 
 
Medical history and physical examination 
 
Review of medications 
 
Vital signs, including height and weight 
 
Performance status 
 
Central pathologic review of prostate core biopsies for histological dx / Gleason score  
 
CT (If allergic to CT scan contrast, obtain MRI with contrast) and/or bone scan, if 
clinically indicated 
 
Hematology, coagulation, and chemistry laboratories 
 
Serum PSA measurement 


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On treatment days (days 1, 8, 15, 22, 29, 36, 43): 
 
Performance status 
 
Adverse events/toxicity evaluation 
 
Hematology and chemistry laboratories, as clinically indicated 
 
Administration of Dupilumab days 1, 8, 15, 22, 29, 36, 43 
 
Interval  history and focused physical examination (including vital signs before and 1 
hour post subcutaneous injection) 
 
On day 57: 
 
Medical history and focused physical examination (including vital signs) 
 
Review of medications 
 
Performance status 
 
Adverse events/toxicity evaluation 
 
Hematology and chemistry laboratories, as clinically indicated 
 
Serum PSA 
 
Radical prostatectomy 
 
Pathologic review of surgical specimen according to standard procedures 
 
Evaluation of harvested prostate gland for secondary endpoints 
Post-operative day 30 and day 60: 
 
Performance status 
 
Adverse events/toxicity evaluation 
 
PSA every 3 months (post-op year 1), then every 6 months (post-op years 2-3) 
Criteria for 
evaluation 
Primary endpoint:  
 
A comparison of pre-dupilumab M2-TAM infiltration in the biopsy vs. post-dupilumab 
M2-TAM infiltration in the RP specimen  
 
Secondary endpoints:  
 
Frequency, type, and severity of adverse events  
 
M2-TAM infiltration in the RP specimen  
 
Quantify the extent of CD8+ T cell infiltration into the prostate from harvested 
prostate glands of treated patients 
 
Quantify the extent of CD4+ T cell and Treg infiltration into the prostate in prostate 
specimens of treated patients 
 
Quantify markers of apoptosis in prostate tumor specimens of treated patients 
using TUNEL staining and expressed as the mean staining percentage in tumor 
tissue 
 
Quantify markers of cell proliferation in prostate tumor specimens of treated 
patients using Ki-67 staining and expressed by the mean staining percentage in 
tumor 
 
Evaluate the proportion of pathological complete responses in prostate tumor 
specimens of treated patients 
Evaluate PSA response rates defined as the proportion of patients who achieve an 
undetectable PSA (<0.1 ng/mL) by 2 months after prostatectomy. 


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Statistical 
methods 
For the primary outcome: pre- and post-treatment M2-TAM infiltration will be compared 
using a paired t-test, or nonparametric signed rank test if data don’t conform to a Gaussian 
distribution. Power is based on the paired t-test.  With 20 patients, we have the power (> 
81%) to detect a decrease of >0.67 standard deviation unit (effect size = 0.67) (14).   This 
is likely to be conservative as we observed a much larger difference in M2-TAM levels 
between primary and metastatic tumors in our data.  Power calculated using PASS v. 11 
(NCSS Software, Kaysville, UT).  
For the secondary analysis of safety, we will use a continuous toxicity monitoring approach 
with sequential dose-limiting toxicity boundaries (13).  Patients will be evaluated for AEs 
after neoadjuvant dupilumab.  We consider a 15% rate of Grade >3 AEs to be 
unacceptable and indication to halt the trial.  Accrual will continue until the number of 
Grade >3 AEs equals or exceeds the boundary for a given number of patients, or the 
completion of 20 patients without crossing any toxicity boundaries.  The table below shows 
the schedule of accrual and associated toxicity boundaries. 
Number of patients:3    4    5    6    7    8    9    10    11    12    13    14    15    16    17    18    19    20 
Toxicity Boundary:  3    3    4    4    4    4    5      5      5      6      6      6      6      7      7      7      7      7 
The AE rate and 95% confidence interval will be calculated, either at trial halt or 
completion of accrual. 
Secondary analyses of other immune infiltrate cells will be compared using a paired t-test, 
or nonparametric signed rank test if data don’t conform to a Gaussian distribution. Other 
secondary analyses will include calculating the rate and 95% confidence interval (CI) for 
complete response rates, and undetectable post-treatment PSA, and paired t-tests for the 
secondary outcome biomarkers listed above.  In exploratory analyses we will evaluate 
whether # of biopsy cores evaluated, patient, or clinical factors correlate with extent of 
decrease in infiltration, although the small sample size limits these analyses purely to 
hypothesis generating. 
Power.  For the primary outcome of pre- vs. post-treatment decrease in M2-TAM 
infiltration, power is based on the paired t-test.  With 20 patients, we have the power (> 
81%) to detect a decrease of >0.67 standard deviation unit (effect size = 0.67) (14).   This 
is likely to be conservative as we observed a much larger difference in M2-TAM levels 
between primary and metastatic tumors in our data.  Power calculated using PASS v. 11 
(NCSS Software, Kaysville, UT). The continuous toxicity monitoring design with n=20 
above has probability = 0.048 of early stopping if the Grade >3 AE rate is <15%.  Toxicity 
boundaries calculated using software developed by Ivanova  (13) 
(http://cancer.unc.edu/biostatistics/program/ivanova/ContinuosMonitoringForToxicity.aspx).  
Safety  
Frequency, types, and grades of adverse events in each treatment group will be measured 
using the NCI Common Toxicity Criteria version 4.0, and will be summarized using 
descriptive statistics. Formal safety assessments will be performed from the time of first 
administration Dupilumab until the 60th postoperative day. 


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TABLE OF CONTENTS 
 
IRB #: 
IRB00182718 ....................................................................................................................................................... 1 
JOHNS HOPKINS UNIVERSITY .......................................................................................................................................... 1 
TABLE OF CONTENTS ........................................................................................................................................................... 7 
1. 
OBJECTIVES .................................................................................................................................................................. 9 
1.1 
Primary Objective .................................................................................................................................................................9 
1.2 
Secondary Objectives ........................................................................................................................................................9 
2. 
BACKGROUND AND RATIONALE ........................................................................................................................ 9 
2.1 
Disease Background...........................................................................................................................................................9 
In Trials 1, 2, and 3, a third randomized treatment arm of DUPILUMAB 300 mg QW did not 
demonstrate additional treatment benefit over DUPILUMAB 300 mg Q2W ................................................... 14 
2.3 
Rationale ................................................................................................................................................................................ 14 
3.1 
Target Population .............................................................................................................................................................. 16 
3.2 
Inclusion Criteria ................................................................................................................................................................ 16 
3.3 
Exclusion Criteria ............................................................................................................................................................... 16 
3.4 
Inclusion of Minorities ...................................................................................................................................................... 17 
3.5 
Prohibited Concomitant Medications ...................................................................................................................... 17 
4. 
REGISTRATION AND ENROLLMENT PLAN .................................................................................................. 17 
4.1 
Registration Procedure ................................................................................................................................................... 17 
4.2 
Expected Enrollment........................................................................................................................................................ 18 
4.3 
Study Centers ...................................................................................................................................................................... 18 
4.4 
Recruitment .......................................................................................................................................................................... 18 
5. 
STUDY PLAN ............................................................................................................................................................... 18 
5.1 
Overview and Schema ................................................................................................................................................... 18 
STUDY SCHEMA: .................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
5.2 
Screening/Pretreatment Evaluation ......................................................................................................................... 21 
5.3 
Treatment Visits ................................................................................................................................................................. 21 
5.4 
Radical Prostatectomy .................................................................................................................................................... 22 
5.5 
Follow-Up Evaluations .................................................................................................................................................... 22 
5.6 
Duration of Therapy ......................................................................................................................................................... 23 
6. 
STUDY TREATMENT ................................................................................................................................................ 23 
6.1 
Description of Study Drug and Supplies ............................................................................................................... 23 
6.2 
Drug Preparation ............................................................................................................................................................... 24 
6.3 
STUDY DRUG ADMINISTRATION ....................................................................................................................... 24 
6.4 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE MEASURES ......................................... 24 
6.5 
CONCOMITANT THERAPY .................................................................................................................................... 26 
7. 
ADVERSE EVENTS AND REPORTING REQUIREMENTS ......................................................................... 28 
7.1 
Recording and Grading .................................................................................................................................................. 29 
7.2 
Unexpected Adverse Events ....................................................................................................................................... 31 
7.3 
Serious Adverse Events and Serious Adverse Drug Reactions .............................................................. 31 
7.4 
Perioperative Adverse Events .................................................................................................................................... 32 
7.5 
Reporting Adverse Events ............................................................................................................................................ 33 
ANNUAL IND REPORT .......................................................................................... ERROR! BOOKMARK NOT DEFINED. 
7 CALENDAR-DAY TELEPHONE OR FAX REPORT ................................. ERROR! BOOKMARK NOT DEFINED. 
15 CALENDAR-DAY WRITTEN REPORT ....................................................... ERROR! BOOKMARK NOT DEFINED. 
7.6 
Pregnancy ............................................................................................................................................................................. 34 


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8. 
OUTCOME ASSESSMENT ..................................................................................................................................... 34 
8.1 
Radical Prostatectomy Specimen ............................................................................................................................. 34 
8.2 
Primary Endpoint ............................................................................................................................................................... 35 
EMAIL: ADEMARZ@JHMI.EDU ....................................................................................................................................... 35 
8.3 
Secondary Endpoints ...................................................................................................................................................... 35 
8.3.4 REGULATORY T CELL (TREG) INFILTRATION ............................................................................................... 37 
8.3.7 PSA RESPONSE RATES ........................................................................................................................................ 37 
9. 
REGULATORY AND REPORTING REQUIREMENTS .................................................................................. 37 
9.1 
Regulatory Responsibilities .......................................................................................................................................... 38 
9.2 
Data Management ............................................................................................................................................................ 38 
9.3 
Study Monitoring and Quality Assurance ............................................................................................................. 39 
10. 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 39 
10.1 Study Design,  Sample Size, and Study Endpoints ........................................................................................ 39 
STOPPING RULES: ............................................................................................................................................................... 41 
10.3 Analysis Populations........................................................................................................................................................ 42 
10.4 Safety Analysis ................................................................................................................................................................... 43 
10.5 Statistical Procedures ..................................................................................................................................................... 43 
11. 
PROTECTION OF HUMAN SUBJECTS ............................................................................................................. 44 
11.1 Ethical Considerations .................................................................................................................................................... 44 
11.2 Protocol Amendments..................................................................................................................................................... 44 
11.3 Written Informed Consent ............................................................................................................................................. 44 
11.4 Protection of Privacy ........................................................................................................................................................ 45 
11.5 Study Termination or Modification ............................................................................................................................ 45 
12. 
REFERENCES ............................................................................................................................................................. 47 
APPENDIX A:  PERFORMANCE STATUS CRITERIA ............................................................................................. 50 
APPENDIX B:  COMMON TOXICITY CRITERIA, VERSION 4.0 ........................................................................... 51 
APPENDIX C:  SERIOUS ADVERSE EVENT (SAE) REPORTING FORM ........................................................ 52 
APPENDIX D:  ABBREVIATIONS AND ACRONYMS .............................................................................................. 54 
APPENDIX E:  DATA AND SAFETY MONITORING PLAN (DSMP), VERSION 4.0 (9/22/11) ................... 57 
 


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1. 
OBJECTIVES 
1.1 
Primary Objective 
 
Evaluate the ability of dupilumab to inhibit M2-TAMs infiltration or prostate cancer 
by comparison of pre-dupilumab M2-TAM infiltration in the biopsy vs. post-
dupilumab M2-TAM infiltration in the RP specimen.  
1.2 
Secondary Objectives 
 
To evaluate the safety and tolerability of DUPILUMAB administered 600 mg s.q. on day 
1, and then 300 mg s.q. on days 8,15, 22, 29, 36, 43.  They will then undergo surgery on 
day 56. 
 
To evaluate the feasibility of administering DUPILUMAB administered 600 mg s.q. on 
day 1, and then 300 mg s.q. on days 8,15, 22, 29, 36, 43.   
 
Quantify the extent of CD8+ T cell infiltration into the prostate from harvested prostate 
glands of treated patients 
 
Quantify the extent of CD4+ T cell and Treg infiltration into the prostate in prostate 
specimens of treated patients 
 
Quantify markers of apoptosis in prostate tumor specimens of treated patients using 
TUNEL staining and expressed as the mean staining percentage in tumor tissue 
 
Quantify markers of cell proliferation in prostate tumor specimens of treated patients 
using Ki-67 staining and expressed by the mean staining percentage in tumor 
 
Evaluate the proportion of pathological complete responses in prostate tumor specimens 
of treated patients 
 
Evaluate PSA response rates defined as the proportion of patients who achieve an 
undetectable PSA (<0.1 ng/mL) by 2 months after prostatectomy. 
 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease Background 
Once prostate cancer (PCa) metastasizes it is incurable and advanced PCa continues to 
kill more than 27,000 men per year in the United States (1).  Yet, localized prostate 
cancer is often curable and even metastatic disease can respond to treatment. 
PCa cells exist in a complex habitat within their microenvironment, co-existing with other 
normal host cells, including hematopoietic precursors, stromal cells, osteoblasts, 
osteoclasts, nerve cells, adipocytes, endothelial cells, and multiple cell types of the 
immune system including macrophages (2). Within the ecosystem of the tumor, these 
host cells provide the cancer cells with a multitude of growth factors and cytokines that 
result in tumor promotion and growth. In turn, the cancer cells provide growth factors to 
the host cells that result in their proliferation and survival.  Disruption of this cooperation 
is a paradigm that could be explored and exploited as a way to suppress tumorigenesis 
and overall, eradicate tumors both at primary and metastatic sites. 
Malignant tumors are associated with a leukocytic infiltrate as part of the reactive stroma 
that is enriched for macrophages (3-7). Macrophages play an important role in the 
regulation of angiogenesis in both normal and diseased tissues, including malignant 
tumors (7-9). It is not clear whether TAMs are derived from peripheral blood monocytes 


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recruited into the tumor from the circulation or from resident macrophages already in the 
healthy tissue before tumor develops and metastasizes(10). However, elevated 
expression of a number of monocyte chemoattractants, including chemokines CCL2, 
CCL3, CCL4, CCL8 and CCL5 (RANTES) by both tumor and stromal cells within the 
tumor microenvironment has been shown to positively correlate with increased M2-TAM 
recruitment within several human tumor types (15-20).  When associated with tumors, 
macrophages demonstrate functional “polarization” towards one of two phenotypically 
different subsets of macrophages: TH1 (also known as M1 macrophages) or TH2 (also 
known as M2 macrophages) (14).  M1 macrophages are known to produce pro-
inflammatory cytokines and play an active role in cell destruction. Conversely, M2 
macrophages primarily scavenge debris and promote angiogenesis and wound repair (2-
10, 15-20).  The M2 macrophage population is phenotypically similar to the TAM 
population that promotes tumor growth and development. Others and we have 
demonstrated the importance of TAMs in promoting PCa tumorigenesis.  TAMs have 
been demonstrated to make up to 50% of the population of cells in PCa bone 
metastases, contributing to cancer cell growth by promoting a permissive growth 
environment through the secretion of matrix degrading enzymes, angiogenic factors 
such as VEGF, and multiple growth factors while simultaneously secreting multiple 
factors that suppress the host immune response (15-20).  
We have demonstrated that Inhibition of IL-4 by blocking IL4r blocks polarization to the 
M2 phenotype and significantly inhibits prostate tumor growth. Human macrophages 
were polarized using phased polarization protocol, each condition in triplicate (21). On 
day 5, 10 ng /mL of the anti-IL4r antibody Dupilumab was added to the cultures. On 
day 9, % of cells exhibiting CD206 and CD163 as markers of M2 polarization was 
determined by FACS sorting per published protocol (Table 2). We next tested the ability 
of IL4r inhibition to inhibit tumor growth in vivo in preclinical mouse models. Parallel 
studies were conducted in human SCID mice using the human cell line PC3 as well as 
the Hi-Myc B6CaP model.  For the PC-3 model, 500,000  cells  were implanted into mice 
(n=12 per group).  When these tumors reached 2mm3 (week 2), animals began 
treatment.  Docetaxel was given as a single dose of 5mg/kg at week 2 per published 
protocol (22-27).  Mice were treated weekly  (weeks 2,3,4,5,6) with a murine specific 
anti-IL4r antibody (rat anti-mouse IL-4R alpha clone 129801 (R&D Systems MAB530) 
since Dupilumab is human specific.  Tumor growth was measured weekly with caliper 
measurements. As single agents, both docetaxel and anti-IL4r antibody inhibited tumor 
growth by 33% (p<0.05).  The combination of docetaxel + anti-IL4r antibody inhibited 
tumor growth by 75% (p<0.01) (Figure 1).  At week 7, tumors were excised and FACS 
analysis was performed to determine the number of CD68+ macrophages as a percent 
of cellular mass as per published protocol (27).  IL4r inhibition significantly decreased 
macrophage infiltration into the tumor mass as compared to control and docetaxel 
treated alone tumors, p<0.001 (Table 3) Similar significant results were demonstrated 
utilizing the B6CaP mouse model (results not shown). 
2.2 
Treatment Background 
2.2.1  Study Agent (DUPILUMAB) Background 
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) 
and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit 
shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 


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signaling via the Type I receptor and both IL-4 and IL-13 signaling through the 
Type II receptor (11, 12).  
Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced 
responses, including the release of proinflammatory cytokines, chemokines and 
IgE  
Dupilumab is produced by recombinant DNA technology in Chinese Hamster 
Ovary cell suspension culture.  
DUPILUMAB (dupilumab) Injection is supplied as a sterile, preservative-free, 
clear to slightly opalescent, colorless to pale yellow solution for subcutaneous 
injection. DUPILUMAB is provided as a single-dose pre-filled syringe with or 
without needle shield in a 2.25 mL siliconized Type-1 clear glass syringe. The 
needle cap is not made with natural rubber latex. Each pre-filled syringe delivers 
300 mg dupilumab in 2 mL which also contains L-arginine hydrochloride (10.5 
mg), L- histidine (6.2 mg), polysorbate 80 (4 mg), sodium acetate (2 mg), sucrose 
(100 mg), and water for injection, pH 5.9.  
Mechanism of Action  
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) 
and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit 
shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 
signaling via the Type I receptor and both IL-4 and IL-13 signaling through the 
Type II receptor.  
Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced 
responses, including the release of proinflammatory cytokines, chemokines and 
IgE.  
Pharmacodynamics  
Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased 
following dupilumab treatment. The relationship between the pharmacodynamic 
activity and the mechanism(s) by which dupilumab exerts its clinical effects is 
unknown.  
Pharmacokinetics  
Absorption  
Following an initial subcutaneous (SC) dose of 600 mg, dupilumab reached peak 
mean ±SD concentrations (Cmax) of 70.1±24.1 mcg/mL by approximately 1 
week post dose.  
Steady-state concentrations were achieved by Week 16 following the 
administration of 600 mg starting dose and 300 mg dose either weekly (twice the 
recommended dosing frequency) or every other week. Across clinical trials, the 
mean ±SD steady-state trough concentrations ranged from 73.3±40.0 mcg/mL to 
79.9±41.4 mcg/mL for 300 mg administered every 2 weeks and from 173±75.9 
mcg/mL to 193±77.0 mcg/mL for 300 mg administered weekly. 


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The bioavailability of dupilumab following a SC dose is estimated to be 64% 
Distribution 
The estimated total volume of distribution was approximately 4.8±1.3 L. 
Elimination  
The metabolic pathway of dupilumab has not been characterized. As a human 
monoclonal IgG4 antibody, dupilumab is expected to be degraded into small 
peptides and amino acids via catabolic pathways in the same manner as 
endogenous IgG. After the last steady-state dose of 300 mg Q2W or 300 mg QW 
dupilumab, the median times to non-detectable concentration (<78 ng/mL) are 10 
and 13 weeks, respectively.  
Dose Linearity  
Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures 
increasing in a greater than dose-proportional manner. The systemic exposure 
increased by 30-fold when the dose increased 8-fold following a single dose of 
dupilumab from 75 mg to 600 mg (i.e., 0.25 times to 2-times the recommended 
dose).  
Weight 
Dupilumab trough concentrations were lower in subjects with higher body weight.  
Immunogenicity 
Development of antibodies to dupilumab was associated with lower serum 
dupilumab concentrations. A few subjects who had high antibody titers also had 
no detectable serum dupilumab concentrations. 
Specific Populations 
Geriatric Patients 
In subjects who are 65 years and older, the mean ±SD steady-state trough 
concentrations of dupilumab were 69.4±31.4 mcg/mL and 166±62.3 mcg/mL, 
respectively, for 300 mg administered every 2 weeks and weekly. No dose 
adjustment in this population is recommended. 
Renal or Hepatic Impairment 
No formal trial of the effect of hepatic or renal impairment on the 
pharmacokinetics of dupilumab was conducted. 
Drug Interaction Studies 
Drug interaction studies have not been conducted with DUPILUMAB. 
 
2.2.2 Safety of DUPILUMAB 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 


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Animal studies have not been conducted to evaluate the carcinogenic or mutagenic 
potential of dupilumab. 
No effects on fertility parameters such as reproductive organs, menstrual cycle length, or 
sperm analysis were observed in sexually mature mice that were subcutaneously 
administered a homologous antibody against IL-4Rα at doses up to 200 mg/kg/week. 
2.2.3. Clinical Trial Experience 
CLINICAL STUDIES 
Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a 
total of 2119 subjects 18 years of age and older with moderate-to-severe atopic 
dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was 
defined by an Investigator’s Global Assessment (IGA) score ≥3 in the overall 
assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity 
Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area 
involvement of ≥10%. At baseline, 59% of subjects were male, 67% were white, 52% of 
subjects had a baseline IGA score of 3 (moderate AD), and 48% of subjects had a 
baseline IGA of 4 (severe AD). The baseline mean EASI score was 33 and the baseline 
weekly averaged peak pruritus Numeric Rating Scale (NRS) was 7 on a scale of 0-10. 
In all three trials, subjects in the DUPILUMAB group received subcutaneous injections of 
DUPILUMAB 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the 
monotherapy trials (Trials 1 and 2), subjects received DUPILUMAB or placebo for 16 
weeks. 
In the concomitant therapy trial (Trial 3), subjects received DUPILUMAB or placebo with 
concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for 
problem areas only, such as the face, neck, intertriginous and genital areas for 52 
weeks. 
All three trials assessed the primary endpoint, the change from baseline to Week 16 in 
the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point 
improvement. Other endpoints included the proportion of subjects with EASI-75 
(improvement of at least 75% in EASI score from baseline), and reduction in itch as 
defined by at least a 4- point improvement in the peak pruritus NRS from baseline to 
Week 16. 
In Trial 3, of the 421 subjects, 353 had been on study for 52 weeks at the time of data 
analysis. Of these 353 subjects, responders at Week 52 represent a mixture of subjects 
who maintained their efficacy from Week 16 (e.g., 53% of DUPILUMAB IGA 0 or 1 
responders at Week 16 remained responders at Week 52) and subjects who were non-
responders at Week 16 who later responded to treatment (e.g., 24% of DUPILUMAB 
IGA 0 or 1 non-responders at Week 16 became responders at Week 52). Treatment 
effects in subgroups (weight, age, gender, race, and prior treatment, including 
immunosuppressants) in Trials 1, 2, and 3 were generally consistent with the results in 
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In Trials 1, 2, and 3, a third randomized treatment arm of DUPILUMAB 300 mg QW did 
not demonstrate additional treatment benefit over DUPILUMAB 300 mg Q2W 
2.3 
Rationale 
2.3.1 Rationale for conducting the study 
Once prostate cancer (PCa) metastasizes it is incurable and advanced PCa continues to 
kill more than 27,000 men per year in the United States (1).  Yet, localized prostate 
cancer is often curable and even metastatic disease can respond to treatment. 
PCa cells exist in a complex habitat within their microenvironment, co-existing with other 
normal host cells, including hematopoietic precursors, stromal cells, osteoblasts, 
osteoclasts, nerve cells, adipocytes, endothelial cells, and multiple cell types of the 
immune system including macrophages (2). Within the ecosystem of the tumor, these 
host cells provide the cancer cells with a multitude of growth factors and cytokines that 
result in tumor promotion and growth. In turn, the cancer cells provide growth factors to 
the host cells that result in their proliferation and survival.  Disruption of this cooperation 
is a paradigm that could be explored and exploited as a way to suppress tumorigenesis 
and overall, eradicate tumors both at primary and metastatic sites. 
Malignant tumors are associated with a leukocytic infiltrate as part of the reactive stroma 
that is enriched for macrophages (2-10). Macrophages play an important role in the 
regulation of angiogenesis in both normal and diseased tissues, including malignant 
tumors (2-10). It is not clear whether TAMs are derived from peripheral blood monocytes 
recruited into the tumor from the circulation or from resident macrophages already in the 
healthy tissue before tumor develops and metastasizes. However, elevated expression 
of a number of monocyte chemoattractants, including chemokines CCL2, CCL3, CCL4, 
CCL8 and CCL5 (RANTES) by both tumor and stromal cells within the tumor 
microenvironment has been shown to positively correlate with increased M2-TAM 
recruitment within several human tumor types (2-10, 15-20).  When associated with 
tumors, macrophages demonstrate functional “polarization” towards one of two 
phenotypically different subsets of macrophages: TH1 (also known as M1 macrophages) 
or TH2 (also known as M2 macrophages).  M1 macrophages are known to produce pro-
inflammatory cytokines and play an active role in cell destruction. Conversely, M2 
macrophages primarily scavenge debris and promote angiogenesis and wound repair (2-
10, 15-20).  The M2 macrophage population is phenotypically similar to the TAM 
population that promotes tumor growth and development. Others and we have 
demonstrated the importance of TAMs in promoting PCa tumorigenesis.  TAMs have 
been demonstrated to make up to 50% of the population of cells in PCa bone 
metastases, contributing to cancer cell growth by promoting a permissive growth 
environment through the secretion of matrix degrading enzymes, angiogenic factors 
such as VEGF, and multiple growth factors while simultaneously secreting multiple 
factors that suppress the host immune response (15-20).  
We have demonstrated that Inhibition of IL-4 by blocking IL4r blocks polarization to the 
M2 phenotype and significantly inhibits prostate tumor growth. Human macrophages 
were polarized using phased polarization protocol, each conditi in triplicate (21). On day 
5, 10 ng /mL of the anti-IL4r antibody Dupilumab was added to the cultures. On day 9, 
% of cells exhibiting CD206 and CD163 as markers of M2 polarization was determined 
by FACS sorting per published protocol (Table 2). We next tested the ability of IL4r 
inhibition to inhibit tumor growth in vivo in preclinical mouse models. Parallel studies 


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were conducted in human SCID mice using the human cell line PC3 as well as the Hi-
Myc B6CaP model.  For the PC-3 model, 500,000  cells  were implanted into mice (n=12 
per group).  When these tumors reached 2mm3 (week 2), animals began treatment.  
Docetaxel was given as a single dose of 5mg/kg at week 2 per published protocol (22-
27).  Mice were treated weekly  (weeks 2,3,4,5,6) with a murine specific anti-IL4r 
antibody (rat anti-mouse IL-4R alpha clone 129801 (R&D Systems MAB530) since 
Dupilumab is human specific.  Tumor growth was measured weekly with caliper 
measurements. As single agents, both docetaxel and anti-IL4r antibody inhibited tumor 
growth by 33% (p<0.05).  The combination of docetaxel + anti-IL4r antibody inhibited 
tumor growth by 75% (p<0.01).  At week 7, tumors were excised and FACS analysis was 
performed to determine the number of CD68+ macrophages as a percent of cellular 
mass as per published protocol (27).  IL4r inhibition significantly decreased 
macrophage infiltration into the tumor mass as compared to control and docetaxel 
treated alone tumors, p<0.001. Similar significant results were demonstrated utilizing the 
Hi-MYC mouse model (results not shown). 
2.3.2 Rationale for dosage selection 
In the Phase III studies utilizing DUPILUMAB the prescribed dosage proposed in 
this trial was considered to be the safe and effective dose.  Specifically, a third 
randomized treatment arm of DUPILUMAB 300 mg QW did not demonstrate 
additional treatment benefit over DUPILUMAB 300 mg Q2W (11,12) 
2.3.3 Rationale for immunobiologic endpoints 
The major efficacy goal of this study is to assess a decrease in M2-TAM infiltration in 
tumors based on our preliminary data.  To do this, we have developed a CD206 antibody 
for immunohistochemical analysis (IHC) and demonstration of M2-TAM infiltration into 
primary and metastatic prostate cancers.  The analysis of M2-TAM infiltration into human 
tumors has previously not been possible because of lack of a specific marker for M2 
macrophages.  Current markers, e.g., CD68, are specific for all human macrophages but 
do not reflect polarization states.  Working with our collaborator Angelo De Marzo, 
Director of the Tissue Core for the Sidney Kimmel Cancer Center (SKCCC) at Johns 
Hopkins School of Medicine, utilizing stringent protocols to assess and quantify antibody 
staining, we have developed an anti-CD206 reagent to allow staining of human tissue 
microarrays to assess M2-TAM infiltration (28, 29, and submitted). Utilizing this antibody, 
we have demonstrated a significant increase in M2-TAMs in prostate tumors compared 
to normal tissue. 
 
We will also quantify the extent of CD8+ T cell and CD4+ T cell infiltration into the 
prostate from harvested prostate glands of treated patients. We will quantify markers of 
apoptosis in prostate tumor specimens of treated patients using TUNEL staining and 
expressed as the mean staining percentage in tumor tissue and quantify markers of cell 
proliferation in prostate tumor specimens of treated patients using Ki-67 staining and 
expressed by the mean staining percentage in tumor.  We will evaluate the proportion of 
pathological complete responses in prostate tumor specimens of treated patients and 
evaluate PSA response rates defined as the proportion of patients who achieve an 
undetectable PSA (<0.1 ng/mL) by 2 months after prostatectomy. 
 
3. 
Patient Selection 


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3.1 
Target Population 
Subjects will include men with multifocal, Gleason 7 or greater, clinically localized 
prostate cancer (NCCN High Risk / Very High Risk) for whom the decision has been 
made to perform radical prostatectomy at Johns Hopkins Hospital. Subjects will be 
identified and recruited through the Outpatient Clinic of the Department of Urology and 
from the Multidisciplinary Prostate Cancer Clinic. 
3.2 
Inclusion Criteria  
To be eligible for this study, patients must meet all of the following criteria: 
 
Histologically confirmed adenocarcinoma of the prostate (clinical stage T1c–T3b, 
N0, M0) without involvement of lymph nodes, bone, or visceral organs 
 
Initial prostate biopsy is available for central pathologic review, and is confirmed 
to show at least 2 positive cores and a Gleason sum of ≥7 
 
Radical prostatectomy has been scheduled at Johns Hopkins Hospital 
 
Age ≥18 years 
 
ECOG performance status 0-1, or Karnofsky score ≥ 70% (see Appendix A) 
 
Adequate bone marrow, hepatic, and renal function: 
o WBC >3,000 cells/mm3 
o ANC >1,500 cells/mm3 
o Hemoglobin >9.0 g/dL 
o Platelet count >100,000 cells/mm3 
o Serum creatinine <3 × upper limit of normal (ULN) 
o Serum bilirubin <3 × ULN 
o ALT <5 × ULN 
o AST <5 × ULN 
o Alkaline phosphatase <5 × ULN 
 
Willingness to provide written informed consent and HIPAA authorization for the 
release of personal health information, and the ability to comply with the study 
requirements (note: HIPAA authorization will be included in the informed 
consent) 
 
Willingness to use barrier contraception from the time of first dose of 
DUPILUMAB until the time of prostatectomy. 
3.3 
Exclusion Criteria 
To be eligible for this study, patients should not meet any of the following criteria: 
 
Presence of known lymph node involvement or distant metastases 
 
Other histologic types of prostate cancers such as ductal, sarcomatous, 
lymphoma, small cell, and neuroendocrine tumors 
 
Prior radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for 
prostate cancer 
 
Prior immunotherapy/vaccine therapy for prostate cancer 
 
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 
Current use of systemic corticosteroids or use of corticosteroids within 4 weeks 
of enrollment (inhaled corticosteroids for asthma or COPD are permitted) 
 
Use of experimental agents for prostate cancer within the past 3 months from 
time of screening 
 
History or presence of autoimmune disease requiring systemic 
immunosuppression (including but not limited to: inflammatory bowel disease, 
systemic lupus erythematosus, vasculitis, rheumatoid arthritis, scleroderma, 
multiple sclerosis, hemolytic anemia, Sjögren  syndrome, and sarcoidosis) 
 
History of malignancy within the last 3 years, with the exception of non-
melanoma skin cancers and superficial bladder cancer 
 
Uncontrolled major active infectious, cardiovascular, pulmonary, hematologic, or 
psychiatric illnesses that would make the patient a poor study candidate 
 
Known prior or current history of HIV and/or hepatitis B/C  
 
Significant eye disease 
3.4 
Inclusion of Minorities 
Men of all races and ethnic groups will be considered for study participation. Candidates 
must conform to all eligibility criteria to be accepted into the study. Minority patients who 
meet entry criteria will be actively recruited, although the trial is not designed to measure 
differences in outcomes between ethnic groups. The estimated breakdown of the target 
population by race and ethnicity is: 80% white/Caucasian, 15% black/African American, 
and 5% comprised of other ethnic minorities. 
3.5 
Prohibited Concomitant Medications 
Concurrent use of other anticancer agents or therapies including other experimental 
treatments is not permitted. Patients may not currently be taking any other form of 
androgen deprivation therapy, antiandrogens, 5-reductase inhibitors, chemotherapy, 
radiation therapy, biologic therapy, immunosuppressive medications, or systemic 
corticosteroids. 
Within 30 days of administration of study drug, patients should not receive vaccines 
including but not limited to the live rotavirus vaccine, the live BCG (bacillus Calmette-
Guerin) vaccine, the live influenza vaccine, the live measles vaccine, the live mumps 
vaccine, the live poliovirus vaccine, the live rubella vaccine, the smallpox vaccine, the 
typhoid vaccine, the varicella vaccine, and the yellow fever vaccine. 
Because of the potential for unknown drug-drug interactions, concurrent use of all other 
agents, over-the-counter medications, herbal remedies, vitamins/minerals, and 
alternative therapies must be documented on the case report form (CRF).
4. 
REGISTRATION AND ENROLLMENT PLAN 
4.1 
Registration Procedure 
Patients who are considered candidates for the study will first be evaluated for eligibility 
by one of the principal investigators, co-investigators, or the research nurse. After 
screening for eligibility, patients who are eligible to participate in the trial must be 
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to the instructions below. A record of patients who fail to meet entry criteria (i.e., screen 
failures) will also be maintained. Registration must be completed before beginning any 
study-related activities. 
Once eligibility is confirmed, each subject will be assigned a unique patient study 
identification number. Treatment must not commence until the patient has received his 
identification number. 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
IRB-approved consent form. Authorized study personnel should fully explain the scope 
of the study to each patient before obtaining informed consent. Patients should be 
advised of any known risks inherent in the planned treatments/procedures, any 
alternative treatment options, their right to withdraw from the study at any time and for 
any reason, and their right to privacy. When obtaining informed consent, study personnel 
should: first, confirm that the patient has received and has had time to read the informed 
consent form (including the research authorization/HIPAA form); next, confirm eligibility 
as defined in Sections 3.2 and 3.3 (inclusion and exclusion criteria); and finally, obtain 
dated and signed informed consent. A copy of the signed informed consent should be 
supplied to the study coordinator. 
4.2 
Expected Enrollment 
A total of 20 patients will be included in this study. The first patients are expected to be 
enrolled in August 2018, once the protocol has been approved by the IRB. With an 
estimated enrollment rate of 2-3 patients per month, accrual is expected to be completed 
in 10 months. 
4.3 
Study Centers 
This is a single-institution study that will be conducted only at Johns Hopkins through a 
collaboration between the Brady Urological Institute and the Sidney Kimmel 
Comprehensive Cancer Center. 
4.4 
Recruitment 
Subjects will be recruited from the outpatient facilities of the Brady Urological Institute, 
and from the outpatient Multidisciplinary Prostate Cancer Clinic of the SKCCC. Patients 
will not receive payment or reimbursement for participation. Every effort will be made to 
include patients of racial and ethnic minorities who fulfill the eligibility criteria. 
5. 
STUDY PLAN 
5.1 
Overview and Schema 
This is a single-center, single arm, open-label phase II study evaluating the safety, anti-
tumor effect, and immunogenicity of neoadjuvant DUPILUMAB given prior to radical 
prostatectomy in men with high-risk localized prostate cancer. Patients will be recruited 
from the outpatient Urology clinic. Men will be treated with dupilumab 600 mg s.q. on day 
1, and then 300 mg s.q. on days 8, 15, 22, 29, 36, 43.  They will then undergo surgery 
on day 57.  14 days after the last dose of Dupilumab, prostate glands will be harvested 
at the time of radical prostatectomy, and prostate tissue will be examined for the 
secondary endpoints.  Follow-up evaluation for adverse events will occur 30 days and 60 
days after surgery. Patients will then be followed by their urologists according to 


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standard institutional practices, but will require PSA evaluations every 3 (±1) months 
during year 1 and every 6 (±2) months during years 2-3. 
                             
  
 
 
. 


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Table 1   STUDY CALENDAR 
Every effort should be made to keep visits, tests, and procedures on schedule. 
Acceptable deviations are listed below. 
  
Screening  
Evaluationa 
Treatment 
Days (1, 
8,15, 22, 29, 
36, 43) (+/- 
1 day) 
Radical 
Prostatectomy 
Day 57 (+/- 3 
days) 
Follow-up, 30, and 
60 Days Post-op 
(+/- 1 wk)h,i 
LTFU (+/- 1 
Month)i 
Informed consent 
X 
  
  
  
  
Medical history 
X 
  
  
  
Review of medications 
X 
X 
X 
X 
  
Physical examination 
X 
X 
  
  
Vital signs 
X 
X 
X 
  
  
Height and weight 
X 
X 
X 
  
  
Performance status 
X 
X 
X 
X 
  
CT and bone scan b 
(X) 
  
  
  
  
Hematology labs, coagulations c 
X 
X 
X 
X 
  
Chemistry labs d 
X 
X 
X 
X 
  
Serum PSA e 
X 
  
X 
X 
X 
DUPILUMAB dose  
  
X 
  
  
  
Toxicity assessment 
     X----------------------------------------------------------------X 
  
Surgical specimen f 
  
  
X 
  
  
Pathologic review g 
X 
  
X 
  
  
a: The screening (pre-treatment) evaluation should be conducted within 42 days (±4 days) of starting protocol therapy. 
b: Staging CT (if allergic to CT scan contrast, obtain MRI with contrast) and bone scans should only be performed if clinically indicated, 
and are not mandatory. 
c: Hematology laboratories include hemoglobin, hematocrit, white blood cell count with differential (including absolute eosinophil 
count), and platelets. In addition, prothrombin time (PT/INR) and activated partial thromboplastin time (APTT) should be checked at 
screening, then as clinically indicated. 
d: Chemistry laboratories include sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, albumin, total 
protein, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase. 
e: Serum PSA should be obtained pre-treatment and on the day of surgery, and as clinically indicated thereafter according to 
institutional practices.  
f: Harvested prostate gland to be evaluated for tumor apoptosis, CD8+ T cell infiltration, as well as other secondary endpoints. 
g: Archival prostate core biopsies to be centrally reviewed at baseline prior to study entry; radical prostatectomy specimens to be 
processed at Johns Hopkins according to standard procedures. 
h: The post-operative evaluations (30 and 60 days after prostatectomy) may take place over the telephone or in person, but patients 
are required to have hematology and chemistry labs collected at this time-point for safety purposes. 
i: PSA should be measured every 3 months (±1 month) in the first year after prostatectomy, and every 6 months (±2 months) in the 
second and third years after prostatectomy. 


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5.2 
Screening/Pretreatment Evaluation  
Before initiating any screening activities, the scope of the study should be explained to 
each patient. Patients should be advised of any known risks inherent in the planned 
procedures, any alternative treatment options, their right to withdraw from the study at 
any time and for any reason, and their right to privacy. After this explanation, patients 
should be asked to sign and date an IRB-approved informed consent form that meets 
the requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, 
January 27, 1981, part 50). 
The pretreatment/screening visit will determine patient eligibility according to the 
inclusion and exclusion criteria. All subjects must undergo a number of baseline 
evaluations as part of this screening visit, as detailed below. All of these evaluations 
should be conducted within 21 ± 4 days of starting the protocol. This information is also 
summarized in the Study Calendar (Table 1). 
 
informed consent 
 
demographic information 
 
medical history, including review of systems 
 
performance status, using ECOG or Karnofsky scales (Appendix A) 
 
physical examination 
 
vital signs: temperature, pulse, sitting blood pressure, respiratory rate 
 
height and weight 
 
current medication list, including drug allergies/adverse events 
 
hematological laboratories (hemoglobin, hematocrit, white blood cell count with 
differential [including absolute eosinophil count], platelets); coagulation profile 
(INR, aPTT) if clinically indicated 
 
serum chemistry profile (sodium, potassium, chloride, bicarbonate, urea, 
creatinine, glucose, calcium, albumin, total protein, bilirubin, ALT, AST, alkaline 
phosphatase) 
 
serum PSA level 
 
CT (If allergic to CT scan contrast, obtain MRI with contrast) and/or bone scan, 
only if clinically indicated (not mandatory) 
 
central pathologic review of prostate core biopsies 
After all relevant screening information is documented, registration should be finalized 
and appropriate documents (i.e., signed informed consent, supporting source 
documentation for eligibility) should be faxed or emailed to the program manager. 
Information on patients who do not meet eligibility criteria to participate in this study (i.e., 
screening failures) should also be captured at the pretreatment visit.
5.3 
Treatment Visits  
The following must be performed on treatment days (days 1, 8,15, 22, 29, 36, 43) (±1 
day) with administration of DUPILUMAB. 
 
performance status 


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 
review of medication list 
 
review of toxicity/adverse events 
 
height/weight 
 
vital signs (before and 1 hour post subcutaneous injection (which is at the end of 
a 1 hour observation period)  
 
physical exam (focused) 
 
hematological laboratories and serum chemistry profile 
 
Administration of DUPILUMAB (see section 6.3 Study Drug Administration) 
5.4 
Radical Prostatectomy 
The following must be performed on the day of radical prostatectomy, which itself should 
occur 56 (±3) days after the administration of first dose of DUPILUMAB. 
 
medical history 
 
performance status 
 
physical examination, including vital signs 
 
review of medication list 
 
review of toxicity/adverse events 
 
hematological laboratories and serum chemistry profile 
 
serum PSA 
 
collection of prostatectomy tissue for analysis of study endpoints 
 
pathological processing of prostatectomy specimen according to standard 
procedures 
5.5 
Follow-Up Evaluations 
Follow-up visit scheduled for 30 days and 60 days after radical prostatectomy may occur 
in the outpatient clinic or by telephone interview. Required evaluations during this follow-
up visits are listed below. Patients should then continue to be followed by their treating 
urologist according to standard institutional practices. 
 
performance status 
 
review of medication list 
 
review of toxicity/adverse events 
 
Patients withdrawing from the study early because of adverse events should be followed 
until the adverse event has either resolved or stabilized. Reasons for premature 
withdrawal should be determined and documented. 
In addition, patients will be required to have a structured assessment of post-operative 
PSA measurements for 3 years. In the first year after prostatectomy, PSA will be 
measured every 3 months (±1 mo). In the second and third years after prostatectomy, 
PSA will be measured every 6 months (±2 mo). These PSA measurements may be 
obtained outside of Johns Hopkins, but the results need to be made available to the 
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5.6 
Duration of Therapy 
Participation in this study will be terminated for any of the following reasons listed below: 
 
the patient decides to withdraw from the study (withdrawal of consent) due to 
unacceptable toxicities or for any other reason 
 
the patient completes all of the protocol procedures and follow-up requirements 
 
there are adverse events that, in the judgment of the investigator, may cause 
severe or permanent injury or are incompatible with continuation on study 
 
there are major violations to the study protocol or the patient is noncompliant with 
treatments, as judged by the investigator 
 
the patient experiences concurrent illness or a change in his condition that, in the 
judgment of the investigator, renders him unacceptable for further treatment on 
study 
 
the patient dies 
 
the patient is lost to follow-up 
 
the study is prematurely terminated for safety or feasibility concerns or other 
reasons 
Patients should be removed from the study when any of the above criteria are met. 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided if possible. When a patient leaves 
the study early, the investigator should make every effort to contact the patient and to 
perform the final follow-up evaluation (even by telephone interview). The reason for 
removal of a patient from the study, and the date of removal, must be appropriately 
documented. 
Patients will be replaced if they are removed from the study after signing the informed 
consent but before receiving DUPILUMAB . Patients receiving at least one dose of the 
study drug will be included in safety analyses, and those also undergoing prostatectomy 
will be used for the efficacy analyses. 
6. 
STUDY TREATMENT 
6.1 
Description of Study Drug and Supplies 
DUPILUMAB (dupilumab) Injection is supplied as a sterile, preservative-free, clear to 
slightly opalescent, colorless to pale yellow solution for subcutaneous injection. 
DUPILUMAB is provided as a single-dose pre-filled syringe with or without needle shield 
in a 2.25 mL siliconized Type-1 clear glass syringe. The needle cap is not made with 
natural rubber latex. Each pre-filled syringe delivers 300 mg dupilumab in 2 mL which 
also contains L-arginine hydrochloride (10.5 mg), L- histidine (6.2 mg), polysorbate 80 (4 
mg), sodium acetate (2 mg), sucrose (100 mg), and water for injection, pH 5.9.  
Under no circumstances is the Investigator allowed to release these clinical supplies for 
use by another physician not named on Form FDA 1572 or to administer study drug to a 
patient who is not enrolled in this study. Study drug must be dispensed at an institution 
specified on Form FDA 1572. 


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6.2 
Drug Preparation 
6.2.1 General Guidelines and Precautions 
Men will be treated with dupilumab 600 mg s.q. on day 1, and then 300 mg s.q. 
on days 8,15, 22, 29, 36, 43.   
Injection or allergic reactions may occur with the administration of monoclonal 
antibodies and other protein-based therapeutics. Precautions for anaphylaxis 
should be observed during DUPILUMAB administration. Supportive measures 
may include, but are not limited to: epinephrine, antihistamines, corticosteroids, 
IV fluids, vasopressors, oxygen, bronchodilators, diphenhydramine, and 
acetaminophen. Please refer to Section 6.4.3 for specific guidelines regarding 
the management of drug reactions. Supportive care measures consistent with 
optimal patient care will be provided throughout the study according to 
institutional standards. 
6.2.2 DUPILUMAB 
 Inspect drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced 
discoloration (solution may have pale-yellow color), or there is foreign particulate 
matter. 
 The desired amount of DUPILUMAB should be withdrawn from the vial(s) and 
diluted to the appropriate final concentration with 0.9% Sodium Chloride 
Injection USP, according to the instructions provided.Discard partially used vials 
of DUPILUMAB 
 Administration of study drug should begin immediately after preparation but no 
later than 6 hours after preparation. If there is a delay in administration of study 
drug such that it will not be administered on the day of preparation, the Principal 
Investigator should be notified immediately. Instructions on how to proceed will 
be provided. 
6.2.3 Placebo or Control 
There will be neither placebo nor active control drug for this study. 
6.3 
Study Drug Administration 
 
Do not mix DUPILUMAB with, or administer as an injection with, other medicinal 
products. 
6.4 
Potential Adverse Events and Supportive Care Measures 
6.4.1 Grading of Administration Reactions 
Injection reactions will be categorized as follows: 
 
Grade 1:  mild reaction; intervention not indicated; (see Section 6.4.3); 


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 
Grade 2:  moderate reaction: responds promptly to symptomatic treatment 
[e.g., antihistamines, non-steroidal anti-inflammatory drugs (NSAIDS), 
narcotics, IV fluids]; prophylactic medications indicated for  24 hours; 
 
Grade 3:  prolonged reaction: recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates); 
 
Grade 4:  life-threatening consequences; pressor or ventilatory support 
indicated; 
 
Grade 5:  death. 
The above grading scale is the CTCAE v 4.03 grading scale for CRS, which is 
nearly identical to the CTCAE v 4.03 grading scale for injection reaction and 
allergic reaction, and therefore considered appropriate for grading all injection 
reactions in this study, irrespective of the underlying mechanism of the reaction. 
The Sponsor’s Medical Monitor or designee should be contacted immediately if 
questions arise concerning the grade of the reaction. 
6.4.2 Premedications and Prophylaxis 
For DUPILUMAB, the following suggested guidelines (which may be modified by 
the investigator according to the institutional guidelines for management of 
anaphylaxis reactions) are measures to be followed if a drug reaction is noted 
after s.c. administration to avoid potential reactions with future administration. 
Treatment (guidelines to be followed): 
 
Acetaminophen 650 mg 
 
Diphenhydramine 50 mg or appropriate dose of equivalent H1 antagonist 
 
Ranitidine 300 mg or appropriate dose of equivalent H2 antagonist at the 
discretion of the investigator 
 
Hydrocortisone 20 to 40 mg (dose selected at the discretion of the 
Investigator) 
 
Prior to next administration (guidelines to be followed): 
 
Acetaminophen 650 mg 
 
Diphenhydramine 50 mg or appropriate dose of equivalent H1 antagonist 
 
Ranitidine 300 mg or appropriate dose of equivalent H2 antagonist at the 
discretion of the investigator 
 
Hydrocortisone 20 to 40 mg (dose selected at the discretion of the 
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6.4.3 Dose Management for Adverse Events considered related to DUPILUMAB 
Temporary interruptions of DUPILUMAB may be required in the event of 
treatment-related toxicity. General guidelines for specific toxicity regarding dosing 
and treatment are provided below. All toxicities will be graded according to NCI 
CTCAE v4.03 (see Section 7.1.2). 
6.4.3.1 Grade 1 or 2 AEs 
Study drug administration may continue despite observation of drug-
related low grade adverse events (CTCAE grade 1 or 2). If the 
investigator in his/her medical judgment considers that a low grade AE is 
of clinical significance or inordinately prolonged, the Investigator may, at 
his/her discretion, delay treatment to allow for resolution. Necessity to 
delay for more than two consecutive doses will require the patient to 
permanently discontinue study drug. No dose reductions are allowed.  
6.4.3.2 Grade 3 or 4 AEs 
Drug administration should be held upon observation of AEs of ≥ Grade 3 
severity to enable patient management, monitoring of the resolution of the 
event, and assessment of the relatedness of the event. An AE of ≥ Grade 
3 that is considered related to DUPILUMAB will result in discontinuation 
of therapy unless other specified in the protocol.  For AEs associated with 
liver function test abnormalities, drug administration may resume upon 
resolution of the AE to ≤ Grade 1 severity unless more than seven days 
elapse before return to ≤ Grade 2 severity or fourteen days have elapsed 
from the last dose. In this case, the AE is considered dose limiting, two 
consecutive doses will have been missed, and study drug administration 
should be discontinued. Following a single missed dose, the treatment 
schedule should resume as if no delay had occurred and the patient 
receive all intended DUPILUMAB doses. 
6.5 
Concomitant Therapy 
DUPILUMAB is the only cancer drug to be administered routinely in this study.  No 
concomitant anti-cancer therapy will be given.  
All concomitant medications and blood products administered during the patient’s 
participation in the study until the post treatment follow-up visit must be recorded in the 
source document and on the electronic Case Report Form (eCRF). All changes in 
infusions, including interruptions and their duration as well as reductions in rate and 
duration must be recorded. 
The following rules concerning concurrent treatment(s) will apply in this study: 
 
      Any other anti-neoplastic therapies including but not limited to chemotherapy or other  
 
     small molecules, biologics, or radiotherapy are not allowed. 
 
 


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 
Patients may not receive other investigational drugs during the period of study 
participation. 
 
Because DUPILUMAB has a mechanism of action dependent upon inhibiting 
macrophages, the use of corticosteroids should be limited to the extent possible.  
Chronic doses of corticosteroids in excess of 10 mg daily of prednisone or 
equivalent is prohibited other than for the management of drug-related adverse 
experiences.  Steroids may be employed in the treatment of suspected 
DUPILUMAB-associated immune-inflammatory or autoimmune AEs in 
consultation with the Sponsor. 
 
The use of other immuno-suppressive agents is prohibited, unless they are being 
used to treat an adverse event.  
 
Use of granulocyte colony stimulating factor, granulocyte-macrophage colony 
stimulating factor or other growth factors is prohibited. 
Patients may receive the following concurrent therapy: 
 
Antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, 
antihistamines, analgesics, antibiotics and other antimicrobials, histamine 
receptor antagonists or proton pump inhibitors, and other medications intended 
to treat symptoms or signs of disease. 
 
Transfusions such as red blood cells and platelets are permitted to treat 
symptoms or signs of anemia or thrombocytopenia and should be documented 
on the concomitant medication form. 
6.6 
Restrictions 
6.6.1 Prior Therapy 
Prior therapy restrictions are described in the inclusion/exclusion criteria 
specified in Section 3. 
6.6.2 Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake 
by the patients during the study. 
6.6.3 Patient Activity Restrictions 
There are no restrictions on patient activities and no requirement for patient 
confinement during the study. 
6.7 
Treatment Compliance 
DUPILUMAB will be administered by healthcare professionals under the supervision of 
the Investigators. Records of DUPILUMAB dose calculation, administration, and dosing 
regimen will be accurately maintained by site staff. The monitor will review dose 
calculation, administration and regimen as well as medication accountability during 
investigational site visits and at the completion of the study. 
6.8 
Packaging and Labeling 
DUPILUMAB will be supplied in bulk, open-label, single-use vials. All investigational 
product will be labelled with a minimum of the protocol number, directions for use, 


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storage conditions, expiry date (if applicable), batch number, the statements “For clinical 
trial use only,” and/or “CAUTION: New Drug – Limited by Federal (United States) Law to 
Investigational Use,” and the Sponsor's name and address. Please see the Pharmacy 
Manual for detailed information about the packaging of the study drug.  
6.9 
Storage and Accountability 
The vials containing study drug should be stored at 2°– 8° C (36°– 46° F) and must not 
be frozen or shaken. Protect from sunlight. To ensure compliance with storage 
conditions, temperature logs will be maintained. 
Because there is no preservative and drug loss occurs over time, administration of study 
drug should begin immediately after preparation but no later than 6 hours after 
preparation (see Pharmacy Manual). If there is a delay in administration of study drug 
such that it will not be administered on the day of preparation, the Clinical Project 
Manager should be notified immediately. Instructions on how to proceed will be 
provided. 
The Investigator or his/her designee is required to maintain accurate drug accountability 
records. A binder containing instructions and the required accountability documentation 
will be provided to the Investigator or his designee. When the study is completed, copies 
of study drug accountability records must be sent to the Sponsor. The original drug 
accountability records must be maintained with the rest of the documentation in 
accordance with Section 9.3 of the protocol. 
Additional details regarding storage, handling, and accountability can be found in the 
Pharmacy Manual. 
6.10 
Investigational Product Disposition at End of Study 
Upon completion or termination of the study, all unopened vials of study medication must 
be returned to MacroGenics or its representative, unless the site has received written 
authorization from MacroGenics to destroy study drug at the site. All drug returns to 
MacroGenics or its representative must be accompanied by the appropriate 
documentation and be clearly identified by protocol number and study site number on 
the outermost shipping container. If MacroGenics approves the destruction of drug at the 
site, the Investigator must ensure arrangements are made for proper disposal and that 
appropriate records of disposal are documented and maintained and copies provided to 
the Sponsor. 
7. 
ADVERSE EVENTS AND REPORTING REQUIREMENTS 
An adverse event (AE) is defined as any untoward medical occurrence (symptom, sign, 
illness or experience) that develops or worsens in a research patient during a clinical 
study or within 30 days post-treatment, regardless of causality. This includes adverse 
clinical or laboratory findings, any adverse drug reaction (ADR), an illness with onset 
during the study, or an exacerbation of a preexisting illness or condition. Cancer 
progression should not be considered an AE, unless the investigator believes that the 
study treatment exacerbated the patient’s condition. Exceptions are if disease 
progression results in death or hospitalization while a patient is on study, in which case 
the disease progression is considered a serious AE. Abnormal findings on physical 
examination or diagnostic procedures are also considered AEs if: they are associated 
with clinical signs or symptoms; they require therapeutic intervention or additional 


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diagnostic testing; they lead to dose modifications/termination of the study drug; or they 
are considered clinically significant by the investigator. All observed or reported AEs, 
regardless of their suspected causal relationship to the study drug, should be recorded 
on the Case Report Form (CRF). 
 The NCI CTCAE version 4.0 will be used for adverse event descriptions and grading 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). 
These criteria are summarized in Appendix B. The type and severity of an AE, as well as 
its potential link to the study drug(s), will determine whether the event requires expedited 
reporting in addition to routine reporting. For all AEs, the investigator must pursue and 
obtain information to adequately determine the causality and outcome of the event, and 
to assess whether it meets criteria for a serious AE. In addition, follow-up of AEs should 
continue until the event and any sequelae resolve or stabilize at a level acceptable to the 
investigator and/or the medical monitor. 
7.1 
Recording and Grading 
7.1.1 Recording 
All observed or volunteered adverse events, regardless of treatment group, 
severity, suspected causality, expectedness, or seriousness will be documented 
on the CRF. 
A clinically significant change in a physical examination finding or an abnormal 
test result (i.e., laboratory value) should be recorded as an AE, if it: 
 
is associated with accompanying symptoms 
 
requires additional diagnostic testing or medical or surgical intervention 
 
leads to a change in study dosing or discontinuation from the study 
 
requires additional concomitant drug treatment or other therapy, or 
 
is considered clinically significant by the investigator 
An abnormal test result that is subsequently determined to be an error does not 
require recording as an AE even if it originally met one or more of the above 
criteria. 
7.1.2 Grading severity 
All adverse events will be graded for intensity on a scale of 0 to 5, according to 
the NCI CTCAE version 4.0 (see Table 2 and Appendix B). These criteria can be 
found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3
.pdf 
Table 2 Intensity of Adverse Event 
Grade 
Description 
0 (none) 
No adverse event or within normal limits. 
1 (mild) 
Transient or mild discomfort; generally non-progressive; no 
limitation in daily activities; no medical intervention required. 


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2 (moderate) 
Mild/moderate limitation in daily activities; some assistance 
may be required; no/minimal medical intervention required. 
3 (severe) 
Marked limitation in daily activities; some assistance usually 
required; medical intervention is required. 
4 (life-
threatening) 
Extreme limitation in daily activities; major assistance required; 
significant medical intervention required. 
5 (death) 
Fatal adverse event. 
 
7.1.3 Attributing causality 
After grading for severity, the investigator must evaluate all clinical AEs and 
abnormal laboratory values for possible causal relationship to the study drug(s). 
Causality attribution will be decided using the criteria outlined in Table 3. 
Table 3 Relationship of Adverse Event to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related to the study drug (An event that does 
not meet any of the criteria below). 
Unlikely 
AE is doubtfully related to the study drug (An event that follows 
a reasonable temporal sequence after drug administration; that 
follows a known or expected response pattern; but that could 
more reasonably be explained by other characteristics of the 
patient’s clinical state). 
Possible 
AE may be related to the study drug (An event that follows a 
reasonable temporal sequence after drug administration; that 
follows a known or expected response pattern; but that could 
just as readily be attributed to a number of other factors). 
Probable 
AE is likely related to the study drug (An event that follows a 
reasonable temporal sequence after drug administration; that 
follows a known or expected response pattern; that is 
confirmed by stopping/reducing the drug dose; and that could 
not be reasonably explained by the characteristics of the 
patient’s clinical state). 
Definite 
AE is clearly related to the study drug (An event that follows a 
reasonable temporal sequence after drug administration; that 
follows a known or expected response pattern; and that is 
confirmed by improvement on stopping/reducing the drug dose 
and reappearance on repeated exposure). 
 
Abnormal laboratory values of clinical significance that were present at baseline 
and did not change in severity or frequency during experimental therapy and 
those that can obviously be attributed to underlying disease will be recorded as 
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7.2 
Unexpected Adverse Events 
An unexpected adverse event is any event not associated by nature or intensity with the 
investigational agent(s) under study. A comprehensive list of adverse events and 
potential risks related to DUPILUMAB is provided in this Protocol and in the Consent 
form. The study agent may cause allergic reactions in very rare instances. A severe 
allergic reaction could be life-threatening. Examples of allergic reactions include: rash; 
shortness of breath; wheezing; sudden drop in blood pressure; swelling around the 
mouth, throat, or eyes; fast pulse; and sweating. 
7.3 
Serious Adverse Events and Serious Adverse Drug Reactions 
The investigator must assess each event to determine if it meets the criteria for 
classification as a serious adverse event (SAE) or serious adverse drug reaction (ADR). 
An SAE/ADR is defined in the Code of Federal Regulations (21CFR312.32) as any 
event that: 
 
results in death 
 
is life-threatening 
 
results in inpatient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability or incapacity 
 
results in congenital anomaly or birth defect 
 
is medically significant in the opinion of the investigator 
All SAEs that occur any time while a patient is on study (i.e., as soon as the informed 
consent has been signed) or within 30 days of the last dose of study drug administration 
must be documented, regardless of the suspected relationship to the investigational 
agent(s). Any SAE occurring more than 30 days after the last dose of the study drug(s) 
must be recorded if a causal relationship to the investigational agent(s) is suspected. 
7.3.1 Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE unless, in 
the investigator’s opinion, study treatment resulted in an exacerbation of the 
patient’s condition. If disease progression results in death or hospitalization while 
on study or within 30 days of the last dose of study drug administration, 
progressive disease will be considered an SAE. 
7.3.2 Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of 
death from the reaction as it occurs. It is not a reaction that, had it occurred in a 
more severe form, might have caused death. 
7.3.3 Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even if < 24 hours) 
resulting from a precipitating treatment-emergent adverse event. For chronic or 
long-term patients, inpatient admission also includes transfer within the hospital 
to an acute or intensive care inpatient unit. Hospitalizations for administrative 
reasons or a non-worsening preexisting condition should not be considered AEs 
(e.g., admission for workup of a persistent pretreatment laboratory abnormality, 
yearly physical exam, protocol-specified admission, or prostatectomy surgery). 


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Hospitalization because of an unplanned event will be deemed an SAE. 
Preplanned treatments or surgical procedures should be noted in the baseline 
documentation. In the case of this study, all patients will have a preplanned 
prostatectomy surgery. 
Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
7.3.4 Significant disability 
This is defines as a substantial disruption of the patient’s ability to conduct 
normal life functions and activities of daily living. 
7.3.5 Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the 
study, the treating physician must be notified immediately. All confirmed 
pregnancies must be immediately reported to the principal investigator and the 
medical monitor, and recorded in the CRF. All pregnancies will be followed until 
resolution (i.e., voluntary or spontaneous termination or birth) and assessed for 
congenital anomalies and birth defects. 
7.3.6 Medical significance 
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient’s status and might lead to medical or surgical intervention 
to prevent any of the above outcomes. Such medically significant events could 
include allergic bronchospasm requiring intensive treatment in the emergency 
room or at home, blood dyscrasias that do not result in inpatient hospitalization, 
or the development of drug dependency or abuse. 
7.4 
Perioperative Adverse Events 
Complications of surgery or those occurring in the early post-operative period will be 
recorded. These include wound complications, estimated blood loss, post-operative 
infections, delayed wound healing, abnormal laboratory values, etc. Duration of hospital 
stay will be recorded. Additional medical examinations will be allowed at the request of 
patients during drug administration or at the discretion of the principal investigator for the 
evaluation of new adverse events that warrant physical examination. During and 
following completion of the study, patients should notify the study staff of any problems 
that occur between visits or following study termination by telephone and, if necessary, 
will be evaluated by the investigator or study personnel at an unscheduled interim visit. 
Operative/perioperative events will be recorded as described in Section 7.1, and their 
severities will be categorized using the NCI CTCAE version 4.0 criteria. The relationship 
of these events to the investigational drug(s) will be determined by the principal 
investigator together with urologist co-investigators and, if necessary, with the primary 
urologic surgeon. Reporting of these events will follow the same guidelines described in 
Section 7.5. 


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7.5 
Reporting Adverse Events 
7.5.1 Reporting serious adverse events (SAEs) 
All SAEs and unknown/unexpected reactions should be reported to the PI  within 
24 hours.  
The lead study coordinator, Alice Jordan should be contacted when reporting an 
SAE or death at 410-955-1239 and ajorda30@jhmi.edu If this person cannot be 
reached within 24 hours, the PI should be contacted at 410-502-3137 or at 
kpienta1@jhmi.edu. The initial report for each SAE or death should include the 
following information (see also Appendix C for SAE Reporting Form): 
 
protocol # and title 
 
patient initials, study identification number, sex, age 
 
date the event occurred 
 
description of the SAE 
 
investigational agent received (and dose level) at the time the SAE 
occurred 
 
description of the patient’s condition 
 
indication of whether the patient remains on study 
Follow-up information including severity, causality, action taken, concomitant 
medications, and outcome should be communicated to the principal investigator 
and study coordinator as soon as possible with an indication whether an 
amendment will need to be made to the protocol, the consent form, or both, as a 
result of this event. 
7.5.2 Reporting requirements for the Sidney Kimmel Comprehensive Cancer Center   
(SKCCC) 
The principal investigator will notify the appropriate regulatory agencies of any 
SAEs occurring during the study period, regardless of causality. These agencies 
include the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Data and 
Safety Monitoring Committee (DSMC), and the Institutional Review Board (IRB) 
and the Institutional Biosafety Committee (IBC) of the Johns Hopkins Medical 
Institutions (JHMI). For SAEs that are fatal, life-threatening, or treatment-related 
but non-life threatening: IRB/IBC reporting by the PI is required within 3 days. For 
unrelated SAEs, IRB/IBC reporting by the PI is required within 15 days. All other 
AEs should be documented on CRFs and submitted according to the standard 
data management guidelines. 
Adverse event information will be collected continuously throughout the duration 
of the study. Participants will be instructed to notify their treating provider of any 
new signs or symptoms, and providers will actively assess patients for adverse 
events at each visit (including by evaluation of laboratory studies). The 
investigator will assess each AE for its severity and for its relationship to the 
study drug, and all events Grade 1 or higher will be documented on CRFs and 
then reported as described above within the required time frame. Any AE 
occurring while a patient is on study (i.e. after informed consent has been signed) 
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this must still be reported if a causal relationship with the study drug is 
suspected. 
For all AEs, the investigator must pursue and obtain information to adequately 
determine the causality and outcome of the event, and to assess whether it 
meets criteria for a SAE. In addition, follow-up of an AE is required until the event 
either resolves or stabilizes. Initial reporting of an AE should include at a 
minimum the patient number, age, the dose at which the event occurred, and the 
type and severity of the event. Follow-up information including causality, 
duration, outcome, action taken, and concomitant medications should be 
reported soon thereafter. 
The principal investigator must keep copies of all CRFs and other AE 
information, including correspondence with the IRB for as long as required to 
comply with national and international regulations (generally at least 3 years after 
study completion). 
 
 
7.5.3 Research Involving). 
7.6 
Pregnancy 
Pregnancy is not an AE unless it results in congenital anomaly or birth defect, in which 
case it is a SAE. If the partner of a male patient should become pregnant while he is 
participating in the study, the patient should inform his treating physician immediately. All 
pregnancies must be reported at once to the principal investigator and medical monitor. 
All confirmed pregnancies will be followed until birth or until voluntary or spontaneous 
termination.
8. 
OUTCOME ASSESSMENT 
8.1 
Radical Prostatectomy Specimen 
Most of the study outcomes in this immunologic trial will depend on collection of prostate 
tissue from prostatectomy specimens. All pathologic specimens will be handled in 
routine fashion by the operating room (OR) staff, except that as soon as the specimen is 
removed the OR nurse will directly page a tissue harvesting technician that is part of the 
Brady Urological Research Institute Prostate Specimen Repository Team. Accessioning 
of pathology specimens will be coordinated in the OR areas by the Departments of 
Urology and Pathology. A study technician will be available to the pathologist receiving 
the specimen to assure that the tissue is handled appropriately for the intended 
bioassays. At the time of harvesting, the pathologist will apply ink and cut the prostate 
specimen in transverse sections. The specimen will be fixed in 10% phosphate buffered 
formalin, and tissue blocks will be paraffin-embedded and sectioned at 4 μm thickness 
for routine histologic evaluation and for immunohistochemical determinations. Fixation 
should occur as soon as possible after operative removal of the prostate, and ideally 
within 30-60 minutes. Assessment of index tumors for Gleason grade, nodal 
involvement, and pathologic staging will be conducted in usual fashion and will be 
provided to the patient for prognostic information. After the pathology report is available, 
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samples will be included. Tumor blocks and/or additional unstained slides will be 
collected for study-specific quantitative immunohistochemical evaluations. 
8.2 
Primary Endpoint 
8.2.1 Analysis of M2-TAM infiltration 
The primary measure of treatment effect in this study will be achieved by 
quantification of M2-TAMS in prostate tumor specimens of treated patients.  
Tissue microarrays (TMAs) from formalin-fixed tumor samples will be analyzed 
for the degree of TAM infiltration using immunohistochemical staining for CD206  
(28, 29). Analyses will be performed in the laboratory of Dr Angelo DeMarzo. The 
contact information for the DeMarzo laboratory is listed below: 
Angelo DeMarzo, MD, PhD 
CRB1 - Room 151 
1650 Orleans Street 
Baltimore, MD 21231 
Phone:  (410) 614-5686 
Fax: (410) 502-9817 
Email: ademarz@jhmi.edu 
 
8.3 
Secondary Endpoints 
8.3.1 Rate of adverse events 
All subjects receiving at least one dose of the study drug will be evaluated for 
safety by monitoring symptoms, physical examinations, and laboratory tests. 
Adverse events will be classified and graded according to the NCI Common 
Toxicity Criteria version 4.0 (see Appendix B). The absolute number and 
frequency of each adverse event will be reported, and subdivided according to 
toxicity grade. A description of adverse events by treatment arm will also be 
reported. A particular adverse event occurring more than once in the same 
subject will be counted only once and at its worse grade. 
8.3.2 Markers of cell proliferation 
TMAs from fixed tumor samples will be analyzed for the degree of tumor cell 
proliferation using the validated marker, Ki-67. This will be achieved by 
immunohistochemical staining (30, 31), using the Ki-67 monoclonal antibody 
(Dako North America, Carpineteria, CA). Quantification of staining percentage 
will be performed using the Aperio ScanScope® CS instrument (Aperio 
Technologies, Vista, CA) as described in Section 8.3.3. This endpoint will be 
expressed as the mean staining percentage in tumor tissue. Assays will be 
performed in the laboratory of Dr DeMarzo. 
8.3.3 CD8+ T cell infiltration 
To assess the immune response to DUPILUMAB, we will quantify the extent of 
CD8+ T cell infiltration into the prostate from harvested prostate glands. This will 
be done using immunohistochemical staining methods. This endpoint will be 
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tissue. We will also attempt to quantify prostatic CD4+ T cell infiltration and Treg 
infiltration, as well as to determine the CD8/Treg ratio and the CD4/Treg ratio.  
Analysis of this endpoint will be achieved by preparing tissue microarrays (TMAs) 
using the highest-grade/largest tumor per patient and sampling it with 100-fold 
redundancy (28-31). All tissues will first be fixed in 10% neutral buffered formalin 
and processed into paraffin blocks. For each immunohistochemical stain (e.g. 
CD8+ T cell stain, CD4+ T cell stain, Treg stain), TMA slides will be scanned using 
the Aperio ScanScope® CS instrument (Aperio Technologies, Vista, CA) and 
TMA cores will first be assigned a diagnosis by the study pathologist and will 
then be  subjected to semi-automated image analysis using the Aperio system. 
For each biomarker, we will divide the area of brown DAB staining by the area of 
epithelial cells on the TMA core, obtaining a staining percentage. The area of 
epithelium will be obtained on each TMA core by staining with cytokeratin-8 and 
using automated image analysis. Cores with both tumor and normal tissue will be 
excluded if they contained >10% of the other component. 
For CD8 staining, slides will be steamed for 20 minutes in citrate antigen retrieval 
solution (Vector Laboratories, Burlingame, CA) followed by  incubation with a 
mouse monoclonal anti-CD8 antibody for 45 minutes at room temperature (Dako, 
Carpinteria, CA). For CD4 staining, slides will be steamed for 40 minutes in high 
pH antigen retrieval solution (Dako, Carpinteria, CA) and then incubated with a 
mouse monoclonal anti-CD4 antibody for 45 minutes at room temperature 
(Serotec, Kidlington, UK). For Treg analysis, cells will be stained for the FoxP3 
protein by steaming slides for 40 minutes in high pH antigen retrieval solution 
(Dako, Carpinteria, CA) and incubating them with a mouse monoclonal anti-
FoxP3 antibody for 45 minutes at room temperature (eBioscience, San Diego, 
CA, 1:1000 dilution). In all cases, poly-HRP-conjugated anti-mouse IgG Ab 
(Dako, Carpinteria, CA) will be used as the secondary antibody. Staining will be 
visualized with diaminobenzidine (Sigma, Saint Louis, MO) and slides will be 
counterstained with hematoxylin. 
Images of each TMA core will be captured by automated scanning of TMA slides 
using the Aperio ScanScope® CS instrument (Aperio Technologies, Vista, CA). 
Captured images will be imported into the TMAJ Images Application program 
(http://tmaj.pathology.jhmi.edu). Histological diagnoses (normal, atrophy, 
prostatic intraepithelial neoplasia, cancer) will be applied to all images used for 
the analyses by a pathologist. In addition, for TMA spots containing more than 
one type of lesion, the percentage of each diagnosis will be noted. All images 
and data will be available for viewing/downloading at 
http://demarzolab.pathology.jhmi.edu/Pubs.html. For image analysis, we will use 
a custom open source software package, FRIDA (Framework for Image Dataset 
Analysis; http://sourceforge.net/projects/fridajhu), for the evaluation of red-green-
blue (RGB) color image datasets, including those generated from scanning of 
tissue microarray slides. To analyze CD4, CD8 and FoxP3 (Treg) staining, hue-
saturation-brightness (HSB) segmentation ranges for brown DAB staining will be 
defined from the tissue microarray image set, and the total number of pixels in 
every image that fall within the defined parameters for brown DAB staining will be 
calculated, reflecting the total area of brown DAB staining for each spot. For 
every spot, a “staining ratio” for each of the three proteins will be calculated by 


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dividing the total area (in pixels) of brown DAB staining by the average TMA spot 
area. 
Previous TMA studies conducted by Angelo DeMarzo, MD PhD have defined the 
extent of T cell infiltration into human prostate glands using prostatectomy 
specimens. In normal prostate tissue, the mean staining percentage for CD8+ T 
cells is 0.29% (interquartile range, IQR, 0.13% - 0.39%) while in tumor tissue, the 
mean percentage of CD8+ T cells is 0.42% (IQR 0.07% - 0.71%). The 
corresponding values for CD4+ T cell infiltration in normal and tumor tissue are 
0.16% (IQR 0.04% - 0.18%) and 0.25% (IQR 0.01% - 0.32%), respectively. The 
corresponding values for Treg infiltration in normal and tumor tissue are 0.03% 
(IQR 0.02% - 0.04%) and 0.06% (IQR 0.02% - 0.08%), respectively (Gurel and 
DeMarzo, unpublished data).  
The above analyses will be performed in the laboratory of Angelo DeMarzo, MD 
PhD. A detailed description of these methodologies has previously been 
published (Zha et al 2001; Faith et al 2004; Gurel et al 2008).  
8.3.4 Regulatory T cell (Treg) infiltration 
The method for quantifying Treg density from harvested prostate tissue is as 
described in Section 8.3.3. This endpoint will be expressed as the mean staining 
percentage in tumor tissue. 
8.3.5 CD4+ T cell infiltration 
The method for quantifying CD4+ T cell density from harvested prostate tissue is 
as described in Section 8.3.3. This endpoint will be expressed as the mean 
staining percentage in tumor tissue. 
8.3.6 Pathological complete responses (pCR) 
This will be defined as the absence of tumor identification by the study 
pathologist on standard histological analysis of the resected prostate specimens. 
The endpoint will be expressed as the proportion of men achieving a pCR. 
8.3.7 PSA response rates 
This will be defined as the proportion of patients who achieve an undetectable 
PSA (<0.1 ng/mL) by 3 months after prostatectomy. The endpoint will be 
expressed as the proportion of men achieving a PSA response. 
8.3.8 Time to PSA recurrence  
This will be defined as the interval from the time of prostatectomy to the time 
when the serum PSA is ≥0.2 ng/mL. PSA will be measured every 3 (±1) months 
during the first post-operative year and every 6 (±2) months during the second 
and third post-operative years. For subjects who have not yet demonstrated PSA 
relapse at the time of censoring, patients will be censored at the date of the last 
assessment that shows a lack of PSA recurrence. This outcome will be 
expressed as a median and will be determined using the Kaplan-Meier method. 
9. 
REGULATORY AND REPORTING REQUIREMENTS 
Contact details for personnel connected with this study are provided on the title page at 
the front of this protocol. Patient registration procedures are described in Section 4. 


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9.1 
Regulatory Responsibilities 
9.1.1 Protocol chair 
The protocol chair (=PI), (Name) is responsible for the following tasks: 
 
Coordinating, developing, writing, submitting, and obtaining IRB-approval for 
the protocol as well as its subsequent amendments. 
 
Assuring that all study personnel are using the correct version of the protocol. 
 
Taking responsibility for the overall conduct of the study and for monitoring 
the progress of the study. 
 
Reviewing and ensuring reporting of serious adverse events (SAEs). 
 
Reviewing data from all patients. 
9.1.2 Study Coordinator 
The study coordinator, (Name), is responsible for the following tasks: 
 
Ensuring that IRB approval has been obtained prior to patient registration, 
and maintaining copies of IRB approvals (including approval of amendments). 
 
Managing patient registration. 
 
Collecting and compiling data from each patient. 
 
Establishing procedures for documentation, reporting, and submission of 
AEs/ SAEs to the protocol chair (Name) and other applicable parties. 
 
Facilitating audits by securing selected source documents and research 
records from participating patients for audit. 
9.1.3 Study personnel 
Study personnel (co-investigators, research nurses) are responsible for these 
tasks: 
 
Following the protocol as written, and Good Clinical Practice (GCP) 
guidelines. 
 
Submitting data to the project manager. 
 
Registering all patients by submitting the patient registration form and signed 
informed consent form promptly. 
 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct the trial according to the protocol. 
 
Maintaining regulatory binders and providing copies of all required documents 
to the project manager. 
 
Collecting/submitting data according to the schedule specified by the 
protocol. 
9.2 
Data Management 
Data collected during this study will be entered into a secure database. The study 
coordinator will be responsible for the initial study configuration and setup of the 
database and for any future changes. 


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9.2.1 Case report forms 
Case report forms (CRFs) will be generated by the study coordinator for the 
collection of all study-related data. Investigators and study personnel will be 
responsible for ensuring that the CRFs are kept up-to-date. 
9.2.2 Source documents 
Investigators and study personnel will record clinical data in each patient’s 
source documents (i.e., the patient’s medical record). Source documentation will 
be made available to support the patient research record. Study monitors will 
review entries on the CRFs at regular intervals, comparing the content with the 
source documents. 
9.2.3 Record retention 
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 should maintain all 
source documents, study-related documents, and the CRFs. Because the length 
of time required for retaining records depends upon a number of regulatory and 
legal factors, documents should be stored until the investigator is notified that the 
documents may be destroyed. In this study, records are to be retained and 
securely stored for a minimum of 3 years after the completion of all study-related 
activities. 
9.3 
Study Monitoring and Quality Assurance 
Data and safety monitoring will follow Level Medium under the SKCCC Data and Safety 
Monitoring Plan. The SKCCC Compliance Monitoring Program will provide external 
monitoring for JHU-affiliated sites in accordance with SKCCC DSMP (Version 6.0, 
02/21/2019).  The SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring. Additionally, scheduled meetings will take place monthly 
and will include the protocol principal investigator, research nurse, data manager, and, 
when appropriate, the collaborators, sub-investigators, and biostatistician involved with 
the conduct of the protocol. 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential 
or real protocol violations), data completeness, and progress of data for secondary 
objectives. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design,  Sample Size, and Study Endpoints 
For the primary outcome: pre- and post-treatment M2-TAM infiltration will be compared using a 
paired t-test, or nonparametric signed rank test if data don’t conform to a Gaussian distribution. 
Power is based on the paired t-test.  With 20 patients, we have the power (> 81%) to detect a 
decrease of >0.67 standard deviation unit (effect size = 0.67) (14).   This is likely to be 
conservative as we observed a much larger difference in M2-TAM levels between primary and 


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metastatic tumors in our data.  Power calculated using PASS v. 11 (NCSS Software, Kaysville, 
UT).  
For the secondary analysis of safety, we will use a continuous toxicity monitoring approach with 
sequential dose-limiting toxicity boundaries (13).  Patients will be evaluated for AEs after 
neoadjuvant dupilumab.  We consider a 15% rate of Grade >3 AEs to be unacceptable and 
indication to halt the trial.  Accrual will continue until the number of Grade >3 AEs equals or 
exceeds the boundary for a given number of patients, or the completion of 20 patients without 
crossing any toxicity boundaries.  The table below shows the schedule of accrual and 
associated toxicity boundaries. 
Number of patients:3    4    5    6    7    8    9    10    11    12    13    14    15    16    17    18    19    20 
Toxicity Boundary:  3    3    4    4    4    4    5      5      5      6      6      6      6      7      7      7      7      7 
The AE rate and 95% confidence interval will be calculated, either at trial halt or completion of 
accrual. 
Secondary analyses of other immune infiltrate cells will be compared using a paired t-test, or 
nonparametric signed rank test if data don’t conform to a Gaussian distribution. Other 
secondary analyses will include calculating the rate and 95% confidence interval (CI) for 
complete response rates, and undetectable post-treatment PSA, and paired t-tests for the 
secondary outcome biomarkers listed above.  In exploratory analyses we will evaluate whether 
# of biopsy cores evaluated, patient, or clinical factors correlate with extent of decrease in 
infiltration, although the small sample size limits these analyses purely to hypothesis generating. 
Power.  For the primary outcome of pre- vs. post-treatment decrease in M2-TAM infiltration, 
power is based on the paired t-test.  With 20 patients, we have the power (> 81%) to detect a 
decrease of >0.67 standard deviation unit (effect size = 0.67) (14).   This is likely to be 
conservative as we observed a much larger difference in M2-TAM levels between primary and 
metastatic tumors in our data.  Power calculated using PASS v. 11 (NCSS Software, Kaysville, 
UT). The continuous toxicity monitoring design with n=20 above has probability = 0.048 of early 
stopping if the Grade >3 AE rate is <15%.  Toxicity boundaries calculated using software 
developed by Ivanova  (13) 
(http://cancer.unc.edu/biostatistics/program/ivanova/ContinuosMonitoringForToxicity.aspx) 
Frequency, types, and grades of adverse events in each treatment group will be measured 
using the NCI Common Toxicity Criteria version 4.0, and will be summarized using descriptive 
statistics. Formal safety assessments will be performed from the time of first administration 
Dupilumab until the 60th postoperative day. 
10.1.2: Early stopping rule for feasibility:  We do not anticipate an increase in the 
surgical difficulty with the use of neoadjuvant DUPILUMAB. Men who have had acute 
(post-biopsy) and prolonged issues (chronic prostatitis) with prostate 
infection/inflammation are fairly routine in urologic surgical practice, and we anticipate 
that the immune infiltrate potentially induced by DUPILUMAB would not pose a 
substantial increase in surgical difficulties. However, in addition to safety, feasibility will 
be monitored separately. The feasibility rule for this study will be based on a change in 
surgical outcomes beyond what may be expected for patients without presurgical 
interventions and that may be attributable to the study drug. These events would include: 
(1) average blood loss in excess of 2500 mL, (2) average operative time in excess of 3.5 
hours, and (3) average hospital stay in excess of 4 days. These values are 


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approximately 2 standard deviations above the average surgical outcomes for men 
undergoing radical prostatectomy at Johns Hopkins Hospital. 
We require that the probability that the surgery will not be complicated by these events 
to be high (≥90%). We will monitor this endpoint after every patient. If it becomes 
apparent that the surgeries are being negatively impacted by the pre-surgical 
investigational treatments, then the study will be suspended for review. This stopping 
rule will halt enrollment if the posterior probability of no complications <0.90 is greater 
than 80%. The prior probability for this rule has a Beta-distribution with parameters of 9 
and 1, based on the expectation that these treatments will not impact the feasibility of 
surgery. Instances where the study would be temporarily suspended are listed below.    
Stopping rules: 
•  Not feasible if both of the first 2 patients have surgical complications. 
•  Not feasible if two of the first 3 patients have complications. 
•  Not feasible if 2 out of the first 4 patients have complications. 
•  Not feasible if 3 out of the first 6 patients have complications. 
•  Not feasible if 4 out of the first 8 patients have complications. 
•  Not feasible if 5 out of the first 10 patients have complications. 
•  Not feasible if 6 out of the first 12 patients have complications. 
•  Not feasible if 7 out of the first 14 patients have complications. 
•  Not feasible if 8 out of 16 patients have complications. 
 
10.2.2 Analysis of the secondary endpoints 
The secondary endpoints of this study have previously been defined (see Section 
8.3). The statistical analysis of these endpoints is described below. Data 
transformation will be performed when they are not normally distributed. 
 
Apoptotic markers. The primary efficacy objective of this study is to observe an 
anti-tumor effect consistent with the agent’s proposed mechanism of action 
(MOA), antibody-dependent cellular cytotoxicity (ADCC). Tumor cell death will be 
quantified by TUNEL staining, Caspase 3 staining, and FcGamma staining and 
will be expressed as the mean staining percentage in tumor samples. Standard 
deviations, 95% confidence intervals, and ranges will also be reported where 
appropriate. Means will be compared pre-treatment (from pre-treatment biopsies) 
vs. post-treatment using two-way analysis of variance (ANOVA).  
 
Proliferation markers. Ki-67 staining will be expressed as the mean staining 
percentage in tumor samples. Standard deviations, 95% confidence intervals, 
and ranges will also be reported where appropriate. Means will be compared pre-
treatment vs. post-treatment using two-way ANOVA. 
 
CD8+ T cell infiltration. Mean CD8+ T cell staining percentage in harvested 
prostate tissues will be reported. The standard deviation, 95% confidence 
interval, median, and range of values will also be reported where appropriate. 
Since the CD8+ T cell quantity is a ratio variable and the distribution is skewed, 
the log transformation will be used for the analysis. Tissue microarrays (TMAs) 
using the highest-grade/largest tumor per patient and sampling it with 100-fold 
redundancy will be used for CD8+ T cell quantification.  We expect that 3-50% of 
the spots per patient will be assigned a carcinoma diagnosis by the study 


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pathologist.  Cores with both tumor and normal tissue will be excluded if they 
contain >10% of the other component.  The percent positive staining score for 
CD8+ T cells in the spots classified as tumor will be used to quantify the outcome.  
The mean will be used to pool multiple spot measurements for each patient.. 
 
Regulatory T cell (Treg) density. The methods for analyzing Treg infiltration will 
be similar to those described for CD8+ T cell infiltration. Descriptive statistics and 
graphical summaries will be provided. In addition, the CD8+/Treg ratio and the 
CD4+/Treg ratio will be computed, and reported using descriptive statistics. 
 
CD4+ T cell density. The methods for quantifying and analyzing CD4+ T cell 
infiltration will be similar to those described for CD8+ T cell infiltration. Descriptive 
statistics and graphical summaries will be provided. 
 
Pathological complete responses (pCR). This will be defined as an absence of 
tumor identification on standard histological analysis of the resected prostate 
specimens. 
 
PSA response rates. This will be defined as an undetectable PSA (<0.1 ng/mL) 
at 3 months after prostatectomy. The proportion of patients achieving a PSA 
response will be compared between treatment arms using the Mantel-Haenszel 
test. 
 
Time to PSA recurrence. This will be defined as the interval from prostatectomy 
to the time when the serum PSA is ≥0.2 ng/mL. For subjects who have not yet 
demonstrated PSA recurrence at the time of censoring, patients will be censored 
at the date of the last assessment that shows a lack of PSA recurrence. For each 
treatment arm, the median time to PSA recurrence after prostatectomy (i.e., the 
median PSA-recurrence-free survival) will be estimated with 95% confidence 
intervals using Kaplan-Meier survival analysis. Comparisons will be sought using 
the log-rank test, stratified by Gleason score. 
 
10.3 
Analysis Populations 
10.3.1 Intention-to-treat population 
All patients who meet eligibility criteria and receive at least one dose of the study 
drug will be included in the analysis of the primary and secondary endpoints, 
even if there are subsequent protocol deviations. However, in cases where 
prostatectomy is not performed or if adequate surgical tissue is not collected, 
then determination of the secondary endpoints (e.g., CD206, 
apoptosis/proliferation marker analysis, tissue CD8+ T cell analysis) will not be 
possible. Patients will be replaced if they are removed from the study after 
signing the informed consent but before receiving the study drug. 
10.3.2 Safety population 
All patients enrolled in the study will be included in the safety analysis population 
and considered evaluable for toxicity from the time of their first dose of the study 
drug(s). Patients never receiving any of the study drugs will not be included in 
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will be summarized by number and percent for categorical data and by 
descriptive statistics for continuous data. 
10.4 
Safety Analysis 
10.4.1 Evaluation of adverse events 
Treatment-emergent adverse events will be translated from investigator terms to 
MedDRA version 6.0 terminology and summarized (number and percentage of 
patients) for all patients who receive at least one dose of the study drug(s). 
Adverse event summaries will be organized by body system, frequency of 
occurrence, intensity (i.e., severity grade), and causality or attribution. Patients 
who experience an adverse event more than once will be counted only once. The 
occurrence with the maximum severity will be used to calculate intensity. 
10.4.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in early treatment 
withdrawal or death will be summarized separately. Narrative paragraphs will be 
generated to describe the circumstances surrounding each SAE and each death. 
10.4.3 Evaluation of laboratory parameters and assays 
Abnormal laboratory parameters (e.g. electrolyte levels, liver function tests, renal 
function tests, complete blood counts) will be summarized, and clinically 
significant changes from baseline will be discussed. 
10.5 
Statistical Procedures 
10.5.1 General 
Most study outcomes will be reported using descriptive statistics: number of 
observations, means, standard deviations, medians, minimum, and maximum 
values. 95% confidence intervals will be provided where appropriate. A P-value 
of ≤0.05 will be used to denote statistical significance. 
10.5.2 Sample size calculation 
For the primary outcome: pre- and post-treatment M2-TAM infiltration will be 
compared using a paired t-test, or nonparametric signed rank test if data don’t 
conform to a Gaussian distribution. Power is based on the paired t-test.  With 20 
patients, we have the power (> 81%) to detect a decrease of >0.67 standard 
deviation unit (effect size = 0.67) (14).   This is likely to be conservative as we 
observed a much larger difference in M2-TAM levels between primary and 
metastatic tumors in our data.  Power calculated using PASS v. 11 (NCSS 
Software, Kaysville, UT).  
For the safety analysis, we will use a continuous toxicity monitoring approach 
with sequential dose-limiting toxicity boundaries (14).  Patients will be evaluated 
for AEs after neoadjuvant dupilumab.  We consider a 15% rate of Grade >3 AEs 
to be unacceptable and indication to halt the trial.  Accrual will continue until the 
number of Grade >3 AEs equals or exceeds the boundary for a given number of 
patients, or the completion of 20 patients without crossing any toxicity 


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boundaries.  The table below shows the schedule of accrual and associated 
toxicity boundaries. 
Number of patients:3    4    5    6    7    8    9    10    11    12    13    14    15    16    
17    18    19    20 
Toxicity Boundary:  3    3    4    4    4    4    5      5      5      6      6      6      6      7      
7      7      7      7 
The AE rate and 95% confidence interval will be calculated, either at trial halt or 
completion of accrual. 
10.5.3 Statistical analysis of primary and secondary endpoints 
For a description of statistical methods used to evaluate the primary and 
secondary study outcomes, please see Section 10.2. 
11. 
PROTECTION OF HUMAN SUBJECTS 
11.1 
Ethical Considerations 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP) guidelines established by the International Conference on Harmonization (ICH), 
and the ethical standards set forth in the Declaration of Helsinki of 2004 (these 
documents may be found at www.wma.net/e/policy/b3.htm and 
www.laakariliitto.fi/e/ethics/helsinki.html). Review of this protocol by the Institutional 
Review Board (IRB)/Ethics Committee (EC), and the performance of all aspects of the 
study including acquisition of informed consent, must also be in accordance with the 
principles elaborated in the Declaration, as well as the ICH guidelines (Code of Federal 
Regulations (CFR), Title 21: Part 50 and Part 312). The principal investigator will be 
responsible for submitting documents to the IRB/EC, and obtaining written approval for 
the protocol prior to study initiation. The approval of both the protocol and the informed 
consent must specify the date of approval, protocol number and version, and 
amendment number. The principal investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or other circumstances that may 
result in added risk to participating patients. 
11.2 
Protocol Amendments 
Before starting the study, the protocol must be approved by the IRB/EC, the JHU 
Institutional Biosafety Committee (IBC), the FDA, and the Recombinant DNA Advisory 
Committee (RAC). Amendments to the protocol are subject to IRB approval before 
instituting. Any amendments made after IRB/EC approval is granted must be 
resubmitted to the IRB/EC for new approval. 
11.3 
Written Informed Consent 
Before obtaining consent, members of the study team must review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available, 
the potential benefits of this program, the risks and the probability of their occurrence, 
and the procedures to minimize these risks. Should an adverse event occur, the 
provisions available to ensure medical intervention must also be reviewed. Why the risks 
are reasonable in relation to the anticipated benefits, incentives, or costs that will/may be 


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incurred as a result of participating in the study, as well as the efforts to maintain 
confidentiality, should also be discussed with the patient. 
Patients will be required to sign and date (in triplicate) a statement of informed consent 
that meets the requirements of the Code of Federal Regulations (Federal Register Vol. 
46, No. 17, January 27, 1981, part 50) and the IRB. The consent form should be 
submitted with the protocol for review and approval by the IRB/EC. The medical record 
should include a statement that written informed consent was obtained (and should 
document the date that it was obtained) before the patient is enrolled in the study. The 
original signed consent document will become part of the patient’s medical record, a 
copy will be forwarded to the project manager pursuant to registration, and a copy will be 
sent home with each patient. 
The consent form must include the following information: 
 
the nature and objectives, potential toxicities, and benefits of the intended study 
 
the length of therapy and follow-up required 
 
alternatives to the proposed therapy (including standard and investigational 
therapies) 
 
the name of the investigator(s) responsible for the protocol 
 
the right of the patient to accept or refuse treatment and to withdraw from 
participation in the study at any time 
11.4 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. 
This may be embedded within the informed consent document. The original signed 
documents will become part of the patient’s medical records, and each patient will 
receive a copy of the signed documents. The use and disclosure of protected health 
information will be limited to the individuals described in the research authorization form. 
The research authorization form must be prepared by the principal investigator and 
approved by the IRB.  
In compliance with US federal regulations, the investigator is required to permit 
representatives of the US Food and Drug Administration (FDA) or other regulatory 
authorities to review and/or copy any medical records relevant to the study in 
accordance with local laws. Patients will be informed of the extent to which their 
confidential health information generated from this study may be disseminated to other 
parties. Should direct access to medical records require a waiver or authorization 
separate from the subject’s statement of informed consent, it is the responsibility of the 
investigator to obtain such permission in writing from the patient. 
11.5 
Study Termination or Modification 
Adverse events and laboratory data from this trial will be assessed by the principal 
investigator and/or medical monitor on an ongoing basis. At least quarterly, data from 
the clinical database will be reviewed. The results of this review will be shared with all 
investigators and MacroGenics  either in writing or as part of a teleconference. SAEs will 
be reviewed as they are reported to the principal investigator or project manager, and 
the medical monitor will make an assessment regarding the safety of continuing or 
modifying the study. This assessment will be shared with the investigators either in 
writing or as part of a teleconference. Should the assessment of either the principal 


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investigator or the medical monitor be that the trial should be terminated, the study will 
then be closed to further accrual. Follow-up safety assessments will be performed for all 
patients who are taken out of the study prematurely.


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12. 
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1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 
Jan;66(1):7-30. 
2. 
Amend SR, Pienta KJ. Ecology meets cancer biology: the cancer swamp promotes the 
lethal cancer phenotype. Oncotarget. 2015 Apr 30;6(12):9669-78. 
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Shiao, S.L., G.C.-Y. Chu, and L.W.K. Chung, Regulation of Prostate Cancer Progression 
by the Tumor Microenvironment. Cancer letters, 2016. 380(1): p. 340-348. 
 
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Pollard, J.W., Tumour-educated macrophages promote tumour progression and 
metastasis. 2004. 4: p. 71. 
 
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Zarif, J.C., R.S. Taichman, and K.J. Pienta, TAM macrophages promote growth and 
metastasis within the cancer ecosystem. Oncoimmunology, 2014. 3(7): p. e941734. 
 
6. 
Hu, W., et al., Alternatively activated macrophages are associated with metastasis and 
poor prognosis in prostate adenocarcinoma. Oncology Letters, 2015. 10(3): p. 1390-
1396. 
 
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Lanciotti, M., et al., The Role of M1 and M2 Macrophages in Prostate Cancer in relation 
to Extracapsular Tumor Extension and Biochemical Recurrence after Radical 
Prostatectomy. BioMed Research International, 2014. 2014: p. 486798. 
 
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Noy, R. and Jeffrey W. Pollard, Tumor-Associated Macrophages: From Mechanisms to 
Therapy. Immunity, 2014. 41(1): p. 49-61. 
 
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Escamilla, J., et al., CSF1 Receptor Targeting In Prostate Cancer Reverses 
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Mahon, K.L., et al., Cytokine profiling of docetaxel-resistant castration-resistant prostate 
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Wenzel, S., et al., Dupilumab efficacy and safety in adults with uncontrolled persistent 
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trial. The Lancet, 2016. 388(10039): p. 31-44. 
 
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Simpson, E.L., et al., Two Phase 3 Trials of Dupilumab versus Placebo in Atopic 
Dermatitis. New England Journal of Medicine, 2016. 375(24): p. 2335-2348. 
13. 
Ivanova A, Qaqish BF, Schell MF.  Continuous toxicity monitoring in phase II trials in 
oncology.  Biometrics 2005; 61:540-5. 
 


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14. 
Lachin JM. Introduction to sample size determination and power analysis for clinical 
trials.  Control Clin Trials 1981; 2:93-113. 
15. 
Gordon, S. and F.O. Martinez, Alternative Activation of Macrophages: Mechanism and 
Functions. Immunity, 2010. 32(5): p. 593-604. 
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Sica A, Schioppa T, Mantovani A, and Allavena P. Tumour-associated macrophages are 
a distinct M2 polarised population promoting tumour progression: potential targets of 
anti-cancer therapy. Eur J Cancer, 42: 717-727, 2006. 
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Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 
promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-
type macrophage polarization. J Biol Chem. 2009 Dec 4;284(49):34342-54. PMCID: 
PMC2797202 
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Loberg RD, Day LL, Harwood J, Ying C, St John LN, Giles R, Neeley CK, Pienta KJ. 
CCL2 is a potent regulator of PCa cell migration and proliferation. Neoplasia, 8: 578-586, 
2006. PMCID: PMC1601934 
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Crowther M, Brown NJ, Bishop, ET, Lewis CE. Microenvironmental influence on 
macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol, 
70: 478-490, 2001. 
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Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of 
macrophages into hypoxic areas of tumors and other ischemic tissues. Blood, 104: 
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Zarif JC, Hernandez JR, Verdone JE, Drake CG, Pienta KJ. A phased strategy to 
differentiate human CD14+monocytes into classically and alternatively activated 
macrophages and dendritic cells.  Biotechniques. 2016 Jul 1;61(1):33-41. PMID: 
27401672 
22. 
Roca H, Hernandez J, Weidner S, McEachin RC, Fuller D, Sud S, Schumann T, 
Wilkinson JE, Zaslavsky A, Li H, Maher CA, Daignault-Newton S, Healy PN, Pienta KJ. 
Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition 
in human cancer. PLoS One. 2013 Oct 4;8(10):e76773. PMID: 24124593 
23. 
Mizutani K, Sud S, McGregor NA, Martinovski G, Rice BT, Craig MJ, Varsos ZS, Roca 
H, Pienta KJ. The chemokine CCL2 increases prostate tumor growth and bone 
metastasis through macrophage and osteoclast recruitment.  Neoplasia. 2009 
Nov;11(11):1235-42. PMCID: 2767225 
 
24. 
Mizutani K, Sud S, Pienta KJ. PCa promotes CD11b positive cells to differentiate into 
osteoclasts. J Cell Biochem. 2009 Mar 1;106(4):563-9. 
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Mizutani K, Roca H, Varsos Z, Pienta KJ. Possible mechanism of CCL2-induced Akt 
activation in PCa cells. Anticancer Res. 2009 Aug;29(8):3109-13. 
 


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26.  
van Golen KL, Ying C, Sequeira L, Dubyk CW, Reisenberger T, Chinnaiyan AM, Pienta 
KJ, Loberg RD. CCL2 induces PCa transendothelial cell migration via activation of the 
small GTPase Rac. J Cell Biochem. 2008 Aug 1;104(5):1587-97. 
27. 
Roca H, Varsos Z, Pienta KJ.  CCL2 protects PCa PC3 cells from autophagic death via 
PI3K/AKT-dependent survivin up-regulation. J Biol Chem. 2008 Sep 5;283(36):25057-
73.  PMID: 18611860 
28. 
Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, Meeker 
AK, Lucia MS, Anders RA, DeMarzo AM, Drake CG. Paucity of PD-L1 expression in 
prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 
2015 Dec;18(4):325-32.  PMID: 26260996 
29. 
Baena-Del Valle JA, Zheng Q, Esopi DM, Rubenstein M, Hubbard GK, Moncaliano MC, 
Hruszkewycz A, Vaghasia A, Yegnasubramanian S, Wheelan SJ, Meeker AK, Heaphy 
CM, Graham MK, De Marzo AM.  MYC drives overexpression of telomerase RNA 
(hTR/TERC) in prostate cancer. J Pathol. 2018 Jan;244(1):11-24. PMID: 28888037 
30. 
Berges RR, Vukanovic J, Epstein JI, et al. Implication of the cell kinetic changes during 
the progression of human prostatic cancer. Clin Cancer Res 1995; 1: 473-480. 
31. 
Rubin MA, Dunn R, Strawderman M, et al. Tissue microarray sampling strategy for 
prostate cancer biomarker analysis. Am J Surg Pathol 2002; 26: 312-319. 
 


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APPENDIX A:  PERFORMANCE STATUS CRITERIA 
            ECOG Performance Status Scale 
              Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue 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 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  
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled, cannot carry on any self-
care, totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 


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APPENDIX B:  COMMON TOXICITY CRITERIA, VERSION 4.0 
 
Adverse events will be described and graded using the NCI Common Toxicity Criteria (Version 
4.0). 
A copy of this document can be downloaded from the CTEP website 
(http://ctep.cancer.gov/forms). 
All treatment areas must have a copy of this document, or must be able to access a copy. 
 
In general, the grading system can be summarized as follows: 
 
 
Grade: 
Severity: 
Description: 
Grade 1 
Mild 
Transient or mild discomfort; generally non-progressive; no 
limitation in daily activities; no medical intervention required. 
Grade 2 
Moderate 
Mild/moderate limitation in daily activities; some assistance 
may be required; no/minimal medical intervention required. 
Grade 3 
Severe 
Marked limitation in daily activities; some assistance usually 
required; medical intervention is required. 
Grade 4 
Life-threatening 
Extreme limitation in daily activities; major assistance required; 
significant medical intervention required. 
Grade 5 
Death 
Death related to an adverse event. 
 
 


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APPENDIX C:  SERIOUS ADVERSE EVENT (SAE) REPORTING FORM 
 
 
Protocol Title: 
 
 
Neoadjuvant Anti-B7-H3 (DUPILUMAB) in Men with Localized High-Risk 
Prostate Cancer  
Protocol 
Number: 
 
 
Principal  
Investigator: 
 
 
Signature  
of PI: 
 
 
 
Date: 
 
 
 
Report Date: 
 
Hospital Admission Date: 
Date of Discovery of 
Event: 
 
 
Report Type: 
  Initial    
  Follow-up 
  Final Follow-
up 
  Death 
  Addendum to: 
 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
  Male 
  Female 
 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of DUPILUMAB 
Dose: 
 
Action taken regarding the study drugs: 
 
 None 
 Interrupted 
 Discontinued 
 
 
Event Onset Date: 
 
Event End Date: 
Relationship to: 
DUPILUMAB 
Underlying Disease 
 
Unrelated 
 
 
 
Probably Unrelated 
 
 
 
Possible Related 
 
 
 
Probably Related 
 
 
 
Definitely Related 
 
 
 
Section C: Brief Description of the Event: 


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Section D: Relevant Medical History 
 
 
 
 
Section E: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify  
 
 
 
 
 
 
 


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APPENDIX D:  ABBREVIATIONS AND ACRONYMS 
ACLS 
Advanced Cardiac Life Support 
ADR 
adverse drug reaction 
ADT 
androgen deprivation therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
APTT 
activated partial thromboplastin time 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
BCG 
bacillus Calmette-Guerin vaccine 
bid 
bis in die (twice a day) 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
⁰C 
degrees Celsius 
Ca++ 
calcium 
CBC 
complete blood count 
CD4+ T cells 
cluster determinant 4–positive T lymphocytes 
CD8+ T cells 
cluster determinant 8–positive T lymphocytes 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl− 
chloride 
cm 
centimeter 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRO 
Clinical Research Office 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CRRMC 
Clinical Research Review and Monitoring Committee 
CT 
computerized tomography 
CTL 
Cell Therapy Laboratory 
CTLA-4 
cytotoxic T lymphocyte-associated antigen 4 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DAB 
3,3′-diaminobenzine tetrahydrochloride 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DMSO 
dimethyl sulfoxide 


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DNA 
deoxyribonucleic acid 
DNase 
deoxyribonuclease 
DPBS 
Dubelcco's phosphate buffered saline 
DSMC 
data and safety monitoring committee 
DTH 
delayed-type hypersensitivity 
EC 
ethics committee 
ECOG 
Eastern Cooperative Oncology Group 
EMLA 
eutectic mixture of local anesthetics 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
G-CSF 
granulocyte-colony stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GnRH 
gonadotropin-releasing hormone  
HA 
hemagglutinin 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
HRPC 
hormone-refractory prostate cancer 
HSA 
human serum albumin 
HSB 
hue-saturation-brightness 
IBC 
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
ID 
intradermal 
IND 
investigational new drug 
INR 
international normalized ratio 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IV 
intravenous 
JHMI 
Johns Hopkins Medical Institutions 
K+ 
potassium 
LDH 
lactate dehydrogenase 
LHRH 
luteinizing hormone releasing hormone 
LNCaP 
AR-positive human prostate cancer cell line derived from a lymph node 
metastasis 
LOI 
letter of intent 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NA 
not applicable 
N/A 
not available 
NCI 
National Cancer Institute 
OR 
operating room 


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PI 
principal investigator 
PO 
per os (by mouth) 
PSA 
prostate-specific antigen 
PSMA 
prostate-specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
quaque die (every day) 
RP 
radical prostatectomy  
RT 
room temperature 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
standard deviation 
SKCCC 
Sidney Kimmel Comprehensive Cancer Center 
TdT 
terminal deoxynucleotidyl transferase 
tid 
ter in die (3 times a day) 
TMA 
tissue microarray  
TRAMP 
transgenic adenocarcinoma of the mouse prostate(mouse model) 
Tregs 
regulatory T lymphocytes 
TUNEL 
TdT-mediated deoxy uridine triphosphate (UTP) nick end-labeling assay 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia (sterile, hypotonic, nonpyrogenic water for 
injection) 
WBC 
white blood cell 


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APPENDIX E:  DATA AND SAFETY MONITORING PLAN (DSMP), Version 4.0 (9/22/11)