Clinical trial NCT04221828
Conditions: Prostate Cancer Prostate Adenocarcinoma Prostate Cancer Adenocarcinoma Prostatic Neoplasm Urogenital Neoplasms Genital Neoplasms, Male Localized Cancer
Keywords: paclitaxel
Sponsor: NanOlogy, LLC
Start date: 2020-10-20; Completion date: 2021-02-08
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the use of NanoPac injected directly into the prostate lesion in men with prostate cancer.

Detailed description:
NanoPac is very small (submicron) particles of the chemotherapy drug, paclitaxel, which is administered intravenously in a number of types of cancer. These submicron particles are injected directly into solid tumors to target cancer at the site of disease with less systemic exposure than intravenously administered chemotherapy. In this study, this submicron particle paclitaxel will be injected directly into the prostate lesion in men with prostate cancer scheduled for prostatectomy on up to three different occasions. All subjects in the study will receive NanoPac and will be evaluated to see if NanoPac is safe, well-tolerated, and has an impact on prostate cancer.

Arms: arm 1: Direct injection of NanoPac at 15 mg/mL at a volume not to exceed the volume of the prostate cancer lesion (no more than 10% of total prostate volume). NanoPac will be administered on up to three occasions, with at least 28 days between each dose.
Interventions: intervention 1: NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension
Intervention descriptions: intervention 1: NanoPac is manufactured using a Precipitation with Compressed Antisolvent (PCA) technique that employs supercritical carbon dioxide and acetone to generate paclitaxel nanoparticles. For clinical administration, the NanoPac powder in vial is suspended with Sterile Reconstitution Solution (1% Polysorbate 80, NF in 0.9% Sodium Chloride for Injection, USP) and then further diluted with 0.9% Sodium Chloride for Injection, USP, to achieve the final clinical formulation.

Protocol documents:
Prot_SAP_001.pdf: 
Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
NanOlogy, LLC 
Version 5.0 
8 Sep 2020 
CONFIDENTIAL 
 
Page 1 of 65 
 
Phase 2 Trial of NanoPac® Focal Therapy for Prostate 
Cancer in Subjects Undergoing Radical Prostatectomy  
 
Protocol Identifying Number:  NANOPAC-2019-01 
IND Sponsor:  NanOlogy, LLC 
Version Number:  5.0 
Date:  8 Sep 2020 
 
 
 
 
 
 
 
 
 
 
 
 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
NanOlogy, LLC 
Version 5.0 
8 Sep 2020 
CONFIDENTIAL 
 
Page 2 of 65 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................................................... 5 
SPONSOR SIGNATURE PAGE ............................................................................................................................... 7 
STATEMENT OF COMPLIANCE ............................................................................................................................. 8 
PROTOCOL SUMMARY ........................................................................................................................................... 9 
1 
KEY ROLES .................................................................................................................................................. 12 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 14 
2.1 
Background Information .................................................................................................................... 14 
2.2 
Rationale ............................................................................................................................................. 17 
2.3 
Potential Risks and Benefits ............................................................................................................ 18 
2.3.1 
Known Potential Risks ................................................................................................... 18 
2.3.2 
Known Potential Benefits .............................................................................................. 18 
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 18 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 19 
4.1 
Description of the Study Design ...................................................................................................... 19 
4.1.1 
Primary Objectives and Endpoints .............................................................................. 20 
4.1.2 
Secondary Objectives and Endpoints ......................................................................... 20 
4.1.3 
Exploratory Endpoints ................................................................................................... 20 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 20 
5.1 
Participant Inclusion Criteria ............................................................................................................ 20 
5.2 
Participant Exclusion Criteria ........................................................................................................... 21 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 21 
5.4 
Participant Withdrawal or Termination ............................................................................................ 22 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 22 
5.4.2 
Handling of Participant Withdrawals or Termination ................................................. 22 
5.5 
Premature Termination or Suspension of Study ........................................................................... 23 
6 
STUDY AGENT ............................................................................................................................................ 23 
6.1 
Study Agent(s) and Control Description ......................................................................................... 23 
6.1.1 
Acquisition ....................................................................................................................... 23 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 23 
6.1.3 
Product Storage and Stability ....................................................................................... 24 
6.1.4 
Preparation ...................................................................................................................... 24 
6.1.5 
Dosing and Administration ............................................................................................ 24 
6.1.6 
Route of Administration ................................................................................................. 25 
6.1.7 
Dose Adjustments/Modifications/Delays .................................................................... 25 
6.1.8 
Duration of Therapy ....................................................................................................... 25 
6.1.9 
Tracking of Dose ............................................................................................................ 25 
6.1.10 
Device Specific Considerations ................................................................................... 26 
6.2 
Study Agent Accountability Procedures ......................................................................................... 26 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 26 
7.1 
Study Procedures/Evaluations ......................................................................................................... 26 
7.1.1 
Study Specific Procedures ............................................................................................ 26 
7.1.2 
Standard of Care Study Procedures ........................................................................... 27 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 27 
7.2.1 
Clinical Laboratory Evaluations .................................................................................... 27 
7.2.2 
Other Assays or Procedures ........................................................................................ 28 


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7.2.3 
Specimen Preparation, Handling, and Storage ......................................................... 29 
7.2.4 
Specimen Shipment ....................................................................................................... 30 
7.3 
Study Schedule .................................................................................................................................. 30 
7.3.1 
Screening ........................................................................................................................ 30 
7.3.2 
Injection Procedure Visits ............................................................................................. 31 
7.3.3 
Follow-up ......................................................................................................................... 32 
7.3.4 
Second and Third Injections ......................................................................................... 32 
7.3.5 
Follow-up Visits .............................................................................................................. 33 
7.3.6 
Final Study Visit – End of Study Visit .......................................................................... 33 
7.3.7 
Prostatectomy ................................................................................................................. 34 
7.3.8 
Early Termination Visit .................................................................................................. 34 
7.3.9 
Unscheduled Visits ........................................................................................................ 34 
7.3.10 
Schedule of Events Table ............................................................................................. 36 
7.4 
Justification for Sensitive Procedures ............................................................................................. 40 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 40 
7.6 
Precautionary Medications, Treatments, and Procedures .......................................................... 40 
7.7 
Prohibited Medications, Treatments, and Procedures ................................................................. 40 
7.8 
Prophylactic Medications, Treatments, and Procedures ............................................................. 40 
7.9 
Rescue Medications, Treatments, and Procedures ..................................................................... 40 
7.10 
Participant Access to Study Agent At Study Closure ................................................................... 40 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 41 
8.1 
Specification of Safety Parameters ................................................................................................. 41 
8.1.1 
Definition of Adverse Events ........................................................................................ 41 
8.1.2 
Definition of Serious Adverse Events .......................................................................... 41 
8.1.3 
Definition of Unanticipated Problems .......................................................................... 42 
8.2 
Classification of an Adverse Event ................................................................................................. 42 
8.2.1 
Severity of Event ............................................................................................................ 42 
8.2.2 
Relationship to Study Agent ......................................................................................... 42 
8.2.3 
Expectedness ................................................................................................................. 43 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 43 
8.4 
Reporting Procedures ....................................................................................................................... 43 
8.4.1 
Adverse Event Reporting .............................................................................................. 43 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 43 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 44 
8.4.4 
Events of Special Interest ............................................................................................. 44 
8.4.5 
Dose Limiting Toxicity.................................................................................................... 45 
8.4.6 
Reporting of Pregnancy ................................................................................................ 46 
8.5 
Study Halting Rules ........................................................................................................................... 46 
8.6 
Safety Oversight ................................................................................................................................ 46 
9 
CLINICAL MONITORING ............................................................................................................................ 47 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 47 
10.1 
Statistical and Analytical Plans ........................................................................................................ 47 
10.2 
Statistical Hypotheses ....................................................................................................................... 47 
10.3 
Analysis Datasets .............................................................................................................................. 48 
10.4 
Description of Statistical Methods ................................................................................................... 48 
10.4.1 
General Approach .......................................................................................................... 48 


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10.4.2 
Analysis of the Primary Endpoint(s) ............................................................................ 48 
10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 48 
10.4.4 
Safety Analyses .............................................................................................................. 49 
10.4.5 
Adherence and Retention Analyses ............................................................................ 49 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 49 
10.4.7 
Planned Interim Analyses ............................................................................................. 49 
10.4.8 
Additional Sub-group Analyses .................................................................................... 50 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 50 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 50 
10.4.11 
Exploratory Analyses ..................................................................................................... 50 
10.4.12 
Concomitant Medication................................................................................................ 50 
10.5 
Sample Size ....................................................................................................................................... 50 
10.6 
Measures to Minimize Bias .............................................................................................................. 50 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 50 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 50 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 51 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 51 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 51 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 52 
13.1 
Ethical Standard ................................................................................................................................. 52 
13.2 
Institutional Review Board ................................................................................................................ 52 
13.3 
Informed Consent Process ............................................................................................................... 52 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants.... 52 
13.3.2 
Consent Procedures and Documentation .................................................................. 52 
13.4 
Participant and Data Confidentiality ................................................................................................ 53 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 53 
13.5 
Future Use of Stored Specimens .................................................................................................... 53 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 54 
14.1 
Data Collection and Management Responsibilities ...................................................................... 54 
14.2 
Study Records Retention .................................................................................................................. 54 
14.3 
Protocol Deviations............................................................................................................................ 55 
14.4 
Publication and Data Sharing Policy ............................................................................................... 55 
15 
STUDY ADMINISTRATION ........................................................................................................................ 56 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 56 
17  
LIABILITY AND INSURANCE .................................................................................................................... 56 
18  
LITERATURE REFERENCES.................................................................................................................... 57 
APPENDIX A: ECOG Performance Scale ............................................................................................................ 60 
APPENDIX B: Sexual Health Inventory for Men (SHIM) ..................................................................................... 61 
APPENDIX C: International Prostate Symptom Score (I-PSS) .......................................................................... 62 
APPENDIX D: NIH Chronic Prostatitis Symptom Index (NIH-CPSI) ................................................................. 63 
APPENDIX E: CYP3A4 Substrates, Inducers and Inhibitors ............................................................................. 64 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original and Accurate - Complete 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CLIA 
Clinical Laboratory Improvement Amendments 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture System 
EMR 
Electronic Medical Record 
EUS-FNI 
Endoscopic Ultrasound Guided Fine Needle Injection 
FCM 
Flow Cytometry 
FDA 
The U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIFU 
High Intensity Focused Ultrasound 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug Application 
IP 
Intraperitoneal 
I-PSS 
International Prostate Symptom Score Questionnaire 
IRB 
Institutional Review Board 
IRE 
Irreversible Electroporation 
ITU 
Intratumoral 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mpMRI 
Multiparametric MRI 
MRI 
Magnetic Resonance Imaging 
TRUS 
Transrectal Ultrasound Fusion 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
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8 Sep 2020 
CONFIDENTIAL 
 
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MR-TRUS 
Magnetic Resonance Imaging-Transrectal Ultrasound Fusion 
NCI 
National Cancer Institute 
NDA 
New Drug Application (Marketing Application) 
NIH-CPSI 
National Institute of Health Chronic Prostatitis Symptom Index 
NOAEL 
No Observed Adverse Events Level 
PCA 
Precipitation with Compressed Antisolvents 
PD 
Pharmacodynamic 
pH 
Hydrogen Ion Concentration 
PI 
Principal Investigator 
PI-RADS 
Prostate Imaging–Reporting and Data System 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PSA 
Prostate-Specific Antigen 
PSMA-PET 
Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) 
Imaging 
PT 
Prothrombin Time 
PTT 
Activated Partial Thromboplastin Time 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDLC 
Systems Development Life Cycle 
SHIM 
Sexual Health Inventory for Men Questionnaire 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TRUS 
Transrectal Ultrasound 
UP 
Unanticipated Problem 
USC 
University of Southern California 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 
 


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 Protocol NANOPAC-2019-01 
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SPONSOR SIGNATURE PAGE 
Protocol Title: 
Phase 2 Trial of NanoPac® Focal Therapy for Prostate Cancer in Subjects Undergoing 
Radical Prostatectomy  
Protocol Number: 
NANOPAC-2019-01 
Version Number:  
5.0 
Date: 
 
8 Sep 2020 
IND Number: 
 
132694 
Study Agent: 
 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension 
Sponsor: 
 
NanOlogy, LLC 
 
231 Bonetti Dr., Suite 240 
 
San Luis Obispo, CA 93401-7310 
 
805-595-1300 
 
The Sponsor for IND 132694, NanOlogy, LLC, has transferred responsibility for all obligations set forth in 21 CFR 
Part 312 to US Biotest, Inc., with regard to the IND; in accordance with 21 CFR Part 312, US Biotest, Inc., shall be 
considered the sponsor with regard to all activities related to the IND. 
 
SIGNATURE 
 
 
 - Name and Title: 
Gere diZerega, MD 
President & CEO, US Biotest, Inc. 
 
__________________________________________  
__________________________ 
 
 
 
Date 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
NanOlogy, LLC 
Version 5.0 
8 Sep 2020 
CONFIDENTIAL 
 
Page 8 of 65 
STATEMENT OF COMPLIANCE 
I have read the attached protocol number NANOPAC-2019-01 entitled, Phase 2 Trial of NanoPac® Focal Therapy 
for Prostate Cancer in Subjects Undergoing Radical Prostatectomy, Version 5.0 dated 8 Sep 2020 and agree to 
comply with the contents of this document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
This document is a confidential communication of US Biotest, Inc. The recipient agrees that no unpublished 
information contained herein will be published or disclosed without prior written permission of US Biotest. 
However, this document may be disclosed to appropriate institutional review boards, ethics review committees, or 
authorized representatives of the Investigator or of boards of health under the condition that they are requested 
to respect the confidentiality of the document. 
The signature of the Principal Investigator below constitutes his/her agreement. 
 
 
__________________________________________ __________________________ 
Signature of Principal Investigator  
 
Date 
 
 
__________________________________________ 
Printed Name of Principal Investigator 
 
 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
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8 Sep 2020 
CONFIDENTIAL 
 
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PROTOCOL SUMMARY 
Title: 
Phase 2 Trial of NanoPac® Focal Therapy for Prostate Cancer in Subjects Undergoing Radical 
Prostatectomy 
 
Précis: 
In this open-label, Phase 2 trial, 18 subjects with adenocarcinoma of the prostate will have 
NanoPac injected under image guidance directly into the dominant lesion in the prostate on 
up to three occasions, with at least 28 days between each dose, with a final study visit 
occurring 12 weeks, (Day 85), after the first injection.  NanoPac will be injected at 15 mg/mL 
concentration, and the total volume administered will be up to the volume of the dominant 
lesion (but not to exceed 10% of the total prostate volume); all study agent will be injected 
directly into the dominant lesion. The volume and dose of NanoPac administered at the 
second and/or third injection will be no greater than the first injection.  If there are any 
safety concerns, as assessed via individual and cumulative assessments conducted at routine 
intervals by the Medical Monitor, the dose concentration and/or volume may be reduced 
within and/or for future subjects.  
 
Tumor volume and serum prostate-specific antigen (PSA) will be determined prior to the first 
NanoPac injection.  
 
During the study the following will be collected/assessed: 
• 
Plasma samples for pharmacokinetic (PK) analysis,  
• 
Ejaculate for paclitaxel presence; 
• 
Blood for routine safety, PSA levels, and flow cytometric (FCM) analysis at intervals; 
• 
Imaging with multiparametric MRI (mpMRI) [Screening and End of Study visits]; 
• 
Imaging of the pelvic lymph nodes may be performed via PSMA-PET scan [Screening 
and End of Study visits]; this is an optional study assessment. 
• 
Prostatectomy (previously scheduled) will occur approximately 92 days post first 
injection: 
o 
 If a prostatectomy is not performed a biopsy will be obtained for clinical 
re-staging of the disease;  
o 
At the time of prostatectomy or biopsy, a tissue sample will be obtained for 
evaluation of immune response via immunohistochemistry; 
o 
Samples of the dominant lesion, ipsilateral lobe of the prostate, 
contralateral lobe of the prostate, and lymph nodes will be collected during 
prostatectomy 
 
Objectives: 
 
Primary objectives:  
• 
To determine the safety and tolerability of up to three intratumoral (ITU) injections, 
with at least 4 weeks between each injection; and  
• 
To determine tumor response to up to three ITU injections of NanoPac, with at least 
4 weeks between each injection. 
 
 
Secondary objectives: 
• 
To evaluate the effects on the tumor of up to three ITU injections of NanoPac, with 
at least 4 weeks between each injection; 
• 
To describe the PK of up to three ITU injections of NanoPac, with at least 4 weeks 
between each injection. 
 
Endpoints: 
The primary endpoints will be: 
• 
Safety and tolerability, as demonstrated by: adverse events (AEs), changes in 
laboratory assessments, physical examination findings, and vital signs; 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
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• 
Tumor response as demonstrated by:  
o 
Gleason score of dominant lesion measured at prostatectomy/biopsy 
compared to Screening (baseline – obtained prior to Day 1) as determined 
from tissue/biopsy samples; 
o 
Change in proportion of dominant lesion designated as adenocarcinoma at 
prostatectomy/biopsy compared to Screening (baseline – obtained prior to 
Day 1)  as determined from tissue/biopsy samples. 
o 
Proportion of subjects with local invasion at the Final study visit (Day 85) 
compared to Screening (baseline – obtained prior to Day 1) as measured by 
mpMRI. 
 
Secondary endpoints: 
a) Effects on the tumor: 
o 
Change in volume of dominant lesion measured at final study visit (Day 85) 
compared to Screening (baseline – obtained prior to Day 1) as measured by 
mpMRI. 
o 
Change in PSA Density measured at final study visit (Day 85) compared to 
Screening (baseline – obtained prior to Day 1)  
o 
Change in PI-RADS score measured at final study visit (Day 85) compared to 
Screening (baseline – obtained prior to Day 1)  
b) Concentration of paclitaxel in the systemic circulation post-injection; 
c) Presence or absence of paclitaxel in ejaculate. 
d) Presence or absence of paclitaxel in the dominant (injected) tumor within the 
prostate, the ipsilateral lobe of the prostate, the contralateral lobe of the prostate, 
and pelvic lymph nodes excised during prostatectomy (as applicable). 
Exploratory endpoints: 
a) Changes in Patient Reported Outcomes (PROs) between baseline and final study 
visit, as measured by the Sexual Health Inventory for men (SHIM), the International 
Prostate Symptom Score (I-PSS), and the National Institute of Health Chronic 
Prostatitis Symptom Index (NIH-CPSI);  
b) Flow cytometric (FCM) evaluation of immune markers in blood samples obtained 
following NanoPac injection: 
c) Determination of immune response in the prostate lesion due to NanoPac injection 
by immunohistochemical (IHC) staining and evaluation of the end of study 
tissue/biopsy samples; 
 
Population: 
Eighteen (18) men with prostate cancer 
 
Phase: 
Phase 2 
 
Number of 
Sites Enrolling 
Participants: 
Up to five (5) 
Description of 
Study Agent: 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (“NanoPac”) for direct 
injection into the dominant lesion at a concentration of 15 mg/mL in an injection volume of 
up to the volume of the dominant lesion (not to exceed 10% of total prostate volume). 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
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8 Sep 2020 
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Study Duration: 
The study duration will be up to 18 months. 
 
Participant 
Duration: 
The study duration is estimated to be approximately 14 weeks for each subject. Additional 
follow-up may occur. 
 
 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2019-01 
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1 
KEY ROLES 
Medical Director 
Gere diZerega, MD 
Professor, University of Southern California (USC) Keck School of Medicine 
President & CEO, US Biotest, Inc. 
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-630-2800 
gere.dizerega@usbiotest.com 
Study Director 
Shelagh Verco, PhD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-704-1179 
shelagh.verco@usbiotest.com 
 
Medical Monitor 
Antony Verco, MD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-762-4615 
tony.verco@usbiotest.com 
Laboratory – PK Samples 
Covance Madison Laboratories Bioanalytical (BA) Group  
3301 Kinsman Blvd, Madison, WI 53704, U.S.A. 
608-442-8200 
Laboratory – Prostate Tissue and Ejaculate Paclitaxel Concentration 
Covance Madison Laboratories Bioanalytical (BA) Group 
3301 Kinsman Blvd, Madison, WI 53704, U.S.A. 
608-442-8200 
Central Laboratory – Immunohistochemistry on Biopsies and Tumor Tissue 
NeoGenomics Laboratories, Inc. 
Attn: Pharma Services Department 
31 Columbia  
Aliso Viejo, CA 92656 
Phone: 949-445-7300 x7103 
Central Laboratory – FCM evaluation on whole blood 
NeoGenomics Laboratories, Inc. 
Attn: Pharma Services Department 
31 Columbia  
Aliso Viejo, CA 92656 
Phone: 949-445-7300 x7103 


Phase 2 Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
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8 Sep 2020 
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Laboratory – Routine Hematology and Biochemistry 
Institution for individual sites 
 
 


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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
The Sponsor for IND 132694, NanOlogy, LLC, has transferred responsibility for all obligations set forth in 21 CFR 
Part 312 to US Biotest, Inc., with regard to the IND. In accordance with 21 CFR Part 312, US Biotest, Inc., shall be 
considered the sponsor with regard to all activities related to the IND. Therefore, references to “Sponsor” 
hereafter in this protocol refer to US Biotest, Inc. 
Name and description of study agent: 
Under IND 073529, NanOlogy, LLC has produced a formulation of nanoparticulate paclitaxel, identified as 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (“NanoPac”), which is the subject of this 
protocol. US Biotest, Inc. (“US Biotest”) is developing NanoPac for the investigational treatment of 
adenocarcinoma of the prostate via direct injection. NanoPac, previously called Nanotax®, is manufactured using a 
Precipitation with Compressed Antisolvent (PCA) technique that employs supercritical carbon dioxide and acetone 
to generate paclitaxel nanoparticles within a well-characterized particle-size distribution. Following PCA, NanoPac 
is filled into 60 mL Type 1, USP, clear-glass vials (306 mg/vial), each of which is closed with a bromobutyl rubber 
stopper and aluminum crimp seal, and sterilized by gamma irradiation. Prior to administration at the 
hospital/clinic, NanoPac will be reconstituted with 1% Polysorbate 80, NF in 0.9% Sodium Chloride for Injection, 
USP, to form a suspension. The suspension will be further diluted with 0.9% Sodium Chloride for Injection, USP to 
achieve the final clinical formulation. This reconstitution and dilution will occur at the clinical site’s pharmacy. 
Nonclinical Summary: 
US Biotest has completed two nonclinical pharmacology studies of NanoPac in the PC-3 human prostate carcinoma 
nude mouse tumor xenograft model, Study PC3-e317 and Study PC3-e319. Results for all NanoPac-treated animals 
were indicative of potential therapeutic activity. Additional data is presented in the NanoPac Investigator’s 
Brochure. 
In Study Number P-PPr-01-2015, NanoPac 37.5 mg/kg, qwk x 1 dose; 12.5 mg/kg, qwk x 3 doses; and 37.5 mg/kg, 
qwk x 3 doses were compared to vehicle and paclitaxel 30 mg/kg, qwk x 3 doses. Treatments with NanoPac and 
vehicle were by intratumoral (ITU) injection. Treatment with either a single dose or three once-weekly doses of ITU 
NanoPac resulted in identical survival extension and an increased number of study survivors/regressions compared 
to vehicle. Dose dependent response could not be determined as dosing with NanoPac at 12.5 or 37.5 mg/kg qwk x 
3 produced the maximum survival extension attainable in the study.  
In Study Number PD-PPr-02-2016, the efficacy of NanoPac was evaluated as part of a NanoDoce (sterile 
nanoparticulate docetaxel) trial in female NCI Ath/nu mice. NanoPac was administered ITU injection at a dose of 
37.5mg/kg qwk x 3 doses, and compared to vehicle (ITU), NanoDoce (ITU) 100mg/kg qwk x 1 dose, 37.5mg/kg qwk 
x 3 doses, and 100mg/kg qwk x 3 doses, and docetaxel 30mg/kg IV qwk x 3 doses. NanoPac reduced mean tumor 
volume by 74.1% by Day 22 compared to vehicle. Body weights for all groups remained stable or increased 
throughout the treatment phase. 
In a GLP toxicity and toxicokinetic (TK) study (Study Number P-TR-06-2018) evaluating a single injection of NanoPac 
into the prostate of rats at 4 mg/mL (1.9-2.2 mg/kg), 10 mg/mL (4.7-5.5 mg/kg), or 40 mg/mL (18.2-21.6 mg/kg) at 
a fixed volume of 0.18 mL, at the terminal interval on Day 4, findings of necrosis with mixed inflammation and 
fibrin deposition were noted in the prostate, with mineralization (kidneys), and mixed inflammation and fibrin 
deposition (urinary bladder, seminal vesicles and iliac lymph nodes) noted in the adjacent tissues. At the recovery 


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interval on Day 28 (± 1), similar findings were observed, with partial/ongoing to complete resolution. Based on the 
study findings, 18.2-21.6 mg/kg (40 mg/mL) was considered the NOAEL, with an associated AUC0-672 of 
517 ng⋅hr/mL.  
Clinical Summary: 
Two clinical studies with NanoPac have been completed. Additional data from these clinical trials is presented in 
the NanoPac Investigator’s Brochure. Ongoing clinical trials using NanoPac include direct injection to pancreatic 
tumors via endoscopic ultrasound guided fine needle injection (EUS-FNI) (NCT03077685) and injection of NanoPac 
into mucinous cystic neoplasms of the pancreas by EUS-FNI (NCT03188991). 
Phase 2a Study in Prostate Cancer 
A Phase 2a study of NanoPac focal therapy of prostate cancer, NANOPAC-2016-02 (NCT03077659), was completed. 
Subjects received intraprostatic injection of NanoPac at 6, 10, and 15 mg/mL in an injection volume of 20% of the 
lobe of the prostate containing the dominant lesion, and were followed for 4 weeks for safety and tolerability prior 
to prostatectomy. 
The primary objective of the study was to evaluate the safety and tolerability of NanoPac when injected into the 
lobe of the prostate containing the dominant lesion. Sixteen subjects were enrolled and received study agent 
according to the protocol. The majority of subjects experienced treatment emergent adverse events (TEAEs) as 
expected, but with minimal frequency, severity, and relation to NanoPac. Overall, the most frequent TEAEs 
occurred in the system organ class (SOC) of gastrointestinal disorders, most of which were in the 6 mg/mL cohort. 
There was no obvious dose-response relationship with respect to the frequencies of the TEAEs at the three 
concentrations of NanoPac. Compared to Taxol, no dose-limiting toxicities (DLTs) or toxicities typically attributable 
to paclitaxel such as neutropenia, thrombocytopenia, peripheral neuropathy, and hypersensitivity reactions such 
as angioedema and urticaria were reported. There were no serious adverse events (SAEs), deaths, or 
discontinuations from the study due to adverse events (AEs).  
Pharmacokinetic (PK)/pharmacodynamic (PD) modeling of Taxol-induced neutropenia suggests toxicity is related to 
the duration and extent of systemic exposure to paclitaxel which correlates with a threshold plasma paclitaxel 
concentration of ≥ 42.7 ng/mL; in contrast, plasma paclitaxel concentrations observed with NanoPac had Cmax 
values of 19 to 20 ng/mL recorded at the earliest sample viz. the 1-hour timepoint. By comparison, a standard 
intravenous (IV) dose of paclitaxel of 175mg/m2 BSA administered over 3 hours resulted in a Cmax of 3,650 ng/ml 
(Paclitaxel Drug Label Information – Teva), about 192x higher than the mean NanoPac concentration achieved in 
the 15mg/mL cohort 1 hour after injection. In alignment with this, from a toxicity and safety perspective, 
intraprostatic injection of NanoPac appears to have a better risk profile compared to IV Taxol administration. The 
original hypothesis of NANOPAC-2016-02, that direct injection of NanoPac into the prostate would result in 
limited, if any, systemic exposure to paclitaxel and should therefore result in only low-grade and transitory AEs is 
therefore supported by the safety findings in the study. 
The secondary objectives of the study were to evaluate 1) tumor response as determined by change in image 
volume on multiparametric MRI (mpMRI) and histologic evaluation via biopsy; 2) the presence of tumor cells in the 
tumor within the prostate, the ipsilateral lobe of the prostate, the contralateral lobe of the prostate, and pelvic 
lymph nodes excised during prostatectomy; 3) the concentration of paclitaxel in the systemic circulation post-
injection and prior to prostatectomy; 4) the presence of paclitaxel in the tumor within the prostate, the ipsilateral 
lobe of the prostate, the contralateral lobe of the prostate, and pelvic lymph nodes excised during prostatectomy; 
and 5) assess the effects of NanoPac on sexual health, urination, and symptoms of chronic prostatitis as measured 


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by the Patient Reported Outcomes (PROs) Sexual Health Inventory for men (SHIM), International Prostate 
Symptom Score (I-PSS), and National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI).  
Due to the small size of the study and the natural slow rate of progression of prostate cancer, the majority of the 
individual outcomes showed no changes or variable results across the three concentrations of NanoPac over 4 
weeks of exposure to NanoPac. The mean volume of the prostate increased between the time of injection and 
prostatectomy, likely due to the local inflammatory reaction generated by NanoPac. Reflecting this, the sexual 
health as measured by the SHIM deteriorated over the course of participation, which can be explained by the 
increased local pressure effects created by the increased prostate volume.  
Notably, the mean total Gleason score remained stable in the 6 mg/mL and 10 mg/mL cohorts, and improved in 
the 15 mg/mL cohort, implying a possible dose-response relationship. The proportion of the primary lesion 
considered adenocarcinoma improved in the 6 mg/mL and 15 mg/mL cohorts, but increased in the 10 mg/mL 
cohort.  When defining efficacy as stable or improved Gleason score, stable or improved proportion of tissue 
considered adenocarcinoma, or stable or improved evidence of local invasion, 1) 13 of 16 subjects had stable or 
improved Gleason scores (all in the 15 mg/mL cohort); 2) 11 of 16 subjects had stable or improved proportions of 
cancer lesion tissue defined as adenocarcinoma (6 of 11 subjects showed reductions in proportion of tissue 
identified as adenocarcinoma while 5 showed no change); and 3) 11 of 16 subjects had stable or improved levels of 
invasion by the cancerous tissue (4 of the 11 subjects showed less invasion into the surrounding tissues, while 7 
subjects showed stable disease). 
When combining the same three parameters above, and defining an improvement in those parameters as a 
weighted positive response in the following manner, 1) if one parameter is improved and the other two 
parameters are stable, then the subject is deemed to have improved, 2) if two parameters improved and the 
remaining parameter remained stable or deteriorated, then the subject is deemed to have improved, or 3) if one 
parameter improved and one deteriorated, the subject is deemed stable and not an improvement, then 6 (60%) 
subjects in the 15 mg/mL cohort improved compared to baseline, whereas 1 (33.3%) subject in each of the 6 
mg/mL and 10 mg/mL cohorts improved. 
Overall, the primary objective of the study was achieved, i.e. preliminary evidence indicates that direct injection of 
NanoPac into the prostate appears safe and tolerable.  The limited duration and size of the study prevents 
definitive evaluation of efficacy, but outcomes warrant further development of NanoPac as a focal therapy for 
prostate cancer.  
Phase 1 Study in Peritoneal Malignancies 
A Phase 1 study of intraperitoneal (IP) NanoPac in subjects with peritoneal malignancies, HSC#11140 
(NCT00666991) was completed. The results of this study were published by Williamson 2015 in the journal Cancer 
Chemotherapy and Pharmacology. 
HSC#11140 was a dose-escalating study evaluating IP administered Nanotax (the same drug as NanoPac, but under 
a different name) at doses of 50-275 mg/m2 given every 28 days until disease progression or unacceptable toxicity 
occurred. Twenty-two subjects were enrolled in the study. IP administration of NanoPac did not lead to increases 
in systemic toxicity over that typically associated with IV paclitaxel. No Grade 2 or higher neutropenia and/or 
Grade 3 or higher neurologic toxicities were reported. Grade 3 thrombocytopenia, considered unlikely to be 
related to study agent, occurred in one subject. The peritoneal concentration-time profile of paclitaxel rose during 
the two days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug 
concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16 


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of the 21 subjects. Four subjects were assessed as stable or had no response and 12 subjects had progressive 
disease. Five of 21 subjects with advanced cancers survived longer than 400 days after initiation of IP NanoPac 
treatment.  
Relevant Literature: 
Several authors have reported results from human trials involving intraprostatic injection of various agents (such 
as viral vectors) for the treatment of local prostate cancer (DeWeese 2001; Johannsen 2007a; Johannsen 2007b; 
Finkelstein 2012; Trudel 2003; Pisters 2004; Gulley 2013; Kramer 2001; Sonpavde 2011; Patel 2009; Shalev 2000; 
Fujita 2006; Belldegrun 2001; van der Linden 2005; Freytag 2002).  
Reports of IV administration of paclitaxel, often in combination with other agents and/or radiotherapy, have 
demonstrated efficacy for the treatment of locally advanced and metastatic prostate cancer (Sanfilippo 2008; 
Hudes 1997; Shepard 2009; Sewak 2010; Hussain 2012; Urakami 2002; Berry 2004; Hudes 1995).  
Importance of the study: 
Prostate cancer is the second most common cancer in men, second only to non-melanoma skin cancer. Despite the 
high prevalence of the disease, it is a constantly-evolving area of medicine, presenting difficult decisions for 
patients and healthcare providers. At present, treatment for prostate cancer consists primarily of either of two 
options:  active surveillance or radical whole-gland therapy. However, this dichotomy fails to reflect the 
heterogeneity of prostate cancer and the nuanced patient experience. Due, in part, to the widespread adoption of 
PSA as a screening tool, more men are being diagnosed with lower-risk, lower-grade cancer. Active surveillance 
may be an appropriate choice for some of these men, as radical whole-gland therapy risks life-altering 
consequences, such as impotence and incontinence. This is supported by the statistic that 49% of men undergoing 
radical prostatectomy are found to have only insignificant or indolent cancer. Nonetheless, prostate cancer has the 
fourth highest mortality rate of any cancer, and 73% of patients initially enrolled on active surveillance who 
ultimately undergo prostatectomy are found to have a significant cancer (Marshall 2015). As such, active 
surveillance not only risks disease progression, but can be psychologically distressing to patients.  
Focal therapy has emerged as a middle ground for prostate cancer treatment. Focal therapy treats localized 
prostate cancer while minimizing treatment-induced damage to adjacent structures. The goal of focal therapy is to 
maintain disease control at acceptable levels while preserving erectile, urinary, and rectal function by avoiding 
damage to the neurovascular bundles, external sphincter, bladder neck, and rectum (Miano 2015). Commonly 
used modalities for focal therapy include cryotherapy, high intensity focused ultrasound (HIFU), irreversible 
electroporation (IRE), photodynamic therapy, and interstitial laser ablation. Aided by advanced imaging techniques 
to locate and target index tumors, focal therapy may be appropriate as an alternative or adjuvant to radical whole-
gland therapies such as prostatectomy in certain patients with prostate cancer (Mendez 2015). 
2.2 
RATIONALE  
This Phase 2 study will include subjects with adenocarcinoma of the prostate scheduled to undergo prostatectomy. 
The study design allows for a safety evaluation of ITU injection of NanoPac into a prostate tumor as focal therapy 
prior to prostatectomy. NanoPac will be injected on up to three occasions 4 weeks (28 days) apart, with 
prostatectomy scheduled approximately 13 weeks (92 days) after the first injection. The proliferative kinetics of 
prostatic cancer are known to be slow and variable both within a tumor and between different Gleason grades 
(Werehera 2011).  It is hypothesized that the period between first injection and prostatectomy is sufficient for 
initial indications of efficacy.  


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The prior clinical trial (NANOPAC-2016-02) evaluating a single intraprostatic injection of NanoPac concentrations 
up to 15 mg/mL showed systemic Cmax concentrations about 0.5% of that of a standard 175mg/m2 IV dose 
administered over 3 hours. We hypothesize that direct injection of NanoPac into the prostate tumor on three 
separate occasions 28 days apart will result in limited systemic exposure to paclitaxel and should therefore result 
in only low-grade and transitory AEs. 
A growing body of evidence supports the use of focal therapy for certain patients with prostate cancer. Existing 
focal therapies have demonstrated inconsistent efficacy and some risk of urinary and erectile complications. 
Taxanes, such as docetaxel and paclitaxel, have demonstrated antitumor activity against prostate cancer in vitro 
and in vivo (Axiak-Bechtel 2013, Shikanov 2008; van Soest 2015). Direct injection, as opposed to IV administration, 
of paclitaxel would allow for higher concentrations of drug to target local disease with reduced systemic toxicity. 
Direct injection of NanoPac to the tumor within the prostate is expected to be more effective than IV paclitaxel 
due to prolonged intraprostatic residence and dissolution, resulting in continuous and greater paclitaxel 
concentrations in the tumor site. 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
In the initial clinical study of intraprostatic NanoPac (NANOPAC-2016-02), no significant side effects considered 
related to NanoPac were reported. Nonclinical testing indicates that intraprostatic injection may lead to 
enlargement of the prostate which may cause urinary outflow obstruction.  
2.3.2 KNOWN POTENTIAL BENEFITS  
The initial clinical study of intraprostatic NanoPac (NANOPAC-2016-02) showed some positive indications of 
potential therapeutic activity. In two nonclinical studies of NanoPac in the PC-3 human prostate carcinoma nude 
mouse xenograft model, results for all NanoPac-treated animals were indicative of potential therapeutic activity. 
Paclitaxel, the active pharmaceutical ingredient of NanoPac, is effective in the IV treatment of metastatic prostate 
cancer. Additional data is presented in the NanoPac Investigator’s Brochure. 
3 
OBJECTIVES AND PURPOSE 
 
The primary objective of this study is to evaluate the safety and tolerability of NanoPac injections, and to evaluate 
the tumor response to NanoPac injected directly into the prostate tumor on up to three separate occasions 4 
weeks (28 days) apart, in subjects diagnosed with prostate cancer and planning prostatectomy.  
The secondary objectives are to assess the effects on the tumor, including changes on mpMRI parameters, PSA 
Density and PI-RADS after NanoPac injections; and to describe the PK of NanoPac injected directly into the tumor. 
In addition, changes in PROs by means of questionnaires will be assessed, immunohistochemistry (IHC) will be 
evaluated on the excised tissue and lymph nodes (as available), and FCM will be performed on blood samples to 
ascertain changes in immunologic response. 
 
 


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4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
The proposed study is a Phase 2, open-label trial in 18 subjects with localized prostate cancer scheduled for 
prostatectomy. Subjects will have NanoPac injected under image-guided transrectal ultrasound (e.g. magnetic 
resonance imaging-transrectal ultrasound fusion [MR-TRUS]) or via transperineal injection with ultrasound, directly 
into the dominant lesion of the prostate cancer on up to three separate occasions 4 weeks (28 days) apart. 
NanoPac will be administered at a concentration of 15 mg/mL to all subjects, and the total volume available for 
administration will be the same volume as the volume of the lesion as determined by mpMRI prior to first 
injection, but not to exceed 10% of the total prostate volume. The same volume and dose of NanoPac will be 
available for administration at the second and third injection. Subjects will be scheduled to undergo radical 
prostatectomy approximately 92 days (13 weeks) after the first injection of NanoPac.  
Prior to study entry, subjects will have undergone ultrasound-guided prostate biopsy to diagnose and stage 
prostate cancer. This biopsy will be used to identify the dominant lesion, which is defined as the lesion with the 
highest Gleason score. The volume of the prostate and the volume of the lesion to be treated will be calculated 
based on an mpMRI scan conducted prior to study participation; if not available, an mpMRI will be conducted to 
obtain details prior to first injection. 
The patient population includes subjects with localized cancer scheduled for prostatectomy who are classified as 
<T3 per TNM classification, Gleason score ≥ 6. The prostate tumor must be able to be visualized on mpMRI. 
Prostate tissue and biopsies will be obtained at the time of prostatectomy (Day 92).  If prostatectomy is delayed 
for any reason, a biopsy will still be performed for tumor restaging.   If prostatectomy is not significantly delayed, 
the biopsy can be taken when the delayed prostatectomy occurs.  If the prostatectomy has been cancelled, the 
biopsy should be taken as planned.  The biopsy location will aim to be same location as the pre-study biopsy for 
comparison purposes.  Routine processing for histopathology will be performed at the local institution and a 
portion of the biopsy material will be provided on slides to a central laboratory for IHC staining and reporting. 
The PK of NanoPac to determine the systemic exposure to paclitaxel will be evaluated at each visit from the day of 
first injection. Ejaculate samples provided during the study will also be evaluated for the presence or absence of 
paclitaxel. 
Blood samples for FCM evaluation will be obtained prior to the first NanoPac injection on Day 1, at the visit on 
Days 15, 43, and 71, and again at the final clinic visit on Day 85 to assess for any immune response detectable in 
the blood.  If Day 43 is an injection visit for a subject, the sample is to be taken prior to NanoPac injection.   
The presence or absence of paclitaxel in the dominant (injected) lesion, ipsilateral lobe, contralateral lobe, and 
regional lymph nodes will be evaluated from the prostatectomy samples (as applicable).  
 
 


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4.1.1 PRIMARY OBJECTIVES AND ENDPOINTS 
  
1. Safety and tolerability as demonstrated by: 
a. AEs, changes in laboratory assessments, physical examination findings, and vital signs. 
 
2. Tumor response as demonstrated by:  
a. Gleason score of dominant lesion measured at prostatectomy/biopsy compared to Screening 
(baseline – obtained prior to Day 1) as determined from tissue/biopsy samples. 
b. Change in proportion of dominant lesion designated as adenocarcinoma at 
prostatectomy/biopsy compared to Screening (baseline – obtained prior to Day 1) as determined 
from tissue/biopsy samples. 
c. 
Proportion of subjects with local invasion at the Final study visit (Day 85) compared to Screening 
(baseline – obtained prior to Day 1) as measured by mpMRI. 
4.1.2 SECONDARY OBJECTIVES AND ENDPOINTS 
The secondary endpoints will be: 
1. Further assessment of effects on the tumor, as demonstrated by: 
a. Change in volume of dominant lesion measured at final study visit (Day 85) compared to 
Screening (baseline – obtained prior to Day 1) as measured by mpMRI. 
b. Change in PSA Density measured at final study visit (Day 85) compared to Screening (baseline – 
obtained prior to Day 1)  
c. 
Change in PI-RADS score measured at final study visit (Day 85) compared to Screening (baseline – 
obtained prior to Day 1)  
2. PK evaluation: 
a. Concentration of paclitaxel in the systemic circulation post-injection;  
b. Presence or absence of paclitaxel in the ejaculate at Days 15, 43, 57, end of study Day 85; and 
c. 
Presence or absence of paclitaxel in the dominant (injected) tumor within the prostate, the 
ipsilateral lobe of the prostate, the contralateral lobe of the prostate, and pelvic lymph nodes 
excised during prostatectomy (as applicable). 
 
4.1.3 EXPLORATORY ENDPOINTS 
 
1. Changes in PROs between baseline and end of study Day 85, as measured by the SHIM, the I-PSS, and the 
NIH-CPSI;  
2. FCM evaluation of immune response in blood samples following NanoPac injection(s); 
3. Determination of immune response in the prostate lesion due to NanoPac injection by IHC staining and 
evaluation of the end of study biopsy; 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Subjects who meet the following criteria will be considered eligible for participation in the study: 


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• 
At least 18 years of age; 
• 
Histopathologically proven adenocarcinoma of the prostate: 
o 
Localized cancer; 
o 
Subjects with tumors classified as <T3 per TNM classification, Gleason score ≥ 6;  
• 
Prostate tumor must be able to be visualized on mpMRI; 
• 
Already considered to be candidate for radical prostatectomy 
• 
Considered appropriate for treatment with paclitaxel therapy;  
• 
Laboratory requirements:  
o 
WBC >2500/mm3 
o 
Neutrophil >1500/mm3 
o 
Hemoglobin >10 mg/dL 
o 
Platelet >100,000/ mm3 
o 
AST and ALT <2.5 x ULN 
o 
Total bilirubin <1.5 x ULN 
o 
Calculated Creatinine Clearance ≥ 30 ml/min 
o 
Normal PT/INR and PTT; 
• 
ECOG of 0 or 1; 
• 
International Prostate Symptom Score (I-PSS) ≤ 20; 
• 
If sexually active, willing to use double condoms from time of NanoPac injection until prostatectomy; 
• 
Agree to all study procedures and provide signed informed consent; 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
If a subject meets any of the following criteria, he must be excluded from the study: 
• 
Evidence of locally advanced or metastatic disease; 
• 
Prostate size ≥ 50 cc; 
• 
Prior prostatectomy, including surgery for any benign condition (such as TURP); 
• 
Anticipated use of concomitant chemotherapy (other than the protocol specified agents), 
immunotherapy, or systemic use of hormonal therapy (such as GnRH analogs, antiandrogens, androgen 
receptor inhibitors, and 5-α reductase inhibitors) while on study prior to surgery; 
• 
Treatment with a prior investigational medication within 30 days of first dose of study agent; 
• 
Any previous local treatment of the prostate (e.g. radiation, HIFU, cryotherapy, Focal Irreversible 
Electroporation, Photodynamic Therapy, Laser Induced Thermometry);  
• 
Any other condition (e.g., psychiatric disorder) that, in the opinion of the Investigator, may interfere with 
the subject’s ability to comply with the study requirements or visit schedule; 
• 
Known sensitivity to any of the study agent components; 
• 
History of prior malignancy that has not been in remission for >5 years, with the exception of basal cell or 
squamous cell carcinoma. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sufficient subjects will be screened to allow for up to 18 subjects to be enrolled in the trial. It is not anticipated 
that any advertising will be required for recruiting to the study.  


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Subjects will be recruited from the Investigators’ clinics and confirmed suitable for Screening (have confirmed 
prostate cancer prior to consenting to the study), screened for eligibility, and will proceed to treatment in 
accordance with the protocol.  
Accrual of subjects is expected to occur over a period of at least 6 months. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from participation in the study at any time upon request. Their reason for 
wanting to withdraw will be documented in the source notes and in the Electronic Data Capture system (EDC). 
• 
A subject who is not suitable to be treated will be withdrawn prior to Day 1, and therefore in all study 
documentation this subject would be considered a screenfail subject. Reasons for failing the screening will 
be documented. 
• 
Subjects may be non-compliant with the study protocol in a way that much of the data is not captured 
which would usually require withdrawal for non-compliance. However, every attempt will be made to 
ensure the subject does come for surgery, and any data points missed would be considered “missing 
data.” A subject would not be withdrawn in this situation. 
• 
Clinical AEs, laboratory abnormalities, or other medical conditions/situations may occur which would 
usually require withdrawal from a study. In this instance it is very important that all of these events be 
captured, followed, and documented, and therefore a subject would not be withdrawn but would 
continue to completion. 
Should the Investigator feel it to be in the best interest of the subject for them to be withdrawn from the study, 
the Investigator will immediately contact the Medical Monitor to discuss the reasons for withdrawal. 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
The Sponsor should be notified immediately when a subject is removed or withdrawn from the study after 
treatment with study agent, as every attempt should be made to capture as much information following treatment 
as possible.  
In the event a subject is withdrawn, they would undergo final study visit evaluations (End-of-Study evaluations) 
(see Section 7.3.8 Early Termination Visit).  
Subjects that refuse or fail to appear for clinic visits and fail to respond to or cooperate with reasonable and 
diligent attempts at contact should not be discontinued from the study unless they fail to present themselves for 
surgery. In the event a subject is unable to be contacted and subsequently does not appear for surgery they should 
be considered lost-to-follow-up. Reasonable and diligent attempts such as dates and content of phone calls, emails 
and registered mail should be recorded in the subject’s record. 
If a subject repeatedly misses study visits or remains non-compliant between the time of NanoPac injection and 
prostatectomy, and where the majority of data is not available, the option to replace that subject exists; however, 
the data that is collected from the non-compliant subject may still be used in the evaluations in this study. 


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5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for the study suspension or termination, will be provided by the 
suspending or terminating party to the other party. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform the Institutional Review Board (IRB) and will provide the reasons for 
the termination or suspension. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants; 
o 
Routine Medical Monitoring determining a safety concern requiring discussion with the Medical 
Director and with the PI may result in termination of study based on unacceptable risk, which will 
consider all safety evaluations and DLTs.   
• 
Insufficient compliance with protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable. 
In the event the study is temporarily suspended, the study may resume once concerns about safety, protocol 
compliance, and data quality are addressed and satisfy the Sponsor, IRB, and/or Food and Drug Administration 
(FDA).  
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
NanoPac will be manufactured by CritiTech, Inc. and provided for use in this study. Study agent will not be shipped 
to the study site until all regulatory documentation has been provided by the site, at which time the study agent 
will be released for shipment. Shipment will be via courier, temperature controlled 59˚ to 86˚F (15˚ to 30˚C), and 
will occur prior to site initiation. Study agent will be shipped to the on-site pharmacy where it will be stored 
according to the conditions required (see Section 6.1.3 Product Storage and Stability). 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
NanoPac is presented as a white powder, provided in a sealed vial within a study kit. 
Study agent for all treatment groups will be supplied to the site in kits with one vial of Sterile Reconstitution 
Solution (1% Polysorbate 80, NF in 0.9% Sodium Chloride for Injection, USP) and one NanoPac 306mg powder-filled 
vial and one pre-printed Instructions for Use (IFU) insert in a 2ct kit. The site will be responsible for providing 0.9% 
Sodium Chloride for Injection, USP and lactated Ringer’s solution.   
Kits will be provided for a once-only use and will be assigned to one subject only. Reconstitution will occur at the 
pharmacy on-site and the reconstituted study agent will be delivered for use by the Investigator. An IFU insert will 
be provided to the Pharmacy ahead of the first subject being enrolled. The IFU will contain information on the 
reconstitution of the drug for 15mg/mL dose level, the storage of the drug once reconstituted, and the timeline 
permitted between reconstitution and use. 


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The vial will be labelled to include details as follows: 
“NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension. 306mg per vial. Lot no.: XXXXXXXXXXX. Prior 
to and after reconstitution, store at 59˚ to 86˚F (15˚ to 30˚C). Caution: New Drug – Limited by federal law to 
investigational use. For single use only. Manufactured by: CritiTech Inc., 1849 East 1450 Road, Lawrence, KS, 
66044.“  
The carton will be labeled with information indicating the content as follows: 
“Each kit contains: 1 vial of NanoPac (sterile nanoparticulate paclitaxel) Powder for Suspension, 306 mg per vial; 1 
vial Sterile Reconstitution Solution for NanoPac Powder for Suspension, 7 mL per vial; 1 instruction sheet for the 
reconstitution of the NanoPac dosing suspension and the dose withdrawal procedure.”  
6.1.3 PRODUCT STORAGE AND STABILITY 
Prior to administration at the hospital/clinic, the dry, sterilized NanoPac vials will be stored at the pharmacy, 
temperature controlled at 59˚ to 86˚F (15˚ to 30˚C). 
Once the NanoPac has been reconstituted it will be delivered to the clinic for use. Reconstitution will occur in the 
pharmacy at the clinical site, and if the reconstituted agent is not being delivered immediately the syringe may be 
stored according to the IFU until delivery. Each syringe must be labelled with the subject’s ID, the volume 
contained in the syringe, and visit information as well as date and time of preparation, for accountability purposes. 
6.1.4 PREPARATION 
Preparation of the study doses will be according to the IFU provided in the study kit. 
A prescription will be provided for each subject detailing the subject ID, volume of NanoPac required and the 
volume of the prostate lesion. The prescription will also note the date and time required for administration, and 
this will be provided to the pharmacy at least 24 hours prior to administration time, or as needed per site process. 
Sites may have electronic systems (such as Vestigo) set up to provide and manage all of this documentation.  
Once the drug has been reconstituted to the required 15 mg/mL, the volume for potential use (being the volume 
of the prostate lesion) will be withdrawn from the vial into a syringe.   
The syringe for administration will be labeled with the subject ID, the volume contained in the syringe as specified 
on the prescription, and the date and time of preparation. 
6.1.5 DOSING AND ADMINISTRATION 
Following successful completion of the Screening period and after all eligibility requirements have been confirmed, 
NanoPac will be administered as an ITU injection into the dominant lesion of prostate cancer.  
Administration will occur on up to three occasions: Day 1, 4 weeks after that at Day 29, and again 4 weeks later at 
Day 57. If the subject is not able to have the second injection at Day 29 they may receive the second injection at 
Day 43; however, they will not be eligible to receive a third injection if the second injection occurs at this delayed 
time point.  
An enema may be performed 12 hours prior to each injection procedure to optimize ultrasound visualization.  


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The subject will be advised to report for the prostate NanoPac injection procedure with a full bladder. At the time 
of injection, a bladder scan will be performed to assess the bladder volume. If the volume is greater than 200 mL, 
the injection procedure will be undertaken. If the volume is less than 200 mL, the subject will be encouraged to 
drink water to increase the bladder volume to 200 mL. A volume of 200 mL is chosen to dilute any drug that can 
potentially extravasate into the bladder at the time of the prostate injection. The subject can have the option of a 
catheter being passed into the bladder to fill to the desired volume. 
 
The subject will be placed in the lithotomy position with perineum exposed and scrotum elevated. Local anesthetic 
will be injected via a 22-gauge needle to perform a periprostatic nerve block. A 22G x 10” needle connected to the 
syringe containing the study agent will be inserted transrectally into the dominant lesion of the prostate under 
real-time TRUS guidance or transperineally via ultrasound. The needle will be retained in the rectum or perineum 
and reinserted into the prostate lesion several times in a fanning pattern to infuse the dominant lesion of the 
prostate with NanoPac. 
  
After the procedure, the subject will be asked to empty the bladder and a post-void residual will be checked with 
the bladder scanner. If the volume in the bladder is greater than 150 mL, an in-and-out catheter will be performed 
to empty the bladder.  
 
6.1.6 ROUTE OF ADMINISTRATION 
NanoPac will be administered as an ITU injection to the tumor within the prostate under TRUS guidance. 
6.1.7 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No dose adjustment or modification in an individual subject is anticipated. The administered volume used for the 
first injection will also be available/used for the second and third injections, keeping dosing consistent.  
However, the Medical Monitor will assess the safety parameters for each subject prior to second and/or third 
injections in order to provide additional safety information to assist with the Investigator’s decision  to proceed to 
the next injection. Documentation of this review will be provided for the study files, and provided to the treating 
Investigator ahead of the scheduled injection visit. If during this safety monitoring it is determined that it would be 
more appropriate to lower the volume delivered for the second or third procedure, dose reduction may occur. In 
this situation, the Medical Monitor will discuss with the Investigator to determine appropriate action required, and 
the reasoning resulting in this reduction will be documented for the study files and in the EDC.  
6.1.8 DURATION OF THERAPY 
NanoPac is being injected directly into the prostate lesion on up to three occasions 4 weeks (28 days) apart. The 
subjects will be followed for 85 days from the day of first injection and will attend regular clinic follow-up visits 
during this time; prostatectomy is scheduled to occur within a week of the final clinic visit, but will allow for up to 6 
weeks following last NanoPac injection. The duration of therapy is therefore 13 weeks, or may be up to 15 weeks if 
the subject receives all three injections. 
6.1.9 TRACKING OF DOSE 
Subjects will receive 15 mg/mL ITU NanoPac at a volume of up to the same volume as their prostate lesion, but no 
more than 10% the volume of the total prostate. The first injection will determine the maximum possible volume 
that can be administered safely, in the opinion of the Investigator as determined during that first injection 


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procedure. The volume administered at the first injection will be the same amount provided for injection at the 
second and third injections, as applicable. If not all the volume is able to be administered, for any reason, the 
actual volume administered will be recorded and the dose delivered can therefore be calculated for each injection. 
It is anticipated that the same volume will be able to be administered at each injection; up to the volume 
administered at the first injection will be provided for the second and third injections, the volume will not be 
higher than at the first injection. In the event there is significant resistance to the injection of NanoPac, the rate of 
injection of NanoPac should be reduced in an attempt to inject the full dose of NanoPac. Ultimately the 
Investigator will determine how much is delivered and this will be documented accordingly. 
Actual volumes administered at each injection will be documented in the subject source and in the EDC. 
6.1.10 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
The Investigator will maintain adequate records showing the receipt, dispensing, return, or other disposition of the 
study agent, including the date, quantity, batch or code number, and identification of subjects (number, initials) 
who received study agent. 
Accountability will be conducted on the vial packaging, the individual vials, and the syringes. 
Under no circumstances will the Investigator supply clinical material to other Investigators or clinicians or allow the 
supplies to be used other than as directed by this protocol without the consent of the Sponsor.  
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
 
7.1.1 STUDY SPECIFIC PROCEDURES  
The following procedures and evaluations will be done as part of this study. 
• 
Complete medical history to be completed, documented, and reviewed by the Investigator within 14 days 
prior to first NanoPac administration, including demographics and review of previous medical records; 
• 
Review and documentation of concomitant prescription and non-prescription medications; 
• 
Review and documentation of diagnosis of adenocarcinoma of the prostate (including biopsy results  and 
mpMRI results) and previous treatments including surgical and chemotherapeutic records. A copy of the 
pathology report confirming the diagnosis must be filed in the subject’s study record.  
o 
The biopsy results will be used to identify the dominant lesion for injection.  
o 
The mpMRI results will provide prostate volume, and dimensions (x3) and volume of the  lesion 
to be injected;  
• 
Comprehensive physical examination, including ECOG Performance Status assessment (Appendix A), and 
vital signs (blood pressure, heart rate, temperature, body weight and height); 


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• 
Questionnaires for determination of PROs, namely SHIM (Appendix B), I-PSS (Appendix C), and NIH-CPSI 
(Appendix D), will be completed at Screening, prior to NanoPac injection (may be Day 1, Day 29, Day 43, 
and/or Day 57) and at the final clinic visit (Day 85); 
• 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.1 Clinical Laboratory 
Evaluations); 
• 
Plasma samples for PK analysis will be taken (see Section 7.2.2 Other Assays and Procedures); 
• 
Possible bladder scan prior to NanoPac injections to assist with visualization, and following voiding after 
the injection procedure if required; 
• 
Imaging with mpMRI prior to first injection and at the final study visit (one week prior to prostatectomy 
[Day 85]). The reports must provide three dimensions and a volume measurement for the lesion being 
treated; 
• 
PSMA-PET scans may be performed prior to first injection and at the final study visit (one week prior to 
prostatectomy; (Day 85) if the site has access to this scan; 
• 
Direct injection of NanoPac into the dominant lesion under TRUS guidance at Day 1, Day 29, and Day 57 
[or at Day 1 and Day 43 for those subjects not able to have a second injection at Day 29, therefore not 
having a third injection]; 
• 
Ejaculate will be collected (see Section 7.2.2);  
• 
Evaluation of excised prostate and lymph nodes after prostatectomy, as applicable. 
Subjects will be required to complete an electronic diary on a daily basis while enrolled in the study.  Completion 
of up to 10 questions will be requested to occur once daily, before bedtime, to  assess the previous 24-hour 
performance.  
The site coordinator will create a subject-specific user account within the TrialMaster system and train the subject 
on how to complete the forms. The coordinator will also request a contact e-mail address for the subject diary 
account to be established; no other study personnel have access to this information. The subject receives an email, 
follows the link, uses the temporary system assigned password to log into the system and establishes their private 
password. This securely activates the account the subject will use to complete the diary. An access and user 
instruction leaflet will be provided to the subject. The data is saved within the protocol specific TrialMaster 
database. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
The subjects being enrolled to this study will be undergoing a scheduled prostatectomy. Routine work-up prior to 
surgery, and the surgery itself, are considered standard of care. Follow-up to surgery will be per standard of care. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Sample collection and processing for clinical laboratory assessments will be taken at Screening and at all other 
visits after the first injection of NanoPac. Samples on NanoPac injection days will be collected prior to the injection 
procedure.  
Clinical laboratory parameters to be measured will be the following: 


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• 
Glucose, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), total bilirubin, direct bilirubin, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total 
protein, albumin, and uric acid; 
• 
Red blood cell count (RBC), hemoglobin (Hgb), hematocrit (Hct), white blood cell count (WBC) including 
differential, reticulocyte count, and platelet count; 
• 
Urinalysis including hydrogen ion concentration (pH), RBC, WBC, protein, and glucose; 
• 
 Serum PSA.  
These tests will be conducted at the local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory 
routinely used by the Investigator. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
PK Samples 
PK samples will be taken at 1 and 2 hours post-injection at the first injection, and pre-injection, 1 and 2 hours post-
injection at second and/or third injection visits, and at all other study visits. PK samples on injection days will allow 
for a +/- 10-minute window around the injection sample timepoints, with T0 = start time of injection. 
Biopsy 
The biopsy(ies) taken immediately prior to prostatectomy or immedately prior to processing the tissue from the 
prostatectomy, will look at the effects of NanoPac on the tumor cells and will be compared with the first biopsy 
taken prior to study participation which confirmed the presence of adenocarcinoma. The biopsy sample(s) will be 
sent to local lab and processed for histologic evaluation and comparison to pre-study biopsy sample where tumor 
was previously identified.  The lab will prepare 3 slides from both biopsy timepoints (pre-study participation and 
pre-prostatectomy or immediately prior to processing the tisse from the prostatectomy) for additional IHC staining 
at NeoGenomics Laboratories, Inc. (NeoGenomics) if sufficient tissue remains available, when requested by 
Sponsor for shipping. 
A second biopsy sample will be prepared for paclitaxel analysis at Covance Laboratories;  this sample will be from 
fresh tissue (not formalin fixed) and kept frozen until shipment requested by Sponsor.  
Prostatectomy Tissue 
Routine clinical evaluation will be performed at the local pathology laboratory on the prostatectomy sample. For 
study purposes, fresh samples, (prior to fixing in formalin),  will also be obtained from the excised prostate and 
pelvic lymph nodes for determination of the presence of paclitaxel on specimens sent to Covance Laboratories; 
these samples will be kept frozen until Sponsor requests shipment; tissue will be processed at the clinical site for 
shipping to NeoGenomics where IHC staining and evaluation will be performed.  
If prostatectomy is significantly delayed, a biopsy should be performed at time surgery was planned.   If only 
slightly delayed, the biopsy and prostatectomy can be done together. 
Imaging 
Imaging with ultrasound and mpMRI will have been conducted prior to study participation as part of the routine 
evaluation and confirmation of adenocarcinoma. If an mpMRI has not been done during routine evaluation (within 
one month of informed consent), it will be required during the Screening period.  These results will serve as the 
pre-treatment (or Baseline) data, prior to NanoPac injection; another study-specific mpMRI will then be conducted 
at the final study visit (one week prior to prostatectomy) at Day 85. 


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PSMA-PET 
Performing PSMA-PET scans will be optional and if done, will be done prior to the first injection and at the final 
study visit (one week prior to prostatectomy, Day 85) to assess the presence of tumor in the lymph nodes.  
Ejaculate 
In the interval between NanoPac injections and prostatectomy, ejaculate will be collected at Day 15,Day 43, Day 57 
and Day 85 for determination of the presence of paclitaxel.   Ejaculate may be collected at home the day prior to 
the study visit and stored in a freezer overnight. 
Immune response assessed by FCM 
Blood samples will be obtained prior to the first NanoPac injection and then at visits on Day 15, Day 43, Day 71 and 
end of study Day 85.  For bloods drawn on Day 43, if this is an injection visit the FCM bloodwork should be drawn 
with the pre-injection PK sample prior to NanoPac injection.  Blood will be drawn, prepared, and shipped same day 
for overnight delivery to NeoGenomics for FCM evaluation. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
PK samples will be drawn at the specified time/visit and stored frozen on-site until the sponsor indicates shipping 
should be performed, at which time they will be batch-shipped to Covance Laboratories (Madison, WI) for analysis. 
Following prostatectomy surgery, a representative section of the prostate tumor (from as close to the biopsy of 
the tumor as possible), the ipsilateral and contralateral lobes as well as up to four associated lymph nodes will be 
obtained from the excised tissue and will be immediately frozen and prepared for shipment to Covance 
Laboratories for analysis of the presence of paclitaxel in the excised sample; this will be done on fresh tissue, (prior 
to fixing in formalin). The remainder of the excised prostate and lymph nodes will be routinely inspected in the 
operating room and sent (unfrozen) to Pathology for histological analysis, and for preparation of slides to be sent 
to NeoGenomics for IHC staining and evaluation.   Should there not be enough tissue available for both samples, 
the tissue going to Covance for paclitaxel analysis takes precedence over the IHC analysis. 
Immediately prior to, or from the tissue sample collected from the prostatectomy, a biopsy sample(s) will be taken 
and sent to Pathology for histopathologic evaluation and comparison with the initial biopsy results obtained 
confirming the presence of adenocarcinoma.   Slides will also be prepared and sent to NeoGenomics for IHC 
staining and evaluation if enough tissue sample is available. 
Serum PSA samples will be obtained at the specified time/visit and will be sent to the local CLIA certified laboratory 
for analysis. Results will be sent to the Investigator for the source record and for entry to the EDC. 
Samples of ejaculate obtained at the time/visit specified will be snap frozen and stored on site until shipping is 
confirmed to be required by the sponsor, at which time all samples will be shipped to Covance Laboratories for 
analysis of the presence of paclitaxel. Ejaculate samples may be obtained at home the day prior to the clinic visit 
and stored in the freezer overnight; samples will be transported from home to the clinic in a cool bag on ice packs 
which will be provided at the prior clinic visit.  
Blood samples for FCM evaluation will be drawn into tubes supplied for this purpose, and shipped to NeoGenomics 
on the day the sample is obtained; samples must remain at ambient temperature until shipped. 
NeoGenomics, the central laboratory for IHC evaluation and for FCM evaluation, will provide a manual to detail the 
requirements for the preparation of the slides and for the blood samples for shipping to their facility. 


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7.2.4 SPECIMEN SHIPMENT 
Routine laboratory samples and PSA samples will be sent to the local laboratory upon collection.  
Samples for paclitaxel assessment will be batch shipped, in a temperature-controlled environment, to Covance 
Laboratories, only when directed by the sponsor.  (Ejaculate, PK and tissue from prostatectomy and biopsy will be 
shipped to Covance). 
Tissue samples for histological evaluation will be sent to the local laboratory upon collection, and slides will be 
prepared at the local laboratory for shipping to NeoGenomics for IHC staining and evaluation; slides will be batch 
shipped when directed by the sponsor.   
Blood drawn for FCM will be shipped at ambient temperature on the same day the blood is drawn, to 
NeoGenomics for evaluation. 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
The following procedures and assessments must be completed, documented and reviewed by the Investigator 
during the screening period within 15 weeks prior to the scheduled prostatectomy, and therefore 14 days prior to 
the first NanoPac injection: 
• 
Written informed consent including comprehensive discussion of the study schedule, procedures, and 
subject protocol requirements; 
• 
Complete medical history, including demographics and review of previous medical records; 
• 
Review and documentation of adenocarcinoma of the prostate diagnosis (including biopsy results, 
ultrasound results, and mpMRI results obtained within one month of consent) and previous treatments 
including surgical and chemotherapeutic records. The biopsy results will be used to identify the dominant 
lesion. The ultrasound results will be used to determine prostate volume and volume of the dominant 
lesion. A copy of the pathology report confirming the diagnosis must be filed in the subject’s study record;  
• 
Review and documentation of all concomitant prescription and non-prescription medications; 
• 
Comprehensive physical examination, including ECOG Performance Status assessment (Appendix A), and 
vital signs (blood pressure, heart rate, temperature, body weight and height); 
• 
Subject completion of SHIM, I-PSS, and NIH-CPSI questionnaires (Appendices B-D); 
• 
Sample collection and processing for clinical laboratory assessments:  
o 
Hematology, biochemistry, urinalysis, and PSA levels; 
• 
Rectal swab will be taken and cultured to aid antibiotic prophylaxis selection for the NanoPac injection;  
• 
Subject will be provided specific information and a prescription for the enema pack to be used 12 hours 
prior to the NanoPac dosing procedure at the next study visit, if applicable; 
• 
mpMRI will be performed prior to the first injection, and considered part of the Screening procedures; 
this may have been performed as part of standard of care within a month prior to informed consent, and 
would therefore not be repeated but data from the mpMRI captured as baseline data; PSMA PET scans 
may be done if available to the site and performed as per schedule of mpMRI. 
• 
Electronic Diary – the subjects will be provided secure access to an electronic diary to be completed daily 
throughout the study; training will be provided at the Screening visit and as needed during the study. 


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7.3.2 INJECTION PROCEDURE VISITS 
 Day 1 –  Day of First NanoPac Injection 
The day of the first NanoPac injection (always considered Day 1) will be scheduled relative to prostatectomy, with 
the first NanoPac injection occurring 13 weeks (92 days) prior to the day planned for prostatectomy. However, the 
realities of medical practice (i.e. the availability of procedure rooms) may require that NanoPac injection and 
prostatectomy occur on different days of the week. For this reason, a window of 2 days either side 92 days prior to 
prostatectomy, plus or minus 2 days = Days 90-94) is permitted for the Day 1 NanoPac injection visit.   
All subsequent follow-up study visits will be scheduled relative to the first NanoPac injection visit (NOT 
prostatectomy), with a window of plus or minus 1 day permitted.   
For example, if prostatectomy is scheduled for a Thursday, all clinic visits leading up to the prostatectomy would 
ideally be scheduled on the preceding Thursdays; however, the plus or minus 2 days window would permit the 
NanoPac injection to be scheduled on a Tuesday, Wednesday or Friday.  Assuming the day of first NanoPac 
injection (Day 1) is a Tuesday, follow-up visits for the next 13 weeks would be scheduled to occur ideally on 
Tuesdays, but could be Monday or Wednesday (allowing for the window). The prostatectomy would occur, as 
scheduled, on Thursday and would be Day 92.  
Following review of all test results from the Screening visit, the following will be conducted on Day 1: 
• 
Review of inclusion and exclusion criteria and determination of eligibility to proceed to treatment; 
• 
Review of electronic diary data; 
• 
Vital signs obtained (blood pressure, heart rate, temperature, and body weight); 
• 
ECOG documented; 
• 
Sample collection and processing for clinical laboratory assessments prior to injection:  
o 
Hematology, biochemistry, urinalysis, and PSA levels; 
• 
Sample collection for FCM evaluation prior to injection; 
• 
Subject completion of SHIM, I-PSS, and NIH-CPSI questionnaires (Appendices B-D); 
• 
Preparation for dosing; 
o 
Subject may have an enema 12 hours prior to dosing; 
o 
Subject will have a bladder scan prior to injection to assist with visualization and post-injection 
following voiding; 
• 
Subject will receive NanoPac (see Section 6.1.5); 
• 
PK samples will be drawn (see Section 7.2.2); 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
AEs will be collected from the time of dosing; 
• 
Subject will be provided antibiotics to take following the procedure, based on the rectal swab culture; 
• 
Subject will be reminded to continue completing daily electronic diary entries. 


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7.3.3 FOLLOW-UP  
Follow-up study visits will be scheduled relative to Day 1, with a window of plus or minus 1 day permitted. 
Day 8 and Day 15 
The subject will return to the clinic for the following evaluations: 
• 
Vital signs will be obtained (blood pressure, heart rate, temperature, and body weight); 
• 
PK samples will be taken; 
• 
Review of electronic diary data;  
• 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.1):  
o 
Hematology, biochemistry, urinalysis, and PSA levels; 
• 
Day 15 only - sample for FCM evaluation will be obtained 
• 
AEs will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
An ejaculate sample will be obtained at the Day 15 visit only. 
The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. Subject will be reminded to continue completing daily electronic diary entries. 
7.3.4 SECOND AND THIRD INJECTIONS 
Day 29, Day 43, and/or Day 57 – as applicable 
On the day of the second and/or third injections of NanoPac the following study-specific procedures will be 
conducted: 
• 
Review of electronic diary data; 
• 
Subject completion of SHIM, I-PSS, and NIH-CPSI questionnaires (Appendices B-D); 
• 
ECOG Performance Status assessment (Appendix A), and vital signs (blood pressure, heart rate, 
temperature, and body weight); 
• 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.):  
o 
Hematology, biochemistry, urinalysis, and PSA levels; 
• 
 Sample for FCM evaluation will be obtained on Day 43 only, and if an injection is being performed the 
sample must be obtained prior to injection; 
• 
An ejaculate sample will be collected on Days 43 and 57 only;  
• 
Preparation for dosing; 
o 
Subject may have an enema 12 hours prior to dosing; 
o 
Subject will have a bladder scan prior to injection to assist with visualization and post-injection 
following voiding. 
• 
Subject will receive NanoPac (see Section 6.1.5); 
• 
PK Samples will be drawn (see Section 7.2.2); 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
AEs will be recorded; 
• 
Subject will be provided antibiotics to take following the procedure, based on the rectal swab culture. 


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The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. Subject will be reminded to continue completing daily electronic diary entries. 
7.3.5 FOLLOW-UP VISITS 
Follow-up visit days will depend on the days of second and third injection; on planned injection days, when an 
injection is not performed, that visit will be considered a follow-up visit. 
Follow-up visits could be any of the following: Day 29, Day 36, Day 43, Day 50, Day 57, Day 64, Day 71 
The subject will return to the clinic for the following evaluations: 
• 
Review of electronic diary data; 
• 
Vital signs will be obtained (blood pressure, heart rate, temperature, and body weight); 
• 
PK samples will be taken (see Section 7.2.2); 
• 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.1):  
o 
Hematology, biochemistry, urinalysis, and PSA levels; 
• 
A sample for FCM evaluation will be taken at Days 43 and 71; 
• 
AEs will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
An ejaculate sample will be collected for all subjects at Days 43 and 57 only. 
The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. Subject will be reminded to continue completing daily electronic diary entries. 
7.3.6 FINAL STUDY VISIT – END OF STUDY VISIT 
Day 85 – (one week prior to  scheduled prostatectomy) 
The subject will return to the clinic for the following evaluations: 
• 
Review of electronic diary data; 
• 
Ejaculate will be collected;  
• 
Subject completion of SHIM, I-PSS, and NIH-CPSI questionnaires (Appendices B-D); 
• 
Comprehensive physical examination, including ECOG Performance Status assessment (Appendix A), and 
vital signs (blood pressure, heart rate, temperature, and body weight); 
• 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.1):  
o 
Hematology, biochemistry, urinalysis, and PSA levels 
• 
A sample for PK analysis will be taken (see Section 7.2.2);  
• 
A sample for FCM evaluation will be taken; 
• 
Concomitant medications will be reviewed and updated as necessary, including post-surgical medications; 
• 
AEs will be recorded; 
• 
mpMRI will be performed; 
• 
PSMA PET scan may be performed as an optional study assessment, if available to the site. 


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The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being.  This visit is considered the final study visit for the subject. At this time the subject will exit the study 
with no further study follow-up requirements, unless there are ongoing AEs which require follow-up. 
7.3.7 PROSTATECTOMY 
Day of Prostatectomy 
The subject will return for their scheduled prostatectomy. Due to the window permitted for the Day 1 NanoPac 
injection visit, the day of prostatectomy may occur anytime between Day 90 and Day 106.  
Following surgery, samples will be provided from the excised tissue (prostate and lymph nodes) for evaluation of 
the presence of paclitaxel; routine histopathology and assessment of tumor cells will be performed at the local 
facility, and additional slides of the tumor will be provided and sent to the central laboratory (NeoGenomics) for 
IHC evaluations. 
Following the prostatectomy, the subject will receive standard of care with their follow up continued as 
recommended by their treating physician. 
If there has been a significant response (as seen in routine follow-up and from mpMRI) which causes the 
Investigator to delay prostatectomy, biopsy will be performed on the day which would have been the 
prostatectomy visit, to assess staging of the disease and status of subject. Biopsies will be provided for routine 
histopathology evaluation at the local laboratory, and slides will be provided for IHC evaluation at the central 
laboratory. In addition, a biopsy will be provided for determination of paclitaxel presence. If prostatectomy is 
delayed, the subject will be requested to provide ejaculate samples every 6 weeks until paclitaxel can no longer be 
detected by assay, or until prostatectomy is performed. During this time the subject  must continue use of double 
condoms, as applicable. A further blood sample for FCM evaluations may be obtained at the time of delayed 
prostatectomy.   
 
7.3.8 EARLY TERMINATION VISIT 
In the event a subject is withdrawn they would, at minimum, undergo final study visit evaluations (End of Study 
evaluations) which include vital signs, laboratory sample collection, PK sample collection, AE collection and 
concomitant medication updates. If a subject is withdrawn at a routine study visit, all evaluations that would have 
been done at that study visit should be completed, as far as possible, and the least amount of information that 
would be captured are the vitals, AEs, and concomitant medications.  
7.3.9 UNSCHEDULED VISITS 
Any unscheduled visits will be documented in the source documents, and any assessments and/or evaluations 
performed will be noted and reviewed. If the unscheduled visit occurs after dosing but prior to surgery, the 
following assessments should be conducted to monitor the ongoing safety of the subject:  
• 
Vital signs will be obtained; 
• 
Review of the electronic diary data; 
• 
AEs will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary. 


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The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. If the Investigator deems it necessary for blood work to be done, this information will be filed in the 
source documents and be available if required at a later date, but laboratory results will not be transcribed into the 
EDC.  


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7.3.10 SCHEDULE OF EVENTS TABLE 
7.3.10.1 SCHEDULE OF SUBJECT VISITS 


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7.3.10.2 SCHEDULE OF ASSESSMENTS 
 
Day -14 
Days 1, 29, 57 or 
Days 1, 43 or 
other 
Days 8, 15, (29), 36, 
(43), 50, (57), 64, 71 
as applicable 
Day 85 
Day 92 
SCREENING 
DAY OF 
INJECTION 
FOLLOW-UP 
VISITS 
FINAL CLINIC 
VISIT 
Prostatectomy / 
Biopsy 
Informed Consent 
X 
  
  
  
  
Medical History 2 
X 
  
  
  
  
Physical Exam 
X 
  
  
X 
  
Vital Signs 
X 
X 
X 
X 
  
ECOG 
X 
X 
  
X 
  
Daily electronic diary 
X 
X 
X 
X 
  
Questionnaires 
X 
X 
  
X 
  
Hematology, Biochemistry, 
Urinalysis 
X 
X 
X 
X 
  
PSA 
X 
X 
X 
X 
  
PK Samples 
  
pre-inj, 1hr, 2hr 3 
X 
X 
  
Ejaculate collection 9 
  
 X 
X 
X 
  
Rectal swab 4 
X 
  
  
  
  
Antibiotics  
  
X 
  
  
  
Biopsy (Pathology and IHC)  
X7 
  
  
  
X 
Radiologic Assessment (mpMRI) 
{ X } 
  
  
X 
  
PSMA PET Scan (optional) 10 
X  
  
  
X 
  
NanoPac Procedure (inc all) 1 
  
X 
  
  
  
Blood for Flow Cytometry (FCM) 8 
  
X 
X 
X 
  
Concomitant therapy  
X 
X 
X 
X 
  
Adverse Events 6 
X 
X 
X 
X 
  
Prostatectomy 5 
  
  
  
  
X 
Excised tissue prep 
  
  
  
  
X 
End of Study 
  
  
  
X 
  


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1 
The day of first NanoPac injection (Day 1) will be scheduled relative to prostatectomy, with NanoPac injection occurring 92 days prior to the day planned 
for prostatectomy with a  window of plus or minus 2 days (92 days prior to prostatectomy, plus or minus two days = 90-94 days). All subsequent study 
visits will be scheduled relative to the day of first NanoPac injection (NOT prostatectomy), with a window of plus or minus one day permitted. 
2 
History includes all events before initiation of NanoPac treatment. 
3  
PK Samples on Day 1 drawn at 1 and 2 hours post-dose; on other injection days PK samples are drawn pre-injection and at 1 and 2 hours post dose; allows 
for a +/- 10-minute window around samples. 
4 
A rectal swab will be taken and cultured during screening to aid antibiotic prophylaxis.  
5 
There is a possibility that following the end of study (Day 85) assessments, should the Investigator/physician and subject elect not to proceed to 
prostatectomy at that time but to delay it to a future date, the subject will be counselled regarding contraceptive use and provision of ejaculate samples 
every 6 weeks until paclitaxel is not detectable, or until prostatectomy is performed, whichever is first. 
6 
AE determination will start immediately following initiation of study treatment.  
7 
Slides from the biopsy pre-study will be provided for IHC evaluation 
8 
Blood for FCM evaluation will be obtained prior to the first NanoPac injection, on Days 15, 43, and 71, and at the final study visit, Day 85 
9 
Ejaculate samples will be collected on Day 15, Day 43 (prior to NanoPac injection), Day 57, and at the final study visit, Day 85. 
10      PSMA PET scan is an optional study procedure and will only be performed if available to the site. 
{ X }    Should be available from pre-study period; if not will need to be performed. Must be collected no earlier than one month prior to consent. 
 
 
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that ITU injection of NanoPac into the lesion in the prostate may qualify as a sensitive 
procedure and as such should be mentioned in this section. 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
All concomitant prescription medications taken during study participation will be recorded on the electronic case 
report forms (eCRFs). For this protocol, a prescription medication is defined as a medication that can be prescribed 
only by a properly authorized/licensed clinician. Medications to be reported in the eCRF are concomitant 
prescription medications, over-the-counter medications, and non-prescription medications. 
Although no interaction studies have been conducted using NanoPac, paclitaxel is metabolized by cytochrome 
P450 isozymes CYP2C8 and CYP3A4 (Taxol Package Insert). Thus, there is a potential for drug interactions with 
concomitantly administered substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and 
inducers (e.g., rifampin) of CYP2C8. There is also the potential for paclitaxel to interact pharmacokinetically with 
CYP3A4 substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and 
triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine). Appendix E provides a 
more extensive list. 
7.6 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable. 
7.7 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Use of concomitant chemotherapy (other than the protocol-specified agents), immunotherapy, or systemic use of 
hormonal therapy (such as GnRH analogs, antiandrogens, androgen receptor inhibitors, and 5-α reductase 
inhibitors) at any time prior to surgery is prohibited. 
7.8 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
12 hours prior to dosing the subject may receive an enema to assist with the visualization when the imaging is 
performed. 
Subject will be instructed to take antibiotics before/after NanoPac injection as prophylactic antibiotic therapy.   
7.9 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable. 
7.10 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable. 
 


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8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments being conducted in this study include: 
• 
AEs, collected at all study visits from the time of dosing; 
• 
Changes in concomitant medications;  
• 
Findings from physical examinations;  
• 
Changes in vital signs. 
• 
Changes in laboratory analytes 
Safety will be reviewed by the Medical Monitor in an ongoing manner via the EDC system, and details will be 
confirmed at routine on-site monitoring visits.  
Additionally, the Medical Monitor will assess the safety parameters for each subject prior to second and/or third 
injections in order to provide the treating Investigator with any signs or symptoms that might suggest the subject is 
not ready for the next injection.  Documentation of this review will be provided for the study files, and provided to 
the treating Investigator ahead of the scheduled injection visit. The ultimate decision lies with the treating 
Investigator.   
Every 3 months the Medical Monitor will review the cumulative study data and this will be documented for the 
files. 
8.1.1 DEFINITION OF ADVERSE EVENTS  
An AE, is any untoward medical occurrence in a patient or clinical trial subject administered an investigational 
product, irrespective of causality. An AE can therefore be any unfavorable and unintended change in structure, 
function, signs, or symptoms temporally associated with the use of a medicinal product, whether or not related to 
the product. Undesirable changes in laboratory values should not be considered AEs unless they are considered 
symptomatic of a clinical condition or diagnosis, are evaluated as clinically significant, or require therapy. 
Worsening of a pre-existing condition is also considered an AE, as is the discovery of an abnormal finding during 
physical exam that was not included in the medical history. Clinical conditions attributable to disease progression 
will be considered AEs and reported on the eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS  
A SAE is any adverse event that meets at least one of following criteria: 
1) Is fatal; 
2) Is life-threatening, meaning the subject was, in the view of the Investigator, at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious 
form or progressed, might have caused death; 
3) Is a persistent or significant disability or incapacity; 
4) Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered a 
hospitalization that is longer than 24 hours, or a hospitalization that requires an intervention to treat 
emergent symptomatology (non-diagnostic); 


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5) Is a congenital anomaly or birth defect; 
6) Other important medical events may be considered a serious adverse experience when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes as listed in #1-5 in this definition. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS  
As this is a Phase 2 study, all unanticipated problems (UPs) will be captured as either AEs or SAEs and will be 
defined and reported accordingly. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
Signs and symptoms will be graded by the Investigator according to the NCI CTCAE v5 grades; Grades 1 through 5 
have unique clinical descriptions of severity for each AE based on the general guideline as follows: 
• 
Grade 1 - Mild:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• 
Grade 2 - Moderate:  Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
• 
Grade 3 - Severe:  Or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
• 
Grade 4 - Life-Threatening:  Urgent intervention indicated 
• 
Grade 5 - Fatal:  Death related to the adverse event.  
8.2.2 RELATIONSHIP TO STUDY AGENT 
The following five-point scale will be used by the Investigator to rate the relationship of the AE to the study agent: 
• 
Definitely related: A clinical event (including laboratory test abnormality) occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or other drugs 
or chemicals. The response to withdrawal of the drug (de-challenge) should be clinically plausible. The event 
must be definitively associated pharmacologically, using a satisfactory re-challenge procedure, if necessary;  
 
• 
Probably related: A clinical event (including laboratory test abnormality) with a reasonable time sequence 
to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and which follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information 
is not required to fulfill this definition; 
 
• 
Possibly related: A clinical event (including laboratory test abnormality) with a reasonable time sequence 
to administration of the drug, but which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear; 
 
• 
Unlikely to be related: A clinical event (including laboratory test abnormality) whose temporal relationship 
to drug administration makes a causal relationship improbable (e.g., the event did not occur within a 


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reasonable time after administration of the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the subject’s clinical condition, other concomitant 
treatments); 
 
• 
Not related: An event for which sufficient information exists to conclude that the etiology of the event is 
unrelated to the study agent. An alternative definitive etiology should be documented by the Investigator. 
 
8.2.3 EXPECTEDNESS  
The definition of expectedness is related to the study agent specifically. An event may be unexpected in the 
subject but that in itself does not qualify as unexpected; review against information available and provided for the 
study agent is what will determine expectedness. 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent in the protocol and within the Investigator’s Brochure. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
All AEs and SAEs must be followed until the event resolves or, in the opinion of the Investigator, become stable/or 
adequately managed. Subjects will be required to spontaneously report any AE. Study personnel will ask open-
ended questions to obtain information about AEs at every visit. Date and time of onset and resolution (if 
applicable) of the AEs will be documented. 
The Sponsor will report any serious, unexpected, and drug-related AEs to applicable regulatory agencies and make 
these reports available to the investigative sites. The Investigator must promptly inform the IRB of such events and 
retain a copy of the notification in the site’s regulatory binder. 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
All AEs (whether or not attributable to the study agent) occurring during the study observed by the Investigator or 
reported by the subject will be recorded on the eCRF. The following information will be recorded for all AEs: 
• 
Name of condition/diagnosis/description 
• 
Onset and resolution dates 
• 
Grade/Severity 
• 
Relationship to study agent 
• 
Action taken 
• 
Seriousness  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAEs, including death, due to any cause which occur during this study, whether or not expected and regardless 
of relationship to study agent, must be reported to the Medical Monitor immediately upon discovery of the event, 
using the SAE reporting form; this form  may be printed and completed then scanned and sent in via email, or it 


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may be completed electronically and emailed directly to the Medical Monitor, and, if necessary, the SAE may be 
reported by phone to: 
Dr. Antony Verco 
Medical Monitor 
US Biotest, Inc. 
Email: tony.verco@usbiotest.com 
Phone: 805-235-9193 
 
24-hour Emergency Contacts: 
Gere diZerega, MD 
or 
Antony Verco, MD 
 
Medical Director 
 
Medical Monitor 
 
805-630-2800  
 
805-235-9193 
The Sponsor will advise the Investigator regarding the nature of any further information or documentation that is 
required. The Investigator should provide the following documentation at the time of notification if available: 
• 
SAE Report Form; 
• 
Concomitant and support medication pages; 
• 
Relevant diagnostic reports; 
• 
Relevant laboratory reports; 
• 
Admission Notes; 
• 
Hospital discharge summary (when available). 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
 
Incidents or events that occur during the conduct of the study and meet the criteria for an AE or SAE will be 
captured in the source documents and in the EDC, and in the case of an SAE, also on the formal reporting form 
designed to capture the required information. Reporting of these events will be in accordance with the rules 
around AE and SAE reporting described in the protocol, including notification of the IRB and/or the FDA as 
required. 
 
8.4.4 EVENTS OF SPECIAL INTEREST  
Subjects may receive up to three administrations of NanoPac and therefore any event seen as a result of the study 
agent will be managed according to best/standard practices.  
Events that are common when performing prostate biopsy will be noted. These include pain (which can be 
persistent and require narcotics) and dysuria (which may require analgesia); complications following prostate 
biopsy include urinary tract infection (UTI), rectal bleeding, hematuria, hematospermia, and urinary retention.  
AEs of special interest that occur due to any of the procedures and/or are related to the study agent (paclitaxel) 
will be documented in the subject’s source records and within the electronic database, and may include the 
following: 
• 
Anaphylaxis/allergic reaction – This could present as a spectrum of symptoms from an urticarial rash to 
cardiovascular and respiratory compromise. These effects would manifest immediately.   
• 
Urinary retention – Subject unable to void and requires catheterization. The decision to catheterize 
depends on individual subject bladder capacity and abdominal discomfort. Interim data from a TK study of 


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intraprostatic injection in rats indicated there was some evidence of swelling of the prostate and resultant 
urinary outflow obstruction. The injection volume in this study has been limited to not exceed 10% of the 
total prostate volume specifically in order to prevent urinary outflow obstruction; however, it could still 
occur and would be of particular interest.    
• 
Urosepsis – Urinary tract infection requiring hospitalization and intravenous antibiotics to monitor and 
stabilize hemodynamics. This would be considered a SAE, as it requires intervention. 
• 
Gross Hematuria – Passing large volumes of clots that impede urinary flow. The subject could have 
intermittent flow or progress to urinary retention. For this situation, bladder catheterization and irrigation 
will be instituted.   
• 
Perineal pain – Severe pain rated greater than 8/10 on a pain score assessment that requires opioid 
analgesia. 
• 
Per-rectal bleeding – Requiring surgical intervention to stem the bleeding after injection. This would be 
considered a SAE as it requires intervention. 
Of particular interest will be signs of systemic toxicity due to paclitaxel exposure. This is unlikely to occur due to 
the mode of administration and dose levels; however, if such signs occur they will be captured as events of special 
interest. Events which may occur and indicate possible systemic exposure include bone marrow suppression, 
anemia and neutropenia, alopecia, peripheral neuropathy, and prolonged periods (3 or more days) of diarrhea, 
nausea and vomiting. 
8.4.5 DOSE LIMITING TOXICITY  
Throughout the study, particular attention will be paid to the possibility of DLT. DLT information will be collected in 
an ongoing manner from the time of dosing until prostatectomy. DLTs considered to be SAEs (Section 8.1.2) will be 
reported within 24 hours. 
Any AE that is considered related or possibly related to NanoPac is potentially a DLT. The definition of a DLT will be 
made by consensus by the Medical Monitor, Sponsor Medical Director, and PI. All AEs of the below specified 
grades will count as DLTs except those that are clearly and incontrovertibly due to disease progression or 
extraneous causes. DLTs include the following: 
• 
Any death not clearly due to the underlying disease or extraneous causes; 
• 
Events which may occur and indicate possible systemic exposure, including anemia and neutropenia, 
alopecia, peripheral neuropathy, and prolonged periods of diarrhea, nausea and vomiting; 
• 
Any ≥ Grade 3 non-hematologic toxicity; 
• 
Any delay of scheduled prostatectomy due to study agent related toxicity; 
• 
AST and ALT levels over 3x ULN; 
• 
Symptomatic urine retention secondary to a study injection-related blockage of the prostatic urethra; 
• 
Neutropenic fever; 
• 
Grade 4 neutropenia lasting 5 days; 
• 
Grade 3 thrombocytopenia with clinically significant bleeding; 
• 
Grade 4 thrombocytopenia; 
• 
≥ Grade 3 diarrhea and vomiting persisting after treatment with optimal anti-diarrheals or antiemetics; 
• 
Grade 3+ electrolyte abnormality that lasts >72 hours, unless the subject has clinical symptoms, in which 
case all grade 3+ electrolyte abnormality regardless of duration should count as a DLT. (Grade 3+ amylase 


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or lipase elevation NOT associated with symptoms or clinical manifestations of pancreatitis does not need 
to be counted as a DLT); 
• 
Severe pain (i.e., pain score ≥ 8/10) requiring opioid management, and which occurs when in the opinion 
of the Investigator all other procedural complications have been excluded, will also be considered a DLT. 
8.4.6 REPORTING OF PREGNANCY  
If sexually active, subjects must use double condoms from time of the first NanoPac injection until after 
prostatectomy. If a subject does not proceed to have the prostatectomy, follow-up ejaculate samples will be 
required to evaluate for presence of paclitaxel until it is no longer detectable or until prostatectomy is performed; 
until this time the subject must continue to use double-barrier birth control to prevent pregnancy in the partner. 
Any pregnancy occurring in a sexual partner while a subject is in the study period between first NanoPac injection 
and prostatectomy must be reported to US Biotest as soon as the Investigator is aware of it. The pregnancy will not 
be considered an SAE; however, information on these pregnancies will be collected and followed for the outcome 
of the pregnancy and the health of the newborn.  
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion, or elective 
termination of a pregnancy for medical reasons will be reported as an SAE, as described in Section 8.4.2. Should 
the pregnancy result in a congenital anomaly or birth defect, a separate SAE report must be submitted. 
Furthermore, all neonatal deaths that occur within 30 days of the birth should be reported as SAE, without regard 
to causality. In addition, any infant death that occurs after the 30-day reporting period that the Investigator 
suspects is related to the in-utero exposure to the study agent should also be reported. 
8.5 
STUDY HALTING RULES  
This is a Phase 2 study, and will be subject to review of all safety and tolerability data in an ongoing manner. 
Following review, the study may be terminated. 
The Medical Monitor may determine that the second injection in each/any subject may proceed as planned, 
however the investigator and the subject always have the right to decline to perform a second and/or third 
injection; the Medical Monitor may determine that it would be more appropriate to lower the second dose (by 
reducing the volume to be administered) to prevent any adverse findings which may appear during this period;  or 
may determine that the safety and tolerability profiles are not acceptable and may determine that more injections 
are not reasonable for the safety of the subject(s); it is also possible that the Medical Monitor will advise that the 
study be stopped. 
The Sponsor is responsible for notifying the FDA of any temporary halts to the study or when a study is terminated; 
the Investigator will be required to notify the IRB accordingly.  
8.6 
SAFETY OVERSIGHT 
Safety will be overseen by the Medical Monitor and at any time may also involve the Medical Director and/or the 
Investigator if any concerns arise. A Safety Management Plan will be drawn up prior to study start. 
All subject study data and the electronic daily diary data will be captured in an EDC system, allowing real-time 
access to ongoing safety and tolerability data. The Medical Monitor will review the data for each subject entered 
to the database on a regular basis, and specifically prior to a scheduled injection visit, throughout the study. In the 


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event the Medical Monitor has any concerns or sees any safety trends emerging during his ongoing reviews, he will 
bring it to the immediate attention of the Medical Director (and the PI, as appropriate). 
During the quarterly review, the Medical Monitor will review all safety data as available in the EDC, provided as 
reports generated directly from the EDC system and provided by the Data Management group. Particular emphasis 
will be placed on the events of special interest, as outlined in Section 8.4.4, and on events which may constitute 
dose-limiting toxicities as outlined in Section 8.4.5. 
9 
CLINICAL MONITORING 
US Biotest monitors, or monitors designated by US Biotest, will conduct scheduled site visits to the investigational 
center for the purposes of monitoring the study. The Investigator agrees to allow these monitors, and other 
authorized Sponsor personnel or designees, access to the subject’s medical records, regulatory binder, study 
binder, eCRFs, and source documents as needed to ensure the conduct of the study is within compliance. In 
addition, the FDA or other government agencies may request an inspection following notification to the site. In 
such an event, the Investigator agrees to notify the Sponsor immediately of the request, and will allow Sponsor 
and inspectors to review records. 
US Biotest will conduct a site initiation visit to provide the Investigator and their staff with a comprehensive 
overview of the protocol and study procedures and to review mutual obligations and requirements of regulatory 
authorities. A regulatory file or binder containing required documentation will be kept at the site for reference and 
inspection. 
Routine monitoring visits will be made to ensure compliance with the study protocol, to review and collect the 
subject’s eCRF and compare with source documents, to ensure adequate records of clinical supplies are 
maintained, and to assess the continued suitability of the investigational site. On completion of the study, the 
monitor will make a final assessment of the conduct of the study and inventory all clinical supplies to be returned 
to US Biotest. 
10 
STATISTICAL CONSIDERATIONS   
10.1 
STATISTICAL AND ANALYTICAL PLANS 
A formal Statistical Analysis Plan (SAP) will be prepared for this trial, and the SAP will be signed off prior to study 
database lock. The events of special interest and/or DLTs (Sections 8.4.4 and 8.4.5) will be identified early in the 
trial to ensure that the Medical Monitor is provided easy to review summaries.  The associated MedDRA SOC and 
PT terms will be approved by the Medical Monitor and included in the SAP.  In addition, if requested by the 
Medical Monitor, medically relevant changes (e.g., 3 x the normal range) and analytes of interest will be defined in 
the SAP and also incorporated into the EDC edit checks once the alert ranges are established. 
To enhance the focus on Safety, timeframes may be established (e.g. within 24-hours of injection) to summarize 
AEs and/or other events, that would become apparent with the ongoing review of the study data, to be highlighted 
in the Clinical Study Report (CSR). 
10.2 
STATISTICAL HYPOTHESES 
 No inferential analyses are proposed; thus, no hypotheses are stated. 


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10.3 
ANALYSIS DATASETS 
All subjects who receive treatment will be included in the outcome presentations. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
In this Phase 2 trial, the focus will be on providing descriptive statistical summaries including tables and graphs. 
The clinical/medical review of these data summaries will determine possible toxicity related issues that could be 
associated with NanoPac and the  effect, if any, of the treatments on the prostate tumor.  
Missing data will not be imputed, as imputation methods are based on assumptions which could affect the 
interpretation of the data.  With the small number of subjects and the early stage in drug development it is 
acknowledged that missing data is not ignorable. The missingness will be displayed and reviewed by the medical 
monitor as part of the overall interpretation of the trial results.  
10.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
The primary objective of this study is to evaluate the safety and tolerability, and preliminary efficacy of NanoPac 
(at a concentration of 15 mg/mL) injected directly into the dominant lesion of the prostate cancer.  
The primary safety assessment will be the AE data, which will also include vital signs and/or laboratory values 
which would be considered medically notable (Section 8.1.1) and any events considered DLTs (Section 8.4.5).  As 
such, the detailed summary tables for vital signs and in particular laboratory analytes will  be part of the traditional 
safety assessment (Section 10.4.4) and referred to in the primary section.  This would allow the CSR to present the 
integrated safety and efficacy information more succinctly. 
Tumor response will be assessed and the changes between Baseline and pre-Prostatectomy evaluated and tabulated 
for the following: 
• 
Gleason score of dominant lesion as determined from biopsy samples. 
• 
Proportion of dominant lesion designated as adenocarcinoma as determined from biopsy samples. 
• 
Proportion of subjects with local invasion as measured by mpMRI. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Further evaluation of tumor response will be assessed and the changes between Baseline and pre-Prostatectomy 
evaluated and tabulated for the following: 
• 
Change in volume of dominant lesion as measured by mpMRI. 
• 
Change in PSA Density 
• 
Change in PI-RADS Score 
To address the additional secondary objective of the concentration of paclitaxel in the systemic circulation, 
concentration data collected as outlined below will, at a minimum be listed: 


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• 
PK samples taken at 1 and 2 hours post-injection at the first injection, and pre-injection, 1 and 2 hours 
post-injection at second and/or third injection visits,  and at all other study visits 
• 
Presence or absence of ejaculate paclitaxel concentration data for Days 15, 43, 57, and end of study Day 
85. 
• 
Presence/absence of paclitaxel in the tumor within the prostate, the ipsilateral lobe of the prostate, the 
contralateral lobe of the prostate, and pelvic lymph nodes.  
10.4.4 SAFETY ANALYSES 
Although the focus of the safety assessment is the interpretation of the AEs as these would contain any relevant 
changes throughout the study which could be seen as a safety signal, the laboratory data, vital signs will be 
presented as traditional safety displays. 
Adverse events will be coded using the MedDRA dictionary.  The events will be summarized by frequency and 
subset by grade/severity and relatedness.  Serious AEs and DLTs will be highlighted with a focus on time to onset 
and duration.  Events of special interest will be noted in the SAP and presented separately.  It is anticipated that 
the AEs will also be presented by injection number and any AEs related to the injection process highlighted.  These 
decisions will be made after the accumulating data is reviewed by the medical monitor.  All decisions will be 
recorded in the SAP. 
The vital signs raw data, collected at each visit, and changes from Day 1 will be tabulated and listed. 
The laboratory analyses will be presented in summary tables with changes from Screening to Day 85. By applying 
the normal ranges (high, normal, and low) shift tables will be generated. Values which are noted by the Investigator 
to be abnormal and clinically relevant will be summarized separately as will any analytes where the shift in category 
is greater than two (e.g., high to low or low to high). 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
 All subjects who are enrolled and treated in the trial will be accounted for. Subjects terminating early will be noted 
and the reasons provided. 
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Complete demographic, medical (coded in MedDRA), and disease history will be summarized. 
10.4.7 PLANNED INTERIM ANALYSES  
An interim analysis is not planned as inferential analyses are not part of the analysis plan.     
10.4.7.1 
SAFETY REVIEW 
The Medical Monitor will monitor safety throughout the study (Section 8.6).  Therefore, no additional safety 
review is planned. 
10.4.7.2 
EFFICACY REVIEW 
There are several assessments which will provide some preliminary efficacy information, and details are included 
in Sections 10.4.2, 10.4.3, and 10.4.11. 


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10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
 Not applicable. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable. 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
All data collected in the trial and any calculated outcomes derived from this data will, at a minimum, be listed with 
the dose group, subject identifier and a timepoint, if relevant. The organization of the listings will support the 
writing of the CSR as outlined in the ICH E3 guidelines. 
10.4.11 
EXPLORATORY ANALYSES 
The changes in the PROs from Baseline to Day 85 will be summarized for the SHIM, the I-PSS and the NIH-CPSI and 
reviewed to provide insight on the possible changes in well-being.  
IHC will be performed on slides obtained from the tumor excised at prostatectomy, and where available on slides 
from the ipsilateral and contralateral lobes of the prostate, and on a subset of lymph nodes excised during 
prostatectomy, and the data will be tabulated (as possible). 
The FCM data will be reviewed on a quarterly basis.  At a minimum all data collected will be listed in the final 
report.   
10.4.12 
CONCOMITANT MEDICATION 
All medication taken during the trial will be, at a minimum, listed with the start and stop date, and  will be coded 
using the World Health Organization (WHO) Drug Dictionary. 
10.5 
SAMPLE SIZE 
The trial has been designed to assess the safety of the 15 mg/mL dose injected three times across an 85-day 
timeframe.  The procedure nQuery Advisor version 8,  POC 2-1 confidence interval for probability of observing a 
rare event, indicates that with 18 subjects the probability of detecting an event that occurs with a base rate of 0.1 
is 85.0%, with a base rate of 0.05 is 60.3% and for a base rate of 0.01 is 16.5%.  
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Not applicable. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable. 


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10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
An eCRF is required and must be completed for each consenting and enrolled subject by qualified and authorized 
personnel. Subjects who fail the screening assessments will not have an eCRF. All data in the eCRF must reflect the 
corresponding source documents. Any corrections to entries made on the eCRF must be documented in a valid 
audit trail. Only data required by the protocol for the purposes of the study should be collected within the EDC. 
The Investigator must maintain adequate and accurate source documents on which the eCRFs for each subject are 
based. They will be separate and distinct from the eCRFs. These records should include detailed notes on: 
• 
Medical history prior to the subject’s involvement in the study; 
• 
Date of informed consent; 
• 
Basic identifying information that links the subect’s medical record with the eCRFs; 
• 
Results of all diagnostic tests performed, diagnoses made, therapy provided, and any other data on the 
condition of the subject; 
• 
Medical condition during the subject’s involvement in the study; 
• 
All Adverse Events; 
• 
Subject’s exposure to the study agent; 
• 
Subject’s exposure to any concomitant therapy; 
• 
All relevant observations and data on the condition of the subject throughout the trial; 
• 
Justification for all entries in the subject’s eCRF.  
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Data required by the protocol will be collected and entered into a validated data management system that is 
compliant with all regulatory requirements. The eCRF is an electronic document designed to record all of the 
protocol-required information to be reported to the Sponsor on each study subject. 
Data recording must follow the instructions described in the CRF Completion Guidelines. The PI has ultimate 
responsibility for the collection and reporting of all clinical data entered on the eCRF. The PI or designee, as 
identified on Form FDA 1572, must electronically sign the completed eCRF for each participating subject to attest 
to its accuracy, authenticity, and completeness. 
The EDC application being used in this study is TrialMaster® version 5.0 from OmniComm Systems. TrialMaster 
studies are hosted from a state-of-the-art data center with rigorous physical and electronic security. All data is 
backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof bunker in Fort Lauderdale, 
Florida. OmniComm has achieved certification with European “Safe Harbor” regulations, meaning that all 
necessary measures are in place to protect subject confidentiality even with the data being stored in a US data 
center. The data management and statistical clinical research organization (CRO), McDougall Scientific Ltd., 
ensures that the development of the eCRF follows their SOPs which are based on the Systems Development Life 
Cycle (SDLC) methodology. Access to the system is restricted by username and password; these are controlled by 
the Data Management CRO. All personnel using the system will be trained and the training documented. All 


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changes to the database are recorded in an audit trail. The database will be locked when all outstanding queries 
have been addressed, all agreed to data is marked as source verified, and the PI has signed off on the eCRF 
contents.  
All software applications used in the collection of data will be properly validated following standard computer 
system validation that is compliant with all regulatory requirements. 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki. Sponsor and 
Investigator will comply with their responsibilities as defined in 21 CFR 312.50-312.70. 
13.2 
INSTITUTIONAL REVIEW BOARD  
Before the start of the study, the study protocol, informed consent form and/or other appropriate documents will 
be submitted to the IRB and/or the authorities in accordance with local legal requirements. It is the responsibility 
of the Investigator to ensure that all aspects of the IRB review are conducted in accordance with current 
regulations. US Biotest and the Investigator must inform each other in writing that all ethical and legal 
requirements have been met before the first subject is enrolled in the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. All changes to the 
consent form will be IRB-approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Subjects being considered for participation in this study will be provided an informed consent form (ICF) to read 
and sign before being permitted to participate. The ICF will describe the study agent and any prior findings from 
previous studies; study procedures including the timing of study clinic visits and their responsibilities to adhere to 
those timelines; any risks which may be associated with the study agent or the procedures being carried out in the 
study; and all other items required under 21 CFR Part 50.25.  
Subjects will be required to provide signed consent prior to the performance of any study-related procedures. The 
Investigator is required to document the process for obtaining informed consent in the source notes. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The Investigator will obtain informed consent from each subject enrolled in the study, in accordance with the U.S. 
FDA regulations 21 CFR 50.20 - 50.27 and the laws and regulations of the state in which the investigation is being 
conducted. The IRB must approve the ICF to be used by the Investigator. The Investigator will provide the Sponsor 
with a copy of the written approval generated by the IRB or Ethics Committee before the Investigator will be 
permitted to enroll subjects into the study. 


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It is the responsibility of the Investigator to ensure that informed consent is obtained from the subject or his/her 
guardian or legal representative before any activity or treatment is undertaken which is not part of routine care. 
This includes, but is not limited to, the performance of diagnostic or therapeutic procedures and the 
administration of the first dose of study agent. The draft version of the informed consent document will be 
modified by each site and reviewed and approved in writing by US Biotest prior to submission to the IRB. 
Should a protocol amendment be made, the subject consent form may be revised to reflect the changes of the 
protocol. If the consent form is revised, it is the responsibility of the Investigator to ensure that an amended 
consent is approved by the IRB and signed by all subjects currently on study as well as those subsequently entered 
in the study. 
The Investigator will not undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The terms of the consent and when it was obtained must also be documented in the 
eCRF. The original, signed informed consent document must be maintained on file at the study site and be made 
available for review during monitoring visits and site audits. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
All local legal requirements regarding data protection will be enforced. All study findings and documents will be 
regarded as confidential. The Investigator and members of his/her research team must not disclose such 
information without prior written approval from US Biotest.  
The anonymity of participating subjects must be maintained to the extent required by law. Throughout 
documentation and evaluation, the subjects will be identified on eCRFs and other documents submitted to US 
Biotest by their initials, birth date, and subject number. The subjects will be told that all study findings will be 
stored and handled in strictest confidence, according to legal requirements, but will be informed that authorized 
research Investigators and agents of the FDA and authorized personnel of US Biotest have the right to inspect their 
medical records. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Samples and data collected under this protocol are specifically for use in the evaluation and analyses being 
conducted in the study. Samples will not be available for purposes other than indicated within this protocol, and 
no genetic testing will be performed. 
Access to stored samples will be limited to personnel authorized to have access at the site prior to shipping to the 
laboratories for analysis/assessment. Samples will be stored using codes assigned by the Sponsor or as required by 
the clinical laboratories.  
Samples will only be retained until analysis is complete, following which samples will be disposed of according to 
the laboratory SOPs. No samples will be retained for any future use. 
Data will be kept in password-protected computers. Only Investigators and those delegated responsibility on the 
Delegation of Authority Log will have access to the samples and data. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Not applicable. 


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14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
Investigator is responsible for ensuring the data is ALCOA-C compliant.   
For electronic source, the institution must provide a secure, validated electronic medical record (EMR) data 
management system that is 21 CFR Part 11 compliant and meets all regulatory requirements, regulations and 
quality standards. 
For paper source, documentation is expected to be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies.  
Source documents will be maintained for recording data for each participant enrolled in the study. Data reported 
in the eCRF derived from source documents should be consistent with the source documents. Any discrepancies 
should be explained and captured in a progress note and maintained in the subject’s official electronic study 
record. 
The EDC application being used in this study is TrialMaster version 5.0 from OmniComm Systems (see Section 12 
Quality Assurance and Quality Control).  
Data recording must follow the instructions described in the eCRF Completion Guidelines. The PI has ultimate 
responsibility for the collection and reporting of all clinical data entered on the eCRF. The PI or designee, as 
identified on the Delegation of Responsibilities Log (and included on Form FDA 1572), must electronically sign 
the completed eCRF to attest to their accuracy, authenticity, and completeness. 
The database will be locked when all outstanding queries have been addressed, all agreed to data is marked as 
source verified, and the PI has signed off on the eCRF contents. 
14.2 
STUDY RECORDS RETENTION  
The Investigator must retain a copy of all study documents in accordance with the FDA or local regulations, 
whichever are the more stringent. 
The Investigator must maintain study documents: 
• 
For a minimum of two years following the date the marketing application (NDA) is approved for the 
indication for which the drug was investigated for;  
• 
For a minimum of two years following the release date of the final report, if no marketing application is 
to be filed, or if the marketing application is not approved for the indication of which the drug was 
investigated or is discontinued and the FDA has been notified; or, 
• 
For a minimum of 15 years after the completion or discontinuation of the study to be filed in support of 
the registration in the European Union. 


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If the Investigator relocates, retires or withdraws from the study for any reason, the study records may be 
transferred to an acceptable designee, such as another Investigator, another institution, or the Sponsor. The 
Investigator must obtain the Sponsor’s written permission before transferring or disposing of any records. 
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), FDA or IRB 
requirements. The noncompliance may be either on the part of the participant, the Investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
These practices are consistent with ICH E6 (R2):  
• 
4.5:  Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1:  Quality Assurance and Quality Control, Section 5.1.1  
• 
5.20:  Noncompliance, Sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations as soon as possible 
after occurrence and identification of the protocol deviation. All deviations must be addressed in study source 
documents, reported to the Sponsor and to the Data Management group.  
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB requirements.  
Serious non-compliance on the part of the site, and an inability of the Sponsor to bring the site back into 
compliance, will be reported to the FDA in accordance with their requirements.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the purposes of 
national and international registration, publication, and information for medical and pharmaceutical professionals. 
If necessary, the authorities will be notified of the Investigator's name, address, qualifications, and extent of 
involvement. The Sponsor will prepare an integrated clinical/statistical report. Publication/presentation of data is 
not allowed without explicit permission from US Biotest. Submission of data for publication/presentation will be 
coordinated and approved by US Biotest in collaboration with the Investigator. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials 
registration policy as a condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include 
drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in subjects or participants, including PK measures and 
AEs. The ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by 
the National Library of Medicine. Data entered to the ClinicalTrials.gov website will be in accordance with the FDA 
requirements for this registration and for publication of study results on that site. 


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15 
STUDY ADMINISTRATION 
The study will be overseen by the Study Manager who will be responsible, together with the Investigator, for 
tracking enrollment, timelines, and deliverables, and other study-related performance. 
All questions regarding the enrollment of subjects, regulatory requirements for the conduct of the study, safety 
reporting, or study conduct should be addressed to the Study Manager or Site Monitor designated by the Sponsor. 
Contact information for the Sponsor is provided near the beginning of this protocol and will be provided to the 
Investigator in separate study documents. 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical and therefore any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the trial. As required by the FDA, a Financial Disclosure Form will be completed by each person 
noted on the FDA Form 1572 for this study at the site, the original will be filed in the TMF, and a copy will remain 
in the site’s regulatory binder. 
17  
LIABILITY AND INSURANCE  
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with all local legal 
requirements. This insurance will cover all parties involved in the trial including, but not necessarily limited to, the 
PI, clinical trial site, and subjects.  
 
 


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18  
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orthotopic prostate cancer. J Pharmaceutic Sci. 2008;98(3):1005-1014. 
Sonpavde G, Thomson TC, Jain RK, Ayala GE, Kurosaka S, Edamura K. GLIPR1 tumor suppressor gene expressed by 
adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer 
preceding radical prostatectomy. Clin Cancer Res. 2011 Nov 15;17(2):1-19. 
Trudel S, Trachtenberg J, Toi A, Sweet J, Li ZH, Jewett M, et al. A Phase I trial of adenovector-mediated delivery of 
interleukin-2 (AdIL-2) in high-risk localized prostate cancer. Cancer Gene Therapy. 2003;10:755-763. 
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van Soest RJ & de Wit R. Irrefutable evidence for the use of docetaxel in newly diagnosed metastatic prostate 
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Werehera PN, Glode LM, La Rosa FG, Lucia MS, Crawford ED, Easterday K, et al. Proliferative tumor doubling times 
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APPENDIX A: ECOG PERFORMANCE SCALE 
 
Patient performance status will be graded according to the Eastern Cooperative Oncology Group (ECOG) scale* as 
described below.  
 
Grade ECOG PERFORMANCE STATUS DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982.  
 
 
 


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APPENDIX B: SEXUAL HEALTH INVENTORY FOR MEN (SHIM) 
 
 
 


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APPENDIX C: INTERNATIONAL PROSTATE SYMPTOM SCORE (I-PSS) 
 


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APPENDIX D: NIH CHRONIC PROSTATITIS SYMPTOM INDEX (NIH-CPSI) 
   
 


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APPENDIX E: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to regularly 
consult frequently updated medical references. 
CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil4,5 
amiodarone4 
aprepitant5  
atorvastatin5 
benzodiazepines 
bortezomib  
brentuximab  
budesonide5  
buspirone5 
calcium channel blockers  
cisapride 
citalopram/escitalopram 
conivaptan5 
glucocorticoids2  
crizotinib 
cyclosporine4 
cyclophosphamide 
dapsone  
darifenacin5  
darunavir5  
dasatinib5 
dihydroergotamine4 
docetaxel  
doxorubicin  
dronedarone5  
eletriptan5  
ergotamine4  
eplerenone5  
erlotinib  
esomeprazole  
estrogens  
etoposide  
everolimus5  
felodipine5  
fentanyl4  
fosaprepitant5  
gefitinib  
haloperidol 
HIV antiretrovirals  
HMG Co-A inhibitors5 
ifosfamide 
imatinib  
indinavir5  
irinotecan 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3  
imatinib 
mifepristone 
nilotinib 
verapamil 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
ciprofloxacin 
cyclosporine 
fluvoxamine 
fosaprepitant 
isoniazid 
nicardipine 
propofol 
quinidine 
ranolazine 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
echinacea 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids2 
modafinil  
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin  
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 


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CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
itraconazole 
ketoconazole  
lansoprazole  
lapatinib  
losartan  
lovastatin5  
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone  
midazolam5 
modafinil  
montelukast 
nefazodone  
nilotinib  
nisoldipine5  
omeprazole 
ondansetron 
paclitaxel  
pazopanib  
quetiapine5  
quinidine4  
saquinavir5  
sildenafil5  
simvastatin5 
sirolimus4,5  
sunitinib  
tacrolimus4,5 
telaprevir  
tamoxifen 
temsirolimus  
teniposide  
tetracycline  
tipranavir5  
tolvaptan5  
triazolam5  
trimethoprim  
vardenafil5  
vinca alkaloids  
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) 
may inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown. 
2 Dexamethasone is considered a weak CYP3A4 inducer. 
3 The  effect  of  grapefruit juice  (strong  vs  moderate  CYP3A4  inhibition) varies  widely among  brands  and  is 
concentration-, dose-, and preparation-dependent. 
4 Narrow therapeutic range substrates 
5 Sensitive substrates 
Websites: https://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687;  
https://www.ebmconsult.com/articles/medications-inhibitors-cyp3a4-enzyme