Conditions: Adenocarcinoma of the Prostate
Keywords: prostate cancer prostatic neoplasms genital neoplasms, male urogenital neoplasms prostatic diseases
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 16
Healthy volunteers: no

Brief summary:
Open-label, dose rising, Phase IIa trial of intratumorally-injected NanoPac® 6, 10, or 15 mg/mL in subjects with prostate cancer scheduled for prostatectomy.

Detailed description:
In this open-label, dose rising, Phase IIa trial with an expanded cohort at the dose of NanoPac® determined to have the best tolerability and safety profile, subjects with prostate cancer scheduled for prostatectomy will have NanoPac® injected under image guidance directly into the lobe of the prostate with the dominant lesion 4 weeks prior to prostatectomy. The study will include a dose escalation phase and a dose confirmation phase.

In the dose escalation phase, NanoPac® concentrations of 6, 10, and 15 mg/mL in an injection volume of 20% of the lobe of the prostate containing the dominant lesion will be studied in cohorts of 3, with cohorts enrolled sequentially starting at the lowest concentration. Following DSMB review of the cohort data the next cohort may begin enrolling, or an additional 3 at the current dose may be enrolled, or if the first dose does not provide adequate safety and tolerability the study may be halted. The dose determined to be the most suitable for further evaluation, defined as the highest dose with an acceptable safety and tolerability profile as determined by the DSMB, will enroll additional subjects to provide a cohort of 12 subjects at that dose level.

Tumor volume and serum prostate-specific antigen (PSA) will be determined prior to NanoPac® injection. Pharmacokinetic samples, PSA, and ejaculate will be collected in the interval between injection and prostatectomy. Imaging with mpMRI will be performed prior to NanoPac® injection and prior to prostatectomy. Prostate and pelvic lymph nodes excised at prostatectomy will be evaluated.

Arms:
arm 1: NanoPac® 6 mg/mL injected into the prostate lobe containing the dominant lesion at a volume of 20% prostate lobe volume arm 2: NanoPac® 10 mg/mL injected into the prostate lobe containing the dominant lesion at a volume of 20% prostate lobe volume arm 3: NanoPac® 15 mg/mL injected into the prostate lobe containing the dominant lesion at a volume of 20% prostate lobe volume

Interventions: intervention 1: NanoPac®
Intervention descriptions: intervention 1: Subjects with prostate cancer scheduled for prostatectomy will have NanoPac® injected intratumorally under image guidance directly into the lobe of the prostate with the dominant lesion 4 weeks prior to prostatectomy.

Protocol document:
Prot_000.pdf: 
Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2016-02 
NanOlogy, LLC 
Version 3.0 
 
08 August 2017 
CONFIDENTIAL 
 
i 
Phase IIa Dose Escalation Trial of NanoPac Focal 
Therapy for Prostate Cancer in Subjects Undergoing 
Radical Prostatectomy  
 
Protocol Identifying Number:  NANOPAC-2016-02 
Principal Investigator:  Inderbir S. Gill, MD, MCh 
IND Sponsor:  NanOlogy, LLC. 
Version Number:  3.0 
Date:  08 August 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2016-02 
NanOlogy, LLC. 
Version 3.0 
 
08 August 2017 
CONFIDENTIAL 
 
ii 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................................................... v 
SPONSOR SIGNATURE PAGE ............................................................................................................................. vii 
STATEMENT OF COMPLIANCE .......................................................................................................................... viii 
PROTOCOL SUMMARY .......................................................................................................................................... ix 
SCHEMATIC OF STUDY DESIGN ......................................................................................................................... xi 
1 
KEY ROLES .................................................................................................................................................... 1 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................ 2 
2.1 
Background Information ...................................................................................................................... 2 
2.2 
Rationale ............................................................................................................................................... 4 
2.3 
Potential Risks and Benefits .............................................................................................................. 4 
2.3.1 
Known Potential Risks ..................................................................................................... 4 
2.3.2 
Known Potential Benefits ................................................................................................ 4 
3 
OBJECTIVES AND PURPOSE .................................................................................................................... 4 
4 
STUDY DESIGN AND ENDPOINTS ........................................................................................................... 5 
4.1 
Description of the Study Design ........................................................................................................ 5 
4.1.1 
Primary Endpoint .............................................................................................................. 5 
4.1.2 
Secondary Endpoints ...................................................................................................... 5 
4.1.3 
Exploratory Endpoints ..................................................................................................... 6 
5 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................... 6 
5.1 
Participant Inclusion Criteria .............................................................................................................. 6 
5.2 
Participant Exclusion Criteria ............................................................................................................. 6 
5.3 
Strategies for Recruitment and Retention ........................................................................................ 7 
5.4 
Participant Withdrawal or termination ............................................................................................... 7 
5.4.1 
Reasons for Withdrawal or Termination ....................................................................... 7 
5.4.2 
Handling of Participant Withdrawals or Termination ................................................... 7 
5.5 
Premature Termination or Suspension of Study ............................................................................. 8 
6 
STUDY AGENT .............................................................................................................................................. 8 
6.1 
Study Agent(s) and Control Description ........................................................................................... 8 
6.1.1 
Acquisition ......................................................................................................................... 8 
6.1.2 
Formulation, Appearance, Packaging, and Labeling .................................................. 9 
6.1.3 
Product Storage and Stability ......................................................................................... 9 
6.1.4 
Preparation ........................................................................................................................ 9 
6.1.5 
Dosing and Administration ............................................................................................ 10 
6.1.6 
Route of Administration ................................................................................................. 10 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 10 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 11 
6.1.9 
Duration of Therapy ....................................................................................................... 11 
6.1.10 
Tracking of Dose ............................................................................................................ 12 
6.1.11 
Device Specific Considerations ................................................................................... 12 
6.2 
Study Agent Accountability Procedures ......................................................................................... 12 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 12 
7.1 
Study Procedures/Evaluations ......................................................................................................... 12 
7.1.1 
Study Specific Procedures ............................................................................................ 12 
7.1.2 
Standard of Care Study Procedures ........................................................................... 13 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 13 


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7.2.1 
Clinical Laboratory Evaluations .................................................................................... 13 
7.2.2 
Other Assays or Procedures ........................................................................................ 13 
7.2.3 
Specimen Preparation, Handling, and Storage ......................................................... 14 
7.2.4 
Specimen Shipment ....................................................................................................... 14 
7.3 
Study Schedule .................................................................................................................................. 14 
7.3.1 
Screening ........................................................................................................................ 14 
7.3.2 
Enrollment/Baseline ....................................................................................................... 15 
7.3.3 
Follow-up ......................................................................................................................... 16 
7.3.4 
Final Study Visit .............................................................................................................. 17 
7.3.5 
Early Termination Visit .................................................................................................. 18 
7.3.6 
Unscheduled Visits ........................................................................................................ 18 
7.3.7 
Schedule of Events Table ............................................................................................. 19 
7.4 
Justification for Sensitive Procedures ............................................................................................. 21 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 21 
7.6 
Precautionary Medications, Treatments, and Procedures .......................................................... 21 
7.7 
Prohibited Medications, Treatments, and Procedures ................................................................. 21 
7.8 
Prophylactic Medications, Treatments, and Procedures ............................................................. 21 
7.9 
Rescue Medications, Treatments, and Procedures ..................................................................... 21 
7.10 
Participant Access to Study Agent At Study Closure ................................................................... 21 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 22 
8.1 
Specification of Safety Parameters ................................................................................................. 22 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 23 
8.2 
Classification of an Adverse Event ................................................................................................. 23 
8.2.1 
Severity of Event ............................................................................................................ 23 
8.2.2 
Relationship to Study Agent ......................................................................................... 23 
8.2.3 
Expectedness ................................................................................................................. 23 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 24 
8.4 
Reporting Procedures ....................................................................................................................... 24 
8.4.1 
Adverse Event Reporting .............................................................................................. 24 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 24 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 25 
8.4.4 
Events of Special Interest ............................................................................................. 25 
8.4.5 
Dose Limiting Toxicity.................................................................................................... 26 
8.4.6 
Reporting of Pregnancy ................................................................................................ 26 
8.5 
Study Halting Rules ........................................................................................................................... 27 
8.6 
Safety Oversight ................................................................................................................................ 27 
9 
CLINICAL MONITORING ............................................................................................................................ 27 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 28 
10.1 
Statistical and Analytical Plans ........................................................................................................ 28 
10.2 
Statistical Hypotheses ....................................................................................................................... 28 
10.3 
Analysis Datasets .............................................................................................................................. 28 
10.4 
Description of Statistical Methods ................................................................................................... 28 
10.4.1 
General Approach .......................................................................................................... 28 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 


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10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 29 
10.4.4 
Safety Analyses .............................................................................................................. 29 
10.4.5 
Adherence and Retention Analyses ............................................................................ 29 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 29 
10.4.7 
Planned Interim Analyses ............................................................................................. 30 
10.4.8 
Additional Sub-group Analyses .................................................................................... 30 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 30 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 30 
10.4.11 
Exploratory Analyses ..................................................................................................... 30 
10.4.12 
Concomitant Medication................................................................................................ 30 
10.5 
Sample Size ....................................................................................................................................... 31 
10.6 
Measures to Minimize Bias .............................................................................................................. 31 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 31 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 31 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 31 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 31 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 32 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 32 
13.1 
Ethical Standard ................................................................................................................................. 32 
13.2 
Institutional Review Board ................................................................................................................ 32 
13.3 
Informed Consent Process ............................................................................................................... 33 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants.... 33 
13.3.2 
Consent Procedures and Documentation .................................................................. 33 
13.4 
Participant and data Confidentiality ................................................................................................ 33 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 34 
13.5 
Future Use of Stored Specimens .................................................................................................... 34 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 34 
14.1 
Data Collection and Management Responsibilities ...................................................................... 34 
14.2 
Study Records Retention .................................................................................................................. 35 
14.3 
Protocol Deviations............................................................................................................................ 35 
14.4 
Publication and Data Sharing Policy ............................................................................................... 36 
15 
STUDY ADMINISTRATION ........................................................................................................................ 36 
15.1 
Study Leadership ............................................................................................................................... 36 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 37 
17  
LIABILITY AND INSURANCE .................................................................................................................... 37 
18  
LITERATURE REFERENCES.................................................................................................................... 38 
APPENDIX A: ECOG Performance Scale ............................................................................................................ 41 
APPENDIX B: Sexual Health Inventory for Men (SHIM) ..................................................................................... 42 
APPENDIX C: International Prostate Symptom Score (I-PSS) .......................................................................... 43 
APPENDIX D: National Institutes of Health Prostatitis Symptoms Questionnaire .......................................... 44 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ASP 
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 
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 
IND 
Investigational New Drug Application 
IP 
Intraperitoneal 
I-PSS 
International Prostate Symptom Score Questionnaire 
IRB 
Institutional Review Board 
IRE 
Irreversible Electroporation 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mpMRI 
Multiparametric MRI 
MRI 
Magnetic Resonance Imaging 
MR-TRUS 
Magnetic Resonance Imaging-Transrectal Ultrasound Fusion 
NCI 
National Cancer Institute 
NDA 
New Drug Application (Marketing Application) 
OHRP 
Office for Human Research Protections 


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PCA 
Precipitation with Compressed Antisolvents 
pCR 
Pathologic Complete Response 
pH 
Hydrogen Ion Concentration 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PSA 
Prostate-Specific Antigen 
PT 
Prothrombin Time 
PTT 
Activated Partial Thromboplastin Time 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SDLC 
Systems Development Life Cycle 
SHIM 
Sexual Health Inventory for Men Questionnaire 
SOC 
Standard of Care 
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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STATEMENT OF COMPLIANCE 
I have read the attached protocol number NANOPAC-2016-02 entitled, Phase IIa Dose Escalation Trial of NanoPac 
Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy, Version 3.0 dated 08 August 2017 
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 IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2016-02 
NanOlogy, LLC. 
Version 3.0 
 
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CONFIDENTIAL 
 
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PROTOCOL SUMMARY 
Title: 
Phase IIa dose escalation trial of NanoPac focal therapy for prostate cancer in subjects 
undergoing radical prostatectomy 
 
Précis: 
In this open-label, dose rising, Phase IIa trial with an expanded cohort at the dose of NanoPac 
determined to have the best tolerability and safety profile, subjects with prostate cancer 
scheduled for prostatectomy will have NanoPac injected under image guidance directly into 
the lobe of the prostate with the dominant lesion four weeks prior to prostatectomy. The 
study will include a dose escalation phase and a dose confirmation phase. 
 
In the dose escalation phase, NanoPac concentrations of 6, 10, and 15 mg/mL in an injection 
volume of 20% of the lobe of the prostate containing the dominant lesion will be studied in 
cohorts of three, with cohorts enrolled sequentially starting at the lowest concentration. 
Following Data Safety Monitoring Board (DSMB) review of the cohort data the next cohort 
may begin enrolling, an additional three at the current dose may be enrolled, or if the first 
dose does not provide adequate safety and tolerability the study may be halted. The dose 
determined to be the most suitable for further evaluation, defined as the highest dose with 
an acceptable safety and tolerability profile as determined by the DSMB, will enroll additional 
subjects to provide a cohort of 12 subjects at that dose level.    
 
Tumor volume and serum prostate-specific antigen (PSA) will be determined prior to 
NanoPac injection. Pharmacokinetic samples, PSA, and ejaculate will be collected in the 
interval between injection and prostatectomy. Imaging with multiparametric MRI (mpMRI) 
will be performed within three months prior to consent and again prior to prostatectomy. 
Prostate and pelvic lymph nodes excised at prostatectomy will be evaluated. 
 
Objectives: 
 
Primary objective: 
• 
To evaluate the safety and tolerability of NanoPac injected directly into the lobe of 
the prostate containing the dominant lesion. 
 
 
Secondary objectives:  
• 
To describe the pharmacokinetics (PK) of NanoPac injected directly into the lobe of 
the prostate containing the dominant lesion; 
• 
To determine the effect of NanoPac on the tumor within the prostate, the ipsilateral 
lobe of the prostate, the contralateral lobe of the prostate, and pelvic lymph nodes. 
 
Endpoints: 
Primary endpoint:  
• 
Safety and tolerability, as demonstrated by adverse events (AE), changes in 
laboratory assessments, physical examination findings, and vital signs. 
 
 
Secondary endpoints: 
• 
Concentration of paclitaxel in the systemic circulation post-injection and prior to 
prostatectomy; 
• 
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; 
• 
Tumor response (change in image volume on mpMRI; histologic evaluation via 
biopsy); 


Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
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• 
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.  
 
Population: 
Up to a maximum of 30 men with adenocarcinoma of the prostate scheduled for radical 
prostatectomy 
 
Phase: 
Phase IIa 
 
Number of 
Sites Enrolling 
Participants: 
Up to two 
Description of 
Study Agent: 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (“NanoPac”) for direct 
injection into the lobe of the prostate containing the dominant lesion at concentrations of 6, 
10, 15 mg/mL in an injection volume of 20% of the lobe of the prostate containing the 
dominant lesion. 
 
Study Duration: 
The study duration will be up to 12 months. 
 
Participant 
Duration: 
The study duration is estimated to be approximately 9 weeks for each subject. Additional 
follow-up may occur. 
 
 
 


Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2016-02 
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SCHEMATIC OF STUDY DESIGN 
 


Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
 Protocol NANOPAC-2016-02 
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08 August 2017 
CONFIDENTIAL 
 
1 
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 Manager 
Shelagh Verco, PhD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-704-1179 
shelagh.verco@usbiotest.com 
 
Principal Investigator 
Inderbir S. Gill, MD, MCh 
Chairman & Professor, Catherine and Joseph Aresty Department of Urology 
Associate Dean, Clinical Innovation, USC Keck School of Medicine 
Founding Executive Director, USC Institute of Urology 
1441 Eastlake Avenue, Los Angeles, CA 90033 
323-865-3794 
inderbir.gill@med.usc.edu 
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 Paclitaxel Concentration & Ejaculate 
Frontage Laboratories, Inc. 
700 Pennsylvania Drive, Exton, PA 19341 
610-232-0100 
Laboratory – Prostate Tissue Tumor Cells 
Department of Pathology, Keck School of Medicine of USC, Hoffman Medical Research Center 
2011 Zonal Avenue #211, Los Angeles, CA 90089-9092 
323-442-1179 


Phase IIa Trial:  NanoPac Focal Therapy for Prostate Cancer in Subjects Undergoing Radical Prostatectomy 
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Laboratory – Routine Hematology and Biochemistry 
University of Southern California Immunohistochemistry Laboratory 
2011 Zonal Ave. HMR #301/308, Los Angeles, CA 90033 
323-442-1156 
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 studies of NanoPac in the PC-3 human prostate carcinoma nude mouse 
tumor xenograft model, Study PC3-e317 and Study PC3-e319.  
In Study PC3-e317, 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. Treatment with either a single dose or three 
once-weekly doses of 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 PC3-e319, the efficacy of NanoPac was evaluated as part of a NanoDoce (nanodocetaxel) trial in female 
NCI Ath/nu mice. NanoPac was administered intra-tumorally (itu) 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. 
Results for all NanoPac-treated animals were indicative of potential therapeutic activity. Additional data is 
presented in the NanoPac Investigator’s Brochure. 


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Clinical Summary: 
NanoPac has not been administered to humans via direct injection into the prostate. The only clinical study of 
NanoPac to date was Protocol HSC#11140, “A Phase I Study of Intraperitoneal Nanoparticle Paclitaxel in Patients 
with Peritoneal Malignancies.” The results of this study were published by Williamson et al. (2015) in the journal 
Cancer Chemotherapy and Pharmacology. 
Protocol HSC#11140 was a dose-escalating study evaluating intraperitoneally (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 patients were enrolled in Protocol HSC#11140. 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 patient. 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 of the 21 subjects. Four subjects were assessed as stable or had 
no response and twelve patients had progressive disease. Five of 21 patients with advanced cancers survived 
longer than 400 days after initiation of IP NanoPac treatment. 
Additional data from this clinical trial is presented in the NanoPac Investigator’s Brochure.  
Relevant Literature: 
To date, clinical studies of paclitaxel injected directly into the prostate have not been published. However, several 
authors have reported results from human trials involving intraprostatic injection of various other agents (such as 
viral vectors) for the treatment of local prostate cancer (DeWeese et al. 2001; Johannsen et al. 2007a; Johannsen 
et al. 2007b; Finkelstein et al. 2012; Trudel et al. 2003; Pisters et al. 2004; Gulley et al. 2013; Kramer et al. 2001; 
Sonpavde et al. 2011; Patel et al. 2009; Shalev et al. 2000; Fujita et al. 2006; Belldegrun et al. 2001; van der Linden 
et al. 2005; Freytag et al. 2002). Further, intravenous administration of paclitaxel, often in combination with other 
agents and/or radiotherapy, has demonstrated efficacy for the treatment of locally advanced and metastatic 
prostate cancer (Sanfilippo et al. 2008; Hudes et al. 1997; Shepard et al. 2009; Sewak et al. 2010; Hussain et al. 
2010; Urakami et al. 2002; Berry et al. 2004; Hudes et al. 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 (Marshall & Taneja, 
2015). 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 (Marshall & Taneja, 
2015). 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 & Taneja, 2015). As such, active surveillance not only risks disease progression, but can be 
psychologically distressing to patients.  


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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 et al. 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 et al. 2015). 
2.2 
RATIONALE  
This Phase IIa study will include patients with adenocarcinoma of the prostate scheduled to undergo a 
prostatectomy. The study design allows for a safety evaluation of direct injection of NanoPac into the lobe of the 
prostate containing the dominant lesion as focal therapy prior to prostatectomy. We hypothesize that direct 
injection of NanoPac into the prostate will result in limited, if any, systemic exposure to paclitaxel and should 
therefore result in only low-grade and transitory AE. 
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 et al. 2013, Shikanov et al. 2008; van Soest & de Wit 2015). Direct injection, as opposed 
to intravenous (IV) administration, of paclitaxel would allow for higher concentrations of drug to target local 
disease with reduced systemic toxicity. Intraprostatic NanoPac 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  
There are no known potential risks from intratumoral injection of NanoPac. 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  
Paclitaxel, the active pharmaceutical ingredient of NanoPac, is effective in the treatment of metastatic prostate 
cancer. 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. 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 injected directly into the 
lobe of the prostate containing the dominant lesion in patients diagnosed with prostate cancer. The secondary 
objectives are to describe the pharmacokinetics (PK) of NanoPac injected directly into the lobe of the prostate 
containing the dominant lesion; and to determine the effect of NanoPac on the tumor within the prostate, the 
ipsilateral lobe of the prostate, the contralateral lobe of the prostate, and pelvic lymph nodes.  
 


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4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
The proposed study is a Phase IIa, open-label, dose-escalating trial with an expanded cohort at the dose of 
NanoPac determined most suitable for further evaluation, defined as the highest dose with an acceptable safety 
and tolerability profile as determined by the Data Safety Monitoring Board (DSMB). Subjects will have NanoPac 
injected under magnetic resonance imaging-transrectal ultrasound fusion (MR-TRUS) guidance directly into the 
lobe of the prostate containing the dominant lesion. Four weeks after injection of NanoPac, the patient will 
undergo radical prostatectomy.  
Prior to study entry, subjects will undergo 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 ultrasound performed during this biopsy will also be used to calculate the volume of the entire 
prostate. The volume of the lobe of the prostate containing the dominant lesion will be determined by calculating 
50% of the total prostate volume as determined by ultrasound at the time of pre-study biopsy. 
The study will include a dose escalation phase and a dose confirmation phase. 
• 
Dose escalation: NanoPac concentrations of 6, 10, and 15 mg/mL in an injection volume of 20% of the 
lobe of the prostate containing the dominant lesion will be studied. Cohorts will be enrolled sequentially 
starting at the lowest concentration. Each cohort will have a planned minimum of three subjects. Data 
from the first three subjects in a cohort will be reviewed and evaluated by the DSMB. The outcome will be 
to determine whether to a) escalate to the next dose; b) add three additional subjects to the current 
dose; or c) expand the previous dose by three subjects.  
• 
Dose confirmation phase: Once the dose deemed appropriate for expansion and further evaluation has 
been determined, subjects will be enrolled to that dose to provide a total of 12 subjects dosed at that 
level. If two doses are similar, subjects will be enrolled to each of the doses; however, the total number of 
subjects treated will remain 12. 
 
4.1.1 PRIMARY ENDPOINT 
The primary endpoint will be safety and tolerability, as demonstrated by adverse events (AE), changes in 
laboratory assessments, physical examination findings, and vital signs. 
4.1.2 SECONDARY ENDPOINTS 
The secondary endpoints will be: 
• 
Concentration of paclitaxel in the systemic circulation post-injection and prior to prostatectomy; 
• 
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; 
• 
Tumor response (change in image volume on mpMRI; histologic evaluation via biopsy); 
• 
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. 
 
 
 


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4.1.3 EXPLORATORY ENDPOINTS 
Not applicable. 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Patients who meet the following criteria will be considered eligible for participation in the study: 
• 
Male; 
• 
At least 18 years of age; 
• 
Histopathologically proven adenocarcinoma of the prostate (Gleason grade ≥ 7);  
• 
Considered to be candidate for radical prostatectomy and 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 
Creatinine <2 mg/dL 
o 
Normal PT/INR and PTT; 
• 
ECOG of 0 or 1 (Appendix A); 
• 
Indication for radical prostatectomy; 
• 
Patient elects for radical prostatectomy; 
• 
If sexually active, willing to use double condoms from time of NanoPac injection until prostatectomy; 
• 
Signed informed consent; 
• 
Patient must be willing to receive an mpMRI. 
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; 
• 
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) 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 (i.e., radiation); 
• 
Any other condition (e.g., psychiatric disorder) that, in the opinion of the Investigator, may interfere with 
the patient’s ability to comply with the study requirements or visit schedule; 


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• 
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 30 subjects to be enrolled in the trial. It is not anticipated 
that any advertising will be required for recruiting to the study. Subjects will be recruited from the Investigators’ 
clinics and screened for eligibility and will proceed to treatment in groups of three.  
Accrual of subjects will 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 (Baseline/Treatment), and 
therefore in all study documentation this subject would be considered a screenfail subject. 
o 
Reasons for failing the screening will be documented in the source notes and in the EDC. 
There is no reason currently anticipated that would cause the Investigator to terminate a subject’s participation in 
the study. Once the treatment has been given it is very important that any events occurring be captured and 
followed for the safety of the subject.  
• 
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 AE, 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) 
which include vital signs, AE collection and concomitant medication updates.  


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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 in the cohort 
exists; however, the data that is collected from the non-compliant subject may still be used in the evaluations in 
this study. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminate 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 Sponsor. If the study is prematurely terminated or suspended, the PI will promptly inform 
the 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 requirement for an ad hoc meeting of the DSMB, 
and/or routine DSMB reviews, will allow for termination of study based on unacceptable risk, 
which will consider all safety evaluations and dose-limiting toxicities (DLT).   
o 
In the dose escalation phase, the study may be terminated if in the first dose cohort one third of 
the subjects experience the same DLT (as defined in Section 6.1.7).  
o 
In the expansion phase of the study, if one third of the subjects (i.e., 4 subjects) experience the 
same DLT, the study will be stopped. 
• 
Insufficient compliance with protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination of futility. 
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) 


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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 Instruction For 
Use (IFU) insert will be provided in each kit and an instructional video will be provided to each site prior to the 
initiation visit, ahead of the first patient being enrolled. The IFU will contain information on the reconstitution of 
the drug for all three dose levels, the storage of the drug once reconstituted, and the timeline permitted between 
reconstitution and use. 
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 and visit information 
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, the volume of the lobe of the prostate 
containing the dominant lesion and the 20% calculation, and noting the cohort to which the subject is assigned. 
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. 


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Once the drug has been reconstituted to the required dose (6, 10, or 15mg/mL, according to cohort assignment), 
the volume for use (being 20% of the lobe of the prostate with the dominant 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, 
the study agent will be administered via direct injection into the lobe of the prostate containing the dominant 
lesion four weeks prior to the scheduled prostatectomy. The dominant lesion is defined as the lesion with the 
highest Gleason score detected on biopsy prior to study enrollment. An enema will be performed 12 hours prior to 
the procedure to optimize ultrasound visualization.  
The patient 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 200mL, 
the injection procedure will be undertaken. If the volume is less than 200mL, the patient will be encouraged to 
drink water to increase the bladder volume to 200mL. A volume of 200mL is chosen to dilute any drug that can 
potentially extravasate into the bladder at the time of the prostate injection. The patient can have the option of a 
catheter being passed into the bladder to fill to the desired volume. 
  
After the procedure the patient will be asked to void 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. 
The patient 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 Halyard 22G x 10” Quinke Point 
needle connected to the syringe containing the study agent will be inserted transrectally into the lobe of the 
prostate containing the dominant lesion under real-time MR-TRUS guidance. The needle will be retained in the 
rectum and reinserted into different ipsilateral regions of the prostate several times in a fanning pattern to infuse 
the lobe of the prostate with NanoPac, avoiding the midline area of the prostate adjacent to the urethra.  
6.1.6 ROUTE OF ADMINISTRATION 
NanoPac will be injected directly into the lobe of the prostate containing the dominant lesion. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
NanoPac will be administered at concentrations of 6, 10, and 15 mg/mL in an injection volume of 20% of the lobe 
of the prostate containing the dominant lesion. The volume of the ipsilateral lobe of the prostate will be evaluated 
by ultrasound prior to study entry and this will be used for calculating the injection volume (Section 4.1).  
Cohorts will be enrolled sequentially starting at the lowest concentration. Each cohort will start with planned 
minimum of three subjects, each receiving a single dose of the study agent. Dose escalation to the next cohort will 
proceed following review of data by the DSMB. Total prostate volume, ipsilateral lobe volume (50% of prostate 
volume), NanoPac dose and NanoPac injection volume will be documented in the Subject’s record. 


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Data from the three subjects in a cohort, including all DLT described in this section will be reviewed and evaluated 
by the DSMB to determine whether the dose received is considered safe and tolerable, and to determine whether 
dose escalation may occur. DLT information will be collected in an ongoing manner from the time of dosing until 
prostatectomy. DLTs considered to be serious adverse events (SAE) will be reported within 24 hours (Section 
8.1.2). To determine dose escalation, the DSMB will review the data on the three subjects once they have 
completed the two-week follow-up visit, and will assess safety and tolerability based on the DSMB Charter. The 
DSMB will determine whether to:  
(a) escalate to the next dose level cohort (no DLT);  
(b) add three additional subjects to the current cohort (one DLT); or  
(c) return to the previous (lower) dose cohort and expand by three subjects (greater than one DLT).  
Included in the DSMB’s review of the AE and general study data pertaining to safety there will be rules for non-
escalation. Any adverse event 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 Principal 
Investigator for AE; DLT are described in Sections 8.4.4 and 8.4.5 and include the following: 
• 
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 2 toxicity lasting for ≥ one week; 
• 
Any delay of scheduled prostatectomy due to study drug related toxicity; 
• 
Symptomatic urine retention secondary to a study injection-related blockage of the prostatic urethra; 
• 
≥ Grade 3 febrile neutropenia (non-respondent to growth factors); 
• 
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; 
• 
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. 
 
The dose selected for further evaluation, defined as the highest dose with an acceptable safety and tolerability 
profile as determined by the DSMB, will enroll a total of 12 subjects. If one or fewer subjects in a six-subject 
cohort, or no subjects in a three-subject cohort at the highest dose, experience DLT, that cohort will be taken into 
the Dose Confirmation Phase. If greater than one subject in a six-subject cohort experience DLT, the previous dose 
will be taken into the Dose Confirmation Phase.  
 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
As this study is evaluating one single dose of NanoPac in each subject, there will be no dose adjustment or 
modification in an individual subject. 
6.1.9 DURATION OF THERAPY 
A single administration of NanoPac is being injected directly into the lobe of the prostate containing the dominant 
lesion; therapy does not continue over an extended period. 


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6.1.10 TRACKING OF DOSE 
Not applicable. 
6.1.11 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 patients (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 NanoPac administration, including review of previous medical records, demographics, and parity; 
• 
Review and documentation of concomitant prescription and non-prescription medications; 
• 
Review and documentation of diagnosis of adenocarcinoma of the prostate (including biopsy results, 
ultrasound results, and mpMRI results) 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 lobe containing the dominant lesion. A copy of the 
pathology report confirming the diagnosis must be filed in the subject’s study record;  
• 
Comprehensive physical examination, including ECOG Performance Status assessment (Appendix A), and 
vital signs (blood pressure, heart rate, temperature, body weight and height); 
• 
Sexual Health Inventory for Men (SHIM) [Appendix B], International Prostate Symptom Score (I-PSS) 
[Appendix C], and National Institutes of Health (NIH) Prostatic Symptoms Questionnaires [Appendix D] will 
be completed at screening and three days prior to prostatectomy; 
• 
Sample collection and processing for clinical laboratory assessments at screening/baseline, 7 days after 
injection (hematology and biochemistry only) 14 and 21 days after injection, and immediately prior to 
prostatectomy as follows: 
o 
Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood urea 
nitrogen (BUN), creatinine, alkaline phosphatase (ALP), total bilirubin, direct bilirubin, aspartate 


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aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total 
protein, albumin, triglycerides, cholesterol, uric acid and calculated creatinine clearance; 
o 
Red blood cell count (RBC), hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), white blood cell count (WBC) including differential, reticulocyte count, and platelet 
count; 
o 
Urinalysis including specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose; 
o 
Prothrombin time (PT) and activated partial thromboplastin time (PTT); 
• 
Pharmacokinetic (PK) samples will be taken on Day 1 at 1, 2, 4, and 6 hours post-injection,  and weekly 
until prostatectomy; 
• 
Serum PSA will be determined prior to NanoPac injection and weekly in the interval between NanoPac 
injection and prostatectomy; 
• 
Bladder scan prior to NanoPac injection to assist with visualization, and following voiding after the 
injection procedure to ensure minimal risk of retention; 
• 
Imaging with mpMRI within 48 hours prior to prostatectomy; 
• 
Direct injection of NanoPac into the prostate lobe containing the dominant lesion under MR-TRUS 
guidance; 
• 
Ejaculate collection to determine presence of paclitaxel; 
• 
Biopsy performed under anesthesia immediately prior to prostatectomy; 
• 
Evaluation of excised prostate and lymph nodes after prostatectomy. 
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  
Clinical laboratory assessments performed at screening/baseline are noted in Section 7.1.1. 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 
Pharmacokinetic (PK) samples will be taken on Day 1 at 1, 2, 4, and 6 hours post-injection,  and weekly until 
prostatectomy. PK samples on Day 1 will allow for a 10-minute window around the samples. 
The biopsy taken immediately prior to 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 sample will be processed for histologic evaluation of the sites where tumor was previously 
identified and whether any tumor kill has been achieved.  
Excised prostate and pelvic lymph nodes will be evaluated to determine presence of paclitaxel and presence of 
tumor cells.  


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Serum PSA will be determined prior to NanoPac injection and weekly during the interval between NanoPac 
injection and prostatectomy. 
Imaging with ultrasound and mpMRI will have been conducted prior to study participation as part of the routine 
evaluation and confirmation of adenocarcinoma. These results will serve as the pre-treatment (or Baseline) data, 
prior to NanoPac injection; another study-specific mpMRI will then be conducted within 48 hours prior to 
prostatectomy, and ultrasound will be performed as part of the prostatectomy procedure.  
In the interval between NanoPac injection and prostatectomy, starting one week after injection, ejaculate will be 
collected on a weekly basis and evaluated for presence of paclitaxel. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
PK samples will be drawn at the specified time/visit and stored frozen on-site until a cohort has completed all 
draws for analysis, at which time they will be batch-shipped to Covance Laboratories (Madison, WI) for analysis. 
Following surgery, a representative section of the prostate and associated lymph nodes will be obtained from the 
excised tissue and will be immediately frozen and prepared for shipment to Frontage Laboratories (Exton, PA) for 
analysis of the presence of paclitaxel in the excised sample. 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.  
Immediately prior to prostatectomy, a biopsy sample will be taken and sent to Pathology for histopathologic 
evaluation and comparison with the initial biopsy results obtained confirming the presence of adenocarcinoma. 
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. 
Samples of ejaculate obtained at the time/visit specified will be snap frozen and stored on site until a cohort of 
subjects has completed, at which time all cohort samples will be shipped to Frontage 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 an ice block which will 
be provided at the prior clinic visit. 
7.2.4 SPECIMEN SHIPMENT 
Samples for paclitaxel assessment will be batch shipped, in a temperature-controlled environment, to Frontage 
labs when all samples for the cohort are available. Routine laboratory samples and PSA samples will be sent to the 
local laboratory upon collection. Tissue samples for histological evaluation will be sent to the local laboratory upon 
collection. 
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 6 weeks prior to the scheduled prostatectomy, and therefore 14 days prior to 
the intended NanoPac injection: 


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• 
Written informed consent including comprehensive discussion of the study schedule, procedures, and 
subject protocol requirements; 
• 
Complete medical history, including review of previous medical records, demographics and parity; 
• 
Review and documentation of adenocarcinoma of the prostate diagnosis (including biopsy results, 
ultrasound results, and mpMRI results obtained within three months 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 lobe 
containing 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); 
• 
SHIM, I-PSS, and NIH questionnaires (Appendices B-D); 
• 
Sample collection and processing for clinical laboratory assessments:  
o 
Hematology, biochemistry, urinalysis, PT and PTT, 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 twelve 
hours prior to the NanoPac dosing procedure at the next study visit. 
 
7.3.2 ENROLLMENT/BASELINE 
DAY 1 – Baseline and Treatment – Day of NanoPac Injection 
The day of NanoPac injection (always considered Day 1) will be scheduled relative to prostatectomy, with NanoPac 
injection occurring four weeks (28 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 two days either side (28 days prior to 
prostatectomy, plus or minus two days) is permitted for the Day 1/NanoPac injection visit.  An extension beyond 
this window for NanoPac injection would require a waiver to be negotiated and obtained in advance from the 
Sponsor. 
All subsequent follow-up study visits (Days 8, 15, and 22) will be scheduled relative to Day 1/NanoPac injection 
visit (NOT prostatectomy), with a window of plus or minus one 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 two days window would permit the 
NanoPac injection to be scheduled on a Tuesday, Wednesday or Friday.  Assuming the day of injection (Day 1) is a 
Tuesday, visits for the next three 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 31.  
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; 
• 
Vital signs obtained; 
• 
PSA sample to be obtained prior to dosing; 


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Preparation for dosing; 
o 
Subject will 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 dose as described previously, according to the cohort allocation; 
• 
PK Samples will be drawn at 1, 2, 4, and 6 hours post-dose. PK samples on Day 1 will allow for a 10-minute 
window around the samples; 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
AE will be collected from the time of dosing; 
• 
Subject will be provided ciprofloxacin 500 mg to take twice a day for three days (or another antibiotic 
regimen as determined by the treating physician’s discretion if resistant organism found on rectal swab 
culture) after NanoPac injection. 
7.3.3 FOLLOW-UP  
Follow-up study visits will be scheduled relative to Day 1/NanoPac injection, with a window of plus or minus one 
day permitted. 
DAY 8 
Seven days after dosing, the subject will return to the clinic for the following evaluations: 
• 
Vital signs will be obtained; 
• 
PK samples will be taken; 
• 
Blood sample for hematology and biochemistry monitoring; 
• 
AE will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
An ejaculate sample will be obtained; 
• 
PSA sample will be obtained. 
The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. 
DAYS 15 AND 22 
At these weekly visits the following evaluations will be performed: 
• 
Vital signs will be obtained; 
• 
PK samples will be taken; 
• 
Blood sample for hematology and biochemistry monitoring - Day 15 only; 
• 
Urine sample for urinalysis - Day 15 only; 
• 
AE will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary; 
• 
An ejaculate sample will be obtained; 
• 
PSA samples will be obtained. 


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The subject will undergo any other evaluations determined necessary by the Investigator to ensure the subject’s 
well-being. 
DAY 29 – DAY OF SCHEDULED PROSTATECTOMY 
Due to the window permitted for the Day 1/NanoPac injection visit, the day of prostatectomy injection may 
actually occur anytime between Day 27 and Day 31.  
Subjects will be attending the facility within 48 hours of the prostatectomy procedure for a routine pre-operative 
work-up (anesthesiology assessment) as standard of care for the surgery. The following assessments may be 
performed during that visit or at any point within 48 hours of the surgery and will form part of the Day 29 data. 
• 
SHIM, I-PSS, and NIH questionnaires will be completed; 
• 
Ejaculate will be collected;  
• 
MP-MRI will be performed; 
• 
Full physical exam, including ECOG status.  
 
The following should be performed on the day of surgery: 
• 
Vital signs will be collected; 
• 
Blood sample for hematology and biochemistry monitoring; 
• 
Urine sample for urinalysis; 
• 
PK samples will be taken;  
• 
A serum sample will be drawn for PSA levels; 
• 
Concomitant medications will be reviewed and updated as necessary, including post-surgical medications; 
o 
Surgical medications will be noted separately and a copy collected/retained for monitoring. This 
information will be available should it be required for further evaluation in the future; however, 
it will not be captured in the EDC as study medication; 
• 
AE prior to surgery will be documented, and those occurring post-surgery will be documented and noted 
to be post-surgical events, some of which may be anticipated.  
On the day of prostatectomy, after anesthesia has been administered, a biopsy will be performed. Immediately 
following biopsy, under the same anesthesia, subjects will have the scheduled prostatectomy and, following 
surgery, samples will be taken from the excised tissue (prostate and lymph nodes) for evaluation of presence of 
paclitaxel and for assessment of tumor cells, as described previously. 
The subject will be followed as per standard of care during the post-surgical period; however, this data is not 
captured as part of the study.  
 
7.3.4 FINAL STUDY VISIT 
The final study visit will be upon discharge from hospital after prostatectomy. At this time the subject will exit the 
study with no further follow-up requirements unless there are ongoing AE not considered related to the surgery 
(see Section 8.3). Following the prostatectomy, the patient will return to standard of care with their follow up 
continued as recommended by their treating physician. 


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7.3.5 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, 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, AE, and concomitant 
medications. 
7.3.6 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; 
• 
AE will be recorded; 
• 
Concomitant medication will be reviewed and updated as necessary. 
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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7.3.7 SCHEDULE OF EVENTS TABLE 
 
 
Screening 
Clinic Visit 
(Up to -14 
days) 
Day 113  
Injection-to-Surgery Interval13 
Day 2913 
(Prostatectomy 
Surgery) 
Hospital 
discharge 
Day 8 
  Day 15 
Day 22 
48-hour 
Window 
Day Of 
Surgery 
Informed Consent 
X 
 
 
 
 
 
 
 
History1 
X 
 
 
 
 
 
 
 
Concomitant 
therapy 
X 
X 
X 
X 
X 
 
X 
X9 
Physical Exam 
X 
 
 
 
 
X 
 
 
ECOG5 
X 
 
 
 
 
X 
 
 
Questionnaires10 
X 
 
 
 
 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
 
X 
X 
 
 
X 
 
Biochemistry 
X 
 
X 
X 
 
 
X 
 
Urinalysis 
X 
 
 
X 
 
 
X 
 
PSA 
X 
X 
X 
X 
X 
 
X 
 
Rectal Swab8 
X 
 
 
 
 
 
 
 
PK Samples  
 
X7 
X 
X 
X 
 
X 
 
Radiologic 
Assessment2 
 
 
 
 
 
X 
 
 
Antibiotics8 
 
X 
 
 
 
 
 
 
Enema12 
 
X 
 
 
 
 
 
 
Bladder Scan 
 
X 
 
 
 
 
 
 
NanoPac6 
 
X 
 
 
 
 
 
 
Ejaculate collection 
 
 
X 
X 
X 
X 
 
 
Biopsy11 
 
 
 
 
 
 
X 
 
Prostatectomy4 
 
 
 
 
 
 
X 
 
Adverse Events3 
 
X 
X 
X 
X 
 
X 
X9 
End of Study 
 
 
 
 
 
 
 
X 
1 
History includes all events before initiation of NanoPac treatment. 
2 
Imaging assessment will utilize multiparametric MRI (mpMRI). 
3 
Adverse event determination will start immediately following initiation of study treatment. 


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4 
Procedure will include ultrasound evaluation at time of biopsy; following prostatectomy, excised prostate and pelvic lymph nodes will be evaluated to 
determine presence of paclitaxel as well as the volume of tumor cells. 
5 
ECOG Performance Status Scale attached as Appendix A 
6 
NanoPac will be administered by direct injection to the lobe of the prostate containing the dominant lesion with the aid of MR-TRUS and MRI 
7  
PK Samples on Day 1 will be drawn at 1, 2, 4, and 6 hours post-dose. PK samples on Day 1 will allow for a 10-minute window around the samples. 
8 
A rectal swab will be taken and cultured during screening to aid antibiotic prophylaxis. Subject will be provided ciprofloxacin 500 mg to take twice a day for 
three days (or another antibiotic regimen as determined by the treating physician’s discretion if resistant organism found on rectal swab culture) after 
NanoPac injection. 
9 
AE and concomitant medications at the end of study visit which are not considered due to the prostatectomy surgery will be followed; those considered 
due to the prostatectomy surgery (such as pain, nausea etc.) will not be captured nor followed 
10 
Questionnaires include Sexual Health Inventory for Men (SHIM), International Prostate Symptom Score (I-PSS), and National Institutes of Health (NIH) 
Prostatitis Symptoms  
11 
Biopsy will be performed immediately prior to prostatectomy under the same anesthesia. 
12 
The evening prior to dosing or on the morning of dosing (12 hours prior to procedure) the subject will receive an enema to assist with the visualization 
when the imaging is performed. 
13 
The day of NanoPac injection (Day 1) will be scheduled relative to prostatectomy, with NanoPac injection occurring four weeks (28 days) prior to the day 
planned for prostatectomy. However, a window of plus or minus 2 days (28 days prior to prostatectomy, plus or minus two days) is permitted for the Day 
1/NanoPac injection visit. All subsequent study visits (Days 8, 15, and 22) will be scheduled relative to the day of NanoPac injection (NOT prostatectomy), 
with a window of plus or minus one day permitted. Because of the window around the day of injection, prostatectomy may actually fall anywhere 
between Day 27 and Day 31. 
 
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that injection of NanoPac into the lobe of the prostate containing the dominant lesion 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). 
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  
Twelve hours prior to dosing the subject will receive an enema to assist with the visualization when the imaging is 
performed. 
Subject will be instructed to take ciprofloxacin 500 mg twice a day for three days (or another antibiotic therapy as 
determined by the treating physician’s discretion) 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: 
• 
AE, collected at all study visits from the time of dosing; 
• 
Changes in concomitant medications;  
• 
Findings from physical examinations;  
• 
Changes in vital signs. 
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, DSMB assessments of safety and tolerability will be 
conducted after every three subjects are dosed and have completed prostatectomy post-NanoPac injection (or 
more frequently if deemed necessary) prior to any dose escalation occurring, as detailed in Section 6.1.7.   
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. 
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 AE 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 AE and 
reported on the eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event (SAE) is any adverse event that meets at least one of following criteria: 
1) Is fatal; 
2) Is life-threatening, meaning the patient 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); 
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 patient and may require medical or surgical 
intervention to prevent one of the outcomes as listed in #1-5 in this definition. 


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8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
As this is a Phase IIa study, all unanticipated problems will be captured as either AE or SAE 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 as mild, moderate, severe, life-threatening, or fatal 
according to the following definitions: 
• 
Mild:  Causing no limitation of usual activity 
• 
Moderate:  Causing some limitations of usual activities 
• 
Severe:  Causing inability to carry out usual activities 
• 
Life-Threatening:  Patient was at immediate risk of death from the event 
• 
Fatal:  Death related to the event. 
Toxicities should be evaluated according to the NCI CTCAE, version 4.0. 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf   
Toxicity grades should be recorded as: 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Life-Threatening, 5 = Fatal. 
8.2.2 RELATIONSHIP TO STUDY AGENT 
Events will be considered drug-related if classified by the Investigator as possible, probable, or definite.  
Association of events to the study agent will be made using the following definitions: 
• 
No relationship to study agent:  the event is not associated with study agent. 
• 
Possibly related to study agent:  the event follows a reasonable temporal association with the study agent 
administration, however could have been produced by the patient’s clinical condition or other therapy. 
• 
Probably related to study agent:  the event follows a) a reasonable temporal association with the study 
agent administration, but b) abates upon discontinuation of study agent and c) cannot be explained by 
the patient’s clinical condition or other therapy.  
• 
Definitely related to study agent:  the event: a) follows a reasonable temporal association with the study 
agent administration, but b) abates upon discontinuation of study agent, c) cannot be explained by the 
patient’s clinical condition or other therapy, and d) reappears on re-exposure to study agent. 
 
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. 


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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
AE should be followed until resolved, stabilized or, if ongoing at End-of-Study (study-related AE only), for a 
minimum of 30 days following the termination of the subject’s participation from the study for any reason. Those 
AE considered to have occurred due to the surgery do not form part of the study, and therefore will be followed 
per routine clinical practice. Subjects will be required to spontaneously report any AE. Study personnel will ask 
open-ended questions to obtain information about AE at every visit. Date and time of onset and resolution (if 
applicable) of the AE will be documented. 
All AE and SAE must be followed until the event resolves or, in the opinion of the Investigator, becomes stable. 
Hospitalization of patients for the scheduled prostatectomy will not be considered an SAE. 
The Sponsor will report any serious, unexpected, and drug-related AE 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 AE (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 AE: 
• 
Name of condition/diagnosis/description 
• 
Onset and resolution dates 
• 
Severity 
• 
Relationship to study agent 
• 
Action taken 
• 
Seriousness  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAE, including death, due to any cause which occurs during this study between the period of dose 
administration and surgical prostatectomy (occurring 28 days following dose), 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, by fax and, if necessary, by phone to: 
Dr. Antony Verco 
Medical Monitor 
US Biotest, Inc. 
Email: tony.verco@usbiotest.com 
Phone: 805-762-4615 
Fax: 805-980-4196 
 


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24-hour Emergency Contacts: 
Gere diZerega, MD 
or 
Antony Verco, MD 
 
Medical Director 
 
Medical Monitor 
 
805-630-2800  
 
805-762-4615 
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 will receive a single administration 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), per rectal bleeding, hematuria, hematospermia, and urinary retention.  
AE of special interest that occur due to the procedure and/or are related to the study agent 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 – Patient unable to void and requires catheterization. The decision to catheterize 
depends on individual patient bladder capacity and abdominal discomfort. Interim data from a 
toxicokinetic study of intraprostatic injection in rats indicated there was some evidence of swelling of the 
prostate and resultant urinary outflow obstruction. The injection volume in the proposed Phase IIa clinical 
study has been limited to 20% of the ipsilateral lobe of the prostate 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 patient could have 
intermittent flow or progress to urinary retention. For this situation, bladder catheterization and irrigation 
will be instituted.   


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• 
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 not expected and is 
unlikely 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 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, and specific reference to these will 
be included in the DSMB Charter for the Board’s review and consideration prior to dose escalation. DLT 
information will be collected in an ongoing manner from the time of dosing until prostatectomy. DLTs considered 
to be SAE (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 Principal Investigator for AE. DLT 
include the following: 
• 
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 2 toxicity lasting for ≥ one week; 
• 
Any delay of scheduled prostatectomy due to study drug related toxicity; 
• 
Symptomatic urine retention secondary to a study injection-related blockage of the prostatic urethra; 
• 
≥ Grade 3 febrile neutropenia (non-respondent to growth factors); 
• 
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; 
• 
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 NanoPac injection until after prostatectomy.  
Any pregnancy occurring in a sexual partner while a subject is in the study period between 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. 


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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 study is a Phase IIa dose escalation study, and dose escalation will be determined following review of all safety 
and tolerability data of a cohort by the DSMB. Following review, the study may be terminated. 
The DSMB may determine that the second set of three subjects should be dosed and complete at the same dose 
level as a current group (to obtain a cohort of 6) to provide additional safety and/or tolerability information 
needed in order to permit dose escalation in the next cohort; they may also determine that it is acceptable to 
proceed with an increased dose in the first three subjects of the next cohort; or they may determine that the 
safety and tolerability profiles are not acceptable and may stop the study. 
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 Data Safety Monitoring Board (DSMB). A detailed DSMB Charter will be drawn up 
prior to study start and the Board will consist of at least three members, one of whom will be the study Medical 
Monitor. 
All subject study 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 throughout the study. In the 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 Principal 
Investigators, as appropriate). 
Upon completion of a cohort, and prior to dose escalation proceeding, the DSMB will convene to review the cohort 
data. A report will be generated outlining any safety concerns from the data available for review in the EDC and 
from data tables generated from the EDC for this specific purpose. This review will take place prior to proceeding 
with either addition of more subjects to a current cohort or proceeding to dose escalate in a new cohort. 
During the DSMB review, members 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 6.1.7. 
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 patient’s medical records, regulatory binder, study 
binder, eCRFs, and source documents as needed to assure 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 


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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 assure compliance with the study protocol, to review and collect the 
patient’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.  
10.2 
STATISTICAL HYPOTHESES 
 No inferential analyses are proposed, thus no hypotheses are stated. 
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 IIa dose escalation trial, the focus will be on providing descriptive statistical summaries including 
tables and graphs for each of the dose groups. The clinical/medical review of these data will determine whether 
there are any issues with toxicity that could be associated with dose and whether there is any effect of the 
treatments on the prostate tumor.  
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 The primary objective of this study is to evaluate the safety and tolerability of three doses of NanoPac 
(concentrations of 6, 10, and 15 mg/mL) injected directly into the lobe of the prostate with the dominant lesion in 
patients diagnosed with prostate cancer. 
The adverse events reported will be coded in MedDRA and summarized by system organ class and preferred term 
for each of the dose groups. Where possible and relevant, these will also be subset temporally by date and time of 
onset (e.g., first 24 hours, up to Day 7); the details of the timeframes will be established medically and presented 


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in the SAP. Events reported as Grade 3 or greater on the ECOG scale (Appendix A) and those that lead to trial 
discontinuation will be noted. Any serious AE and any deaths will be summarized separately. 
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 Day 1 to Days 15 and 29. 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). The SAP may capture medically relevant 
changes (e.g., 3 x the normal range) and analytes which meet this criterion will also be presented separately. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
To address the secondary objective of the concentration of paclitaxel in the systemic circulation post-injection and 
prior to prostatectomy, the pharmacokinetic (PK) samples taken on Day 1 at 1, 2, 4, and 6 hours post-injection,and 
weekly until prostatectomy will be presented (at a minimum) by individual listings. If some concentration data is 
above the detectable limit and can be reported numerically, this data will be tabulated and graphed for individuals 
and by dose group. This will be supported by the ejaculate paclitaxel concentration data for Days 8, 15, 22, and 29, 
which will be tabulated as mean values for each of the dose groups. 
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 will provide insight into the tumor 
environment. 
The tumor response (change in image on mpMRI) will employ the radiological assessments at screening and pre-
prostatectomy, and will be summarized for the mpMRI. Where possible, changes between Screening and the pre-
prostatectomy assessments will be highlighted with change scores for continuous data and shift tables for 
categorical data for the dose groups. The histological evaluation of the biopsies, taken prior to screening 
confirming adenocarcinoma and prior to prostatectomy, will be summarized and treated in the same manner as 
the mpMRI data. 
The presence of tumor cells in the tumor within the prostate and, if tumor is present, the volume of tumor cells, 
the ipsilateral lobe of the prostate, the contralateral lobe of the prostate, and pelvic lymph nodes excised during 
prostatectomy will be tabulated for each of the dose groups. 
10.4.4 SAFETY ANALYSES 
All safety analyses will be presented as part of the primary endpoint analysis. 
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 for each of the dose 
groups. 


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10.4.7 PLANNED INTERIM ANALYSES  
An interim analysis is not planned 
10.4.7.1 
SAFETY REVIEW 
Not applicable. 
10.4.7.2 
EFFICACY REVIEW 
Although this study is not designed to evaluate efficacy, there are several assessments which will provide some 
preliminary efficacy information, and details are included in 10.4.3. above. 
In addition, PSA levels collected at screening, as well as Days 1, 8, 15, 22, and 29 will be presented graphically and 
summarized by dose group as raw values and changes from Day 1 to determine whether the PSA levels change 
with time and dose group. The ejaculate paclitaxel data for Days 8, 15 and 22 and pre-prostatectomy will be 
tabulated as present or absent for each of the dose groups.  
In addition, one of the purposes of doing the biopsy immediately prior to prostatectomy is to provide information 
on whether the biopsy can accurately portray the effects of the drug when compared to the pre-screening biopsy, 
so that in the future if the drug provides any efficacy this information will be able to be obtained prior to a subject 
requiring radical prostatectomy.  
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 clinical study report (CSR) as outlined in the ICH E3 guidelines. 
10.4.11 
EXPLORATORY ANALYSES 
Not applicable.  
10.4.12 
CONCOMITANT MEDICATION 
All medication taken during the trial will be, at a minimum, listed with the study date start and stop. For this small 
clinical trial, the medications will not be coded using the World Health Organization (WHO) Drug Dictionary. 


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10.5 
SAMPLE SIZE 
There is no formal sample size calculation for this Phase IIa safety study. However, to provide a reference for the 
ongoing safety review of each cohort and the possible expansion of a cohort with safety concerns, nQuery Advisor 
(Version 6) employing the procedure “confidence interval for the probability of observing a rare event” 
determined that, for an event with an occurrence rate of 0.33, the probability of detecting it with 3 subjects is 
69.9% vs 91.0% for 6 subjects, and for an event rate of 0.05 the probability of detecting the event was 14.3% and 
26.5% for 3 and 6 subjects respectively. The rationale to expand the final cohort to 12 subjects, from either 3 or 6 
subjects, was based on the “reasonable gain” in detection rate that each additional subject would provide in this 
early phase exploratory trial.  
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. 
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 patient are 
based. They will be separate and distinct from the eCRFs. These records should include detailed notes on: 
• 
Medical history prior to the patient’s involvement in the study; 
• 
Date of informed consent; 
• 
Basic identifying information that links the patient’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 patient; 
• 
Medical condition during the patient’s involvement in the study; 
• 
All AE; 
• 
Patient’s exposure to the study agent; 
• 
Patient’s exposure to any concomitant therapy; 
• 
All relevant observations and data on the condition of the patient throughout the trial; 
• 
Justification for all entries in the patient’s eCRF.  


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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 Principal Investigator 
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 4.2.1 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 patient confidentiality even with the data being stored in a US data 
center. The data management and statistical 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 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 assure 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 patient 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. 


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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 patient enrolled in the study, in accordance with the U.S. 
Food and Drug Administration (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 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. 
It is the responsibility of the Investigator to ensure that informed consent is obtained from the patient 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 patient number. The subjects will be told that all study findings will be 


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stored and handled in strictest confidence, according to legal requirements, but will be informed that authorized 
research Investigators and agents of the FDA, the National Cancer Institute, 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. 
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 accuracy, completeness, legibility, and timeliness of the data 
reported.  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 
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 participant’s official electronic study 
record. 
The EDC application being used in this study is TrialMaster® version 4.2.1 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 


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necessary measures are in place to protect patient confidentiality even with the data being stored in a US data 
center. The data management and statistical 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 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.  
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. 
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:  
• 
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.  


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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.  
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.  
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 patients or participants, including pharmacokinetic 
measures and AE. 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. 
15 
STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
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. 


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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 
Principal Investigator, clinical trial site, and subjects.  
 
 


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18  
LITERATURE REFERENCES  
Axiak-Bechtel SM, Kumar SR, Dank KK, Clarkson NA, Selting KA, Bryan JN, Rosol TJ, et al. Nanoparticulate paclitaxel 
demonstrates antitumor activity in PC3 and Ace-1 aggressive prostate cancer cell lines. Invest New Drugs. 
2013;31:1609-1615. 
Belldegrun A, Tso AL, Zisman A, Naitoh J, Said J, Pantuck A, et al. Interleukin 2 gene therapy for prostate cancer: 
Phase I clinical trial and basic biology. Human Gene Therapy. 2001 May 20;12:883-892. 
Berry WR, Hathorn JW, Dakhil SR, Loesch DM, Jackson DV, Gregurich MA, et al. Phase II randomized trial of weekly 
paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer. 
Clin Prostate Cancer. 2004 Sept;3(2):104-111. 
DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M et al. A Phase I trial of CV706, a replication-
competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following 
radiation therapy. Cancer Res. 2001;61:7464-7472. 
Finkelstein SE, Rodriguez F, Dunn M, Farmello MJ, Smilee R, Janssen W, et al. Serial assessment of lymphocytes and 
apoptosis in the prostate during coordinated intraprostatic dendritic cell injection and radiotherapy. 
Immunotherapy. 2012 April;4(4):373-382. 
Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M, et al. Phase I study of replication-
competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate 
cancer. Cancer Res. 2002;62:4968-4976. 
Fujita R, Teh BS, Timme TL, Mai WY, Satoh T, Kusaka N, et al. Sustained long-term immune responses after in situ 
gene therapy combined with radiotherapy and horomonal therapy in prostate cancer patients. Int J Radiat Oncol 
Biol Phys. 2006;65(1):84-90. 
Gulley JL, Heery CR, Madan RA, Walter BA, Merino MJ, Dahut WL. Phase I study of intraprostatic vaccine 
administration in men with locally recurrent or progressive prostate cancer. Cancer Immonl Immunother. 
2013;62(1):1521-1531. 
Hudes GR, Nathan FE, Khater C, Greenberg R, Gomella L, Stern C, et al. Paclitaxel plus estramustine in metastatic 
hormone-refractory prostate cancer. Sem Oncol. 1995;22(5)(Suppl 12):41-45. 
Hudes GR, Nathan F, Khater C, Haas N, Cornfield M, Giantonio B, Greenberg R, Gomella L, Litwin S, Ross E, Roethke 
S, McAleer C. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-
refractory prostate cancer. J Clin Oncol. 1997;15(9):3156-3163. 
Hussain A, Wu Y, Mirmiran A, DiBiase S, Goloubeva O, Bridges B, et al. Long-term follow-up of a prospective trial of 
trimodality therapy of weekly paclitaxel, radiation, and androgen deprivation in high-risk prostate cancer with or 
without prior prostatectomy. Int J Radiat Oncol Biol Phys. 2012;82(1):167-174. 
Johannsen M, Gneveckow U, Taymoorian K, Thiesen B, Waldofner N, Scholz R et al. Morbidity and quality of life 
during thermotherapy using magnetic nanoparticles in locally recurrent prostate cancer: Results of a prospective 
phase I trial. Int J Hyperthermia. 2007;23(3):315-323. 


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Johannsen M, Gneveckow U, Thiesen B, Taymoorian K, Cho CH, Waldofner N, et al. Thermotherapy of prostate 
cancer using magnetic nanoparticles: Feasibility, imaging, and three-dimensional temperature distribution. Eur 
Urol. 2007;52(6):1653-1561. 
Kramer G, Steiner GE, Sokol P, Handisurya A, Klingler HC, Maier U, et al. Local intratumoral tumor necrosis factor-α 
and systemic IFN- α2b in patients with locally advanced prostate cancer. J Interferon Cytokin Res. 2001;21:475-
484. 
Marshall S, Taneja S. Focal therapy for prostate cancer: The current status. Prostate Int. 2015;3:35-41. 
Mendez MH, Joh DY, Gupta R, Plascik TJ. Current trends and new frontiers in focal therapy for localized prostate 
cancer. Curr Urol Rep. 2015;16:35. 
Miano R, Asimakopoulos AD, Da Silva RD, Bove P, Jones SJ, De La Rosette JJ, Kim FJ. Focal therapy for prostate 
cancer: Current status and future perspectives. Minverva Urol Nefrol. 2015;67:263-280. 
Patel P, Young JG, Mautner V, Ashdown D, Bonney S, Pineda RG, et al. A Phase I/II clinical trial in localized prostate 
cancer of an adenovirus expressing nitroreductase with CB1984. Molecular Ther. 2900 July;17(7): 1292-1299. 
Pisters LL, Pettaway CA, Troncoso T, McDonnell TJ, Stephens LC, Wood CG, et al. Evidence that transfer of 
functional p53 protein results in increased apoptosis in prostate cancer. Clin Cancer Res. 2004;10:2587-2593. 
Sanfilippo NJ, Taneja SS, Chachoua A, Lepor H, Formenti SC, et al. Phase I/II study of biweekly paclitaxel and 
radiation in androgen-ablated locally advanced prostate cancer. J Clin Oncol. 008;26(18):2973-2978. 
Sewak S, Kosmider S, Ganju V, Woollett A, Yeow EG, Le B, et al. Phase II study of paclitaxel and vinorelbine (Pacl-
Vin) in hormone-refractory metastatic prostate cancer: Double-tubulin targeting. Internal Med J. 2010;40:201-208. 
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multiple and repeat injections in patients with localized prostate cancer. J Urol. 2000 June;163:1747-1750. 
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paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy. J Urol. 2009;181:1672-1677. 
Shikanov S, Shikanov A, Gofrit O, Nyska A, Corn B, Domb AJ. Intratumoral delivery of paclitaxel for treatment of 
orthotopic prostate cancer. J Pharmaceutic Sci. 2009;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. 
van der Linden RRM, Haagmans BL, Mongiat-Artus P, van Doornum GJ, Kraaij R, Kadmon D, et al. Virus specific 
immune responses after human neoadjuvant adenovirus-mediated suicide gene therapy for prostate cancer. 
European Urol. 2005;48:153-161. 
van Soest RJ & de Wit R. Irrefutable evidence for the use of docetaxel in newly diagnosed metastatic prostate 
cancer: Results from the STAMPEDED and CHAARTED trials. BMC Medicine. 2015;13:304. 


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Urakami S, Igawa M, Kikuno N, Yoshino T, Kishi H, Shigeno K, et al. Combination chemotherapy with paclitaxel, 
estramustine and carboplatin for hormone refractory prostate cancer. J Urol. 2002;168:2444-2450. 
Williamson SK, Johnson GA, Maulhardt HA, Moore KM, McMeekin DS, Schulz TK, et al.. A phase I study of 
intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies. Cancer Chemother 
Pharmacol. 2015 May;75(5):1075-1087. 
 
 


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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: NATIONAL INSTITUTES OF HEALTH PROSTATITIS SYMPTOMS 
QUESTIONNAIRE 
 


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SAP_001.pdf: