Clinical trial NCT03077685
Conditions: Locally Advanced Pancreatic Adenocarcinoma
Keywords: pancreatic neoplasms digestive system neoplasms pancreatic diseases digestive system diseases pancreatic adenocarcinoma pancreatic cancer
Sponsor: NanOlogy, LLC
Start date: 2017-12-01; Completion date: 2023-03-15
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Open-label, dose-escalating, Phase IIa trial of NanoPac® to treat subjects with locally advanced pancreatic adenocarcinoma via direct intratumoral injection.

Detailed description:
In this open-label, dose-escalating, Phase IIa trial, subjects with locally advanced pancreatic adenocarcinoma will receive intratumoral (ITU) NanoPac® (Sterile Nanoparticulate Paclitaxel) via endoscopic ultrasound-guided direct injection.

Subjects will be enrolled in sequential cohorts of NanoPac® at escalating doses, at a volume based on up to 20% of calculated tumor volume (with a maximum injection volume of 5 mL per subject). During the first phase of the trial (dose escalation), each cohort will have three subjects, with cohorts enrolled sequentially starting at the lowest concentration. Following DSMB review of the cohort data, the next cohort may begin enrolling, an additional three subjects 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 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), will be the dose used in the second phase of the study which will enroll 22 additional subjects who will receive two injections of NanoPac® at the same dose one month apart. In the third phase of the study, up to 30 subjects will receive up to four injections of NanoPac at the same dose, one month apart.

Plasma samples will be taken at various time points on the day of NanoPac® injection as well as once at each of the study visits, to characterize the pharmacokinetics (PK) of ITU NanoPac®.

Subjects will be followed for 12 months after NanoPac® injection for safety, overall survival (OS), progression-free survival (PFS), CA-19-9 levels, carcinoembryonic antigen (CEA) levels, reduction in pain, and tumor response to therapy (as shown by imaging).

Arms: arm 1: Intratumorally injected NanoPac® at a volume of up to 20% tumor volume arm 2: Intratumorally injected NanoPac® at a volume of up to 20% tumor volume arm 3: Intratumorally injected NanoPac® at a volume of up to 20% tumor volume arm 4: Intratumorally injected NanoPac® at a volume of up to 20% tumor volume. The dose administered in the second phase will be determined during the dose escalation phase. Subjects will receive two NanoPac® administrations, with the second injection administered one month after the first injection. arm 5: Intratumorally injected NanoPac® at a volume of up to 20% tumor volume. The dose administered in the third phase will be determined during the dose escalation phase. Subjects will receive four NanoPac® administrations, with the injections administered one month apart.
Interventions: intervention 1: NanoPac®
Intervention descriptions: intervention 1: Subjects with locally advanced pancreatic adenocarcinoma will receive intratumoral (ITU) NanoPac® (Sterile Nanoparticulate Paclitaxel) via endoscopic ultrasound-guided direct injection.

Protocol documents:
Prot_000.pdf: 
Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
NanOlogy, LLC 
Version 7.0 
25 March 2020 
CONFIDENTIAL 
 
i 
Phase IIa Trial Evaluating the Safety of Intratumoral 
Injection of NanoPac in Subjects with Locally Advanced 
Pancreatic Adenocarcinoma 
Protocol Identifying Number: NANOPAC-2016-05 
IND Sponsor: NanOlogy, LLC 
IND #: 132692 
Version Number: 7.0 
25 March 2020 
 
 
 
 
 
 
 
 


Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
NanOlogy, LLC 
Version 7.0 
25 March 2020 
CONFIDENTIAL 
 
ii 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................................................... 5
SPONSOR SIGNATURE PAGE ............................................................................................................................... 7
STATEMENT OF COMPLIANCE ............................................................................................................................. 8
PROTOCOL SUMMARY ........................................................................................................................................... 9
SCHEMATIC OF STUDY DESIGN for dose escalation ...................................................................................... 11
1
KEY ROLES..................................................................................................................................................12
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......................13
2.1 
Background Information .................................................................................................................... 13
2.2 
Rationale ............................................................................................................................................. 15
2.3
Potential Risks and Benefits ............................................................................................................15
2.3.1 
Known Potential Risks ................................................................................................... 15
2.3.2 
Known Potential Benefits .............................................................................................. 15
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 16
4
STUDY DESIGN AND ENDPOINTS.........................................................................................................16
4.1 
Description of the Study Design ...................................................................................................... 16
4.2 
Endpoints ............................................................................................................................................ 18
4.2.1 
Primary Endpoint ............................................................................................................ 18
4.2.2 
Secondary Endpoints .................................................................................................... 18
4.2.3 
Exploratory Endpoints ................................................................................................... 18
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 18
5.1 
Participant Inclusion Criteria ............................................................................................................ 18
5.2 
Participant Exclusion Criteria ........................................................................................................... 19
5.3 
Strategies for Recruitment and Retention ...................................................................................... 19
5.4 
Participant Withdrawal or Termination ............................................................................................ 20
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 20
5.4.2 
Handling of Participant Withdrawals or Termination ................................................. 20
5.5 
Premature Termination or Suspension of Study ........................................................................... 21
6 
STUDY AGENT ............................................................................................................................................ 21
6.1 
Study Agent(s) and Control Description ......................................................................................... 21
6.1.1
Acquisition.......................................................................................................................21
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 21
6.1.3 
Product Storage and Stability ....................................................................................... 22
6.1.4 
Preparation ...................................................................................................................... 22
6.1.5 
Dosing and Administration ............................................................................................ 22
6.1.6 
Route of Administration ................................................................................................. 23
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 23
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 24
6.1.9 
Duration of Therapy ....................................................................................................... 24
6.1.10 
Tracking of Dose ............................................................................................................ 24
6.1.11 
Device Specific Considerations ................................................................................... 24
6.2 
Study Agent Accountability Procedures ......................................................................................... 24
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 25
7.1 
Study Procedures/Evaluations ......................................................................................................... 25
7.1.1 
Study Specific Procedures ............................................................................................ 25


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 Protocol NANOPAC-2016-05 
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7.1.2 
Standard of Care Study Procedures ........................................................................... 26
7.2
Laboratory Procedures/Evaluations................................................................................................27
7.2.1 
Clinical Laboratory Evaluations .................................................................................... 27
7.2.2 
Other Assays or Procedures ........................................................................................ 27
7.2.3
Specimen Preparation, Handling, and Storage .........................................................28
7.2.4 
Specimen Shipment ....................................................................................................... 28
7.3 
Study Schedule .................................................................................................................................. 29
7.3.1
Screening ........................................................................................................................29
7.3.2 
Day of NanoPac Injection ............................................................................................. 29
7.3.3 
Follow-Up Visits .............................................................................................................. 30
7.3.4
Final Follow-up Study Visit ...........................................................................................31
7.3.5 
Early Termination Visit .................................................................................................. 32
7.3.6
Unscheduled Visits ........................................................................................................32
7.3.7 
Schedule of Events Table – DOSe escalation subjects ........................................... 33
7.3.8
Schedule of Events Table – second phase subjects................................................34
7.3.9 
Schedule of Events Table – third phase subjects ..................................................... 35
7.4 
Justification for Sensitive Procedures ............................................................................................. 36
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 36
7.6 
Precautionary Medications, Treatments, and Procedures .......................................................... 36
7.7 
Prohibited Medications, Treatments, and Procedures ................................................................. 36
7.8 
Prophylactic Medications, Treatments, and Procedures ............................................................. 36
7.9 
Rescue Medications, Treatments, and Procedures ..................................................................... 37
7.10
Participant Access to Study Agent At Study Closure ................................................................... 37
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 37
8.1 
Specification of Safety Parameters ................................................................................................. 37
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 38
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 38
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 38
8.2 
Classification of an Adverse Event ................................................................................................. 38
8.2.1
Severity of Event ............................................................................................................38
8.2.2
Relationship to Study Agent .........................................................................................39
8.2.3 
Expectedness ................................................................................................................. 39
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 39
8.4 
Reporting Procedures ....................................................................................................................... 40
8.4.1 
Adverse Event Reporting .............................................................................................. 40
8.4.2 
Serious Adverse Event Reporting ............................................................................... 40
8.4.3 
Unanticipated Problem Reporting ................................................................................ 41
8.4.4 
Events of Special Interest ............................................................................................. 41
8.4.5 
Reporting of Pregnancy ................................................................................................ 41
8.5 
Study Halting Rules ........................................................................................................................... 41
8.6 
Safety Oversight ................................................................................................................................ 42
9 
CLINICAL MONITORING ............................................................................................................................ 42
10
STATISTICAL CONSIDERATIONS .......................................................................................................... 43
10.1
Statistical and Analytical Plans ........................................................................................................ 43
10.2
Statistical Hypotheses ....................................................................................................................... 43
10.3
Analysis Datasets .............................................................................................................................. 43


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10.3.1 
Missing Data ................................................................................................................... 43
10.4
Description of Statistical Methods...................................................................................................43
10.4.1 
General Approach .......................................................................................................... 43
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 44
10.4.3
Analysis of the Secondary Endpoint(s).......................................................................44
10.4.4 
Safety Analyses .............................................................................................................. 44
10.4.5 
Adherence and Retention Analyses ............................................................................ 45
10.4.6 
Baseline Descriptive Statistics .....................................................................................45
10.4.7 
Planned Interim Analyses ............................................................................................. 45
10.4.8 
Additional Sub-Group Analyses ................................................................................... 46
10.4.9
Multiple Comparison/Multiplicity...................................................................................46
10.4.10
Tabulation of Individual Response Data ..................................................................... 46
10.4.11
Exploratory Analyses.....................................................................................................46
10.4.12
Concomitant Medication................................................................................................ 46
10.5
Sample Size .......................................................................................................................................46
10.6
Measures to Minimize Bias .............................................................................................................. 47
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 47
10.6.2 
Evaluation of Success of Blinding ............................................................................... 47
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 47
11
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 47
12
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 48
13
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 48
13.1
Ethical Standard ................................................................................................................................. 48
13.2
Institutional Review Board ................................................................................................................ 49
13.3
Informed Consent Process ............................................................................................................... 49
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ... 49
13.3.2 
Consent Procedures and Documentation .................................................................. 49
13.4
Participant and Data Confidentiality ................................................................................................ 50
13.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 50
13.5
Future Use of Stored Specimens .................................................................................................... 50
14
DATA HANDLING AND RECORD KEEPING..........................................................................................50
14.1
Data Collection and Management Responsibilities ...................................................................... 50
14.2
Study Records Retention..................................................................................................................51
14.3
Protocol Deviations............................................................................................................................52
14.4
Publication and Data Sharing Policy ............................................................................................... 52
15
STUDY ADMINISTRATION ........................................................................................................................ 53
15.1
Study Leadership ............................................................................................................................... 53
16
CONFLICT OF INTEREST POLICY .......................................................................................................... 53
17  
LIABILITY AND INSURANCE .................................................................................................................... 53
18  
LITERATURE REFERENCES.................................................................................................................... 54
APPENDIX A: ECOG Performance Scale ............................................................................................................ 56
 


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LIST OF ABBREVIATIONS
AE
Adverse Event 
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
AST
Aspartate Aminotransferase 
ASP
Alkaline Phosphatase
BUN
Blood Urea Nitrogen
CEA 
Carcinoembryonic Antigen 
CLIA 
Clinical Laboratory Improvement Amendments 
CO2
Carbon Dioxide
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
DSMB 
Data Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
EDC 
Electronic Data Capture System
EUS
Endoscopic Ultrasound
eCRF 
Electronic Case Report Form 
FDA 
The U.S. Food and Drug Administration 
FDG-PET
Fluorodeoxyglucose-Positron Emission Tomography 
FNA
Fine Needle Aspiration
GCP
Good Clinical Practice
GGT 
Gamma-Glutamyltransferase
Hct 
Hematocrit 
Hgb
Hemoglobin
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
IRB
Institutional Review Board
ITU 
Intratumoral  
IV 
Intravenous
LDH 
Lactate Dehydrogenase 
MAC 
Monitored Anesthesia Care 
MCH
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
NCI
National Cancer Institute
NDA 
New Drug Application (Marketing Application) 
OHRP
Office for Human Research Protections 
PCA 
Precipitation with Compressed Antisolvents 
pH 
Hydrogen Ion Concentration 
PI
Principal Investigator 


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PK
Pharmacokinetics 
PT
Prothrombin Time
PTT
Activated Partial Thromboplastin Time
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SDLC 
Systems Development Life Cycle 
SOC
Standard of Care
TEAE
Treatment-emergent Adverse Event
ULN
Upper Limit of Normal
UP
Unanticipated Problem
USC
University of Southern California
VAS 
Visual Analog Score 
WBC 
White Blood Cell
 




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 Protocol NANOPAC-2016-05 
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8 
STATEMENT OF COMPLIANCE
I have read the attached protocol number NANOPAC-2016-05 entitled, Phase IIa Trial Evaluating the Safety of 
Intratumoral Injection of NanoPac in Subjects with Locally Advanced Pancreatic Adenocarcinoma, Version 7.0 dated 
25 March 2020 and agree to comply with the contents of this document. 
I agree to comply with applicable FDA regulations and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 
This document is a confidential communication of US Biotest, Inc. The recipient agrees that no unpublished 
information contained herein will be published or disclosed without prior written permission of US Biotest. 
However, this document may be disclosed to appropriate institutional review boards, ethics review committees, or 
authorized representatives of the Investigator or of boards of health under the condition that they are requested 
to respect the confidentiality of the document. 
The signature of the Principal Investigator below constitutes his/her agreement. 
 
 
__________________________________________ __________________________ 
Signature of Principal Investigator  
 
Date 
 
 
__________________________________________ 
Printed Name of Principal Investigator 
 
 


Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
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PROTOCOL SUMMARY
Title: 
Phase IIa Trial Evaluating the Safety of Intratumoral Injection of NanoPac in Subjects with 
Locally Advanced Pancreatic Adenocarcinoma 
 
Précis:
In this open-label, dose rising, Phase IIa trial, subjects with locally advanced pancreatic 
adenocarcinoma will receive intratumoral (ITU) NanoPac (sterile nanoparticulate paclitaxel) 
via endoscopic ultrasound (EUS)-guided direct injection. Prior to study entry, subjects in the 
dose escalation phase of the study will complete at least one course of standard of care 
(SOC) IV chemotherapy and hematologic recovery will be confirmed before NanoPac is 
administered; subjects enrolling to the second and third phases will have initiated their SOC 
IV chemotherapy. 
  
Subjects in the dose escalation phase will be enrolled in sequential cohorts of NanoPac 6, 10, 
and 15 mg/mL at up to 20% of the calculated tumor volume (with a maximum injection 
volume of 5 mL per subject). Each cohort will have three subjects, 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 
subjects 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 most suitable for 
further evaluation, defined as the highest dose with an acceptable safety and tolerability 
profile (as determined by the DSMB), will be the dose used in the second phase of the study 
which will enroll 22 additional subjects who will receive two injections of NanoPac at the 
same dose, one month apart.  In the third phase of the study, up to 30 subejcts will receive 
up to four injections of NanoPac at the same dose, one month apart.  
 
Plasma samples will be taken on the day of NanoPac injection pre-injection and at 1, 2, 4, 6, 
and 24 hours after injection, as well as at each of the study visits in the dose escalation phase 
of the study, and at 1 and 2 hours after each injection and at all other study visits in the 
second and third phases of the study, to characterize the pharmacokinetics (PK) of 
intratumoral NanoPac.  
 
Subjects will be followed for 3 months after NanoPac injection for safety, overall survival 
(OS), progression-free survival (PFS), CA-19-9 levels, carcinoembryonic antigen (CEA) levels, 
reduction in pain, and tumor response to therapy (as shown by imaging). A follow-up visit 
may be conducted at 6 months, as applicable.  Subjects in the second phase of the study, 
following their 1 month follow-up, will receive a second injection, and these subjects will be 
followed for a further 6 months after this second injection.  Subjects in the third  phase of the 
study will receive up to four injections, 1 month apart, and will be followed for 6 months 
after their last injection. 
 
Objectives:
Primary objective: 
 
To evaluate the safety and tolerability of NanoPac injected directly into pancreatic 
cancer by EUS-guided injection. 
 
Secondary objectives:  
 
To describe the PK of NanoPac when administered into the tumor within the 
pancreas. 
 
To determine whether any of the NanoPac cohorts (6, 10, or 15 mg/mL) show signs 
of preliminary efficacy. 
 
To determine if two to four injections of NanoPac (1 month apart at the determined 
dose for this cohort) shows signs of preliminary efficacy.  
 


Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
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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 (as determined 
by PK analysis); 
 
Tumor response (RECIST as per Eisenhauer et al. 2009); 
 
Reduction in pain (as measured by the visual analog scale [VAS]); 
 
Change in tumor marker CA19-9; 
 
Change in tumor marker CEA.  
 
Population:
Up to 65 subjects with locally advanced pancreatic adenocarcinoma
Phase:
Phase IIa
Number of 
Sites enrolling 
participants:
Up to five
Description of 
Study Agent: 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension (“NanoPac”) at 
concentrations of 6, 10, and 15 mg/mL administered into the tumor within the pancreas via 
EUS-guided fine needle injection. 
 
Study Duration:
Up to 48 months. 
 
Participant 
Duration: 
Estimated to be up to 7 months for each subject in the dose escalation phase of the study, up 
to 8 months for each subject in the second phase of the study, and up to 10 months for 
subjects in the third phase of the study. Additional follow-up may occur.
 


Phase IIa Trial: Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer
Protocol NANOPAC-2016-05
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SCHEMATIC OF STUDY DESIGN FOR DOSE ESCALATION


Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
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Version 7.0 
 
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1
KEY ROLES
Medical Director 
Gere diZerega, MD 
President & CEO, US Biotest, Inc. 
Professor, USC Keck School of Medicine 
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 
Medical Monitor
Antony Verco, MD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-235-9193 
tony.verco@usbiotest.com 
Laboratory – PK Samples 
Covance Madison Laboratories Bioanalytical (BA) Group  
3301 Kinsman Blvd, Madison, WI 53704 
608-442-8200 
Central Laboratory – Immune response, Flow cytometry  
NeoGenomics Laboratories, Inc. 
Attn: Pharma Services Department  
31 Columbia  
Aliso Viejo, CA 92656  
949-445-7300 x7103 
 
 


Phase IIa Trial:  Intratumoral Injection of NanoPac in Subjects with Pancreatic Cancer 
 Protocol NANOPAC-2016-05 
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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1
BACKGROUND INFORMATION 
The Sponsor for IND 132692, 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: 
NanOlogy, LLC (NanOlogy) has produced a formulation of nanoparticulate paclitaxel, identified as NanoPac® 
(sterile nanoparticulate paclitaxel) Powder for Suspension (NanoPac), which is the subject of this protocol. 
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 a clear 60mL Type 1, USP, clear-
glass vial (306 mg/vial) as a powder fill of nanoparticulate paclitaxel, 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: 
Nonclinical studies of NanoPac in animal models of pancreatic cancer have not yet been completed. NanoPac 
demonstrated preliminary safety and efficacy when injected intratumorally (ITU) in animals with solid tumors; this 
data (as well as data from additional animal models) is presented in the NanoPac Investigator’s Brochure.  
Two in vivo nonclinical pharmacology studies were conducted to determine the effects of nanoparticulate 
paclitaxel in a PC3 nude mouse tumor xenograft. 
In the first study, mice were administered NanoPac (37.5 mg/kg, qwk x 1), NanoPac (12.5 mg/kg, qwk x 3), 
NanoPac (37.5 mg/kg, qwk x 3), paclitaxel (30 mg/kg, qwk x 3), or vehicle (0.1% w/v Polysorbate 80 in saline, qwk x 
3). Treatments with NanoPac and vehicle were by ITU injection. Treatment with three weekly doses of NanoPac at 
12.5 or 37.5 mg/kg resulted in significant 92% and 89% TGI tumor growth inhibition, respectively, on Day 32 (P < 
0.01 for both). Treatment with 12.5 or 37.5 mg/kg paclitaxel resulted in the maximally possible, significant 64% 
tumor growth delay (P < 0.001, logrank) and seven and three partial regressions, respectively. The survival 
extensions afforded to animals treated with NanoPac therapy are evident.  
In the second PC3 nude mouse tumor xenograft study, mice treated with NanoPac (37.5 mg/kg, qwk x 3) via ITU 
injection demonstrated a median tumor volume of 126 mm3 on Day 60; whereas in the vehicle group, all but one 
animal was deceased prior to Day 60 and the only animal remaining on Day 60 had a tumor volume of 1268 mm3.  
Clinical Summary: 
NanoPac has not previously been administered to the human pancreas via endoscopic ultrasound (EUS)-guided 
fine needle injection. Two clinical trials with NanoPac have been completed to date.  
Clinical trial HSC#11140, “A Phase I Study of Intraperitoneal Nanoparticle Paclitaxel in Patients with Peritoneal 
Malignancies,” was conducted under IND 073529. The results of this study were published by Williamson et al. 


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(2015) in the journal Cancer Chemotherapy and Pharmacology. Clinical trial HSC#11140 was a dose-escalating 
study evaluating intraperitoneally (IP)-administered NanoPac (under the name Nanotax®) at doses of 50-275 
mg/m2 given every 28 days until disease progression or unacceptable toxicity occurred. Twenty-two subjects were 
enrolled. 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 medication, occurred in one subject. The 
peritoneal concentration-time profile of paclitaxel rose during the two days after dosing to peritoneal fluid 
concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the 
entire dose cycle. Best response assessments were made in 16 of the 21 subjects. Four subjects were assessed as 
stable or had no response and twelve subjects had progressive disease. Five of 21 subjects with advanced cancers 
survived longer than 400 days after initiation of IP NanoPac treatment. There were no cases of bowel obstruction. 
Additional data from this clinical trial is presented in the NanoPac Investigator’s Brochure.  
Clinical trial NANOPAC-2016-02, entitled “Phase IIa Dose Escalation Trial of NanoPac Focal Therapy for Prostate 
Cancer in Subjects Undergoing Radical Prostatectomy,” was an open-label, dose-rising study to evaluate the safety 
and tolerability of NanoPac administered via intraprostatic injection in men with localized adenocarcinoma of the 
prostate containing the dominant lesion. Injection was performed under magnetic resonance imaging-transrectal 
ultrasound fusion (MR-TRUS) guidance directly into the lobe of the prostate containing the dominant lesion. A total 
of 16 subjects were enrolled to the study, three in the 6 mg/mL dose group, three in the 10 mg/mL dose group, 
and 10 in the 15 mg/mL dose group. The majority of subjects experienced treatment emergent adverse events 
(TEAEs) as expected, but with minimal frequency, severity, and relation to NanoPac. The most frequent TEAEs 
occurred in the system organ class of gastrointestinal disorders, most of which were in the 6mg/mL cohort. There 
was no obvious dose-response relationship with respect to the frequencies of the TEAEs at the three 
concentrations of NanoPac. No DLTs or toxicities typically attributable to IV paclitaxel such as neutropenia, 
thrombocytopenia, peripheral neuropathy, and hypersensitivity reactions such as angioedema and urticaria were 
reported. There were no SAEs, deaths, or discontinuations from the study due to AEs. The mean total Gleason 
score remained stable in the 6mg/mL and 10mg/mL cohorts, and improved in the 15mg/mL cohort, implying a 
possible dose-response relationship. The proportion of the primary lesion considered adenocarcinoma improved in 
the 6mg/mL and 15mg/mL cohorts but increased in the 10mg/mL cohort. PSA Density decreased (mean change 
from Baseline) in all three cohorts. 
Under IND 073529, protocol NANOPAC-2016-01, a Phase II study of four concentrations of intraperitoneal 
NanoPac plus six cycles of IV carboplatin and paclitaxel in subjects with platinum-sensitive recurrent stage III 
epithelial ovarian cancer undergoing second cytoreductive surgery, is completed and in the reporting phase.  
Under IND 132692, protocol NANOPAC-2017-01, a trial of intracystic injection of NanoPac in subjects with 
mucinous cystic pancreatic neoplasms, has recently completed enrollment. 
Relevant Literature: 
Paclitaxel, formulated as ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 
(“nab-paclitaxel”) is FDA-approved as first-line treatment, in combination with gemcitabine, for metastatic 
adenocarcinoma of the pancreas (ABRAXANE Package Insert). Numerous studies have confirmed that pancreatic 
cancer is sensitive to paclitaxel when administered as an intravenous infusion (Scheithauer et al. 2016; Ueno et al. 
2016; Hosein et al. 2013; Von Hoff et al. 2013; Zhang et al. 2013; Ko et al. 2012). Paclitaxel has been administered 
via direct injection to the pancreas for the treatment of pancreatic cysts (Oh et al. 2008; Oh et al. 2011; DeWitt et 
al. 2014).  


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Importance of the study: 
Pancreatic cancer is an aggressive and rapidly fatal malignancy. In 2013, pancreatic cancer was diagnosed in 
approximately 45,220 Americans and caused 38,460 deaths. It is the ninth most common cancer, yet it is the 
fourth leading cause of cancer death (Eskander et al. 2016). The incidence of pancreatic cancer is rising and it is 
expected to be the second leading cause of cancer-related death by 2030 (Matrisian & Berlin 2016). At the time of 
diagnosis, more than 80% of patients with pancreatic cancer have metastatic or inoperable disease (Chiorean & 
van Hoff 2016), which is reflected in the five-year overall survival rate of less than 8% (Eskander et al. 2016; Gong 
et al. 2016). 
Pancreatic cancer demonstrates a limited response to the intravenous administration of chemotherapy (Cantore et 
al. 2000). This is likely due to the desmoplastic, fibrotic microenvironment created by pancreatic cancer, which 
blocks transport and diffusion of small molecules (Heinemann et al. 2014). Surgery is the only potentially curative 
treatment for pancreatic cancer (Eskander et al. 2016), yet only 10-20% of patients are candidates for surgery at 
initial presentation and, even with surgery, up to 92% of patients will experience disease recurrence within two 
years (Smyth & Cunningham 2015; Gong et al. 2016).  
2.2 
RATIONALE  
This Phase IIa study will include subjects with adenocarcinoma of the pancreas. Only those subjects who are not 
candidates for surgery will be enrolled in the study. The study design allows for a safety evaluation of EUS-guided 
fine needle injection of NanoPac into the tumor within the pancreas.  
Pancreatic cancer cells are particularly sensitive to paclitaxel, which outperforms gemcitabine in an in vitro model 
of chemoresistant pancreatic cancer (Indolfi et al. 2016). ABRAXANE is FDA-approved as first-line treatment, in 
combination with gemcitabine, for metastatic adenocarcinoma of the pancreas and has demonstrated significant 
efficacy in numerous clinical studies (Scheithauer et al. 2016; Ueno et al. 2016; Hosein et al. 2013; Von Hoff et al. 
2013; Zhang et al. 2013; Ko et al. 2012). In order to inject pancreatic cancer directly, a minimally invasive 
procedure known as EUS-guided fine needle injection is proposed for this Phase IIa study. The safety and feasibility 
of this procedure have been demonstrated in numerous studies (Wang et al. 2011; Kaplan et al. 2015). 
In contrast with IV administration, direct injection of paclitaxel should allow for higher concentrations of drug to 
target local disease with reduced systemic toxicity. ITU NanoPac is expected to be more effective than IV 
paclitaxel, as the EUS-guided fine needle injection will bypass the fibrotic stroma that acts as a barrier to IV 
chemotherapy. NanoPac may also allow for prolonged residence and dissolution within the pancreas, 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 ITU injection of NanoPac. 
2.3.2 KNOWN POTENTIAL BENEFITS  
There are no known potential benefits of ITU injection of NanoPac. However, paclitaxel formulated as ABRAXANE 
is FDA-approved as first-line treatment, in combination with gemcitabine, for metastatic adenocarcinoma of the 


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pancreas and has demonstrated significant efficacy in numerous clinical studies of pancreatic cancer (Scheithauer 
et al. 2016; Ueno et al. 2016; Hosein et al. 2013; Von Hoff et al. 2013; Zhang et al. 2013; Ko et al. 2012).  
3 
OBJECTIVES AND PURPOSE
The primary objective of this study is to evaluate the safety and tolerability of NanoPac injected directly into 
pancreatic cancer by EUS-guided fine needle injection. Secondary objectives are (a) to describe the 
pharmacokinetics of NanoPac when administered into the tumor within the pancreas, and (b) to determine 
whether any of the 6, 10, and 15 mg/mL NanoPac dose cohorts show signs of preliminary efficacy, and (c) to 
determine if the selected dose from the escalation phase of the study, when injected on up to four occasions 1 
month apart, shows signs of preliminary efficacy .  
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
In this open-label Phase IIa trial, subjects with locally advanced pancreatic adenocarcinoma will have completed at 
least one course of chemotherapy as part of Standard of Care (SOC) in the dose escalation phase of the study. 
Once there is sufficient hematologic recovery (see Section 5.1), subjects will receive ITU NanoPac via EUS-guided 
direct injection. Subjects will be followed for overall survival (OS), progression-free survival (PFS), CA-19-9 levels, 
carcinoembryonic antigen (CEA) levels, reduction in pain, and tumor response to therapy (as shown by imaging) 
while on study.  Additional information on PFS and OS may be obtained at 9 and 12 months after the initial 
NanoPac injection. 
 
Subjects will be enrolled in sequential, escalating cohorts of NanoPac at concentrations of 6, 10, or 15 mg/mL 
injected directly into the tumor within the pancreas at up to 20% tumor volume (with a maximum of 5 mL volume 
being administered to any subject). The study will include a dose escalation phase, a second phase which allows for 
subjects to receive two injections of NanoPac 1 month apart, and a third phase which allows for subjects to receive 
up to four injections of NanoPac 1 month apart. 
 
For subjects enrolling to the second and third phases, at the dose selected from the dose escalation phase, 
subjects will have intiated their IV chemotherapy prior to first injection.  
 
Tumor Volume Calculations 
If more than one lesion is present in the pancreas of a subject, the Investigator will select a single target lesion and 
will treat only this target lesion. The single target lesion must have a diameter of at least 1.5 cm but no more than 
6 cm as demonstrated via imaging within 6 weeks of study entry.  A CT scan will be performed between the 
Screening visit and the Day of Injection Visit in the second and third phases of the study to obtain a study baseline 
image against which future imaging will be compared. The tumor volume measurement and injection volume will 
be determined immediately prior to the NanoPac injection procedure using the ultrasound image. The ultrasound 
image obtained at the time of the NanoPac injection procedure will provide the lesion measurement at the widest 
point of the tumor. Tumor volume may be calculated as 
3 if not automatically calculated via the 
imaging software.    
Based on these tumor volume calculations at the time of the NanoPac injection procedure, an amount of NanoPac 
equal to 20% of tumor volume, not to exceed 5 mL in any subject, may be injected into the tumor. The Investigator 


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may use his discretion, on a subject-by-subject basis, to inject the entire 20% tumor volume or to use a lesser 
amount as he deems necessary for each individual subject’s safety. Examples of tumor volume and injection 
volume calculations are provided in the table below.   Pharmacy will provide the Investigator with 5mLs of 
reconstituted NanoPac for use in the procedure room, and documentation detailing the volume calculations in the 
procedure room will be provided in the source.  
 
Examples to Demonstrate Volume Calculations1
Ultrasound 
Measured 
Diameter (cm)
Tumor Volume 
(mL) 
V=1/6 
d3
Injection Volume 
(mL) 
(20% Tumor Volume)
Total (mg) 
NanoPac 
Administered
at 6 mg/mL
Total (mg) 
NanoPac 
Administered
at 10 mg/mL
Total (mg) 
NanoPac 
Administered
at 15 mg/mL
1.5 
1.8
0.4 
2.4 
4.0 
6.0 
2.0
4.2
0.8
4.8
8.0
12.0
2.5 
8.2
1.6 
9.6 
16.0
24.0
3.0
14.1
2.8
16.8
28.0
42.0
3.5 
22.4 
4.5 
27.0
45.0
67.5
4.0 
33.5 
5.02
30.03
50.03
75.03
4.5 
47.7 
5.02
30.03
50.03
75.03
5.0 
65.4 
5.02
30.03
50.03
75.03
5.5 
87.1 
5.02
30.03
50.03
75.03
6.0 
113.0 
5.02
30.03
50.03
75.03
1 All values in table have been rounded to a single decimal. The calculations for total NanoPac administered were 
performed with the rounded injection volume as this would be the amount administered in a clinical setting. 
2 Twenty percent (20%) of the volume of tumors this size would exceed the 5 mL maximum injection volume and 
thus could not be administered. In such a situation, where 20% tumor volume exceeds 5.0 mL, the maximum 5 mL 
of NanoPac would instead be administered as the injection volume. 
3 Based on 5 mL maximum injection volume.  
 
Dose Escalation of Cohorts 
Cohorts will be enrolled sequentially starting at the lowest dose (6 mg/mL). Each cohort will have a planned 
minimum of three subjects. All data from the first three subjects in a cohort will be reviewed and evaluated by the 
Data Safety Monitoring Board (DSMB) to determine whether the dose received is considered safe and tolerable, 
and to determine if dose escalation may occur. The DSMB will review the data on the three subjects once they 
have completed the 2-week follow-up visit, and will assess safety and tolerability based on the DSMB Charter, 
which will include reference to dose-limiting toxicities (DLTs). Safety and tolerability parameters which will be used 
to determine whether escalation may proceed are outlined in Section 6.1.7. 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 (more than one DLT).  
 
The dose most suitable for further evaluation will be the highest dose with an acceptable safety and tolerability 
profile as determined by the DSMB. If one or fewer subjects in a six-subject cohort, or no subjects in a three-
subject cohort at the highest dose, experience a DLT, that cohort may be taken into the second phase. If greater 
than one subject in a six subject cohort experience a DLT, the previous dose may be taken into the second phase. 
 


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Second Phase of Study 
Once the dose deemed appropriate for expansion and further evaluation has been determined by the DSMB, an 
additional 22 subjects will be enrolled to the study and this cohort of subjects will receive two NanoPac injections 
to their lesion one month apart.  
 
Third Phase of Study 
Up to 30 additional subjects will be enrolled to receive up to four NanoPac injections to their lesion, 1 month 
apart. 
 
PK Analysis
Plasma samples will be taken on the day of injection prior to injection and at 1, 2, 4, 6, and 24 hours after NanoPac 
injection, as well as at all other study visits in the dose escalation phase of the study, and at 1, and 2 hours after 
each injection and at all other study visits in the second and third phases of the study, to characterize the 
pharmacokinetics of ITU NanoPac. Subjects will be followed for 3 months after NanoPac injection for safety and 
response to therapy. A further follow-up may be conducted at 6 months as appropriate for the subject (see Section 
7.3.4).  Subjects in the second phase of the study, following their 1 month evaluations, will receive a second 
injection, and these subjects will be followed for a further 6 months after this second injection (study completion 
at Month 7).  Subjects in the third phase of the study will receive up to four injections 1 month apart, and will be 
followed for a further 6 months after their last injection (study completion at Month 9 if all injections are 
received). 
 
4.2 
ENDPOINTS 
4.2.1 PRIMARY ENDPOINT 
The primary endpoint will be safety and tolerability, as assessed by adverse events (AE), changes in vital signs, 
laboratory results, and physical examination at one month following NanoPac injection. 
4.2.2 SECONDARY ENDPOINTS 
The secondary endpoints will be: 
 Concentration of paclitaxel in the systemic circulation post-injection (as determined by PK analysis); 
 Tumor response (RECIST as per Eisenhauer et al. 2009); 
 Reduction in pain (as measured by the visual analog scale [VAS]); 
 Change in tumor marker CA19-9; 
 Change in tumor marker CEA. 
 
4.2.3 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: 


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Signed informed consent;
 
Age 18 years; 
 
Histologically/cytologically confirmed locally advanced pancreatic adenocarcinoma; 
 
At least one lesion with a diameter of at least 1.5 cm but no more than 6 cm as documented via imaging 
(within 6 weeks of Screening); 
 
Subject is not a candidate for surgery; 
 
Completion of at least one standard of care IV chemotherapy course for subjects in the dose escalation 
phase of the study. IV chemotherapy will be initiated prior to first NanoPac injection for subjects in the 
second and third phase; hematologic recovery with a platelet count  75 x 109
9/L 
must be confirmed prior to study entry; 
 
Performance Status (ECOG) 0-1 at study entry; 
 
Life expectancy of at least 3 months; 
 
Adequate marrow, liver, and renal function at study entry; 
o 
ANC 
9/L 
o 
 9.5 grams/dL 
o 
Platelets 
9/L 
o 
Total 
 
o 
 2.5x institutional ULN 
o 
 
 
Appropriate steps taken to minimize or avoid the potential for pregnancy for subjects of child-bearing 
potential.* 
* Note: A female patient is considered to be of childbearing potential unless she has had a hysterectomy, is at least 
one year postmenopausal or has undergone tubal ligation. For the purposes of this study, adequate birth control 
includes at least one medically approved and highly effective method of birth control, defined as those which result 
in a low failure rate (i.e., < 1% per year) when used consistently and correctly, such as implants, injectables and oral 
contraceptives combined with the use of double condoms. Only male patients whose vasectomy has been confirmed 
by semen analysis at least 3 months after the vasectomy are allowed not to use acceptable contraceptive methods. 
5.2
PARTICIPANT EXCLUSION CRITERIA
If a subject meets any of the following criteria, he or she must be excluded from the study: 
 
Thrombotic or embolic events; 
 
Acute or subacute intestinal occlusion; 
 
History of inflammatory bowel disease; 
 
Known hypersensitivity to study drugs; 
 
Known drug or alcohol abuse; 
 
Pregnant or breastfeeding women; 
 
Previous or concurrent history of non-pancreatic malignancy except for non-melanoma skin cancer. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sufficient subjects will be screened to allow up to 65 subjects to be enrolled in the trial. Subjects will be recruited 
at up to five study sites. It is not anticipated that any advertising will be required for recruiting to the study. 
Subjects will be recruited and screened for eligibility and will proceed to treatment in groups of three in the dose 


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escalation phase of the study. The first three subjects in the second phase will also be reviewed by the DSMB 
following their second injection to confirm safety in this group; the DSMB will be provided information on the first 
three subjects in the third phase following completion of their injections to confirm safety in this group.  
5.4
PARTICIPANT WITHDRAWAL OR TERMINATION
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Subjects are free to withdraw from participation in the study at any time upon request. The reason for wanting to 
withdraw will be documented in the source notes and in the Electronic Data Capture system (EDC). The final study 
visit is planned for 6 months after the last NanoPac injection. For subjects wishing to pursue other treatment 
options (such as other clinical trials) sooner than 6 months after NanoPac injection, the final study visit may be 
conducted sooner.  
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 administered. 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, 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.  
Subjects that refuse or fail to appear for clinic visits following NanoPac injection and fail to respond to or cooperate 
with reasonable and diligent attempts at contact should not be discontinued from the study, but 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 following NanoPac injection, and where the 
majority of data is not available, the option to replace that subject exists. However, the data that is collected from 
the non-compliant subject may still be used in the evaluations in this study. 


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5.5
PREMATURE TERMINATION OR SUSPENSION OF STUDY
This study may be temporarily suspended or prematurely 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 DLTs.   
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 second phase of the study, where subjects receive two NanoPac injections one month 
apart, if one third of the subjects (i.e., 4 subjects) experience the same DLT the study may be 
stopped, future subjects in the second phase may receive a single NanoPac injection (second 
injection not administered), or remaining subjects may receive a lower dose of the study drug  as 
determined by the DSMB. 
o 
In the third phase of the study, where subjects receive up to four NanoPac injections 1 month 
apart, if one third of the subjects (i.e., 10 subjects) experience the same DLT the study may be 
stopped or future subjects in the third phase may receive fewer NanoPac injections. 
 
Insufficient compliance with protocol requirements; 
 
Data that are not sufficiently complete and/or evaluable; 
 
Determination of futility. 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed and 
satisfy the Sponsor, IRB, and/or FDA. 
6
STUDY AGENT
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 ACQUISITION 
NanoPac will be manufactured by CritiTech, Inc. (Lawrence, KS) 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 and the site is 
ready for study initiation, at which time the study agent will be released for shipment. Shipment will be via courier, 
temperature controlled at 
to 
and will occur prior to the site initiation visit. 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). 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
NanoPac is presented as a white powder, provided in a sealed vial within a study kit. 


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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) , one NanoPac 306 mg powder-filled 
vial, and one pre-printed Instructions for Use (IFU) insert in a 2ct kit. The site will be responsible for providing 0.9% 
Sodium Chloride for Injection, USP and lactated Ringer’s solution.   
Kits will be provided for a once-only use and will be assigned to one subject only. Reconstitution will occur at the 
pharmacy on-site and the reconstituted study agent will be delivered for use by the Investigator. An IFU insert will 
be provided in each kit and an instructional video will be provided to each site prior to the Initiation Visit, ahead of 
the first subject 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, the dose withdrawal procedure, 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 
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 contents 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 clinical site’s 
pharmacy, temperature controlled at 
to 
 
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 vial used and each syringe must be labelled with the subject’s ID 
and visit information for accountability purposes. 
6.1.4 PREPARATION 
A prescription will be provided for each subject detailing the subject ID, the cohort to which the subject is 
assigned, and the date and time required for administration. This will be provided to the Pharmacy at least 24 
hours prior to administration time. 
Once the drug has been reconstituted to the required dose (6, 10, or 15mg/mL, according to cohort assignment), 
the maximum injection volume of 5 mL will be withdrawn, as described in the IFU, from the vial into a syringe. The 
precise volume to be injected will be determined by the physician prior to the injection procedure using EUS. The 
syringe for administration will be labeled with the subject ID and the date and time of preparation.  
6.1.5 DOSING AND ADMINISTRATION 
On the day of NanoPac administration, the subject will receive parenteral antibiotic prophylaxis. The subject will be 
positioned in the left lateral decubitus position and will be sedated by an anesthesiologist or delegate using 


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monitored anesthesia care (MAC) with or without airway intubation. A linear array echoendoscope will be inserted 
via the mouth and advanced to the stomach or duodenum, whichever provides the best access to the tumor. The 
tumor will be measured using electronic calipers and the size recorded.  
The stylet will be removed from a 22-gauge fine needle aspiration (FNA) needle and the needle filled with the 
study treatment, NanoPac, from the syringe provided. The needle will be luer locked into the accessory channel of 
the echoendoscope. Doppler ultrasound imaging will be used to verify lack of intervening vascular structures in 
path to tumor. Using a 22-gauge needle, NanoPac will be injected (according to the cohort, at a concentration of 6, 
10, or 15 mg/mL) using multiple passes of the needle in a fan-like pattern of withdrawal and reinsertion, fanning to 
the periphery of the tumor to ensure that NanoPac is infused evenly throughout the entirety of the tumor. The 
Investigator will use their discretion to inject NanoPac in a volume up to 20% of the tumor volume (calculated as 
described in section 4.1), with a maximum injection volume of 5 mL in any subject.  
6.1.6 ROUTE OF ADMINISTRATION 
NanoPac will be administered directly into the tumor within the pancreas using EUS-guided direct injection. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
NanoPac will be administered in concentrations based on cohort assignment. Investigators will use their discretion 
to administer a volume of up to 20% of the tumor volume (as calculated in Section 4.1). Volume administered will 
not exceed 5 mL in any subject. In the dose escalation phase of the study, the first cohort will receive 6 mg/mL 
NanoPac; the second cohort will receive 10 mg/mL NanoPac; and the third cohort will receive 15 mg/mL NanoPac.   
Cohorts will be enrolled sequentially starting at the lowest dose (6 mg/mL). Each cohort will have a planned 
minimum of three subjects, each receiving a single dose of the study agent. Escalation to the next cohort will 
proceed following review of data by the DSMB. Data from the three subjects in a cohort, including all DLTs 
described in this section, will be reviewed and evaluated by the DSMB to determine if the dose received is 
considered safe and tolerable, and to determine if dose escalation may occur. The DSMB will review the data on 
the three subjects once they have completed the 2-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). 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 second 
phase. If greater than one subject in a six-subject cohort experience DLT, the previous dose will be taken into the 
second phase of the study. 
 
The dose administered in the second and third phases of the study will be the highest dose considered to be safe 
and tolerable in the dose escalation pahse.   
Included in the DSMB’s review of AEs and general study data pertaining to safety (such as laboratory results and 
questionnaire responses) 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 AEs; DLTs will, in addition, include the following : 
 
-biliary events (including but not limited to symptomatic pancreatitis or cholangitis, 
excluding asymptomatic time-limited pancreatic enzyme elevations); 
 
 


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Grade 3 diarrhea and vomiting lasting more than 72 hours, or Grade 4 diarrhea and vomiting;
 
Grade 4 neutropenia lasting 5 days; 
 
Grade 4 thrombocytopenia; 
 
Grade 4 biliary toxicity; 
 
Any life-threatening event (unless there is a clear alternative explanation that the event is not related to 
the procedure or the investigational product itself). 
 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
As this study is evaluating one single administration of NanoPac in each subject in the dose escalation phase of the 
study, there will be no dose adjustment or modification in an individual subject.  
In the second and third phases of the study, where more than one NanoPac injection will be given to each 
participant, there is a possibility that the dose may be adjusted (reduction in number of injections) based on 
safety, and this will be discussed and determined between the Investigator and the Medical Monitor on a case by 
case basis.  The DSMB may also determine, upon review of the first three subjects in this phase, that adjustment is 
required for the remaining subjects in this cohort. 
It is possible that the full 20% tumor volume for a particular subject will not be able to be administered, and the 
Principal Investigator will determine this at the time of injection. In the event not all of the calculated volume of 
NanoPac can be administered, the amount not injected will be measured once the needle is removed and the 
volume remaining will be noted in the source document. 
6.1.9 DURATION OF THERAPY 
A single administration of NanoPac is being injected directly into the tumor within the pancreas on either a single 
occasion (dose escalation phase) or on up to fours occasions 1 month apart (two in the second phase, or up to four 
in the third phase). Each administration/dose of NanoPac is delivered in approximately 5 minutes, and does not 
continue over an extended period. 
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 
investigational drug, including the date, quantity, batch or code number, and identification of subjects (number, 
initials) who received study medication.  
Accountability will be conducted using the records held by the Pharmacy including details on vial packaging, the 
individual vials, and the syringes.  No used vials or syringes will be kept for accountability purposes, they will be 
disposed of according to the standard operating procedures at the institutions.  


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If the investigator determines that the full volume of NanoPac (20% tumor volume as calculated in Section 4.1) 
cannot be administered, the Investigator will document the amount of NanoPac injected, and the volume 
remaining, in the source document and in the EDC. 
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 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 pancreas and previous treatments 
including surgical and chemotherapeutic records. A copy of the pathology report confirming the diagnosis 
and the imaging reports must be filed in the subject’s study record.  
 
Confirmation of hematologic recovery (
9
9/L) must be obtained 
prior to NanoPac administration and filed in the subject’s study record; 
 
Comprehensive physical examination, including ECOG Performance Status assessment (see Appendix A), 
and vital signs (blood pressure, heart rate, temperature, body weight and height); 
 
In the second phase of the study, prior to injection a CT Scan will be obtained to provide baseline data on 
dimensions and volume of the lesion to be injected; 
 
Pharmacokinetic (PK) samples will be taken on Day 1 prior to injection, and at 1, 2, 4, 6, and 24 hours 
post-injection, and again at all study visits post-injection for subjects in the dose escalation phase of the 
study; for subjects in the second and third phases of the study, PK samples will be obtained prior to each 
injection and at 1 and 2 hours post injection, and at all other study visits. 
 
In the third phase of the study, a blood sample will be obtained from subjects for exploratory evaluation 
of immune markers (using flow cytometry at a central laboratory) prior to injection at each injection visit 
and also at the 6-month follow-up visit.  
 
Serum CA-19-9 levels obtained at screening, on the day of NanoPac administration prior to injection 
(NanoPac Day 1), and at 2 weeks, 4 weeks, 2 months, 3 months, and 6 months post-injection for the 
subjects in the dose escalation phase of the study;  for the subjects in the second and third phases the 
sample at injection visits will be taken prior to injection, and these subjects will have samples taken at all 
remaining study visits. 
 
Serum carcinoembryonic antigen (CEA) levels obtained at screening, on the day of NanoPac 
administration prior to injection, and at 2 weeks, 4 weeks, 2 months, 3 months, and 6 months post-
injection for the subjects in the dose escalation phase of the study;  for the subjects in the second and 
third phases the sample at injection visits will be taken prior to injection, and these subjects will have 
samples taken at all remaining study visits. 
 
Samples will be collected and processed for clinical laboratory assessment at screening, and on the day of 
NanoPac injection prior to treatment; and at 2 weeks, 4 weeks, 2 months, 3 months, and 6 months post-


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injection for the subjects in the dose escalation phase of the study;  for the subjects in the second and 
third phases the sample at the injection visit will be taken prior to injection, and these subjects will have 
samples taken at all remaining study visits. 
 
Assessments will include: 
o 
Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood urea 
nitrogen (BUN), creatinine, serum lipase, serum amylase, alkaline phosphatase, total bilirubin, 
direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-
glutamyl transferase (GGT), 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, platelet count, 
and absolute neutrophil count (ANC); 
o 
Urinalysis including specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose; 
o 
Prothrombin time (PT) and activated partial thromboplastin time (PTT); 
 
Pain will be assessed with the visual analog scale (VAS) at screening, on the day of NanoPac 
administration (pre- and post-injection), and at 2 and 4 weeks, 2 months, 3 months, and 6 months post-
injection for the subjects in the dose escalation phase of the study;  for the subjects in the second and 
third phases the assessments at injection visits will be conducted pre- and post-injection and at all other 
study visits.. 
 
Imaging with CT scan will have occurred prior to injection (within 6 weeks in order to estimate tumor 
volume), at 3 months post-injection, and at end-of-study (6 months after NanoPac injection) for the 
subjects in the dose escalation phase of the study;  for the subjects in the second phase of the study a CT 
Scan will be obtained following consent and prior to first injection, 3 months past first injection (at the 
Week 12 visit), and at the 6 month visit; for the subjects in the third phase of the study a CT Scan will be 
obtained following consent and prior to first injection, 3 months after the first injection (at the Week 12 
visit) which will be their fourth injection visit (if they have all four injections), at the 6 month visit, and at 
the 9 month visit. Should the subject withdraw from the study at any time, a scan will be conducted as 
part of the end of study procedures. Additional imaging may be performed at the Investigator’s discretion 
as per institutional SOC and all resulting images will be collected for the subject’s record. 
 
EUS-guided fine needle injection of the tumor within the pancreas with 6, 10, or 15 mg/mL NanoPac at a 
volume up to 20% of tumor volume (as calculated in Section 4.1), depending on study cohort assignment.  
Subjects in the dose escalation phase of the study will receive one injection on Day 1. In the second phase 
of the study, once the selected dose for expansion is confirmed, subjects will receive NanoPac on two 
occasions, at Day 1 and again at the Week 4 visit.  In the third phase of the study subjects will receive 
NanoPac on up to four occasions, at Day 1, Week 4, Week 8, and Week 12. 
 
Subjects will be “admitted” to the hospital during the post-injection period for up to 23 hours, for 
observation and capture of AEs, and to permit the acquisition of the 6-hour and 24-hour PK samples for 
subjects in the dose escalation phase of the study. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
The subjects being enrolled to the dose escalation phase of this study will have received at least one course of 
standard neoadjuvant IV chemotherapy, and their platelet and neutrophil recovery will meet inclusion criteria for 


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participation. Subjects in the second and third phases of the study will have IV chemotherapy initiated prior to first 
injection.   
Following EUS-guided fine needle injection of NanoPac, the care of the subject will be as dictated by the protocol 
but will allow for any other standard care the Investigators would routinely provide (such as pain relief, additional 
clinic visits, etc.). Following ITU injection of NanoPac, IV chemotherapy should not be initiated within one month if 
at all possible for subjects in the dose escalation phase of the study. Following the 4-week follow-up visit, at which 
point the primary endpoint for safety and tolerability has been reached, further chemotherapy will be permitted as 
per institutional standard of care. If chemotherapy is required prior to the 4-week visit, the Investigator must 
contact the study Medical Monitor to discuss and document the decision-making process.  For subjects in the 
second and third phases of the study SOC IV chemotherapy will have been initiated prior to first injection and 
chemotherapy administered while on study will be recorded in the concomitant medication forms. 
Information on standard care and treatment post-injection(s) to the 3-month visit, 6-month follow-up visit, and 9-
month follow-up visit for subjects in the third phase of the study, will be captured as appropriate. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Clinical laboratory assessments will be conducted at the local CLIA certified laboratory routinely used by the 
Investigator. 
The following laboratory tests will be performed at screening, on the day of NanoPac injection, and at 2 
weeks, 4 weeks, 2 months, 3 months, and 6 months post-injection for the subjects in the dose escalation 
phase of the study;  for the subjects in the second and third phases the sample at injection visits will be taken 
prior to injection, and these subjects will have samples taken at all remaining study visits: 
 
Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood urea nitrogen 
(BUN), creatinine, serum lipase, serum amylase, alkaline phosphatase, total bilirubin, direct bilirubin, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), 
lactate dehydrogenase (LDH), total protein, albumin, triglycerides, cholesterol, uric acid and calculated 
creatinine clearance; 
 
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, platelet count, and absolute neutrophil count 
(ANC); 
 
Urinalysis including specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and glucose; 
 
Prothrombin time (PT) and activated partial thromboplastin time (PTT); and 
 
Tumor markers CA-19-9 and CEA (to evaluate tumor response to therapy). 
7.2.2 OTHER ASSAYS OR PROCEDURES 
For subjects in the dose escalation phase of the study pharmacokinetic (PK) samples will be taken on Day 1 prior to 
NanoPac injection, and at 1, 2, 4, 6, and 24 hours post-injection. Subjects will be in hospital overnight in order to 
obtain the 6- and 24-hour PK samples. In addition, a PK sample will be obtained at each study visit. Subjects in the 


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second and third phases of the study will provide PK samples pre-injection and 1 and 2 hours post injection at 
injection visits,  and at all other study visits. 
PK samples within the first 4 hours on the day of injection will allow for a 10-minute window around the samples. 
The remaining samples within the first 24 hours in the dose escalation pahse of the study will allow for a 30-minute 
window. 
In the third phase of the study a blood sample will be obtained at each injection visit, prior to injection and at the 
6-month follow-up visit.  Samples will be processed and sent to a central laboratory (NeoGenomics; Alisa Viejo, CA) 
for immune  marker assessment via flow cytometry. 
Imaging with CT scan will occur within 6 weeks prior to NanoPac injection for study eligibility in the dose escalation 
group, at three months post-injection, and at end-of-study (six months after NanoPac injection). Subjects in the 
second phase of the study will have a CT Scan following consent and prior to first injection, and at the 3 and 6 
month follow-up visits.  Subjects in the third phase will have CT Scans following consent and prior to first injection, 
and at 3, 6, and 9 month follow-up visits. 
Should the subject withdraw from the study at any time, a scan will be conducted as part of the end of study 
procedures. Additional imaging may be performed at the Investigator’s discretion and all resulting images will be 
collected for the subject’s record. 
Pain assessment will be conducted with the visual analog scale at all study visits. On the day(s) of NanoPac 
administration the pain assessment will be conducted prior to and following the procedure. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
PK samples will be drawn at the specified time/visit, prepared 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. Procedures for processing for storage will be provided prior to study initiation. 
Blood samples for flow cytometry will be drawn at the specified time/visit, prepared and shipped on the same day 
to the central laboratory for this evaluation, NeoGenomics.  A kit for sample preparation and instructions will be 
provided. 
Serum samples for routine laboratory assessments 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. 
7.2.4 SPECIMEN SHIPMENT 
Routine laboratory samples will be sent to the local laboratory upon collection.  
Shipment process for the PK samples will be provided once established with the laboratory, prior to study 
initiation, and details will be provided to the site in their Regulatory Binder. 
Shipment of the sample for flow cytometry will occur on the same day as the blood draw.  A manual describing 
details for (preparation and) shipping will be provided to the sites. 


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7.3
STUDY SCHEDULE
7.3.1
SCREENING
Assessments, visits, and other assays performed in the interval between the end of IV chemotherapy and before 
consent to the study for NanoPac injection in the dose escalation cohorts will be performed according to the 
institution’s standard of care and are not considered part of this study. 
9
109/L, subjects will be eligible to enroll to the dose escalation phase of the study to receive treatment with
NanoPac. Subjects in the second and third phases of the study will have initiated IV chemotherapy prior to first 
NanoPac injection. 
The following procedures and assessments must be completed, documented and reviewed by the Investigator 
during the screening period, within 28 days prior to NanoPac injection: 
 
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 pancreatic adenocarcinoma with a diameter of at least 1.5 cm but not 
more than 6 cm as determined by imaging; diagnosis and previous treatments including surgical and 
chemotherapeutic records. A copy of the pathology report confirming the diagnosis must be filed in the 
subject’s study record;  
 
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); 
 
Visual analog scale for pain assessment; 
 
Sample collection and processing for clinical laboratory assessments (see Section 7.2.1);  
 
Imaging with CT scan will have occurred recently to confirm and document tumor volume and estimate 
the injection volume required on day of NanoPac administration. For the subjects in the second and third 
phases of the study a CT Scan will be required between Screening and prior to injection for detailed 
baseline assessment and comparison purposes.  Final injection volume will be determined with 
ultrasound during the EUS-guided injection procedure.  
 
7.3.2 DAY OF NANOPAC INJECTION 
All screening assessments must have completed prior to the first injection visit, and all results and 
inclusion/exclusion criteria must have been confirmed.  
 
Prior to the procedure: 
 
Comprehensive physical examination, including ECOG Performance Status assessment;  
 
Vital signs will be obtained and a visual analog scale for pain assessment will be completed pre- and post-
injection. 
 
Adverse events occurring in the period between screening and this visit must be confirmed as either 
ongoing or completed. Adverse events occurring prior to the procedure will be considered history, and 


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those occurring after NanoPac administration will be documented separately as TEAE, with a start date on 
or after administration. 
 
Concomitant medication will be reviewed and updated as necessary; 
 
Sample collection prior to injection, and processing for clinical laboratory assessments (Section 7.2.1):  
 
Subjects will receive NanoPac as described in Sections 4.1 and 6.1.5, according to the cohort allocation; 
 
In the dose escalation cohorts: 
 
PK Samples will be drawn prior to NanoPac injection, and then 1, 2, 4, 6, and 24 hours post-injection. 
 
Subjects will be admitted to the hospital for an overnight stay in order to assess adverse events in the 
immediate post-injection period, and to obtain the 6- and 24-hour PK samples. 
In the subjects enrolling in the second and third phases of the study: 
 
PK samples will be drawn prior to NanoPac injection, and then 1 and 2 hours post-injection.  No overnight 
hospitalization is required. 
 
Only subjects in the third phase of the study will have a blood sample drawn for immune marker 
assessment prior to injection at each of the injection visits occurring. 
 
7.3.3 FOLLOW-UP VISITS 
After NanoPac injection on Day 1 (and the overnight hospital stay for subjects in the dose escalation cohorts), 
subjects will return to the clinic in 2 weeks for the first study-specific follow-up visit. Subsequent follow-up visits 
will occur at 4 weeks post-injection, two months post-injection, and three months post-injection, and where 
possible a further visit will be conducted six months post-injection.  
 
Subjects in the second phase of the study will follow the above schedule to Week 4 at which time they will have a 
second NanoPac injection. They will return to the clinic 2 weeks after the second injection and then at the 
scheduled visits from Week 8 through to Month 6; one further follow-up visit – which may be by phone call - at 
month 7 (6 months following last injection) is possible. 
 
Subjects in the third phase of the study will receive up to four NanoPac injections.  Assuming all injections are 
given, the subject will have a follow-up visit 2 weeks after each injection visit attending the site on Days 1, Week 4, 
Week 8, and Week 12 for injections and on Weeks 2, 6, 10, and 14 for follow-up visits.  Additional follow-up visits 
will occur on Weeks 16, 20, and 24.  
 
The Week 4 (1-month) visit will be the primary endpoint study visit for all subjects in the dose escalation phase of 
the study, the Week 8 (2-month) visit will be the primary endpoint study visit in the second phase of the study 
(which is one month following the second injection), and the Week 16 visit will be the primary endpoint visit in the 
third phase of the study (1 month after last injection). All further visits will be conducted to assess the secondary 
endpoints and to document any progression of disease during this time period.  
 
Dose escalation phase: 
The following procedures will be performed at the Week 2, Week 4, Week 8 (2-month) and Week 12 (3-month) 
clinic visits: 
 
Vital signs obtained; as needed, a directed physical exam may be performed; 


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o 
At Week 4 a comprehensive physical exam, including vital signs and ECOG Performance Status 
assessment, will be performed. 
 
Visual analog scale for pain assessment; 
 
ECOG Assessment; 
 
Concomitant medications reviewed; 
 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
 
PK sample obtained; 
 
AE collection; 
 
Imaging with CT scan will be performed at the Week 12 (3-month) visit. 
 
Second phase of study; two injections: 
 
The same procedures as above will be carried out to the Week 4 (1-month) visit. 
 
At the Week 4 visit the subject will have a second NanoPac injection via EUS and in addition to the visits 
noted above, the same follow-up procedures will be carried out at Week 6 (2 weeks after the second 
injection). 
 
Third phase of study; up to four injections: 
 
The same procedures as above will be carried out to the Week 4 (1-month) visit. 
 
At the Week 4 visit the subject will have a second NanoPac injection via EUS and in addition to the visits 
noted above, the same follow-up procedures will be carried out at Week 6 (2 weeks after the second 
injection).  This will be repeated for the third and fourth injections, having two week follow-up visits 
conducted at Weeks 10, 14, 16, 20, and 24. 
 
For subjects in the third phase of the study, a blood sample will be drawn for immune marker assessment 
at the 6-month follow-up visit. 
 
7.3.4 FINAL FOLLOW-UP STUDY VISIT  
This final visit will be conducted at a time point after the 3-month visit, as close to six months as possible, in the 
dose escalation phase.  Subjects in the second phase will complete a final clinic visit as close to six months as 
possible, with a follow-up phonecall to occur one month later.  Subejcts in the third phase of the study will 
complete their final study visit as close to nine months as possible.  
Subjects may decide to withdraw participation prior to this point and at that time this visit should be conducted if 
possible.  
At the final study visit, the following procedures will be performed: 
 
Vital signs obtained; 
 
Concomitant medications; 
 
AE collection; 
 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
 
PK Sample obtained; 
 
Visual analog score to record pain symptoms; 
 
ECOG Assessment; 
 
Imaging with CT scan and disease status assessment. 


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No further follow-up will be required or requested of subjects after this visit in the dose escalation cohorts. In the 
second phase of the study where subjects receive a second injection at the Week 4 visit, one further follow-up will 
be conducted at 7 months by phone. 
Sites will be requested to provide information on progression and progression free survival (PFS) and overall 
survival (OS) on all study participants in the second and third phases at the 9 and 12 months time point following 
first NanoPac injection.  This information will be provided for information only, and will not be used to support a 
study endpoint. 
7.3.5
EARLY TERMINATION VISIT
In the event a subject is withdrawn they would, at minimum, undergo End-of-Study evaluations, which include the 
procedures described in Section 7.3.4 above. 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 must be captured are the vitals, AEs, 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. 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 transcribed into the EDC, and any imaging assessments which may be performed will 
also be noted in the EDC. If during the period the subject is on study they undergo additional EUS procedures these 
will be documented in the EDC and reports on findings provided for information, as appropriate. 


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7.3.7 SCHEDULE OF EVENTS TABLE – DOSE ESCALATION SUBJECTS 
 
Screening3, 8
Day 1 
(Injection) 
24 Hours 
Post-Injection 
Week 2 
Week 4 
(1 Month) 
Week 8 
(2 Months) 
Week 12 
(3 Months) 
6 Months
(Final Study 
Visit)
Informed Consent 
X 
 
 
 
 
 
History1
X 
 
 
 
 
 
Concomitant 
therapy
X 
X 
 
X 
X 
X 
X 
X 
Physical Exam
X
X
X
X
X
X
X
ECOG2
X
X
X
X
X
X
X
Pain Assessment6
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Clinical Laboratory 
Tests (section 7.2.1)
X
X
X
X
X
X
X
PK Samples5
X
X
X
X
X
X
X
Imaging7
X
X
X
NanoPac4
X
Adverse Events
X
X
X
X
X
X
X
 
 
1
History includes all events before initiation of NanoPac treatment.
2
ECOG Performance Status Scale attached as Appendix A
3 
During the interval after the conclusion of intravenous chemotherapy but prior to injection with NanoPac, subjects will visit the clinic for evaluation and hematologic assessment according to 
their institut
9
9/L.
4
Prophylactic antibiotics will be administered prior toNanoPac injection; NanoPac will be administered by EUS-guided fine needle injection; subjects will be admitted to the hospital for overnight 
observation. 
5 
PK Samples on Day 1 will be drawn prior to injection and at 1, 2, 4, 6, and 24 hours post-dose, PK samples will also be obtained at each study visit thereafter. PK samples within the first 4 hours 
on Day 1 will allow for a 10-minute window around the samples. The remaining samples within the first 24 hours will allow for a 30-minute window. 
6 
Pain will be assessed with the visual analog scale 
7 
Imaging with CT scan will occur within 6 weeks of NanoPac administration, at three months post-injection, and at end-of-study (six months after NanoPac injection). Should the subject withdraw 
from the study at any time, a scan will be conducted as part of the end of study procedures. Additional imaging may be performed at the Investigator’s discretion as per institutional SOC and all 
resulting images will be collected for the subject’s record.  
8 
Screening will occur up to 4 weeks prior to injection  
 
 
 
 
 


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7.3.8 SCHEDULE OF EVENTS TABLE – SECOND PHASE SUBJECTS 
 
 
Screening3, 
8 
Day 1 
(Injection) 
Week 2 
Week 4 
(1 Month) 
 
Week 6 
Week 8 
(2 Months) 
Week 12 
(3 Months) 
 
Week 24 
(6 Months) 
Week 28-30 
(phone call) 
Informed 
Consent
X 
 
 
 
 
 
 
 
History1
X
 
 
Concomitant 
therapy 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
X
X 
X 
X
X 
X 
X 
ECOG2
X
X
X
X
X 
X
X
X
Pain 
Assessment6
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital Signs 
X
X
X
X
X 
X
X
X
Clinical 
Laboratory Tests 
(section 7.2.1)
X 
X 
X 
X 
X 
X 
X 
X 
PK Samples5
X
X
X
X
X
X
X
Imaging7
X
 
X
X 
NanoPac4 
X
X
Adverse Events
X
X
X
X
X
X
X
X
1
History includes all events before initiation of NanoPac treatment.
2
ECOG Performance Status Scale attached as Appendix A
3 
9/L and 
9/L.
4
Prophylactic antibiotics will be administered prior toNanoPac injection; NanoPac will be administered by EUS-guided fine needle injection
5 
PK Samples will be drawn prior to injection and at 1 and 2 hours post-dose, and at all other study visits. PK samples on the injection days will allow for a 10-minute window.  
6 
Pain will be assessed with the visual analog scale 
7 
Imaging with CT scan will occur during the Screening period (prior to NanoPac administration), and at three and six months post-first-injection. Should the subject withdraw from the study at 
any time, a scan will be conducted as part of the end of study procedures. Additional imaging may be performed at the Investigator’s discretion as per institutional SOC and all resulting images 
will be collected for the subject’s record.  
8 
Screening may occur up to four weeks prior to injection  
 
 
 
 
 
 


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7.3.9 SCHEDULE OF EVENTS TABLE – THIRD PHASE SUBJECTS 
 
Screening3, 8
Day 1, 
Weeks 4 and 
8 
(Injection)
Weeks 2, 6, 
10 
Week 12 
(Injection) 
Weeks 14, 
16, 20 
Week 24 
(6 Months) 
9 Months 
(Final Study 
Visit) 
Informed Consent
X
History1
X 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
Physical Exam
X 
X 
X 
X 
X 
X
X
ECOG2
X 
X 
X 
X 
X 
X
X
Pain Assessment6
X 
X 
X 
X 
X 
X
X
Vital Signs 
X 
X 
X 
X 
X 
X
X
 Clinical Laboratory Tests 
(section 7.2.1)
X 
X 
X 
X 
X 
X 
X 
PK Samples5  
 
X
X 
X 
X 
X
X
Blood for FCM9 
 
X 
 
X 
X
 
Imaging7
X 
 
 
X 
X
X
NanoPac4
 
X 
 
X 
 
 
Adverse Events
 
X 
X 
X 
X 
X
X
1
History includes all events before initiation of NanoPac treatment.
2
ECOG Performance Status Scale attached as Appendix A
3 
9
9/L.
4
Prophylactic antibiotics will be administered prior toNanoPac injection; NanoPac will be administered by EUS-guided fine needle injection
5 
PK Samples on injection days will be drawn prior to injection and at 1 and 2 hours post-dose; PK samples will also be obtained at all other study visits. PK samples on injection days post-injection 
will allow for a 10-minute window around the samples.  
6 
Pain will be assessed with the visual analog scale pre-and post-injection on injection days. 
7 
Imaging with CT scan will occur at the time of Screening, prior to NanoPac administration, at three months post-first-injection but prior to final injection, at three months following final injection 
(at Week 24), and at end-of-study (9 months after first NanoPac injection). Should the subject withdraw from the study at any time, a scan will be conducted as part of the end of study 
procedures. Additional imaging may be performed at the Investigator’s discretion as per institutional SOC and all resulting images will be collected for the subject’s record.  
8 
Screening may occur up to 4 weeks prior to injection  
9 
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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that EUS-guided fine needle injection of NanoPac into the tumor within the pancreas, 
including the anesthesia necessary for the injection, 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 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  
No precautionary medications, treatments, or procedures are included in this protocol; they may, however, be 
administered at the discretion of the Investigator, anesthesiologist, or the subject’s primary care provider or 
oncologist. All medications will be recorded. 
7.7 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Use of concomitant chemotherapy (other than the protocol specified agents), immunotherapy, or radiation 
therapy during the 4 weeks following NanoPac injection is prohibited in the dose escalation cohorts of the study.    
If chemotherapy is to be initiated the PI must contact the study Medical Monitor to discuss the assessments made 
to determine the need to initiate therapy, and document date to start and medications prescribed. This will all be 
entered to the EDC at the next study visit, but the Medical Monitor must be made aware of this as soon as 
possible.  
In the second and third phases of the study subjects may be receiving concurrent IV chemotherapy, however 
immunotherapy and radiation therapy is prohibited during the 4 weeks following  NanoPac injections. 
7.8 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prophylactic antibiotics will be administered on the day of NanoPac injection and any other prophylactic 
medications will be administered according to the institution’s standard of care. 


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7.9
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
Rescue medications, treatments, and procedures will be performed according to the institution’s standard of care, 
and will be documented in the source documents and in the study data as needed. 
7.10 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable. 
8
ASSESSMENT OF SAFETY
8.1
SPECIFICATION OF SAFETY PARAMETERS
Safety assessments to be conducted in this study include:
 
Adverse events, collected at all study visits from the time of dosing; 
 
Changes in concomitant medications;  
 
Findings from physical examinations; 
 
Changes in vital signs; and 
 
Changes in laboratory parameters. 
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 will be conducted after every three 
subjects are dosed and have completed 2 weeks’ follow-up post-NanoPac injection (or more frequently if deemed 
necessary). 
Safety and tolerability will be assessed by the DSMB prior to any dose escalation occurring.   
Included in the DSMB’s review of the AEs and general study data pertaining to safety (such as laboratory results 
and questionnaire responses) 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 AEs; DLTs will, in addition, include the 
following: 
 
pancreatico-biliary events (including but not limited to symptomatic pancreatitis or cholangitis, 
excluding asymptomatic time-limited pancreatic enzyme elevations); 
 
 
 
Grade 3 diarrhea and vomiting lasting more than 72 hours, or Grade 4 diarrhea and vomiting; 
 
Grade 4 neutropenia lasting 5 days; 
 
Grade 4 thrombocytopenia; 
 
Grade 4 biliary toxicity; 
 
Any life-threatening event (unless there is a clear alternative explanation that the event is not related 
with the procedure or the investigational product itself). 
Events of special interest (Section 8.4.4) will be specifically reviewed and will form part of the review between 
doses, and the DSMB review will provide and document oversight as detailed in the DSMB Charter. 


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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 AEs unless they are considered symptomatic of a clinical 
condition or diagnosis, are evaluated as clinically significant, or require therapy. Worsening of a pre-existing 
condition is also considered an AE, as is the discovery of an abnormal finding during physical exam that was not 
included in the medical history. Clinical conditions attributable to disease progression will be considered AEs and 
reported on the eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (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 subject was, in the view of the Investigator, at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious 
form or progressed, might have caused death; 
3) Is a persistent or significant disability or incapacity; 
4) Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered a 
hospitalization that is longer than 24 hours, or a hospitalization that requires an intervention to treat 
emergent symptomatology (non-diagnostic); 
5) Is a congenital anomaly or birth defect; 
6) Other important medical events may be considered a serious adverse experience when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes as listed in #1-5 in this definition. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
As this is a Phase IIa study, all unanticipated problems will be captured as either AEs or SAEs and will be defined 
and reported accordingly. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
Signs and symptoms will be graded by the Investigator 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:  Subject was at immediate risk of death from the event 


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Fatal:  Death related to the event.
Toxicities should be evaluated according to the NCI CTCAE, version 4.0; see 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.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 possibly, probably, or definitely related to 
the study agent. 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 subject’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 subject’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 
subject’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 drug specifically. An event may be unexpected in the 
subject but that in itself does not qualify as unexpected; review against information available and provided for the 
study agent is what will determine expectedness. 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent, in the protocol and within the Investigator’s Brochure. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Adverse events will be recorded throughout the study and at early termination, and will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Adverse events ongoing at the final study visit must be 
followed until resolution or until the Investigator determines them to be stable and/or adequately managed.  
Subjects will be required to spontaneously report any AEs. Study personnel will ask open-ended questions to 
obtain information about AEs at every visit. Date and time of onset and resolution (if applicable) of the AE will be 
documented. 
All SAEs must be followed until the event resolves or, in the opinion of the Investigator, becomes stable.  


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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 AEs (whether or not attributable to the study agent) occurring during the study observed by the Investigator or 
reported by the subject will be recorded on the eCRF. The following information will be recorded for all AEs: 
 
Name of condition/diagnosis/description; 
 
Onset and resolution dates; 
 
Severity; 
 
Relationship to study agent; 
 
Action taken; 
 
Seriousness.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAEs, including death, due to any cause which occurs during this study, whether or not expected and regardless 
of relationship to study agent, must be reported to the Medical Monitor immediately upon discovery of the event, 
using the SAE reporting form, by email or fax and, if necessary, by phone to: 
Dr. Antony Verco 
Medical Monitor 
E-mail: tony.verco@usbiotest.com 
Phone: 805-235-9193 
Fax: 805-980-4897 
 
24-hour Emergency Contacts: 
Gere diZerega, MD 
or 
Antony Verco, MD 
 
Medical Director 
 
Medical Monitor 
 
805-630-2800  
 
805-235-9193 
 
The Study Manager, Dr. Shelagh Verco, should be copied on all correspondence via email at 
Shelagh.verco@usbiotest.com, and can be reached by phone 805-704-1179. 
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). 


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8.4.3
UNANTICIPATED PROBLEM REPORTING 
Unanticipated 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 FDA as required. 
8.4.4
EVENTS OF SPECIAL INTEREST 
Of particular interest will be signs of systemic toxicity due to paclitaxel exposure; this is not expected and is 
considered unlikely given the mode of administration and dose levels. Pancreatitis has occurred after injection of 
the pancreas; subjects will be monitored for pancreatitis, in particular during the first 36 hours after the 
procedure, and will be encouraged to report symptoms such as abdominal pain with or without nausea/vomiting. 
Pain is an adverse event also associated with pancreatic injection, in particular pain in the mid-epigastrium and/or 
the back. Additional events sometimes associated with pancreatic injection include vomiting, peritonitis, 
retroperitoneal bleeding, abscess formation, and fistula formation. 
8.4.5 REPORTING OF PREGNANCY  
Female subjects must take a pregnancy test before receiving any treatment. A female patient is considered to be 
of childbearing potential unless she has had a hysterectomy, is at least one year postmenopausal or has undergone 
tubal ligation. For the purposes of this study, adequate birth control includes at least one medically approved and 
highly effective method of birth control, defined as those which result in a low failure rate (i.e. < 1% per year) 
when used consistently and correctly, such as implants, injectables and oral contraceptives combined with the use 
of double condoms. Only male patients whose vasectomy has been confirmed by semen analysis at least 3 months 
after the vasectomy are allowed not to use acceptable contraceptive methods. 
Any pregnancy occurring in a subject or a subject’s sexual partner during the study or within 6 months after 
injection of NanoPac must be reported to US Biotest as soon as the Investigator is aware of it. The pregnancy will 
not be considered an SAE; however, information on these pregnancies will be collected and followed for the 
outcome of the pregnancy and the health of the newborn.  
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion, or elective 
termination of a pregnancy for medical reasons will be reported as an SAE, as described in Section 8.4.2. Should 
the pregnancy result in a congenital anomaly or birth defect, a separate SAE report must be submitted. 
Furthermore, all neonatal deaths that occur within 30 days of the birth should be reported as SAEs, 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 treatment 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 the 
safety and tolerability data in a cohort by the DSMB. Following review, at any time point, the study may be 
terminated. Should this occur, all subjects who have received treatment will be followed to the completion of their 
3-month follow-up/primary end of study visit to ensure all safety data is collected on all treated subjects. 


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The DSMB will review data from the first three subjects in each cohort once they complete the 2-week follow-up 
visit after NanoPac injection. The DSMB may determine that a further three subjects should be treated at the same 
dose as a current cohort to provide additional safety and/or tolerability information needed in order to determine 
if dose escalation should proceed; they may also determine that it is acceptable to proceed with an increased dose 
in 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 FDA of any temporary halts to the study or when a study is terminated; the 
Investigator will be required to notify the IRB accordingly. 
8.6 
SAFETY OVERSIGHT 
Safety will be overseen by the Medical Monitor and the Data Safety Monitoring Board (DSMB). 
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. 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, and a report will be generated outlining any safety concerns from the data available for review in the EDC.  
This review will take place prior to proceeding with either addition of more subjects to a current cohort or 
proceeding to dose escalation in a new cohort. 
DSMB will again convene following the first three subjects in the second phase of the study completing a 2 week 
follow-up after their second NanoPac injection to review safety data.  Subject recruitment to this cohort of 
subjects will continue and if during the review the DSMB have concerns regarding future subjects receiving a 
second injection they may propose alternative actions (which may include reducing the dose of the injections or 
not permitting two injections in future patients, reverting to a single injection).   
DSMB will also convene following the first three subjects in the third phase of the study completing a 2 week 
follow-up after their fourth NanoPac injection to review safety data.  Subject recruitment to this cohort of subjects 
will continue and if, during the review, the DSMB have concerns regarding future subjects receiving additional 
injections they may propose alternative actions (which may include reducing the dose of the injections or not 
permitting third and fourth injections in future patients, reverting to only two injections).   
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 Sections 6.1.7 and 8.1. 
 
9 
CLINICAL MONITORING 
US Biotest monitors, or monitors designated by US Biotest, will conduct scheduled site visits to the investigational 
centers for the purposes of monitoring the study. The Investigator agrees to allow these monitors, and other 
authorized Sponsor personnel or designees, access to the subject’s medical records, regulatory binder, study 
binder, eCRFs, and source documents as needed to assure that the conduct of the study is within compliance. In 


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addition, FDA or other government agencies may request an inspection following notification to the site. In such an 
event, the Investigator agrees to notify the Sponsor immediately of the request, and will allow Sponsor and 
inspectors to review records. 
US Biotest will conduct a site initiation visit to provide the Investigator and their staff with a comprehensive 
overview of the protocol and study procedures and to review mutual obligations and requirements of regulatory 
authorities. A regulatory file or binder containing required documentation will be kept at the site for reference and 
inspection. 
Routine monitoring visits will be made to assure compliance with the study protocol and regulatory requirements, 
to review and verify the subject’s eCRF by comparing 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 after a final 
review of the data by the medical monitor and  prior to study database lock.  The focus of the SAP will be to 
present the accumulated safety information from the three phases (dose escalation and one dose, two monthly 
doses and four monthly doses) that will provide insight into and dose-response relationship that may exisit for the 
safety and preliminary efficacy (e.g. changes in Ca19-9, CEA, plasma levels of paclitaxel) outcomes. 
AEs of special interest will be summarized and the MedDRA terms provided; these will be tabulated separately 
with groupings as described in section 10.4.4.1 below. 
10.2 
STATISTICAL HYPOTHESES 
No formal statistical inference (i.e., “p-values”) will be applied. The results of this trial will be based on descriptive 
statistics only. 
10.3
ANALYSIS DATASETS
In this safety and tolerability trial, all subjects who are enrolled and receive a minimum of one dose of study agent 
will be included in the descriptive analysis.  
10.3.1 MISSING DATA 
Data will be presented as observed and no missing data imputation will be performed. All effort will be made to 
capture sufficient information to allow for medical interpretation of the results. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 


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The focus of the trial will be on the safety and tolerability of the dose-escalated treatments. The general approach 
will be to highlight any trends that cause concern for the reviewing medical monitoring team (i.e., dose-limiting 
toxicities (DLTs)).  
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)
Not applicable. The primary objective is to evaluate the safety and tolerability as demonstrated by AE, changes in 
laboratory assessments, physical examination findings and vital signs.  
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary endpoints will be summarized descriptively. These will include supportive information to provide 
context for the dose(s) chosen to move forward for a future study, as follows:  
 
Concentration of paclitaxel in the systemic circulation post-injection (as determined by PK analysis); 
 
Tumor response (including RECIST 1.1 as per Eisenhauer et al. 2009); 
 
Reduction in pain (as measured by the visual analog scale [VAS]); 
 
Change in tumor marker CA19-9; 
 
Change in tumor marker CEA. 
See also Section 10.4.11, Exploratory Analyses, for further details. 
10.4.4 SAFETY ANALYSES 
10.4.4.1 
ADVERSE EVENTS 
Adverse events (AE) recorded during the trial will capture medically relevant changes found during the physical 
exam, and medically relevant changes in vital signs and laboratory analytes found during the course of the trial. In 
addition, spontaneously reported or observed events will be recoded 
Events reported at or after the application of NanoPac will be considered TEAE. All reported events will be listed by 
subject number and assigned treatment, investigator term, MedDRA coded term, total NanoPac injections 
administered to date, date/study day (from initial treatment) and number of days post the most recent injection for 
onset and cessation, severity (using the NCIC severity grading), and relationship to study medication. Only the TEAE 
will be tabulated.  
The dose escalation of phase 1, will be presented separately to provide insights into the increasing dose per injection.  
Here the primary safety analysis will focus on the data at the 3-month follow-up period. Additional tabulations 
including safety data up to and including the 6-month follow-up visit will also be presented.  
The dose confirmation part of Phase 1 (i.e. one dose of 15 mg), Phase 2 (2 doses one month apart) and Phase 3 (4 
doses one month apart) will be the second comparative focus.  Tables and listings will be formatted to allow for 
comparisons of frequency, adjust for number of subjects in the cohort, for AEs. 
Adverse event reports will be coded using the most recent version of MedDRA, signed off by the Medical Monitor, 
and presented by system organ class and preferred term. All AE and abnormal laboratory variables will be assessed 
according to the NCI-CTCAE v4.0 grading system. The number of subjects reporting and number of events reported 
will be presented in frequency tables (overall, by intensity, by relationship and by outcome) for each dose cohort. 


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Adverse events of special interest will be presented separately. The criteria for the most frequently reported 
events will be determined in the SAP after reviewing the data.  
10.4.4.2 
LABORATORY ANALYTES 
Quantitative laboratory data will be summarized as mean values and change from screening scores (i.e., change = 
time point-screening) presented by dose level for each sampling time point. For tests with normal range provided, 
the clinical status and its change from screening (Normal/High Abnormal/Low Abnormal) will be summarized using 
shift tables for each dose group. Analytes of particular interest (e.g., hematological tests) may be graphed by 
subject with the dose indicated; these special analytes will be confirmed in the SAP. 
10.4.4.3 
VITAL SIGNS 
Vital signs (systolic and diastolic blood pressure, heart rate, temperature and body weight) will be tabulated and 
mean raw values and changes from baseline scores (change = baseline-visit) where baseline is the last 
measurement prior to the study agent application, for each treatment group. 
10.4.4.4 
ECOG 
The ECOG scale will be tabulated by treatment dose using shift tables to summarize and highlight and changes in 
category across the visits. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
All subjects who enter the trial will be accounted for and any reasons for early termination noted – including 
disease progression.  
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Complete demographic and baseline data will be tabulated. The medical history, which will be coded in MedDRA, 
will be presented. The disease history data, with a focus on the previous treatment and current staging, and the 
information collected on the procedure to apply the treatment will also be summarized.  
10.4.7 PLANNED INTERIM ANALYSES  
There are no formal interim analyses planned. There will be an ongoing safety and tolerability review by the 
Medical Monitor and regular DSMB meetings between cohorts.  
10.4.7.1 
SAFETY REVIEW 
Safety Review is described in Section 8.1.  
10.4.7.2 
EFFICACY REVIEW 
Imaging with CT scan will occur within six weeks prior to the injection procedure, every-three-months intervals for 
the time the subject remains in the study  or if the subject’s condition deteriorates. Tumor markers and pain 
assessments will be performed at each visit to guide the clinical oversight. 


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10.4.8 ADDITIONAL SUB-GROUP ANALYSES
Subjects who perform particularly well (i.e., experience minimal AEs) may be compared to those who perform 
more poorly. This topic, and the criteria for defining each group, will be detailed in the SAP. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY
Not applicable, as no inferential analyses will be employed.
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
All data collected in the eCRF will at a minimum be listed; listings will support the tabulated data/outcomes.  
10.4.11
EXPLORATORY ANALYSES
Pharmacokinetic (PK) parameters (i.e., AUC, Cmax, Tmax) will be calculated based on the plasma concentration data 
for the first 24 hours. Concentration data collected at subsequent visits will be summarized separately. The 
method of summary will include tabulations by dose group and individual subject plots of concentration across 
time, if the data is amenable to these concepts. The final decision will be made after a review of the data and 
recorded in the SAP. 
Tumor markers (CA-19-9 and CEA) will be summarized as mean values by dose group across time as well as mean 
changes from baseline. The SAP will clarify if doubling of marker concentration is considered a notable event. Any 
notable events will be highlighted. 
Pain assessment scores will be summarized as mean values by dose group across time as well as mean changes 
from baseline scores.  
10.4.12 
CONCOMITANT MEDICATION 
All medication taken during the trial will be, at a minimum, listed with the start and stop dates. For this small 
clinical trial, the medications will not be coded using the WHO Drug Dictionary. 
10.5 
SAMPLE SIZE 
As there are no formal inferential statistical analyses planned, the sample size estimates below are provided for 
informational purposes only to help with decision-making around the cohort size and the rarity of events that 
could be detected. 
Defining the primary endpoint explicitly requires understanding the primary purpose of the study. If, in this case, 
the primary purpose of the study is dose-finding, then the incidence of DLTs would be an appropriate endpoint. 
When choosing events that will qualify as DLTs, it’s important to consider the rarity of events given the small 
number of subjects. For example, if a particular adverse event is known to occur in only 5% of subjects, there is a 
26.5% chance it will appear in a particular cohort of 6 subjects, and a 60.3% chance it will occur during the study of 
18 subjects. If the event only occurs in 1% of patients, there is only a 6% chance it will appear in a given 6-subject 
cohort, and a 16.5% chance it will be observed in the entire study. So rarity is a factor that should be considered 
when deciding which adverse reactions to include as part of the endpoint. Estimates were obtained using the 
“confidence interval for probability of observing a rare event” calculation in nQuery 6.01. 


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The rationale to expand the second phase to 22 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. 
The calculations were performed using nQuery Advisor 6.01 “confidence interval for probability of observing a rare 
event”. With 22 subjects the probability of detecting the 0.1 event rate is 90.2% as well as some probability of 
detecting much rarer events (19.8% probability of detecting an event with a base rate of 0.01, and 67.6% 
probability of detecting an event with a 0.05 base rate).    
 
The additional 30 subjects in the third phase and the total number of subjects (i.e. 65) across all three phases 
increases the probability of detection proportionally as can be seen in the table below.  Calculations were 
perfomed in nQuery version 8.5.1.0 , procedure POC2-1 “confidence interval for probability of observing a rare 
event”. 
Probability of Observing a Rare Event 
Rare Event Frequency
Sample Size 
0.1
0.05
0.01 
12
71.8%
46.0%
11.4%
22
90.2%
67.6%
19.8% 
30
95.8%
78.5%
26.0% 
65
99.9%
96.4%
48.0% 
The table assumes that each subject has an equal probability of having the adverse event, and so could be 
conservative, if there is any dose related effect; the actual dose given increases across the phases. 
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. All data in the eCRF must reflect the corresponding source document. Any corrections to entries made 
on the eCRF must be documented in a valid audit trail. Only data required by the protocol for the purposes of the 
study should be collected within the EDC. 
The Investigator must maintain adequate and accurate source documents on which the eCRFs for each subject are 
based. They will be separate and distinct from the eCRFs. These records should include detailed notes on: 


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The medical history prior to the subject’s involvement in the study;
 
Date of informed consent; 
 
The basic identifying information that links the subject’s medical record with the eCRFs; 
 
The results of all diagnostic tests performed, diagnoses made, therapy provided, and any other data on 
the condition of the subject; 
 
The medical condition during the subject’s involvement in the study; 
 
All AEs; 
 
The subject’s exposure to the study medication; 
 
The subject’s exposure to any concomitant therapy; 
 
All relevant observations and data on the condition of the subject throughout the trial; 
 
Justification for all entries in the subject’s eCRF.  
12 QUALITY ASSURANCE AND QUALITY CONTROL 
Data required by the protocol will be collected and entered into a validated data management system that is 
compliant with all regulatory requirements. The eCRF is an electronic document designed to record all of the 
protocol-required information to be reported to the Sponsor on each study subject. 
Data recording must follow the instructions described in the CRF Completion Guidelines. The PI has ultimate 
responsibility for the collection and reporting of all clinical data entered on the eCRF. The PI or designee, as 
identified on Form FDA 1572, must electronically sign the completed eCRF for each participating subject to attest 
to its accuracy, authenticity, and completeness. 
The EDC application being used in this study is TrialMaster® version 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. 


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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 subject is enrolled in the study. 
Amendments to the protocol will be subject to the same requirements as the original protocol. All changes to the 
consent form will be IRB-approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
13.3
INFORMED CONSENT PROCESS 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Subjects being considered for participation in this study will be provided an informed consent form (ICF) to read 
and sign before being permitted to participate. The ICF will describe the study agent and any prior findings from 
previous studies; study procedures including the timing of study clinic visits and their responsibilities to adhere to 
those timelines; any risks which may be associated with the study agent or the procedures being carried out in the 
study; and all other items required under 21 CFR Part 50.25.  
Subjects will be required to provide signed consent prior to the conduct of any study-related procedures. The 
Investigator is required to document the process for obtaining informed consent in the source notes. 
Subjects in the second and third phases of the study will have a different ICFs to those in the dose escalation phase 
of the study, due to the different study schedules being followed. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The Investigator will obtain informed consent from each subject enrolled in the study, in accordance with the U.S. 
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 the ICF to be used by the Investigator. The 
Investigator will provide the Sponsor with a copy of the written approval generated by the IRB or Ethics Committee 
before the Investigator will be permitted to enroll subjects into the study. 
It is the responsibility of the Investigator to ensure that informed consent is obtained from the subject or his/her 
guardian or legal representative before any activity or treatment is undertaken which is not part of routine care. 
This includes, but is not limited to, the performance of diagnostic or therapeutic procedures and the 
administration of 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. 


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The Investigator will not undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The terms of the consent and when it was obtained must also be documented in the 
eCRF. The original, signed informed consent document must be maintained on file at the study site and be made 
available for review during monitoring visits and site audits. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
All local legal requirements regarding data protection will be enforced. All study findings and documents will be 
regarded as confidential. The Investigator and members of his/her research team must not disclose such 
information without prior written approval from US Biotest.  
The anonymity of participating subjects must be maintained to the extent required by law. Throughout 
documentation and evaluation, the subjects will be identified on eCRFs and other documents submitted to US 
Biotest by their initials, birth date, and subject number. The subjects will be told that all study findings will be 
stored and handled in strictest confidence, according to legal requirements, and that authorized research 
Investigators and agents of the FDA, the NCI, 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. 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, after which they 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.  


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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 subject’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 
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 the accuracy, authenticity, and completeness of the data. 
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 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 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 FDA has been notified; or, 
 
For a minimum of 15 years after the completion or discontinuation of the study to be filed in support of 
the registration in the European Union. 


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If the Investigator relocates, retires or withdraws from the study for any reason, the study records may be 
transferred to an acceptable designee, such as another Investigator, another institution, or the Sponsor. The 
Investigator must obtain the Sponsor’s written permission before transferring or disposing of any records. 
14.3
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), or 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.  
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, and reported to the Sponsor and the Data Management group.  
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to 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 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, Inc. Submission of data for publication/presentation will 
be coordinated and approved by US Biotest in collaboration with the Investigator. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials 
registration policy as a condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include 
drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in subjects or participants, including 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 FDA requirements for this registration and for publication of study results on that site. 


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15 STUDY ADMINISTRATION
15.1
STUDY LEADERSHIP
The study will be overseen by the Study Manager who will be responsible, together with the Investigators, for 
tracking enrollment, timelines, and deliverables, and other study-related performance. 
All questions regarding the enrollment of subjects, regulatory requirements for the conduct of the study, safety 
reporting, or study conduct should be addressed to the Study Manager or Site Monitor designated by the Sponsor. 
Contact information for the Sponsor is provided near the beginning of this protocol and will be provided to the 
Investigator in separate study documents. 
16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical and therefore any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the trial. As required by 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 
ABRAXANE Package Insert. Celgene Company. Rev July 2015. 
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fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and 
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solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
Eskander MF, Bliss LA, Tseng JF. Pancreatic adenocarcinoma. Curr Probl Surg. 2016 Mar;53(3):107-54. 
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oncological therapy. World J Gastrointest Oncol. 2015 December;7(12):466-472. 
Ko AH, Truong TG, Kantoff E, Jones KA, Dito E, Ong A, Tempero MA. A phase I trial of nab-paclitaxel, gemcitabine, 
and capecitabine for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2012 Dec; 70(6):875. 
Matrisian LM, Berlin JD. The past, present, and future of pancreatic cancer clinical trials. Am Soc Clin Oncol Educ 
Book. 2016;35:e205-15. 
Oh, H. C., Seo, D. W., Lee, T. Y., Kim, J. Y., Lee, S. S., Lee, S. K., et al. New treatment for cystic tumors of the 
pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointestinal endoscopy, 2008;67(4):636-642. 
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Scheithauer W, Kornek G, Prager G, Stranzl N, Laengle F, Schindl M, Friedl J, Klech J, Roethlin S, Zielinski C. Phase II 
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369(18):1691-703. 
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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.  

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Phase IIa Trial Evaluating the Safety of Intratumoral 
Injection of NanoPac in Subjects with Locally Advanced 
Pancreatic Adenocarcinoma 
 
Protocol Number: 
NANOPAC-2016-05 
Study Phase  
IIa                          
Trial Design: 
Open-label, Dose Escalation Study including both a Dose-Escalation Phase
(Single Dose) and a Second Phase (Two Doses) 
Medication/dosage: 
NanoPac® (sterile nanoparticulate paclitaxel) Powder for Suspension 
at concentrations of 6, 10, and 15 mg/mL administered into the 
tumor within the pancreas via endoscopic ultrasound-guided fine needle 
injection 
 
Population 
Up to 65 subjects with locally advanced pancreatic adenocarcinoma  
Study/Treatment 
duration: 
Up to 48 months 
Sponsor Contact 
Shelagh Verco 
US Biotest 
231 Bonetti Dr., Suite 240 
San Luis Obispo, CA  
93401-7310, USA 
 
Tel: (805) 704-1179 
Email: shelagh.verco@usbiotest.com 
Analysis Contact 
Chungui Wang 
Alimentiv Inc.. 
789 Don Mills Road, Suite 802 
Toronto, ON 
M3C 1T5, Canada 
Tel: (416) 673-9470  
Email: jim.wang@alimentiv.com 
 
Version: 
Final 
Date: 
2023-04-03 


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SIGNATURE APPROVAL PAGE 
 
1 of 2 
 
Date of Final Protocol (including 
all amendments) 
25-Mar-2020 (version 7.0) 
07-Aug-2019 (version 6.0) 
09-Nov-2018 (Version 5.0) 
26-MAR-2018 (Version 4.0) 
08-JAN-2018 (Version 3.0) 
23-FEB-2017 (Version 2.1) 
 
Date of Final Plan: 03-Apr-2023 
 
I have reviewed the Statistical Analysis Plan.  My signature below confirms my agreement 
with the contents and intent of this document. 
 
Digital Signatures 
 
Author: 
 
Chungui Wang 
Senior Statistician 
Alimentiv Inc. 
 
Reviewed by: 
 
Hong Chen 
Sr. Director, Statistics & Principal
Statistician 
Alimentiv Inc. 
 
 


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SIGNATURE APPROVAL PAGE
2 of 2
Date of Final Protocol (including 
all amendments)
25-Mar-2020 (version 7.0)
07-Aug-2019 (version 6.0)
09-Nov-2018 (Version 5.0)
26-MAR-2018 (Version 4.0)
08-JAN-2018 (Version 3.0)
23-FEB-2017 (Version 2.1)
Date of Final Plan: 03-Apr-2023
I have reviewed the Statistical Analysis Plan.  My signature below confirms my agreement 
with the contents and intent of this document.
Reviewed by:
Shelagh Verco
Director Clinical Trials
US Biotest
Date (dd-mmm-yyyy)
Gere diZerega, MD
President and CEO
US Biotest, Inc.
Date (dd-mmm-yyyy)


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LIST OF ABBREVIATIONS.................................................................................. 7 
1 
BACKGROUND .......................................................................................... 9 
2 
OBJECTIVES ............................................................................................. 9 
2.1 
Primary Objective ........................................................................................ 9 
2.2 
Secondary Objectives ............................................................................... 10 
3 
STUDY DESIGN AND ENDPOINTS ......................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Primary Endpoint ....................................................................................... 11 
3.3 
Secondary Endpoints ................................................................................ 11 
3.4 
Study Timeline and Schedule of Events .................................................... 12 
3.4.1 
Schedule of Events Table  Dose Escalation Subjects.................................... 12 
3.4.2 
Schedule of Events Table  Second Phase Subjects ...................................... 12 
3.4.3 
Schedule of Events Table  Third Phase Subjects .......................................... 13 
4 
DATA MANAGEMENT ............................................................................. 13 
4.1 
Data Collection and Database Construction ............................................. 13 
4.2 
Coding ....................................................................................................... 14 
4.3 
Pharmacokinetics (PK) Data ..................................................................... 14 
4.4 
Adverse Events of Special Interest ........................................................... 14 
5 
CHANGE TO ANALYSIS AS OUTLINED IN THE PROTOCOL .............. 14 
6 
STATISTICAL METHODS ........................................................................ 15 
6.1 
Sample Size .............................................................................................. 15 
6.2 
Missing Data ............................................................................................. 16 
6.3 
Data Conversion for Analysis .................................................................... 16 
6.4 
Calculated Outcomes ................................................................................ 17 


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6.5 
Analysis Population ................................................................................... 22 
6.6 
Interim Analysis/ Data Monitoring .............................................................. 22 
6.7 
Analysis Methods ...................................................................................... 22 
7 
RESULTS ................................................................................................. 22 
7.1 
Study Subjects .......................................................................................... 22 
7.1.1 
Patient Disposition .......................................................................................... 22 
7.1.2 
Demographics and Baseline Characteristics ................................................... 22 
7.1.3 
Medical and Surgical History ........................................................................... 23 
7.1.4 
Pregnancy Test ............................................................................................... 23 
7.1.5 
NanoPac Administration .................................................................................. 23 
7.2 
Primary Outcomes .................................................................................... 23 
7.2.1 
Adverse Events ............................................................................................... 23 
7.2.2 
Laboratory Assessments ................................................................................. 24 
7.2.3 
Physical Examination ...................................................................................... 24 
7.2.4 
Vital Signs ....................................................................................................... 25 
7.3 
Secondary Outcomes ................................................................................ 25 
7.3.1 
Plasma Paclitaxel Concentration ..................................................................... 25 
7.3.2 
Tumor Responses ........................................................................................... 25 
7.3.3 
VAS Pain Assessment .................................................................................... 26 
7.3.4 
Tumor Marker CA19-9..................................................................................... 26 
7.3.5 
Tumor Marker CEA ......................................................................................... 26 
7.4 
Other Outcomes ........................................................................................ 26 
7.4.1 
Eastern Cooperative Oncology Group (ECOG) ............................................... 26 
7.4.2 
Prior and Concomitant Medications ................................................................. 26 
7.4.3 
Concomitant Procedures ................................................................................. 27 


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Appendix A: ECOG Performance Scale .......................................................... 27 


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LIST OF ABBREVIATIONS 
 
Abbreviations 
Abbreviation Definition 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
APR 
Analysis Programming Requirements - detailed programming 
specifications 
required 
to 
convert 
the 
EDC 
data 
into 
analysis/presentation data sets. 
ATC 
Anatomical Therapeutic Chemical Classification System 
 
BMI 
Body Mass Index 
BLQ 
Below the Limit of Quantitation 
CA19-9 
Cancer Antigen 19-9 or Carbohydrate Antigen 19-9 
CEA 
Carcinoembryonic Antigen 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DLC 
Data Logic Check- A combination of programmed and visual checks 
based on the CRF, protocol, and sponsor input, designed to identify 
incomplete or illogical data.  
DLT 
Dose-Limiting Toxicities 
DMP  
Data Management Plan - details of how data are managed throughout 
the trial 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 


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Abbreviation Definition 
Alimentiv 
Alimentiv Inc., company contracted to perform the data management, 
statistical programming and analysis functions 
LLOQ 
Lower Limit of Quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities (coding for AEs) 
 
 
PK 
Pharmacokinetics 
PT 
Preferred Term (from MedDRA coding dictionary) 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class (from MedDRA coding dictionary) 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
 


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1 
BACKGROUND 
In this open-label, dose rising, Phase Iia trial, subjects with locally advanced pancreatic 
adenocarcinoma will receive intratumoral (ITU) NanoPac (sterile nanoparticulate 
paclitaxel) via endoscopic ultrasound-guided direct injection. Prior to study entry, subjects 
will complete at least one course of standard of care (SOC) IV chemotherapy and 
hematologic recovery will be confirmed before NanoPac is administered. Subjects 
enrolling to the second and third phases will have initiated their SOC IV chemotherapy. 
Subjects will be enrolled in sequential cohorts of NanoPac 6, 10, and 15 mg/mL at up to 
20% of the calculated tumor volume (with a maximum injection volume of 5 mL per 
subject). Each cohort will have three subjects, 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 subjects 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 most suitable for further evaluation, 
defined as the highest dose with an acceptable safety and tolerability profile (as 
determined by the DSMB), will be the dose used in the second phase of the study which 
will enroll 22 additional subjects who will receive two injections of NanoPac at the same 
dose, one month apart. In the third phase of the study, up to 30 subjects will receive up to 
four injections of NanoPac at the same dose, one month apart. Subjects will be followed 
for three months after the first NanoPac injection for safety, overall survival (OS), 
progression-free survival (PFS), CA-19-9 levels, carcinoembryonic antigen (CEA) levels, 
reduction in pain, and tumor response to therapy (as shown by imaging). A follow-up visit 
may be conducted at six months, as applicable. Subjects in the second phase of the study, 
following their one-month follow up, will receive a second injection; subjects in the second 
phase will have a follow-up phone call a month after the 6 month follow-up visit, which will 
be 6 months following the second injection. Subjects in the third phase of the study, 
receiving 4 injections, will be followed to nine months after first injection (six months 
following last injection). 
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of NanoPac 
injected directly into pancreatic cancer by endoscopic ultrasound-guided (EUS-guided) 
injection.  


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2.2 
Secondary Objectives 
The secondary objectives are: (a) to describe the pharmacokinetics (PK) of NanoPac 
when administered into the tumor within the pancreas; (b) to determine whether any of the 
NanoPac cohorts (6, 10, or 15 mg/mL) show signs of preliminary efficacy; and (c) to 
determine if two to four injections of NanoPac (one month apart at the determined dose 
for this cohort) shows signs of preliminary efficacy 
3 
STUDY DESIGN AND ENDPOINTS 
3.1 
Study Design 
In this open-label, dose rising, Phase Iia trial, subjects with locally advanced pancreatic 
adenocarcinoma will have completed at least one course of chemotherapy as part of SOC. 
Once there is sufficient hematologic recover, subjects will receive ITU NanoPac via 
endoscopic ultrasound-guided direct injection. 
Subjects will be enrolled in sequential, escalating cohorts of NanoPac at concentrations 
of 6, 10, or 15 mg/mL injected directly into the tumor within the pancreas at up to 20% 
tumor volume (with a maximum of 5 mL volume being administered to any subject).  
The study will include a dose escalation phase and a second phase. Subjects in the 
second phase will have initiated their SOC IV chemotherapy and will receive two injections 
of NanoPac at the highest acceptable dose found in the dose escalation phase, one month 
apart. Subjects in the third phase will have initiated their SOC IV chemotherapy or have it 
scheduled to begin, but may receive the first NanoPac injection prior to IV chemotherapy 
is started. 
Dose Escalation of Cohorts 
Cohorts will be enrolled sequentially starting at the lowest dose (6 mg/mL). Each cohort 
will have a planned minimum of three subjects. All data from the first three subjects in a 
cohort will be reviewed and evaluated by the Data Safety Monitoring Board (DSMB) to 
determine whether the dose received is considered safe and tolerable, and to determine 
if dose escalation may occur. 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, which will include reference to dose-limiting toxicities (DLTs). 
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 (more than one DLT). 
The dose most suitable for further evaluation will be the highest dose with an acceptable 
safety and tolerability profile as determined by the DSMB. If one or fewer subjects in a six-
subject cohort, or no subjects in a three-subject cohort at the highest dose, experience a 


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DLT, that cohort may be taken into the Second Phase. If greater than one subject in a six 
subject cohort experiences a DLT, the previous dose may be taken into the Second Phase. 
Second Phase of Study 
Once the dose deemed appropriate for expansion and further evaluation has been 
determined by the DSMB, an additional 22 subjects will be enrolled to the study and this 
cohort of subjects will receive two NanoPac injections to their lesion one month apart. 
Third Phase of Study 
Up to 30 additional subjects will be enrolled to receive up to four NanoPac injections to 
their lesion, 1 month apart. 
3.2 
Primary Endpoint 
The primary endpoint will be safety and tolerability, as assessed by adverse events (AE), 
changes in vital signs, laboratory results, and physical examination at one month following 
NanoPac injection. 
3.3 
Secondary Endpoints 
The secondary endpoints will be: 
 
Concentration of paclitaxel in the systemic circulation post-injection (as determined 
by PK analysis); 
 
Tumor response (RECIST as per Eisenhauer et al. 2009); 
 
Reduction in pain (as measured by the visual analog scale [VAS]); 
 
Change in tumor marker CA19-9; 
 
Change in tumor marker CEA. 


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3.4 
Study Timeline and Schedule of Events 
3.4.1 
Schedule of Events Table  Dose Escalation Subjects 
 
3.4.2 
Schedule of Events Table  Second Phase Subjects 
 


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3.4.3 
Schedule of Events Table  Third Phase Subjects 
 
4 
DATA MANAGEMENT 
4.1 Data Collection and Database Construction 
Data will be collected at the sites via an electronic data capture (EDC) system.  The study-
specific application will be developed based on the protocol requirements and following 
the full Systems Development Lifecycle (SDLC).  The development and management of 
the trial application, including security and account administration, will adhere to the 
Standard Operating Procedures (SOPs) at Alimentiv Inc. (Alimentiv).  All participants will 
be trained in the use of the application, and the training documented prior to each site 
being given access to the system. 
The application design will, where appropriate, provide choice fields in the form of 
checkboxes, buttons and lists to aid in ensuring high quality standardized data collection.  
In addition, Data Logic Checks (or data Edit Checks) will be built into the application based 
on variable attributes (e.g., value ranges), system logic (e.g., sequential visit dates) and 
variable logic (e.g. onset date must be before cessation date).  Visual review and data 
responses will be overseen by a trained data manager. 
The database will be locked when all the expected data has been entered into the 
application, all query responses have been received and validated, the designated data 
has been noted as monitored in the system and each investigator has signed off the 
casebook for each of their study subjects.  The data coding must be accepted by the 


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Sponsor and any Serious Adverse Events (SAEs) reconciled with the pharmacovigilance 
data base working with the Medical Monitor. 
The data management processes are outlined in the project specific Data Management 
Plan (DMP). DMP and all related documentations are on file at Alimentiv and are identified 
by the project code NA03NAE. 
All programming will be performed in SAS EG 8.3 Update 7. 
4.2 
Coding 
Adverse Events and medical history will be coded in MedDRA version 20.0 and signed off 
by US Biotest, Inc. All concomitant medications will be coded using WHO Drug Dictionary 
version March 1, 2017. All coding will be reviewed and signed off by the Medical Monitor 
or designee prior to data base lock. 
4.3 
Pharmacokinetics (PK) Data 
The PK analysis of plasma paclitaxel concentration will be performed by Covance Inc.  
The concentration data will be provided to Alimentiv in Excel data sheets to be read 
into SAS system for descriptive summaries. 
For Dose Escalation Phase subjects, PK parameters AUC, Cmax, and Tmax within 24 
hours of injection day will be calculated by Alimentiv using the plasma paclitaxel 
concentration data provided by Covance Inc. 
4.4 
Adverse Events of Special Interest 
Following AEs are of special interest to the sponsor and will be analyzed separately:  
Vomiting, Peritonitis, Retroperitoneal bleeding, Abscess formation, 
Fistula formation, Gastrointestinal bleed, Neutropenia, Abdominal pain, 
Pancreatitis, Neutropenic fever, Sepsis, Thrombocytopenia, Anemia. 
After all AEs are recorded in EDC, the sponsor will review the AE list and highlight all 
AEs of Interest. Alimentiv w
 
5 
CHANGE TO ANALYSIS AS OUTLINED IN THE PROTOCOL 
According to Section 10.4.11 of the Protocol, an exploratory analysis is planned for PK 
parameters AUC
 Cmax, and Tmax within 24 hours of the injection:  
Pharmacokinetic (PK) parameters (i.e., AUC, Cmax, Tmax) will be calculated based 
on the plasma concentration data for the first 24 hours. 


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After the Protocol was updated to Version 7 (March 25th, 2020), all subjects of the Second 
Phase and Third Phase will have three PK samples drawn at injection day: 
PK samples will be drawn prior to NanoPac injection, and then 1- and 2-hours post-
injection.  
For subjects of the Second and the Third Phase, because of only three concentrations 
(one pre-dose and two post dose) the calculation and analysis of AUC, Cmax, and Tmax are 
not applicable and will not be conducted. Their concentration data will still be summarized 
and listed. 
6 
STATISTICAL METHODS  
Descriptive summaries of continuous data will consist of the mean, standard deviation, 
median, minimum, and maximum. Categorical data will be summarized with frequencies 
and percentages. All data will be listed by subject and treatment. This study was not 
powered for inference, and so no inferential analyses will be included.  
6.1 
Sample Size 
As there are no formal inferential statistical analyses planned, the sample size estimates 
below are provided for informational purposes only to help with decision-making around 
the cohort size and the rarity of events that could be detected. 
Since a purpose of the study is dose-finding, the incidence of DLTs would be an 
appropriate endpoint for the sample size consideration. If a particular adverse event is 
known to occur in only 5% of subjects, there is a 26.5% chance it will appear in a particular 
cohort of 6 subjects, and a 60.3% chance it will occur during the study of 18 subjects. If 
the event only occurs in 1% of patients, there is only a 6% chance it will appear in a given 
6-subject cohort, and a 16.5% chance it will be observed in the entire escalation phase.  
The rationale to expand Second Phase to 22 subjects, from either 3 or 6 subjects, was 
in this early phase exploratory trial. With 22 subjects the probability of detecting the 0.1 
event rate is 90.2% as well as some probability of detecting much rarer events (19.8% 
probability of detecting an event with a base rate of 0.01, and 67.6% probability of 
detecting an event with a 0.05 base rate).  
The additional of up to 30 subjects in the third phase and the total number of subjects (i.e. 
65) across all three phases increases the probability of detection proportionally as can be 
seen in the table below. Calculations were performed in nQuery version 8.5.1.0, procedure 
POC2-1 
confidence interval for probability of observing a rare event
. 


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The table assumes that each subject has an equal probability of having the adverse event, 
and so could be conservative, if there is any dose related effect; the actual dose given 
increases across the phases. 
6.2 
Missing Data 
Data will be presented as observed and no missing data imputation will be performed. All 
effort will be made to capture sufficient information to allow for medical interpretation of 
the results.   
6.3 
Data Conversion for Analysis 
In order to summarize quantitative endpoints, e.g. lab test results, some data collected as 
text values need to be converted to numeric values for analysis. Following conventional 
rules will be applied for this study. 
 
xx lab results will be converted to 0.99 * xx. The adjustment is -1% of value 
xx. 
 
results will be converted to 1.01 * xx. The adjustment is +1% of value 
xx. 
 
Some PK concentration values may be marked as Below the Limit of Quantification 
xx
 xx is the Lower Limit of Quantitation (LLOQ). For 
the summary of paclitaxel concentration in this study, all BLQ values will be set to 
LLOQ / 2.  
Above data conversions are only applied to data descriptive summaries. In by-subject data 
xx
xx
ented. 
 data submission and analysis, all EDC and external data will be converted 
to SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) datasets. In 
the creation of SDTM and ADaM datasets, original lab test results from different sites 
(laboratories) need to be converted to results in SI units (the International System of Units). 
For some tests, data rounding may be applied during the conversion. The details will be 
ments. 


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6.4 
Calculated Outcomes 
The following are key endpoints derived from data captured at the sites via the EDC 
system.  Complete documentation of the calculations and data manipulation required to 
go from the CRF database to the analysis database are contained in the companion 
document - the study Analysis Programming Requirements (APR). 
Outcome 
Calculation 
Comment 
Baseline value 
Value reported prior to treatment 
injection 
If multiple values collected 
prior to treatment initiation, 
non-missing value closest to 
the date/time of treatment 
injection is considered 
baseline 
Change from 
Baseline 
Value collected at time point (Visit)  
Baseline value 
 
% Change from 
Baseline 
= 100 * Change from Baseline / 
Baseline value 
It will be calculated for tumor 
markers CEA and CA19-9 
Study Day 
= the days from Day 1 (the First 
Injection Date) to the event date 
= Date of Event  Date of Day 1 + 
1, if the event occurs on or after 
Day 1, 
= Date of Event  Date of Day 1, if 
the event occurs before Day 1 
 
Time in Trial 
(days) 
= Study completion/withdrawal date 
 date of informed consent date + 
1 day 
 


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Outcome 
Calculation 
Comment 
Duration from 
Initial Diagnosis 
to Screening 
= Date of Screening Visit  Date of 
Diagnosis + 1 
= Date of Screening Visit  Scan 
Date of Target Lesion + 1 
 
Disease 
Progression 
status is determined to be 
progressive disease by any 
imaging modality after treatment 
injection; 
= No, otherwise 
Disease status is assessed 
by investigator and recorded 
additional imaging forms  
Overall Survival 
(OS) 
= the days from Day 1 (Injection 
Date) to the date of death if the 
subject died 
= the days from Day 1 (Injection 
Date) to the end of study date or 
the early withdrawal date 
Censor data will be included 
in Survival Analysis 
Survival Time 
from Diagnosis 
= the days from diagnosis to the 
date of death if the subject died 
 
Disease 
Progression as 
per RECIST 
= Yes, if there is at least a 20% 
increase in the sum of the longest 
dimension of all target lesion(s), 
and with an absolute increase of at 
least 5 mm 
 


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Outcome 
Calculation 
Comment 
Progression-
Free Survival 
(PFS) / Time to 
Disease 
Progression 
= the days from Day 1 (Injection 
Date) to the date that the subject 
experienced disease progression 
and/or death 
= the days from Day 1 (Injection 
Date) to the end of study date or 
the early withdrawal date, if the 
subject did not experience disease 
progression or death 
Censor data will be included 
in Survival Analysis 
Reduction in 
Pain 
= Pain score on Day 1 before 
injection  Pain score post 
treatment 
 
Tumor Volume 
= 1/6 *  * (d1 * d2 * d3), if three 
tumor diameters d1, d2, and d3 are 
recorded 
= 1/6 *  * (d12 * d2), if only two 
tumor diameters d1 and d2 are 
recorded, where d1  d2 
= 1/6 *  * (d13) if only one tumor 
diameter d1 is recorded. 
 
Cmax 
= the largest paclitaxel 
concentration value within 24 
hours of each injection 
It is only calculated for dose 
escalation subjects 
Tmax 
= the earliest time that paclitaxel 
concentration reaches Cmax 
It is only calculated for dose 
escalation subjects 
AUC 
= Area under the concentration curve 
from hour-0 to hour-24  
It is only calculated for dose 
escalation subjects 


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Outcome 
Calculation 
Comment 
Treatment 
Emergent 
Adverse Event 
(TEAE) 
= No, if onset date/time of AE is 
before the date/time of NanoPac 
injection 
= Yes, otherwise 
According to conservative 
rule, all AEs that cannot be 
determined as started before 
NanoPac injection will be 
considered as TEAE 
TEAE at 3-
month Period 
= Yes, if TEAE onset data/time is 
on or before the 3-month follow-
up visit 
= Yes, if the subject does not 
attend 3-month follow-up visit but 
TEAE onset date/time is within 3 
months (91 days) after first 
injection 
= No, otherwise 
 
TEAE at 6-
month period 
= Yes, if TEAE onset data/time is 
on or before the 6-month follow-
up visit 
= Yes, if the subject does not 
attend 6-month follow-up visit but 
TEAE onset date/time is within 6 
months (183 days) after first 
injection 
= No, otherwise 
 


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Outcome 
Calculation 
Comment 
TEAE within 4-
week Post-
Treatment 
= No, if onset date of the TEAE is 
after the date of Week 4 Visit, for 
the subjects from Dose-escalation 
Phase and attended Week 4 Visit 
= No, if onset date of the TEAE is 
after Day 28, for subjects from 
Dose-escalation Phase but did 
not attend Week 4 Visit 
= No, if onset date of the TEAE is 
after the date of Week 8 Visit, for 
subjects from Second Phase and 
attended Week 8 Visit 
= No, if onset date of the TEAE is 
beyond 28 days after the second 
injection, for subjects from 
Second Phase but did not attend 
Week 8 Visit 
= No, if onset date of the TEAE is 
after the date of Week 16 Visit, for 
subjects from Third Phase and 
attended Week 16 Visit 
= No, if onset date of the TEAE is 
beyond 28 days after the last 
injection, for subjects from Third 
Phase but did not attend Week 16 
Visit 
= Yes, otherwise 
According to conservative 
rule, all TEAEs that cannot 
be determined as onset 
beyond 4 Weeks after last 
treatment are considered as 
onset within 4-week post 
treatment period 
 


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6.5 
Analysis Population 
All enrolled subjects who receive NanoPac injection will be the analysis population for all 
outcome analyses. 
6.6 
Interim Analysis/ Data Monitoring 
There are no formal interim analyses planned. There will be an ongoing safety and 
tolerability review by the Medical Monitor and regular DSMB meetings between dose 
escalation cohorts. 
6.7 
Analysis Methods 
All calculations and analyses will be performed using SAS EG 8.3 Update 7 at Alimentiv 
Inc. in London, Canada.  Continuous data will be summarized via PROC MEANS - mean, 
standard deviation, median, and range, while categorical data will be presented as counts 
and percentages (or proportions) via PROC FREQ for the descriptive displays.  
All outcomes will be summarized by cohort (i.e., dose level), and visit, if applicable. 
No statistical inference will be made for all outcomes. 
7 
RESULTS 
All enrolled and treated subjects will be the analysis population for all analyses. All data 
collected in EDC will be at a minimum listed.  
Because of the different injection and visit structures of the three study phases, i.e., dose 
escalation, Second Phase, and Third Phase, all study completion/discontinuation, safety 
and efficacy data will be summarized separately by study phase. All other summaries, i.e., 
baseline data and medical history, will be presented by cohort, i.e., NanoPac dose level. 
7.1 
Study Subjects 
7.1.1 
Patient Disposition 
All enrolled and treated subjects will be accounted for. All early discontinuations will be 
summarized by primary reason of discontinuation. 
Time in trial will also be summarized. 
7.1.2 
Demographics and Baseline Characteristics  
Demographic (age, sex, ethnicity, and race), baseline body measurements (height, 
weight, and calculated BMI), and baseline vital signs (systolic and diastolic blood 
pressures, heart rate, and body temperature) will be summarized. 


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7.1.3 
Medical and Surgical History 
Medical history will be coded in MedDRA and presented in a by cohort table by System 
Organ Class (SOC) and Preferred Term (PT). 
7.1.4 
Pregnancy Test 
Pregnancy test will be conducted at Screening Visit. The date of pregnancy test and test 
result will be listed. 
7.1.5 
NanoPac Administration 
All NanoPac administration data, including administration date, time, dose level (mg/mL), 
study phase, tumor diameters measured by ultrasound, tumor volume, calculated 
NanoPac volume to be administrated (mL), actual volume (mL) and actual dose (mg) 
administrated, will be listed. 
7.2 
Primary Outcomes 
The primary endpoint will be safety and tolerability, as demonstrated by adverse events 
(AE), changes in laboratory assessments, physical examination findings, and vital signs.  
All primary outcomes will be descriptively summarized. No statistical inference will be 
made for primary endpoint.  
All Second Phase and Third Phase data will be summarized separately due to the different 
visit structures and the extra study treatment. 
7.2.1 
Adverse Events 
Only treatment emergent adverse events (TEAEs) will be summarized. Three sets of 
TEAE summaries will be prepared for: All TEAEs, TEAEs onset within 4 weeks after 
treatment completion (i.e. Week 4 for dose escalation subjects, Week 8 for second phase 
subjects, and Week 16 for third phase subjects), TEAEs onset within the 3-month follow-
up period, and TEAEs onset within the 6-month follow-up period. For each set, summaries 
will be provided by dose level cohort, and include: 
 
Brief summary of TEAEs - include the total number of TEAEs, serious TEAEs, and 
death 
 
TEAEs by MedDRA System Organ Class (SOC) and Preferred Term (PT)  
 
TEAEs by MedDRA SOC, PT, and severity 
 
TEAEs by MedDRA SOC, PT, and relationship to NanoPac treatment 
 
TEAEs by MedDRA SOC, PT, and outcome 
 
Serious TEAEs by MedDRA SOC, and PT 
Adverse events of special interest will be presented, separately, by dose level cohort, SOC 
and PT. 


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All these summaries will include the counts and frequencies of events, and of subjects 
who had events.  
All TEAEs will be listed by subject. Death and other serious TEAEs will be listed 
separately. 
7.2.2 
Laboratory Assessments 
For biochemistry, hematology and coagulation, laboratory assessments with quantitative 
results, including assessments at each visit and change from baseline at post-baseline 
visits, will be summarized by treatment group, and visit for each test. For urinalysis, 
specific gravity and pH will be summarized. 
Each no-missing lab 
 (e.g. normal/low/high for quantitative 
results, and normal/abnormal for qualitative results) will be calculated based on the normal 
reference ranges provided by the lab. The status will be summarized using shift tables 
from baseline to each post- baseline time point. 
All lab data will be presented in by-subject data listing.  
Following lab tests are required for the study: 
Chemistry: Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, 
glucose, blood urea nitrogen (BUN), creatinine, serum lipase, serum amylase, 
alkaline 
phosphatase, 
total 
bilirubin, 
direct 
bilirubin, 
aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), lactate dehydrogenase (LDH), total protein, albumin, 
triglycerides, cholesterol, and uric acid. 
Hematology: 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. 
Coagulation: Prothrombin time (PT) and activated partial thromboplastin time (PTT). 
Urinalysis: Specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose. 
7.2.3 
Physical Examination 
All abnormal findings from the physical examination after study treatment will be recorded 
as AEs. The analysis of physical examination will be included in AE summaries. The date 
of physical examination will be provided in by-subject data listing. 


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7.2.4 
Vital Signs 
Height at screening visit and other vital signs (weight, BMI, systolic and diastolic blood 
pressure, heart rate, and temperature) at each visit will be summarized by treatment 
cohort. 
Change of vital signs from baseline values will be summarized for all post-dose visits. 
Unscheduled vital signs will only be presented in by-subject data listing.  
7.3 
Secondary Outcomes 
7.3.1 
Plasma Paclitaxel Concentration  
For subjects in the dose escalation phase, PK samples for paclitaxel concentration are 
collected on Day 1 prior to injection and at 1, 2, 4, 6, and 24 hours after NanoPac injection, 
as well as at all other study visits. Subjects in second phase and third phase of the study 
will provide PK samples at pre injection, and at 1 and 2 hours post injection on both 
injection occasions (Day 1 and Week 4), and at all study visits. 
For dose escalation subjects, PK parameters AUC, Cmax, and Tmax calculated from injection 
day concentration data will be summarized by dose level cohort and scheduled time point.   
All numeric paclitaxel concentration data above the Lower Limit of Quantitation (LLOQ), 
i.e. the detectable limit, will be tabulated by cohort using the arithmetic mean, standard 
deviation, coefficient of variation, median, and range. All BLQs (Below the Limit of 
in the by-subject data listing. 
For dose escalation phase subjects, graphs of Day 1 individual and mean paclitaxel 
concentration data will be generated.  
For subjects of the second phase and third phase, paclitaxel concentration data of all 
injections (Day 1, Week 4, Week 8, and Week 12) will be graphed. 
Pharmacokinetic (PK) parameters AUC and Cmax will be summarized using the arithmetic 
and geometric means, standard deviation, median, range, and % CV (coefficient of 
variation). Tmax will be summarized by the median and range of its values.   
7.3.2 
Tumor Responses 
Tumor responses as per RECIST will be measured by CT scan or other imaging method 
within six weeks prior to the injection procedure, 3-month follow-up visit, and 6-month 
follow-up visit in all subjects, and 9 month follow-up visit in the third phase subjects. The  
size (longest diameter and calculated volume). The size of target lesion and change of 
size from baseline will be tabulated by dose level cohort. Disease status (complete 
response, partial response, stable disease, progressive disease, unevaluable) will be 
summarized using counts and frequencies by dose level cohort.  


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Disease progression (Yes/No) as defined in section 6.3 will be summarized using counts 
and frequencies. Survival analysis will be conducted for analysing the overall survival and 
the progression-free survival, and the Kaplan-Meier estimates of median, 25th and 75th 
percentiles of the survival time will be provided by dose level cohort. Overall survival and 
progression-free survival curves will be presented in Kaplan-Meier plots. 
All CT scan and additional imaging data will be listed. 
7.3.3 
VAS Pain Assessment 
Pain will be assessed using the visual analog scale (VAS) at all study visits, and will be 
conducted prior to and following the injection day(s) of NanoPac administration. 
VAS pain assessment scores, including scores at visit and reduction in pain scores, will 
be summarized by dose level cohort. 
7.3.4 
Tumor Marker CA19-9 
Serum CA19-9 levels will be obtained at Screening Visit, on the day of NanoPac 
administration prior to injection (Study Day 1), and at all other study visits. 
CA19-9 concentration at visit, changes from baseline, and percent change from baseline 
will be summarized by dose level cohort and visit. Doubling of CA19-9 concentration, i.e. 
Percent Change  100% will be flagged in the data listing. 
7.3.5 
Tumor Marker CEA 
Serum carcinoembryonic antigen (CEA) levels will be obtained at Screening Visit, on the 
day of NanoPac administration prior to injection (Study Day 1), and at all other study visits. 
CEA concentration at visit, changes from baseline, and percent change from baseline will 
be summarized by dose level cohort and visit. Doubling of CEA concentration, i.e. Percent 
Change  100% will be flagged in the data listing. 
7.4 
Other Outcomes 
7.4.1 
Eastern Cooperative Oncology Group (ECOG) 
Eastern cooperative oncology group (ECOG) performance status scale will be obtained at 
all study visits.  
ECOG scale will be summarized as frequencies by treatment group and visit. The scale 
will also be summarized using a shift table from baseline to post-baseline visit. 
7.4.2 
Prior and Concomitant Medications 
A summary of all concomitant medications taken during the course of the study will be 
presented in tabular form by therapeutic drug class (ATC Level 2 code) and generic drug 
name (ATC Level 4 code) using the World Health Organization (WHO) Drug Dictionary 


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(WHODD). The summaries will be provided for medications prior to and following the 
injection separately. 
7.4.3 
Concomitant Procedures 
All concomitant procedures performed during the study will be listed.  
 
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.