Clinical trial NCT03188991
Conditions: Pancreatic Mucinous-Cystic Neoplasm
Keywords: pancreatic cystic neoplasm pancreatic cyst pancreatic mucinous cyst pancreatic neoplasms digestive system neoplasms pancreatic diseases mucinous cystic neoplasm
Sponsor: NanOlogy, LLC
Start date: 2017-09-29; Completion date: 2020-06-29
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate intracystic NanoPac® (Sterile Nanoparticulate Paclitaxel) administered via endoscopic ultrasound-guided fine needle injection (EUS-FNI) in subjects with mucinous cystic pancreatic neoplasms.

Detailed description:
In this open-label, dose rising trial, subjects with mucinous cystic pancreatic neoplasms will receive intracystic NanoPac® via endoscopic ultrasound-guided fine needle injection (EUS-FNI).

In the dose escalation phase, subjects will be enrolled in sequential cohorts of NanoPac® at 6, 10, and 15 mg/mL at volumes sufficient to fill the cyst, at least equal to the amount of cyst fluid aspirated. 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 at the current dose may be enrolled, or if the first dose does not provide adequate safety and tolerability the study may be halted. The dose determined to be the most suitable for further evaluation, defined as the highest dose with an acceptable safety and tolerability profile (as determined by the DSMB), will be the dose used in the second phase of the study which will enroll 9 additional subjects. Subjects enrolled in the second phase of the study will also receive a second injection of NanoPac at the same dose 12 weeks after the first NanoPac injection..

Plasma samples will be taken on the day(s) of NanoPac® injection at 1 and 2 hours after injection, as well as at each of the subsequent study visits, to characterize the pharmacokinetics (PK) of intracystic NanoPac®.

Subjects will be followed for 6 months after the first NanoPac® injection for safety, tolerability and cyst response to therapy (as shown by imaging).

Arms: arm 1: Single intracystic injection of NanoPac® at a dose of 6 mg/mL in a volume sufficient to fill the cyst, at least equal to the amount of cyst fluid aspirated arm 2: Single intracystic injection of NanoPac® at a dose of 10 mg/mL in a volume sufficient to fill the cyst, at least equal to the amount of cyst fluid aspirated arm 3: Single intracystic injection of NanoPac® at a dose of 15 mg/mL in a volume sufficient to fill the cyst, at least equal to the amount of cyst fluid aspirated arm 4: Intracystic injection of NanoPac®. The dose administered in the second phase will be determined during the dose escalation phase. Subjects will receive two NanoPac® injections, with the second injection administered 12 weeks after the first injection.
Interventions: intervention 1: NanoPac®
Intervention descriptions: intervention 1: NanoPac® (Sterile Nanoparticulate Paclitaxel) for intracystic injection via endoscopic ultrasound-guided injection (EUS-FNI)

Protocol documents:
Prot_000.pdf: 
A Trial Evaluating Escalating Doses and the Safety of 
Intracystic Injection of NanoPac® in Subjects with 
Mucinous Cystic Pancreatic Neoplasms 
 
Protocol Identifying Number: NANOPAC-2017-01 
IND Sponsor: NanOlogy, LLC 
IND #: 132692 
 
Version Number:  4.0 
Dated:  3 September 2019 
 
 
 
 
 
 
 


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 ............................................................................................................ 16 
2.3.1 
Known Potential Risks ................................................................................................... 16 
2.3.2 
Known Potential Benefits .............................................................................................. 16 
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 16 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 17 
4.1 
Description of the Study Design ...................................................................................................... 17 
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 ............................................................................................ 19 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 19 
5.4.2 
Handling of Participant Withdrawals or Termination ................................................. 20 
5.5 
Premature Termination or Suspension of Study ........................................................................... 20 
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 ................................................................................................. 22 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 23 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 23 
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 .............................................................................................. 24 
7.1 
Study Procedures/Evaluations ......................................................................................................... 24 
7.1.1 
Study specific procedures ............................................................................................. 24 


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7.1.2 
Standard of care study procedures ............................................................................. 26 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 26 
7.2.1 
Clinical Laboratory Evaluations .................................................................................... 26 
7.2.2 
Other Assays or Procedures ........................................................................................ 26 
7.2.3 
Specimen Preparation, Handling, and Storage ......................................................... 27 
7.2.4 
Specimen Shipment ....................................................................................................... 27 
7.3 
Study Schedule .................................................................................................................................. 27 
7.3.1 
Screening ........................................................................................................................ 27 
7.3.2 
Day of NanoPac Injection ............................................................................................. 28 
7.3.3 
Follow-up Visits .............................................................................................................. 29 
7.3.4 
Final Follow-up Study Visit (Week 24/6-Months) ...................................................... 29 
7.3.5 
Early Termination Visit .................................................................................................. 29 
7.3.6 
Unscheduled Visits ........................................................................................................ 30 
7.3.7 
Schedule of Events Table – Dose escalation ............................................................ 31 
7.3.8 
Schedule of Events Table  – Second phase .............................................................. 32 
7.4 
Justification for Sensitive Procedures ............................................................................................. 33 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 33 
7.6 
Precautionary Medications, Treatments, and Procedures .......................................................... 33 
7.7 
Prohibited Medications, Treatments, and Procedures ................................................................. 33 
7.8 
Prophylactic Medications, Treatments, and Procedures ............................................................. 33 
7.9 
Rescue Medications, Treatments, and Procedures ..................................................................... 33 
7.10 
Participant Access to Study Agent At Study Closure ................................................................... 33 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 34 
8.1 
Specification of Safety Parameters ................................................................................................. 34 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 34 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 35 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 35 
8.2 
Classification of an Adverse Event ................................................................................................. 35 
8.2.1 
Severity of Event ............................................................................................................ 35 
8.2.2 
Relationship to Study Agent ......................................................................................... 35 
8.2.3 
Expectedness ................................................................................................................. 36 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 36 
8.4 
Reporting Procedures ....................................................................................................................... 36 
8.4.1 
Adverse Event Reporting .............................................................................................. 36 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 37 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 37 
8.4.4 
Events of Special Interest ............................................................................................. 37 
8.4.5 
Reporting of Pregnancy ................................................................................................ 38 
8.5 
Study Halting Rules ........................................................................................................................... 38 
8.6 
Safety Oversight ................................................................................................................................ 38 
9 
CLINICAL MONITORING ............................................................................................................................ 39 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 39 
10.1 
Statistical and Analytical Plans ........................................................................................................ 39 
10.2 
Statistical Hypotheses ....................................................................................................................... 40 
10.3 
Analysis Datasets .............................................................................................................................. 40 
10.4 
Description of Statistical Methods ................................................................................................... 40 


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10.4.1 
General Approach .......................................................................................................... 40 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 40 
10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 40 
10.4.4 
Safety Analyses .............................................................................................................. 41 
10.4.5 
Adherence and Retention Analyses ............................................................................ 41 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 41 
10.4.7 
Planned Interim Analyses ............................................................................................. 41 
10.4.8 
Additional Sub-group Analyses .................................................................................... 41 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 41 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 41 
10.4.11 
Exploratory Analyses ..................................................................................................... 42 
10.4.12 
Concomitant Medication................................................................................................ 42 
10.5 
Sample Size ....................................................................................................................................... 42 
10.6 
Measures to Minimize Bias .............................................................................................................. 42 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 42 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 42 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 42 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 42 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 43 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 43 
13.1 
Ethical Standard ................................................................................................................................. 43 
13.2 
Institutional Review Board ................................................................................................................ 43 
13.3 
Informed Consent Process ............................................................................................................... 44 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ... 44 
13.3.2 
Consent Procedures and Documentation .................................................................. 44 
13.4 
Participant and Data Confidentiality ................................................................................................ 45 
13.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 45 
13.5 
Future Use of Stored Specimens .................................................................................................... 45 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 45 
14.1 
Data Collection and Management Responsibilities ...................................................................... 45 
14.2 
Study Records Retention .................................................................................................................. 46 
14.3 
Protocol Deviations............................................................................................................................ 47 
14.4 
Publication and Data Sharing Policy ............................................................................................... 47 
15 
STUDY ADMINISTRATION ........................................................................................................................ 48 
15.1 
Study Leadership ............................................................................................................................... 48 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 48 
17  
LIABILITY AND INSURANCE .................................................................................................................... 48 
18  
LITERATURE REFERENCES.................................................................................................................... 48 
APPENDIX A: ECOG Performance Scale ............................................................................................................ 51 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASP 
Aspartate Aminotransferase 
ASP 
Alkaline Phosphatase 
BUN 
Blood Urea Nitrogen 
CEA 
Carcinoembryonic Antigen 
CLIA 
Clinical Laboratory Improvement Amendments 
CO2 
Carbon Dioxide 
CRO 
Clinical Research Organization 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture System 
eCRF 
Electronic Case Report Form 
EUS-FNA 
Endoscopic Ultrasound-Guided Fine Needle Aspiration 
EUS-FNI 
Endoscopic Ultrasound-Guided Fine Needle Injection 
FDA 
The U.S. Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 
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 
IND 
Investigational New Drug Application 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MAC 
Monitored Anesthesia Care 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MRCP 
Magnetic resonance cholangiopancreatography 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
OHRP 
Office for Human Research Protections 
PCA 
Precipitation with Compressed Antisolvents 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Prothrombin Time 
PTT 
Activated Partial Thromboplastin Time 


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RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDLC 
Systems Development Life Cycle 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
UP 
Unanticipated Problem 
USC 
University of Southern California 
WBC 
White Blood Cell 
 
 
 
 




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STATEMENT OF COMPLIANCE 
I have read the attached protocol number NANOPAC-2017-01 entitled, A Trial Evaluating Escalating Doses and the 
Safety of Intracystic Injection of NanoPac® in Subjects with Mucinous Cystic Pancreatic Neoplasms, Version 4.0 
dated 3 September 2019 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 NanOlogy, LLC.  The recipient agrees that no unpublished 
information contained herein will be published or disclosed without prior written permission of NanOlogy.  
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 
 
 


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PROTOCOL SUMMARY 
Title: 
A Trial Evaluating Escalating Doses and the Safety of Intracystic Injection of NanoPac® in 
Subjects with Mucinous Cystic Pancreatic Neoplasms 
 
Précis: 
In this open-label, dose rising trial of NanoPac (Sterile Nanoparticulate Paclitaxel), subjects 
with mucinous cystic pancreatic neoplasms will receive intracystic NanoPac via endoscopic 
ultrasound-guided fine needle injection (EUS-FNI). 
  
In the dose escalation phase, subjects will be enrolled in sequential cohorts of NanoPac at 6, 
10, and 15 mg/mL at volumes sufficient to fill the cyst, at least equal to the amount of cyst 
fluid aspirated. 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 at the current 
dose may be enrolled, or if the first dose does not provide adequate safety and tolerability 
the study may be halted. The dose determined to be the most suitable for further evaluation, 
defined as the highest dose with an acceptable safety and tolerability profile (as determined 
by the DSMB), will be the dose used in the second phase of the study which will enroll 9 
additional subjects. Subjects enrolled in the second phase of the study will also receive a 
second injection of NanoPac at the same dose 12 weeks after the first NanoPac injection. 
 
Plasma samples will be taken on the day(s) of NanoPac injection at 1 and 2 hours after 
injection, as well as at each of the subsequent study visits, to characterize the 
pharmacokinetics (PK) of intracystic NanoPac.  
 
Subjects will be followed for 6 months after the first NanoPac injection for safety, tolerability, 
and cyst response to therapy (as shown by imaging). Cyst fluid will also be extracted and 
analyzed for cyst fluid markers. 
 
Objectives: 
 
Primary objective: 
• 
To evaluate the safety and tolerability of NanoPac injected directly into mucinous 
cystic pancreatic cysts by endoscopic ultrasound-guided injection. 
 
 
Secondary objectives:  
• 
To describe the pharmacokinetics of NanoPac when administered into the cyst 
within the pancreas; 
• 
To determine whether any of the NanoPac concentrations (6, 10, or 15 mg/mL) 
show signs of preliminary efficacy. 
• 
To determine if the selected dose from the escalation phase shows signs of 
preliminary efficacy when injected on two occasions 12 weeks apart. 
 
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); 
• 
Cyst volume response (imaging). 
 
Population: 
Up to 30 subjects with mucinous cystic pancreatic neoplasms. 
 


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Number of 
Sites enrolling 
participants: 
Five 
Description of 
Study Agent: 
NanoPac (Sterile Nanoparticulate Paclitaxel) Powder for Suspension at concentrations of 6, 
10, and 15 mg/mL administered into the cyst within the pancreas via EUS-FNI at a volume 
equal to the volume of cyst fluid aspirated. 
 
Study Duration: 
The study duration will be up to 24 months. 
 
Participant 
Duration: 
The participant duration is estimated to be up to six and a half months for each subject  
 
 
 


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SCHEMATIC OF STUDY DESIGN FOR DOSE ESCALATION 
 
 
 
 


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1 
KEY ROLES 
Medical Director 
Gere diZerega, MD 
Professor, USC Keck School of Medicine 
President & CEO, US Biotest, Inc. 
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-630-2800 
gere.dizerega@usbiotest.com 
Study Manager 
Shelagh Verco, PhD 
US Biotest, Inc.  
231 Bonetti Dr., Suite 240, San Luis Obispo, CA 93401 
805-704-1179 
shelagh.verco@usbiotest.com 
Medical Monitor 
Antony Verco, MD 
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, U.S.A. 
608-442-8200 
Laboratory – Routine Hematology and Biochemistry 
CLIA Certified laboratory routinely used by the investigators. 
Laboratory - Imaging services 
Imaging laboratory routinely used by the investigators. 
 
 


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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 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 neoplasms have not yet been completed. NanoPac 
demonstrated promising safety and efficacy when injected intratumorally in animals with solid tumors; this data 
(as well as data from additional animal models) is presented in the NanoPac Investigator’s Brochure.   
NanOlogy conducted two in vivo nonclinical pharmacology studies to determine the effects of nanoparticulate 
paclitaxel in a PC3 nude mouse tumor xenograft. 
In the first PC3 nude mouse xenograft 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 intratumoral 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 xenograft study, mice treated with NanoPac (37.5 mg/kg, qwk x 3) via intratumoral 
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-guided fine 
needle injection (EUS-FNI). The only clinical study of NanoPac to date was Protocol HSC#11140, “A Phase I Study of 
Intraperitoneal Nanoparticle Paclitaxel in Patients with Peritoneal Malignancies,” which was conducted under IND 
073529. The results of this study were published by Williamson 2015 in the journal Cancer Chemotherapy and 
Pharmacology. 


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Protocol 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 in Protocol HSC#11140. IP administration of Nanotax 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 Nanotax treatment. There were no cases of bowel obstruction. Additional data from this clinical trial is 
presented in the NanoPac Investigator’s Brochure.  
A Phase 2 study under IND 073529 is ongoing. Protocol NANOPAC-2016-01 is a Phase 2 study of four 
concentrations of IP NanoPac plus six cycles of IV carboplatin and paclitaxel in subjects with platinum-sensitive 
stage III epithelial ovarian cancer undergoing cytoreductive surgery.   
A Phase 2a study under IND 132694 of NanoPac focal therapy of prostate cancer has completed enrollment and is 
in the reporting stage. Subjects received intratumoral injection of NanoPac at 6, 10, and 15 mg/mL in an injection 
volume of 20% of the lobe of the prostate containing the dominant lesion, and were followed for four weeks for 
safety and tolerability prior to prostatectomy. 
A Phase 2a study under IND 132692 of NanoPac therapy for locally advanced pancreatic adenocarcinoma is 
ongoing. Subjects will receive EUS-administered intratumoral injection of NanoPac at 6, 10, and 15 mg/mL at up to 
20% of the calculated tumor volume, and will be followed for up to six months for safety and tolerability. 
Relevant Literature: 
Multiple studies have confirmed the activity of paclitaxel against pancreatic cysts (Oh 2008; Oh 2009; Oh 2011; Oh 
2014; DeWitt 2014). Pancreatic cysts are, in some cases, a precursor to pancreatic cancer and paclitaxel, 
formulated as Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) (“nab-
paclitaxel”), is FDA-approved for IV treatment of metastatic pancreatic cancer. 
Importance of the study: 
Pancreatic cystic neoplasms are being detected with increasing frequency due to improved cross-sectional imaging 
and routine examination (Pitman 2010). Mucinous pancreatic neoplasms represent approximately 75% of all 
pancreatic cystic neoplasms and are divided into two categories: intraductal papillary mucinous neoplasms 
(IPMNs) and mucinous cystic neoplasms (MCNs). Both types of mucinous pancreatic neoplasms may present with 
symptoms such as abdominal pain, pancreatitis, jaundice, weight loss, malabsorption, nausea, vomiting, and 
palpable abdominal mass (Tanaka 2005; Muthusamy 2016).  
Mucinous pancreatic neoplasms have malignant potential, thus each patient diagnosed is at risk for developing 
pancreatic cancer (Farrell 2015; Sarr 2000). In a study of 401 patients with pancreatic cysts, 11% of resected cysts 
contained invasive cancer (Ferrone 2009). Patients diagnosed with IPMN have a 40% chance of invasive cancer and 
58% have underlying malignant features, while those with MCN have a malignancy risk that varies between 10% 
and 50% (Greer 2016; Allen 2007). To avoid progression to pancreatic cancer, an aggressive and rapidly fatal 
disease, all patients with mucinous pancreatic cysts should be carefully evaluated and offered treatment (National 
Cancer Institute 2016; Fernández-del Castillo 1995). An emerging treatment for mucinous pancreatic cysts is cyst 
fluid aspiration followed by treatment with ethanol lavage as an ablative agent in order to induce cell death by 


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membrane lysis, protein denaturation, and vascular occlusion (Jani 2011; DeWitt 2009). However, studies 
examining cyst volume response to ethanol injection failed to standardize their techniques and ethanol 
concentration/volume, and a ten-year study conducted by Gómez 2016 demonstrated that only 9% of patients 
experienced complete cyst resolution (Gomez 2016; Kirtane 2016). 
Current methods for determining malignancy within mucinous cysts provide unreliable results. It is difficult to 
identify cyst histology without resection. Approximately 25% of non-operative histologic diagnoses are inaccurate. 
Physicians compensate for this deficit by recommending that patients with cysts with features such as symptoms, 
positive cytology, mural nodules, or greater than 3 cm undergo surgical resection (Pitman 2010). Due to the 
concerns of mucin leakage, pancreatic fistulae, and recurrence, the standard surgical treatment for invasive and 
non-invasive MCNs and IPMNs is pancreatectomy with lymph node dissection, rather than focal non-anatomic 
resections or resections without lymphadenectomy or splenectomy (Tanaka 2012). In a study of 37 high-volume 
centers (2694 patients), the pancreatectomy mortality rate was reported to be 1.3%, increasing to 3.0% in patients 
80 years of age and over, with overall complication rates ranging from 20.0% to 72.2% (Tamirisa 2016). In patients 
that can be diagnosed with a malignancy rate of less than 3%, the risk of death from pancreatectomy is higher than 
that of malignancy (Allen 2007). Even after surgery, the recurrence rates of cysts can be as high as 20% (Tanaka 
2012). Untreated cysts, however, may progress to malignant disease while under observation (Allen 2007). 
2.2 
RATIONALE  
This study will include subjects with mucinous cystic pancreatic neoplasms. The study design allows for a safety 
evaluation of EUS-FNI of NanoPac into a cyst within the pancreas.   
A first-in-man, Phase I safety and pharmacokinetic (PK) trial in patients with malignancies of the peritoneal cavity 
(IND 073529, Protocol HSC# 11140; Williamson 2015) found that IP delivery of NanoPac was well tolerated, with 
no NanoPac-related deaths or dose-limiting toxicities reported. In addition, adverse treatment reactions commonly 
noted during IV paclitaxel therapy were avoided, as NanoPac does not contain the solvent Cremophor-EL. 
Peritoneal fluid paclitaxel PK demonstrated a concentration-time profile that increased to a significantly high 
concentration (mean of all doses = 5,711 ng/mL after 2 hours) and remained elevated over the 2-week sampling 
period. In contrast, plasma PK data for the study subjects show that peak serum NanoPac concentration was low 
and near the limit of detection in peripheral blood, and plasma paclitaxel concentrations were well below the 
threshold plasma concentration of 42.7 mg/mL associated with neutropenia (Gianni 1995).  
Multiple studies have confirmed the activity of paclitaxel against pancreatic cysts (Oh 2008; Oh 2009; Oh 2011; 
DeWitt 2014; Moyer 2016). Pancreatic cysts are, in some cases, a precursor to pancreatic cancer and paclitaxel, 
formulated as Abraxane, is FDA-approved for IV treatment of metastatic pancreatic cancer. It is hypothesized that 
the use of NanoPac should result in increased efficacy and decreased toxicity as compared with Taxol® or Abraxane 
due, at least in part, to the slow release of paclitaxel from the suspended nanoparticle. Instillation of NanoPac 
directly into the pancreatic cyst should create a depot of paclitaxel which is slowly released from the nanoparticles, 
resulting in prolonged local paclitaxel exposure. Clearance from the pancreas should be reduced, with lower 
systemic levels of paclitaxel, further limiting systemic toxicity.  
In the proposed trial, NanoPac will be administered via EUS-FNI, a procedure with well-reported safety in treating 
pancreatic neoplasms (Oh 2008; Oh 2011; Oh 2014; Moyer 2016). In studies of paclitaxel injections of pancreatic 
cysts, up to 68.74 mL of paclitaxel at concentrations of 2-3 mg/mL was injected into cysts within the pancreas 
without evidence of systemic hematopoietic toxicity (Oh 2009). The most common adverse events (AE) were 


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pancreatitis and abdominal discomfort. It has been suggested that pancreatitis after paclitaxel injection is likely 
due to the Cremophor EL excipient in Taxol, which is not required for the formulation of NanoPac (Mills 2000). 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
NanoPac has not been administered to subjects with pancreatic cysts. However, there have been studies of 
experimental injections of paclitaxel and ethanol into pancreatic cysts. The most common AE in studies of 
paclitaxel and ethanol injected into pancreatic cysts were pancreatitis and abdominal discomfort (Oh 2008; Oh 
2009; Oh 2011; Oh 2014; DeWitt 2009; DiMaio 2011; DeWitt 2014; Park 2016).  
• 
Ethanol lavage (without paclitaxel): In a double-blind study of subjects with unilocular pancreatic cysts, 
two of the 17 subjects receiving ethanol lavage administered under EUS guidance experienced abdominal 
pain, one subject experienced intracystic hemorrhage and one subject experienced acute pancreatitis 
(DeWitt 2009). A retrospective review of subjects with pancreatic cysts undergoing repeated sessions of 
EUS-guided ethanol lavage reported that one of the 13 patients had minor abdominal pain; no patients 
developed pancreatitis. In a recent study of 91 patients with pancreatic cysts not eligible for surgery, Park 
2016 found that 18 subjects had mild abdominal pain, eight subjects developed fever without evidence of 
infection, and three subjects developed mild pancreatitis. 
• 
Paclitaxel (with ethanol): A prospective study of fourteen patients receiving EUS-guided ethanol lavage 
with paclitaxel injection for cystic tumors of the pancreas resulted in six patients with hyperamylasemia 
(without abdominal pain), one patient with mild pancreatitis and abdominal pain, and one patient with 
mild, vague abdominal pain lasting one month (Oh 2008). Oh 2009 evaluated the response of 10 subjects 
with oligolocular pancreatic cysts to EUS-guided ethanol lavage with paclitaxel injection; only one of the 
patients experienced mild pancreatitis and no other complications were observed. Forty-seven subjects 
with pancreatic cysts received EUS-guided ethanol lavage with paclitaxel injection and were followed for 
more than one year after treatment; fever without bacteremia (n=1), vague abdominal discomfort lasting 
two weeks (n=1), and mild pancreatitis (n=1) were reported (Oh 2011). In a prospective study of EUS-
guided pancreatic cyst ablation with ethanol and paclitaxel, DeWitt 2014 report adverse reactions in 
seven of 22 patients undergoing a total of 31 ablation procedures, including abdominal pain alone in four 
patients (13%), pancreatitis in three patients (10%), peritonitis in one patient (13%), and gastric wall cyst 
in one patient (3%). A study by Oh 2014 aimed to evaluate the systemic effect of EUS-guided ablation with 
ethanol and paclitaxel, finding that five of 10 patients had mild, self-limited abdominal pain, one patient 
had vomiting soon after the procedure, and one patient had intracystic bleeding during the procedure 
without sequelae.  
2.3.2 KNOWN POTENTIAL BENEFITS  
There are no known potential benefits of intracystic injection of NanoPac. However, multiple studies have 
confirmed the activity of paclitaxel injected directly into pancreatic cysts (Oh 2008; Oh 2009; Oh 2011; DeWitt 
2014).  
3 
OBJECTIVES AND PURPOSE 
The primary objective of this study is to evaluate the safety and tolerability of NanoPac injected directly into 
mucinous cystic pancreatic neoplasms by EUS-FNI. Secondary objectives are (a) to describe the PK of NanoPac 


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when administered into the cyst within the pancreas, (b) to determine whether any of the NanoPac dose 
concentrations (6, 10, or 15 mg/mL) show signs of preliminary efficacy, and (c) to determine if the selected dose 
from the escalation phase shows signs of preliminary efficacy when injected on two occasions 12 weeks apart. 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
In this open-label trial, up to 30 subjects with mucinous cystic pancreatic neoplasms will have undergone 
endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) as part of Standard of Care (SOC). Once there is a 
diagnosis and confirmation of mucinous cystic pancreatic neoplasm, subjects will receive intracystic NanoPac via 
EUS-FNI. Subjects will be followed for cyst response to therapy (as shown by imaging) and concentration of 
paclitaxel in the systemic circulation post-injection (as determined by PK analysis). 
In the dose escalation phase, subjects will be enrolled in sequential, escalating cohorts of NanoPac at 
concentrations of 6, 10, or 15 mg/mL injected directly into the cyst within the pancreas at a volume sufficient to fill 
the cyst, at least equivalent to the amount of fluid removed from the cyst (single injection). In the second phase, 
subjects will receive two injections of NanoPac 12 weeks apart at the dose selected in the dose escalation phase. 
Cyst Volume Calculations 
If more than one cyst is present in the pancreas of a subject, the Investigator will select a single target cyst and will 
treat only this target cyst. The single target cyst must have a diameter of at least 1.5 cm and no more than 4 cm; 
the diameter will be measured at the widest point of the cyst. In the dose escalation phase, imaging with magnetic 
resonance cholangiopancreatography (MRCP), CT scan, or FDG-PET will be used prior to enrollment to visualize and 
measure the cyst to confirm subject eligibility; the same imaging modality used prior to enrollment will be 
repeated at the Week 12 and Week 24 timepoints. In the second phase of the study, a CT scan will be performed 
between the Screening visit and Day 1 to obtain a baseline image against which future CT scans (at the Week 12 
and Week 24 timepoints) will be compared. The CT scan at Week 12 will be performed prior to NanoPac injection, 
however the exact cyst diameter (three dimensional) will be based on measurements performed with endoscopic 
ultrasound during the NanoPac injection procedure. Injection volume will be at least equal in volume to the 
amount of fluid removed from the cyst, but may be a larger volume to fill the cyst as determined visually by the 
Investigator during the endoscopic ultrasound procedure. The exact volume administered to the cyst will be 
documented in the source.  
Dose Escalation of Cohorts 
In the dose escalation phase, 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 (DLT). 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).  


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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. 
Second Phase 
Once the dose deemed appropriate for expansion and further evaluation has been determined by the DSMB, an 
additional 9 subjects will be enrolled at that dose level. Subjects in the second phase will also receive a second 
NanoPac injection to their cyst (at the same dose) 12 weeks after the first NanoPac injection.  If any subject has a 
CT Scan following the first NanoPac injection and the cyst cannot be identified/visualized (at Week 12) the subject 
will not have a second injection and will be followed-up at Week 24 to obtain a CT Scan; visits between Week 12 
and Week 24 will not be required for these subjects. 
PK Analysis 
Plasma samples will be taken on the day(s) of injection at 1 and 2 hours after NanoPac injection, as well as at all 
other study visits, to characterize the PK of intracystic NanoPac. Subjects will be followed for six months after the 
first NanoPac injection for safety and response to therapy (see Section 7.3.4). 
4.2 
ENDPOINTS 
 
4.2.1 PRIMARY ENDPOINT 
The primary endpoint will be safety and tolerability, as assessed by AE, changes in vital signs, laboratory results, 
and physical examination at four weeks following NanoPac injection. Safety and tolerability will continue to be 
assessed until the end-of-study visit. 
4.2.2 SECONDARY ENDPOINTS 
The secondary endpoints will be: 
• Concentration of paclitaxel in the systemic circulation post-injection (as determined by PK analysis); 
• 
Cyst volume response (imaging). 
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: 
• 
Signed informed consent; 
• 
Age ≥18 years; 


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• 
Recently confirmed mucinous cystic pancreatic neoplasm; may be confirmed by presence of mucin, cyst 
fluid carcinoembryonic antigen (CEA) above 192 U/L, or other reliable diagnostic means such as 
endomicroscopy; KRAS analysis may also be performed at the discretion of the Investigator; 
• 
Unilocular cyst with diameter of at least 1.5 cm and no more than 4 cm; 
• 
Subjects of child-bearing potential must follow adequate contraceptive measures. 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 condoms. * 
* 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. 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: 
• 
Positive cytology indicating malignancy; 
• 
Thrombotic or embolic events; 
• 
Absolute neutrophil count ≤1.5 x 109/L and platelets ≤100 x 109/L 
• 
Total bilirubin >3x ULN; 
• 
GGT, AST, and ALP >1.5x ULN; 
• 
Creatinine clearance < 60 mL/min/1.73 m2; 
• 
Elevated serum lipase; 
• 
Hepatobiliary dysfunction within 3 months*; 
• 
Interventions of the upper gastrointestinal tract (i.e. Endoscopic Retrograde Cholangiopancreatography 
[ERCP] or EUS) within 1 month*; 
• 
Known hypersensitivity to study agent; 
• 
Known drug or alcohol abuse; 
• 
Pregnant or breastfeeding women. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sufficient subjects will be screened to allow for up to 30 subjects to be enrolled in the trial. Subjects will be 
recruited at up to five study sites in the US.  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 
during dose escalation. The first three subjects in the second phase will also be reviewed by the DSMB following 
their second NanoPac injection to confirm safety in this group. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from participation in the study at any time upon request.  Their reason for 
wanting to withdraw will be documented in the source notes and in the Electronic Data Capture system (EDC). The 
final study visit is planned for six months after the first NanoPac injection. 


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A subject who is not suitable to be treated will be withdrawn prior to Day 1 (Baseline/Treatment), and therefore in 
all study documentation this subject would be considered a Screenfail Subject. Reasons for failing the screening 
will be documented in the source notes and in the EDC. 
All subjects should continue to be monitored after initiation of treatment (NanoPac injection) unless they 
communicate a decision to discontinue protocol follow-up.  It is very important that any events occurring be 
captured and followed for the safety of the subject. If any further treatment is needed, this will be documented 
and the response imputed as disease progression.  
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. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for the study suspension or termination, will be provided by the 
suspending or terminating party to sponsor. If the study is prematurely terminated or suspended, the Principal 
Investigator (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 DLT.   
o 
In the dose escalation phase, the study may be terminated if in the first dose cohort one third of 
the subjects experience the same DLT (as defined in Section 6.1.7).  
o 
In the  second phase of the study, if one third of the subjects (i.e., 3 subjects) experience the 
same DLT the study may be stopped or remaining subjects may receive a lower dose of the study 
drug, or be limited to receive only one injection, as determined by the DSMB. 


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• 
Insufficient compliance with protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination of futility. 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed and satisfy 
the sponsor, IRB, and/or Food and Drug Administration (FDA).  
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
NanoPac will be manufactured by CritiTech, Inc. (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 59˚ to 86˚F (15˚ to 30˚C), 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 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. 
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 with at least the following information: 
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.” 


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6.1.3 PRODUCT STORAGE AND STABILITY 
Prior to administration at the hospital/clinic, the dry, sterilized NanoPac vials will be stored at the Pharmacy, 
temperature controlled at 59˚ to 86˚F (15˚ to 30˚C). 
Once the NanoPac has been reconstituted it must 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 storage 
instructions in the IFU must be followed. Each vial used and each syringe must be labelled with the subject’s ID and 
visit information for accountability purposes. 
6.1.4 PREPARATION 
Preparation of the study doses will be according to the IFU provided in the study kit. 
A prescription will be provided for each subject detailing the subject ID, noting the cohort to which the subject is 
assigned, and the volume of drug to be prepared, as determined by the Investigator based upon a preliminary 
estimate of cyst volume. The prescription will also note the date and time required for administration. The 
prescription 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 15 mg/mL, according to cohort assignment), a 
suitable volume for use (as provided on the prescription) will be withdrawn, as described in the IFU, from the vial 
into a syringe. The syringe for administration will be labeled with the subject ID, the volume contained in the 
syringe as specified on the prescription, and the date and time of preparation.  
6.1.5 DOSING AND ADMINISTRATION 
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 
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 cyst. The 
cyst 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 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 the path to the cyst. The needle tip will be maintained in the cyst for the 
duration of the procedure. Using a syringe, the Investigator will use their discretion to aspirate the cyst fluid 
(usually up to 80% of the original volume of the cyst). The volume withdrawn will be documented in the source, 
and a sample will be sent for analysis. The needle will then be filled with the study treatment, NanoPac, from the 
syringe provided by the Pharmacy, and NanoPac will be injected at a volume sufficient to fill the cyst, at least equal 
to the volume of cyst fluid aspirated. The injection volume to fill the cyst will be determined visually by the 
Investigator during the endoscopic ultrasound procedure, and the exact volume administered to the cyst will be 
documented in the source and captured in the electronic case report form (eCRF).    
6.1.6 ROUTE OF ADMINISTRATION 
NanoPac will be injected directly into the cyst within the pancreas using endoscopic ultrasound guidance. 


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6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
NanoPac will be administered in concentrations based on cohort assignment. Investigators will administer a 
volume at least equal to the volume of cyst fluid aspirated. 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 DLT 
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 two-week follow-up visit, and will assess safety and tolerability 
based on the DSMB Charter. The DSMB will determine whether to: (a) escalate to the next dose level cohort (no 
DLT); (b) add three additional subjects to the current cohort (one DLT); or (c) return to the previous (lower) dose 
cohort and expand by three subjects (greater than one DLT). 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 
study 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 highest dose considered to be safe and tolerable in the dose escalation phase will be the dose administered in 
the second phase of the study. The dose will be administered twice in the second phase, as two single NanoPac 
injections 12 weeks apart. 
Included in the DSMB’s review of AE and general study data pertaining to safety (such as laboratory results and 
questionnaire responses) there will be rules for non-escalation. Any AE that is considered related or possibly 
related to NanoPac is potentially a DLT. The definition of a DLT will be made by consensus by the Medical Monitor, 
Sponsor Medical Director, and Principal Investigator for AE. DLT will include the following: 
• 
Any Grade 4 toxicity of any duration; 
• 
Grade 3 and higher pancreatico-biliary events (including but not limited to symptomatic pancreatitis or 
cholangitis, excluding asymptomatic time-limited pancreatic enzyme elevations); 
• 
Grade 3 and higher febrile neutropenia; 
• 
Grade 3 diarrhea and vomiting lasting more than 72 hours; 
• 
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 
In the dose escalation phase, this study is evaluating one single administration of NanoPac in each subject, 
therefore there will be no dose adjustment or modification in an individual subject.  
In the second phase of the study, where each subject will receive two NanoPac administrations 12 weeks apart, 
the possibility of adjusting the dose for the second injection based on safety may be discussed and determined 
between the Investigator and the Medical Monitor on a case-by-case basis. Upon review of the first three subjects 
in the second phase, the DSMB may also determine that adjustment is required for the remaining subjects in this 
cohort. 


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6.1.9 DURATION OF THERAPY 
NanoPac will be injected directly into the cyst within the pancreas on either a single occasion or on two occasions 
12 weeks apart. Each NanoPac administration/dosing occurs over a period of 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. 
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; 
• 
Imaging with EUS-FNA will have occurred prior to consenting to participate in the study as this procedure 
is required to confirm the diagnosis of mucinous cystic pancreatic neoplasm using cyst fluid markers. 
Mucinous cystic pancreatic neoplasm may also be confirmed by the presence of mucin, or by 
endomicroscopy. 
• 
In the dose escalation phase, imaging (MRCP, CT scan, or FDG-PET) results will be used to document the 
location and size of the cyst to be treated. If multiple cysts are present, the location of each will be 
documented, and selection of the target cyst to be treated will be at the discretion of the Investigator. 
Treatment of non-targeted cysts will follow institutional SOC. 


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• 
In the second phase of the study, a CT scan will be obtained before the first NanoPac injection to provide 
baseline data on dimensions and volume of the lesion to be injected; 
• 
A copy of the cytology report and the imaging reports supporting the diagnosis must be filed in the 
subject’s study record; 
• 
Comprehensive physical examination, including ECOG Performance Status assessment (Appendix A), and 
vital signs (blood pressure, heart rate, temperature, body weight and height); 
• 
PK samples will be taken at 1 and 2 hours post-NanoPac injection, and again at all study visits post 
injection; 
• 
Samples will be collected and processed for clinical laboratory assessment at Screening, and on the day(s) 
of NanoPac injection prior to treatment; and at Week 1, Week 2, Week 4, Week 8 (two months), Week 12 
(three months), and Week 24 (six months, end of study visit) post-injection for subjects in the dose 
escalation phase. Subjects in the second phase will have additional samples collected at Week 14 and 
Week 16. Assessments will include: 
o 
Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood urea 
nitrogen (BUN), creatinine, serum lipase, serum amylase, alkaline phosphatase (ASP), total 
bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyltransferase [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); 
• 
EUS-FNA of the cyst fluid; cyst fluid will be collected after aspiration and analyzed for CEA in the dose 
escalation phase of the study.  In the second phase where subjects will receive two injections of NanoPac, 
the cyst fluid will be collected and the volume documented, and this will be divided up for CEA analysis 
and a small amount will be stored for paclitaxel presence/absence evaluation. 
• 
EUS-FNI of the cyst within the pancreas with NanoPac at a volume equal to or greater than the volume of 
cyst fluid aspirated. Subjects in the dose escalation phase will receive one injection on Day 1. Subjects in 
the second phase of the study will receive two injections - the first administration will be on Day 1 and the 
second administration will be at the Week 12 visit. 
• 
Documentation of the volume of cyst fluid aspirated, volume of NanoPac injected, and volume of 
NanoPac remaining in the syringe (as applicable); 
• 
The same imaging modality performed prior to enrollment and used to confirm eligibility (MRCP, CT scan, 
or FDG-PET) will occur at three months post-injection and at end-of-study (six months after NanoPac 
injection) for the subjects in the dose escalation phase of the study. Subjects in the second phase of the 
study will have a CT scan following consent and prior to first injection, at the Week 12 visit prior to second 
NanoPac injection, and again at the Week 24 (six month) visit at end of study. 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. Any data collected from additional procedures 
conducted while the subject is on study will be available for review and  may be provided to US Biotest. 


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7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Following EUS-FNI 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 treatment of multiple cysts, pain relief, 
additional clinic visits, etc.). Following intracystic injection of NanoPac, EUS-guided aspiration of the NanoPac-
treated cyst should not be initiated within six months except as specified by the protocol. However if it is required 
prior to the end-of-study visit, the Investigator must contact the study Medical Monitor to discuss and document 
the decision-making process. 
Information on standard care and treatment post-injection(s) to the final visit will be captured as appropriate. Any 
data collected from additional procedures conducted at the final visit will be provided to US Biotest. 
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 Week 1, 
Week 2, Week 4, Week 8 (two months), Week 12 (three months), and at Week 24 (six months) post-injection for 
subjects in the dose escalation phase. Subjects in the second phase will have additional samples collected at Week 
14 and Week 16: 
• 
Sodium, potassium, chloride, carbon dioxide (CO2), calcium, phosphorus, glucose, blood urea nitrogen 
(BUN), creatinine, serum lipase, serum amylase, alkaline phosphatase (ASP), total bilirubin, direct 
bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase 
[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). 
7.2.2 OTHER ASSAYS OR PROCEDURES 
PK samples will be taken on day(s) of injection at 1 and 2 hours post-injection. In addition, a PK sample will be 
obtained at each study visit. PK samples within the first 2 hours after injection will allow for a 10-minute window 
around the samples, resulting in a total 20-minute window. PK samples for Week 1 will allow for a 1-day window 
around the samples (±1 day on either side). PK samples for Week 2, Week 4 (one month), Week 14 (if applicable), 
and Week 16 (if applicable) will allow for a 2-day window around the samples (±2 days on either side), and samples 
for Week 8 (two month) will allow for a 1-week window (±1 week on either side).  In the dose escalation phase of 
the study there will be a 1-week window (±1 week on either side) for the Week 12 visit, and a 2-week window (±2 
weeks on either side) for PK samples collected for the Week 24 (six month) visit. In the second phase where two 
injections of NanoPac are given, there will be a 1-week window (±1 week on either side) for the Week 12 visit, and 


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the visits at Week 14 and Week 16 will be conducted with a 2-day window from the date of second injection; the 
Week 24 visit in this group of subjects will allow a 1-week window for PK sample collection. 
Imaging with EUS-FNA will have occurred prior to consent, to confirm the diagnosis of mucinous cystic pancreatic 
neoplasm using cytology and pancreatic cyst fluid markers. Mucinous cystic pancreatic neoplasm may also be 
confirmed by the presence of mucin, or by endomicroscopy. A copy of the reports supporting the diagnosis must 
be filed in the subject’s study record. The location of the cyst(s) will be documented. 
During the dose escalation phase, imaging (MRCP, CT scan, or FDG-PET) will be documented prior to study 
participation and again at Week 12 and at Week 24. In the second phase of the study, a CT scan will be performed 
between the Screening visit and the first Day of Injection Visit to obtain a study baseline image against which 
future CT scans at the Week 12 and Week 24 timepoints will be compared. Should the subject withdraw from the 
study at any time, a scan will be conducted as part of the end-of-study procedures. The location of the cyst will be 
documented with imaging. If multiple cysts are present, selection of the cyst to be treated will be at the discretion 
of the Investigator. Treatment of non-selected cysts will follow institutional SOC.  
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
For all subjects PK samples will be drawn at the specified time/visit, prepared and stored frozen on-site, and 
samples will be batch-shipped to Covance Laboratories for analysis. Procedures for processing for storage will be 
provided prior to study initiation. 
In the second phase of the study, at the Week 12 visit prior to second dose of NanoPac, any cyst fluid available for 
paclitaxel presence assessment will be stored frozen on-site, and samples will be batch-shipped to Frontage 
Laboratories for analysis. 
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 and for 
entry to the electronic case report form (eCRF). 
7.2.4 SPECIMEN SHIPMENT 
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, or at another time interval determined by the Sponsor, 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.  Samples for paclitaxel evaluation will also be stored frozen at the site and batch 
shipped to Frontage as directed by the Sponsor. 
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. 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
When subjects have a diagnosis of a mucinous pancreatic cyst, confirmed by analysis of cyst fluid aspirated using 
EUS-FNA or by endomicroscopy, they will be eligible for consideration to enroll to the study to receive treatment 
with NanoPac.  


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The following procedures and assessments must be completed, documented and reviewed by the Investigator (up 
to and) 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 mucinous cystic pancreatic neoplasm with a diameter of at least 1.5 cm and 
no more than 4 cm; diagnosis and previous treatments including surgical and chemotherapeutic records. A 
copy of the reports 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); 
• 
Sample collection and processing for clinical laboratory assessments (see section 7.2.1); 
• 
In the second phase of the study, CT scan between screening and Day 1 for detailed baseline 
measurement. Final injection volume will be determined with ultrasound during the endoscopic-guided 
procedure. 
7.3.2 DAY OF NANOPAC INJECTION 
 
All Screening assessments must have completed prior to this visit, all results confirmed, and inclusion and 
exclusion criteria confirmed.  In the dose escalation phase of the study the following applies to Day 1 (the single 
day of NanoPac injection) and, in the second phase, applies to both injection days on Day 1 and Week 12. 
Prior to the procedure: 
• 
Comprehensive physical examination, including ECOG Performance Status assessment;  
• 
Vital signs will be obtained; 
• 
AE occurring in the period between Screening and this visit must be confirmed as either ongoing or 
completed. AE occurring prior to the procedure will be considered history, and those occurring after 
NanoPac administration will be documented separately as treatment emergent adverse events (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); 
• 
In the second phase of the study, a CT scan will be performed at the Week 12 visit before the second 
injection; 
• 
EUS-FNI of the cyst within the pancreas with NanoPac at a volume sufficient to fill the cyst that is at least 
equal to the volume of cyst fluid aspirated; 
• 
Cyst fluid will be extracted and analyzed for carcinoembryonic antigen (CEA), and the aspirated cyst fluid 
volume will be documented. In the second phase of the study, at the Week 12 visit, prior to the second 
NanoPac injection, cyst fluid will again be aspirated and analyzed for CEA, and if sufficient sample is 
available it will also be sent for paclitaxel evaluation (presence or absence). 
• 
Subject will receive NanoPac as described in Sections 4.1 and 6.1.5, according to the cohort allocation, and 
the injection volume will be documented, as well as the remainder in the syringe; 
• 
PK Samples will be drawn at 1 and 2 hours post-injection. 
 


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7.3.3 FOLLOW-UP VISITS 
 
Subjects will return to the clinic  one week after the first NanoPac injection for the first study-specific follow-up 
visit. Subsequent follow-up visits will occur at Week 2, Week 4, and Week 8. Subjects in the dose escalation phase 
will have a follow-up visit at Week 12. Subjects in the second phase will have additional follow-up visits at Week 14 
and Week 16. 
The Week 4 (1-month) visit will be the primary endpoint (safety and tolerability) study visit for subjects in the dose 
escalation phase. The Week 16 (one month following the second NanoPac injection) visit will be the primary 
endpoint study visit for subjects in the second phase. All further visits will be conducted to assess the ongoing 
safety and the secondary endpoints.  
The following procedures will be performed at the Week 1, Week 2, Week 4, Week 8 (2-month), Week 14 (as 
applicable), and Week 16 (as applicable) clinic visits. The procedures will also be performed at the Week 12 (3-
month) clinic visits for subjects in the dose escalation phase: 
 
• 
Vital signs obtained; as needed, a directed physical exam may be performed; 
o 
 At Week 4 a comprehensive physical exam, including vital signs will be performed. 
• 
ECOG Assessment; 
• 
Concomitant medications reviewed; 
• 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1); 
• 
PK sample obtained; 
• 
AE collection. 
• 
Imaging will be performed at the Week 12 (3-month) visit for all subjects. 
7.3.4 FINAL FOLLOW-UP STUDY VISIT (WEEK 24/6-MONTHS) 
The assessments completed at this visit will be used to support the primary (safety) endpoints, and will be used for 
the secondary (preliminary efficacy) endpoint analysis. The following procedures will be performed: 
• 
Vital signs obtained; as needed, a directed physical exam may be performed; 
• 
Concomitant medications; 
• 
AE collection; 
• 
Sample collection and processing for clinical laboratory assessments (Section 7.2.1);  
• 
PK Sample obtained; 
• 
ECOG Assessment; 
• 
Imaging and disease status assessment. 
Any data collected from additional procedures conducted during the study may be provided to US Biotest. 
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, AE, and concomitant medications. 


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7.3.6 UNSCHEDULED VISITS 
Any unscheduled visits will be documented in the source, 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 filed in the source and be available if required at a later date, but laboratory results will not be 
transcribed into the EDC. 
 


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7.3.7 SCHEDULE OF EVENTS TABLE – DOSE ESCALATION 
 
 
 
Screening7 
Day 1 
(Injection)8 
Week 1 
(±1 day) 
Week 2 
(±2 days) 
Week 4 
(±2 days) 
Week 8 
(±1 week) 
Week 12 
(±1 week) 
24 Weeks/ 
6 Months 
(±2 weeks) 
Informed Consent 
X 
 
 
 
 
 
 
 
History1 
X 
 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam2 
F 
T 
T 
T 
F 
T 
T 
T 
ECOG3 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, 
Biochemistry, and 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Cyst fluid CEA 
 
X 
 
 
 
 
 
 
PK Samples4  
 
X 
X 
X 
X 
X 
X 
X 
Imaging5 
 
 
 
 
 
 
X 
X 
NanoPac6 
 
X 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
1 
History includes all events before initiation of NanoPac treatment. 
2 
F = Full Physical Exam; T = Targeted Physical Exam 
3 
ECOG Performance Status Scale attached as Appendix A. 
4  
PK Samples on Day 1 will be drawn at 1 and 2 hours post-dose, PK samples will also be obtained at each study visit thereafter. 
5 
Imaging with MRCP, CT scan, or FDG-PET will occur prior to Screening to confirm size of mucinous cystic pancreatic neoplasm. The same imaging modality used to confirm eligibility will be 
repeated at Week 12 and Week 24.  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. Should the subject withdraw from the study at any time, a scan will be conducted as part of the end-of-study procedures. 
6 
Prophylactic antibiotics will be administered prior to NanoPac injection; NanoPac will be administered by endoscopic ultrasound-guided fine needle injection. 
7 
Screening will occur up to four weeks prior to injection. 
8 
There is a 10-minute window (±10 minutes on either side) around samples taken within the first 2 hours during Day 1 (injection). 
 


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7.3.8 SCHEDULE OF EVENTS TABLE  – SECOND PHASE 
 
 
Screening7 
Day 1 
(Injection) 
Week 1 
(±1 day) 
Week 2 
(±2 days) 
Week 4 
(±2 days) 
Week 8 
(±1 week) 
Week 12 
(±1 week) 
Week 149 
(±2 days) 
Week 169 
(±2 days) 
Week 24/ 
6 Months 
(±1 week) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History1 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam2 
F 
T 
T 
T 
F 
T 
T 
T 
T 
T 
ECOG3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, 
Biochemistry, and 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cyst fluid CEA 
 
X 
 
 
 
 
X8 
 
 
 
PK Samples4  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging5 
X 
 
 
 
 
 
X 
 
 
X 
NanoPac6 
 
X 
 
 
 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1 
History includes all events before initiation of NanoPac treatment.  
2 
F = Full Physical Exam; T = Targeted Physical Exam 
3 
ECOG Performance Status Scale attached as Appendix A. 
4  
PK Samples on Day 1 and Week 12 will be drawn at 1 and 2 hours post-dose. PK samples will also be obtained at each study visit thereafter. There is a 10-minute window (±10 minutes on either 
side) around samples taken within the first 2 hours during Day 1 (injection) and Week 12. 
5 
Imaging with CT scan will occur during the Screening period (prior to NanoPac administration), and at Week 12 and Week 24. Should the subject withdraw from the study at any time, a scan will 
be conducted as part of the end-of-study procedures. 
6 
Prophylactic antibiotics will be administered prior to NanoPac injection; NanoPac will be administered by endoscopic ultrasound-guided fine needle injection. 
7 
Screening will occur up to four weeks prior to first injection.  
8 
If sufficient sample is obtained, in addition to CEA analysis the fluid will be evaluated for presence of paclitaxel  
9 
Week 14 and Week 16 visits should be 2 weeks and 4 weeks after the second injection; all other visits are scheduled from Day 1.


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Sponsor acknowledges that EUS-FNI of NanoPac into the cyst 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 eCRF. 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. 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, at any time during the study (Screening to the final visit) is to be discussed with the Medical Monitor 
before any action is taken.  The subject may be permitted to remain on study but there is a chance that the subject 
may be required to be withdrawn at this time. EUS-FNA of the cyst receiving NanoPac subsequent to the injection 
procedure(s) is also strongly discouraged at any time during the study. 
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 SOC. 
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 and in the study data as needed. 
7.10 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable. 


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8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments being conducted in this study include: 
• 
AE, collected at all study visits from the time of dosing; 
• 
Changes in concomitant medications;  
• 
Findings from physical examinations; 
• 
Changes in vital signs; 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 two 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 AE and general study data pertaining to safety (such as laboratory results) 
there will be rules for non-escalation. Any adverse event that is considered related or possibly related to NanoPac 
is potentially a DLT. The definition of a DLT will be made by consensus by the Medical Monitor, Sponsor Medical 
Director, and Principal Investigator for AE. DLT will include the following: 
• 
Any Grade 4 toxicity of any duration; 
• 
Grade 3 and higher pancreatico-biliary events (including but not limited to symptomatic pancreatitis or 
cholangitis, excluding asymptomatic time-limited pancreatic enzyme elevations); 
• 
Grade 3 and higher febrile neutropenia; 
• 
Grade 3 diarrhea and vomiting lasting more than 72 hours; 
• 
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). 
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. 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended change in structure, function, signs, or symptoms 
temporally associated with the use of a medicinal product, whether or not related to the product. Undesirable 
changes in laboratory values should not be considered AE unless they are considered symptomatic of a clinical 
condition or diagnosis, are evaluated as clinically significant or require therapy. Worsening of a pre-existing 
condition is also considered an AE, as is the discovery of an abnormal finding during physical exam that was not 
included in the medical history. Clinical conditions attributable to disease progression will be considered AE and 
reported on the eCRF. 


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8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event (SAE) is any AE 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) 
All unanticipated problems in this trial will be captured as either AE or SAE and will be defined and reported 
accordingly. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
Signs and symptoms will be graded by the Investigator as mild, moderate, severe, or life threatening 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 
• 
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 possible, probable, 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. 


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• 
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 agent specifically. An event may be unexpected in the 
subject but that in itself does not qualify as unexpected; review against information available and provided for the 
study agent is what will determine expectedness. 
Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent, in the protocol and within the Investigator’s Brochure. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
AE 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 AE. Study personnel will ask open-ended questions to obtain 
information about AE at every visit. Date and time of onset and resolution (if applicable) of the AE will be 
documented. 
All SAE must be followed until the event resolves or, in the opinion of the Investigator, becomes stable.   
The sponsor will report any serious, unexpected and drug-related AE to applicable regulatory agencies and make 
these reports available to the investigative sites. The Investigator must promptly inform the IRB of such events and 
retain a copy of the notification in the site’s regulatory binder. 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
All AE (whether or not attributable to the study agent) occurring during the study observed by the Investigator or 
reported by the subject will be recorded on the eCRF. The following information will be recorded for all AE: 
• 
Name of condition/diagnosis/description; 
• 
Onset and resolution dates; 
• 
Severity; 
• 
Relationship to Investigational Agent; 


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• 
Action taken; 
• 
Seriousness.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
All SAE, 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: 
Antony Verco, MD 
Medical Monitor 
Email: 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 at 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). 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
 
Unanticipated incidents or events that occur during the conduct of the study, meeting 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. 


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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 SAE, without regard 
to causality. In addition, any infant death that occurs after the 30-day reporting period that the Investigator 
suspects is related to the in utero exposure to the study treatment should also be reported. 
8.5 
STUDY HALTING RULES  
This study is a 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 timepoint, the study may be terminated.  
Should this occur, all subjects who have received treatment will be followed to the completion of their end-of-
study visit to ensure all safety data is collected on all treated subjects. 
The DSMB will review data from the first three subjects in each cohort once they complete the two-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 DSMB. 
The DSMB, comprising the Medical Director and at least two independent key opinion leaders in the field of study, 
will review all safety and tolerability parameters at regular intervals throughout the study. 
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 


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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 escalate in a new cohort. 
The DSMB will convene once the first three subjects in the second phase of the study have completed their Week 
14 visit (two weeks after their second injection) to review safety data. Subject recruitment to this cohort of 
subjects will continue during the review. If the DSMB have concerns regarding future subjects receiving a second 
injection then they may propose alternative actions, which may include reducing the dose of the injections or 
limiting future subjects to a single injection. 
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, eCRF, and source documents as needed to assure the conduct of the study was within compliance. In 
addition, the FDA or other government agencies may request an inspection following notification to the site. In 
such an event, the Investigator agrees to notify the sponsor immediately of the request, and will allow sponsor and 
inspectors to review records. 
US Biotest will conduct a Site Initiation Visit to provide the Investigator and their staff with a comprehensive 
overview of the protocol and study procedures and to review mutual obligations and requirements of regulatory 
authorities. A regulatory file or binder containing required documentation will be kept at the site for reference and 
inspection. 
Routine monitoring visits will be made to 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 prior to study 
database lock. 


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10.2 
STATISTICAL HYPOTHESES 
  No inferential analyses are proposed, thus no hypotheses are stated. 
10.3 
ANALYSIS DATASETS 
 All subjects who receive treatment will be included in the outcome presentations. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
In this dose escalation trial, the focus will be on providing descriptive statistical summaries including tables and 
graphs for each of the dose groups. The clinical/medical review of these data will determine if there are any issues 
with toxicity that could be associated with dose and if there is any effect of the treatments on the mucinous cystic 
pancreatic neoplasm.  
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 The primary objective of this study is to evaluate the safety and tolerability of three doses of NanoPac 
(concentrations of 6, 10, and 15 mg/mL) injected directly into mucinous cystic pancreatic neoplasms. 
The adverse events reported will be coded in MedDRA and summarized by System Organ Class (SOC) and Preferred 
Term (PT) for each of the dose groups. Where possible and relevant, these will also be subset temporally by date 
and time of onset (e.g. first 24 hours, up to Day 7); the details of the timeframes will be established medically and 
presented in the SAP. Events reported as DLT and those that lead to trial discontinuation will be noted. Any serious 
AE and any deaths will be summarized separately. 
The vital signs raw data, collected at each visit, and changes from Day 1 will be tabulated and listed. 
The laboratory analyses will be presented in summary tables with changes from Day 1 to Days 14 and 28. By 
applying the normal ranges (high, normal and low) shift tables will be generated. Values which are noted by the 
investigator to be abnormal and clinically relevant will be summarized separately as will any analytes where the 
shift in category is greater than two (e.g. high to low or low to high). The SAP may capture medically relevant 
changes (e.g. 3 x the normal range), and analytes which meet this criterion will also be presented separately. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
To address the secondary objective of the concentration of paclitaxel in the systemic circulation post-injection, the 
PK samples taken on Day 1 at 1 and 2 hours post-injection, and again at all study visits post injection (Weeks 1, 2, 
4, 8, 12 and 24) will be presented (at a minimum) by individual listings. If some concentration data is above the 
detectable limit and can be reported numerically, this data will be tabulated and graphed for individuals and by 
dose group.  
To determine if there are any indications of efficacy, the cyst volume at screening will be compared with the 
volume calculated for the images at Weeks 12 and 24 (or early termination).  Although the number of subjects 
within each dose group is low (3 to 6 subjects), if there is some evidence that the change from baseline is greater 
with the higher dose(s) as seen in scatterplots and mean value summary tables, then this would be suggestive of a 


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possible treatment effect (i.e. increased dose = increased effect).  The by-subject listings will also include possible 
predictor factors (e.g. gender, CEA at baseline) which will be specified in the SAP by the medical/clinical input.  If 
helpful some of the factors may also be included in the summary displays (i.e. graphs and tables) to aid in 
interpretation. 
10.4.4 SAFETY ANALYSES 
All safety analyses will be presented as part of the primary endpoint analysis. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
All subjects who are enrolled and treated in the trial will be accounted for. Subjects terminating early will be noted 
and the reasons provided. 
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Complete demographic, medical history (coded in MedDRA) and disease history will be summarized for each of the 
dose groups. 
10.4.7 PLANNED INTERIM ANALYSES  
A formal interim analysis is not planned.  However there will be ongoing data review and report preparation for 
the DSMB as outlined in the DSMB Charter. 
10.4.7.1 
SAFETY REVIEW 
The safety review will be ongoing for this dose-escalation trial, as outlined in sections 6.1.7 and 8.1 
10.4.7.2 
EFFICACY REVIEW 
There is no formal plan to review the imaging data results on an ongoing basis.  However given the early phase of 
development, if there is an increase in the number of early terminations due to disease progression, a formal 
safety review may be instigated. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Not applicable. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable. 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
All data collected in the trial and any calculated outcomes derived from this data will, at a minimum, be listed with 
the dose group, subject identifier and a timepoint, if relevant. The organization of the listings will support the 
writing of the Clinical Study Report (CSR) as outlined in the ICH E3 guidelines. 


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10.4.11 
EXPLORATORY ANALYSES 
Not applicable. 
10.4.12 
CONCOMITANT MEDICATION 
All medication taken during the trial will be, at a minimum, listed with the start and stop dates.  For this small 
clinical trial, the medications will not be coded using the WHO Drug Dictionary. 
10.5 
SAMPLE SIZE 
There is no formal sample size calculation for this safety study. However, to provide a reference for the ongoing 
safety review of each cohort and the possible expansion of a cohort with safety concerns, nQuery Advisor (version 
6) employing the procedure “confidence interval for the probability of observing a rare event” determined that, for 
an event with an occurrence rate of 0.33, the probability of detecting it with 3 subjects is 69.9% vs 91.0% for 6 
subjects and for an event rate of 0.05 the probability of detecting the event was 14.3% and 26.5% for 3 and 6 
subjects respectively.    
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Not applicable. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable.  
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
An eCRF is required and must be completed for each consenting and enrolled subject by qualified and authorized 
personnel. Subjects who fail the Screening assessments will not have an eCRF. All data in the eCRF must reflect the 
corresponding source 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 eCRF for each subject are 
based.  They will be separate and distinct from the eCRF.  These records should include detailed notes on: 
• 
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 eCRF; 
• 
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; 


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• 
All AE; 
• 
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 their accuracy, authenticity, and completeness. 
The EDC application being used in this study is TrialMaster® version 4.2.1 from OmniComm Systems. TrialMaster 
studies are hosted from a state-of-the-art data center with rigorous physical and electronic security. All data is 
backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof bunker in Fort Lauderdale, 
Florida. OmniComm has achieved certification with European “Safe Harbor” regulations, meaning that all 
necessary measures are in place to protect patient confidentiality even with the data being stored in a US data 
center. The data management and statistical CRO, McDougall Scientific Ltd., ensures that the development of the 
eCRF follows their SOPs which are based on the Systems Development Life Cycle (SDLC) methodology. Access to 
the system is restricted by username and password; these are controlled by the Data Management CRO. All 
personnel using the system will be trained and the training documented. All changes to the database are recorded 
in an audit trail. The database will be locked when all outstanding queries have been addressed, all agreed-to data 
is marked as source-verified, and the PI has signed off on the eCRF contents.  
All software applications used in the collection of data will be properly validated following standard computer 
system validation that is compliant with all regulatory requirements.   
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki. Sponsor and 
Investigator will comply with their responsibilities as defined in 21 CFR 312.50-312.70. 
13.2 
INSTITUTIONAL REVIEW BOARD  
Before the start of the study, the study protocol, informed consent form and/or other appropriate documents will 
be submitted to the IRB and/or the authorities, in accordance with local legal requirements. It is the responsibility 
of the Investigator to assure that all aspects of the IRB review are conducted in accordance with current 
regulations. US Biotest and the Investigator must inform each other in writing that all ethical and legal 
requirements have been met before the first subject is enrolled in the study. 


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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 any study-related procedures are carried out. The 
Investigator is required to document the process for obtaining informed consent in the source notes. 
Subjects in the second phase of the study will have a different informed consent form than those in the dose 
escalation phase of the study due to variation in study schedules. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The Investigator will obtain informed consent from each subject enrolled in the study, in accordance with the U.S. 
FDA regulations 21 CFR 50.20 - 50.27 and the laws and regulations of the state in which the investigation is being 
conducted.  The IRB must approve 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. 
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. 


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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 eCRF and other documents submitted to US 
Biotest by their initials, birth date, and their 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, and 
no genetic testing will be performed. 
Access to stored samples will be limited to personnel authorized to have access at the site prior to shipping to the 
laboratories for analysis/assessment. Samples will be stored using codes assigned by the Sponsor or as required by 
the clinical laboratories.  
Samples will only be retained until analysis is complete, following which samples will be disposed of according to 
the laboratory SOP. No samples will be retained for any future use. 
Data will be kept in password-protected computers. Only Investigators and those delegated responsibility on the 
Delegation of Authority Log will have access to the samples and data. 
13.5 
FUTURE USE OF STORED SPECIMENS  
 
Not applicable. 
 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported.  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 


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For electronic source, the institution must provide a secure, validated electronic medical record (EMR) data 
management system that is 21 CFR Part 11 compliant and meets all regulatory requirements, regulations and 
quality standards. 
Source documents will be maintained for recording data for each participant enrolled in the study. Data reported 
in the eCRF derived from source documents should be consistent with the source documents. Any discrepancies 
should be explained and captured in a progress note and maintained in the participant’s official electronic study 
record. 
The EDC application being used in this study is TrialMaster version 4.2.1 from OmniComm Systems. TrialMaster 
studies are hosted from a state-of-the-art data center with rigorous physical and electronic security. All data is 
backed up daily to Iron Mountain, in Ohio and is also backed up to a hurricane-proof bunker in Fort Lauderdale, 
Florida. OmniComm has achieved certification with European “Safe Harbor” regulations, meaning that all 
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 SOP 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 the FDA or local regulations, 
whichever are the more stringent. 
The Investigator must maintain study documents: 
• 
For a minimum of two years following the date the marketing application (NDA) is approved for the 
indication for which the drug was investigated for;  
• 
For a minimum of two years following the release date of the final report, if no marketing application is 
to be filed, or if the marketing application is not approved for the indication of which the drug was 
investigated or is discontinued and the FDA has been notified; or, 
• 
For a minimum of 15 years after the completion or discontinuation of the study to be filed in support of 
the registration in the European Union. 
If the Investigator relocates, retires or withdraws from the study for any reason, the study records may be 
transferred to an acceptable designee, such as another Investigator, another institution, or the sponsor.  The 
Investigator must obtain the sponsor’s written permission before transferring or disposing of any records. 


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14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), FDA or IRB 
requirements. The noncompliance may be either on the part of the participant, the Investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations as soon as possible 
after occurrence and identification of the protocol deviation. All deviations must be addressed in study source 
documents, reported to the Sponsor and to the data Management group.  
The noncompliance may be either on the part of the participant, the Investigator, or the study site staff. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly.  
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB requirements.  
Serious non-compliance on the part of the site, and an inability of the Sponsor to bring the site back into 
compliance, will be reported to the FDA in accordance with their requirements.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
By signing the study protocol, the Investigator agrees with the use of results of the study for the purposes of 
national and international registration, publication, and information for medical and pharmaceutical professionals.  
If necessary, the authorities will be notified of the Investigator's name, address, qualifications, and extent of 
involvement. The sponsor will prepare an integrated clinical/statistical report. Publication/presentation of data is 
not allowed without explicit permission from US Biotest. Submission of data for publication/presentation will be 
coordinated and approved by US Biotest in collaboration with the Investigators. 
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 the 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 enrolment, timelines, and deliverables, and other study-related performance. 
All questions regarding the enrollment of subjects, regulatory requirements for the conduct of the study, safety 
reporting, or study conduct should be addressed to the Study Manager or Site Monitor designated by the sponsor.  
Contact information for the sponsor is provided near the beginning of this protocol and will be provided to the 
Investigator in separate study documents. 
 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical and therefore any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the trial.  As required by the FDA, a Financial Disclosure Form will be completed by each person 
noted on the FDA Form 1572 for this study at the site, the original will be filed in the TMF and a copy will remain in 
the site’s regulatory binder. 
17  
LIABILITY AND INSURANCE  
The sponsor will take out reasonable third-party liability insurance coverage in accordance with all local legal 
requirements. This insurance will cover all parties involved in the trial including, but not necessarily limited to, the 
principal Investigator, clinical trial site, and subjects. 
18  
LITERATURE REFERENCES  
Abraxane Package Insert. Celgene Company. Rev July 2015. 
Allen, P. J., & Brennan, M. F. The management of cystic lesions of the pancreas. Adv Surg. 2007;41:211-228. 
DeWitt, J., McGreevy, K., Schmidt, C. M., & Brugge, W. R. EUS-guided ethanol versus saline solution lavage for 
pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc. 2009;70(4):710-723. 
DeWitt, J. M., Al-Haddad, M., Sherman, S., LeBlanc, J., Schmidt, C. M., Sandrasegaran, K., et al. Alterations in cyst 
fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel. Endosc. 
2014;46(06):457-464. 
DiMaio, C.J., DeWitt, J.M. and Brugge, W.R. Ablation of pancreatic cystic lesions: the use of multiple endoscopic 
ultrasound-guided ethanol lavage sessions. Pancreas. 2011;40(5):664-668. 
Farrell, J. J. Prevalence, diagnosis and management of pancreatic cystic neoplasms: current status and future 
directions. Gut Liver. 2015;9(5):571-589. 


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Fernández-del Castillo, C., & Warshaw, A. L. Cystic tumors of the pancreas. Surg Clin N Am. 1995;75(5):1001. 
Ferrone, C. R., Correa-Gallego, C., Warshaw, A. L., Brugge, W. R., Forcione, D. G., Thayer, S. P., et al. Current trends 
in pancreatic cystic neoplasms. Arch Surg. 2009;144(5):448-454. 
Gaujoux, S., Brennan, M. F., Gonen, M., D'Angelica, M. I., DeMatteo, R., Fong, Y., et al. Cystic lesions of the 
pancreas: changes in the presentation and management of 1,424 patients at a single institution over a 15-year 
time period. J Am College Surgeons. 2011;212(4):590-600.  
Gómez, V., Takahashi, N., Levy, M. J., McGee, K. P., Jones, A., Huang, Y., et al. EUS-guided ethanol lavage does not 
reliably ablate pancreatic cystic neoplasms (with video). Gastrointest endosc. 2016;83(5):914-920. 
Gianni, L., Kearns, C. M., Giani, A., Capri, G., Vigano, L., Lacatelli, A., et al. Nonlinear pharmacokinetics and 
metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 
1995;13(1):180-190. 
Greer, J. B., & Ferrone, C. R. Spectrum and classification of cystic neoplasms of the pancreas. Surg Oncol Clin N Am. 
2016;25(2):339-350. 
Hosein PJ, de Lima Lopes Jr G, Pastorini VH, Gomez C, Macintyre J, Zayas G, et al. A phase II trial of nab-Paclitaxel as 
second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol. 2013 Apr 1; 36(2):151-6. 
Jani, N., Bani Hani, M., Schulick, R. D., Hruban, R. H., & Cunningham, S. C. Diagnosis and management of cystic 
lesions of the pancreas. Diagn Ther Endosc. 2011:1-10. 
Kirtane, T., & Bhutani, M. S. EUS for pancreatic cystic neoplasms: The roadmap to the future is much more than 
just a few shades of gray. Asian Pac J Trop Med. 2016;9(12):1218-1221. 
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. 
Mills, K. M., Johnson, D. M., Middlebrooks, M., & Burton, G. V. Possible Drug‐Associated Pancreatitis after 
Paclitaxel‐Cremophor Administration. Pharmacother: J Human Pharmacol Drug Ther. 2000;20(1):95-97. 
Moyer, M. T., Dye, C. E., Sharzehi, S., Ancrile, B., Mathew, A., McGarrity, T. J., et al. Is alcohol required for effective 
pancreatic cyst ablation? The prospective randomized CHARM trial pilot study. Endosc Int Open, 2016;4(05):E603-
E607. 
Muthusamy, V. R., Chandrasekhara, V., Acosta, R. D., Bruining, D. H., Chathadi, K. V., Eloubeidi, M. A., et al. The 
role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms. Gastrointest Endosc, 
2016;83(3):481-488. 
National Cancer Institute (2016). SEER Stat Fact Sheets: Pancreas Cancer 
http://seer.cancer.gov/statfacts/html/pancreas.html Accessed September 13, 2016. 
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. Gastrointest Endosc. 2008;67(4):636-642. 


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Oh, H. C., Seo, D. W., Kim, S. C., Yu, E., Kim, K., Moon, S. H., et al. Septated cystic tumors of the pancreas: is it 
possible to treat them by endoscopic ultrasonography-guided intervention? Scand J Gastroenterol. 
2009;44(2):242-247. 
Oh, H. C., Seo, D. W., Song, T. J., Moon, S. H., Park, D. H., Lee, S. S., et al. Endoscopic ultrasonography-guided 
ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterol. 2011;140(1):172-179. 
Oh, H. C., Seo, D. W., Kim, S. H., Min, B., & Kim, J. Systemic effect of endoscopic ultrasonography-guided pancreatic 
cyst ablation with ethanol and paclitaxel. Dig Dis Sci. 2014;59(7):1573-1577. 
Park, W. G., & Pasricha, P. J. The conundrum of pancreatic cysts: are we finally moving the (EUS) needle? 
Gastroenterol. 2011;140(1):28-31. 
Park, J.K., Song, B.J., Ryu, J.K., Paik, W.H., Park, J.M., Kim, J., et al. Clinical outcomes of endoscopic 
ultrasonography–guided pancreatic cyst ablation. Pancreas. 2016;45(6);889-894. 
Pitman, M. B., Lewandrowski, K., Shen, J., Sahani, D., Brugge, W., & Fernandez‐del Castillo, C. Pancreatic cysts. 
Cancer Cytopath. 2010;118(1):1-13. 
Sarr, M. G., Carpenter, H. A., Prabhakar, L. P., Orchard, T. F., Hughes, S., van Heerden, J. A., et al. Clinical and 
Pathologic Correlation of 84 Mucinous Cystic Neoplasms of the Pancreas: Can One Reliably Differentiate Benign 
From Malignant (or Premalignant) Neoplasms?. Ann Surg. 2000;231(2):205–212. 
Scheithauer W, Kornek G, Prager G, Stranzl N, Laengle F, Schindl M, et al. Phase II trial of capecitabine plus nab-
paclitaxel in patients with metastatic pancreatic adenocarcinoma. J Gastrointest Oncol. 2016 Apr 7; 2:234. 
Tamirisa, N. P., Parmar, A. D., Vargas, G. M., Mehta, H. B., Kilbane, E. M., Hall, B. L., et al. Relative contributions of 
complications and failure to rescue on mortality in older patients undergoing pancreatectomy. Ann Surg. 
2016;263(2):385-391. 
Tanaka, M., Chari, S., Adsay, V., Fernandez-del Castillo, C., Falconi, M., Shimizu, M., et al. International consensus 
guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the 
pancreas. Pancreatol. 2006;6(1-2):17-32. 
Taxol Package Insert. Bristol-Myers Squibb Company. Rev April 2011. 
Ueno H, Ikeda M, Ueno M, Mizuno N, Ioka T, Omuro Y, et al. Phase I/II study of nab-paclitaxel plus gemcitabine for 
chemotherapy-naive Japanese patients with metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2016; 
3(77):595-603. 
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with 
nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31; 369(18):1691-703. 
Williamson, S. K., Johnson, G. A., Maulhardt, H. A., Moore, K. M., McMeekin, D. S., Schulz, T. K., et al. A phase I 
study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies. Cancer 
chemother pharmacol. 2015;75(5):1075-1087. 
Zhang DS, Wang DS, Wang ZQ, Wang FH, Luo HY, Qiu MZ, et al. Phase I/II study of albumin-bound nab-paclitaxel 
plus gemcitabine administered to Chinese patients with advanced pancreatic cancer. Cancer Chemother 
Pharmacol. 2013 Apr 1; 71(4):1065-72. 
 


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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) 
 
A Trial Evaluating Escalating Doses and the Safety of 
Intracystic Injection of NanoPac○
R  in Subjects with 
Mucinous Cystic Pancreatic Neoplasms 
 
Protocol Number: 
NANOPAC-2017-01 
Study Phase  
                          
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 cyst within the 
pancreas via endoscopic ultrasound-guided fine needle injection (EUS-FNI) 
at a volume equal to the volume of cyst fluid aspirated 
 
 
Population 
Up to 30 subjects with mucinous cystic pancreatic neoplasms 
 
Study/Treatment 
duration: 
Up to 24 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 
Hong Chen 
McDougall Scientific Ltd. 
789 Don Mills Road, Suite 802 
Toronto, ON 
M3C 1T5, Canada 
Tel: (416) 673-9467  
Email: hchen@mcdougallscientific.com 
 
Version: 
Final 
 
Date: 
21-Aug-2020 


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CONFIDENTIAL 
 
SIGNATURE APPROVAL PAGE 
 
1 of 2 
 
Date of Final Protocol 
(including all amendments) 
13-Dec-2018 (Version 3.1) 
01-FEB-2018 (Version 2.0) 
15-JUN-2017 (Version 1.1) 
02-MAY-2017 (Version 1.0) 
 
Date of Final Plan: 21-Aug-2020 
 
I have reviewed the Statistical Analysis Plan.  My signature below confirms my 
agreement with the contents and intent of this document. 
 
Digital Signatures 
 
Author: 
 
Jim Wang 
Senior Statistician 
McDougall Scientific Ltd. 
 
 
Reviewed by: 
 
Hong Chen 
Chief Analytics Officer 
McDougall Scientific Ltd. 
 
 


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CONFIDENTIAL 
 
SIGNATURE APPROVAL PAGE 
 
2 of 2 
 
Date of Final Protocol 
(including all amendments) 
13-Dec-2018 (Version 3.1) 
01-FEB-2018 (Version 2.0) 
15-JUN-2017 (Version 1.1) 
02-MAY-2017 (Version 1.0) 
 
Date of Final Plan: 21-Aug-2020 
 
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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CONFIDENTIAL 
 
LIST OF ABBREVIATIONS.................................................................................. 6 
1 
BACKGROUND .......................................................................................... 8 
2 
OBJECTIVES ............................................................................................. 8 
2.1 
Primary Objective ........................................................................................ 8 
2.2 
Secondary Objectives ................................................................................. 8 
3 
STUDY DESIGN AND ENDPOINTS ........................................................... 9 
3.1 
Study Design ............................................................................................... 9 
3.2 
Primary Endpoint ....................................................................................... 10 
3.3 
Secondary Endpoints ................................................................................ 10 
3.4 
Study Timeline and Schedule of Events .................................................... 11 
3.4.1 
Schedule of Events Table – Dose Escalation Phase ............................. 11 
3.4.2 
Schedule of Events Table – Second Phase ........................................... 12 
4 
DATA MANAGEMENT ............................................................................. 13 
4.1 
Data Collection and Database Construction ............................................. 13 
4.2 
Coding ....................................................................................................... 13 
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 ........................................................................ 14 
6.1 
Sample Size .............................................................................................. 14 
6.2 
Missing Data ............................................................................................. 15 
6.3 
Data Conversion for Analysis .................................................................... 15 
6.4 
Calculated Outcomes ................................................................................ 15 
6.5 
Analysis Population ................................................................................... 16 


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6.6 
Interim Analysis/ Data Monitoring .............................................................. 16 
6.7 
Analysis Methods ...................................................................................... 16 
7 
RESULTS ................................................................................................. 17 
7.1 
Study Subjects .......................................................................................... 17 
7.1.1 
Patient Disposition ................................................................................. 17 
7.1.2 
Demographics and Baseline Characteristics ......................................... 17 
7.1.3 
Medical History ...................................................................................... 17 
7.1.4 
Pregnancy Test ...................................................................................... 17 
7.1.5 
NanoPac Administration ........................................................................ 18 
7.1.6 
Cyst Fluid CEA ...................................................................................... 18 
7.2 
Primary Outcomes .................................................................................... 18 
7.2.1 
Adverse Events ...................................................................................... 18 
7.2.2 
Vital Signs .............................................................................................. 19 
7.2.3 
Laboratory Assessments ....................................................................... 19 
7.2.4 
Physical Examination ............................................................................. 20 
7.3 
Secondary Outcomes ................................................................................ 20 
7.3.1 
Plasma Paclitaxel Concentration ........................................................... 20 
7.3.2 
Cyst Responses ..................................................................................... 20 
7.4 
Other Outcomes ........................................................................................ 20 
7.4.1 
Eastern Cooperative Oncology Group (ECOG) ..................................... 20 
7.4.2 
Prior and Concomitant Medications ....................................................... 20 
7.4.3 
Concomitant Procedures ....................................................................... 21 
Appendix A: ECOG Performance Scale .......................................................... 22 


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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 
BLQ 
Below the Limit of Quantification / Below Limit of Quantitation 
BMI 
Body Mass Index 
CEA 
Carcinoembryonic Antigen 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
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 


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Abbreviation 
Definition 
EDC 
Electronic Data Capture 
EUS-FNA 
Endoscopic Ultrasound-Guided Fine Needle Aspiration 
EUS-FNI 
Endoscopic Ultrasound-Guided Fine Needle Injection 
FDG-PET 
Fluorodeoxyglucose‐Positron Emission Tomography 
LLOQ 
Lower Limit of Quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities (coding for AEs) 
MRCP 
Magnetic resonance cholangiopancreatography 
MRI 
Magnetic resonance imaging 
MSL 
McDougall Scientific Ltd - CRO contracted to perform the data 
management, statistical programming and analysis functions 
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 trial of NanoPac (Sterile Nanoparticulate Paclitaxel), 
subjects with mucinous cystic pancreatic neoplasms will receive intracystic NanoPac via 
endoscopic ultrasound-guided fine needle injection (EUS-FNI). This study will include a 
dose escalation phase and a second phase. 
In the dose escalation phase, subjects will be enrolled in sequential cohorts of NanoPac 
at 6, 10, and 15 mg/mL at volumes sufficient to fill the cyst, at least equal to the amount 
of cyst fluid aspirated. 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 
at the current dose may be enrolled, or if the first dose does not provide adequate safety 
and tolerability the study may be halted. The dose determined to be the most suitable for 
further evaluation, defined as the highest dose with an acceptable safety and tolerability 
profile (as determined by the DSMB), will be the dose used in the second phase of the 
study which will enroll 9 additional subjects. Subjects enrolled in the second phase of the 
study will also receive a second injection of NanoPac at the same dose 12 weeks after the 
first NanoPac injection.  
Subjects will be followed for 6 months after the first NanoPac injection for safety, 
tolerability, and cyst response to therapy (as shown by imaging). Cyst fluid will also be 
extracted and analyzed for cyst fluid markers. 
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of NanoPac 
injected directly into mucinous cystic pancreatic cysts by endoscopic ultrasound‐guided 
injection. 
2.2 
Secondary Objectives 
The secondary objectives are: (a) to describe the pharmacokinetics (PK) of NanoPac 
when administered into the cyst within the pancreas; (b) to determine whether any of the 
NanoPac concentrations (6, 10, or 15 mg/mL) show signs of preliminary efficacy; and (c) 
to determine if the selected dose from the escalation phase shows signs of preliminary 
efficacy when injected on two occasions 12 weeks apart.  
 
 
 


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3 
STUDY DESIGN AND ENDPOINTS 
3.1 
Study Design 
In this open-label trial, up to 30 subjects with mucinous cystic pancreatic neoplasms will 
have undergone endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) as part 
of Standard of Care (SOC). Once there is a diagnosis and confirmation of mucinous cystic 
pancreatic neoplasm, subjects will receive intracystic NanoPac via ultrasound-guided fine 
needle injection (EUS-FNI). Subjects will be followed for cyst response to therapy (as 
shown by imaging) and concentration of paclitaxel in the systemic circulation post-injection 
(as determined by PK analysis).  
The study will include a dose escalation phase and a second phase. 
In the dose escalation phase, subjects will be enrolled in sequential, escalating cohorts of 
NanoPac at concentrations of 6, 10, or 15 mg/mL injected directly into the cyst within the 
pancreas at a volume sufficient to fill the cyst, at least equivalent to the amount of fluid 
removed from the cyst.  
In the second phase, subjects will receive two injections of NanoPac 12 weeks apart at 
the dose selected in the dose escalation phase. 
Cyst Volume Calculations 
If more than one cyst is present in the pancreas of a subject, the Investigator will select a 
single target cyst and will treat only this target cyst. The single target cyst must have a 
diameter of at least 1.5 cm and no more than 4 cm; the diameter will be measured at the 
widest point of the cyst. In the dose escalation phase, imaging with magnetic resonance 
cholangiopancreatography (MRCP), CT scan, or FDG-PET will be used prior to enrollment 
to visualize and measure the cyst to confirm subject eligibility; the same imaging modality 
used prior to enrollment will be repeated at the Week 12 and Week 24 time points. 
In the second phase of the study, a CT scan will be performed between the Screening visit 
and Day 1 to obtain a baseline image against which future CT scans (at the Week 12 and 
Week 24 time points) will be compared. The CT scan at Week 12 will be performed prior 
to NanoPac injection, however the exact cyst diameter (three dimensional) will be based 
on measurements performed with endoscopic ultrasound during the NanoPac injection 
procedure. Injection volume will be at least equal in volume to the amount of fluid removed 
from the cyst, but may be a larger volume to fill the cyst as determined visually by the 
Investigator during the endoscopic ultrasound procedure. The exact volume administered 
to the cyst will be documented in the source. 
Dose Escalation of Cohorts 
 


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In the dose escalation phase, 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 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 (DLT). 
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.  
Second Phase 
Once the dose deemed appropriate for expansion and further evaluation has been 
determined by the DSMB, an additional 9 subjects will be enrolled at that dose level. 
Subjects in the second phase will also receive a second NanoPac injection to their cyst 
(at the same dose) 12 weeks after the first NanoPac injection. If any subject has a CT 
Scan following the first NanoPac injection and the cyst cannot be identified/visualized (at 
Week 12) the subject will not have a second injection and will be followed-up at Week 24 
to obtain a CT Scan; visits between Week 12 and Week 24 will not be required for these 
subjects. 
3.2 
Primary Endpoint 
The primary endpoint will be safety and tolerability, as assessed by AE, changes in vital 
signs, laboratory results, and physical examination at four weeks following NanoPac 
injection. Safety and tolerability will continue to be assessed until the end-of-study visit. 
3.3 
Secondary Endpoints 
The secondary endpoints will be: 
• 
Concentration of paclitaxel in the systemic circulation post-injection (as determined 
by PK analysis); 
• 
Cyst volume response (imaging).


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3.4 
Study Timeline and Schedule of Events 
3.4.1 
Schedule of Events Table – Dose Escalation Phase 
 
 
 


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3.4.2 
Schedule of Events Table – Second Phase 
 


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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 McDougall.  All participants will be trained in 
the use of the application, and the training documented prior to each site being initiated. 
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 
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 McDougall and are 
identified by the project code NA04NAG. 
All programming will be performed in SAS version 9.4. 
4.2 
Coding 
Adverse Events and medical history will be coded in MedDRA version 20.0 or the most 
current version of MedDRA at the beginning of coding process, and signed off by US 
Biotest, Inc.  
All concomitant medications will be coded using WHO Drug Dictionary version March 1, 
2017 or the most current version of WHODD at the beginning of coding process.  


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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 McDougall in Excel data sheets to be read 
into SAS system for descriptive summaries. 
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. 
5 
CHANGE TO ANALYSIS AS OUTLINED IN THE PROTOCOL 
According to the Protocol, in addition to the summaries of TEAEs for whole study period, 
where possible and relevant, the TEAEs will also be summarized by different time frames 
(e.g. first 24 hours, up to Day 7).  
In consideration of the objective of this analysis, the AE summarized by time frame will be 
limited to the TEAEs of Second Phase subjects with two injections. For those subjects, 
two additional TEAE summaries will be provided based on AE onset time: 1) onset before 
the second injection and, 2) onset on or after the second injection. 
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; therefore, no inferential analysis will be included.  
6.1 
Sample Size 
There is no formal sample size calculation for this safety study. However, to provide a 
reference for the ongoing safety review of each cohort and the possible expansion of a 
cohort with safety concerns, nQuery Advisor (version 6) employing the procedure 
“confidence interval for the probability of observing a rare event” determined that, for an 
event with an occurrence rate of 0.33, the probability of detecting it with 3 subjects is 


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69.9% vs 91.0% for 6 subjects and for an event rate of 0.05 the probability of detecting 
the event was 14.3% and 26.5% for 3 and 6 subjects respectively.   
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. 
• 
All “< xx” lab results will be converted to 0.99 * xx. The adjustment is -1% of xx. 
• 
All “> xx” lab results will be converted to 1.01 * xx. The adjustment is +1% of xx. 
• 
Some PK concentration values may be marked as Below the Limit of Quantification 
(BLQ) or reported as “< xx”. Here xx is the Lower Limit of Quantitation (LLOQ). For 
the summary of paclitaxel concentration in this study, all BLQ values will be set to 
0. 
Above data conversions are only applied to data descriptive summaries. In by-subject data 
listings, original reported data “< xx”, “> xx”, or “BLQ” will be presented. 
For this study’s 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 
provided in SDTM and ADaM’s define.xml files and their support documents. 
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 
Study Day 
= the days from Day 1 (Injection Date) 
to the event date 
 
Time in Trial 
(days) 
= Study completion/withdrawal date – 
date of informed consent date + 1 day 
 


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Outcome 
Calculation 
Comment 
Baseline value 
= Value reported prior to treatment 
injection 
If multiple values collected 
prior to treatment injection, 
non-missing value closest 
to the date/time of 
treatment injection is 
considered as baseline 
value 
Change from 
Baseline 
= Value collected at time point (Visit) – 
Baseline value 
 
BMI 
= 10000 * (Weight in kg) / (Height in 
cm)2 
Value will be rounded to 
keep one decimal point 
Treatment 
Emergent 
Adverse Event 
(TEAE) 
= No, if onset date/time 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 
Tumor Volume 
= 1/6 * π * (d1 * d2 * d3), if three tumor 
diameters d1, d2, and d3 are 
recorded 
= 1/6 * π * (d12 * d2), if only two tumor 
diameters d1 and d2 are recorded, 
where d1 ≥ d2 
= 1/6 * π * (d13) if only one tumor 
diameter d1 is recorded. 
This calculated tumor 
volume will be used in 
efficacy analysis (section 
7.3.2).  EDC captured 
tumor volume, if non-
missing, will be presented 
in data listing 
 
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 
A formal interim analysis is not planned. However, there will be ongoing data review and 
report preparation for the DSMB as outlined in the DSMB Charter. 
6.7 
Analysis Methods 
All calculations and analyses will be performed using SAS version 9.4 under the Windows 
Server 2012R2 operating system at McDougall Scientific Ltd. in Toronto, Canada.  


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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 (dose level), and visit, if applicable. Outcomes 
of two study phases will be summarized separately because of the differences of treatment 
and visit schedules.  
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.  
All summaries will be presented by cohort, i.e., NanoPac concentration level.  
Because of the extra NanoPac injection and the different visit structures, all safety and 
efficacy outcomes of the second phase subjects will be summarized separately. 
The eligibility data of screen failures will be presented in a separate listing. 
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 temperature) will be summarized. 
7.1.3 
Medical History 
Medical history will be coded in MedDRA and presented in by-cohort tables by System 
Organ Class (SOC) and Preferred Term (PT). 
7.1.4 
Pregnancy Test 
Pregnancy test will be conducted at Screening Visit. For female subjects, the childbearing 
potential (yes/no), the date of pregnancy test and test result will be listed. 


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7.1.5 
NanoPac Administration 
NanoPac administration data at study Day 1 and Week 12 (second phase subjects only), 
including administration date, time, dose level, will be listed. Cyst diameters measured by 
ultrasound, cyst volume, volume of cyst fluid aspirated, and volume of NanoPac 
administrated will be summarized by cohort. 
7.1.6 
Cyst Fluid CEA 
According to inclusion criteria, pre-screening cyst fluid CEA analysis should be performed 
for all enrolled subjects. Prior to NanoPac injection(s) on Day 1 and Week 12 (second 
phase subjects only), cyst fluid is aspirated and analyzed for CEA.  
All CEA results will be summarized by visit and cohort. 
7.2 
Primary Outcomes 
The primary endpoint will be safety and tolerability, as assessed by AE, changes in vital 
signs, laboratory results, and physical examination at one month following the completion 
of NanoPac administration, i.e., at Week 4 for dose escalation phase subjects and at Week 
16 for the second phase subjects. Safety and tolerability will continue to be assessed until 
the six month end-of-study visit. 
All primary outcomes will be descriptively summarized. No statistical inference will be 
made for primary endpoint.  
7.2.1 
Adverse Events 
Only treatment emergent adverse events (TEAEs) will be summarized. Summaries will be 
provided by dose level cohort, and include: 
• 
Summary of TEAEs - include the total number of TEAEs, serious TEAEs, DLT, 
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 
• 
Unexpected TEAEs by MedDRA SOC and PT, if enough data available  
Adverse events of special interest will be presented, separately, by dose level cohort, 
SOC and PT. 
All these summaries will include the counts and frequencies of events, and of subjects 
who had events.  


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 For second phase subjects with two injections, additional TEAE summaries will be 
presented for two time-frames: onset prior and post the 2nd injection. 
All TEAEs will be listed by subject. Death and other serious TEAEs will be listed 
separately. 
7.2.2 
Vital Signs 
Vital Signs (weight, BMI, systolic and diastolic blood pressure, heart rate, and 
temperature) will be summarized by dose level cohort and visit. 
Change of vital signs (weight, BMI, systolic and diastolic blood pressure, heart rate, and 
temperature) from baseline values will be summarized for all post-injection visits.  
Unscheduled vital signs will only be presented in by-subject listing. 
7.2.3 
Laboratory Assessments 
Laboratory assessments with quantitative results, including raw assessments at each visit 
and change from baseline at post-baseline visits, will be summarized by dose level cohort, 
and visit for each test.  
Each no-missing lab result’s normal/abnormal status (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; 
Urinalysis: Specific gravity, hydrogen ion concentration (pH), RBC, WBC, protein, and 
glucose; 
Coagulation: Prothrombin time (PT) and activated partial thromboplastin time (PTT). 


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7.2.4 
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. 
7.3 
Secondary Outcomes 
7.3.1 
Plasma Paclitaxel Concentration  
Two PK samples for paclitaxel concentration are collected on each injection day, i.e. Day 
1 for dose escalation subjects and Day 1/Week 12 for second phase subjects, at 1 and 2 
hours post-injection. One PK sample is collected at each post-baseline visit. All 
concentration data will be descriptively summarized.  
All BLQ values will be set as 0 in doing the summaries. Original value “BLQ” will be used 
in data listings. 
If applicable, paclitaxel concentration data will be graphed for individuals and by dose 
group. BLQ values will be displayed as 0 in the graphs. 
7.3.2 
Cyst Responses 
Cyst diameter and volume are measured by imaging (Magnetic resonance 
cholangiopancreatography (MRCP), CT scan, Fluorodeoxyglucose‐Positron Emission 
Tomography (FDG-PET), MRI, Ultrasound, or other imaging methods) at Screening Visit, 
Week 12 Visit and Week 24 Visit. The size and calculated volume of target cyst and 
changes of from baseline will be tabulated by dose level cohort. 
Spaghetti plots of visit vs. target cyst volume will be provided. If applicable, different dose 
levels, and gender will be indicated on the plots.  
All cyst data will be presented in the by-subject data listings. Gender and baseline CEA 
will be included in the listings. 
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 summarized as frequencies by treatment group and 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.  
 
 


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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.